AP224A - Azabenzimidazoles in the treatment of asthma, arthritis and related diseases. - Google Patents

Abstract

A series of imidazo

Description

ASA^ur?T'Z IMIDAZOLFE TN THE TREATMENT Ο^ρ ASTHMA, ΑΡΤΗΡΙΤΤΕ ANP RET.ATEP DISEASES

Backcround o^r the Invention

The present invention is directed to azabenzimidazoles of formula I, which as inhibitors of platelet activating factor (PAF) and of LTD^ receptor 1 indin.c sites are useful in the treatment or prevention o^£ asthma, arthritis, psoriasis and a wide range of i n^rlammator'’ disorders.

Kre^t et al., in H.S. Patent 4,661,596, describe comoourds which are disubstituted naphthalenes, dihycronaph+halenes or tetralins having the formula

wherein the dotted lines represent optional double bonds, R.ⁿ is ?-pvridvl, '’-quinolyl, 2-pvrazinvl,

2-CTuinoxa. limd , 2-thiazolvl, 2-benzothiazolvl, ?-exazolvl, 2-benzoxazolvl, 1-alkvl-2-imidazolvl or

1-a 1kvl-?-benzimidazolvl and is hvdroxv, lower alknyv, lower alkyl or perfluoro alkvl. These 25 comoouncs inhibit lipoxyaenase enzyme and antaaonize the e^£rects of leukotriene D4, and so are useful in the prevention and treatment of asthma.

BAD ORIGINAL ft

Egqler et al., in copendinq International application PCT/US8⁷/02745, filed October 19, 1987 have described sinilarlv active compounds, including chromans of the formula

y ** wherein P is substantially' defined as above, R^fa is arvl or heteroaryl, X^a is, for example, oxygen or CH₀,

V-\ and x is C=0 or CHOH.

More recently, International Application

PCT/TJS89/009·⁷?, Publication No. WO 89/08653, describes the preparation of l-C&bamvlbenzvlimidazo(4,5-c)pvridines useful as PAF antagonists..

Summary of the Invention

The present invention comprises compounds of the formula

and a pharmaceutically acceptable acid addition salt thereof, vzherein Het is

ORIGINAL

AP Ο Ο Ο 2 2 4

A is -CK_?-O-, -CH=CH-, -C(CH₃)=CH-, -CH_nNH-, -C=C-,

-NHCH_-, -ICHJ -, -0-, CH.S(O) -, -NHCO-, -CONH- or .' .- n 2 m cvcloalkyleno having three to nix carbon atoms; v: is

P..

BAD ORIGINAL . *^?±ξ?Σ -

B in -NHCH_n-, -CH₂O-, -CH(CH₃)O-, -CiCH^O-, -0-, — Q- '

-CH_OCH - or -NHCO-y

- '+> .7 n is an integer of 1 to 2y m is an integer of 0 to 2; R is hvdrogen, fluor$j?^Mluoro,qhloro, f methyl, methoxy or triflporomethyly and R, and R* are each hvdrogen, fluoro, chloro, methyl, methoxv, acetyl, ''jfiSP*''* · nitro, amino, carboxy, trifluoromethylsulfonylamino or trif]uoromethvl with the proviso that when B is -0- W

SAD ORIGINAL &

AP 0 0 0 2 2 4

A preferred croup of compounds are those wherein

Het is

-CH 0-, -OCH₂ each hvdrocen

-O- or -CH(CH )-0-; and R₁ and P._o are

BAD ORIGINAL

-6Pspecialiw preferred within this group are the corpou^.cs wherein Het is

where P is 5-flvoro; A is -CH=CH~; W is and B is -CH_nO~, wherein Het is

where P is 6-fluoro; A is -CH=CH-; W is

bad ORIGINAL

AP 0 0 0 2 2 4 vfrrc Γ is ’-chloro; A is -CH=CH-; W 1 r

o.’.c F is -CF.^O-, wherein Pet is

and B is -OCH^-, wherein Het is

where P is 6-^fluorn; A is -CH=CH-; W is

BAD ORIGINAL ft

-8wherein Het where Π is 5-fluoro; A is -CH_oO; W is and B i

where P is hvdrogen; A is -CH?O-; W is

BAD ORIGINAL Q

AP 0 0 0 2 2 4

-Qar.d is —C -, wbcreir Het ii

v.tp'-e P 5 s 6-fluoro; A is -CH„O-; w is

and R is -OCH - , wherein Het i:

where R is ’-chloro; A is -CH=CH-; V is and P is -CKiCH_JO-, wherein Het is

BAD ORIGINAL ft

-10v;here R l? 5-fluoro; A is -CH=CH-; V’ is

and	P	is -CK{CH„)0-, j	wherein Het j.s
			f'x'	1
				JL \ JL ' T~'
		R		1 .
vhere	F is 7-chloro; .	A i s	-CHn0-; W is
				s
			A
and	B	is -0-, wherein	Het	is

BAD ORIGINAL £

AP 0 0 0 Z 2 4 are R is -O-, wherein Het ie

arc¹. B is -CH^O-, vhereir. Het is

where P. is 5-fluoro; A is -(CH₀)_Q-; V⁷ is ard B is -CH^O-, vzherein Het is.

6A0 ORIGINAL Bi

-lⁿis 5,6-dif1uoro; A in -CH^O-; W is and Π i

-CH^O- and wherein Het is where P and B i

in 7-chloro; A is W is

-CH^O-, wherein Het is

v,'br^rG R is 6-fluoro; A is -CF^O-; W is

BAD ORIGINAL 0

AP 0 0 0 2 2 4

-1 3.? -C^W„O-, wherein Het

where R ·'s G-fluoro; A is -CH^O-; V⁷ is end B is -CK^O--.

The present invention includes a pharmaceutical composition for administration to a mammal which comprises a platelet activating factor inhibiting and leukotriene D4 receptor blocking amount of a compound of formula T and a pharmaceuticall”· acceptable carrier.

The present invention also includes a method o*⁷ inhibiting platelet activating factor and blocking leukotriene D4 receptors in a mammal in need of such treatment which comprises administering to said mammal e. platelet activating factor inhibiting and leukotriene T4 receptor blocking amount of a compound ο*^{7 c}ormula I. ^T,re~erred is a method vherein the mammal is a human srfferinn from asthma, arthritis, psoriasis, shock, gastrointestinal ulcers, mvocardinl infarction or a stroke. The PAF antagonists of the present invention are also useful in preventing refection in organ transplants.

BAD ORIGINAL

-14As previous I¹'’ nertioner), the compounds of the pre-son*· invention are very unique in that thev possess the ^avaoit to both inhibit PAF and block LTD4 rpc'-ptors. Hence their ability to affect two different r?thwa”s to inflammatory disorders makes them extremely useful as medicinal agents.

Detailed Description of the Invention

Compounds of the present invention are prepared throuch the formation of that portion of the structure designated -R- and to a lesser extent bv the formation of '-.hat portion designated -A-.

When A is -NHCO- or -CONH-, or when B is -NHCOthe oorroounds of formula T are prepared bv coupling the appropriate amine with the requisite acid as follows:

F~

BAD ORIGINAL

AP 0 0 0 2 2 4

his coupling is carried out bv reaciino the '.rprccria'-f! acid with approximately an equimolar amount cf 1-hydroyyber.zotriazole and dicvclohex''lcarbodiimide , to form in situ an activated ester, and subsequently reacting said ester with the desired amine. As one skilled in the art recognizes, a vide variety of activated esters can be used in place of that formed bv 1 -ha'drexvbenzotriazole . In addition, diimides other than d?cvclohexvlcarbodiimide can also be emploved with similar results.

he reaction is carried out in a reaction-inert solvent such as dimethyl,formamide, dimethvlsul foxide or ?’-methvl-?-pyrrolidone. Reaction time is dependent on reaction temperature. At room temperature the reaction proceeds .in I?-·⁷? hours, while under heatinc at 50-75^pC the reaction is complete in 30 minutes to a few hours. The product is isolated b quenching the reaction with water followed by extraction with a water immiscible solvent such as ethvl acetate. Purification o^r the product is bv recr^stallization, HPLC or flash column chromatograph''.

BAD ORIGINAL ft

-16Cnirnounds of the Dresent invention wherein P is -CH(CH₃)0-, CiCH₃)_?O-, -0- or -0CH_o- are prepared bv coupling the following fragments:

Het-A-V’-CH^OH

Het-A-V-CH(CH )OH

Het-A-w-OH

Het-c-T-C(CK,) -OH

J z

The reaction is conveniently carried out by reaetinc about equimolar amounts of the two hvdroxv reagents with an equimolar amount, plus a 10-20% excess, of triphenvlphosphine and an equimolar amount, plus a 50% excess of diethvl asodicarboxvlate in a reaction-inert solvent such as drv tetrahydrofuran.

The reaction is usually carried out under nitrogen or some inert qas at room temperature. Reaction time under *hese conditions is about from 12-24 hours, while shorter reaction times can be achieved by gentlv heat:no the reaction.

BAD ORIGINAL ft

AP 0 0 0 2 2 4

-17The product can be obtained b” renovinc the r^a^'t'or. Fnlvent ar.d ourifvjno the res’due bv recr’Tt -a 11 i ration or colunn chromatoaraph”.

Compounds of the present invention vzhere P is -CP_nC- or -C^wnOCH_o- are prepared bv an alkylation reaction emcioino the follovina fragments:

CH

where X = Cl or Br and £ is 0 or 1.

The reaction is conducted in a water-miscible aprotic solvent such as dimethvlformamide, dir.ethvlsulfoxide or N-methyl-2-pyrrolidone. In practice, one mole each of the reacting fragments are combined in an appropriate solvent to which is added three ecruivalents of an alkali metal carbonate, such as ro^arsium. carbonate. The reaction, which can be carried out a⁴- room temperature, is completed in .5 to 5 hours.

Z'lternatel”, an alkali metal hvdride in a molar amount ecual to the alcohol being alkvlated can be used in place of the carbonate.

The product is isolated bv diluting the reaction mixture with water followed by extraction of the oroduct with a water-immiscible solvent such as ethvl

BAD ORIGINAL

-1810

acetate or chloroform. Purification of the product is c?.?-ried cut bv recrystallization or chromatograph^',

Compounds cf formula I wherein B is -(CB_n)_n- are cTthesized bv the catalytic reduction of the corresponding olefin. In practice the olefin is shaken with SI palladium-on-charcoal in a hydrogen atmosphere at a pressure of about 30 psi in a reaction-inert solvent of methanol-tetrahydrofuran at room temperature for 12-24 hours.

^mhe product is isolated bv filtering the spent catalvct and removing the solvent. The product can be purified bv means alreadv mentioned.

Compounds of formula I wherein B is

BAD ORIGINAL

AP 0 0 0 2 2 4

In practice, about eouimolar amounts of the reouisi⁴-e did and carbonyl compounds are combined with .- catalytic amount of an acid such as £-tolueneaulfoni c acid and heated in a reaction-inert solvent which is capable of drmina an azeotrope with water, such as benzene or toluene, in such a manner that the water is removed from the reaction in a Dean Stark trap. When the appropriate amount of water has been collected the reaction is complete.

The product is. isolated by removing the acid catalvst with a base wash followed bv removal of the solvent. Purification is bv previouslv described means .

Comccunds of formula I wherein P is -MIICH_n- are nrcrcrcd b^,r reactinn the fracments

BAD ORIGINAL

->n-

in the presence of a reducing agent such as sodium horohvdride or sodium cvanoborohvdride.

F?:perimentally, about, equal equivalent amounts of *-hp aopropriate amine and aldehvde are combined in a reaction-inert solvent such as methanol containing about an equivalent amount of the reducing agent. The reaction can be conducted at room temperature for a... reaction time of several hours.

The product is isolated by the addition of a w^ter * immiscible solvent such as ethvl acetate followed by aeneous washings and removal of the appropriate solvent. Purification of the product is bv recrvstallization or chromatograph^.

Synthesis of compounds of formula I wherein W is

is achieved bv base hvdrolys.is of the corresponding lower alkvl ester. Tn practice, t.he ester dissolved in

BAD ORIGINAL

APO 00 2 2 4 _ ι _ m° 5 ύτ¹'·' 2 rnr.taininr et least ar oouimolar amrvpt o ^r ar aqueous r2 kali metal h”droxide, rimh as sodium r.vcrctiGe, ? s heated to reflux ^fnr 1-? hours.

^mhe product is isolated by removal of the solvent, addition of water to the residue and precipitation of the product b'- adiustmont of the pH with aqueous acid, hurl ficcition is by conventional means.

Compounds of formula 1 wherein A is a trans olefin o.a^ be c^ⁿ'mrted tc a cis olefin b^w photolvsis. Tn practice a sample of the compound of formula I wherein ' Isa trans olefin in a reaction-inert solvent such as actonitrile.'methanol is exposed to natural or artificial light for a period of several davs.

The solvent is removed and the residual product wherein A is a ois olefin is purified by conventional means .

As previously Indicated, the compounds of formula I form pharmaceuticalli’ acceptable acid addition salts. Said pharmaoeuticallv-acceptable acid addition salts include, but are not limited to, those with HCl, HBr, HNO,, H„SC₄, H₃PC₄, CH₃SO₃H, p-CH C_gH₄SC^H, CH₃CO_?H, culconic acid, tartaric acid, maleic acid and succinic acid. In the case of those compounds cf the formula iI) which contain a further basic nitrocren, it will, of course, be possible to form diacid addition salts (ο.σ., the dihvdrochloride) as well as the usual mcnoacid addition salt. Said pharmaceuticallvacceptable cationic salts include, but are net limited to, those cf sodium, potassium, calcium, magnesium, ammonia, N,N¹-dibenzvlethvlenediamine , N-methvlclvcamine (meglumine), ethanolamine and diethanolamine.

BAD ORIGINAL Si

As one skilled in the art recognizes, compounds of fe-mula I h?.”e the potential for containing cis-trar.s rle-'ins, ci s-trans-conformational structures and 'metric carbon atoms. All these potential isomers are considered within the scope of the present i r.venticn.

Concerning the biological activity of the present cor,prunes, it is known tha.t arachidonic acid is metabolised in mammals by means of two distinct pathways, one leading to prostaglandins and thromboxanes, the other to several oxidative products called leukotrienes, which are designated by letter number combinations such as B4 , C4, 04 and F4 . The first step in this oxidative pathway is the oxidation of arachidonic acid under the influence of

5-lipoxvgennse enzyme, an enzyme which is inhibited by many of the compounds (I) of the present invention, thus blocking the synthesis of all leukotrienes. Supplementing this enzvme inhibitory activity is the general abilitv of the present compounds to antagonize oeptidvl leukotrienes (e.g., block LTD4 receptors), and to antagonize platelet activating factor (e.g., block PAF receptors). These activities themselves provide the mechanism sufficient for the utilitv of the present compounds in the treatment or prevention of asthma (where T.TC4 , LTE4, PAF and LTD4 are understood to be mediators), arthritis (where LTD4, LTR4 a.nd PAF are understood to be a mediator in inflammation), psoriasis (where PAF, LTD4 and. LTB4 are understood to be a mediator), inflammatory bowel disorder (where leukotrienes and PAF are understood to be mediators),

BAD ORIGINAL

AP 0 0 0 2 2 4

-Vtraumatic shock (where PAF and leukotriere? are int¹ jested) , stroke (where leuk^hrienes and PAF are r-’-’iaterrl , ulcers (where Lmc4 and L?D4 are understood tc be mediators) and irvocardial infarction (where PAF, ^TTF4 and 1^24 are understood to fc- a mediator) .

For a review concerning leukotrien.es, see Failev et al., Ann. Reports Med. Chem. It, pp. 203-21^-7 (1982).

~he i n vitro activity of the compounds cf the formula (I) is tested as follows. RBL-1 cells, ma:trained in ntonnlaver form are crown for 1 or 2 davs ir. sr:nner culture in Minimum Essential Medium (Eagle) with Earl' s Salts plus 15% Fetaⁿ Bovine Serum supplemented with antibiotic/antj.mycotic solution (CTFCC) . ^mhe cells are washed one time with RPMI 1640 (C-TFCC) and resuspended in Ρ.ΓΜΙ 1640 plus 1 microM clvtathione to a cell densitv of 1 x 10 cells/ml. A volume of 0.5 ml of the cell suspension is incubated at 2C°C with 0.001 ml of dimethvlsulfoxide solution of drug for 10 minutes. The reaction is started bv a simultaneous addition of 0.005 ml (14C)-arachidonic acid in ethanol and 0.002 ml A23187 in dimethvlsulfoxide to give final concentrations of 5.0 and 7.6 microM, respectively. After a 5 minute incubation at ?C^CC, the reaction is stopped bv the addition of 0.27 ml acetonit.rile/acetic acid (100/0.3) and the media is clarified by centrifucation. Analysis of the product profile is made by a 0.2 ml injection of the clarified supernatant into HPLC. The separation of radioactive products is effected on a radial PAX CM column (5 mm T.D., Waters) with a solvent svstem of acetor. j tr j. le/F_o0/acetic acid (0.1%) with a linear

BAD ORIGINAL ft

-?4» are*· or.i tri le qrad.ient from 35% to 70% over 15 minuter.

at ¹ m.l/minute. Quantitation is accomplished with a

Berthold Radioactivity Monitor equipped with a built-in ; nPeorator and a 0.3 ml flow cell mixing 2.4 ml/minute

OnnirQuor (NEN) with column effluent. Integration u^its for each product are calculated at a percentage of total integration units, and then compared to the averaoe control levels. The results are expressed as

Percent of Control and are plotted vs the log of druc concer t ration. ^he values are estimated bv

Graphical inspection.

be platelet activating factor (PAF) receptor assav tests the ability of a compound to compete with radiolabeled PAF for specific PAF receptor sites on rabbit platelet homogenate.

