NZ237902A - Organosilicon-substituted piperidine derivatives and medicaments. - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £37902 437 9 0 2 Priority Date(s): Complete Specification Filed: '2^".<+r"3j can Obxy IX;.

Publication Date: .S.FERJMft , /$tt........

NEW ZEALAND PATENTS ACT, 1953 Date: COMPLETE SPECIFICATION NOVEL NOJIRIMYCIN DERIVATIVES N-Z. PATENT OFFICE 22 APR 1991 We, MERRELL DOW PHARMACEUTICALS INC., a corporation organized under the laws of the State of Delaware, having an office at 2110 East Galbraith Road, Cincinnati, Ohio 45215, United States of America, hereby declare the invention for which ? / we pray that a patent may be granted to XflB/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by page la) 23 7 9 0 2 NOVEL NOJIRIMYCIN DERIVATIVES This invention relates to novel N-derivatives of 1-deoxy nojirimycin, to the method for their preparation and to their use in the treatment of diabetes and their use against retro-viruses, particularly in the treatment of acquired immuno-deficiency syndrome (AIDS).

More specifically the invention relates to 1-deoxy nojirimycin derivatives of the formula OH I Q I R1-Si-R3 the geometric isomers thereof, and the pharmaceutical!^ acceptable salts thereof wherein VS JAK199S .// N M01469A - lt\- 23 7 9 0 1 is Cx_7 alkylene, (CH2)mCH=CH(CH2)n, (CH2)mC=C(CH2)n, (CH2)mCH=C=CH(CH2)n, (CH2)p phenylene, (CH2)m cyclo-pentenylenef (CH2)m cyclohexenylene, (CH2)pT, wherein T, together with the silicon atom to which it is attached forms a 5 to 6 atom cyclic silicane, said cyclic silicane optionally having a double bond, with m being 1, 2 or 3, n being 0, 1 or 2, p being 0, 1, 2, 3 or 4, is C1-7 alkyl, Cx_-j alkoxy, mono- or polyhydroxy Cj^g alkyl, mono- or polyalkoxy C^.g alkyl, chloro C^.g alkyl, and R3 are Cj^q alkyl, (CH2)p-X,Y-substituted phenyl, with X and Y each being H, OH, halogen, C2_6 alkyl, C^g alkoxy, CP3, CN, N02, SH or -S-C^g alkyl, with the proviso that when Q is (CH2)pT, then one of Rx, R2 or R3 is deleted.

As used herein, Q is a divalent moiety bridging the 1-deoxy-nojirimycin with the silicon atom to which Q is attached. In all instances the moieties of Q are directly 20 attached to the nitrogen atom of the 1-deoxy nojirimycin. The alkylene moiety includes the straight, branched and cyclized manifestations of saturated lower aliphatic hydrocarbons including such alkylene moieties derived from alkyl radicals such as methyl, ethyl, n-propyl, isopropyl, 25 n-butyl, cyclopropyl, pentyl, hexyl, cyclohexyl, cyclohexyl-methyl, preferably n-butyl, n-propyl, methyl or ethyl, (yielding, of course such moieties as for example (-CH2-), (-CH2-CH2"), (-CH2CH2CH2-), (-CH2-(C6H10-h wherein the silicon is preferably attached at the meta-position of the 30 cyclohexyl moiety, and the like). Preferably the moiety of (CH2)mCH=CH(CH2)n is in its trans configuration, and preferably m is 1 and n is zero. Preferably, the (CH2)m cyclopentenylene and cyclohexenylene moieties have their unsaturation at the carbon atom to which the silicon is M01469A 217 902 attached [e.g. CH2—Si^- or CH,~~^Z| ].

I Preferably, for the (CH2)p phenylene moiety,p is 1 or 2 and the -SiRjRjRj moiety is attached to the phenyl moiety at its 3-position. Preferred (CH2)DT moieties are illustrated as (CH2>p-0 ' (CH2)p-<^si ' (CH2)p~0 and /S\ / \ / \ (CH2> P-Oci with p preferably being 1 or 2.

/ \ In those instances wherein Rj^ is Cj_7 alkyl or C1-7 alkoxy, methyl, ethyl, methoxy and ethoxy are preferred.

When Rx is hydroxy C1_& alkyl, hydroxymethyl is preferred. When R-l is polyhydroxy Cj^g alkyl it is preferred that there be 1, 2 or 3 OH radicals, each one of which is attached to a different carbon atom of the Cj.g alkyl moiety and in such instances it is preferred that the hydroxy be located on carbon atoms other than the carbon atom attached directly onto the silicon atom; the same concepts also be true for the mono- and polyalkoxy substituted Cj^g alkyl moieties in which case methoxy is preferred. Preferably the (CH2)pX,Y-substituted phenyl moieties are those wherein both X and Y are H, or one is H and the other is OH, chloro, methyl or methoxy or both are OH, CI, methyl or methoxy. In general, in those instances wherein the Q radical contains a (CH2)m moiety it is preferred that m be 1 or 2, and when Q contains (CH2)n moieties n preferably is zero or 1. For convenience, the i fi R1-^i-R3 moiety and the -Q-j3i-R2 moiety of Formula I will R2 R3 also be referred to as -SiR1R2R3 and -Q-Si-R1R2R3, respectively. In general the trans- isomers are preferred over the cis- isomers.

The pharmaceutical^ acceptable salts of the compounds of formula I include salts formed with non-toxic organic or M01469A L 3 7 y 0 z inorganic acids such as, for example, from the following acids: hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic acid, acetic, propionic, tartaric, 5 citric, lactic, malic, mandelic, cinnamic, palmitic, itaconic and benzenesulfonic and the like.

In general the compounds of this invention are prepared by chemical reactions and procedures which are analogously known in the art and the selection of a particular route to any specific compound is governed by principles well known and appreciated by those of ordinary skill in the art.

In general the compounds of this invention may be prepared according to the reaction scheme outlined below.

MQ1469A 23 79 0 2 Reaction Scheme A DMF NEt3 X'-Q-SiR1R2R3" R0-V^\^0H \ .OR N Q-SiR^Rs (2) (3) H2Pd/C HCOOH/MeOH/Pd/C OH HO JLw Neutralization \ ,OH H HCOO0 Q-S1R2R2R3 (4) wherein Q-SiR1R2R3 is as previously defined, R is E or Bz, Bz 30 is benzyl, a preferred hydroxy-protecting group, X' is halogeno, mesylate or tosylate.

The synthesis of Reaction Scheme A is initiated by the condensation of an optionally hydroxy-protected 1-deoxy nojirimycin with an excess quantity (= three times) of the appropriate X'-Q-SiR1R2R3 reactant in the presence of an M01469A - 5 - 2 3 7 3 0 2 excess of triethylamine (NEt3) in dimethyl formamide (DMF). Preferably X' is the iodide. The so-produced compounds (3) are purified, preferably using chromatographic techniques and are then deprotected according to standard procedures 5 well known in the art. Preferably deprotection is effected by using transfer hydrogenation with formic acid in methanol with Pd/C or by catalytic hydrogenation, preferably using palladium on carbon in an appropriate solvent, e.g. ethanol.

When transfer hydrogenation is utilized, the deprotected 10 products (4) are in the form of quaternary salts with the HCOO® anion and thus must be neutralized; the neutralization preferably being effected using an ion exchange resin such as Dowex AX-8.

In those instances wherein Q represents a bridging moiety containing an unsaturation (e.g., allylic, allenic, acetylenic, cyclopentenylene, cyclohexenylene or the unsaturated (CH2)pT moieties) it is preferred that the 2-, 3-and 6-position hydroxy groups not be protected in view of 2q the difficulties encountered when removing the benzyl protecting groups unless special procedures are employed (e.g., when Q contains such unsaturated moieties a process using sodium in ammonia is preferred). In those instances wherein Q is other than an unsaturated moiety, and it is 2^ preferred that the 2-, 3- and 6-positions bear a benzyl protecting group, "normal" procedures (as outlined above) may be employed for their removal. The benzyl groups may also serve as a means for obtaining the products in a more purified form. Although not required the 4-position OH group may also bear a protecting group.

