CA2234081A1 - Processes and intermediates for preparing 1-(2-[2-isoxazol-3-ylbenzofuran-5-yloxy]ethylamino)-3-phenoxy-2(s)-ol - Google Patents
Processes and intermediates for preparing 1-(2-[2-isoxazol-3-ylbenzofuran-5-yloxy]ethylamino)-3-phenoxy-2(s)-ol Download PDFInfo
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- CA2234081A1 CA2234081A1 CA002234081A CA2234081A CA2234081A1 CA 2234081 A1 CA2234081 A1 CA 2234081A1 CA 002234081 A CA002234081 A CA 002234081A CA 2234081 A CA2234081 A CA 2234081A CA 2234081 A1 CA2234081 A1 CA 2234081A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
A process for preparing the compound of formula (I) by treating the compound of formula (IV) with an aqueous mineral acid. A compound of formula (II) wherein R1 is hydrogen and R2 and R3 together form a single bond or R1 and R2 together form a single bond and R3 is hydrogen or a group of formula (III). The compound of formula (I), its pharmaceutically acceptable salts and prodrugs are useful as hypoglycemic and antiobesity agents. They are also useful in increasing lean meat deposition and/or improving the lean meat to fat ratio in edible animals, i.e. ungulate animals and poultry.
Description
W O 97/16432 PCT~E~Ç~D~ -PROCESSES AND INTERMEDIATES FOR PREPARING 1-(2-r2-lSOXA70L-3-YLBENZOFURAN-5-YLOmETHYLAMlNO)-3-PHENOXY-2(S)-OL
Backaround of the Invention The present invention relates to certain cG,..pounds of the formula I depicted below. More particularly, the invention relates to processes and intermer~ s for use in the prepari~tion of the compound of formula 1- The co",pound of formula 1, its ph&r.naceutically ~Cc-Fl~le s~lts and prodrugs have utility as hypoglycemic and 10 antiol~esity agents. The c~sr-pound of the formula 1, its ph&.l"~reutic~lly accept ~le salts and prodrugs are also useful in i--cr~ J lean meat del-osilion and/or improving the lean meat to fat ratio in edible ar ..i5is, i.e. ungulate ~.i.~&ls and poultly The co,l-pound of formula I and its pha.ll.Aceutically acceptable salts and prodrugs effectively lower blood glucose levels when a.ll..;. ~i;.ler~d orally to mammals 15 with hyperglycemia or ~' ~s.
The cG,.lpound of formula I aiso d~cla~~es weight gain when &d~..il,.;~Lered to m~-l----&~.15. The ability of these compounds to affect weight gain is due to activation of B aJ-~ner!Jic ~ t~l~ which stimulate the me'-'-l.s~., of adipose tissue. T h e S mellitus is ch~., 1~ ed by ~ oli~ defects in production and 20 utilization of o---Lol-ydrates which result in the failure to maintain il~prop,iGle blood sugar levels. The result of these defects is ~ ed blood glucosa or hyperglycemia.
Research in the treatment of ~ etes has c~ red on atl~:r",.~t~ to normalize fasting and posl~r~r, "-' blood glucose levels- Current l~ rl~ include ad.,.i"i~l,alion of exogenous insulin, oral admini~ lion of drugs and dietary II.e~, ~s.
Two major forms of ~~~~ s mellitus are r~cGy.. i~ed. Type I diabetes, or insulin-dependent h~tes, is the result of an ~hsclute de~; ~ocy of insulin, the hormone which reg~ 'es c&Lohydrate ~ n. Type ll diabetes, or non-insulin dependent ' ~' 3tes, often occurs with norrnal, or even elevated levels of insulin and appears to be the result of the inability of tissues to r~sl~ond approprialely to insulin.
30 Most of the Type ll "-~etics are also obese.
B-Adrenergic receptc.rs can be divided into Bl, B2 and B3-subtypes Activation of B,-leceptors invokes inc.eases in heart rate while activation of B2-receptors induces relA~tAtion of smooth muscle tissue which produces a drop in blood pressure and the 35 onset of smooth muscle tremors. Activation of B~-lecepl~,r~ stimulates lipolysis (the breakdown of A-lipose tissue triglycerides to glycerol and free fatty acids), and thereby W O 97/16432 PCT~B9G~'~C~
promotes the loss of fat mass. Compounds that stimulate B3-recepto" will have anti-obesity activity. In addition, cGinpounds which are B3 s.dlenoceptor ayoni~l~ have hypoglycemic or anti~ activity, but the l..echr-nisn. of this effect is unknown. A
compound that s~ ;iely stimulates B3-receptors, i.e., has little or no Bl or B2-activity, will have the desired anti~ tic and/or anti-obesity activity, but without the undesirable effects of i- ~cr~ heart rate (131-effect) or muscle tremor (B2-effect). The use of B3-acJIenoceptor L~or.i~b as antidiabetic, hypoglycemic and antiobesity agents has been frustrated, how~,or, by the lack of selectivity of these agents for B3-adrenoceptors over the other two other adrenocept~.r~, B1 and B2. The compound of formula 1, its pharmA~eutic~lly "ccept~le salts and prodrugs are selective B3 adrenoceptor agon~ . The co~-~pound of forrnula 1, its ph&r."Aceutics~y acceptable salts and prodrugs are des.;.i~ecl in co-pen 'i )g United States Ar,cli ~icn Serial No.
08/076026, assiy.~c;l to the assignee of this ~FIjc~tion and inco,l,o,ale-J herein in its entirety.
SummarY of the Invention The presel)t invention relates to ~rl~cesses and interme~istes useful in the prepr-r~lion of the compound of the formula ~ OH H
O - ~N~ - o/~< N\o W O 97/16432 PCT~13~6/~
The term ~halo~, as used herein, unless otherwise in~ d, includes chloro, fluoro, bromo and iodo.
The tQrm ~alkyl~, as used herein, unless otherwise indicated, includes saturatedmonovalent hyJ-oc~Lon radicals having sl~ ~,hl, br~nched or cyclic moieties or ~ 5 coi"~..,alions thereof.
The term ~one or more s~hstihlents,Y as used herein, includes from one to the maximum number of s~hstituents possiLle based on the number of available bondingsites.
The term ~llealilly~ âS used herein includes preventative lleallllelll.
Detailed Des.;,i~lion of the Invention The proces~s and products of tha pr~senl invention are illustrated in the following reaction scheme.
W O 97/16432 PCT~9~'nCS~ -SCHEME
O O
O N"~
~ o O--~--'N--~ I~H2 ~/ ~U H'~ H
W O 97/16432 PCT/1~3G,'00~03-SCHEME (continued) ~' ~N/~ o~\/~N~ ~
~/ ~ / O~O H
H O~¢~<N_ 0 5 'N~~~<N_O
~ O H H
CA 0223408l l998-04-06 W O 91/16432 PCT~B96/00803-R~fer. ing to the scheme compound 1 is treated with phenol in the presence of a base to form cGmpound 2. The base for use in this step is sel~Led from the group colllpriai--g alkali metal hydrides, such as NaH, and alkali metal alkoxides such as sodium -butoxide. The reaction is ~te~ted in an aprotic polar solvent such as DMF or 5 THF. The reaction is l~r~re.~bly carried out using NaH in DMF.
