WO1996038465A1 - DERIVES ALKYLE-2β-MORPHOLINO-ANDROSTANE - Google Patents

DERIVES ALKYLE-2β-MORPHOLINO-ANDROSTANE Download PDF

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Publication number
WO1996038465A1
WO1996038465A1 PCT/EP1996/002346 EP9602346W WO9638465A1 WO 1996038465 A1 WO1996038465 A1 WO 1996038465A1 EP 9602346 W EP9602346 W EP 9602346W WO 9638465 A1 WO9638465 A1 WO 9638465A1
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Prior art keywords
alkyl
substituted
androstane
moφholino
androstane derivative
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PCT/EP1996/002346
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English (en)
Inventor
Alexander Cupples Campbell
Nial Morton Hamilton
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Akzo Nobel N.V.
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Priority to AU61896/96A priority Critical patent/AU6189696A/en
Publication of WO1996038465A1 publication Critical patent/WO1996038465A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

Definitions

  • the invention relates to alkyl substituted 2 ⁇ -morpholino-androstane derivatives, a process for the
  • Androstanes are steroids having a skeleton of the formula hexadecahydro-10,13-dimethyl-lH- cyclopenta[a]phenanthrene.
  • the compounds with only a 13-methyl group are named 19- 10 norandrostanes.
  • Androstanes with an ethyl side-chain at the 17-position are named pregnanes.
  • the term androstane may, however, also be read as 19-norandrostane, pregnane, or 19-norpregnane. In the experimental section the usual chemical names are used.
  • Anaesthetic activity means activity of an hypnotic agent capable of inducing or maintaining general anaesthesia. These steroids may carry substituents at several positions (see for example British patents 1,376,892, 1,380,248, 1,430,932, 1,570,394, 1,377,608, and 1,581,234; and US
  • the compounds of the invention can be used for sedation and analgesia and for the treatment of GABA related diseases, such as anxiety (for instance panic attack), stress, sleep disorders, post natal depression, and premenstrual tension, and for the alleviation of seizure.
  • GABA related diseases such as anxiety (for instance panic attack), stress, sleep disorders, post natal depression, and premenstrual tension, and for the alleviation of seizure.
  • the invention relates to alkyl substituted 2 ⁇ -mo ⁇ holino-androstane derivatives, bonded at their 2 ⁇ -position to the nitrogen of a group of formula I:
  • R a represents (3-6C) alkyl
  • Rt j represents H or (3-6C) alkyl
  • Y is O or S; or a pharmaceutically acceptable salt thereof.
  • Preferred compounds according to this invention are androstane derivatives of formula II:
  • R a represents (3-6C) alkyl
  • Rj represents H or (3-6C) alkyl
  • R j , R 7 , and R3 are independently selected from H and methyl
  • R4 is 2H, (H,OH) or O
  • Z is CN or CO-CH_X;
  • X is selected from H, halogen, OH, CN, N3, SCN, (1-6C) alkyl (optionally substituted by halogen), cyclohexyl, (1-6C) alkoxy, phenoxy, phenyl-(l-6C) alkoxy, (1-6C) acyloxy, (1-6C) acylthio, pyrrolidinyl, piperidinyl, mo ⁇ holinyl, thiomo ⁇ holinyl and amino which is optionally substituted by (1-6C) alkyl; Y is O or S; and the dotted lines are optional bonds, H(5) being absent when the 4,5- or 5,6-linkage is a double bond; or a pharmaceutically acceptable salt thereof.
  • Particularly useful compounds according to the invention are steroids of the formula III:
  • R a , R5, R4, X and Y have the previously given meanings; or a pharmaceutically acceptable salt thereof.
  • Preferred compounds are steroids of the invention wherein R a represents a propyl or isopropyl group, and R5 represents H, propyl, or isopropyl.
  • Other preferred compounds are steroids of formula III wherein R4 is 2H or O.
  • Also preferred are steroid derivatives of formula III wherein X is H, Cl, OH, CN, N3, SCN, (1-6C) acyloxy or
  • steroids of formulae I-III wherein R a is an alkyl group with 3 or 4 carbon atoms, such as n-propyl, isopropyl, sec-butyl, and isobutyl.
  • R a being propyl or isopropyl or a pharmaceutically acceptable salt thereof.
  • mo ⁇ holine (and terms derived therefrom) is used for mo ⁇ holine as well as for thiomo ⁇ holine.