J U It should be noted that when the above comment is made concerning the protection of the 2-, 3- and 6-OH functions, the nomenclature is that which is used in sugar chemistry using the positions of glucitol as shown in Formula I. In 35 that instance, the OH radical of the hydroxymethyl moiety is M01469A - 6 - 237 9 0 2 at the 6-position, the other beta OH is at the 3-position and the two alpha OH groups are at the 2- and 4-positions. In that instance it is the 2-, 3- and 6-position hydroxy groups which would be protected prior to the condensation 5 reaction (the 4-position OH group, in any situation, normally need not be protected). In the instances wherein the compounds are named as piperidine derivatives the compounds (1 and 4) would be 2 ((J)-hydroxymethyl-l-[RjRjRjSi-Ql-Sa^&fSa-piperidinetriols and thus for 10 Structures 2 and 3 the OH functions at the 2-, 4- and 5-positions of the piperidine would be protected with a benzyl protecting group.

To illustrate the nomenclature of the compounds of this invention as piperidine derivatives the structured compound would be named [2R-(2B,3a,40,5a]-2-hydroxymethyl-l-[l-(3,3-dimethyl-3-sila-l-cyclohexenyl)methyl]-3,4,5-piperidinetriol, 1-Deoxy nojirimycin may be obtained by reducing nojirimycin (5-amino-5-deoxy-D-glucopyranose) using the method of Tetrahedron Letters, 24., 2125-2144, 1968, as referenced in European Patent Application 89 112284.8 published on January 10, 1990, with publication No. 0350012, ■3 e The preparation of 1-deoxy nojirimycin and its hydroxy- M01469A 27 t i V i 0 w ^ protected analogs (2) are also disclosed in the specific examples disclosed herein.

The X-Q-SiR1R2R3 reactant are either known compounds or may be prepared by methods analogously known in the art.

The following examples illustrate the preparation of the compounds of this invention.

EXAMPLE 1 Preparation of 3-(TRIMETHYLSILYL)-1-PROPANOL, METHANESULFONATE Methanesulfonylchloride (0.73 ml, 9 mmol) was added dropwise to a solution of 3-(trimethylsilyl)-l-propanol (1.2 ml, 7.56 mmol) cooled at 0°C in 20 ml of dichloro-methane. After 45 minutes stirring, the reaction mixture was partitioned between water and dichloromethane, the organic phase was separated, the solvent was evaporated under reduced pressure to afford the expected 3-(trimethylsilyl)-1-propanol, methanesulfonate in crude quantitative yield.

EXAMPLE 2 Preparation of ( 3 - IQDOPROP YL1TRIMETHY SI LANE An ethereal solution of magnesium iodide was prepared by adding 4.85 g (19 mmol) of iodine to 0.46 g (19 mmol) of magnesium in suspension in 40 ml of dry ether. 28 ml of this solution was added to a solution containing the crude 3-(trimethylsilyl)-l-propanol, methanesulfonate in 10 ml of ether. The reaction mixture was stirred for 3 hours at room M01469A 23 7 y 0 z temperature and then partitioned between ether and water, the organic phase was separated and further washed with aqueous sodium thiosulfate. After evaporation of the solvent, 1.6 g of (3-iodopropyl)trimethysilane was obtained 5 as a colorless liquid.

EXAMPLE 3 Preparation of 10 (3-BRQMOPROPYL)TRIMETHYLSILANE 1.02 ml (10.9 mmol) of phosphorous tribromide in 20 ml of ether was added to a cooled (0°C, -10°C) solution of 4 g (30.2 mmol) of 3-(trimethylsilyl)-l-propanol in 40 ml of dry ether. The reaction mixture was brought back to room temperature and refluxed for 15 minutes. After bulb to bulb distillation of the crude reaction mixture 4.3g of (3-bromo-propyl)trimethylsilane were isolated as a colorless liquid.

EXAMPLE 4 Preparation of 4-(TRIMETHYLSILYL)-BUTANOIC ACID A solution containing 3 g (15.4 mmol) of (3-bromo-propyl)-trimethylsilane in 3 ml of dry ether was added to 0.375 g (15.4 mmol) of magnesium turnings in ether (40 ml final volume of solution). After 1 hour of reflux gazeous 30 carbondioxide was bubbled through the reaction mixture (3 g, 77 mmol of dry ice). After 2 hours of stirring at room temperature the reaction mixture was partitioned between aqueous ammonium chloride and ether. The organic phase was separated, the aqueous phase was further acidified with 35 hydrochloric acid IN and extracted with ether. Ethereal phases were pooled and the solvent was removed under reduced M01469A - 9 - 237 9 02 pressure. Separation of the expected 4-trimethylsilyl-butanoic acid from dimer of starting (3-bromopropyl)tri-methylsilane was finally performed by acid base extraction. 0.62 g of 3-(trimethylsilyl)-butanoic acid was isolated as a 5 colorless liquid.

EXAMPLE 5 Preparation of 10 4-(TRIMETHYLSILYL)-1-BUTANOL 1.5 ml (11.4 mmol) of a 1 molar solution of borane dimethylsulfide was added to a cooled (0°C) solution of 0.61 g (3.8 mmol) of 4-(trimethylsilyl)-butanoic acid in ^ 20 ml of dry tetrahydrofuran. After work-up using the standard procedure (methanol, tetramethylethylene diamine) and flash chromatography purification on silica gel eluted with a 9:1 mixture of hexane and ethyl acetate, 0.4 g of 4-(trimethylsilyl)-l-butanol was obtained as a colorless 20 liquid.

EXAMPLE 6 Preparation of 4-(TRIMETHYLSILYL)-1-BUTANOL. METHANESULFONATE Starting from 0.4 g (2.53 mmol) of 4-(trimethylsilyl)-!-butanol, 0.245 ml (3.16 mmol) of methanesulfonyl chloride 30 and 0.528 ml (4.3 mmol) of triethylamine, and using the same procedure as for the preparation of 3-(trimethylsilyl)-l-propanol, methanesulfonate, 0.5 g of the expected 4-(tri-methylsilyl)-l-butanol, methanesulfonate was obtained.

M01469A - 10 - 2 3 7 9 0 Z EXAMPLE 7 Preparation of 4-(IODOBUTYL)TRIMETHYLSILANE Using the same procedure as described for the preparation of 3-(iodopropyl)trimethylsilane, starting from 0.5 g (2.53 mmol) of 4-(trimethylsilyl)-l-butanol methane sulfonate and 12 ml of a 0.34 M ethereal solution of magnesium iodide, 0.5 g of 4-(iodobutyl)trimethylsilane was isolated as a colorless liquid.

EXAMPLE 8 Preparation of 14-BROMO-2-BUTYNYL)TRIMETHYLSILANE 4-(trimethylsilyl)-2-butynol [J. Pernet, B. Randrianoelina, and L. Miginiac/ Tetrahedron Letters, 25, 651, (1984)] (10 g, 70 mmol) is dissolved in dry diethyl ether (150 ml) and phosphorous tribromide (2.2 ml, 23.3 mmol) is added dropwise. Then the mixture is refluxed, 2,. protected from the light during 2.5 hours. The reaction is washed twice with water, once with aqueous sodium bicarbonate and then once with water. The organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure to afford the expected bromide (4-bromo-2-butynyl)trimethylsilane (1.4 g, 97%) which is used without •3 U purification.