Compound 3 is formed by treating compound 2 with C~,H5CH2NH(CH2)20H in a (Cl-C6)alkanol. A pr~ ad alkanol is ethanol. Compound 4 is formed by treating compound 3 with hydrogen in the pr~sence of a hydrogenation catalyst such as Pd(OH)2 on C or Pd on C in a (C1-C~,) alkanol such as ethanol or propanol. Preferably 10 the alkanol is athanol. Compound 4 is reacted with a carbonyl compound such as an aldehyde or ketone to form a mixture of CGII ~pounds 5 & _. Aldehydes useful in the pr6ctice of this part of the invention include aliphatic aldehydes, such as ;~c~ hyde, and aromatic aldehydes such as ben~aldehyde.
Useful ketones may be ej~ei..r"~ ' by ~'.,, halic ketones, e.g., acetone and 15 methyl ethyl ketone; cyt,'~";yl ketones such as cyciohexanone and arylalkyl ketones such as acet~ heoGI~e. A pr~a..ed c&rLonyl compound is cyclohex~ol~e. The reaction is ~r~ed in a solvent such as a (Cl-C~,)alkanol, ,~r~ferhbly methanol.
Compound 5 or 6, or a mixture thereof, is treated with compound 7 and an azodic~rl,onyl '~ oxide, such as ~o. I;cr-l Lon~l dipropoxide or diethexoxide, or diamine, such as A~ot"--~bonyldipiperidine in the pr~sence of a suitable trialkyl- or triarylphosphine such as (C4H9)3P or (CBH5)3P, respec~i~rely, or (C6H5)3P supported on a polymer (e.g. (C~,H5)3P polymer supported, Aldrich Cat. No. 36,645-5, which is a 2%
divinylbenzene cross-linked polystyrene containing 3 mmol phosphorous per gram resin) to produce compound 8. The lea~,1ion is effected in a solvent such as benzene, toluene or THF. A pr~l~r,ad solvent is toluene. Compound 7 is prepared accordingto the method in United States Ar, li- ~-on Serial No. 08/~76026.
Compound 8 is treated with an aqueous mineral acid to produce compound 1. Useful mineral acids include HCI, H2S04, NaHS04, HBr and H3P04. The preferredmineral acid is NaHS04.
When treating 1"-'- tes mellitus and/or hyperglycemia generally sAtisfAr-tory results are obtained when the compound of formula I and the pharmaceutically acceplable salts thereof (hereinafter referred to as Uthe active compounds") areadm ,iaLered to mammals, including man, via either the oral or the parenteral route.
W O 97/16432 PCT~B96/~803 -AJ",i-,i~l.alion by the oral route is pr~er,ed, being more convenient and avoiding the pos5il lli~ pain and illilalion of i.,js~ n. I lov,~ cr, in circu.n~ ces wher~ the patient cannotSJ.~ "Dvlthem6~ ion,orabso~lionf~lle~JJ.~9oraladmi~ liGnisimpaired~
âS by ~';;eqse or other abnormality, it is essenliâl that the drug be ad~.,i"i;.lered 5 pare.,l~rally. By either route, the dosnge is in the range of about 0.01 1o about 50 mg/kg body weight of the subject per day, pr~f~r~bly about 0.1 to about 25 mg/kgbody weight per day, admin l red singly or as a divided dose. However, ti1e optimum dosage for the individual subject being treated will be determined by the personresponsible for the l,~al",enl, generally smaller doses being admini;.lered initially and 10 ther~a~ler ine.~r.l6r.l~ made to determine the most suitable dosage. Tnis will vary according to the particular cG~-~pound ~r -rl~yed and with the subject being treated.
When l.u~li..g obesity, in conjunction with ~: s and/or hyperglycemia, or alone, generally satisfactory results are obtained when the active compounds are&dm'l-_' ed at a daily dosnDe of from 0.01 milligram to about 50 ~ ar))s per kilogram of animal body weight, pr~ bly given in divided doses 4 times a day, or in sustained release form. For most large ~- .Ln ~r, .&ls, the total daily ~osAç~e is from about 0.1 milligrams to about 6000 milligrams, ~,r~rably from about 1 milligrams to about 1500 milligrarns. In the c~se of a 70 kg adult human, the total daily dose will generally be from about 0.1 milligrams to about 1500 milligrams. This dosAge regirnen may be ~justed to provide the optimal tl .er~eutic respcsnse.
The active compounds are used in cGm - In &lion with a pharmaceutically Acc~Ft- ~ carrierordiluent. Suitable ph&-- ~~ceuticAlly accept ~l8 carriers include inert solid fillers or diluents and sterile A~lueous or org~1 ~ solutions. The active compound will be present in such pharmAce~icA' comrosilions in amounts sufficien1 to provide the desired dos~ge amount in the range described above. Thus, for oral administration the compounds can be combined with a s~ e solid or li~uid carrier or diluent to form cArs~ ~s, tablets, p~v,d~ra, syrups, solutions, suspensions and the like. The pharmAreuticAI corrposilions may, if desired, contain additional components such as flavorants, s~lsotoners, l~x~ and the like.
The tablets, pills, c~s~ ~ s~s, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and W O 97/16432 PCT~B96~'~C803-a svleotoning agent such as sucrose, lactose or saccharin. When a dosage unit form is a cArsule, it may contain, in Ad-JitiGn to ,n&l~,i&ls of ths above type, a liquid carrier such as a fatty oil.
Various other materials may be l~resent as coatings or to modify the physical 5 form of the dosage unit. For i"Y.l~ nce, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active iny,~ nt, sucrose as a ~.Y~eetcr. 19 agent, methyl and propyl,~.&r~bens as preservatives, a dye and a flavoring such as cherry or orange flavor.
The active compounds may also be al~ .lered pare~ r-~lly. For parer,l~:r~l 10 ad", ,i~ lion the active compounds can be combined with sterile aqueous or organic media to form injQctr~l~ solutions or suspensions. Solutions or sus.pensions of these active compounds can be pr~pared in water suitably mixed with a surfactant such as hydroxypropyl~ s~. n spQ ~ions can also be pre~PrecJ in sesame or peanut oil, ethanol, water, polyol (e.g., glycerol, propylane glycol and liquid polyethylene glycol), 15 s~ ' e mixtures thereof, v~t~ I~IQ oils, N-methyl glucarnine, polyvinylpyrrolidone and mixtures thereof in oils as well as ~ueous solutions of water-soluble ph&...,~ceuticAIIy ~c~Ft-'le salts of the compounds. Under ordinary cor~Jitioi)s of ~ r.,ge and use, these prep~ulions contain a preservative to prevent the growth of microor~anis",s.
The inje~-' e solutions prt,p~ed in this manner can then be administered 20 intravenously, i,lt.~peritol.0ally, s~ Ihcut~neously, or intramusc~ ly, with intramuscular adminic.ll~lion being the prd~7l.ecl pare"ter~l route in man.
The ph~-"n~elJtic~l forms sui~AI l~ for i"je ' ' le use include sterile aqueous solutions or di_per~ions and sterile po~ s for the exlemporarleous preparation of sterile injectable solutions or ~Jis,~e.~ions. In all cases, the form must be sterile an 25 must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microo,y~i_."s such as bacteria and fungi.
The effective dosAge of the active ingredient employed may vary depending on the particular compound er";.l~yed, the mode of acl", ,i~ lion, the condition being 30 treated and the severity of the condition being treated.
The active compounds also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible animals, i.e., ungulate animals and poultry.