  • (3-6C) alkyl used in the definition of R a and R j means a branched or unbranched alkyl group having 3 to 6 carbon atoms, for example n-propyl, isopropyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, or 4-methylpentyl.
  • (1-6C) alkyl means a branched or unbranched alkyl group having 1-6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, or n-hexyl.
  • acyl as used in (1-6C) acyloxy and (1-6C) acylthio means a 1-oxo-alkyl having 1-6 carbon atoms.
  • (1-6C) alkoxy means alkyloxy having 1-6 carbon atoms, wherein alkyl has the same meaning as previously given for the ( 1 -6C) alkyl group.
  • halogen means fluoro, chloro, bromo or iodo.
  • the alkyl substituted 2 ⁇ -mo ⁇ holino-androstane derivatives of the invention can be prepared by methods commonly known in the art.
  • a general method is condensation of a suitably substituted mo ⁇ holine to the 2 ⁇ -position of an androstane derivative by bringing together the substituted mo ⁇ holine (or thiomo ⁇ holine) or a salt thereof and a 2,3-epoxy-androstane or 2,3-epoxy-19-norandrostane derivative, which is suitably protected when necessary.
  • the steroid obtained is isolated and purified by procedures well known in the art, followed, when required, by the introduction of a substituent at the 21 -position of the steroid.
  • Substituted mo ⁇ holine derivatives can also be prepared according to literature procedures (G. Bettoni et al., Tetrahedron. 1980, ___, 409).
  • Chiral substituted mo ⁇ holino derivatives may also be prepared by conversion of ⁇ -amino acids to an alkyloxirane, according to the method as disclosed in B. Koppenhoefer et al., Synthesis, 1994, 1 141.
  • the invention therefore also includes a process for the preparation of a chiral (3-6C) alkyl substituted 2 ⁇ -mo ⁇ holino-androstane derivative wherein a suitable ⁇ -amino acid is converted into a oxirane, which is converted into a chiral alkyl substituted mo ⁇ holine derivative, which is condensed at the 2 ⁇ -position of an androstane derivative by bringing together the substituted mo ⁇ holine or a salt thereof and a 2,3-epoxy-androstane or 2,3-epoxy-19-nor- androstane derivative, which is suitably protected when necessary, after which the optionally present protective groups are removed.
  • a suitable ⁇ -amino acid is converted into a oxirane
  • a chiral alkyl substituted mo ⁇ holine derivative which is condensed at the 2 ⁇ -position of an androstane derivative by bringing together the substituted mo ⁇ holine or a salt thereof and a 2,3-epoxy-a
  • the steroid obtained is isolated and purified by procedures well known in the art, followed, when required, by the introduction of a substituent at the 21 -position of the steroid.
  • L-valine can be converted into the chloro acid derivative using sodium nitrite and aqueous hydrochloric acid, after which the acid moiety is reduced into an alcohol with lithium aluminum hydride in ether.
  • Potassium hydroxide treatment results in the (R)-oxirane, which can be ring opened using aminoethanol, which compound can be tosylated using tosyl chloride in pyridine, ring closed with sodium methanolate, after which the remaining N-tosyl group can be cleaved, for instance with sodium/1 -pentanol, after which hydrochloric acid treatment provides the hydrochloride salt of (R)-2- isopropyl mo ⁇ holine.
  • (R)-2-isobutylmo ⁇ holine can be prepared from L-leucine, and (R)-2-sec- butylmo ⁇ holine from L-isoleucine.
  • the substituted mo ⁇ holino moiety may contain one or more chiral carbon atoms, and the com- pounds may therefore be obtained as pure stereoisomers, or as a mixture of stereoisomers.
  • Methods for obtaining the pure stereoisomers are well known in the art, e.g. by synthesis with chiral induction, crystallisation, or by chromatography.
  • the compounds of the invention may be converted into a pharmaceutically acceptable salt by treating the free base with a pharmaceutically acceptable organic or inorganic acid such as HCl,
  • HBr HI
  • H2SO4, H3PO4 acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
  • the therapeutic index of compounds of the invention is compared with the therapeutic index of corresponding analogues comprising an unsubstituted mo ⁇ holinyl group.