M01469A 23 7 9 0 EXAMPLE 9 Preparation of _ ( 4-BROMO-2- (E) BUTENYL) TRIMETHYLSILANE 5 4-(Trimethylsilyl)-2(E)-butene-l-ol [H. Mastalerz, J. Org. Chem., 49, 4094, (1984)] (10 g, 70 mmol) is dissolved in dry diethyl ether (150 ml) and phosphorous tribromide (2.2 ml, 23.3 mmol) is added dropwise. Then the mixture is ^ refluxed, protected from the light during 2.5 hours. The reaction is washed twice with water, once with aqueous sodium bicarbonate and then once with water. The organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure to afford the expected 15 bromide (4-bromo-2-(E)butenyl)-trimethylsilane (1.4 g, 97%) which is used without purification.

EXAMPLE 10 Preparation of DIMETHYL (3-IODOPROPYL1PHENYLSILANE Dimethyl(3-chloropropyl)phenylsilane [J.W. Wilt, W.K.

Chwang, C.F. Dockus and N.M. Tomiuk, J. Am. Chem. Soc., 100, 5534, (1978)] (9 g, 48.8 mmol) and sodium iodide (29.5 g, 195 mmol) are refluxed in acetone during 24 hours. The mixture is filtered and the solvent is evaporated under reduced pressure. The residue is dissolved in diethyl ether and washed with water. The organic layer is dried with sodium sulfate, filtered and concentrated under reduced pressure to afford pure dimethyl(3-iodopropyl)phenylsilane as a slightly yellow oil (12.5 g, 93%).

M01469A 237902 EXAMPLE 11 Preparation of BENZYL(IODOMETHYL)DIMETHYLSILANE Benzyl(bromomethyl)dimethylsilane (Colm, Earborn and Foad M.S., Malmond j. Organomet. Chem., 209, 13 (1981)] (12 g, 0.05 mmol) and sodium iodide (45 g, 0.3 mmol) are refluxed with stirring in acetone (500 ml) during 24 hours. The reaction mixture is cooled, filtered and the solvent is evaporated under reduced pressure. The residue is dissolved in ether and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl(iodomethyl)dimethylsilane (13.7 g, ^ 95%) as a slightly yellow oil.

EXAMPLE 12 Preparation of t-BUTYL(IODOMETHYL)DIMETHYLSILANE t-Butyl(chloromethyl)dimethylsilane [Makoto Kumada, Mitsuo Ishikawa, Sajiro Meada and Katsuyata Ikura, J. Organometal. Chem. 2, 146, (1964)] (16.4 g, 0.1 mmol) and sodium iodide (60 g, 0.4 mmol) in acetone (500 ml) are refluxed with stirring during 24 hours. The reaction mixture is cooled, filtered and the solvent is evaporated under reduced pressure. The residue is dissolved in ether and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford t-butyl(iodomethyl)dimethylsilane (20.9 g, 80%) as a slightly yellow oil.

M01469A 237902 EXAMPLE 13 Preparation of 5-AZIDO-3,6-DI-Q-BENZYL-5-DEOXY-D-GLUCOFURANOSE The azide 5-azido-3,6-di-0-benzyl-5-deoxy-l,2-0-iso-propylidene-a-D-glucofuranoside (U.G. Nayak and R.L.

Whisler, J. Org. Chem., 33, 3582 (1968) (15.02 g, 35.3 mmol) was dissolved at 0°C in 100 ml of a 9:1 mixture of 10 trifluoro-acetic acid and water. The mixture was stirred at 0°C during 2 h. The trifluoroacetic acid was evaporated under reduced pressure at room temperature. The residue was taken with ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated ^ under reduced pressure. Flash chromatography on silica gel and elution with a 1:1 mixture of hexane and ethyl acetate, followed by recrystallization in a mixture of hexane and ethyl acetate afforded the expected compound 5-azido-3,6-di-O-benzyl-5-deoxy-D-glucofuranose.

EXAMPLE 14 Preparation of METHYL 5-AZIDO-3,6-DI-Q-BENZYL-5-DEOXY-D-GLUCOFURANOSIDE To a solution of 5-azido-3,6-di-0-benzyl-5-D-gluco-furanose (10.23 g, 26.5 mmol) in methylene chloride (170 ml) 30 was added methanol (11 ml) and borontrifluoroetherate (1.5 ml). The mixture was stirred 24 h at room temperature. The reaction mixture was successively washed with a saturated aqueous solution of sodium bicarbonate and then with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silica gel and elution with a 1:1 mixture M01469A 237902 of hexane and ethyl acetate afforded methyl 5-azido-3,6-di-O-benzyl-5-deoxy-D-glucofuranoside as a colorless oil (9.15 g, 85%).

EXAMPLE 15 Preparation of METHYL 5-AZIDO-2,3,6-TRI-Q-BENZYL-5-DEOXY-D-GLUCOFURANOSIDE To a suspension of sodium hydride (1.2 g, 27.5 mmol), 55% in mineral oil, washed three times with pentane) in anhydrous tetrahydrofuran (200 ml) was added quickly drop-wise the alcohol methyl 5-azido-3,6-di-0-benzyl-5-deoxy-D-^ gluco-furanoside (9.15 g, 22.9 mmol) in tetrahydrofuran (50 ml) at room temperature and under nitrogen. The mixture was stirred during 3 h at room temperature, the mixture was yellow. Then n-Bu4N+I" (76 mg, 0.20 mmol) was added followed by benzyl bromide (3.30 ml, 27.5 mmol) added dropwise. The 20 mixture was stirred overnight at room temperature. After hydrolysis with saturated aqueous ammonium chloride tetrahydrofuran was evaporated under reduced pressure. The residue was diluted with water and extracted three times with ether. The organic phase was dried over sodium sulfate. 25 Filtration and evaporation under reduced pressure afforded an oil. Flash chromatography on silica gel and elution with a 20:80 mixture of ethyl acetate and hexane afforded the expected compound methyl 5-azido-2,3,6-tri-0-benzyl-5-deoxy-D-glucofuranoside as a colorless oil (10.88 g, 97%).

M01469A 237902 EXAMPLE 16 Preparation of _ 5-AZIDO-2,3,6-TRI-O-BENZYL-5-DEOXY-D-GLUCOFURANOSE 5 Methyl 5-azido-2,3,6-tri-0-benzyl-5-deoxy-D-glucofurano-side (10.8 gr 22.2 mmol) was dissolved at room temperature in tetrahydrofuran (20 ml). The solution was cooled at -10°C and trifluoroacetic acid (120 ml) was added dropwise •L0 followed by addition of water (20 ml) . The mixture was stirred at 0°C during 24 h. The mixture was evaporated under reduced pressure without heating. The residue was taken with ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silica gel and elution with a 20:80 mixture of ethyl acetate and hexane afforded 5-azido-2,3,6-tri-0-benzyl-5-deoxy-D-glucofuranose as a colorless oil (9.63 g, 90%).

EXAMPLE 17 Preparation of 5-AZIDO-2,3,6-TRI-Q-BENZYL-5-DEOXY-D-GLUCONIC ACID-V-LACTONE To a solution of the lactol 5-azido-2,3,6-tri-0-benzyl-5-deoxy-D-glucofuranose (9.36 g, 20 mmol) in acetone (240 ml) cooled to 0°C, Jones' reagent 2 M (11.5 ml) was 3Q added dropwise until the color was orange. The excess of Jones' reagent was destroyed with 2-propanol (0.5 ml). The mixture was concentrated under reduced pressure. The residue was taken with water and extracted with ether. The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure so as to afford an oil. Flash chromatography on silica gel and elution with a 1:9 M01469A 237402 mixture of ethyl acetate and hexane afforded the Y~lactone 5-azido-2,3,6-tri-0-benzyl-5-deoxy-D-gluconic acid-y-lactone.