Homogenate Preparation:

Note: All centrifugation is carried out room temperature.

All tubes and pipets used during homogenate preparation are plastic.

Five hundred milliliters’of a rabbit blood mixture 's purchased from Rockland, Inc., Gilbertsville, PA.

'he blood mixture is 4 parts blood: 1 part 4% sodium citrate iv/v), and is obtained b” heart puncture from normal, approximately 8-month old New Zealand white rabbits. The blood mixture is delivered overnight on vet ice (approx. 8 °C).

The blood mixture is centrifuged at 514 g for 10 minutes. The supernatant platelet-rich plasma is gentlv laid over Ficoll-Pacrue (Pharmacia) at a ratio of 9 parts plasma:? parts Ficoll (v/v) . The plasma/FicoJ.l

BAD ORIGINAL g.

AP 0 0 0 2 2 4

-2 5nixture is centrifuged at 856 σ for 20 minuter.

^T,oc?-»-ed at the interface of the plasma and Ficoll la”er?, the rlste’et laver is collected and washed in a buffer containinc 150 mM NaCl, 10 mM Tris and 1 mM ΕΠΤΑ (p-H ^.5) . This mixture is centrifuoed at 1926 σ for 25 minutes. Τίρ resulting oellet is resuspended in the ^aCl/Tris/EPTA buffer and centrifuged again (1926 q, 25 minuses). This time the pellet is resuspended in a sob, ium-*ree buffer (10 mM Tris, 1 mM EDTA, 5 mM MnCl₀ (pH ⁿ.5)l arc cer.trifuoed at 1 926 σ for 25 minutes. ^mhe platelet pellet is resusoended in about 10 ml of sodium-free bv.^rcer. This suspension is quick-frozen in a methanol/dr'·' ice bath and thawed quickly three times before beinq *rozen again for storage in 1 ml aliquots at -70^cC. Protein concentration of the suspension is determined bv a Bio-Rad assay.

Assay Conditions:

Note: All concentrations civen are FINAL concentrations in 250 ul.

The following are added to a 12 x 75 mm polystyrene tube:

(]) 5 u1 of one of the following:

/λ. DMSO (to determine total binding)

B. 1 μΐ RAF (to determine non-specific binding)

C. 30 ul - 15)0 uM. compound in DMSO (2) 25 ul 3H-PAF (specific activity 30-60

Ci/mmol) in sodium-^ree buffer + 0.25% bovine serum albumin (BSA) (Apnrox. 10,000 cpm/25 ul) (?) 220 μ 1 homogenate preparation (0.1 mq/ml) ir sodium-^ree buffer + 0.25% BSA.

BAD ORIGINAL ft

--<S£f5fc’

-2 0Tho reaction tubes are incubated ?+ 25°C for 45 r.ir.utes. Tour ml o^£ cold sodium-free buffer + 0.25%

PSA are added to each tube. The contents are guicklv -il*ered through a Whatman GF/C filter with a Yeda reparation device. The filter is washed 3X with 4 ml rodium-free/PSA buffer. The filter is transferred to a scintillation vial. IJltrafluor scintillation fluid is added. The vial is caoped, vortexed and counted for 2F .

Data Calculation and Analysis:

Percent specific binding is calculated using the formula % SB = (X - NSB)/(TB - NSB) , where X = cpm sample

NSB = cpm non-specific binding TB = cpm total binding

Percent specific binc^ng is graphed as a f^ption of compound concentration. -^s that concentration at which 50% SB occurs. Alternatively, the TC_Cft is □ U calculated using the logistic dose-response (Hill plot) option of the VAX Biostat utility. The inhibitory constant (Ki) is calculated bv using the formula

Ki = (TC₅₀,/(1 + (L/Kd)1 where L = concentration of ligand added (nMJ = cpm added/cpm of 1 nF 3H-PAF

Ed = 0.83 nM (dissociation constant)

The leukotriene Γ>4 (LTD4) receptor assav tests the ability of a compound to compete with radiolabeled T.TP4 'or specific LTD4 receptor sites on guinea pig lung membranes. In this test, normal 3-4 week-old guinea pigs are acclimatized under standard conditions for 3

BAD ORIGINAL £,

AP 0 0 0 2 2 4 d?vr prior to beir.c sacrificed. Final animal aoe:

-'¹ dei'T . The guinea i?in? arc stunned b·· a blow to the !'3ck of the neck, and er?anauir?*-ed, bv cutting the carotid ar^er”. 'the chest ca'-it’’ is opened and the lungs are removed, rinsed in. 50 mb Tris buffer (pH τ. 0) ano nlaoed in clean buffer. Tn this and all subsecuent operations, all tissue and buffer are kept on ice throuchout the preparation, and all centrifugation is carried out at 4°C. Bronchi and connective tissue _are '-rimmed from the lungs. The tissue is weighed and placed in 50 ml polycarbonate tubes with buffer at a ra'-io of 1 cm tissue/3 mi. buffer. The tissue is homogenized bv a Tekmar Tissumizer at full speed for 30 seconds and centrifuged in a fovall SS-34 rotor at 3250 rpm x 15 minutes. The supernatant is centrifuged at 19,000 rpm x 10 minutes. The resulting pellet is resuspended in buffer with the Tissumizer at medium speed (position 75) for 10 seconds. The resuspension is acain centrifuged at 19,000 rpm x 10 minutes. The resulting pellet is resuspended bv the Tissumizer at. slow speed (position 50) for 10 seconds in 1 ml buffer/g of starting tissue. This fine? suspension is stirred at 4°C while aJiguoted to pol”propylene tubes arc stored, at -70°C. The following are added to a 12 x “5 mm. polystyrene tube· (1) 25 nicroL of one of the following

A. Di.methvlsulfoxi.de (to determine total binding)

E. 1 microM LTD4 (to determine non-specific binding)

C. 30 nanoM - 100 microb comeound in di methvlsu1 foxice

BAD ORIGINAL ft

Λ*·:

28(2) Ρ.Ρ25 ml 3H-LTD4 (specific activitv 30-60 i'i-'mmol·) in 50 mM Tris (pH 7.0) ·*· 10 nirroM ^T.-cvsteine '\,POP - 15,000 cpm/0.025 ml) '3) 0.2 ml diluted membrane preparation (1 mg/ml) (The preparation is diluted in 50 mieroM Tris buffer + MoCl^ such that in 200 microL protein, a 10 mieroM MgCl^ concentration is achieved).

^mh.e reaction tubes are incubated at 25°C for 30 minutes. Four ml of cold Tris buffer + 10 mieroM MgCl^ are added to each tube. The contents are guicklv filtered, through a Whatman GF/C filter with a Yeda separation device. The filter is washed 3X with 4 ml ^ris-MgCl^ buffer. The filter is transferred to a scintillation vial. Ultrafluor scintillation fluid is added. The vial is capped, vortexed and counted for 3 .a.’ - ..&♦(*** hours. Percent specific binding is calculated using the formula . -% SB = (X - NSB)/(TB - NSB) , where X = cpm sample

NSB = cpm non-specific binding

TB = cpm total binding

Percent specific binding is graphed as a function of compound concentration. IC^ is that concentration at which SB occurs. Ki is calculated by usinc the formula

Ki = (TC₅₀)/[1 + (L/Kd)] where ^T. = concentration of liqand added (mieroM) = cpm added/cpm of 1 mieroM 3H-LTD4

Kd 1 mieroM (dissociation constant)

BAD ORIGINAL ft

AP 0 Οϋ 2 2 4

- ? ° Τη evaluate the compounds o^c the formula (I) in i v'Q, the'· are tested b *-lie so-called PAF lethality essa·· crecedure·

Vaterials vice: CD1 males, all approximatelv the same vejcht (approximately 26 crams), 12 per croup.

Vehicle far oral druc dosing: EES (5% ethanol, 5% emulphor, 80^c saline). Stored at room temperature.

Ernes: For routine screening at 50 mg/kg, ,20 mg drug is dissolved in 4 ml FES, using sonication in a sorioator bath or grinding in a Ten Broeck grinder to dissolve drug if necessary. If solubility is st.ill a problem, the drug is used as a suspension.

Vehicle for i.v. Injection: Saline with 2.5 mg/ml Bc'-ine Serum Albumin (BSA, Sigma #A4378) and 0.05 mg/ml Propranolol (Sigma #P0084). Prepared ^resh daily and kept at room temperature.

Platelet Activating Factor (PAF): A 10 microM stock solution is prepared bv dissolving 1 mg PAF (Calbiochera #429460) in 0.18 ml ethanol. This is stored at -20°C and is diluted in vehicle (see above) the dav of use. The concentration of PAF used is calibrated so that when injected at 0.1 ml/10 grams bodv weicht, it will kill approximately 80% of untreated controls. This is usually about 0.028 g/kg (a 1 to 2024 dilution from stock). The solution is prepared in class containers and is used with glass s”rinces to minimize surface adhesion by the PAF. It is kept at room temperature.

Positive Control: Phenidone is used at 25 mg/kq fits approximate ΕΓ> 50).

BAD ORIGINAL

-30r-'efhod: 45 minutes before PAF injection, mice are trea+ed orall·’ with drug usinr 0.1 ml,/)0 grams bodv weinht, ^birb’-five to 40 minutes later the'⁷ are placed under a heat lamp to dilate the caudal vein for PAF iniection. PAF is iniected i.v. at 0.1 ml/10 grams bod” weight, and. death follows usually within 30 minutes, rarelv after 60 minutes. Results are eroressed as percent mortalitv as compared to controls. Because the assay appears to be sensitive to endogenous catecholamines (i.e., beta econists protect the mice), Propranolol is used to overcome this potential problem. It also helps if the mice are acclimated to the room before testing, and if room noise and temperature are kept moderate and constant. The heat lamp distance should be calibrated so as to permit vasodilation without visible stress to the mice. Fasting the mice should be avoided.

Variations:

c :-r ·,ι

1. The time for oral dosing can be changed.

?. Intravenous drug dosing is possible bv coinjecting the drug with PAF in the same volume and vehicle as described above. For coiniection, PAF is prepared at twice the desired concentration in saline with BSA and Propranolol as above, and the drug is prepared at twice the desired concentration in the same vehicle. The two preparations are mixed in equal volumes immediatelv before injection.

For use in the prevention or treatment of asthma, arthritis, psoriasis and gastrointestinal ulcers in a mammal, including man, a compound of the formula (I) is gi”en a PAF inhibiting and leukotriene D4 receptor

BAD ORIGINAL '-Ιοοχίησ amount o^f about 0.5-50 mq/ko/da”, jn single ci ihnc.ec: ba; 1’· doses. Λ mare preferred dosage ranoe is -s me/kg/b.a*·, although in particular cases, at the discretion of the attendinc phvsician, doses outside broader ranoe mar be required, ⁿhe preferred route of administratior is qenerallv oral, but parenteral administra^inn (e.g., intramuscular, intravenous, intradermal) will be preferred in special cases, e.o., where oral absorption is impaired as bv disease, or the patient is unable to swallow.

The compounds of the present invention are cererallv administered in the form of pharmaceutica1 compositions comprising at least one of the compound of the formula (I), together with a pharmaoeuticallv acceptable vehicle or diluent. Such compositions are cenerallv formulated in a conventional manner utilizing solid or liquid vehicles or diluents as appropriate to the mode of desired administration: for oral administration, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders and tho like; and, for parenteral administration, in the form, of j.niectable solutions or suspensions, and the like.

The prepon⁴- invention is illustrated by the following examples, but is not limited to the details f hereof .

BAD ORIGINAL ft

-32EXAMPLE 1

1-14-(3-(5-Fluorobenzothiazol-?-vImethoxy) ohenvlaminomethyl]phenyl]-2-methvl-lH-imidazo( 4,5-clpvridine (Het = 5-fluorobenzothiazol-2-^1;

A = -CH_?O-; W = 1,3-C Ιψ and B = KHCH,)

To a mixture of 31 mg of 3-(5-fluorobenzothiazol2-yinethoxy) aniline and 102 mg of sodium cvanoborohc'dride in 15 ml of methanol and 386 u 1 of glacial acetic acid was added 3A sieve? (400 mo) and the mixture allowed to stir at room temperature for 5 mi mites . 1-(υ-formvlphenvl)-2-methvl-lH-imi dazo(4,5-r]pyridine (384 mg) was added over a period of one minute and the reaction mixture stirred at room temperature for one hour.

The reaction mixture was diluted with ethyl acetate (75 ml) which was then washed Jfith a Antlirated i>_kS, sodium bicarbonate solution (? x 75 ml) and solution (1 x 75 ml). The solution was separated, dried over sodium sulfate and concentrated in vacuo to give 1.18 g of product as a yellow solid, which was further purified bv chromatographing on 75 g of silica usinc POC ml of 4% methanol-methvlene chloride. The fractions containing the product were combined and concentrated to give 447 mg of a white foam.

Recryrtallization from diisopropvl ether-methvlene chloride gave a pure product, m.p. 151-152°C.

BAD ORIGINAL ft

AP 0 0 0 2 2 4

-33Anai. Caleb. Tr C _{n O}H _n _N^OSF · ¹ H„<~>:

. Γ 4 J ?>

	C, 66.6;	*> F, 4.6;	N, 13.9.
ουnd :	C , 66.8;	F, 4.3;	M , 1 3.8 .
The MT. (CnCl^	, 300 MHz)	showed	absorotiop at. 0.51
5.41 (OF) anc	4.44 (OH,	d, J =	5.6 Hz) delta.

The hydrochloride salt was prepared by treating an ethanol solution of the product with ethyl acetate saturated with bydrormn chloride, m.p. 160°C, dec.

FXAMPTF ?

Fnnlovinci the procedure of Example 1 and starting with the appropriate reaoents, the following compounds wore prepared

Het

A

W

B m.p.°C

BAD ORIGINAL

-34The NMR (CDC1-, 300 MHz) shewed t/V) and 5.39 (OH) delta.

Anal. Calcd. for C_nRH„ON ?F:

C, 67.9; H, 4.5;

.absorption at 2.53

C, 67

-CH-,0-

N, 14.1 . N, 13.9.

-NHCH₀13R-139

The NMP (CDC1₃, 300 KHz) showed (3H) and 5.32 (2H) delta.

.An a 1 absorption at 2.53

Calcd. for C-_nH-_cON_c:

J U 43 3

C, 75.7; H, 5.4;

Found :

-CH=CH-

N, 14.7 N, 14.7.

-NHCH₂- 177-178

The NMR (CDCl^, 300 MHz) showed absorption at 2.56 (3H) and 4.54 (2H) delta.

Anal. Calcd. for C P N₅SF:

C, 69.6; H, 4.6; N, 14.0

Found: C, 70.0; H, 4.6; N, 14.0.

E D ORIGINAL

AP Ο Ο Ο 2 2 4

-3 sEXAMRLE 3 ¹ -'4 -'3 -(2-Qu i η ο]-2-νIret hoxv)phen”1methoxvTphen'· 1 ’ -'’-meth'-l - 1 H-i mida zo ^f 4,5-c 1 ρ·>'_Γi dine (Het =

-mdnolv]; A -CH„C·-; W = 1,3-C H ; and F = -CH.O-) 6 4 2

To a solution consistino of 493 mg of 3-(ouincl-2Inothoxv)benzvl alcohol, 323 ma of 1 -(p-hvdroxvphenvl)-f-metha'l-lH-imidazo [ 4,5-cl pvridine and 48R ma jq of trinhervlnhosphine in lh ml of drv tetrahvdrofuran v.vm added '’’Ah 1 of diethyl azodioarboxvlate and the ^v-eaction mixture allowed to stir under nitrogen at room remperaturo overnight. The reaction solvent was ror,o”ed in. vacuo and the residue chromatographed on

80 g silica usina 800 ml each o^ 2,4 and 6% methanol in methvlene chloride (v:v). The fractions containing the product were combined and concentrated to give 522 mg. The product was further purified by recrystaliization from ethvl acetate-hexane, 416 mg, m.p.

127-129°C.

The NMR (300 MHz, CnCl₃) showed (?H) and 5.41 (2H) delta.

absorption at 5.12

(	Ana1 .	Calcd.	+or C K 3 0 2 4 C, 75.-7;	°2N4: H, 5.2; N,	11.5
25	Round	:	C, 7 5.2;	H, 5.1; H,	11.2.
	HRMS :	Calcd:	472.1 900
		Round :	472.186-7

BAD ORIGINAL

-|fe-36EXAMPLE 4 ftar'-inn with the appropriate reacents and imino the rrcc'-'chire of Example 3, the following compounds were prepared

B m.p.°C

157-158 t

BAD ORIGINAL $

AP 0 00 2 2 4

-77NMP fine MHz, CDC1 I : ^.55 (31!) , 5.14 (7!

(71:) ce.Ha.

and

Λγ

Caivd or C„₈H_?1O„N₄FS:

C, f’.'⁷; H, 4.3; N, 11.3. C, 6 7.0; H, 4.0; N, 11.0.

r ου rd :

306 136?

