AU747664B2 - Intermediates for the preparation of endothelin receptor antagonists - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

Name of Applicant: Actual Inventors: Address for Service: Invention Title: SmithKline Beecham Corporation Juan Ignacio LUENGO AND John Duncan ELLIOT DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 End utelin receptor antagonists ^r^%v^«<~oA^sGar 4-e repw'^o The following statement is a full description of this invention, including the best method of performing it known to us: Q\OPER\PDB\6764S-96DIV 14/12/99 -1A- INTERMEDIATES FOR THE PREPARATION OF ENDOTHELIN RECEPTOR ANTAGONISTS FIELD OF THE INVENTION This application is a divisional application derived from Australian Patent Application No. 67645/96, the entire contents of which are incorporated herein by reference.

The present invention relates to novel pyrazoles and their use as synthetic intermediates for endothelin receptor antagonists.

Endothelin (ET) is a highly potent vasoconstrictor peptide synthesized and released by the vascular endothelium. Endothelin exists as three isoforms. ET-1, 10 ET-2 and ET-3. [Unless otherwise stated "endothelin" shall mean any or all of the isoforms of endothelin]. Endothelin has profound effects on the cardiovascular system. and in particular, the coronary, renal and cerebral circulation. Elevated or abnormal release of endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of cardiovascular, cerebrovascular, respiratory and 15 renal pathophysiology. Elevated levels of endothelin have been reported in plasma o from patients with essential hypertension, acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis, and patients with uraemia undergoing dialysis.

In vio, endothelin has pronounced effects on blood pressure and cardiac output. An intravenous bolus injection of ET (0.1 to 3 nmol/kg) in rats causes a transient, dose-related depressor response (lasting 0.5 to 2 minutes) followed by a sustained, dose-dependent rise in arterial blood pressure which can remain elevated for 2 to 3 hours following dosing. Doses above 3 nmol/kg in a rat often prove fatal.

Endothelin appears to produce a preferential effect in the renal vascular bed.

It produces a marked, long-lasting decrease in renal blood flow, accompanied by a significant decrease in GFR, urine volume, urinary sodium and potassium excretion.

Endothelin produces a sustained antinatriuretic effect, despite significant elevations in atrial nariuretic peptide. Endothelin also stimulates plasma renin activity. These findings suggest that ET is involved in the regulation of renal function and is involved in a variety of renal disorders including acute renal failure, cyclosporine Aplhrotoxicity, radio contrast induced renal failure and chronic renal failure.

WO 97/04772 PCTfUS96/12581 Studies have shown that in vivo, the cerebral vasculature is highly sensitive to both the vasodilator and vasoconstrictor effects of endothelin. Therefore, ET may be an important mediator of cerebral vasospasm, a frequent and often fatal consequence of subarachnoid hemorrhage.

ET also exhibits direct central nervous system effects such as severe apnea and ischemnic lesions which suggests that ET may contribute to the development of cerebral infarcts and neuronal death.

ET has also been implicated in myocardial ischernia (Nichols Phbim. 99: 597-601, 1989 and Clozel and Clozel, Cic e. 65: 1193-1200, 1989) coronary vasospasm (Fukuda ",LaLL. Lharm. 165: 301-304, 1989 and Luscher, CIL.. 83: 701, 199 1) heart failure, proliferation of vascular smooth muscle cells, (Takagi, Biochem Biophvs. Res. Commun.; 168: 537-543, 1990, Bobek jj, AmL. J, Ebysiol 258:408-C415, 1990) and atherosclerosis, (Nakaki Bich Biophvs. Res, Commun. 158: 880-881, 1989, and Lerman ",Ne EgJ gf Mj 325: 997-1001, 1991). Increased levels of endothelin have been shown after coronary balloon angioplasty (Kadel CLAL, No. 2491 Qr 82: 627, 1990).

Further. endothelin has been found to be a potent constrictor of isolated mammalian airway tissue including human bronchus (Uchida "ja, Eur. o.n Phrm 154: 227-228 1988, LaGente, Cli. .xAllergy 20: 343-348, 1990; and Springall uiiL, Lact 337: 697-701, 199 Endothelin may play a role in the pathogenesis of interstitial pulmonary fibrosis and associated pulmonary hypertension, Glard Third Interniational Conference on Endothelin, 1993, p.

34 and ARDS (Adult Respiratory Distress Syndrome), Sanai C1AL, Supra. p. 112.

Endothelin has been associated with the induction of hemorrhagic and necrotic damage in the gastric mucosa (Whittle Ci~L,. J.Pam 95: 1011-1013, 1988); Raynaud's phenomenon, Cinniniello ",aL Lancet 337: 114-115, 199 1); Crohn's Diqeaiqe and ulcerative colitis. Munch et al.. Lancet. Vol. 339.

p. 38 1; Migraine (Edmeads, Headache, Feb. 1991 p 127); Sepsis (Weitzberg ~L Cic ho 3 222-227, 199 1; Pittet c~aL, Ann, Suirg. 213: 262-264, 199 1), Cyc losporin- induced renal failure or hypertension (Eur. J. Pharmacol., 180: 191 192, 1990, Kine IM,. 37: 1487-1491, 1990) and endotoxin shock and other -2- WO 97/04772 PCT/US96/12581 endotoxin induced diseases (Biochem. Biophvs. Res. Commun., 161: 1220-1227, 1989, Acta Physiol. Scand. 137: 317-318, 1989) and inflammatory skin diseases.

