WO1994013690A1 - Nouveaux steroides - Google Patents

Nouveaux steroides Download PDF

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Publication number
WO1994013690A1
WO1994013690A1 PCT/GB1993/002537 GB9302537W WO9413690A1 WO 1994013690 A1 WO1994013690 A1 WO 1994013690A1 GB 9302537 W GB9302537 W GB 9302537W WO 9413690 A1 WO9413690 A1 WO 9413690A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound according
diene
oxoandrosta
hydroxy
compound
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.)
Ceased
Application number
PCT/GB1993/002537
Other languages
English (en)
Inventor
Michael John Ashton
Michael Thomas Withnall
Sven Jan-Anders Karlsson
Bernard Yvon Jack Vacher
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.)
Rhone Poulenc Rorer Ltd
Original Assignee
Rhone Poulenc Rorer Ltd
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 Rhone Poulenc Rorer Ltd filed Critical Rhone Poulenc Rorer Ltd
Priority to AU56574/94A priority Critical patent/AU5657494A/en
Publication of WO1994013690A1 publication Critical patent/WO1994013690A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
    • C07J5/0092—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by an OH group free esterified or etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17

Definitions

  • the present invention relates to novel antiinflammatory, immunosuppressive, and antiallergic compounds and to processes for their preparation.
  • the invention also relates to pharmaceutical compositions containing the compounds.
  • the invention also relates to the pharmacological uses of the compounds.
  • this invention relates to new
  • the object of the invention is to provide a steroid which possesses high antiinflaimmtatory, immunosuppressive and
  • a large number of natural and synthetic steroids are known, and many of them are useful in the treatment of human and animal subjects.
  • Steroids which have antiinflammatory properties are known, but they suffer from the disadvantage that, after administration, they cause unwanted side-effects outside the organ or tissue which is desired to be treated.
  • the present invention provides compounds which have never been described hitherto and which possess a remarkable combination of very useful antiinflammatory activity with a very low ability to produce undesired side-effects, to an extent which has never before been found in steroid compounds.
  • R 1 is hydrogen or fluorine
  • R 2 is propyl or trans-prop-1-enyl
  • the 1,2-position is saturated or is a double bond
  • the more preferred compounds are those where is a double bond.
  • Each of the compounds of formula I can exist in two diastereoisomeric forms because two different configurations are possible at the carbon atom in the 20 position.
  • the invention includes the (2OR)- and
  • the compounds are extremely valuable in the local treatment of inflammatory, allergic and immunological
  • diseases include those currently treated by known steroids, such as diseases of the respiratory system, e.g. asthma and rhinitis, diseases of the skin, e.g. eczema, and diseases of the gastrointestinal tract, e.g. inflammatory bowel disease.
  • diseases of the respiratory system e.g. asthma and rhinitis
  • diseases of the skin e.g. eczema
  • diseases of the gastrointestinal tract e.g. inflammatory bowel disease.
  • the compounds of the invention are much more desirable than any previously known compounds.
  • the compounds of formula I can be prepared by the application or adaptation of known methods, by which is meant methods used hitherto or described in the literature.
  • the compounds of this invention may be prepared, for example, by the following reactions.
  • compounds of formula I are prepared by the methylation of compounds of the general formula II, hereinbefore depicted, wherein R 1 and R 2 are as hereinbefore defined, by known methods, for example by reaction with a base followed by reaction with methyl iodide.
  • compounds of formula I are prepared by the reaction of compounds of the general formula III, hereinafter depicted, wherein R 1 and R 2 are as hereinbefore defined, and