EXAMPLE 18 Preparation of .. 2,3 r 6-TRI-0-BENZYL-5-DE0XY-D-GLUC0NIC ACID-8-LACTAM —1 To a solution of the lactone 5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-gluconic acid-y-lactone (8.16 g, 17 mmol) in ethanol (180 ml) was added lindlar catalyst (1.7 g). The mixture was hydrogenated under atmospheric pressure during 24 h. Filtration and evaporation under reduced pressure afforded an oil which was crystallized in a mixture of hexane and ether. The lactam 2,3,6-tri-0-benzyl-5-deoxy-D-gluconic acid-5-lactam was obtained as white crystals (7.4 g, 96%). mp: 85-85.5°C.

EXAMPLE 19 Preparation of 2,3/6-TRI-O-BENZYL-l,5-DIDEOXY-l,5-IMINO-D-GLUCITOL To a solution of 2,3,6-tri-0-benzyl-5-deoxy-D-gluconic acid 6-lactam (compound described in Example 18) (0.75 g, 1.6 mmol) in dry tetrahydrofuran (15ml) was added a 10 M solution of borane in methyl sulfide (0.58 ml) under nitrogen at 0°C. The mixture was stirred 15 min at 0°C, 30 min at room temperature, then refluxed during 6 h and finally stirred overnight at room temperature. The mixture was cooled to 0°C and the excess of borane was destroyed with methanol and stirred 1 h at room temperature. The M01469A 23 7 9 0 reaction mixture was treated with gazeous hydrochloric acid and refluxed during 1 h. The solvents were evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium 5 bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with ethyl acetate afforded 2,3,6-tri-O-benzyl-1,5-dideoxy-l,5-imino-D-glucitol which crystallized in methanol 10 (0.655 g, 90%); m.p. 73-74°C.

EXAMPLE 20 Preparation of 1,5-DIDEOXY-l.5-(f 4-(TRIMETHYLSILYL)-2-BUTYNYL1IMINO)-D-GLUCITOL A solution of l,5-dideoxy-l,5-imino-D-glucitol (0.5 g, nn 3.06 mmol) and (4-bromo-2-butynyl)trimethylsilane (0.943 g, 4.6 mmol) is dissolved in dimethylformamide (15 ml) containing water (0.5 ml). Triethylamine (0.85 ml) is added. The mixture is heated at 80°C during 24 hours. The solvent is evaporated under reduced pressure. Flash chromatography on silica gel and elution with a 8:2 mixture of chloroform and methanol affords 1,5-dideoxy-l,5-{[4-(trimethylsilyl)-2-butynyl]imino}-D-glucitol as an amorphous solid (0.24 g, 27%). 35 M01469A 23 EXAMPLE 21 Preparation of 1,5-DIDEOXY-l,5-f r 4-(TRIMETHYLSILYL)-2(Z)-BUTENYL1IMINO)-D-GLUCITOL 1,5-Dideoxy-l,5-{[4-(trimethylsilyl)-2-butynyl]imino}-D-glucitol (0.1 g, 0.35 mmol) is dissolved in methanol (5 ml) and lindlar catalyst (25 mg) is added. The mixture is ^ hydrogenated at atmospheric pressure overnight. The catalyst is filtered off and the solvent is evaporated under reduced pressure to afford 1,5-dideoxy-l,5-{[4-(trimethylsilyl)-2(Z)-butenyl]imino}-D-glucitol as an amorphous solid (0.09 g, 90%). 1, 5-DIDEOXY-l,5-(f 4-(TRIMETHYLSILYL)-2(E)-BUTENYL1IMIN0)-D-GLUCITOL A solution of 1,5-dideoxy-l,5-imino-D-glucitol (also known as 1-deoxynojirimycin) (0.5 g, 3.06 mmol) and (4-bromo-2-(E)butenyl)trimethylsilane (0.95 g, 4.6 mmol) in a mixture of dimethylformamide (10 ml), water (0.5 ml) and triethylamine (0.85 ml) is heated at 80°C during 24 hours. The solvents are evaporated under reduced pressure. Flash chromatography on silica gel and elution with a 8:2 mixture of chloroform and methanol affords 1,5-dideoxy-l,5-{[4-(trimethylsilyl)-2(E)-butenyl]-imino}-D-glucitol as a foam (0.12 g, 14%).

EXAMPLE 22 Preparation of M01469A 19 237 9 0 EXAMPLE 23 Preparation of 1.5-DIDEOXY-2.3,6-TRI-Q-BENZYL-l,5-(f 3-(DIMETHYLPHENYL-SILYL)-PROPYL 1IMINO)-D-GLUCITOL A solution of l,5-dideoxy-2,3,6-tri-0-ben2yl-l,5-imino}-D-glucitol (0.433 g, 1 mmol) and dimethyl(3-iodopropyl)-phenylsilane (0.912 g, 3 mmol) in a mixture of dimethyl-10 formamide (6 ml) and triethylamine (0.42 ml) is heated at 80°C during 24 hours. The solvents are evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to ^ afford an oil. Flash chromatography on silica gel and elution with a 8:2 mixture of hexane and ethyl acetate affords the expected product l,5-dideoxy-2,3,6-tri-o-benzyl-l,5-{[3-(dimethylphenylsilyl)-propyl]imino}-D-glucitol as a colorless oil (0.493 g, 81%).

EXAMPLE 24 Preparation of 1.5-DIDEOXY-l,5-(\3-(DIMETHYLPHENYLSILYL)PROPYL!IMINO)-D-GLUCITOL 1,5-Dideoxy-2,3,6-tri-0-benzyl-l,5-{[3-(dimethylphenyl-silyl)propyl]imino}-D-glucitol (0.45 g, 0.74 mmol) is dissolved in a 9:1 mixture of methanol and formic acid (10 ml), and palladium 10% on charcoal (0.45 g) is added. The mixture is stirred overnight at room temperature. The catalyst is removed by filtration. The solvents are evaporated under reduced pressure. The residue is dissolved in water and passed through a column of Amberlyst A26 OHe.

M01469A - 20 - 2 3 7 9 0 C Water is evaporated under reduced pressure and flash chromatography on silica gel and elution with a 8:2 mixture of chloroform and methanol affords the expected product 1,5-dideoxy-1,5-{[3-(dimethylphenylsilyl)-propyl]imino}-D-5 glucitol as an amorphous solid (0.208 g, 83%).

EXAMPLE 25 Preparation of 1,5-DIDEOXY-2,3,6-TRI-O-BENZYL-l,5-f T(BENZYLDIMETHYLSILYL)-METHYL 1IMINO)-D-GLUCITOL A solution of l,5-dideoxy-2,3,6-tri-0-benzyl-l,5-imino-D-glucitol (0.433 g, 1 mmol) and benzyl(iodomethyl)dimethyl-silane (0.87 g, 3 mmol) in a mixture of dimethylformamide (6 ml) and triethylamine (0.42 ml) is heated at 80°C during 24 hours. The solvents are evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed 2® with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 8:2 mixture of hexane and ethyl acetate affords the expected product l,5-dideoxy-2,3,6-tri-0-benzyl-l,5-2^ {[(benzyldimethylsilyl)methyl]imino}-D-glucitol as a colorless oil (0.386 g, 65%).

M01469A 237 9 02 EXAMPLE 26 Preparation of 1,5-DIDEOXY-l> 5-ff(BENZYLDIMETHYLSILYL)METHYL 1IMINO)-D-GLUCITOL 1,5-Dideoxy-2,3,6-tr i-O-benzyl-1,5-{ [ (benzyldimethyl-silyl)methyl]imino}-D-glucitol (0.3 g, 0.5 mmol) is dissolved in a 9:1 mixture of methanol and formic acid (10 ml), and palladium 10% on charcoal (0.3 g) is added. The mixture is stirred overnight at room temperature. The catalyst is removed by filtration. The solvents are evaporated under reduced pressure. The residue is dissolved in water and passed through a column of Amberlyst A26 OH®. Water is evaporated under reduced pressure and flash chromatography on silica gel and elution with a 8:2 mixture of chloroform and methanol affords the expected product 1,5-dideoxy-1,5-{[(benzyldimethylsilyl)-methyl]-imino}-D-glucitol as an amorphous solid (0.09 g, 55%).