W O 97/16432 PCT~B9G~C8~ 7 -Animal feed comp~s ';~ns effective for i,.cleasi"g lean meat deposition and for improving lean meat to fd ratio in poultry, swine, sheep, goats, domestic pets and cattle are generally prepared by mixing the compounds of the preser,l invention with - a sufficient amount of animal feed to provide from about 1O3 to 500 ppm of the 5 compound in the feed.
Animal feed sl~FF~ nl~ can be prepale~l by aJI"ixi~g about 75% to 95% by weight of an active compound with about 6% to about 25% by weight of a s~lt~hle carrier or diluent. ~arriers s~ litr' 1~ for use to make up the feed supplement cGmposilions include the fe'lov~;.,g: alfalfa meal, soybean meal, c~ nseed oil meal, 10 linseed oil meal, sodium chlc.ide, cornmeal, can mcl -ses, urea, bone meal, corncob meal and the like. The carrier promotes a unKorm distribution of the active ingredients in the finished fee~d into which the S'~F Flen,ent is blended. It thus pe,~r",s an important function by ensuring proper distribution of the active ingredienl: throughout the feed.
If the s~F'e "er,l is used as a top .l~essi"g for the feed, it likewise helps toensure u~if~ ilr of distribution of the active ", ial across the top of the d,essed feed.
The pr~ ed medicated swine, cattle, sheep and goat feeds generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for 20 these ~-, llals usually being about 50 to 300 grams per ton of feed.
The pr~f~r,ed poultry and do" ,ealic pet feeds usually contain about 0.01 to 400grams and prefe~ly 10 to 400 grams of active ingredient per ton of feedl.
For par~nt~..1 admini~ I;on in animals, the active compound may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin 25 of the head or ear of the animal in which i"cr~ase in lean meat dep~osition and improvement in lean mean to fat ratio is sought.
In general, pL.tll)l6r~ dlll ,i~ lion involves injection of a sufficient amount of the active compound to provide the animal with 0.01 to 100 mg/kg/day of body weight of the active ingredient. The ,cr~"ed dosage for swine, cattle, sheep and goats is in 30 the range of from 0.01 to 50 mg/kg/day of body weight of active ingredient; whereas, the pl~r,~d dose level for poultry and domestic pets is usually in the range of from 0.01 to 35 mg/kg/day of body weight.
CA 0223408l l998-04-06 W O 97/16432 PCT~B96/00803-Paste formulations can be prepared by dispersing the active compound in a ph~-r.,.aceutically ~o~ eFt~ oil such as peanut oil, ses~.e oil, corn oil or the like.
Pellsts containing an effective amount of tha active compound can be prepared by &d.nkiog the effective amount of active compound with a diluent such as carbowax, 5 carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process.
It is, of course, recGy~ ~ that rnore than one pellet may be ad~ . ~' .i~t~. ~d to an animal to achie~.fc the desired dose level which will provide the i..cre&sG in lean meat depGsiliGn and i")~ro~rament in lean meat to fat ratio desired. Moreover, it has been 10 found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal's body.
The active compounds have several adv~ eou~ features. For tha pet owner or vt,lerinariar) who wishes to i..cr~asG Icanness and trim unwanted fat from pet animals, the active compounds provide the means by which this can be accomplished.
15 For the poultrymen and swine raisers, use of the active cor -pounds yields leaner animals which cG,..r,.~d higher prices from the meat industry.
GCMS's were taken on 8 Hewlett Packard 58gO GC in tandem with a Hewlett Packard Model 5971A Mass S~-~ ';o netector using a HP-1 12 m capillary column.
Column conditions were as f ll~ initial temp, 133~C; ramp of 19~C/min; final temp, 20 310~C.
NMR's were taken on a Bruker AM-250 MHz sp6cl-~,r.-eler.
MS were taken on I l~ s~t Packard 5989 Mass Spectrometer Particle Beam (Cl)+. lons obtained were (M + 1)+.
FyAMpLE 1 (S)-1.2-e~oxv~ l.e.~oxs~. ro~,~n~
To 80.0 gm (0.85 mol) of phenol in 150 mL of DMF at 0~C was added, in portions, 37.4 gm (0.94 mol, 1.1 equiv) of sodium hydride (60% by weight dispersion in mineral oil). After 1.5 hours 220 gm (0.85 mol) of (S)-qlycidyl nosylate [(2S)-glycidyl 3-nitrobenzenesulfonate, pu-chas~ from Seprachem (Marl~boro,JI., MA 01762)] was 30 added in two portions to the reaction slurry. Tha reaction mixture was allowed to stir overnight at room temperature. TLC analysis of the ho"~ogeneous reaction mixturein "- hd that the reaction was essentially complete. The reaction mixture was cooled to 0~C and quenched with 500 mL of saturated ~1ueous ammonium chloride. The -W O 97/16432 PCT~:B9Gi'~D~03-mixture was then diluted with 2 L of ethyl acetate and 500 mL of water. The organic layer was separated and the A~lUeOUS eA~ ed three times with 1 L ethyl ~cetAte. The combined organic layers were washed with brine and then dried with sodium sulfate.
The volatiles were then removed in vacuo, at room temperature, and the DMF at a 5 ter"perc~ re of about 45~C whilQ maintaining the vacumn. The crude oil was used without additional pulif;c~liGn into the next step (ll-eoleltical yield assumed).
TLC (silica gel) Rf = 0.80 (60: 40% hexanes/ethyl acetate).
9~10~2 (M~3 = 150, t, = 1.46 min.
1H NMR (CDC13) ~ 7.26-7.33 (m, 2H), 6.91-7.00 (m, 3H), 4.18-4.24 (Im,1 H), 3.91-10 3.87 (m, lH), 3.31-3.38 (m, 1H), 2.87-2.91 (m, lH), 2.73-2.77 (m, lH).
F'~ LE 2 (S)-1-r~ l 2 hf.' o~ th~l)-aminol-3~1.e..ox~r ~rc.~ .-2~DI
The crude oil (0.85 mol) from the previous step was diluted with 300 mL of ethanol and then treated with 125 mL (0.88 mol, 1.04 equiv) of N-benzylethanolamine.
The reaction mixtur~ was heated ovemight at 50~C, at which time TLC analysis indicated that the r~a_t;on was cGr~ The solution was used directly into the next step (theoretical yield assumed).
A sample was conc~nt~aleJ at this point for analysis:
TLC (silica gel) R, = 0.50 (95: 5 methylene chloride/methanol).
GCMS: Cl8H23N03 (M+) = 301, t, = 7.29 min.
lH NMR (CD30D) ~ 7.17-7.36 (m, 7H), 6.85-6.93 (m, 3H), 3.934.03 (m, 2H), 3.80-3.87 (m, 1 H), 3.70 (s, 2H), 3.55-3.65 (m, 2H), 2.60-2.77 (m, 4H).
~XAMPLE 3 (S)-1 -r2-Hvdro~ tl ,~I)-aminol-3-~ e noxv-.Jro,~ -2-ol To the ethanolic solution of 0.85 mol of the title product of Cxa mr le 2, prepared in the previous step, was added 10.0 gm of 20% palladium hydroxide on carbon. After hydrogenation at 50 PSI in a Parr apparatus, TLC analysis showed that the starting material was consumed. The catalyst was removed by filtration through a bed of Celite~. The reaction mixture was then diluted with 1 L of acetonitrile and u/ashed three times with 250 mL of hexanes to remove the mineral oil added with the sociium hydride in Example 1. The volatiles were removed in vacuo and the residue dissolved in 1 L
of ethyl acetate. Upon cooling to 0~C, a solid precipitated. A second crop from 700 CA 0223408l l998-04-06 W O 97/16432 PCT~B~
mL of 4:3 hexanes/ethyl acetate provided a total of 148 gm of title product as a white solid (83% overall based on the (S)-glycidyl nosylate used in Example 1).