  • -COX represents a group of formula IV hereinafter depicted, wherein R 3 is as hereinafter defined, with methanethiol or an alkali metal salt thereof , e . g . sodium methanethiolate .
  • -COX is an active derivative of a carboxy group, for example a group of the general formula:-
  • R 3 represents an alkyl, preferably ethyl, group.
  • R 2 is as hereinbefore defined, in the presence of perchloric acid.
  • compounds of formula V can be prepared by the following reaction sequence.
  • Aqueous perchloric acid solution (75ml;70%w/v) is added rapidly to a vigorously stirred suspension of fluocinolone acetonide (100g) in heptane (2.251) containing butanal (30ml) under an atmosphere of nitrogen.
  • the suspension is stirred at ambient temperature for 5.5 hours.
  • the solvent is decanted and the residue is washed with fresh heptane (250ml) and decanted.
  • the residue is then partitioned between water (1.21) and dichloromethane (2.51).
  • Aqueous perchloric acid solution (75ml;70%w/v) is added rapidly to a vigorously stirred suspension of fluocinolone acetonide (100g) in dichloromethane (1.51) under an atmosphere of nitrogen, then a solution of butanal (22ml) in
  • Example 4A The dichloromethane solution of 16 ⁇ ,17 ⁇ -butylidenedioxy- 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ ,21-dihydroxypregna-1,4-diene-3,20-dione obtained in.
  • Example 4A above can be used directly in the oxidation step in Example 4B without prior drying or isolation of solid material.
  • Triethylamine (15.5ml) is added to a stirred solution of (20R)-16 ⁇ ,17 ⁇ -butylidenedioxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-3- oxoandrosta-l,4-diene-17 ⁇ -carboxylic acid (50.0g) in dry tetrahydrofuran (1 litre) under nitrogen. After stirring for 20 minutes, diethyl chlorophosphate (25.0g) is added.
  • the present invention also includes within its scope pharmaceutical formulations which comprise an effective amount of at least one of the compounds of formula I in association with a pharmaceutically acceptable carrier or coating.
  • An object of the invention is to provide a topical antiinflammatory, immunosuppressive and antiallergic steroid, or a pharmaceutical composition thereof, for the following: topical treatment of skin conditions such as dermatitis, psoriasis, sunburn, eczema, neurodermatitis and anogenital pruritis;
  • the topical treatment of such conditions by steroid compounds of this invention is associated with no side-effects or minimal side-effects associated with typical systemic steroid activity, such as suppression of hypothalamus- pituitary-adrenal function, mobilisation of glucose store ⁇ , collagen di ⁇ orders, mineralocorticoid function, adrenal atrophy, osteoporosis and suppression of bone growth and atrophy of thymic tissue.
  • inactivation of the steroid can be by metabolism in the target organ or, after uptake into the general circulation, e.g. by metabolism or excretion.
  • Such compounds are often referred to as "soft" steroids.
  • Bound [ 3 H] dexamethasone is separated from free dexamethasone by a dextran coated charcoal technique and is quantified by liquid scintillation counting.
  • the IC 50 concentration reducing [ 3 H] dexamethasone binding by 50% is calculated from the plot of the fraction bound against added steroid
  • Monocytes are obtained from blood samples taken from normal human donors. The leukocyte population is washed, applied to a discontinuous metrizamide gradient, and
  • the monocyte-enriched interface is aspirated, the cells washed and total and differential counts performed to determine the number of monocytes. Cells are allowed to adhere to 96-well plates for 1 to 2 hours, and thereafter incubated
  • TNF- ⁇ is assayed by use of an enzyme-linked immunosorbent assay.
  • the IC 50 is the steroid concentration reducing TNF- ⁇ release by 50%. Inhibition of TNF- ⁇ release from human peripheral blood monocytes:
  • Rat liver H4IIE cells are cultured for 4 days until the cells are confluent.