EXAMPLE 27 Preparation of 1,5-DIDEOXY-2 «3.6-TRI-O-BENZYL-l,5-(f (t-BUTYLDIMETHYLSILYL)-METHYL 11MINOl—D-GLUCITOL A solution of 1,5-dideoxy-2,3,6-tri-O-benzyl-1,5-imino-D-glucitol (0.433g, 1 mmol) and t-butyl(iodomethyl)dimethyl- w silane (0.77 g, 3 mmol) in a mixture of dimethylformamide (6 ml) and triethylamine (0.42 ml) is heated at 808C during 24 hours. The solvents are evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford M01469A - 22 - O T ~T A / - / 0 f] ^ V' J -J \J /' an oil. Flash chromatography on silica gel and elution with a 8:2 mixture of hexane and ethyl acetate affords the expected product 1,5-dideoxy-2,3,6-tri-O-benzyl-1,5—{[(t-butyldimethylsilyl)-methylJimino}-D-glucitol as a colorless oil (0.42 g, 75%).

EXAMPLE 28 Preparation of 1,5-DIDEOXY-l.5-(f(t-BUTYLDIMETHYLSILYL)METHYL1IMINO}-D-GLUCITOL 1,5-Dideoxy-2,3,6-tri-O-benzyl-1,5-{[(t-butyldimethyl-^ silyl)methyl]imino}-D-glucitol (0.4 g, 0.72 mmol) is dissolved in a 9:1 mixture of methanol and formic acid (10 ml), and palladium 10% on charcoal (0.5 g) is added. The mixture is stirred overnight at room temperature. The catalyst is removed by filtration. The solvents are evaporated under reduced pressure. The residue is dissolved in water and passed through a column of Amberlyst A26 OH®. Water is evaporated under reduced pressure and flash chromatography on silica gel and elution with a 8:2 mixture of chloroform and methanol affords the expected product 1,5-dideoxy-1,5-{[(t-butyldimethylsilyl)-methyl]imino}-D-glucitol as an amorphous solid (0.127 g, 61%).

M01469A • • 237902 EXAMPLE 29 Preparation of 1,5-DIDEOXY-2,3,6-TRI-Q-BENZYL-l,5-(f(DIMETHYLPHENYLSILYL)-METHYL 1IMINOl-D-GLUCITOL A solution of 1,5-dideoxy-2,3,6-tri-O-benzyl-1,5-imino- D-glucitol (0.433 g, 1 mmol) and phenyl(iodomethyl)dimethyl- * silane [Chih-Tang Huang and' Pao-Jen Wang, Hua Hsiieh Hsiieh 10 Pao, 25., 341, (1959)] (0.77 g, 3 mmol) in a mixture of dimethylformamide (6 ml) and triethylamine (0.42 ml) is heated at 80°C during 24 hours. The solvents are evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 8:2 mixture of hexane and ethyl acetate affords the expected product l,5-dideoxy-2,3,6-tri-O-benzyl-1,5-{[(dimethylphenylsilyl)-methyl] imino}-D- on glucitol as a colorless oil (0.37 g, 64%).

EXAMPLE 30 Preparation of 1, 5-DIDEOXY-l, 5- ( f (DIMETHYLPHENYLSILYL )METHYL 1 IMINO)-P-GLUCITOL 1,5-Dideoxy-2,3,6-tri-O-benzyl-1,5-{[(dimethylphenyl-silyl)methyl]imino}-D-glucitol (0.35 g, 0.60 mmol) is dissolved in a 9:1 mixture of methanol and formic acid (10 ml), and palladium 10% on charcoal (0.35 g) is added. The mixture is stirred overnight at room temperature. The catalyst is removed by filtration. The solvents are evaporated under reduced pressure. The residue is dissolved M01469A - 24 - (* copy available on request) N.Z. PATENT OFFICE -1 DEC 1992 RECEIVED 23' in water and passed through a column of Amberlyst A26 OH®. Water is evaporated under reduced pressure and flash chromatography on silica gel and elution with a 8:2 mixture of chloroform and methanol affords the expected product 1,5-5 dideoxy-1,5-{[(dimethylphenylsilyl)-methyl]imino}-D-glucitol as an amorphous solid (0.139 g, 75%). 1,5-DIDEOXY—2,3,6-TRI-O-BENZYL-l,5-f[(TRIMETHYLSILYL)-METHYL]IMINO)-D-GLUCITOL A solution of 1,5-dideoxy-2,3,6-tri-0-benzyl-l,5-imino-D-glucitol (0.1 g, 0.24 mmol) and (iodomethyl)trimethylsilane (0.45 ml, 3.1 mmol) in a mixture of dimethylformamide (3 ml) and triethylamine (0.44 ml) is heated at 80°C during 24 hours. The solvents are evaporated under reduced 20 pressure. The residue is dissolved in ethyl acetate, washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 8:2 mixture of hexane and ethyl acetate affords the 2^ expected product l,5-dideoxy-2,3,6-tri-O-benzyl-1,5- {[(trimethylsilyl)methyl]imino}-D-glucitol as a colorless oil (0.09 g, 75%).

EXAMPLE 31 Preparation of M01469A - 237 9 EXAMPLE 32 Preparation of It5-DIDEOXY-l.5-(f(TRIMETHYLSILYL)METHYL1IMINO)-D-GLUCITOL 1,5-Dideoxy-2,3,6-tri-O-benzyl-1,5-{[(trimethylsilyl)-methyl]imino}-D-glucitol (0.075 g, 0.14 mmol) is dissolved in a 9:1 mixture of methanol and formic acid (12 ml), and palladium 10% on charcoal (0.3 g) is added. The mixture is stirred overnight at room temperature. The catalyst is removed by filtration. The solvents are evaporated under reduced pressure. The residue is dissolved in water and neutralized with AG1-X8, 20-50 mesh, OHe form. The resin is removed by filtration, water is removed by lyophilization ^ and the expected product 1,5-dideoxy-l,5-{[(trimethylsilyl)-methyl]imino}-D-glucitol is obtained as an amorphous solid (0.016 g, 45%).

EXAMPLE 33 Preparation of 1,5-DIDEOXY-2,3.6-TRI-Q-BENZYL-l,5-(t3-(TRIMETHYLSILYL) -25 PROPYL!IMINO)-D-GLUCITOL A solution of l,5-dideoxy-2,3,6-tri-O-benzyl-1,5-imino-D-glucitol (0.34 g, 0.78 mmol) and (3-iodopropyl)trimethylsilane (0.57 gr, 2.34 mmol) in a mixture of dimethylform-3Q amide (5 ml) and triethylamine (0.33 ml) is stirred at room temperature during 24 hours. The solvents are evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced 35 pressure to afford an oil. Flash chromatography on silica gel and elution with a 8:2 mixture of hexane and ethyl M01469A 2~1 -y A <*, 3 ! & u £ acetate affords the expected product l,5-dideoxy-2,3,6-tri-O-benzyl-1,5-{[3-(trimethylsilyl)-propyl]imino}-D-glucitol as a colorless oil (0.405 g, 94%).