TLC (silica gel) Rf = 0.50 (80: 20 methylene chloride/l"eU,&nol).
GCMS: Cl,Hl,NO3 (M+) = 211, t, = 4.32 min.
lH NMR (CD30D) ~ 7.21-7.28 (m, 2H), 6.91-6.94 (m, 3H), 4.02-4.18 3.93-3.95 (m, 2H), 3.61-3.76 (m, 2H), 2.68-2.92 (m, 4H).
rLE 4 ('~;)-2-~ e ~o~ tfly~ L ~4-Siidec~ yl)ethanol ~1) and ~S)-l-(l-Oxa-4aza-sPlror4.5ldec 4 vl)-3-l l.e.-oxy ~-rov ..-2-ol ~2) To a solution of 3.0 gm (14.2 mmol) of the title product of Ex~.,ple 3 in 35 mL
of methanol was added 2.95 mL (28.6 mL, 2.0 equiv) of cyclohQx~none. After stirring overnight analysis by GCMS shov~6~ that the starting l..al~rial was consumed. The volatiles were removed in vacuo l~ v.ed by azeolr~_~ic removal of trace methanol with toluene. 'H NMR indicated an appro3c;."~tely 2.5: 1 ratio of (1) to (2). The crude 15 product (containing trace amounts of cyclol .ex~lone) was used without further purification in the next step.
GCMS: C"H25NO3 (M+) = 291, t, = 6.51 min (for both compounds).
(1) diagnostic signals lH NMR (CD30D) ~4.3~4.42 (m, 1H), 3.59-3.67 (m, 2H), 3.16-3.26 ~n~
Backaround of the Invention The present invention relates to certain cG,..pounds of the formula I depicted below. More particularly, the invention relates to processes and intermer~ s for use in the prepari~tion of the compound of formula 1- The co",pound of formula 1, its ph&r.naceutically ~Cc-Fl~le s~lts and prodrugs have utility as hypoglycemic and 10 antiol~esity agents. The c~sr-pound of the formula 1, its ph&.l"~reutic~lly accept ~le salts and prodrugs are also useful in i--cr~ J lean meat del-osilion and/or improving the lean meat to fat ratio in edible ar ..i5is, i.e. ungulate ~.i.~&ls and poultly The co,l-pound of formula I and its pha.ll.Aceutically acceptable salts and prodrugs effectively lower blood glucose levels when a.ll..;. ~i;.ler~d orally to mammals 15 with hyperglycemia or ~' ~s.
The cG,.lpound of formula I aiso d~cla~~es weight gain when &d~..il,.;~Lered to m~-l----&~.15. The ability of these compounds to affect weight gain is due to activation of B aJ-~ner!Jic ~ t~l~ which stimulate the me'-'-l.s~., of adipose tissue. T h e S mellitus is ch~., 1~ ed by ~ oli~ defects in production and 20 utilization of o---Lol-ydrates which result in the failure to maintain il~prop,iGle blood sugar levels. The result of these defects is ~ ed blood glucosa or hyperglycemia.
Research in the treatment of ~ etes has c~ red on atl~:r",.~t~ to normalize fasting and posl~r~r, "-' blood glucose levels- Current l~ rl~ include ad.,.i"i~l,alion of exogenous insulin, oral admini~ lion of drugs and dietary II.e~, ~s.
Two major forms of ~~~~ s mellitus are r~cGy.. i~ed. Type I diabetes, or insulin-dependent h~tes, is the result of an ~hsclute de~; ~ocy of insulin, the hormone which reg~ 'es c&Lohydrate ~ n. Type ll diabetes, or non-insulin dependent ' ~' 3tes, often occurs with norrnal, or even elevated levels of insulin and appears to be the result of the inability of tissues to r~sl~ond approprialely to insulin.
30 Most of the Type ll "-~etics are also obese.
B-Adrenergic receptc.rs can be divided into Bl, B2 and B3-subtypes Activation of B,-leceptors invokes inc.eases in heart rate while activation of B2-receptors induces relA~tAtion of smooth muscle tissue which produces a drop in blood pressure and the 35 onset of smooth muscle tremors. Activation of B~-lecepl~,r~ stimulates lipolysis (the breakdown of A-lipose tissue triglycerides to glycerol and free fatty acids), and thereby W O 97/16432 PCT~B9G~'~C~
promotes the loss of fat mass. Compounds that stimulate B3-recepto" will have anti-obesity activity. In addition, cGinpounds which are B3 s.dlenoceptor ayoni~l~ have hypoglycemic or anti~ activity, but the l..echr-nisn. of this effect is unknown. A
compound that s~ ;iely stimulates B3-receptors, i.e., has little or no Bl or B2-activity, will have the desired anti~ tic and/or anti-obesity activity, but without the undesirable effects of i- ~cr~ heart rate (131-effect) or muscle tremor (B2-effect). The use of B3-acJIenoceptor L~or.i~b as antidiabetic, hypoglycemic and antiobesity agents has been frustrated, how~,or, by the lack of selectivity of these agents for B3-adrenoceptors over the other two other adrenocept~.r~, B1 and B2. The compound of formula 1, its pharmA~eutic~lly "ccept~le salts and prodrugs are selective B3 adrenoceptor agon~ . The co~-~pound of forrnula 1, its ph&r."Aceutics~y acceptable salts and prodrugs are des.;.i~ecl in co-pen 'i )g United States Ar,cli ~icn Serial No.
08/076026, assiy.~c;l to the assignee of this ~FIjc~tion and inco,l,o,ale-J herein in its entirety.
SummarY of the Invention The presel)t invention relates to ~rl~cesses and interme~istes useful in the prepr-r~lion of the compound of the formula ~ OH H
O - ~N~ - o/~< N\o W O 97/16432 PCT~13~6/~
The term ~halo~, as used herein, unless otherwise in~ d, includes chloro, fluoro, bromo and iodo.
The tQrm ~alkyl~, as used herein, unless otherwise indicated, includes saturatedmonovalent hyJ-oc~Lon radicals having sl~ ~,hl, br~nched or cyclic moieties or ~ 5 coi"~..,alions thereof.
The term ~one or more s~hstihlents,Y as used herein, includes from one to the maximum number of s~hstituents possiLle based on the number of available bondingsites.
The term ~llealilly~ âS used herein includes preventative lleallllelll.
Detailed Des.;,i~lion of the Invention The proces~s and products of tha pr~senl invention are illustrated in the following reaction scheme.