-CH_nO157-153

NMR (300 MHz, CDC1 ): 5.17 (?H) and 5.38 (?H) delta .

Anal. Calcd. for C_ -,Ο„Ν .F:

23 7 a

Found :	C, C,	72.8; 7 2.8;	H, H,	4.8; 4.6;	N, 11.3. N, 11.3.
Hvdrochloride	Salt:					700-207
F	-CHnO-		γ	R	-0-	210-21]
		k-	Λ

NMR (300 MHz, CDClj: 7.54	(3H)	, 4.3 (2H)	and 5.41
(211) delta.
.Aral. Calcd. <or C3(?Hn,NzO	3SF:
C, 6 6.3; H,	4.4;	N , 1 0.3 .
Found : C, 6 6.4; H,	4.3;	N, 10.7.
7vdrochloride Salt:			22^-228

BAD ORIGINAL

-CH_nCIU

-CH_oO- 161-163

Aral. Calcd. for C^g C, 0

Found: C, 7 0

N, 11.3 N, 11.2

-ch₂o13^-138

Anal. Calcd. for C^i^gN^OCl:

C, 73.7. h, 5.0; N, 11.1.

Found: C, 73.6; H, 4.4; N, 10.9.

-CH_oO- 183-185

Anal. Calcd. for C_ogH^^N₄O^C1:

C, 70.7; H, 4.3; N, 11.4.

Found: C, 70.6; R, 4.4; N, 10.9.

-CH_oO/.

175 (dec)

BAD ORIGINAL ft

AP 0 0 0 2 2 4 _ 1 C, _

5 (dec)

Anal. Calci

F ound:

for C^pH_niN₄O₃FP^-HCl.?H_?O C , 5 4.5; Η , 4.3; Ν, 9.1. C , 5 4.3; Η , 3.9; Ν, 9.6.

EXAMPLE 5

1—[4—[3—(5—F]uorobenzothiazol-?-vl-transethenvl) phenvlnipthox’.'l phenvl 1 -2-methvl-lHimidazof4,5-clpvridine (Het = 5-fluorobenzothiazol2-vl; A = (trans) -CH=CH-; W = 1,3-C^? and P = -CH₉0-)

Following the procedure of Example 3 and starting with 406 ng of 3-(5-fluorobenzothiazol-2-ylethenvl)bcnzvl alcohol, 320 ma of l-(£-hvdroxvphenvl)-?-methvl) H-imidazo l ^?· , 5-c] pyridine , 410 mg of triphenvlphosphine and 269 u¹ of diethyl azodioarboxvlate in 8 ml of drv tetrahvdrofuran there was obtained 460 mg of crude product which was recrvr+al] ized ^£ror, di isopropyl ether - inethvlene chloride, 39? mg, m.p. 1 97-199°C.

The ΝΜΓ. 1300 MHz, CPCl^) showed absorption at 2.53 (3H) and 5.20 (2H) delta.

Aral. Calod. Am C_O0H_n1 ON SF:

C, ’⁷0.'^z; H, 4.3; N, 13.4.

Found: C, 70.7; H, 4.1; N, 11.4.

BAD ORIGINAL 4

-40^r’he hvdrochlori de salt of the product was prepared treat:nc an ethanol solution o+ the product with eth'-l acetate saturated with hvdrogen chloride, m.p. 759-767 °c.

EXAMPLE 6

Starting with the appropriate reagents and using the procedure of Examole 3, the following analogs were orenared

BAD CDiGINAL

AP 0 0 0 2 2 4

NMP (30Π MHz, CDC1.J 2.52 i3H) and 5.20 (7H>

Anal. Calcd. ^for C_niH^,0N₄Cl:

21.3 4

C, 7 4.0; H , 4.6; N, 11.1. Found.: C, 7 3.8; H, 4.3; N, 11.3.

H”drochloride Salt:

Anal. Calcd. for C H ON C12HC1:

312 3 4

F^und:

-CH=CH(trans) delta .

255-25'

C , 6 4.7; f , 4.4; H, 9.7. C, 6 4.2; H, 4.3; N, 9.5.

-CH^O- 70S

NMR (300 MHz, CDC1₃) 2.54 (3H) and 5.18 (2H)

Anal. Calcd. for C_.H_.ON.:

3124 4

Found :

-CH=CH(trans)

-CH_o0177-1^8

NMR (300 MHz, CDCl.^) 7.55 (3H) and 5.70 (2H) delta .

Anal. Calcd. for C_O1H_,CN.F:

2 3 4

C, 75.8; H, 4.8; N, 11.4. Found: C, 75.6; H, 4.6; M, 11.2.

Hydrochloride Salt

766-ⁿ68

BAD ORIGINAL

-CH=CH(trans)

-CH_n095-200

AMP (300 KHz, CDC1₃) 2.5? (3H) delta. HP.MF: Calcd.: 468.1952

Found: 468.1961

-CH=CH(trans)

-CH_nO112-115

NMR (300 MHz, CDCl^ delta .

(3H) and 5.33 <2H)

delta.

and 5.32 (2H)

-CH₂O- 205-206

Anal. Calcd. ‘or C_?8H_?0N₅C8F:

C, 67.5; Η, 4.?_; n, 14.1.

Found: C, 67.5; H, 4.3; N, 13.7.

BAD ORIGINAL A

AP 0 0 0 2 2 4

CE

-4Ί-

-C=CHtrans:

-CH_o0- 165-166

NMR (300 MHz, rnCl,l (3H) and 5.20 f?H) ci e 11 a .

Anal. Caleb, for C__AH„.N.0SF:

^r' 2 3 4 ^p^und

-CH=CH(trans)

C , 1.1; Η , 4.6; N, 11.1. c, -mm; r, a.].,, m, 10.8.

-CH_nO160-161 delta .

NMR (300 MHz,	CPC13) 5.	32 (s, 2H) and
Anal. Caleb.	f°r C29H21N^OSF:
	C, 70.7;	H, 4.3; N, 11
Found :	C, 70.6;	H, 4.1; N, 11
		Ar
! I -CH	?-ch2-	1
A		J

215-^20 (HC1)

NMR (300 MHz, DMSO-d,) .55 (3H) and 5.19 (2H1 d e 11 a .

PWS : Cal cd, Found :

0.2 1 0 ^Q 480.2108.

BAD ORIGINAL

-ΔύΥΥ.ΜΑΥΥΥ.

^Ί - ^r 4 - f ? - ( 6-Fluorober.noth i azo1 -?.-vlraethnyv) phenvlmefhoxv] pher.vl 1 -?-methvl-lH-imi.dazo [ 4 , 5-el pvridine (bet = 6-fluorobenzothiazol-3-vl; A = CH^O-;

W = 1 ,3-C-H ; and B = -CH„O-) b 4

Following the procedure of Example 3, 331 mg of ‘•'ίρ product o^r Preparation L, 349 me of triphenvlphesphine, 35 0 me cf the product of Preparation B and 5 30 u 1 of d.iethvi azodicarboxvlate in 10 ml of drv r e⁴: rahvdrofuran gave, after chromatooraphing on 05 g of silica nel using from 5% methanol - 98% raethvlene chloride iv-.v) to 6% methanol - 94% nethvlene chloride (v:v), 2^3 mg cf the titled product, m.p. 137-138°C.

The NMR (300 MHz, CDCl^) showed absorption at 2.51 (s, 3H), 5.13 (s, 2H) and 5.48 is, 2H) delta.

Anal. Calcd.	for C2gH21N4O9FSϊ C, 67.7; H, 4.3; H,	11.3
Found :	C, 67.4; K, 3.9; N,	11.1.
	EXAMPLE 8
Starting with	the appropriate reagents and using

the procedure of Example 3, the following compounds were prepared:

BAD ORIGINAL

AP 0 0 0 2 2 4 ρ,

CH_nO- 1 “0-1 m-r- (3CC MHz, CDCl^l ⁿ . 5 2 Is, 3H), 5.1? ic, ' . 15 ( c, 2 H) delta.

. Calcd. for Ω_?ηΗ_Γη\_Λ0_?Β^:

^?ound :

?H)

C , 6 5.4; p , 3.9; _N , 1 0 . c,.

C, 65.1; H, 3.6; N, 10.6.

bbt (300 bHz, CDC1_?) ', d 5.39 ( s , 2 H) delta.

base Spec.; Calcd.:

round :

-CH^n- BP-85 ^z (dec)

2.50 (s, 3H), 5.11 (s, 25)

506.4 ^06 b⁺

BAD ORIGINAL t

( ⁷O0 MHz , DMPC>-d_f ) 1 . P (d, υ>) and ? . 50 in

Anal. Cal cd.	-cn C,,	H \ c ‘>5' 4'	· nH	<”· Ί .
	C, 6 1	.6; H,	5.0;	‘ · t	9.3 .
Γ c v r c1 :	C, 61	v,	5.3;	U,	n

CH,

I ³

-CH-O166-168 (HCl) ypo (300 p/g_z DMOS-d_r .50 ( n , 3”) delta .

Mass Spec.: Calcd.:

Fcurd :

1.61 (¢3, ?H, J=6.3Hz) and

510.6

510 M⁺

-c-oCH.

137-139

BAD ORIGINAL

AP 0 no 2 2 4

-4CDCIJ

4 If π a1. Calcd.

C,

Found.: C _r for C_F 0.0 ; H ,

H, ? -t

4.6; d 4.4; N

31?)

0 . r . 10.0.

Anal. Calcd C

Found: C . for C , 71.3; , 70.9;

-CH„O

F, 4.4; F, F, 4.1; N,

-OCF_?9.P.

9.6.

745-746 (7FC1)

9 (r, Fill

244-746

BAD ORIGINAL

ΕΧΆΝΡΤ.Γ 9

- ^Γ '· - ^Γ - ί 5 - pi vcrobenco-.h.; azc 1 - Imethoxv) im.t ·-. ho?-··’me thy ’ 1 nhcr’' 1- -?-methvl-lH-iridazo(4 , 5-c'l p'’ri dir.e bvdroch’cride (Het = 5-fluorobenzoth.i azel-2 —1; A = -Cl\0; b =1,3-C H₄; and

B = -CH_nCCH_n-) to a sc’u + icn o- 443 nc of the product of reparation 5 in 3 ml of d ime + h.”l fomanide was added 5 ro c.~ Ί 1'·- c >d?um hvdride. After sfirrina for 15 rrnu-es, C50 re of the product of Preparation P was added, and -he reac+ion mixture stirred -or 30 minutes. Th<= reaction was diluted with water and extracted with eth·’?. acetate. The extracts were washed with water and a. brine solution and dried o”er sodium sulfate, removal o- the solvent, cave 830 mg of crude product which was chromatographed on 110 g of silica gel using from ⁹ to 4 to 6% methanol - Of to to 94% methvlene chloride (”-:v) , to qive 113 mg o- product.

The product was dissolved in ethvl acetate and

treated with a	IN	solution of h'-drogen	chloride in
e f h. e , Q 5 . f no,	τη .	p. 168-1?PPC.
The hMB (300	Mbs, py?C-r. ) showed r	absorotion. at
?.rc is, ·:···), 4	. € 8	is, 3H) and . 0 3 ( s ,	T Π! d e 11 a .
bass Spec .		Calcd. 51n.6; Found:	?10+ .
In a 5imi 1	ar	manner, the product 0	- Preparation

and 3- < ?-flunroben?otbi a zol --'’Imethwl -hin) ber.z^vlb r m i d e a a v e i-^f4-f3-(5-fluorobenzofhiazol-3-\’lmethr’lthio) oh.cn/’lmethoxv] phenvll -methyl-1H-imidazof4,5-c] η· τ i c i r. e , m.p. 119 — 1Ί ^c C .

BAD ORIGINAL a

AP 0 0 0 2 2 4 ^’he NMR showed absorption at 2.48 (s, 311) , 4.52 Ή' a—' 5.05 (s, 2H1 delta.

EXM’PbF 10

T'p’.nc the procedure o* Example 3, and startinq ^,:^h the reruisite startinu materials, the following •orroounds were prepared re-

m.p.°C

169-170

ΜΜΓ (300 MHz, CDC1₃) 2.5? (s, 3H), 3.88 (s, 3H) ard 5.42 (s, 2H) delta.

Mass Spec.: Calcd 686.7; Found: 686⁺

-CH=CH(trans)

-CH_OC106-107

MM? (300 MHz, CPC1₃) 2.52 (f, 3H) and 5.17 (s, ?H) de1 ta .

Found :

Calcd. for C-_fH^₀N C:

C, 2 9.4; H, 5.6; N, ' 9 . ^Q C, 79.4; lb 5.3; N, 9.7

-CH=CH(t. r a n s )

CH.

I ³ -CHO160-165 (dec) (2HC1)

BAD ORIGINAL

KKK (300 Ml’z, PKFO-d ) 2.52 (s, 3H) and ‘: , 2 - 6 . 3^1: r ) delta.

1.68 (d,

202-205 (HCl)

1'KP (300 KHz, PKSO-d ) 1.6” (d, 3H, J = .5^{1 1} s, 3 H ) delta.

^Mas-~ Soec.: Calcd. 506.6 Found 506

6.2Hz) and

Ca led

-CH=CI3(trans)

-CH_oO231-233

Found;

. for C_??H^r₄SOF:

C, 69.9; H, 5.5; C, 69.2; H, 5.2;

N, 11.2. K , 11.0 .

190-195 (dec) (HC1)

BAD ORIGINAL s

AP 0 0 0 2 2 4

Caleb . ^r cu n d nMcn-d ) ' r s 0 Ci . ? 0 1

S n r·. h 4 f,.

example 11 t rar.r- 3 - ( 3-Carboy'-ben z vl )-4-(4-( 2-methv 1-1F:.r.icarr ^r 4 , 5-r ] p'T id-1 -'· 1 ] pLenoxv) -6- ( 5-f luorobenzothiazol-2-vlmethox'·) chroman (Het = 5-f luorobensothi a no □-0-l ; A ~ -CH„O-; V.' = trans-

CTH ; and F = -0-)

To 12 ml of methanol was added 316 mg of the metbv] ester of the titled product (Example 10, compound No. 1) and 6 ml of 6N aqueous sodium hvdroxide solution and the resulting reaction mixture heated to refu.x for 1.5 hours. The methanol was removed in vacuo and the residue poured into 150 ml of water.

Eth'T. acetate was added to the aqueous solution and the ov adjusted to about with IN hvdrochlorio acid. The resvldind precipitate was fi Itered sr.d dried 205 mg, rm r o r a .Anal. Calcd. Tr C F N C, 64.4;

Found; C , 6 4.0;

'he NMR (300 MHz, DMSO-d (s, 3H) and 5.55 (s, 2H) ₄O₅FS.r>H,O:

H, 4.7; N, 7.9.

F, 4.2; N, ?.8.

' showed absorption delta.

at

BAD ORIGINAL 0

EXAMPtF I'

- ' -- ' ' - (5 - F I uo r oben z o th i ?. ? ^r 1 - ~ · 1 -<· i s -e f he n* 11 rhc:.·· ’ v> ^{u 1} rhe n.'· 1 ] -2-mcth”l-1H-imidazc ' 4 , 5-c 1 cridine (Het - 5 - * luer obenro^h i a zo 1 - 2Ί ;

A = (cf ) -C’!=CH-; V-; = 1,3-C π · and ^D = -CH„O-) f 4 z

A solution of 6 3. me of the product of F.xannle 5 in 4 1 e^r acetonitrile and 2 1 e^c ncthanol was allowed te stand at room temperature exnosed to light for 6 dmm. The solvent was recover and the product,

6=.p me, was assaved to about 10% startinn material and 20% of the titled product. The residue was purified b'· ehrorratooraphing on 15 g cf silica cel to give 50.2 mg of product. A small portion was reervsta11ited from e^hyl acetate - hexane.

HEMS: Calcd.: 492.1422

Pound : 492.1384.

The nmr (300 MHz, CDC1₇) showed absorption at 2.49 (s, 3H) arc 5.17 (s, 211) delta.

EXAMPLE 13

Osina the procedure of Example 3 and startinc with the appropriate reagents, the following compounds were Γ ΓΘΓΓ. ?€: <’

BAD original &

AP Ο Ο Ο 2 2 4

-CH=CH(trarn)

-5 3-CH^O•.nal. Calcd. for 0^₇Η_Ο7Μ_ΛΟ;

, 6 6.0; H, 4.9; N, 11.4 ound· C, 65.7; H, 4.9; N, 11.4

-CH---CH(trans )

? 5 6 - 2 5 fi (3HC1I

-ΟΗ,,Ο- 249-^50

NMR (300 MHz, CDCl^l 2.52 (s, 3H) and 5.10 (s, 2F) delta.

-CH=CH(trans)

-CF„0140-14:

₂₅ IV'P (300 I'Kz, CPC1₃) 2.50 (s, 3H) , 3.87 (s, 3H) and 5.17 (r, ⁿH) delta

Aral. Calcd. for C_OQN_n1N SOF:

Found :

C, 70.ⁿ; H, 4.3; N, 11.4. C, 70.5? H, 4.1; N, 11.3.

BAD ORIGINAL ft

(trans)

-orn

169-1^1

MM? (300 MHz, CPCl^l 2.5^ (s, 3H) and 5.23 (s, 3F) r Ί

-CI!=CH(trans *

NMR (300 MHz, CDC1₃) 2.49 (ε, 3H) , arc ^c.5 3' (s, ?F) delta.