EXAMPLE 34 Preparation of 1Q 1,5-DIDEOXY-l,5-(r 3-(TRIMETHYLSILYL)PROPYL1IMINO)-D-GLUCITOL 1,5-Dideoxy-2,3,6-tri-O-benzyl-1,5-{[3-(trimethylsilyl)-propyl]imino}-D-glucitol (0.39 g, 0.7 mmol) is dissolved in a 9:1 mixture of methanol and formic acid (30 ml), and palladium 10% on charcoal (2 g) is added. The mixture is stirred overnight at room temperature. The catalyst is removed by filtration. The solvents are evaporated under reduced pressure. The residue is dissolved in water and neutralized with AG1-X8, 20-50 mesh, OH9 form. The resin is removed by filtration, water is removed by lyophilization and the expected product 1,5-dideoxy-l,5—{[(trimethylsilyl)-propyl]imino}-D-glucitol is obtained as an amorphous solid (0.17 g, 85%).

EXAMPLE 35 Preparation of 1,5-DIDEOXY-2.3,6-TRI-O-BENZYL-l,5-(f 4-(TRIMETHYLSILYL)- BUTYL 1-IMINO)—D-GLUCITOL A solution of l,5-dideoxy-2,3,6-tri-O-benzyl-1,5-imino-D-glucitol (0.043 g, 0.1 mmol) and (4-iodobutyl)trimethylsilane (0.088 g, 0.3 mmol) in a mixture of dimethylformamide (0.8 ml) and triethylamine (0.04 ml) is stirred at room temperature during 24 hours. The solvents are evaporated M01469A - 27 - 23 7 9 0 under reduced pressure. The residue is dissolved in ethyl acetate, washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica 5 gel and elution with a 8:2 mixture of hexane and ethyl acetate affords the expected product l,5-dideoxy-2,3,6-tri-O-benzyl-1,5—{[4—(trimethylsilyl)butyl]imino}-D-glucitol as a colorless oil (0.05 g, 90%).

EXAMPLE 36 Preparation of 1,5-DIDEOXY-l,5-(T 4-(TRIMETHYLSILYL)BUTYL 11MINO)-D-GLUCITOL 1,5-Dideoxy-2,3,6-tri-O-benzyl-1,5—{[4—(trimethylsilyl) butyl]imino}-D-glucitol (0.05 g, 0.09 mmol) is dissolved in a 9:1 mixture of methanol and formic acid (15 ml), and palladium 10% on charcoal (0.2 g) is added. The mixture is stirred overnight at room temperature. The catalyst is removed by filtration. The solvents are evaporated under reduced pressure. The residue is dissolved in water and neutralized with AG1-X8, 20-50 mesh, OH0 form. The resin is removed by filtration, water is removed by lyophilization ^ and the expected product 1,5-dideoxy-l,5-{[4-(trimethylsilyl) butyl ]imino}-D-glucitol is obtained as an amorphous solid (0.02 g, 75%).

M01469A 9 "? -? C yj • > p y ifea EXAMPLE 37 Preparation of 1,5-DIDEOXY-l,5-IMIN0-D-GLUCIT0L: DEOXYNOJIRIMYCIN 2,3,6-Tri-O-benzyl-1,5-dideoxy-l,5-imino-D-glucitol (0.2 g, 0.46 mmol) is dissolved in a 9:1 mixture of methanol and formic acid (10 ml) under an inert atmosphere and palladium 10% on charcoal (0.4 g) is added. The mixture is ^ stirred overnight at room temperature. The catalyst is removed by filtration. The solvents are evaporated under reduced pressure. The residue is dissolved in methanol and the solution is filtered through a membrane (Millex-SR 0.5uM). Evaporation of solvent gives a sticky solid which is further triturated in ethanol to give the expected 1,5-dideoxy-l,5-imino-D-glucitol as a beige powder (60 mg, 80%).

EXAMPLE 38 Preparation of IE)-3-TRIMETHYLSILYL-2-PROPEN-1-PL 2 g (15.6 mmol) of l-trimethylsilyl-2-propyn-l-ol in 10 ml of dry ether are added dropwise to an ice-cooled solution of sodium bis(2-methoxyethoxy) aluminum [Red-Al. 3.4 M in toluene, (7.3 ml, 25.1 mmol)] in 10 ml of dry ether. The reaction mixture is then further stirred during 2^ hours at room temperature and poured into an ice-cooled sulfuric acid (1 N) ether mixture. If necessary the pH is adjusted to be slightly basic, the organic phase is then removed and the aqueous phase is further extracted with ether. The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure.

M01469A - 29 - 237902 Rapid flash chromatography of the residue on a silica gel column eluted with a 8:2 mixture of hexane and ethyl acetate affords the expected (E)-3-trimethylsilyl-2-propen-l-ol as a colorless liquid (1.8 g, 90%).

EXAMPLE 39 Preparation of (E)-3-TRIMETHYLSILYL-2-PROPEN-l-OL, METHANESULFONATE 1.6 ml (11.5 mmol) of triethylamine and 0.74 ml (9.6 mmol) of methanesulfonylchloride in 10 ml of dry dichloromethane are successively added to an ice-cooled ^ solution of 1 g (7.6 mmol) of (E)-3-trimethylsilyl-2-propen-l-ol in 20 ml of dry dichloromethane. The reaction mixture is then further stirred during 3 hours at room temperature and poured into a water-dichloromethane mixture, the organic phase is removed, the aqueous phase is further extracted with dichloromethane. The organic phases are combined and washed with sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.1 g of a yellowish liquid which is further bulb to bulb distilled under reduced pressure (water pump, oven temperature 150-200°C) to afford 0.8 g (50%) of the expected (E)-3-trimethylsilyl-2-propen-l-ol, methanesulfonate.

M01469A EXAMPLE 40 Preparation of 1.5-DIDEOXY-l,S-([3-(TRIMETHYLSILYL)-2-PROPENYL]IMINO)-D-GLUCITOL A solution of 1,5-dideoxy-l,5-imino-D-glucitol (0.052 g, 0.32 mmol) and (E)-3-trimethylsilyl-2-propen-l-ol, methanesulfonate (0.133 g, 0.63 mmol) in a mixture of dimethyl-formamide (2 ml) and triethylamine (0.09 ml, 0.63 mmol) is heated at 80°C during 20 hours. Solvents are evaporated under reduced pressure and the residue is flash chromato-graphed on a silica gel column, eluted with dichloromethane: ethanol 9:1 to 7:3 to give 0.022 g (35%) of the expected 15 1,5-dideoxy-l,5-{[3-(trimethylsilyl)-2-propenyl]imino}-D-glucitol as a white powder.

EXAMPLE 41 Preparation of l-METHYL-3-TRIMETHYLSILYL-BENZENE A mixture of 9.2 g (50 mmol) of 3-bromo-toluene and 5.84 g (50 mmol) of chlorotrimethylsilane in 100 ml of dry ether are added dropwise to 1.2 g (50 mmol) of magnesium turnings in a few milliliters of ether, some crystals of iodine are added to start the reaction. The reaction mixture is refluxed for 20 hours after the end of the addition and then poured into a saturated solution of ammonium chloride (200 ml). The aqueous solution is further extracted with ether, the ethereal extracts are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4.4 g of a yellowish liquid. Flash chromatography on M01469A 237902 a silica gel column and elution with petroleum ether give 2.3 g (30%) of the expected l-methyl-3-trimethylsilyl-benzene as a colorless liquid.

EXAMPLE 42 Preparation of l-BROMOMETHYL-3-TRIMETHYLSILYL-BENZENE A mixture of 2.5 g (15 mmol) of l-methyl-3-trimethyl-silyl-benzene and 3.1 g (16.5 mmol) of N-bromosuccinimide in 80 ml of carbon tetrachloride are refluxed in the presence of a catalytic amount of benzoyl peroxide. When succinimide has totally precipitated at the surface, the hot mixture is filtered. The filtrate is evaporated under reduced pressure, the residue obtained is dissolved in a brine-chloroform mixture. The organic phase is separated, dried over sodium sulfate, filtered and evaporated to afford 4 g of a on yellowish liquid. Flash chromatography on silica gel and elution with petroleum ether give 2g (60%) of the expected l-bromomethyl-3-trimethylsilyl-benzene as a colorless liquid.