W O 97/16432 PCT~9~'nCS~ -SCHEME
O O
O N"~
~ o O--~--'N--~ I~H2 ~/ ~U H'~ H
W O 97/16432 PCT/1~3G,'00~03-SCHEME (continued) ~' ~N/~ o~\/~N~ ~
~/ ~ / O~O H
H O~¢~<N_ 0 5 'N~~~<N_O
~ O H H
CA 0223408l l998-04-06 W O 91/16432 PCT~B96/00803-R~fer. ing to the scheme compound 1 is treated with phenol in the presence of a base to form cGmpound 2. The base for use in this step is sel~Led from the group colllpriai--g alkali metal hydrides, such as NaH, and alkali metal alkoxides such as sodium -butoxide. The reaction is ~te~ted in an aprotic polar solvent such as DMF or 5 THF. The reaction is l~r~re.~bly carried out using NaH in DMF.
Compound 3 is formed by treating compound 2 with C~,H5CH2NH(CH2)20H in a (Cl-C6)alkanol. A pr~ ad alkanol is ethanol. Compound 4 is formed by treating compound 3 with hydrogen in the pr~sence of a hydrogenation catalyst such as Pd(OH)2 on C or Pd on C in a (C1-C~,) alkanol such as ethanol or propanol. Preferably 10 the alkanol is athanol. Compound 4 is reacted with a carbonyl compound such as an aldehyde or ketone to form a mixture of CGII ~pounds 5 & _. Aldehydes useful in the pr6ctice of this part of the invention include aliphatic aldehydes, such as ;~c~ hyde, and aromatic aldehydes such as ben~aldehyde.
Useful ketones may be ej~ei..r"~ ' by ~'.,, halic ketones, e.g., acetone and 15 methyl ethyl ketone; cyt,'~";yl ketones such as cyciohexanone and arylalkyl ketones such as acet~ heoGI~e. A pr~a..ed c&rLonyl compound is cyclohex~ol~e. The reaction is ~r~ed in a solvent such as a (Cl-C~,)alkanol, ,~r~ferhbly methanol.
Compound 5 or 6, or a mixture thereof, is treated with compound 7 and an azodic~rl,onyl '~ oxide, such as ~o. I;cr-l Lon~l dipropoxide or diethexoxide, or diamine, such as A~ot"--~bonyldipiperidine in the pr~sence of a suitable trialkyl- or triarylphosphine such as (C4H9)3P or (CBH5)3P, respec~i~rely, or (C6H5)3P supported on a polymer (e.g. (C~,H5)3P polymer supported, Aldrich Cat. No. 36,645-5, which is a 2%
divinylbenzene cross-linked polystyrene containing 3 mmol phosphorous per gram resin) to produce compound 8. The lea~,1ion is effected in a solvent such as benzene, toluene or THF. A pr~l~r,ad solvent is toluene. Compound 7 is prepared accordingto the method in United States Ar, li- ~-on Serial No. 08/~76026.
Compound 8 is treated with an aqueous mineral acid to produce compound 1. Useful mineral acids include HCI, H2S04, NaHS04, HBr and H3P04. The preferredmineral acid is NaHS04.
When treating 1"-'- tes mellitus and/or hyperglycemia generally sAtisfAr-tory results are obtained when the compound of formula I and the pharmaceutically acceplable salts thereof (hereinafter referred to as Uthe active compounds") areadm ,iaLered to mammals, including man, via either the oral or the parenteral route.
W O 97/16432 PCT~B96/~803 -AJ",i-,i~l.alion by the oral route is pr~er,ed, being more convenient and avoiding the pos5il lli~ pain and illilalion of i.,js~ n. I lov,~ cr, in circu.n~ ces wher~ the patient cannotSJ.~ "Dvlthem6~ ion,orabso~lionf~lle~JJ.~9oraladmi~ liGnisimpaired~
âS by ~';;eqse or other abnormality, it is essenliâl that the drug be ad~.,i"i;.lered 5 pare.,l~rally. By either route, the dosnge is in the range of about 0.01 1o about 50 mg/kg body weight of the subject per day, pr~f~r~bly about 0.1 to about 25 mg/kgbody weight per day, admin l red singly or as a divided dose. However, ti1e optimum dosage for the individual subject being treated will be determined by the personresponsible for the l,~al",enl, generally smaller doses being admini;.lered initially and 10 ther~a~ler ine.~r.l6r.l~ made to determine the most suitable dosage. Tnis will vary according to the particular cG~-~pound ~r -rl~yed and with the subject being treated.
When l.u~li..g obesity, in conjunction with ~: s and/or hyperglycemia, or alone, generally satisfactory results are obtained when the active compounds are&dm'l-_' ed at a daily dosnDe of from 0.01 milligram to about 50 ~ ar))s per kilogram of animal body weight, pr~ bly given in divided doses 4 times a day, or in sustained release form. For most large ~- .Ln ~r, .&ls, the total daily ~osAç~e is from about 0.1 milligrams to about 6000 milligrams, ~,r~rably from about 1 milligrams to about 1500 milligrarns. In the c~se of a 70 kg adult human, the total daily dose will generally be from about 0.1 milligrams to about 1500 milligrams. This dosAge regirnen may be ~justed to provide the optimal tl .er~eutic respcsnse.
The active compounds are used in cGm - In &lion with a pharmaceutically Acc~Ft- ~ carrierordiluent. Suitable ph&-- ~~ceuticAlly accept ~l8 carriers include inert solid fillers or diluents and sterile A~lueous or org~1 ~ solutions. The active compound will be present in such pharmAce~icA' comrosilions in amounts sufficien1 to provide the desired dos~ge amount in the range described above. Thus, for oral administration the compounds can be combined with a s~ e solid or li~uid carrier or diluent to form cArs~ ~s, tablets, p~v,d~ra, syrups, solutions, suspensions and the like. The pharmAreuticAI corrposilions may, if desired, contain additional components such as flavorants, s~lsotoners, l~x~ and the like.
The tablets, pills, c~s~ ~ s~s, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and W O 97/16432 PCT~B96~'~C803-a svleotoning agent such as sucrose, lactose or saccharin. When a dosage unit form is a cArsule, it may contain, in Ad-JitiGn to ,n&l~,i&ls of ths above type, a liquid carrier such as a fatty oil.
Various other materials may be l~resent as coatings or to modify the physical 5 form of the dosage unit. For i"Y.l~ nce, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active iny,~ nt, sucrose as a ~.Y~eetcr. 19 agent, methyl and propyl,~.&r~bens as preservatives, a dye and a flavoring such as cherry or orange flavor.
The active compounds may also be al~ .lered pare~ r-~lly. For parer,l~:r~l 10 ad", ,i~ lion the active compounds can be combined with sterile aqueous or organic media to form injQctr~l~ solutions or suspensions. Solutions or sus.pensions of these active compounds can be pr~pared in water suitably mixed with a surfactant such as hydroxypropyl~ s~. n spQ ~ions can also be pre~PrecJ in sesame or peanut oil, ethanol, water, polyol (e.g., glycerol, propylane glycol and liquid polyethylene glycol), 15 s~ ' e mixtures thereof, v~t~ I~IQ oils, N-methyl glucarnine, polyvinylpyrrolidone and mixtures thereof in oils as well as ~ueous solutions of water-soluble ph&...,~ceuticAIIy ~c~Ft-'le salts of the compounds. Under ordinary cor~Jitioi)s of ~ r.,ge and use, these prep~ulions contain a preservative to prevent the growth of microor~anis",s.
The inje~-' e solutions prt,p~ed in this manner can then be administered 20 intravenously, i,lt.~peritol.0ally, s~ Ihcut~neously, or intramusc~ ly, with intramuscular adminic.ll~lion being the prd~7l.ecl pare"ter~l route in man.