  • the medium is replaced by fresh medium, containing steroid under test (0-100nM) which is added to triplicate wells. After overnight incubation as above, the medium is removed and the cells are lysed and the extract is equilibrated at 37°C with ⁇ -ketoglutarate and pyridoxal phosphate in phosphate buffer, pH 7.3, in a final volume of lml.
  • Tyrosine aminotransferase activity is initiated by adding tyrosine and incubating at 37°C for 10 minutes. The reaction is stopped by adding aqueous sodium hydroxide solution (10M).
  • the ultra-violet absorbance of the para- hydroxybenzaldehyde is measured by a plate reader at 340nm. The maximal absorbance change achieved with the standard
  • the absorbance change for each concentration of steroid under test is calculated as a fraction of the maximal absorption achievable and plotted against steroid concentration.
  • the ED50 is determined as the concentration causing an increase in
  • IC 50 0.3nM.
  • Test compounds are suspended in 1% carboxymethyl- cellulose/0.2% Tween 80 at double the required strength and sonicated to form a suspension. This is administered intra-tracheally (i.t.) to male rats (Sprague-Dawley strain, 6 in each group, each weighing about 350g) at 0 hours and 24 hours, with the first dose being co-administered with saline and the second with Sephadex G200 [cross-linked dextran] (lOmg/ml) giving a final Sephadex concentration of 5mg/ml.
  • Sephadex G200 cross-linked dextran
  • I.t. dosing is carried out under halothane anaesthesia (4% in oxygen, at 4 litres/minute for 3 minutes). At 48 hours, the rats are killed, final body weight is recorded, and the lungs and thymus are removed and weighed. The doses reducing the Sephadex-induced oedema and the thymus weight by 30% (ED30) are calculated. Airway selectivity is defined as the ratio of thymus involution (ED 30 ) and inhibition of lung oedema
  • Airway selectivity 10.
  • mice Ovalbumin sensitised mice are challenged with antigen injected into the right ear intradermally under halothane anaesthesia (4% in oxygen, 4 litres/minute for 2 minutes) 18 hours after topical treatment with the steroids [as above in (i)]. The mice are killed 1 hour later, and a 5mm disc is punched out of each ear, and weighed. The dose reducing the oedema, by 50% (ED 50 ) is determined as above.
  • ED 50 0.016 ⁇ g/ear.
  • the compounds are administered in a form suitable for the area of the body to be treated.
  • the compounds are usually administered as aerosols or,
  • compositions for the treatment of diseases of the skin they are usually administered as creams, ointments or lotions.
  • Such formulations are prepared by the application or adaptation of known methods such as the following.
  • the steroids may be administered in a conventional pharmaceutical carrier such as creams, ointments, lotions, emulsions, solutions, foams, or the like.
  • the steroid compounds of this invention may be used for topical treatment of skin conditions, in the range of about 0.0001 to about 5%, preferably about 0.05 to about 2%, by weight of the vehicle.
  • the steroids may be administered as a dry powder, for example in a single dose inhaler or a multidose inhaler, or as a suspension or a solution in a metered dose aerosol unit or in a
  • nebuliser with a suitable carrier, or the like.
  • suitable carrier or the like.
  • Such devices are well known in the art and standard modes of preparation may be employed or adapted.
  • Such formulations for inhalation typically contain from about 10 to about 4,000, preferably from about 100 to about 1,600, ⁇ g per dose. Still further, steroids of this invention may be
  • anal or peri-anal formulations e.g. foams, solutions or suspensions and suppositories.
  • Formulation as liposomes may be used as described in the specification of WO 92/13873.
  • Slow release oral formulations such as formulations for release into the intestine or colon or both, e.g. slow release tablets, may also be employed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