EXAMPLE 43 Preparation of 1,5-DIDEOXY-l, 5-[( f 3- (TRIMETHYLSILYL) PHENYL 1 METHYL"> IMINoj-D-GLUCITOL A solution of 1,5-dideoxy-l,5-imino-D-glucitol (0.128 g, 0.78 mmol) and l-bromomethyl-3-trimethylsilyl-benzene (0.3 g, 1.23 mmol) in a mixture of dimethylformamide (5 ml) 3 5 and triethylamine (0.17 ml) is heated at 100°C during M01469A 2<*r "=>» 3 / *3 y ^ hours. Solvents are evaporated under reduced pressure and the residue is flash chromatographed on a silica gel column, eluted with dichloromethane:ethanol 9:1 to 7:3 to give 0.1 g (40%) of the expected 1,5-dideoxy-l,5-[{[3-(trimethylsilyl)-5 phenyl]methyl}imino]-D-glucitol as a white powder.

EXAMPLE 44 Preparation of 1,5-DIDEOXY-l,5-( f 3- f TRIMETHYLSILYL) PROPYL 1 IMINO)-D-GLUCITOL Step A: 3-Iodopropyltrimethylsilane A stirred solution of 3-chloropropyltrimethylsilane (5.0 g, 33 mmol) and Nal (7.5 g, 50 mmol) in acetone (45 ml) was heated at a reflux for 16 hours. The solution became dark yellow (iodine) with a white precipitate (NaCl). The 2® resultant mixture was cooled to room temperature and filtered to remove the NaCl. The salt was washed with acetone (3 x 5 ml). The washings were combined with the filtrate and concentrated (25°C/10 Torr) leaving a two-phase mixture. The concentrate was partitioned in ethyl acetate (50 ml) and 2^ water (25 ml). The organic layer was separated, washed with aqueous sodium metabisulfite 10% (10 ml), water (20 ml), dried (MgS04), and concentrated (250°C/10 Torr) to give 6.0 g of a pale yellow oil. This crude oil was distilled through a six-inch Vigreux column (removing some unreacted chloropropyltrimethylsilane) under water aspirator vacuum giving 4.2 g (50%) of a colorless oil: b.p. 72°C/10 Torr.

M01469A 237902 Step B: 1,5-Dideoxy-l,5-([3-(trimethylsilyl)propyl!imino)-D-qlucitol A well stirred mixture of 1,5-dideoxy-l,5-imino-D-5 glucitol (0.50 g, 3.1 mmol), 3-iodopropyltrimethylsilane (1.1 g, 4.6 mmol) and sodium bicarbonate (0.38 g, 4.6 mmol) in sulfolane (5 ml) was heated at 90°C for 3 hours and then cooled to room temperature. The mixture was diluted with water (5 ml), acidified with 1 M HC1 (5 ml) to pH 2-3, and allowed to stir at room temperature for 1 hour. The mixture was washed with hexane (3 x 5 ml) and adjusted to pH 8 with 1 M sodium hydroxide (3.2 ml) precipitating the crude product. The mixture was cooled to 5°C (ice-water bath), filtered, and the filter cake was washed with ice-water ^ (2x3 ml) and air-dried for 1 hour to give 0.64 g of a white solid. The solid was dissolved in hot (80°C) water (12 ml) and cooled to give 0.56 g (66%) of the desired product as white plates.

Enzymes which catalyze the hydrolysis of complex carbohydrates, e.g. a-glycosidases, convert non-absorbable ^ carbohydrates into absorbable sugars. The rapid action of these enzymes, particularly following the intake of high levels of carbohydrates, lead to acute high levels in blood glucose which, in the case diabetics, lead to undesirable manifestations, thus it has been a long-sought goal to find 30 compounds which will obviate the hyperglycemia caused by dietary improprieties. Similarly, in the case of obesity the control of high levels of blood glucose, with its subsequent conversion to fat, caused by the catalysis of carbohydrates has inspired the quest for compounds which will obviate the 3^ problems associated with dietary improprieties. "Dietary M01469A 237 902 improprieties" means eating habits associated with overeating, overdrinking, and failure to maintain a balanced diet such as the excessive intake of carbohydrates, which metabolize to glucose and which lead to obesity.

The compound of the present invention are administered to subjects in need of such therapy, e.g., mammals such as humans. The compounds of this invention (I) are potent and long-lasting inhibitors of a-glucosidase and, by standard laboratory methods for determining serum glucose levels, are shown to be useful for the treatment of disease states caused by the underutilization and/or overproduction of serum glucose without adversely affecting the rate of transport across cell membranes. Thus, the compounds are useful in the treatment of diabetes and obesity.

In the practice of this invention, an effective amount of a compound of this invention is that amount required to reduce the amount of serum glucose (relative to a control) following the ingestion of carbohydrates convertible to on absorbable glucose. The specific dosage for the treatment of any specific patient suffering from either disease state will depend upon such factors as size, type and age of the patient as well as the patients' dietary habits and the severity of the disease state, all of which are factors normally familiar to and considered by the attending diagnostician treating the patient. Generally, the compounds are to be administered orally at a dose of 0.01 to 2 milligrams per kilogram of body weight (MPK) with a dose of 0.025 to 0.5 MPK being preferred. The compounds 30 preferably are to be administered orally at mealtimes in single or multiple unit doses containing 1 mg to 10 mg. Of course, in the treatment of obesity, the term includes the practice of treating the disease as well as continued administration of dose regimens suitable for the maintenance 3^ of the desired weight for the patient.

M01469A - 35 - 23 7 9 0 It is also to be found that the compounds of the instant invention (I) will exert an inhibitory effect on glycosidase enzymes that are essential for elaboration of the final structure of the oligosaccharide side-chains of glyco-^ proteins, particularly the HIV (gp 120) glycoprotein. Suitable assay techniques, e.g. syncytial formation, the reverse transcriptase assay, immunofluorescence tests and election microscopy, may be used to evaluate the effects on HIV viral growth and for determining dose regimens. Anti-viral effects may be confirmed by immunofluorescence with serum for virally infected patients. In the treatment of the HIV related disease states (e.g., AIDS), as well as other retroviral glyco-protein-related disease states, unlike the treatment of diabetes and obesity, the compounds of this invention may be administered by parenteral means; specific doses being within the above stated dose range for treatment of diabetes and obesity. In addition to treating AIDS with the compounds of this invention, the compounds of this invention may also be effectively utilized in conjunctive 20 therapy with compounds known to be useful in treating patients with AIDS such as for example 2,3-dideoxycytidine, 2,3-dideoxyadenine, interferon, interleukin-2 and the like.

In practising the end-use application of the compounds 25 of this invention, the compounds are preferably incorporated in a pharmaceutical formulation comprising a pharmaceutical carrier in admixture with a compound of this invention. The term "pharmaceutical carrier" refers to known pharmaceutical excipients useful in formulating pharmaceutically active 30 compounds for internal administration to animals, and which are substantially non-toxic and non-sensitizing under conditions of use. The compositions can be prepared by known techniques for the preparation of tablets, capsules, elixirs, syrups emulsions, dispersions and wettable and 35 effervescent powders, and can contain suitable excipients known to be useful in the preparation of the particular type M01469A 9 % 1 c. n ^ » J ' J J :L of composition desired. Suitable pharmaceutical carriers and formulation techniques are found in standard texts, such as Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

As is true for most classes of therapeutic agents certain subgeneric groups and certain specific compounds are preferred. For the compounds embraced within this application the preferred sub-generic groups are those wherein Q is C1-7 alkylene, (CH2)mCH=CH(CH2)n, (CH2)p phenylene, (CH2)m cyclopentenylene, (CH2)m cyclohexenylene or (CH2)pT moieties. Preferred R2 moieties are C1-7 alkyl, phenyl or a hydroxylated alkyl, and preferred R2 and R3 moieties are ci-iq alkyl, phenyl or benzyl.