The ph~-"n~elJtic~l forms sui~AI l~ for i"je ' ' le use include sterile aqueous solutions or di_per~ions and sterile po~ s for the exlemporarleous preparation of sterile injectable solutions or ~Jis,~e.~ions. In all cases, the form must be sterile an 25 must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microo,y~i_."s such as bacteria and fungi.
The effective dosAge of the active ingredient employed may vary depending on the particular compound er";.l~yed, the mode of acl", ,i~ lion, the condition being 30 treated and the severity of the condition being treated.
The active compounds also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible animals, i.e., ungulate animals and poultry.
W O 97/16432 PCT~B9G~C8~ 7 -Animal feed comp~s ';~ns effective for i,.cleasi"g lean meat deposition and for improving lean meat to fd ratio in poultry, swine, sheep, goats, domestic pets and cattle are generally prepared by mixing the compounds of the preser,l invention with - a sufficient amount of animal feed to provide from about 1O3 to 500 ppm of the 5 compound in the feed.
Animal feed sl~FF~ nl~ can be prepale~l by aJI"ixi~g about 75% to 95% by weight of an active compound with about 6% to about 25% by weight of a s~lt~hle carrier or diluent. ~arriers s~ litr' 1~ for use to make up the feed supplement cGmposilions include the fe'lov~;.,g: alfalfa meal, soybean meal, c~ nseed oil meal, 10 linseed oil meal, sodium chlc.ide, cornmeal, can mcl -ses, urea, bone meal, corncob meal and the like. The carrier promotes a unKorm distribution of the active ingredients in the finished fee~d into which the S'~F Flen,ent is blended. It thus pe,~r",s an important function by ensuring proper distribution of the active ingredienl: throughout the feed.
If the s~F'e "er,l is used as a top .l~essi"g for the feed, it likewise helps toensure u~if~ ilr of distribution of the active ", ial across the top of the d,essed feed.
The pr~ ed medicated swine, cattle, sheep and goat feeds generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for 20 these ~-, llals usually being about 50 to 300 grams per ton of feed.
The pr~f~r,ed poultry and do" ,ealic pet feeds usually contain about 0.01 to 400grams and prefe~ly 10 to 400 grams of active ingredient per ton of feedl.
For par~nt~..1 admini~ I;on in animals, the active compound may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin 25 of the head or ear of the animal in which i"cr~ase in lean meat dep~osition and improvement in lean mean to fat ratio is sought.
In general, pL.tll)l6r~ dlll ,i~ lion involves injection of a sufficient amount of the active compound to provide the animal with 0.01 to 100 mg/kg/day of body weight of the active ingredient. The ,cr~"ed dosage for swine, cattle, sheep and goats is in 30 the range of from 0.01 to 50 mg/kg/day of body weight of active ingredient; whereas, the pl~r,~d dose level for poultry and domestic pets is usually in the range of from 0.01 to 35 mg/kg/day of body weight.
CA 0223408l l998-04-06 W O 97/16432 PCT~B96/00803-Paste formulations can be prepared by dispersing the active compound in a ph~-r.,.aceutically ~o~ eFt~ oil such as peanut oil, ses~.e oil, corn oil or the like.
Pellsts containing an effective amount of tha active compound can be prepared by &d.nkiog the effective amount of active compound with a diluent such as carbowax, 5 carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process.
It is, of course, recGy~ ~ that rnore than one pellet may be ad~ . ~' .i~t~. ~d to an animal to achie~.fc the desired dose level which will provide the i..cre&sG in lean meat depGsiliGn and i")~ro~rament in lean meat to fat ratio desired. Moreover, it has been 10 found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal's body.
The active compounds have several adv~ eou~ features. For tha pet owner or vt,lerinariar) who wishes to i..cr~asG Icanness and trim unwanted fat from pet animals, the active compounds provide the means by which this can be accomplished.
15 For the poultrymen and swine raisers, use of the active cor -pounds yields leaner animals which cG,..r,.~d higher prices from the meat industry.
GCMS's were taken on 8 Hewlett Packard 58gO GC in tandem with a Hewlett Packard Model 5971A Mass S~-~ ';o netector using a HP-1 12 m capillary column.
Column conditions were as f ll~ initial temp, 133~C; ramp of 19~C/min; final temp, 20 310~C.
NMR's were taken on a Bruker AM-250 MHz sp6cl-~,r.-eler.
MS were taken on I l~ s~t Packard 5989 Mass Spectrometer Particle Beam (Cl)+. lons obtained were (M + 1)+.
FyAMpLE 1 (S)-1.2-e~oxv~ l.e.~oxs~. ro~,~n~
To 80.0 gm (0.85 mol) of phenol in 150 mL of DMF at 0~C was added, in portions, 37.4 gm (0.94 mol, 1.1 equiv) of sodium hydride (60% by weight dispersion in mineral oil). After 1.5 hours 220 gm (0.85 mol) of (S)-qlycidyl nosylate [(2S)-glycidyl 3-nitrobenzenesulfonate, pu-chas~ from Seprachem (Marl~boro,JI., MA 01762)] was 30 added in two portions to the reaction slurry. Tha reaction mixture was allowed to stir overnight at room temperature. TLC analysis of the ho"~ogeneous reaction mixturein "- hd that the reaction was essentially complete. The reaction mixture was cooled to 0~C and quenched with 500 mL of saturated ~1ueous ammonium chloride. The -W O 97/16432 PCT~:B9Gi'~D~03-mixture was then diluted with 2 L of ethyl acetate and 500 mL of water. The organic layer was separated and the A~lUeOUS eA~ ed three times with 1 L ethyl ~cetAte. The combined organic layers were washed with brine and then dried with sodium sulfate.
The volatiles were then removed in vacuo, at room temperature, and the DMF at a 5 ter"perc~ re of about 45~C whilQ maintaining the vacumn. The crude oil was used without additional pulif;c~liGn into the next step (ll-eoleltical yield assumed).
TLC (silica gel) Rf = 0.80 (60: 40% hexanes/ethyl acetate).
9~10~2 (M~3 = 150, t, = 1.46 min.
1H NMR (CDC13) ~ 7.26-7.33 (m, 2H), 6.91-7.00 (m, 3H), 4.18-4.24 (Im,1 H), 3.91-10 3.87 (m, lH), 3.31-3.38 (m, 1H), 2.87-2.91 (m, lH), 2.73-2.77 (m, lH).
F'~ LE 2 (S)-1-r~ l 2 hf.' o~ th~l)-aminol-3~1.e..ox~r ~rc.~ .-2~DI
The crude oil (0.85 mol) from the previous step was diluted with 300 mL of ethanol and then treated with 125 mL (0.88 mol, 1.04 equiv) of N-benzylethanolamine.
The reaction mixtur~ was heated ovemight at 50~C, at which time TLC analysis indicated that the r~a_t;on was cGr~ The solution was used directly into the next step (theoretical yield assumed).
A sample was conc~nt~aleJ at this point for analysis:
TLC (silica gel) R, = 0.50 (95: 5 methylene chloride/methanol).
GCMS: Cl8H23N03 (M+) = 301, t, = 7.29 min.
lH NMR (CD30D) ~ 7.17-7.36 (m, 7H), 6.85-6.93 (m, 3H), 3.934.03 (m, 2H), 3.80-3.87 (m, 1 H), 3.70 (s, 2H), 3.55-3.65 (m, 2H), 2.60-2.77 (m, 4H).