Anal. Calcd. ^£or N SG,F :

C, 6 3.^,- H, 3.9; N,

Foundr C, 63.4; H, 3.9; N,

5.12 is, 2 H)

0 . 3 . 10.1.

w-’drochloride :

Anal. Calcd. ^ror C, H_?SO,F₃·HCl:

C, 5 9.7; f 1, 3.8; N, 9.6.

Fcuod; C, 6θ.4; _Hf 3.6; _N> 9.4.

BAD ORIGINAL ft

AP 0 0 0 2 2 4

-CF=CF- -iCH„)- -CH.,0- lⁿ6-12P (trar.s)

(300 MHz,	CPC	1 1 1 *3	.80 (m, PHI,	1.90 (m
2)1) , 2.48	( s ,	3H)	and 4.06 (t,	2H) del
. Calcd.	^or		nN,SOF: 3 c.
	c,	t7 . 3	H, 5.4; N,	11.5.
d :	c,	6^.6	; H, 5.2; N,	11 . 9 .

NMR (300 MHz, CDC1_?) 2.49 <s, 3H), 3.23 (t, 2H), 3.43 (t, 2H) and 5.10 (s, PH) delta.

FP.MS: Calcd.: 494.15^7

Found : 494.1579.

^F (300 MHz, CDCl ) 2.48 is, 3H), 4.66 (s, PH) c‘ri 5.11 (s, ?E) delta.

Kpvp. c_a τ cd.. : 5 0 ^Q . 1 3 16

Found : 509.1^58

BAD ORIGINAL ft

-o-

NMR (?PP MHz, CPC1₃) 2.54 (s, 3H),

Anal. Calcd. for C,.H__N,SO.F:

31254 ?

C, 69.4; Η, 4.7; N, Found: C, 69.0; H, 4.5; N,

5.44 is, 2H).

10.4 .

10.3 .

HMH (?nn fiH_z, CPC1 ) 2.35 (m, 2Π), 2.54 (s, 2H) , (n, 2 H) , 6.95 M, 1H) delta.

’'as? Free. 5 34 bad original ft

AP Ο Ο Ο 2 2 4

-οοη ddt. (3OC yu-, CDCIJ 7.50 is, 3H) , 5 JO (s, 7H), 5.27 If, ΓΉ) delta.

J^J * 3 ? Γ S Γ 9 O , P C

-CH_O-

-OCH - !⁷9-lP. 1

NAP (300 MHz, CDC1 1 7.48 (s, 3H), 5.70 is, 7H), 5.5 7 is, 7H) delta.

Anal. Calcd. for C „F_n3N₄S(\F.·

Found :

-CH=CHftrans )

C, 69.0; F, 6.0; N, 10.1. C, 69.8; F , 4.3; N, 10.0.

o

-CH^O190-193

FMP (300 MHz, CPCip is, 3H), 5.10 is, 7F) ,

6.54 'η, 7H) delta.

Anal . Calcd. for C

C, 5 8.4; TI, 4J; F , 10.1 Found: C, 58.0; H, 4.3; F, 9.8.

H d C FF · HCl · 'J’^C ; 27 ]Q 4'7

BAD ORIGINAL A

(300 MHz, ΟΠΟΙ ) ?.54 (_£, 3Η), 5.44 (r, 7Η)

c. e 11 a .

^rc>ur d

-CH_o0-

N, 10.4

N, 10.3

-CH.,0- 113-115

HMR (300 MHz, CDC1 1 7.49 is, 3H), 5.11 (s, 7H) , ^c.?7 (s, 2H) delta.

235-738

Mass Spec. 427 Hydrochloride Salt

OCH.

-CH„O- 701-203

HMP (300 MHz, CRC1J 2.51 (s, ?Hl, 3.93 (s, 3H), j

- . 7 0 ( s , 7H) delta.

4^mgss Spec. 572 bad original s

AP 0 0U2 2 4

-CH=CH(trans )

I 67-16^Q vyp (300 bHz,

CDCl^) .64 (AR doublet, *'a s? Poec . 5 0 8.

7.53 (s, ?H) , 5.31 (s, 3H) = 16Hr).

EbAbPP 14

- [ 4- r 3- ( 5-FTuoroben'’o⁺-.hiaznl-3-vlmetho::v) ρη'Ί Ptb.·”! 1 phenvl] - 7-methyl - lH-imidazof4,5-c¹p-ridine (Fiet = 5-fluorobenzothiazol-?-vl;

A = -CH^O-; ?’ = 1,3-C₆H₄7 and B = -(CH_?)_O-)

A. 3- (5-f luorobenzothiazol-2-vlmethoxv) benzvl tri,phenvl phosphonium bromide

A mixture of 2.01 g of the product of Pre.paration

P and 1.5 g of triphenvlphosphine in 100 ml of toluene were heated to reflux for 70 hours. ^The reaction mixture was cooled and the solids filtered and dried, 7.0 c .

P . 1-(4-(3-(5-fluorobenzothi a so1-2-vImethox) phenvie t henv 1 ] pher.v 1¹ - 2 -rieth'd - IB - imida zo' 4 , 5-cl ovridine______ (’sine the procedure of Preparation El, 1.55 σ of '-he product of Example 14A, 500 mg of the product of Preparation C and ,^c78 ml of 2.5b solution. of n-butyl li^Lum in 40 ml of drv tetrah’’drofuran nave, after workur and. ebromatocraph”, 311 mg of the titled p r c c u c t, m.p. 17 8-181^c C.

BAD ORIGINAL

- F. 0, - (?-f¹uorobenzothiazo1-7Imethox”) ph ,.^j z. · !^c' z h' 11 nh'T'' 1 ] — 2 — p··c t z' I — 1H — im c a z o — ' ‘ , 2 - e ¹ r^-r i dine_____ •:tt zp nf 300 mn cf the product of Fxample 14C

100 pz- of 5% pa 11 adium-on-charcoa 1 in 10 ml of -.no! and 10 ml of tetrahvdr^e_{uran wa}c shaken in a h’-drocen in a•‘-nnpoherc at 30 Dsi for 30 hours. The •titered and the filtrate concentrated in • ·acv.c to ci”f· ”00 mo of an oil. Flash chroisatooraphinn on. si'ica ne] cave 32 mo of a semi-solid which was 'zor*·zta 11 izod ^fror eth'·! acetate-hexane 14 mo, m.p.

^mhe NMR (300 MHz, CPCl^) showed absorption at 2.5 ^fs, 3H), 2.02 (m, 4H) and 5.44 (s, ?H) delta.

Mass Spec.: Calcd. 494.15^7,- Found: 494.1570 . EXAMPLE 15

1-(4-(3-( 5-Fluorobenzothiazol-2-vlaminocarbonv1)phenvlmethoxv]phenyl]-2-methyl-lH-imidazo(4 , 5-c] pvridine (-Het = 5-fluorobenzothiazol-7-vl;

A = -NHCO-; W = 1,3-C.H.; and B = -CH_O-) b 4 z

A . 1-(4-( l-rethoxycarbonvlpherylrethox'’) phenn-ll -7methy'1-ΙΗ-i midazo ( 4 , 5-c] pyridine_

Ur’nr the procedure of Example 3, ⁷75 ma of meth’·’! ?-f-drox'Teth”lbenzoat.e, 1.05 c of the product ο* Frereratior A, 122 ma rf triphenvl phosphine and ⁷3 ul of diethvl azodzearboxy!ate in 10 ml of drv te^rab’drefuran cave 886 mg o? the desired product as a z emi-solid.

bad original

AP 0 0 0 2 2 4

-00.B . 1 - ! *’ — ( 2 — c a rbnyvohe n '* lme t h, ox v) cb e r.'⁷1¹ — 2 - ire t h' I — 1 ^w— ir.:d?.rr[4,!;-rir<-ridin>?

To a stirred solution c * ssn pc c^x the oroduct of

Γxap1 e 2 5A in l^r r) of mefhar.ol was added 5.9 ml of a ’.P) solution of aoueous sodium hvdroxide and the resv.tlinr reaction mixture heated to reflux for 4 hours. The methanol w? removed in vacuo and the ’-o''dual solution ( 5 ml) was diluted with 15 ml o^£ wafer and the pH adjusted vzith 2N hvdrochloric acid to about -. The resultinc precipitate was filtered and dried, C 4 ⁿ mg, m.p. 255-258°C.

C . 1-)4-)3-(5-fluorobennefhiazol-?-vlaminocarbcny1) phenvlmethoxv]phenyl]-2-methy1-1H-imidaze )4,5-c]d't id. ine

To a stirred suspension cf 300 mg of the product of Example 15B, 14⁷ mg of 2-amino-5-fluorobenzothiazole and 191 ng _of 1-hvdroxybennofriazole in 20 ml of dimethy1 formamide was added 189 mg cf dicvclchexvlcarbod.iimide and the reaction mixture · allowed to stand for 3 davs. The reaction mixture was diluted with 400 ml cf ethyl acetate and washed with water (1 x 400 ml), 0.5N aoueous sodium hvdroxide solution (1 x ί'Ό ml) and water (1 x 400 ml). The organic layer was dried and ccr.centraf ed to aive ^d0C mg of solid which van chromafegraphed on silica crel with ~.5% methanolmeth”lene chloride (v:v) , 231 mg. A sample war, reccfta.lli zed from ethvl acetate-hexane, m.p.

244-246^cC.

The (300 MHz, CDCl^) shewed absorption at 2.44 is, 3H) and 5.31 (s, 211) delta.

SAD ORIGINAL ft

Haled. C η \ Π SF· ' 28 '¹0 5 ⁿ

C, 6 6.0; Η , c, 65.0; H,

EXAMPLE I 6 . f_! ; 3 . P ;

K¹ IT • r - -J · ·

Ν , 1 3 . 4 .

- (2-Methvl-IH-imi da 70 1 4,5-c ] pvr id -1 -y 1) ben 7 a 1 f.ehvde , 3 - ( 5 -f luorober.zothiarol -2-viethen'’] ) ?!’.(-.”]σ1”Γ0ΐ acetal (Het = 5-f luorobenzothiazol-?'1; a - (trans) - CH=CH-; V7 = 1,3-C.H.; and 6 4

A mixture of 625 me of 3-(5-fluorobenzothiazol2-y lether.”’ ) nhenvlglycol, 517 mg of l-(4-fornvlphenvi)2-m.ethvl-lH-imidazo [ 4,5-c] pyri dine and 452 mg of

4-tolueresulfonic acid in 60 ml of toluene was refluxed v.’ifh a Dean-Stark trap ^ror 4 hours. The resulting suspension was cooled, diluted with 4C0 ml of ethvl acetate and washed with 40 ml of IN aaueous sodium hydroxide, wafer (1 x 40 m) and a brine solution. The crcanic phase was dried over magnesium sulfate and concentrated to give 1.1 g of crude product which' was ehromatccraphed on silica gel (7.5% methanol-^q2.5% r.o'-hvlere chloride - v;y) , 941 me. The purified

7' a t e r i	al	was	^riturated with hexane	(10 0 ml) to give
0 5 ma		P .	105°C (dec.).
T		NNP	(300 mHz, CDCl^) showed	absorption at
2 . 5 5 (	c r	3H) ,	3.90 (m, IH), 4.50 (t,	1 H ) , 5.31 it, 1
and c .	?c	( s ,	H?) delta.

bad ORIGINAL &

AP 0 0 0 2 2 4

HXAMPbF 1 ' Γ’-.-τ +-procedure o' rxr'r'.ole 16, ar.c start inn ' '’-‘f. the a p proDr i a t e roaoentr, +-he follov/inu ooipooupdr '.•ere orer-ared:

Mass Spec. Calcd Found for C,,H._cNC-SF: 552.163? 16 15 3 : 552.1625.

-CF_OC>^vas? Spec. Calr-d for

C R N 0 SF· ?P 23 4 3

538 . 14-^5 538.1544.

BAD ORIGINAL &

PV^^MP',P ¹ £ ¹ - ^r 4- [ ? - ( 5-Fluoroben~ c·*-hi azo] - 2 —¹ · 1 car bam’·¹1 ' r ]·.·' n '· Ino hoxv 1 oh or.¹· 1 - ? -met h'· ] -1 H-iridazo [ 4,5-c¹ pvricir.e (He t = 5-fIuorobenzothia?ol-?-vl;

Λ = -CONF-; V; = 7,3-C_rF,; and H = -CH„O-)

Csino the cc^eral coup!inc crocedure of Example ¹.5C, 3 me of S-^luorobcr.zothiazol-C-oarboxvlio acid, ] .^8 me >^^c 7 _ r z_ (3-aminophenvImothoxv) chenvli-2-meth”·!I H-; m: dr zc i 4 , 5-c 1 p’*ridine , ’z me of 1-hvdroxvbenzot r i z zo 1 e az·’ ^c 3 mg of dic^c 1 oh expire rbodi imide in 5 ml ο¹⁷ d ireth'·! formamide crave 500 me of crude product. The remi-solid was chromatocjraphed on silica gel (5% methanol-?5% methvlene chloride - v;v) to cive 131 mg.

A sna.1 1 portion was reervsta] ] ized from ethyl acetate hexane, m.p. 222-2?4°c.

The NMR (300 MHz, CPCl^) showed (s, 3H) and 5.18 (s, 2H) delta.

Anal. Calcd. for gH^pN^SO^F:

C, 66.0; H, Fou r d : C, 6 5.5 ; H, absorption at 2.50

4.0; N, 13.7. 3.9; N, 13.3 .

BAD ORIGINAL Q

AP 0 0 0 2 2 4

ΕΡΑΜΡΤΓ 1^G • · - l Ρ'Τid- 2-’· 1 ) ( 4 - ( ?. -m-ath.vlimida zo (4 , 5 -o¹ P’-ri d-l-'-l) benzV.ox’-’i benzamide (Het = 2-p'-rid”l;

A = -VHCO-; l·⁷ = 1.,2-C ; and P = -nCH_n.··. methvl 2-(4-( 2-methviin? daze Γ 4 , s-cl pvrid-1-vl Ihenz''loxvlbenzoate

- [ 2- Me tb’· 1 imi dero f 4,5-c' svr id -1 - vl 1 ben ? vl alcohol i 2 . 2 ^Γ· c, , netbvl ralvcvlate (1.67 σ) and tr iphe-'-lphosphi ne (2.88 a) were dissolved in dr'·’ -etrah'/drofuran (50 ml). r>iethvlazodioarboxi’late (2.0? c) was added dropwise over 5 minutes. The resulting solution was stirred at room temperature for ' hour then evaporated to drvness under vacuum. The residue was chromatoaraphed on silica (Merck, Kieselgel ^0) eluting with dichloromethane/methanol (97:3 v:v). The product containing fractions were evaporated and the residue crystallized from ether to give 3.5 g of -he desired product, m.p. 126-128°C.

. 2-(4-( 2-methvlimidazo[4,5-c]pyrid-l-vl) benzvloxylbenzoic acid

Methyl 2-(4-(2-methvlimidazo(4,5-olpvrid-l-vl)ter7loxl benzoate (3.73 g) was dissolved in industri al -ethanol (IOC ml) and ?N sodium, hydroxide solution (20 ?_) was added. The solution was stirred at room tem.peravi.ire Wr ° hours then e”arorated to low bulk.

The concentrated solution was poured into water, washed with di chloromethane (2 x 50 ml ) then acidified with slacial acetic acid. This mixture was reextracted with di'-h.loromethane (3 x 75 ml) . The combined acid ar'tracts were- dried over sodium sulfate, filtered, and

BAD ORIGINAL e’-?.porated to drvness to '-told the titled produr⁴·, ;.' c, r..o. :-?i9°c.

C. ^v- (p'-r id -2-y ] ) -2- [ 4- ( 2-methv 1 i mi dazo [ 4,5-c] py r i d - 1 -v 1) herzvoxvbenzami de

2- [ 4- ( 2-f'.eth'⁷lini d.azo [ 4,5-c ] pvrid -1 - vl) benzv lox^v 1 bs’'zrir acid 11.44 a) was stirred in drv dichlorome^hme (50 ml) and three drops of dimethvlformamide v.-e-e added. Oxalvl. chloride (1 .02 c) was added drcrw’se over 5 minutes and the resulting solution stirred at room temperature for 2 hours then evaporated tr fr'”'.ess. The residue was redissolved in drv dichlcrcmethane (20 ml) and cooled in an. .ice bath. 2-Aminopvricine (1.13 a) was dissolved in dichloromcthane (20 ml) and cooled in an .ice bath. The cold solution of the acid chloride was then added to the ?-aminepyridine solution over 3 minutes and the reaction mixture stirred for 30 minutes then poured into ethvl acetate (300 ml). The organic solution was washed with water (2 x 100 ml), dried over sodium sulfate, filtered, and evaporated to drvness. The residue was purified bv column chromatography silica (Merc);, Fieselael 60) elutinc with dichloromethane/ methanol (O'⁷:? v?v). The product containing fractions were carcrated and the residue washed with ether to yield the title amide a. white solid, 760 mg, m.p.

1 0 - 2 1 3 ⁰ C .

Anal. Calcd. for C ^0., . $H_n0 :

C, 70.3; H, 5.0; N, 15.8

Found : C , ⁿ 0.2 ; H , 4.8; N , 1 5.7 .