Stéroïdes répondant à la formule (I), dans laquelle --- représente une liaison simple ou double; R1 représente hydrogène ou fluor; et R2 représente propyle ou trans-prop-1-ényle; leurs mélanges racémiques; leurs diastéréoisomères; leurs procédés de préparation; compositions pharmaceutiques les contenant; et leurs procédés d'utilisation, notamment comme agents anti-inflammatoires.
PCT/GB1993/002537 1992-12-11 1993-12-13 Nouveaux steroides Ceased WO1994013690A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56574/94A AU5657494A (en) 1992-12-11 1993-12-13 New steroids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929225923A GB9225923D0 (en) 1992-12-11 1992-12-11 New compositions of matter
GB9225923.3 1992-12-11

Publications (1)

Publication Number Publication Date
WO1994013690A1 true WO1994013690A1 (fr) 1994-06-23

Family

ID=10726486

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/002537 Ceased WO1994013690A1 (fr) 1992-12-11 1993-12-13 Nouveaux steroides

Country Status (5)

Country Link
AU (1) AU5657494A (fr)
GB (1) GB9225923D0 (fr)
IL (1) IL107994A0 (fr)
WO (1) WO1994013690A1 (fr)
ZA (1) ZA939338B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7091187B2 (en) 2002-07-08 2006-08-15 Pliva-Istrazivacki Institut D.O.O. Compounds, compositions and methods for treatment of inflammatory diseases and conditions
US7157433B2 (en) 2002-07-08 2007-01-02 Glaxosmithkline Istrazivacki Centar Zagreb Compounds, compositions as carriers for steroid/nonsteroid anti-inflammatory; antienoplastic and antiviral active molecules
US7208518B2 (en) 2003-07-25 2007-04-24 Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. Substituted furochromene compounds of antiinflammatory action
US7384975B2 (en) 2003-07-25 2008-06-10 Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. Substituted furochromenes, preparation thereof and their antiinflammatory action
US7446097B2 (en) 2001-01-09 2008-11-04 Glaxosmithkline Istrazivacki Centar Zagreb D.O.O Conjugates of immune cell specific macrolide compounds with anti-inflammatory compounds for improved cellular targeting of anti-inflammatory therapy
EP2070940A1 (fr) 2003-04-24 2009-06-17 GlaxoSmithKline istrazivacki centar Zagreb d.o.o. Conjugués avec activité anti-inflammatoire
EP2196469A1 (fr) 2004-10-27 2010-06-16 GlaxoSmithKline istrazivacki centar Zagreb d.o.o. Conjugués avec activité anti-inflammatoire

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0004741A2 (fr) * 1978-04-05 1979-10-17 Syntex (U.S.A.) Inc. Dérivés d'acide thioétianique, leur préparation et leur utilisation pharmaceutique
GB2137206A (en) * 1980-02-15 1984-10-03 Glaxo Group Ltd Androstane 17-carbothioc acid derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0004741A2 (fr) * 1978-04-05 1979-10-17 Syntex (U.S.A.) Inc. Dérivés d'acide thioétianique, leur préparation et leur utilisation pharmaceutique
GB2137206A (en) * 1980-02-15 1984-10-03 Glaxo Group Ltd Androstane 17-carbothioc acid derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
D. J. KERTESZ AND M. MARX: "Thiol esters from steroid 17-beta-carboxylic acids: carboxylate activation and internal participation by 17-alpha-acylates.", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 51, no. 12, 13 June 1986 (1986-06-13), WASHINGTON, US, pages 2315 - 2328, XP002181480, DOI: doi:10.1021/jo00362a028 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7446097B2 (en) 2001-01-09 2008-11-04 Glaxosmithkline Istrazivacki Centar Zagreb D.O.O Conjugates of immune cell specific macrolide compounds with anti-inflammatory compounds for improved cellular targeting of anti-inflammatory therapy
US7928078B2 (en) 2001-01-09 2011-04-19 Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. Conjugates of immune cell specific macrolide compounds with anti-inflammatory compounds for improved cellular targeting of anti-inflammatory therapy
US7091187B2 (en) 2002-07-08 2006-08-15 Pliva-Istrazivacki Institut D.O.O. Compounds, compositions and methods for treatment of inflammatory diseases and conditions
US7157433B2 (en) 2002-07-08 2007-01-02 Glaxosmithkline Istrazivacki Centar Zagreb Compounds, compositions as carriers for steroid/nonsteroid anti-inflammatory; antienoplastic and antiviral active molecules
EP2070940A1 (fr) 2003-04-24 2009-06-17 GlaxoSmithKline istrazivacki centar Zagreb d.o.o. Conjugués avec activité anti-inflammatoire
US7579334B2 (en) 2003-04-24 2009-08-25 Glaxosmithkline Istrazivacki Centar Zagreb Compounds with anti-inflammatory activity
US7208518B2 (en) 2003-07-25 2007-04-24 Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. Substituted furochromene compounds of antiinflammatory action
US7384975B2 (en) 2003-07-25 2008-06-10 Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. Substituted furochromenes, preparation thereof and their antiinflammatory action
EP2196469A1 (fr) 2004-10-27 2010-06-16 GlaxoSmithKline istrazivacki centar Zagreb d.o.o. Conjugués avec activité anti-inflammatoire

Also Published As

Publication number Publication date
IL107994A0 (en) 1993-12-12
GB9225923D0 (en) 1993-02-03
AU5657494A (en) 1994-07-04
ZA939338B (en) 1994-08-25

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