~XAMPLE 3 (S)-1 -r2-Hvdro~ tl ,~I)-aminol-3-~ e noxv-.Jro,~ -2-ol To the ethanolic solution of 0.85 mol of the title product of Cxa mr le 2, prepared in the previous step, was added 10.0 gm of 20% palladium hydroxide on carbon. After hydrogenation at 50 PSI in a Parr apparatus, TLC analysis showed that the starting material was consumed. The catalyst was removed by filtration through a bed of Celite~. The reaction mixture was then diluted with 1 L of acetonitrile and u/ashed three times with 250 mL of hexanes to remove the mineral oil added with the sociium hydride in Example 1. The volatiles were removed in vacuo and the residue dissolved in 1 L
of ethyl acetate. Upon cooling to 0~C, a solid precipitated. A second crop from 700 CA 0223408l l998-04-06 W O 97/16432 PCT~B~
mL of 4:3 hexanes/ethyl acetate provided a total of 148 gm of title product as a white solid (83% overall based on the (S)-glycidyl nosylate used in Example 1).
TLC (silica gel) Rf = 0.50 (80: 20 methylene chloride/l"eU,&nol).
GCMS: Cl,Hl,NO3 (M+) = 211, t, = 4.32 min.
lH NMR (CD30D) ~ 7.21-7.28 (m, 2H), 6.91-6.94 (m, 3H), 4.02-4.18 3.93-3.95 (m, 2H), 3.61-3.76 (m, 2H), 2.68-2.92 (m, 4H).
rLE 4 ('~;)-2-~ e ~o~ tfly~ L ~4-Siidec~ yl)ethanol ~1) and ~S)-l-(l-Oxa-4aza-sPlror4.5ldec 4 vl)-3-l l.e.-oxy ~-rov ..-2-ol ~2) To a solution of 3.0 gm (14.2 mmol) of the title product of Ex~.,ple 3 in 35 mL
of methanol was added 2.95 mL (28.6 mL, 2.0 equiv) of cyclohQx~none. After stirring overnight analysis by GCMS shov~6~ that the starting l..al~rial was consumed. The volatiles were removed in vacuo l~ v.ed by azeolr~_~ic removal of trace methanol with toluene. 'H NMR indicated an appro3c;."~tely 2.5: 1 ratio of (1) to (2). The crude 15 product (containing trace amounts of cyclol .ex~lone) was used without further purification in the next step.
GCMS: C"H25NO3 (M+) = 291, t, = 6.51 min (for both compounds).
(1) diagnostic signals lH NMR (CD30D) ~4.3~4.42 (m, 1H), 3.59-3.67 (m, 2H), 3.16-3.26 ~n~
2.95-3.02 (m, 1H), 2.61-2.69 (m, 2H).
(2) diagnostic signals 'H NMR (CD30D) ~ 3.80-3.89 (m, 2H), 3.05-3.13 (m, 2H).
r~lrLE 5 1 -(2-S2-12 ~ - - 1 3vlben7Aofuran-5-vloxvlethvlamino)~-pl~el-oxy -2(S)-ol To a solution of 685 mg (2.35 mmol, 2.0 equiv) of the mixture of the title products of Example 4 (from the previous step) in 15 mL of toluene was added 238 mg (1.18 mmol, 1.0 equiv) of 5-hydroxy-2-[1,2,4]oxP~ ol-3-ylbenzouran, (prepared accor~' .g to the method r~;sclQsed in United States P~rFli~-tion Serial No. 08/076026) 600 mg (2.35 mmol, 2.0 eq~liv) of azodicarbonyldipiperidine, followed by 616 mg (2.35 mmol, 2.0 equiv) of triphenylphosphine. The ,~ac;iion mixture was stirred overnight.
The solids (reduced azo-derivative) were filtered ofl, and the wlal;~vcs removed from the filtrate in vacuo. The residue was then triturated with 15 mL 3: 1 hexanes/ethylAcetAte and the solids (triphenyphoshine) were filtered off. The volatiles W O 97/16432 PCT~B~6/008q~-from the filtrate were then removed in vacuo and the residue containin~ (S)4-[2-(2-[1 ,2,4]oxadiazol-3-ylbenzouran-5-yloxy)-ethyl]-phenoxymethyl-1 -oxa-4-aza-spiro[4.5]decane, was treated with 15 mL of 10% ~lueous sodium l~is~lf~tP to cleave - the oY~7Oli line group and form the title compound. Neutralization with saturated 5 aqueous sodium bic~Lonate was f~llov/ed by extraction three times with 15 mL ethyl acetate, drying with sodium sulfate, and removal of the volatiles in vacuo. The residue was chn~"-~loy,~phed on silica gel, eluting with 95: 5 ethyl AcePto./~"~U,&r,ol. The product-containing fractions were cGr"~ ,ed and evaporated in vacuo to provide 310 mg (66%) of title product as a white solid.
TLC (silica gel) R,= 0.20 (95: 5 ethyl ~cetAt~/~"~tl,~ol).
MS: C2lH2,N305 (M+1)+ = 396 1H NMR (DMSO-d~) ~9.79 (s, 1H), 7.62-7.66 (m, 2H), 7.22-7.29 (rn, 3H), 7.06 7.10 (m, 1 H), 6.90 6.93 (m, 3H), 4.05-4.09 (m, 2H), 3.86- 3.96 (m, '~, 2.91-2.96 (m, 2H), 2.60-2.82 (m, 2H).
(S)~r2-(2-r1 ,2,41Oxadiazol~ vlLe.~ ura-- S vloxy)~thyll~l enoxy...el.l"/l-1-oxa-q ' ~L ~ r4.51decan~
Due to the illhelelll instability of the title compound and the inability to thoroughly chan~cie,i~e it in the unpurified reaction mixture, a purer sample was 20 prepared by l.~ neril of the title compound of Example 5, prep red above, with 1.0 equiv of cyclohexanone in methanol. Evaporation of the volatiles in vacuo provided title product for further ~ly ;~.
MS: C27H2~N3O5 (M+1)+= 476
(2) diagnostic signals 'H NMR (CD30D) ~ 3.80-3.89 (m, 2H), 3.05-3.13 (m, 2H).
r~lrLE 5 1 -(2-S2-12 ~ - - 1 3vlben7Aofuran-5-vloxvlethvlamino)~-pl~el-oxy -2(S)-ol To a solution of 685 mg (2.35 mmol, 2.0 equiv) of the mixture of the title products of Example 4 (from the previous step) in 15 mL of toluene was added 238 mg (1.18 mmol, 1.0 equiv) of 5-hydroxy-2-[1,2,4]oxP~ ol-3-ylbenzouran, (prepared accor~' .g to the method r~;sclQsed in United States P~rFli~-tion Serial No. 08/076026) 600 mg (2.35 mmol, 2.0 eq~liv) of azodicarbonyldipiperidine, followed by 616 mg (2.35 mmol, 2.0 equiv) of triphenylphosphine. The ,~ac;iion mixture was stirred overnight.