BAD ORIGINAL ft

AP 0 0 0 2 2 4

-Γ

EXAMPLE 20

Γ:·ν*;ίηπ v^;th the apt ro pr 5 a te reaoents and urine *rhe prnr··dvre r^£ Frannie 2, the fellovine normeuncs '•ere rr ere. red:

-CH=CH(trans)

-CH_?O- 3-F 193-194

NMR (300 MHz c.eIta .

Anal. Calcd.

pr’j r d ;

CDC1₃):

for C F C , 6? .

C, 68 .

2.50 Ip,

3H) and 5.18

N OFF : 20 4 2

2; F, '.Ο Η, 3.2

-CH^ON,

N,

11.0.

10.9.

3-E 119-121

BAD ORIGINAL 4 yvp (am MHz, CPCl·,) : 2.48 (s, 3H) , 5.1¹ (s,.2H) .35 (-, (O') delta.

Anal. C;

Fr>ur.c :

-CH„O- Η 147-149 ¹ ·) delta.

Anal. Calcd. t_r,_r C._nF,,N,OSF:

0 .- j 4

Found :

C , 7 1.1; H , 4.6; N, 11.1. C , 71.1; F , 4.4; Μ , 11.0.

MMP (300 MHz, Cr»Cl₃) 7.49 (s, 3H) and 5.44 (s, 2H) de-1 + a.

Anal. Calcd. for C H M,5C F:

2 n 4 3

F^und :

C, 6 7.'’; H, 3.2; M, 9.9.

C , 6^.4,- H , 4.6; Μ , 1 0 . 1 .

-CH.O- H 200 (dec) bad original £

AP 0 0 0 2 2 4

-6 9•·τ (300 MHz, CPC1,) 2.58 (r, ?H) and 6.24 (s, ?K>

’alcd. ^for C.k SOC1:

~ o u p. ~ :

(trap s)

H

153-155

EXE (300 MHz, CPC1,) .'’.SI (s, 3H) and ^c.18 (s, ?H) delta.

Anal. Calcd. for C H_?f)N SOC1,:

Found :

C, 64.1; H, 3.7; N, 10.3 C, 64.3; H, 3.8; N, 8.5.

-CH=CH(trans) I j

-CFTO154-156

NMP (300 MHz, CDCl,) 7.50 (s, 3H), 3.8ⁿ (s, 3H) arc 5.1^ (s, 2H) delta.

Anal. Calod. for C H^SO,,:

Found :

C, 7 1.4; Η , 4.8; M, 11 . 1 . C , 7 1.9; η , 4.9; Ν, 11.0 .

BAD ORIGINAL

I

-CH=CH(trarr)

-CH^OK 221-22? (HCl )

Anal . Ca.¹ cd

Found :

PREPARATION A

1- ¹ ρ-Hvdroxvphenv1)-2-methvl-lH-imidazo[ 4,5-clpyridine

I . 3-r.itro-4-(p-hydroxvphenylamino)pyridine ^mo a stirred mixture of 50.2 g of p-hydroxvaniline and 38.⁷ g of sodium bicarbonate in 1.5 1 of ethanol was added, dropwise 73 g of 3-nitro-4-chloropvridine in .0 1 o^x ethanol. After stirring overniaht at room temperature, the resulting solids were filtered, washed, with water (2 1) and dried, 85.4 g.

. 3-amino-4-(p-hydroxvphenvlamino)pvridine

A mixture of 4 2.^-7 g o^£ the comDound of Preparation

I^I ad 6 a c^f Panev nickel in 300 ml o^c ethanol was shaker. i.r a h'-drogen atnorrhere at ar initial pressure c* 50 psi at room temperature overniaht. The re.ta’vst war filtered and washed v.o th acetic acid until the wash was clear. The filtrate and washings were combined and concentrated in ^vacuo to aive the product as a dark

BAD ORIGINAL

AP 0 00 2 2 4 ¹ - (p-aco to::vohen'· 1) - - neth'·¹ -1H - imidan.o f 4 , 5-cl cyr i ii ne

Λ stirred mixture of ^4.3 c of the compound of Prerar;:-ion A? in 1.3 1 cf acetic anhydride w?.c heated at reflux overnight. ’’’he solvent was removed in. vacuo r.rd the resulting oil dissolved in 1 1 of water and the pH ad-ius^.ed to 7 with 7N hvdrochloric acid. The acid solution was extracted with methvlene chloride (3 x 71 ^r' ml) and the pH of the aqueous adjusted to 5 with a N sodium hvdroy'de solution. The basic nhase was extracted with ethyl acetate (3 x 500 ml). The acueous ¹ aer was saved and the orcanic extracts were combined, dried and concentrated to give 31.8 σ of a brown solid. The solids were chromatographed on 1.5 kg of silica dioxide using methylene chloride and methvlene chloride - ethanol 2, 4 and 6%. The fractions containing the desired material were combined and concentrated in vacuo to give 15.7 g of the titled product as an oil.

The acueous laver was treated with 4N hvdrochloric acid to give a pH of . It was extracted with ethvl acetate, and the extracts combined and concentrated to cive 4 1.3 a o^£ l-(o-hvdroxvphenvl)-2-me*-hvl-lHimid.f ?o [ 4,5-c] pvridine as a tan solid.

. 1- (p-hvdroxwnhenvi) -7-methvl-lfI- imi da co [4,5-clpypi d ino

To a stirred mixture of 15.7 g of the oil isolated in Preparation A3 in 750 ml of methanol was added 4.7 σ of solid sodium, hvdroxide and 47 ml of water. After stirrine tvzo hours at room temperature the reaction mixture is added to 600 ml o* a saturated sodium chloride solution, the pH adjusted to 7 with 7N

BAD ORIGINAL

u λ'f* 1 yerh 1 <v i	C' ιΓ P cl	the product extracted w’>h eth”l
acetate <'	·, p n 0 ml).	Tie extracts were combined,
i'id eve-	s-ed ium. sul^	ate and correct rated in vacuo to
η v - p 10.3 c	cf product	as a brown solid. A small
r,-. r. r i e w a ?	reervsta11i	nod from methano1-methvlene
c h 1 c r i d e , m	. p . ?c5-26’CC. PREPARATION B
1- (p-P··	d r ox'/me the 1 f ·	phen”l 1-2-methvl-lH-imi danc, 5-cl c'-ridine

3-nitrc-4- (ρ-h''d rex vme t hi'lphenv lamino) nvr id ine ^Tn a manner similar to Preparation A1 88.5 g of

3-n i t '-o-d-ch loropyridi ne , 68.^-7 g of 4-aminebenz'd alcohol arc 46.9 g of sodium bicarbonate in 500 ml of ethanol to give 56.3 σ o^r the titled intermediate.

?. 3-am.ino-4-(p-hydroxvmethvlphenvlamj no)pyridine

Using the reduction procedure of Preparation A?, 9.0 q of the product from Preparation BI, 1.8 g of Rar.ev Nickel in 6?.5 ml of ethanol and 18^.5 ml of tetrahydrofuran gave the titled product which was used withcu⁴: hirther purification.

. ¹ - Ip-acotoxvmethvlphenvl)-2-methyl-lH-imidazo[4,5-clpyridine

Emplovinq the procedure cf Preparation A3, 39.5 σ cf cri;c-- product obtained bv the procedure of Preparation B? in 4~? ml o^f acetic anhydride was heated tc reflux f’erriqht. Vork-υρ gave 18.8 σ of product, m.p.

3 5 -1 3 ~ ° C .

BAD ORIGINAL ft

AP 0 0 0 2 2 4 . ’ - I p-h’·(: rox’Tnet h v 1 phenv1) - ? -nethv 1 -1 If - in ida po' j ' 5-c ^{* 1 * * * * *} n’·ri dine m in. Preparation .44, IE.A a o^r the product of Preparation p? in 53.4 m.l of water and ?]5 ml c>f t-fR anol containing 5.34 π o* sodium, hvdroxide was stirred at room temperature until all solids dissolved. Torh-up· cave 13.9 c cf the titled product, m.n. ypa-is-o_C.

PREPARATION C

- 4-^rorm'~l pherr'l) -2-meth 1 -¹ H-ί mi daze ( 4,5 - c 1 per id j ne

To 20 ml of methvlene chloride containinc 890 pi o^r dimethyl?ul^coxide cooled to -60°C and maintained under a nitrogen atmosphere was added dropwise ⁷66 yl of cxa.lvl chloride over a 5 minute period while maintaining +-he temperature at -60°C. After stirring for minutes at -60°C, 1.50 g of the product of Preparation. P in 20 m.l of drv methvlene chloride was added dropvi?e over a 20 minute period. The reaction mixture was stirred at -60°C for 30 minutes and then at -35°C for 15 minutes. The reaction was again cooled to -60°C and treated with 4.37 u1 of triethvlamine dropwise over a ^r minute period. The reaction mixture was then diluted with 75 ml of methvlene chloride and washed with a saturated sodium bicarbonate solution (3 x 'TP ml) and a brine solution (1 x 100) , and dried over sodium, sulfate. The solvent was removed in vacuo and ^he 1 .4° c residual chromatographed on 150 g of silica usinc methanol-methvlene (5:95 - v_:v). The fractions containinc the product were combined and concentrated to dr vn ess, 1.29 g.

BAD ORIGINAL ft

PPFPAP.ATI ΟΝ Γ>

m- ( 5 -F luorobeη.~eth iaζο¹ - 7 - '· lmethox ' a n i 1 i ne . 1 - ( 5 - ~ 1 uo r obc r ~ o t h i a z o 1 - -v Imetbnv' ·) -3-nitrnbPⁿ:ene

A mixture of 5.0 π of ?-chlorometh'· 1-5-^luoroben.zoth.i azole , 3.37 σ of m-nitropheno1, 7.58 g o^r pod'cir carbonate, 7.97 c of cesium carbonate and 7 .4 4 _c o^£ sodium iodide in 150 ml cd acetone was heated to reflux overnight. 'he solids were filtered and washed ν’⁴·!, acetone, and the filtrate and washincs were combined and concenrated to cr-np«5. The residue' was taken up in eth”·! acetate (150 ml) which was washed v-' th. 1Π sodium hydroxide solution, water and a brine solution. The organic phase was dried cmer sodium sulfate and concentrated to qjve 7.48 g of a tan solid which was chromatographed or. 500 g of silica using 4 1 of methvlene chloride - hexane <7:1 - v;v), 2 1 (9:1 v:v) and 4 1 of methylene chloride alone. The fractions containing the product were combined and concentrated to give 6.33 g of the titled product.

The NAP (300 MHz, CDCl^) showed absorption at 5.54 ( 7 Η1 delta.

In a similar manner, starting with 7-chloromefhvl-5-tri f luorom.ethvlbenzothi azole and 3-hn'drox bpn’v! alcohol and following this procedure, 3 - (5tri ~ lurcometh] benzothiazol-7-'^,lmethox)benzol alcohol was prepared, m.p. ll⁷-iin°c, ?-chlorom.ethy 1-5-fluorobenzothiazole and 7, '’-dihvdrcxynaphthaler.e gave 2-(5*1 u.c roben70thiazol-7-vlmethoyy) -⁷-hvdroxyraphtha 1ene , m.p. 718-72P°C, 7-chlorometh'H-6-f 1 uorocuinoline and m-re sc rci no 1 gave 3 - (6- f luomcu ino 1-7-)J me thoxy τ phenol ,

m.n. 14 6-14 8^C C end 7-chloromethvl-5-f1uorobenzothiazol

BAD ORIGINAL &

AP 0 0 0 2 2 4 reth-1 3-h''d rox”mande 1 ate nave methyl 3-(5-fluorobe- y, ή -,_{: c}< - ? -v Inethov”) mardo 1 a te , m.o. 99-191°C.

. · ^r~ ^ς 1 norobenzot hi a so 1 - .’-vi methoxy) ar. i line

Tc GO ml o~ drv pthanol saturated with hvdrogen chic-ride arc under a nitrogen atmosphere at O’C was added f.31 c of the product of Preparation DI. To the resulting reaction mixture was added 4.6^Ί σ pt iron rm-’d^r ir portions and the reaction stirred at room ^.emre mature under nitrogen over a period of two davs < r ^r- hours ) .

The reaction was diluted with water (1 1) and the rv nd-usted to P with 3N sodium hvdroxi.de. The aoueous was extracted with et.hvl acetate ¢3 x 500 ml), which was washed with wafer and a brine solution. The organic phase was dried over sodium sulfate and concentrated to give 5.83 g of material. The residue was chromatographed on 400 g of silica using 15% ethvl acetate - methylene chloride. The fractions containing the product were combined and concentrated to give

3.45 g of product.

The nmr (CDC1_?, 300 MHz) showed absorption at 5.49 f”) arc 3.70 (b, ?H) delta.

BAD ORIGINAL n - I ~ - 5 'r c r c b e n no t h i a η o1-2- * · 1-1 r a n se⁴- nenvl) an: ¹ ine . ’ - ι'5 - f luor¹ nnothi ano 1-2-v1-1rans-ethen1) -3n : t r e 1> e η 7 e n e

To a suspension o⁴⁷ . 6 π of f-f luorobenzothiazol2-v.Imethvl tripher.'-l phosnhonium chloride in 100 ml of dr'- tenrahvdrofrran under a nitrogen atmosphere and codec to -45°C wa.s added 1.3 ml of a 1.6y solution of r^-bu⁴-’·! lithium and the mixture stirred at -45°C for 1C minutes and at 0^cC for 10-15 minutes. The mixture was then cccd-d to -45^CC and 2.5 a of m-n i trober.n.a Idehvde in 25 ml of drv tetrahvdrofurar was added over a Deriod of :O minutes. The reaction mixture was allowed to stir an -45°C for one hour and was then allowed to warm tc 0^cC.

The reaction mixture was concentrated in vacuo and the residue partitioned between water (500 ml) and e⁴-'·!'/! acetate (2 x 500 ml) . The organic phase was washed with water and a brine solution and dried over sodium sulfate. Removal of the solvent nave 3.0 g of crude product which was purified by recrvstallization ^frcr eth”l acetate - hexane, 2.1 g, m.p. 180-182°C.

’n a similar manner was orenared 4-(5-fluorobenzo’S-ethpr'^l-n-butano¹. (NYR - 300 YHz , . n c:

c s m b. c η ι, ι n <m., 4H) , 2.5 (m, 2 0) and 3.65 (m, 2H) by phen'.’l 5 - f luoroben not h ia no1-2-v Ime thvl chloride and ?-hvdro\vtetrahdropvran , ’-he-droymethv 1-5- (5-fluerobennothianol-2-l-transe t h q n 1.) · ii ran m.o. 13⁷-140°C, b reacting triphenvl

5-f 1 v.orcbennothia zol-2-vlmethvl phosphonium chloride and 5-hdrnxvnetbl furfural and methyl 2-met.hoxv

BAD ORIGINAL ft

AP 0 0 0 2 2 4 ” — ¹ ~ - f 1 uⁿ r ?hv n. n o e h i a z o 1 — 2 — 'Ί — t r a n s — e t h. e n.·· 1 ) benzoate , r . n . ’ ^p -1 4 0 ⁰ C , bv reacting tricher,'· 1 S-'lnoroben’o‘•hx'rrl-l-r'etb’·’ phosphor ium chloride and methvl ? - no the.'·>· - 5 - fornv1benzoate .

m- ( 5 - f luorobe n?othiazol-2-\'l-tr an. ~- ether'·¹. ) aniline

Following the procedure of Preparation o' '•bp rrrdimt of Preparation El, 1.3? σ of

E? , 1.^8 g iron powder chloride and 5 C c?’-e 1 ml of ethanol saturated with hydrogen. 2~ g o^c. the titled nrod.uct.

PREPARATION F

3- (Quinol-2-ylmethoxy) ben.zvl alcohol A mixture o⁴⁷ 1.0 g of '’-chloromethylouinoline , ~00 ma of 3-h'’d.roxvbenzy 1 alcohol and 2.33 g of potassium carbonate in 20 ml of drv dimethylformamide was stirred at room temperature overnight. The mixture was poured into 600 ml of water and extracted with ethvl acetate (3 x 200 ml). The extracts were combined, washed with water, IN sodium hvdroxide solution and brine, dried over sodium sulfate and concentrated in vacuo, 1.3R g. The residual oil was chromatographed on 100 g of silica using 000 ml of 2% methanol-methvlene chloride fw) and 1 1 of 4% rx-thanol - methn-’lene chloride (v:v) . The fractions mr.tair.ir.Q the titled product were combined and concentrated to give 1.02 g of product.

In a similar manner 4-(5-fluorobenzothiazol·-?”lmef.hX'X·· 1-4 ’-h'’drox''diphenyl, m . n. ^p 1 0-2 11 ° C was nrepared ^frnm 2-ch.loromethvI-5-fluorobenzothiazole and

4,4-d ih.vd roxdiphenv1, 3-15-flnorobenzothiazol-2yImethvlthio)benzvl alcohol was prepared from 2-mercantobenz v1 alcohol and

ORIGINAL &

''-chd orometh'· 1-5-'^e’luoroher.zo⁺'hi azole arc '’-ethox'·- z^v'¹ όv 2 - - ( ' - ' ] uorob^n-rthi a z o 1 - 2 -' · 1 z'c t s c;··) chromar., m . r , ϊ p ° -11 ~ ' C was prepared f rom 2-chlc**omethvl-5j fluorobenzothiazo 1 e and. 2-Ptbo::''carbon·· 1 -~-hvdr^x”ch roman.