  • the therapeutic index (T.I.) is defined as the ratio of the lethal dose in 50% of the animals (LD50) and the hypnotic dose (HD50), which is the dose of the compound which, following intravenous administration over 10 sec. causes a loss of righting reflex in 50% of the animals for a period of no less than 30 sec.
  • the compounds of the invention may be administered parenterally, and for humans preferably in a dosage of 0.001-10 mg per kg body weight.
  • the compounds may by means of pharmaceutically suitable liquids be applied as an injection preparation in the form of a solution, suspension, or emulsion.
  • Pharmaceutically acceptable additives such as colorants, which do not interfere with the function of the active compounds, can be used for making dosage units.
  • the compounds are preferably administered intravenously.
  • N-bromosuccinimide (254 g) in water (2.4 1) was added pent- 1-ene (100 g). After stirring for 6 days, sodium hydroxide pellets (72.7 g) were added and the solution was stirred at room temperature for 2.5 h. N-(Phenylmethyl)ethanolamine (199 ml) was added and the mixture was stirred for 3 days. After extraction with diethyl ether, the organic phase was washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure.
  • Citric acid 105 mg was added to (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2S)-2-propyl-4-mo ⁇ holinyl]- pregnane-1 1,20-dione (250 mg) in methanol (2 ml). After dissolution the solvent was removed under reduced pressure to give (2 ⁇ .3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2S)-2-propyl-4-mo ⁇ holinyl]pregnane- 1 1,20-dione 2-hydroxy-l,2,3-propanetricarboxylate (1 : 1 ) salt (320 mg); [ ⁇ ]r j , +107° (c 0.5).
  • Citric acid (147 mg) was added to (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2R)-2-propyl-4-mo ⁇ holinyI]- pregnane-11.20-dione (350 mg) in methanol (1.5 ml). After dissolution the solvent was removed under reduced pressure to give (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2R)-2-propyl-4-mo ⁇ holinyl]pregnane- 11,20-dione 2-hydroxy-1.2,3-propanetricarboxylate (1 : 1 ) salt (430 mg); [ ⁇ jrj +97° (c 0.8).
  • (2R)-(l-methylethyl)oxirane (135 g) (prepared from L-valine by the method of B. Koppenhoefer et al., Synthesis, 1994, 1 141) was added dropwise over 2 h to a vigorously stirred solution of ethanolamine (383 ml) and water (260 ml) at 4 °C. The mixture was stirred for a further 1.5 h at 4 °C and then for about 60 h at ambient temperature.
  • (2R)-2-(l-Methylethyl)mo ⁇ holine hydrochloride (17.7 g) and potassium carbonate (7.4 g) were added to a stirred mixture (3.5:1) of (2 ⁇ ,3 ⁇ ,5 ⁇ )-2,3-epoxypregnane-l l,20-dione 20-cyclic 1,2- ethanediyl acetal and its 3 ⁇ ,4 ⁇ -epoxy isomer (10 g) (prepared as described in British Patent 1,039,441) in 1 ,2-ethanedioI (200 ml).
  • the mixture was heated at 80 °C in an atmosphere of nitrogen for 1 h until effervescence subsided, then heated at 140 °C for 17 h.
  • the mixture was then poured into water (2 I) and the precipitated solid was filtered off and washed with water.
  • the solid was suspended in a mixture of methanol (90 ml) and water (20 ml), and methanesulfonic acid (5.8 ml) was added with stirring. After 45 min at room temperature, the solution was concentrated in vacuo, poured into water (800 ml) and extracted with ethyl acetate. After adding aqueous sodium carbonate until the pH exceeded 9, the mixture was extracted with dichloromethane.
  • Citric acid (501 mg) was added to a suspension of (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2R)-2-(l- methylethyl-4-mo ⁇ holinyl]pregnane-l 1,20-dione (1.2 g) in ethanol (5 ml). After dissolution, the solvent was removed under reduced pressure.
  • (2R)-2-(l-Methylethyl)mo ⁇ holine hydrochloride (42 g) and sodium hydroxide flakes (10 g) were added to a stirred mixture (4:1) of (2 ⁇ ,3 ⁇ ,5 ⁇ )-2,3-epoxypregnan-20-one cyclic 1,2- ethanediyl acetal and its 3 ⁇ ,4 ⁇ -epoxy isomer (24 g) (prepared as in British Patent 1,039,441) in ethanediol (250 ml).
  • the mixture was heated at 120 °C for 22 h and poured into water.
  • the solid was filtered off and stirred with 10% aqueous methanesulfonic acid (200 ml) for 1 h.