The following compounds of Formula 5 illustrate the preferred specific compounds: oh .oh (5) r M01469A

Claims (28)

23 7 9 02 R' r1 -CH2-Si(CH3)3 -(CH2)3-Si(CH3)3 "CH*-0 / \ ch3 ch3 10 -(CH2)4-Si(CH3)3 -CH2-Si(CH3)2C6H5 ■^-Gi Si / \ ch3 ch3 15 -CH2-Si(CH3)2C2H5 -CH2-Si(CH3)2C3H7 -ch2-w Si / \ ch3 ch3 20 -CH2-CH=CH-Si(CH3)3 (trans) 25 -CE2-& n) si(ch3)3 -CH2-<pIT^Si(CH3)3 -CH^Si / \ ch3 ch3 -ch2-</ Si(CH3)3 30 -(CH2)3-Si(CH3)2CH2OH - (ch2) 3-s i (ch3) 2ch2chohch2oh 35 M01469A - 38 - * 237902 WHAT If WE CLAIM IS: wiiat 10 claimed 10;—

1. A compound of the formula OH HO. *OH .OH R1-Si-R3 Rr the geometric isomers thereof, and the pharmaceutically acceptable salts thereof wherein; Q is q.7 alkylene, (CH2)mCH=CH(CH2)n, (CH2)mC=C(CH2)n, (CH2)mCH=C=CH(CH2)n, (CH2)p phenylene, (CH2)m cyclopentenylene, (CH2)m cyclohexenylene, or (CH2)pT, wherein T, together with the silicon atom to which it is attached forms a 5 to 6 atom cyclic silicane, said cyclic silicane optionally having a doubl'e bond, with m being 1, 2 or 3, n being 0, 1 or 2, p being 0, 1, 2, 3 or 4, M01469A N.Z. PATENT OFFICE - 39 - 5 h -1 DEC 1992 RECEIVED 23 7 9 0 2 R2 is C1-7 alkyl, C1-7 alkoxy, mono- or polyhydroxy C^g alkyl, mono- or polyalkoxy alkyl, or chloro Cj^g alkyl, and R2 and R3 are C^g alkyl, or (CH2)p-x,Y-substituted phenyl, with X and Y each being H, OH, halogen, C2_6 alkyl, Cj.g alkoxy, CF3, CN, N02, SH or -S-C^g alkyl, with the proviso that when Q is (CH2)pT, then one of Rlf R2 or R3 is deleted.

2. A compound of claim 1 wherein Q is C1_7alkylene, (CH2)mCH= CH(CH2)n, (CH2)mCSC(CH2)n, or (CH2)mCH=C=CH(CH2)n, with m being 1 or 2 and n being 0 or 2, and is C^_7alkyl or C^_7alkoxy.

3. The compound of Claim 1 wherein Q is a C1-7 alkylene.

4. The compound of Claim 3 wherein Rlf R2 and R3 are Cj_ 7 alkyl.

5. The compound of Claim 4 wherein the C1-7 alkyl is methyl.

6. The compound of Claim 3 wherein Rx is a hydroxylated Cj_7 alkyl.

The compound of Claim 1 wherein Q is (CH2)mHC=CH(CH2)n , with m and n being as defined in claim 1.

8. The compound of Claim 7 wherein Rx, R2 and R3 are CL_ 7 lower alkyl.

9• The compound of Claim 1 wherein Q is (CH2)pT, with p and T being as defined in claim 1.

10. The compound of Claim 9 wherein Rx and R2 are C1-7 alkyl and R3 is deleted.

11. The compound of Claim io wherein the cyclic silicane of (CH2)pT is unsaturated, with p and T being as defined in claim 1. M01469A 40 23 7 9 0 2

12. The compound of Claim 1 wherein Q is -CH2-phenylene and Rx, R2 and R3 are each C1-7 alkyl.

13. The compound of Claim 1 wherein -Q-Si-R1R2R3 is -CH2-Si-(CH3)3.

14. ' The compound of Claim 1 wherein -Q-Si-R1R2R3 is -(CH2)3-Si(CH3)3.

15. The compound of Claim 1 wherein -Q-Si-R1R2R3 is -(CH2)4-Si(CH3)3.

16. The compound of Claim 1 wherein -Q-Si-R1R2R3 is -CH2Si(CH3)2C5H5.

17. The compound of Claim 1 wherein -Q-Si-R1R2R3 is -CH2Si(CH3)2C2H5.

18. The compound of Claim 1 wherein -Q-Si-R1R2R3 is -CH2Si(CH3)2C3H7.

19. The compound of Claim 1 wherein -Q-Si-R1R2R3 is t rans-CH2-CH=CH-Si(CH3)3.

20. The compound of Claim 1 wherein -Q-Si-RjRjRj is - (CH2) 3-Si (CH3) 2CH2OH.

21. The compound of Claim 1 wherein -Q-Si-R1R2R3 is -(CH2)3-Si( CH3 )2CH2CHOHCH2OH. M01469A - 41 23 7 90 2

22. The compound of Claim 1 wherein -Q-Si-R1R2R3 is -CH^si / \ ch3 ch3 .

23. The compound of Claim 1 wherein -Q-Si-R1R2R3 is Si(CH3)3

24. The compound of Claim 1 wherein -Q-Si-R1R2R3 is -CH2-<^Z>—Si(CH3)3

25. A pharmaceutical composition comprising a compound of any one of claims 1 to 24 and a pharmaceutically acceptable carrier. M01469A - 42 - % 23 7 902

26. A method for the process of preparing compounds of the formula OH HO, ,0H \ .OH Rl-Si-R3 Ro the geometric isomers thereof, and the pharmaceutically acceptable salts thereof wherein: Q is cx_7 alkylene, (CH2)mCH=CH(CH2)n, (CH2)mC=C(CH2)n, (CH2)mCH=C=CH(CH2)n, (CH2)p phenylene, (CH2^m cyclopentenylene, (CH2)m cyclohexenylene, or (CH2)pT, wherein T, together with the silicon atom to which it is attached forms a 5 to 6 atom cyclic silicane, said cyclic silicane optionally having a double bond, with m being 1, 2 or 3, n being 0, 1 or 2, p being 0, 1, 2, 3 or 4, Rx is C1-7 alkyl, C1-7 alkoxy, mono- or polyhydroxy cl-6 aiky1' mono- or polyalkoxy C^g alkyl, or chloro Cj^g alkyl, and R2 and R3 are C^q alkyl, or (CH2)p-x,Y-substituted phenyl, with X and Y each being H, OH, halogen, C1-6 alkyl, Cj.g alkoxy, CF3, CN, N02, SH or -S-C1-6 alkyl, with the proviso that when Q is (CH2)pT, then one of Rlf R2 or R3 is deleted, IN / v ^ISDECM ^ \ M01469A - 43 - 7902 which comprises condensing an optionally hydroxy-protected compound of the formula or ro .or \ h wherein R is H or an optional protecting group with a reactant X' -Q-SiR]_R2R3 wherein Q, R1# R2 and R3 are as defined in claim 1 and X' is halogeno, mesylate or tosylate followed by the removal of any hydroxy-protecting group and, if necessary, neutralizing any anion formed during the deprotection process.

27. a compound of the formula as defined in claim 1 and the pharmaceutically acceptable salts thereof substantially as herein described with reference to any example thereof.

28. A method as defined in claim 26 for the process of preparing compounds of the general formula defined therein substantially as herein described with reference to any example thereof. (flee&eu-jdouoPrtfteHflcajtriovs HOC. . By the authorised agents A J PARK & SON M01469A 44