PREPARATION G

4-h'vcrcvy-6- (5-f luorobenzothi azol-2-vlmethoxv) chroiran 1 . 6-hydro?·'.· chroman-4-one

IQ A mixture of 36 g cf f-rpthox'>chroir,an-4-ore and

2^ftP m2 o^r 42’ hydrogen bromide solution in 2 90 ml of glacial acetic acid was heated to reflux for 3 hours. The solver! was renewed in vacuo and the residue diluted wbh 2 1 of water and stored in a refriaerator overnight. The resulting solid was filtered, washed wizh water and dried, 25.7 g. The original filtrate was extracted with ethvl acetate and the organic laver dried over sodium sulfate and concentrated to give an additional 4.75 g of the titled product.

2. 6-(5-flucrobenzothiazol-?-ylmethoxv)chroman-4-one

Starting with 2.7 g of E-chloromethvl-5-fluorobenzothiazfw , 2.0 g of the product of Preparation Cl and 5.P c of potassium carbonate in. Ph ml of drv dim^th”!formamide and following the procedure of

Pr°raration , cave 1.17 c o^r the desired product.

BAD ORIGINAL fl

AP 0 0 0 2 2 4 ί‘-fluorober.zcthiazf'] Imethrx'’) irtvre o^c 1.8 8 σ o~ the ornet of Prepare⁴ for !'? ir. “5 ml of mefhasol end 75 ml of fetrahvdro’urar coe-ed to h-5°C under nitroaen was added 216 me of sod’vm borohydride in two nortions. The cooling was removed and the reaction mixture stirred at ♦errercture 'or 25 minutes. An additional ^5 ml ov tefrah'’drofuran was added and the mixture heated to .- C' C for if minutes. Additional bcrohvdr.ide (216 mg) was added and the reaction continued ^ror 10 minutes. Acetone (5 ml) was added and the solvents removed in y.acy o. The residue was partitioned between water and ethl acetate. ^mhe organic laver was separated, washed with wafer and a brine solution and dried over sodium sulfate. Removal of the solvent gave 1.64 g of the product, which was recrvstallized from diisopropvl ether - methylene 849 mg, m.p. 13’-138°C.

bad ORIGINAL

ΡΠΕ PA PAT ΏΝ h — ¹ - - Ε ¹ u ο γο’·ι·.·> η. ζ ο t h i a ζ ο 1 — “ — 1 -1 r a η s — e t he η ' 1 ' — henry] alcohol . moth··! ?-I S-'luorcbenzothianol-l-vl-trans___ethen'-l) benzoate_

Esino the procedure of Preparation El ano startinc with 5 . ή 5 o cf 5-^jrluorobenzothiazol-2-”lmethv] triphor’·] phosphonium chloride (prepared b reacting 4.0 c o- 2-ch1 cronethl-5-fhmrober.nothiazole and . 2 c cf triphenvlphcsDhine in 50 ml o^r toluene at re'lux temperature for 17 hours) , .61 ml c>^{c 1} . 6M £-bvt”l ’bhium solution in. hexane and 2.0 g of methvl l-'orirvl ben mate in SO ml of dr tetrahvdrofurar. there was obtained 2.92 g of the titled product, m.p. i 72-l⁷3^cC.

Tn a similar manner triphenvl 5-chlorobenzothi azcl-2-ylmethy 1' phosphonium chloride was reacted with methyl 3-f orm.vlbenzoate to give methvl 3-(5ch loroben.zcth i a zo1-2-vl-trans-ethenvl) benzoa te , m.p. 16P-169°C, triphenvl 5-fluorobenzothiazol-2-vlmethvl nhcsphcniun chloride was reacted with ethvl ?.-^xorn^vlc''cloheyvlcarbo;:vlate to give ethvl 3-(5luorobenzc^l'lazol-2-yl-tranr-ethen^1) cyclohexΙο ^r rbc--yl ate , m.p. 6 7-^0 °C, triphenvl 5-f ] uorobt-nzo^f'hiazcl-.'-lrethvl phosphonium chloride was reacted with meth'·! 2-formvlbenzoate to aive methvl 2-(5~ 1 ucrobe r z ^r~t h i a z o 1 - 2 - v 1 -t rans-ethenn’l ) benzoate , m.p. 1:9-¹ PC’C and. friphenvlbenzofur-r-vlmethvlphosphonium bromide was reacted with methvl 3-forry’l benzoa-t-e to give meth.'·] 3 - (benze f ur-2-1-t. ran s-etherr-l ) benzoa t e , m.p. °Γ-1Ρ0Ε.

BAD ORIGINAL ft

AP 0 0 0 2 2 4

-ς i 3 . 3 - ( 5- ^ri.uornbpr.:othi azo 1-3-”1 -trap s-ethenvl ) bepp-.-l alcohol

To a stirred solution of 300 mo of the product oPrerr*·?+· ion Hl in 15 ml of dr” tctrahvdrofuran at -T°C W3? add->d dropwise 1.3 tl of a 1 . OK solution o^r d^{4 5 *}'sobvtvlaluminum hvdride in totrahvdrofuran and the resultinn reaction mixture allowed to stir at -ng°c f_nr hour

The reaction was slowl” allowed to warm to ^{r; c} c vmr a tvr hour period and was quenched with 3 m?. o^r r-h’/l acetate. The reaction was added to 100 ml o*

5^C acueous sulfuric acid and extracted with e-t-hvl ace*a.te (2 x 100 ml) . The combined extracts were washed with water < ?. x 20 ml) and a brine solution (2 x 20 mi), dried over magnesium sulfate and ocnoentrated to give 200 m.q o^f product. Chromatography on silica cel using 2% ethyl acetate - 98% methvlene chloride (v:v) gave 157 mg of pure product, m.p. 129-13O°C.

An alternate procedure for preparing this benzol alcohol comprises condensing isophthalaldehyde with 2-nethyl-5-fluorobenzothiazole in the presence of acetic anhvdride and zinc chloride in hot xylene followed bv the reduction of the 3-( 5-f luorober.zoA i a ?o⁷-2-vl-trans-ethenvl) benzaldehyde product with, .-opium borohydride to provide the appropriate benz’d U1 g* ° h r* 1

Ip a similar manner ethvl 3-(5-fluorobcrznthiazrl2- 1-trans-et hen” 1) cvo F.ohexv lea rbox” la te was reduced to 1 -h.vdrox.vmethv 1-3 - ( 5 - f luorobenz.othiazo 1 - 2-vl-transeth.envl) cvr 2 ohexane , m.p. 95-9^-7 °C .

BAD ORIGINAL

Τη a similar manner were oreDaren 3-f5-^rInorobenzo‘.-h ia zo 2 - 2-’· 1-t ran s-e⁴ hencl) bep pj~ 1 a Ircbol, m.p. 2 16~ ~ ^c P , i - h ’-d rcyymetbs v-⁷- (5-f 2 uorobenzoth ia zo 1 - 2 -v 1 -*- ho?-’·) chroman, m.p. 152-154^:C, 4- ( 5-f luorohen.zo⁴hin7n1 - ⁿ-yl-trans--e<-hen^vl) her.;” 1 alcohol, m. r>. 7^6 —

6 ^c C , ?-?benzofur-2-yl-trnns-etheny1) benzyl alcohol ,

m.p. 104-10 6 ^rC, 3-(5-chloroberzothiazoI-⁰-’,'l-transcthcn’· 1) benzyl alcohol and 2-methoxy-5 (5-flucrobeη z o ⁴h 1 a-o * — 2-y 1 — t ran, s — e t. hen) nl 1 ber.zvl alcohol , m.p.

2 ~ -18 9 ^c C .

PP.FPAPATTOM I

3-(puino1-2-yl-trans-eth”l)benzyl alcohol ' · ?- (cninol-2-yl-trans,-ether.v?_) benzaldehyde

A solution of 10.0 ml of 2-methvlcuino]jne 20.9 ml of acetic anhydride and 9.91 g of isophthalaldehvde in 200 ml of xylene was heated to reflux under nitrogen for 7 hours. The cooled, reaction was diluted with 1 1 of ethvl acetate and the resulting solution was washed, with, a 10% sodium bicarbonate solution (3 x 250 ml) and a brine solution, and dried over sodium sulfate. The orcanic laver was concentrated in vacuo to cive 21. g o⁴ a vellow solid. The residue was chromatoaraphed on 1 kg of silica usin.c P 1 of methvlene chloride, 4 1 of 32 e^4b”l acetate - methvlene chloride (v;v) and 8 1 of ^qc. ethvl acetate - methvlene chloride (v_;v) . The fractions containinc the product were combined and (-cnees, trated to give 8.2^-1 g of the titled product .

n a similar manner isophthalaldehvde was reacted with 2-methvl-’-chloroguinoline to give 3- (7-chlorocuinol-O-ylethenyl) benzaldehyde , m.p. 24p-l5Q°c , with 1 , .’-dimethvlbenzimicazole to cive 3- (1-methylbenzimidazol -2-ylethen.yllbenzalcleh.vde , m.p. ¹18-120°C. ,

BAD ORIGINAL

ΑΡ ο 0 ο 2 2 4 with 2-m^r t h’ · 1 - 5-ch 1 c roben coxa ?c-1 e to 3-(5-chloro¹r.z r-x it z o 7 - 7-<·· 1 c + hen.'· 1) benz a Ideh’-’de , m.p. 140-14?°C, ’•.fh •'.petby]-4,6-dichlorobennothiazole to qi«p 3 - ( ‘ , 6-diet 1 orobenzoth i a zo 1 - ?-v] ethen”! ) ben.zaldehvde , m.p. 7 Π-313 ⁰ C.

7-(2-quincl-2-vl-tre.ns-ethenvl) benzol alcohol

Ftartina with 560 mo o^c the product of Preparation ’) and P? mo cf sodium borohvdride in 30 ml of methanol and 10 ml o^x tetrahydrofuran and using the procedure of Preoarattor G3 cave 461 mg of the titled product as a ’··; H * c solid

Tn a similar manner were prepared 3-(5-chlorobornoxazol - 2-v¹ethenvl)benzvl alcohol, m.p. 114-116° c ,

3-(1-methyIbenzimidazol-2-viethenyl)benzvl alcohol,

m.p. 17 2 -17 4 ⁰ C, 3- (7-ch.loroqui.no 1-2-yle thenyl) benzvl alcohol, m.p. 138-140°C and 3-(4,6-dichlorobenzothiazol-2-y]ethenvl)benzvl alcohol, m.p. 177-179°C.

2. 3-(2-oui no1-2-ylethy3) benzol alcohol

A mixture cf 315 mg of the product of Preparation 12 and 100 mo of 10% pa 1ladium-on-charcoal in 25 ml of methanol was shaken in a hydrogen atmosphere at a pressure of 20 psi at room temperature for 80 minutes. ^r'he catal'Tt was filtered and the filtrate concentrated no give 340 me of a vellow oil. The residue was chromatocraphed cn 30 g of silica using 25% eth”d acetate - methvlene chloride (v:v). The fractions containinn ⁺be product were combined and concentrated to rive 314 pg cf a vellow oil which cr-stallized.

Tn a similar manner 3-(7-ch!oroquinol-?-v]ethenvl.) benzyl alcohol was reduced to 3- (7-chloroouinol-l-ylethvl) benzyl alcohol, m.p. 115-116°C,

BAD ORIGINAL

-TIPPER A RAT T ΟN J

- ' ~-Ch1c ropeino 1-2-v1-1ran s-ether.v 1) benz vl a 1 coho 3

3- I -ch 1 oroovi nc-1 - 9- y 1-t rans-ethere·¹ * benzaldehyde

St .a-*· ina with 6.56 c of ?-methvl-7-chlornouirolirc, 19.4 ml o^r acetic anhydride and 4.95 q of ir?rhthala Idehvde in 10C ml of xvlene and using the procedure of Preparation i;_f there was obtained 5.64 σ p-‘ -he desired product as 71 yellow solid.

3. 3 - ( ~-ohlorocuinol-° - y¹ - trans-ethen” 1) benz'-l alcohol . rim: the procedure nf Preparation T2 and starting w;-h 5.6 cr ο the product ol⁷ Preparation J1 and 720 ma cf sodium borchvdride in 300 ml of methanol and 100 ml o- tetrahydrofuran there was obtained 3.9? g of the titled product, m.p. 138-14O’C.

PREPARATION K

2-(5-Fluorobenzothiazol-2-vl-trans-ethenvl) 6-hydroyvmet.hvlpyridine

2-hyd ro:y/methvl-pyrid i ne-6-carbox aldehyde To a cooled (O’C) solution of 2.0 g of 2,6pyridinedicarboxaldehvde in 50 ml of methanol was added fO mg cf sodium borohydride and the mixture stirred fcr 10 minutes. The mixture was allowed to warm to mor temperature and v?a? allowed to stir for 15 venufes. A few drops of acetone were added and the m<‘ -hanol removed in vacuo. The residue was dissolved ?n ^00 ml of methvlene chloride and the organic solution washed with water (1 x 250 ml) and a brine solution U x 250 ml) and dried over sodium sulfate.

The solvent was, removed in vacuo and the residue chromatographed on silica gel to give 324 mg of the desired product as a yellow oil.

BAD ORIGINAL ft

AP000224

- ( 5 - f luoro ben. zot h i a z c 2 - 2 -v 1 ran s -e t hen v 1) ( — h c r o?x to f h' 1 P'-’r i di no .A suspension of 1.25 c cf 5-fiuorobenzothiazol2-dneth’ friphenvlphosphcnium chloride in 8 ml of drv refrahvdrofuran cooled to -40°7 and under a nitrogen .atmosphere va? added 1.82 ml of a 1.6M solution of r-but.vi lithium in hexane dropwise. After stirring for ¹8 minutes the temperature was raised to 0°C for 18-15 minutes. The mixture was then cooled to -40°C acain and 2CG me of the product of Preparation F] ’.-.'as added in. 19 ml of dr tetrahydrofuran. The reaction was stirred for one hour and then allowed tc warm to room temperature overnicht. The reaction mixture was concentrated, in vacuo and the residue partitioned between 3CQ ml of water and ethvl acetate (2 x 300 ml). The organic extracts were combined, washed with water and a brine solution and dried over sodium sulfate.

The solvent was removed in vacuo and the residue chromatographed on silica gel using 2.5% methanol - 97.5% methylene chloride (v:v). The fractions containing the product were combined and d under vacuum, 290 mg, m.p. 1’9-181°C.

’PREPARATION L

3-(6-flucrobennothiazol-f-'Ί methoxv)benzvl alcohol A mixture of 215.5 mg of 3-hvdroxybenzy1 alcohol,

350 m.c cf 2-chloromethvl-6-f 1 ucrobenzothiazole and 598 mg of potassium carbonate in 8 ml cf dimeth]formamide was stirred overnicht under a nitrccen afriosphere at room temperature. The reaction mixture was poured into water anc extracted with ethvl acetate.

BAD ORIGINAL

nraanlc chase va? secarat f

with a IN

Ivent nave 440 ma of a solid which was chromatoara^,~hed fried ever sodium. o: if

reth'dprf· chloride (v_:v) to cive 33 mg of product, r:. o . 9 Q - 1 C 0 ⁰ C .

Γ· a similar procedure 3 - ( 5,6 -d 1²⁷1 uorobenzo*•1? - zc1-2-v lme th.v loxy) her.7 v 1 alcohol, m.n. 98-100°C,

- '^r - 2 luorober.r f h 1 a zol - 3 -y ime thoxv ¹ her,?··! a¹ oohcl, m.n. 13°-140^cC, 3 - ( - ch 1 crocu: inol - 2-y lme thy lox” ) benzvl a 1 coho 1, m.p. 128-129^, and 3- ( 2-pyrldy lmetho::”) bencl alcohol, NMR (300 MHz, CDCl₃) 5.10 (s, 2H) were

PREPARATION M alpha-methyl 3-(6-fluoroauinol-2-ylmethoxv)benzvl alcohol . 3- (6-fluoroauinol-2-ylmethoxy) acetophenone

Using the procedure of Preparation L, 3.65 g of

3-hvdroyyacetophenone, 5.0 g of 2-chloromethv1-6fluorocuinoline and 8.6 a of potassium carbonate in 100 ml of dimethvl^ermamide cave, after chromaf^craphirn on 500 a o^2- silica gel, 2. 6 σ of *Ίρ titled. · '’!* d u c t, m.n. 9 - 8 0 ° C .

alpha metb.vl 3-( 6-f luoroou i nol-2lmethoyv) bernd alcohol

To a solution o²” ~⁷ 0 ma c,f the compound of

Preparation Ml in 35 ml of methane¹ and, 20 ml of Tetrahvdrofuran was added 99 ma ο²” sodium borohvdride once. After stirrina at room temperature the reaction mixture was con and. the residue

BAD ORIGINAL

-δ⁷partit i or.ed between water and ethvl acetate. The organic phase was separated, washed with water and a brine solution and dried over sodium sulfate. Concentration cave 800 mg of product which was purified bv chromatographing on 85 of silica gel using from 15% efb'd acetate - 85¾ methvlene chloride (v:v) to 20% 80¾ of the same solvents, 768 mg, m.p. 60-62^oC.