  • Methanesulfonic acid (0.065 ml) was added to (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2R)-2-(l-methylethyl)- 4-mo ⁇ holinyl]pregnan-20-one (445 mg) in methanol (5 ml). After dissolution the solvent was removed under reduced pressure to give (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2R)-2-(l-methylethyI)-4- mo ⁇ holinyl]pregnan-20-one methanesulfonate (1:1) salt (540 mg). [ ⁇ ] D +103° (c 0.7).
  • Trimethylsilyl trifluoromethanesulphonate (5.5 ml) was added dropwise to a stirred mixture of triethylamine (4.5 ml) and (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2R)-2-(l-me ⁇ ylemylM- ⁇ o ⁇ holinyl]- pregnan-20-one (5 g) in dichloromethane (50 ml), keeping the temperature below 15 °C. After 2 h the mixture was washed twice with 2% aqueous sodium carbonate and the solvent was removed under reduced pressure. The residue was treated with hot heptane (20 ml) and the solution was decanted from the residual solids.
  • N-Bromosuccinimide (2.32 g) was added portionwise to a solution of (2 ⁇ ,3 ⁇ ,5 ⁇ )-3,20- bis(trimethylsilyloxy)-2-[(2R)-(l-methylethyl)-4-mo ⁇ holinyl]pregn-20-ene (7 g) in tetrahydrofuran (70 ml) keeping the temperature below 15 °C. After 2 h dilute hydrochloric acid (2M) (14 ml) was added keeping the temperature below 15 °C. After a further 2 h the solution was adjusted to pH 9 with 5% aqueous sodium carbonate and diluted to 400 ml with water.
  • Methanesulfonic acid (0.065 ml) was added to a mixture of (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2R)-2-(l- methylethyl)-4-mo ⁇ holinyl]-21-thioacetylpregnan-20-one (520 mg) in methanol (5 ml). After dissolution the solvent was removed under reduced pressure to give (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy- 2[(2R)-2-( 1 -methylethyl)-4-mo ⁇ holinyl]-21 -thioacetylpregnan-20-one methanesulphonate (1 : 1 ) salt (610 mg); [ ⁇ ] D +118° (c 0.8).
  • (2S)-2-chloro-4-methylpentanol (188.8 g) [prepared as described by B. Koppenhoefer and V. Schurig, Org. Synth., 1988, 66, 151-172.] was added a solution of sodium hydroxide (71.84 g) in water (265 ml). The mixture was stirred vigorously for 1 h at room temperature, followed by 2 h at 40-45 °C. The reaction mixture was cooled to 18 °C and ethanolamine (375.7 ml) was added rapidly, the internal temperature rising to 32 °C. The mixture was stirred in an ice-bath for 1 h and then at room temperature for 15 h.
  • This hydrochloride (19.2 g) and sodium hydroxide flakes (4.3 g) were added to a stirred mixture (9:1) of (2 ⁇ ,3 ⁇ ,5 ⁇ )-2,3-epoxypregnane-l l,20-dione 20-cyclic 1 ,2-ethanediyl acetal and its 3 ⁇ ,4 ⁇ -epoxy isomer (5.0 g) (prepared as described in British Patent 1,039,441) in 1 ,2-ethanediol (50 ml).
  • the mixture was heated at 120 °C for 4 h and then poured into water and extracted with ethyl acetate.
  • Citric acid (202.4 mg) was added to (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2R)-2-(2-methylpropyl)-4- mo ⁇ holinyl]pregnane- 11,20-dione (499 mg) in methanol (10 ml). After dissolution the solvent was removed under reduced pressure to give (2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-[(2R)-2-(2-methylpropyl)- 4-mo ⁇ holinyl]pregnane-l 1,20-dione 2-hydroxy-l,2,3-propanetricarboxylate (1:1) salt (645 mg); [ ⁇ ] D +93.3° (c 0.8).
  • (2S,3S)-2-Chloro-3-methylpentanol 100 g [prepared by the method of B. Koppenhoefer and V. Schurig, Org. Synth., 1988, 66, 151-172.] was added quickly to a solution of sodium hydroxide (34.6 g) in water (71 ml) at 4 °C. The mixture was stirred vigorously at room temperature for 1.5 h and then at 45 °C for a further 2 h. Ethanolamine (181.1 ml) and water (55.5 ml) were then added and the resulting mixture was stirred at room temperature for 24 h. The water and excess ethanolamine were removed under reduced pressure and the residue was diluted with dichloromethane and filtered. Removal of the dichloromethane under reduced pressure afforded crude (2R,3S)-l-(2-hydroxyethyl)amino-3-methyl-pentan-2-ol (101.7 g).
  • (2R)-2-[(lS)-l-methylpropyl]mo ⁇ holine hydrochloride (19.2 g) and potassium carbonate (7.4 g) were added to a stirred mixture (9:1) of (2 ⁇ ,3 ⁇ ,5 ⁇ )-2,3-epoxypregnane-l l,20-dione 20-cyclic 1,2-ethanediyl acetal and its 3 ⁇ ,4 ⁇ -epoxy isomer (10 g) (prepared as described in British Patent 1,039,441) in 1,2-ethanediol (200 ml).
  • the mixture was heated at 70 °C in an atmosphere of nitrogen for 1 h until effervescence subsided, then heated at 120 °C for 19 h.