The solids (reduced azo-derivative) were filtered ofl, and the wlal;~vcs removed from the filtrate in vacuo. The residue was then triturated with 15 mL 3: 1 hexanes/ethylAcetAte and the solids (triphenyphoshine) were filtered off. The volatiles W O 97/16432 PCT~B~6/008q~-from the filtrate were then removed in vacuo and the residue containin~ (S)4-[2-(2-[1 ,2,4]oxadiazol-3-ylbenzouran-5-yloxy)-ethyl]-phenoxymethyl-1 -oxa-4-aza-spiro[4.5]decane, was treated with 15 mL of 10% ~lueous sodium l~is~lf~tP to cleave - the oY~7Oli line group and form the title compound. Neutralization with saturated 5 aqueous sodium bic~Lonate was f~llov/ed by extraction three times with 15 mL ethyl acetate, drying with sodium sulfate, and removal of the volatiles in vacuo. The residue was chn~"-~loy,~phed on silica gel, eluting with 95: 5 ethyl AcePto./~"~U,&r,ol. The product-containing fractions were cGr"~ ,ed and evaporated in vacuo to provide 310 mg (66%) of title product as a white solid.
TLC (silica gel) R,= 0.20 (95: 5 ethyl ~cetAt~/~"~tl,~ol).
MS: C2lH2,N305 (M+1)+ = 396 1H NMR (DMSO-d~) ~9.79 (s, 1H), 7.62-7.66 (m, 2H), 7.22-7.29 (rn, 3H), 7.06 7.10 (m, 1 H), 6.90 6.93 (m, 3H), 4.05-4.09 (m, 2H), 3.86- 3.96 (m, '~, 2.91-2.96 (m, 2H), 2.60-2.82 (m, 2H).
(S)~r2-(2-r1 ,2,41Oxadiazol~ vlLe.~ ura-- S vloxy)~thyll~l enoxy...el.l"/l-1-oxa-q ' ~L ~ r4.51decan~
Due to the illhelelll instability of the title compound and the inability to thoroughly chan~cie,i~e it in the unpurified reaction mixture, a purer sample was 20 prepared by l.~ neril of the title compound of Example 5, prep red above, with 1.0 equiv of cyclohexanone in methanol. Evaporation of the volatiles in vacuo provided title product for further ~ly ;~.
MS: C27H2~N3O5 (M+1)+= 476
Claims (8)
1. A compound of the formula wherein R1 is hydrogen and R2 and R3 together form a single bond or R1 and R2 together form a single bond and R3 is hydrogen or a group of the formula
2. The compound according to claim 1 wherein R1 and R2 together form a single bond and R3 is a group of formula III.
3. The compound according to claim 1 wherein R1 and R2 together form a single bond and R3 is hydrogen.
4. The compound according to claim 1 wherein R2 and R3 together form a single bond and R1 is hydrogen.
5. A process for preparing a compound of the formula which comprises treating the compound of the formula aqueous mineral acid.
6. The process according to claim 5 wherein the compound of formula IV
is prepared by treating the compound of the formula or mixtures thereof with the compound of formula in the presence of azodicarbonyldipiperidine and triphenylphosphine.
is prepared by treating the compound of the formula or mixtures thereof with the compound of formula in the presence of azodicarbonyldipiperidine and triphenylphosphine.
7. The process according to claim 6 wherein a mixture of the compounds of formulae V and VI is prepared by treating the compound of formula with cyclohexanone.
8. A process for preparing the compound of formula whi c h comprises the steps of a) treating the compound of the formula with cyclohexanone to form a mixture of the compounds of formulae and b) treating the compound of formula V or VI or a mixture thereof, with the compound of formula to form the compound of formula ;
and c) treating the compound of formula IV with an aqueous mineral acid to form the compound of formula I.
and c) treating the compound of formula IV with an aqueous mineral acid to form the compound of formula I.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US815395P | 1995-10-31 | 1995-10-31 | |
| US60/008,153 | 1995-10-31 |
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| Publication Number | Publication Date |
|---|---|
| CA2234081A1 true CA2234081A1 (en) | 1997-05-09 |
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ID=21730067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002234081A Abandoned CA2234081A1 (en) | 1995-10-31 | 1996-08-15 | Processes and intermediates for preparing 1-(2-[2-isoxazol-3-ylbenzofuran-5-yloxy]ethylamino)-3-phenoxy-2(s)-ol |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0861240A1 (en) |
| JP (1) | JPH10513480A (en) |
| KR (1) | KR19990067172A (en) |
| CN (1) | CN1201455A (en) |
| AU (1) | AU6628596A (en) |
| BR (1) | BR9611217A (en) |
| CA (1) | CA2234081A1 (en) |
| CZ (1) | CZ130898A3 (en) |
| HR (1) | HRP960502A2 (en) |
| HU (1) | HUP9900090A3 (en) |
| IL (1) | IL123623A0 (en) |
| PL (1) | PL327997A1 (en) |
| TR (1) | TR199800710T2 (en) |
| WO (1) | WO1997016432A1 (en) |
| YU (1) | YU57396A (en) |
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| US20120253481A1 (en) * | 2011-03-29 | 2012-10-04 | General Electric Company | Hart channel interface component including redundancy |
| EP2653464B1 (en) * | 2012-04-20 | 2017-09-27 | Rohm and Haas Company | Benzylamine hydrophobe |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| PL312005A1 (en) * | 1993-06-14 | 1996-04-01 | Pfizer | Binary amines as antidiabetic and antiobesitic agents |
-
1996
- 1996-08-15 IL IL12362396A patent/IL123623A0/en unknown
- 1996-08-15 CA CA002234081A patent/CA2234081A1/en not_active Abandoned
- 1996-08-15 HU HU9900090A patent/HUP9900090A3/en unknown
- 1996-08-15 BR BR9611217A patent/BR9611217A/en not_active Application Discontinuation
- 1996-08-15 EP EP96925934A patent/EP0861240A1/en not_active Withdrawn
- 1996-08-15 WO PCT/IB1996/000803 patent/WO1997016432A1/en not_active Application Discontinuation
- 1996-08-15 CN CN96198046A patent/CN1201455A/en active Pending
- 1996-08-15 CZ CZ981308A patent/CZ130898A3/en unknown
- 1996-08-15 PL PL96327997A patent/PL327997A1/en unknown
- 1996-08-15 TR TR1998/00710T patent/TR199800710T2/en unknown
- 1996-08-15 AU AU66285/96A patent/AU6628596A/en not_active Abandoned
- 1996-08-15 KR KR1019980703123A patent/KR19990067172A/en not_active Application Discontinuation
- 1996-08-15 JP JP9506054A patent/JPH10513480A/en active Pending
- 1996-10-29 HR HR60/008,153A patent/HRP960502A2/en not_active Application Discontinuation
- 1996-10-30 YU YU57396A patent/YU57396A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997016432A1 (en) | 1997-05-09 |
| PL327997A1 (en) | 1999-01-04 |
| CZ130898A3 (en) | 1999-03-17 |
| JPH10513480A (en) | 1998-12-22 |
| KR19990067172A (en) | 1999-08-16 |
| TR199800710T2 (en) | 1998-08-21 |
| IL123623A0 (en) | 1998-10-30 |
| EP0861240A1 (en) | 1998-09-02 |
| AU6628596A (en) | 1997-05-22 |
| HUP9900090A2 (en) | 1999-10-28 |
| HRP960502A2 (en) | 1998-04-30 |
| MX9803497A (en) | 1998-09-30 |
| BR9611217A (en) | 1999-04-06 |
| CN1201455A (en) | 1998-12-09 |
| HUP9900090A3 (en) | 1999-11-29 |
| YU57396A (en) | 1998-11-05 |
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