In a similar manner was prepared alpha methyl 3-(5-flunrobentothiazol-2-ylmethoxv)benzyl alcohol,

m.n. 5-9 0 ⁰ C.

PREPARATION N

3-(5-f1uorobenzothiazol-2-ylmethoxy)phenvlisopropanol

To a solution of 920 mg of 3-(5-fluorobenzothiazol-Z-yimethoxy) acetophenone, m.p. 124-125°C, prepared by the procedure of Preparation Ml, in 25 ml of dry tetrah’/drofuran cooled to 0°C was added 3.05 ml of a 1..5M solution of methyl magnesium bromide in toluene - tetrahydrofuran over a period of 5 minutes. After stirring the reaction for 30 minutes the reaction mixture was poured into water (500 ml), the pH adjusted to 5 and the product extracted with ethyl acetate. The orcaric phase was washed with water and a brine solution and dried over sodium sulfate. Removal of the · solvent cave 1.0 g of product which was ourified bv chromatoaranhirg on silica cel to give 438 mg of a ”eliow oil.

BAD ORIGINAL ft

-88PFFPARATION Ο

4-Pdroxv-6- p-chloronnincl-r-vlmethoxv) chroman ¹. 6-(-chloroouinol-P-vlmethoxv)chroman-4-one

Starting with 1.04 σ of 2-chloromethyl-7-chlorocuinoline, 808 mg of the product of Preparation G1 and

l.~ g of potassium carbonate in 20 ml of dimethvlformamide and using the procedure of Preparation F gave 1.2° c of the titled product, m.p. 163-164^eC.

jq 2 . 4-hvdroxy-6-(7-chloroguinol-2-vlmethoxy)chroman

Usinc the procedure of Preparation G3 and starting with 1.01 g of the product of Preparation 01 and 125 me of sodium borohvdride in 40 ml of methanol and 40 ml of tetrahydrofuran cave 1.0 g of product, m.p. 139-140^0.

In a similar manner was prepared 4-hvdroxv-6-(6fluorocuinol-2-ylmethoxv)chroman, m.p. 141-142°C,

1- hydroxy-7-(5-fluorobenzothiazol-2-ylmethoxy)naphthalene, m.p. 120-122°C and 4-hydroxy-6-(2-quinol2- yImethoxy)chroman, m.p. 135-137°C.

' PREPARATION P

3-5-FIucrobenzothiazol-2-vlmethoxy)benzvl bromide

To a solution of 1.04 g cf 3-(5-fluorobenzothiasol-2-ylmethoxy)benzyl alcohol (Preparation L) in f0 ml of drv tetrahydrofuran was added 2.38 g of carbontetrabromide and 1.89 g of triphenylphosphine and the reaction stirred under nitrogen at room temperature ^ror 1.5 hours. he reaction mixture was filtered, treated with 100 ml of water and extracted with ethyl acetate. The extracts were washed with water and a brine solution and dried over sodium sulfate. The solvent was removed and the residual brown solid chromatographed on 200 g of silica gel using from -5-10% r·

BAD ORIGINAL

AP 0 00 2 2 4

-89eth”l acetate - 95-90% hexane (v:v). The fractions containinc + he product were combined and concentrated to rive 91C me of the titled product, m.p. 99-100^cC.

Tn a similar manner, 3-(5-fluorobenzothiazol-2vlmeth''!thio) benzyl alcohol was converted to 3-(5fluorobenzothiazol-2-vlmethvlthio)benzvl bromide , m.p. 163-165°C.

PREPARATION Q (+) cis-3-(3-Methoxvcarbonvlbenzvl)-4-hvdroxv-6(5-fluorobenzothiazol-2-vlroethoxv)chroman

To a cold (0^rC) solution of 500 mg of (+)-ois-3( 3-carboxvbenzvl)-4-hvdroxv-6-(5-fluorobenzothiazol2-vlm.ethcxv) chroman (EPO Application 313295-A; published October 17, 1988) in 10 ml of diethyl ether and 30 ml of tetrahvdrofuran was added an excess of ft diazomethane and the reaction stirred at 0°C for 2 hours. The reaction was allowed, to warm to room temperature and .5 ml of acetic acid was added followed after 30 minutes* by 100 ml of water and 100 ml of diethvl ether. The organic phase was washed with a brine solution, dried over sodium sulfate and concentrated to cive 550 mg of a foam.

PREPARATION R

3-(Phenylethenvl)benzvl alcohol

l. methyl 3-(pheny1-trans-ethenyl) benzoate

Urine the procedure of Preparation Hl, 2.37 g of triohenyl benzvl phosphonium chloride (Aldrich), 1.0 g of methvl 3-carbonvlbenzoate and 2.44 ml of 2.5M solution of T3-butvl lithium in hexane in 50 ml (total) of tetrabc’drcfuran gave 208 mg of the titled product,

m. o. 1O3-1C9°C.

BAD ORIGINAL

-902 . 3- (phenvl -trans-ethenyl) benzyl alcohol

Employinc the procedure of Preparation H2, 186 mg of the conduct ο^£ Preparation Pl and 1.64 u1 of a 1M solution of diisobutyla]uminum hydride in tetrahvdrofur?. dissolved in 15 ml of drv tetrahvdrofuran at -^_r'^rC for one hour and 0°C for 2-3 hours cave on work-up 107 mg of the titled product, m.p. 91-9?°C.

PREPARATION S

3-(7-Chlcrocuinol-7-vl-trans-e+henvl)-alphamethylbenzyl alcohol

To a solution of 1.0 g of the product of Preoaration J1 in 20 ml o^ dr^v tetrahvdrofuran cooled to 0°C was added 2.61 ml of a 1.5M solution of methvl macnesium bromide in tetrahvdrofuran. After 30 minutes a few drops of water was added to the reaction mixture and the solvent removed in vacuo. The residue was treated with 100 ml of water and 100 ml of methylene chloride. The organic layer was washed with a brine solution, dried over sodium sulfate and concentrated in vacuo. The residue vas chromatographed on silica using methvlene chloride - ethvl acetate (85:5; v;v) to give 980 me of the oroduot as a pale vellow solid.

In a similar manner 3-(5-fluorobenzothiazol-21-trans-ethenyl) -alpha-methvlbenzvl alcohol m.p.

~]4 -1τ 6 °C was prepared bv the reactjon of methyl msonesium bromide and 3-(5-fluorobenzothiazol-2v1-1rans-ethenv1) benzaIdehvde (Preparation T) .

bad original &

AP 0 00 2 2 4

-91 »

PREPARATION T

3- ! ^r--FI uorobenzcthiazol-I-^l-trans-ethenv1) benzaldehyde

To a solution of 1.5 g of 3-(5-fluorobenzothiaco¹-2-vl-trans-ethenvl)benzvl alcohol (Preparation b'2) in 40 ml o- methylene chloride and 25 ml of dimethvl.su] foxide at -60°C was added a solution of .64 ml c- oxalvl chloride in 20 ml of drv methylene chloride containing .74 ml of dimethylsulfoxide. After stirring at -60°C for 35 minutes the reaction mixture was allowed to warm to -35°C for 25 minutes. The mixture was again cooled to -€0°Ο and 3.65 ml of triethvlamine was added over a period of 5 minutes.

The mix-ure was allowed to warm to room temperature and was treated with 200 ml of water. The organic phase was washed with a brine solution, dried over sodium sulfate and concentrated in vacuo to give after trituration with ethyl acetate - hexane 1,2 g, A sample was recrvstallized from ethyl acetate - hexane, m.p. 151-152^OC.

PREPARATION U

3-(6-Fluoroguinol-2-vl-trans-ethenyl)-alphamethylbenzyl alcohol ¹ . 3- (6-f luorocTuinol-2-vl-trans-ethenyl) benzaldehyde bring the procedure of Preparation II, 5.04 g of °-methw?-6-fluoroguino1ine, 4.20 g of isophthaldehvde and 2.P6 ml of acetic anhydride in 100 ml of xylene cave 4.40 c of the titled product as a pale vellow solid, m.p. 110-111 °C.

BAD ORIGINAL

-92•

3-( 6-f luorr.nuinol-?-yl-trans-ethen''l' -alphanethvlbenz.wl alcohol_

Employing the procedure of Preparation S, 500 mg j of the product of Preparation T1 and 1.32 ml of a 1.5M solution of methvl magnesium bromide in tetrahvdrofuran in ¹o ml of tetrahydrofuran cave 430 mg of product,

m.p. 107-109°C.

PREPARATION V

3~ (Pyrid-2-y1-trans-ethenvl) benzyl alcohol ¹. methv] 3-(pyrid-2-yl-trans-ethenyl)benzoate (’sine the procedure of Preparation HI, 750 mg of reth'-l 3-formvlbenzoate, 2.14 g of triphenvl 2pvridvlmethvl phosphonium chloride and 2.0 ml of a 2.5M solution of n-butvl lithium in 30 ml of dry tetrahvdrofuran gave 496 mg of the titled product.

7. 3-(pyrid-2-vl-trans-ethenyl)benzyl alcohol

Employing the procedure of Preparation R2, 409 mg of the product of Preparation VI and 4.5 pi of a 1M solution of diisobutylaluminum hvdride in tetrahvdrofuran in 15 ml of dry tetrahydrofuran gave 351 mg of the titled product.

PREPARATION W

3-(5-Fluornbenzothiazol-7-vlethyl)benzvl alcohol

-· methvl 3-/5-fluorobenzothiazol-7-vlethvl) benzoate

A mixture of ⁷00 mg of the product of Preparation

Hl and 71P mg of 10^s pa1ladium-on-charcoa1 in 30 ml of methar.o] was shaken in a hvdroqen atmosphere at 40 psi for 4 hours. The catalyst was filtered and the filtrate concentrated in vacuo. The residue was flash chromatographed on silica (80% methylene chloride - 20% methanol - v:v) to give 359 mg of titled product.

bad ORIGINAL £

AP 0 0 0 2 2 4

- 9 3 ~ »

The product of Preparation W1 (350 mg) was reacted '•-i fh 1.1 ml of a 1. ON solution of lithium aluminum '-.vdride in 10 ml of dr” tetrahvdrofuran by the procedure of Preparation H2 to give on work-up 208 mg of product as a vellow solid.

PREPARATION X

3-(5-Flucrobenzothiazol-2-vlaminomethyl)benzyl alcohol

A mixture of 1.38 g of 3-hvdroxvmethylbenzaldehvde, 1.^π g of 2-amino-5-fluorobenzothiazole and 2ⁱⁿ0 me of o-toluene sulfonic acid in 100 ml of toluene were refluxed with a Dean-Stark trap for 18 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in 50 ml o^£ drv tetrahvdrofuran and 50 ml of methanol and cooled to 0°C. To the resulting solution vzas added 945 mg of sodium borohydride over a period of 20 minutes. The reaction mixture was stirred at 0°C for 2 hours, was hvdrolyzed by the addition of an ammonium chloride solution and was concentrated to a small volume in vacuo. The residual suspension was added tc 200 ml of water, the pH adjusted to 10 and the resulting mixture extracted with ethyl acetate (2 y 200 mi). The extracts were combined, washed with water and a brine solution and dried over magnesium sulfate, removal in vacuo of the solvent gave 2 g of material which was chromatographed on silica gel to give 235 mg ο¹ pure product.

The NMR (300 MHz, CDC1„) showed absorption at 4.45 (r, 2H) and 4.55 (s, 2H).

BAD ORIGINAL Ofl

-94PREPARATION Y

- (5-Π uorobencothiacol-2-yl-trans-ethenvl) phenylnl'' c ο 1 · meth'-j 3-vinvlbenzoate

To a stirred suspension of 590 mq of methyl triphen.vlphosphonium iodide in 50 ml of drv tetrah’’drofuran cooled to -50°C was added dropwise 5.3 ml of ⁿ.5M n^_butvl lithium in hexane. The resulting mixture was allowed to warm to 0’C over a period of one hour. ⁿbe mixture was then cooled to -70°C and 2.0 g of r.fc-tr'·! 3-fcrmvlbenzoate in 20 ml of drv tetrahvd.rofuran was added dropwise over a period of 20 minutes. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was concentrated in vacuo and the residue treated with water (200 ml) and extracted with diethyl ether (2 x 700 ml). The extracts were combined, washed with water end a brine solution and dried over magnesium sulfate. Removal of the solvent gave 2 g of an oil which was flash chromatographed on silica gel (30% ethyl acetate - hexane; v:v), 2.0 g. Distillation in vacuo gave 1.36 g.

7. 3-methoxycarhonyIphenylglvcol

Stari-lnc with 1.3 g of the product of Preparation

1'1 and υεΐ.ησ the procedure of J. Am. Chem. Soc. 110, 3^C37 (1988) there was obtained 970 mg of the titled rroduct as an oil.

BAD ORIGINAL

AP 0 0 0 2 2 4

-95?. acetone 3-methoxvcarbonvlphenvlglycol ketal

A mixture of 900 mo of the product of Preparation Y2 and 5-10 mg of 4-toluenesul for.ic acid in 20 ml of 2, 2-dimetho::ypropane was allowed to stand for 2 days. The mixture was concentrated and the residue treated vi-'-h 300 ml diethyl ether. The ether solution was washed with 300 ml o^r a saturated sodium bicarbonate sclu^icn, water (300 ml) and a brine solution (300 ml). The orcanir phase was dried and concentrated to an oil, 1.0 g ’-’hich was flash chromatographed on silica (35% ethvl acetate - hexane; v:v) to give 940 mg of product.

4. acetone 3-hvdroxymethvlphenvlglycol ketal

Using the procedure of Preparation H2, 936 mg of the product of Preparation Y3 and 9.9 ml of a 1.0M solution of diisobutyl aluminum hydride (tetrahvdrofuran) in 20 ml of dry tetrahydrofuran gave 820 mg of the titled product as an oil.

5. acetone 3-formylphenvlglycol ketal

Employing the procedure of Preparation S 800 mg o* the product of preparation Y4, 545 pi (600 mg) of dimethv]sulfoxide, 469 pi (682 mg) of oxalyl chloride and 2.88 ml (1.74 g) of triethyl amine in 20 ml of moth'’} chloride gave 671 mg of the desired product as r oil.

BAD ORIGINAL Ά

-966. acetere 3-( 5-f 1 uorobenzoth j azol-?-vl-transethopvl) phen''lal vcol ketal

Following the procedure of Preparation El, 665 mg of the product Preparation Y5, 1.87 σ of 5-fluorobenzcthiazcl-?-vl triphenvl phosphonium chloride and 15 vl of 2.5M n-butvl lithium solution (hexane) in 20 ml of dry tetrahvdrofuran gave, on work-up, 942 ma cf product, m.p. 74-77°C.

. 3-<5-fluorobenzothiazol-2-vl-trans-ethenvl) ohenvlalvcol

A suspension of 925 mg of the product of Preparation Y6 in 10 ml of tetrahydrofuran was treated with 5 ml of 2N hvdrochloric arid and allowed to stand for 30 hours. The reaction mixture was diluted with vater (200 ml) and the product extracted with ethvl acetate (2 x 200 ml). The extracts were combined, washed with a saturated sodium bicarbonate solution, water (1 x 40 ml) and a brine solution. The organic phase was dried over magnesium sulfate and concentrated to aive 1 g of solid which was recrvstallized from ethvl acetate - hexane, 660 mg, m.p. 1?6-128°C.

Mass Spec. 315⁺

PREPARATION 2

4-Hydroxv-6-(5-fluorobenzothiazol-2vl-trans-ethenyl)chroman

1. 6-meth”]chroman-4-one glycol ketal

A mixture o^f . 2 g of 6-methy lchroman-4-one,

4.12 c cf glvcol and 360 mg of 4-toluenesulfonic acid in Ό0 ml of benzene was refluxed with a Dean-Stark trap ^r or 16 hours. The mixture was diluted with

BAD ORIGINAL

AP O 0 0 2 2 4 d i ethv1

-97e⁴her (200 ml) and washed with a saturated .••odium bicarbonate solution (2. x 400 ml), water (1 x 470 ml I and a brine solution (1 x 400 ml). The organic phase was dried over magnesium sulfate and concentrated to give an oil. The residue was flash chromatographed on silica (30% ethvl acetate - hexane; v;v) to give 7.2 c of product.

2. 6-bromomethvlchroman-4-one glycol ketal

Λ mixture of 7.2 g of the product of Preparation ~ ¹ , 6.2 g o^ N-bromosuccinimide and 720 mg of benzovlperoyide in 200 ml of carbontetrachloride was heated to reflux Tr 4 hours. '’’he solvent was removed in vacuo and the residue treated with 400 ml of diethvl ether. ^mhe solution was washed with a saturated sodium bicarbonate solution (1 x 400 nil), water (1 x 400 ml) and a brine solution (1 x 400 ml) and the organic phase dried over magnesium sulfate. Removal of the solvent cave 6 g of an oil which was flash chromatographed on silica (30% ethyl acetate - hexane; v:v) to give 2.3 g of the titled product as an oil.

3. 6-formylchroman-4-one glycol ketal

A mixture o^r 2.3 g of the product of Preparation 22 and 11.3 g of bis (tetra-n-butylammonium) dichromate T 100 ml of chloroform was refluxed for 2 hours. The mixture was cooled to 0^rC, diluted with 100 ml of d?ethvl ether and treated with 10 g of silica gel. The mixture was filtered and the solids washed with 400 ml a* diethvl ether. The filtrates were combined and concentrated to give 2 o of an oil. The residue was

BAD ORIGINAL Ά

-98flash chronatographed on silica (50% ethvl acetate hexane; ':’·) to give 630 mg of the title product as a ’•el low solid, m.p. 0-7 3 °C.