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Abstract

L'invention concerne des dérivés 2β-morpholino-androstane substitués par alkyle, liés en position 2β à l'azote d'un groupe de la formule (I) dans laquelle Ra désigne alkyle (3-6C); Rb désigne H ou alkyle (3-6C), et Y désigne O ou S; ou un de leurs sels pharmaceutiquement acceptables. Ces stéroïdes constituent des anesthésiques intraveineux extrêmement puissants. Ces composés présentent des délais d'action rapides et des courbes idéales de 'durée de sommeil' / 'récupération jusqu'à parfaite coordination'.
PCT/EP1996/002346 1995-06-02 1996-06-03 DERIVES ALKYLE-2β-MORPHOLINO-ANDROSTANE WO1996038465A1 (fr)

Priority Applications (1)

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AU61896/96A AU6189696A (en) 1995-06-02 1996-06-03 Alkyl 2beta-morpholino-androstane derivatives

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Application Number Priority Date Filing Date Title
EP95201454.6 1995-06-02
EP95201454 1995-06-02

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WO1996038465A1 true WO1996038465A1 (fr) 1996-12-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013224291A (ja) * 2012-04-20 2013-10-31 Rohm & Haas Co ベンジルアミン疎水性物質
CN104193695A (zh) * 2014-09-03 2014-12-10 哈尔滨工业大学 一种吗啡啉类化合物的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3225034A (en) * 1962-07-09 1965-12-21 Organon 2beta-amino-steroids
EP0583811A1 (fr) * 1992-07-22 1994-02-23 Akzo Nobel N.V. Derivé 21-Chloro-Pregnane
EP0656365A1 (fr) * 1993-12-02 1995-06-07 Akzo Nobel N.V. Dérivés 2-bêta-morpholino de androstane

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3225034A (en) * 1962-07-09 1965-12-21 Organon 2beta-amino-steroids
EP0583811A1 (fr) * 1992-07-22 1994-02-23 Akzo Nobel N.V. Derivé 21-Chloro-Pregnane
EP0656365A1 (fr) * 1993-12-02 1995-06-07 Akzo Nobel N.V. Dérivés 2-bêta-morpholino de androstane

Non-Patent Citations (3)

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Title
G. H. PHILLIPS: "Structure Activity Relationships in Steroidal Anaesthetics", JOURNAL OF STEROID BIOCHEMISTRY, vol. 6, no. 5, 1975, pages 607 - 613, XP002012177 *
G. H. PHILLIPS: "Structure Activity Relationships in Steroidal Anaesthetics", MOLECULAR MECHANISMS IN GENERAL ANAESTHESIA (A GLAXO SYMPOSIUM, PUBL. 1974), 1973, LONDON, GB, pages 32 - 47, XP002012178 *
L. FIELDING ET AL: "Stereochemistry of Some Anaesthetic Steroids by 13C NMR", BULLETIN OF MAGNETIC RESONANCE, vol. 17, no. 1-4, 1995, PHILADELPHIA, pages 208 - 209, XP002012179 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013224291A (ja) * 2012-04-20 2013-10-31 Rohm & Haas Co ベンジルアミン疎水性物質
KR101517468B1 (ko) 2012-04-20 2015-05-04 롬 앤드 하아스 컴패니 벤질아민 소수성분
US9156776B2 (en) 2012-04-20 2015-10-13 Rohm And Haas Company Benzylamine hydrophobe
CN104193695A (zh) * 2014-09-03 2014-12-10 哈尔滨工业大学 一种吗啡啉类化合物的合成方法

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