. c- I 5-fluorobenzothiazol-?-vl-trans-ethen”l) chroman-4-one glvcol ketal brine the procedure of Preparation El and startinn with 1.68 g of 5-fluorebenzothiazol-2-ylmethyl trinhenvlphosphcnium chloride, 650 mg of the product of Preparation 73 and 1.3 pi of 7.5M n-butyl lithium (hexane) ir. 2 0 ml of tetrahydrofuran there was obtained ~5 3 irq c^r the desired product.

5. 6-( 5-fluorobenzothiazol-2-vl-trans-ethenvllchroman-4-cne

Following the procedure of Preparation Y7, 750 mg of the product of Preparation 74 and 5 ml of 2N hvdrochloric acid in 10 ml of tetrahvdrofuran gave 513 mg of the titled product as a solid, m.p.

19-’-199°C.

6. 4-hydroxv-6-(5—fluorobenzothiazol-2wl-trans-ethenyl)chroman

Starting with 489 mg of the product of Preparation 75 and S'⁷ mg of sodium borohydride in 10 ml of methanol and 0 jt-,1 cf drv tetrahvdrofuran and employing the procedure cf Preparation G3, 446 mg of the titled nrocuct was obtained, m.p. 184-186°C.

BAD ORIGINAL &

AP Ο Ο Ο 2 2 4

-99PREPAR.ATION ΑΑ

1—{4 — ί3-Aminophen.vimethoxy ]phenvl)-2-methvllH-jm.idazo[4,5-clpvridine

Ufjp.o the procedure of Example 3, 500 mg of

3-ar i n.ohenzvl alcohol, 1.01 σ of the product of Prepar.-yior A, 1.1 σ of triphenylphosphine and 848 mg of dietbvl azodicarboxylate in 20 ml of dry tetrahvdrofuran cave 370 mg of the desired product, m.p.

₁₀ 18^-185^(3.

PREPARATION BB

5-Fluoroben.zothi a7.ole-2-carhoxy lie Acid 1 . 5-^luoroben20thiazole-?-carboxaldehvde

To a stirred solution of 36 g of 5-fluorobenzo15 ⁴hiazole in 100 ml of diethyl ether cooled to -70°C was added dropwise over a 5 minute period 9.4 ml of a ?.5M solution. o^r n-butyl lithium in hexane. The reaction mixture was allowed to warm to -50°C for one- hour and was then cooled to -78°C. Drv dimethylformamide (2.8 ml) vas added dropwise and the reaction mixture allowed to warm to room temperature over a period of two hours. The reaction was diluted with 300 ml of diethyl ether and washed with IN hydrochloric acid (1 x 40 m¹), water (1 x 40 ml), a saturated sodium bicarbonate solution (1 x 40 ml) and dried over rac-esiun sulfate. The solvent was removed and the residual product flash chromatographed on silica (50% ethvl acetate - hexane; v:v) to give 24.7 g of the titled product, m.p. 105-107°C.

BAD original &

-1005-f.luorobenzothiazole-2-carboxyl io acid

To a solution of 00 mq of the product of Prenararinr, PEI i 20 ml of e+hanol was added 256 me of silver oxide -ollov/ed bv 0.6 ml of 2M aoueous sodium hvdroxide solution and the resulting reaction mixture stirred at room temoerature for 4 hours. The solids vzere filtered ard the f:Itrate concentrated in vacuo. The residue was dissolved in 100 ml of water and extracted with dieth'/l ether. The aqueous was made sljghtlv acidic with lb h'-droohlcric acid and extracted with chloroform C⁷ x 100 ml). The extracts were combined, dried and corw-entrated to give 62 mg o- product, m.p. 123°C (dec) .

PREPARATION CC

3-(5-Fluorobenzothiazol-2-ylmethoxy)phenvlqlycol

A mixture of 750 mg of methyl 3-(5-fluorobenzothianol-?-ylmethoxy)mandelate and 190 mg of sodium borohydride in 10 ml of methanol was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue treated with water and extracted with ethvl acetate. The extracts were combined, dried over sodium sulfate and concentrated to give 700 mg of the titled product, m.o. 115°C.

PREPARATION DP

3-(6-Chloro-l,3-benzthiazin-?-vl-transethenvl) benzyl alcohol ¹. 3-(6-chloro-l,3-benzthiazin-2-yl-transetfenvl)benzvl alcohol t-butvldimethvlsilvl ether

A mixture of 1.08 g of 2-methv]-fi-chloro-1,3benzthiaz?ne 1.51 g of 3-formlbenzvl alcohol tbutvldimethylsilvl ether and 5 drops of piperidine in

BAD ORIGINAL a

AP 0 0 θ 2 2 4

-1 01'8 md ο⁴⁷ benzene was heated tc reflux in a Dean-Stark rrr 1 hour. An additional 5 drops 0⁴⁷ piperidine

•.•ere added and the refluxing continued from 30 hours.

The mixture was diluted with £00 ml of ethvl acetate and washed with wafer (1 x 40 ml) and brine (] x ml). The organic laver was dried over magnesium pulsate and concentrated to 2 g of crude product which was oi-ir-omatographed cn silica gel using 5% ethyl acetate in hexane (v;v) , 188 me, m.p. 58-60°C.

. 3 - < 6-chloro-l, 3-benz + hl azin-2-vl-tran.sethcn.vl) benzyl alcohol__

Starring with 173 nig cf the product of Preparation EDI ard 0.5 ml 0⁴⁷ tetrabutvlammonium fluoride and using the procedure of Preparation GG3 cave 39 mg of the desired product, m.p. 143-145°C.

PREPARATION EE

3-(5-Fluorobenzothiazol-2-ylmethylsulfinyl)benzyl alcohol and 3-(5-fluorobenzothiazol-2ylmethvlsulfcnvl)benzyl alcohol

To stirred solution of 822 mg of 3-(5-fluorobenzothiazo¹-2-vlmethvlthio)benzvl alcohol in 20 ml of methvlene chloride cooled to 0°C was added 929 mg of 50-60^- m-chloroperbenzoic acid and the reaction mixture stirred at O’C for one hour. The reaction was diluted with £00 ml of ethyl acetate and extracted with a T,turate<? solution of sodium bicarbonate (2 x 40 ml), wafer (1 :: 40 ml) and a brine solution (1 x 40 ml).

The orcanic phase was dried ever magnesium sulfate and concent rated to cive 2 g of solid material, which on Lash chromatographing on silica gel gave (2.5%

BAD ORIGINAL 0+

-102m.e'hanol in. methylene chloride; v:v) 691 mg of the oran.ce sulfone, m.p. ?78-130°C and 188 ma o^4- the ‘uiifoxid.c as a white solid, m.p. 145-14⁷°C.

PREPARATION FF

1- ( 7-Fluoro-4-h'’droxvphenv’l) -2-methvl-iHimidazo[4,5-c]pvridine

1. ?-nitro-4-(2-fluoro-4-hydroxypheny1amino)pvridine a suspension of 2.86 σ of 2-fluoro-4-hvdrox”ani/ine and 2.08 g of sodium bicarbonate in 25 ml of ethanol was added dropwise 3.93 σ of 3-nitro-4chloropyridine in 25 ml of ethanol over a period of 15 minutes. The reaction was stirred overnight at room temperature and was then heated to reflux for 8 hours. The precipitate was filtered, washed with ethanol and water, and dried, 5.28 g. The product was purified by chromatographing on 600 g of silica gel. A small sample was recrystallized from isopropanol m.p. 7’5-?⁷6°C.

2. 7-amino-4-(2-fluoro-4-hvdroxvphenvlamino)pvridine_

A mixture of 3.73 a of the product Preparation FF1 and 7 a o*⁷ 10% palladium on charcoal in 100 ml of tetrahvdrofuran and 100 ml o⁴⁷ methanol was shaken in an. atmosphere of hvdrogen at room temperature and an initial pressure of 30 p.s.i. After 30 minutes the spent catalvst was filtered and the filtrate oonr-entrated to dryness, 3.19 g. A sample vras reorvstallized from isoprooanol-hexane, m.p. 209°C (dec) .

BAD ORIGINAL

AP Ο Ο Ο 2 2 4 . 2 - ( ~ - f luoro-.4-acetnxyoher” 1) -2-methvl' F’- F re da zo J , 5-c 1 pyridine

Acetic anhvdride C5 ml) containing 3.09 g of the p’-cduct cf Preparation FF2 was heated to reflux under ritronen for 4 hours. The reaction was cooled to room temperature and concentrated in vacuo to drvness. The residue was chromatographed on 350 g of silica gel urine 4% methanol in methvlene chloride (v:v) to give

3.30 g ο⁴⁷ a product as a white foam and 1.96 g of an eff-whife foam. The latter material was used in the next reaction step without further purifioation.

4. ¹ - ί ?-fluoro-4-hvdroxyphenyl)-?-methvl-1Himidazo f 4,5-c) pvr.idine_

To 30 ml of water and 80 ml of methanol was added

1.92 o of the product of Preparation FF3 and 538 mg of sodium hvdroxide and reaction stirred at room temperature for 3 hours under nitrogen. The reaction was poured into 1 1 of water and the pH adjusted to 6-7 with IN hvdrochloric acid. After chilling in ice, the precipitate was filtered and dried, 1.07 g. A small sample was recrystallized from methanol, m.p. 2940c.

PREPARATION GG

- (5-Fluorobenzothiazol-2—'Ί)fm-hvdroxvmethvlphenvl) cyclopropane ¹. 3-I5-fluorobenzothiazol-3-vl-trans-ethenvl)benzyl alcohol t-butvldimethvlsilvl ether

To 160 rnl of dimethylformamide containing 2.0 g of 3-I5-fluorobenzothiazol-2-vi-trans-ethenyl)benzvl alcohol and 1.19 g of imidazole was added 1.37 q of t-butvldimethvlsi1yl chloride and the reaction mixture stirred overnight under nitrogen at room temperature.

BAD ORIGINAL ft

S’

Α^ί(·ΡΓ 48 hours of reaction time, the mixture was poured :^c 00 ml of ethyl acetate and washed with water (? '·.

ml), a IN hvdrochloric arid solution (? x 150 ml), Veter (1 x 000 ml·) and a brine solution (1 x 200 ml). The organic laver was separated, dried over sodium sulfate and concentrated to a white solid. The residue was recrvstallized from ethvl acetate - hexane, 1.57 g,

m.o. 91-93 °C.

l-ί 5-fluorobenzothianol-2-vl)-2-(m-(t-butvldjmethvlsilvloxymethyl] phenvl) cyclopropane

Tc 160 mg of 60% sodium hvdride washed free of oil usinc pentane was added 86⁷ of trimethylsulfoxonium iodide and the flask purged with nitrogen and evacuated several times. Dimethvlsulfoxide (5 ml) was added and the reaction mixture stirred 15-20 minutes at room temperature. The product of Preparation GG1 (1.5 g) in 10 ml of warm dimethylsulfoxide was added to the rest of the reagents chilled to 20°C. The resulting yellow suspension was stirred at room temperature for 21 hours and was then added to 200 ml of water. The aoueous was extracted with ethvl acetate which was then washed with water (3 x 100 ml) and a brine solution (1 x 100 ml). The organic phase was dried over sodium sulfate and concentrated to give 1.74 q of a vellow oil. The residue was chromatoqraphed on 300 g of silica cel using 5% ethvl acetate in hexane (v:v) to give 560 mg o^ product. Rechromatographing cave 284 mg of pure intermediate, m.p. 56-58°C.

BAD ORIGINAL

V

AP Ο Ο Ο 2 2 4

-1051-(5-fluorobenzothiazcl-2-vl)-?-(m-hvdroxvmethylphcnvl) eye]opropane___

To a solution of 252 mq of the product of Preparation GG? .in 8 ml of tetrahydrofuran cooled to O’C under nitrogen was added tetrabutylammonium ^luoride dropwise. The reaction was allowed to warm to room temperature and was then diluted with ethyl ,-w<Tate and washed with water and a brine solution, and dried over sodium sulfate. Removal of the solvent gave 0?P me of solid which was chromatographed on 100 g of silica gel (5% ethyl acetate in methvlene chloride, v:v) to give 153 mg of a clear oil.

Claims (25)

1. A compound of the formula and a pharmaceutically acceptable acid addition salt thereof, wherein Het is

R bad original £

AP 0 0 0

2 2 4

-1C7A is -CH^-Ο-, -C=C-, -CH=CH-, -CiCH₃)=CH-, -CP^NP-, -NPCP--, -(CH,) -, -0-, -CH-S(O) -, -NHCO-, -COUP- or cvcloalk”lene having three to six carbcr. atoms;

W is

BAD ORIGINAL

-108-

CH

-CH^OCH - or -MHCO-;

z is an integer of 1 to 2; m is an integer of 0 to 2; R s hydrogen, fluoro, difluoro, chloro, dichloro methyl, methoxy or trifluoromethv1; and R_n and R_n are each hvdrogen, fluoro, chloro, methvl, methoxv, acetal, nitro, amino, carboxv, trifluoromethvIsulfonvlamino or trifluorornethyl with the proviso that when Ft is -O- W i s co₂h or

BAD ORIGINAL &

AP 0 0 0 2 2 4

-109A compound of claim 1, wherein Het in

-CH_n0-, -0CH₂-, -0- or -CHiCH₃)-0-; and R and R_? each hydrogen.

3. The compound of claim 2, wherein Het is are where R is 5-fluoro;

A is -CH=CH-; V! is and Π is -CH_nO-.

BAD ORIGINAL ft

-110- wbere R is 6-fluoro; A is

CK=CH-; W is

CH=CH-; W is where R is 7-chloro; A is

BAD ORIGINAL £

AP 0 0 0 2 2 4m

-in.

6. The compound of claim 2, wherein Het in where R is 6-fluoro; A is -CH^O-; V is and B is -OCH?-.

7. The compound of claim 2, wherein Het is where R is 6-fluoro; A is -CH=CH-; F is and B is -CHiCH^O-.

8. The compound of claim 2, wherein Het is

BAD ORIGINAL

-lig- and B is -0-.

The compound is where R is hvdroqen; A is -CH^O-;

and B is -0-.

10. The compound of claim 2, wherein Het where R is 6-fluoro; A is

BAD ORIGINAL &

AP 0 0 0 2 2 4

-113and B is -OCH^-.

11. The compound e ⁴⁷ claim 2, wherein He⁴-. 5.5 where R is 7-chloro; A is -CH=CH-; W is and B is -CI! (CH^ )0-.

12. The compound of claim 2, wherein Het is where R is 5-fluoro; A is -CH=CH-; V is and B is -CH(CH₃)O-.

13. The compound of claim 2, wherein He⁴- is

BAD ORIGINAL where P. is -chloro; A s -CH_OD and B is -0wherein Kef is

14. The compound of claim and B is -0-.

15. The compound of claim wherein Het is

BAD ORIGINAL

AP 0 0 0 2 2 4 and B is -CH^O-.

16. ^mhe compound of claim 2, wherein Bo⁴- _1P

If where P. is 5-fluoro; A is -(CH₀)_?-; W is and B is -CH_nO-.

17. The compound of claim 2, wherein Het is where R is 5,6-difluoro; A is -CH_o0-; V is

BAD ORIGINAL a*

-11 6 IS. The compound of claim 2, wherein Het is where R is 7-chloro; A is -(CH_n)_o-; V’ is and B is -Ci^O.

19. The comDOund of claim 2, wherein Het is where R is 6-fluoro; A is -CH_o0-; W is

BAD ORIGINAL

AP 0 0 0 2 2 4

-11 R

20. The compourc’ cf claim 2, wherein Het- ’ s where P is 6-fluoro; A is -CH₉0-; W is and B is -CH_nO-.

21. A method of inhibiting platelet activatinc factor and blocking leukotriene D4 receptor in a mammal in need of such treatment which comprises administering to said mammal a platelet activating factor inhibitnc and leukotriene D4 receptor blocking amount of a compound according to claim 1.

22. A method of claim 21 wherein the mammal is a human suffering from asthma, said compound administered to prevent or relieve the svmptoms of said, asthma.

23. A method of claim. 21 wherein the mammal is a human suffering from arth.ritis, said compound administered to prevent or relieve the svmptoms of said arthritis.

24. A method of claim 21 wherein the mammal is a human suffering from psoriasis, said compound administered to prevent or relieve the svmptoms of said psoriasis .

BAD ORIGINAL

25. A method of claim 21 wherein the mammal in a human suffering from. Gastrointestinal distress, raid compound administered to prevent or relieve gastrointestinal ulcers.

26. A method cf claim 21 wherein the mammal is a human suffering from cardiovascular disease, said compound administered to prevent or relieve ir.vocard^fa' infarction.

27. a method of claim 21 wherein the mammal is a human suffering ^frow cardiovascular disease, said compound administered to prevent or relieve stroke.

28. A method of claim 21, wherein the mammal is a human suffering ^Frow shook, said compound administered to prevent or relieve the svmptoms of said shock.

29. A pharmaceutical composition for administration to a mammal which comprises a platelet activating factor inhibiting and leukotriene D4 receptor blocking amount of a compound accordina to claim 1 and a pharmaceutically acceptable carrier.