(Clin Res. 41:451 and 484. 1993).

Endothelin has also been implicated in preclampsia of pregnancy. Clark U aL, Am. J. Obstet. Gvnecol. March 1992, p. 962-968; Kamor eAL, N. Eng. LQf Mi,. Nov 22, 1990, p. 1486-1487; Dekker MaL, Eur J. Ob. and Gvn. and Rep. Bio.

(1991) 215-220; Schiff etaL, Am. J. Ostet. Gvnecol. Feb 1992, p. 624-628; diabetes mellitus, Takahashi itLL, Diabetologia (1990) 33:306-310; and acute vascular rejection following kidney transplant, Watschinger L, Transplantation Vol. 52, No. 4, pp. 743-746.

Endothelin stimulates both bone resorption and anabolism and may have a role in the coupling of bone remodeling. Tatrai tal Endocrinology Vol. 131, p.

603-607.

Endothelin has been reported to stimulate the transport of sperm in the 15 uterine cavity, Casey etL, J. Clin. Endo and Metabolism, Vol. 74, No. 1, p. 223- 225, therefore endothelin antagonists may be useful as male contraceptives.

Endothelin modulates the ovarian/menstrual cycle, Kenegsberg, J. of Clin. Endo.

and Met., Vol. 74, No. 1, p. 12, and may also play a role in the regulation of penile vascular tone in man, Lau CLL, Asia Pacific J. of Pharm., 1991, 6:287-292 and 20 Tejada ea, J. Amer. Physio. Soc. 1991, H1078-H1085. Endothelin also mediates a potent contraction of human prostatic smooth muscle, Langenstroer et a.

J. Urology Vol. 149, p. 495-499.

Thus, endothelin receptor antagonists would offer a unique approach toward the pharmacotherapy of hypertension, acute and chronic renal failure, ischemia induced renal failure, sepsis-endotoxin induced renal failure, prophylaxis and/or treatment of radio-contrast induced renal failure, acute and chronic cyclosporin induced renal failure, cerebrovascular disease, crbrovascular spasm, subarachnoid hemorrhage, myocardial ischemia, angina, congestive heart failure, acute coronary syndrome, myocardial salvage, unstable angina, asthma, primary pulmonary hypertension, pulmonary hypertension secondary to intrinsic pulmonary disease, atherosclerosis, Raynaud's phenomenon, ulcers, sepsis, migraine, glaucoma, -3- P:\OPER\PDB\67645-96.343 9/12/99 -4endotoxin shock, endotoxin induced multiple organ failure or disseminated intravascular coagulation, cyclosporin-induced renal failure and as an adjunct in angioplasty for prevention of restenosis, diabetes, diabetic retinopathy, retinopathy, diabetic nephropathy, diabetic macrovasular disease, atherosclerosis, preclampsia of pregnancy, bone remodelling kidney transplant, male contraceptives, infertility and priapism and benign prostatic hypertrophy.

AU 67645/96 relates to compounds represented by Formula and pharmaceutical compositions containing these compounds, and their use as endothelin receptor antagonists which are useful in the prevention or treatment of a variety of cardiovascular and renal diseases 10 including by not limited to: hypertension, acute and chronic renal failure, cyclosporin induced nephrotoxicity, benign prostatic hypertrophy, pulmonary hypertension, migraine, stroke, S. subarachnoid haemorrhage, cerebrovascular vasospasm, myocardial ischemia, angina, congestive heart failure, unstable angina, coronary vasospasm and myocardial salvage, the sequelae of diabetes including but no limited to: atherosclerosis, diabetic nephropathy, diabetic 15 retinopathy, retinopathy, diabetic macrovascular disease; and as an adjunct in angioplasty for prevention of restenosis.

ee AU 67645/96 further relates to a method for antagonizing endothelin receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula 4A SUMMARY OF THE INVENTION The present invention now relates to intermediate useful in the preparation of certain compounds of Formula Accordingly, the present invention provides a compound of Formula (11):

R

5

R

1 wherein R' is independently hydrogen or C 1 6 alkyl;

R

3 and R.

5 are independently C0 2

R

6 OH, RI 3 OH, CI 8 alkoxy, S(O)q R, 1, N(R 6 2 N02,Br, F, I, Cl, CFNCO R 1 CR, -X-R 9 6 2 )moR, 6

-(CH

2 )m'R, 6 or -X(CH 2

,R

8 wherein each methylene group within -X(CH2),R 8 may be unsubstituted or substituted by one .E or two -(CH 2 )nAr groups;

R

4 is independently R 1 1, OH, C 1 5 alkoxy, S(O)qRj 1, N(R 6 2 Br, F, 1, Cl or NHCOR 6 wherein C 1 5 alkoxy may be unsubstituted or substituted by OH, methoxy or halogen; and

R,

5 is independently hydrogen, Ar, C 1 6 alkyl, cyclopropylmethyl, cyclopropylethyl or XAr.

R

6 is independently hydrogen or 8 alkyl;

R

7 is independently hydrogen, C 1 alkyl, C- 2 10 alkenyl or C2- 8 alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R 6 2 C0 2

RI

2 halogen or XCI-, 0 alkyl; or

R

7 is (CH 2

R

8 is independently R, 1, C0 2

R

7

CO

2

C(R

1 1 2

O(CO)XR

7

PO

3

(R

7 2

SO

2

NR

7

R,,

NR

7 S0 2 R CONR 7

SO

2

R

1 1 S0 3

R

7 S0 2

R

7 P(O)(0R 7

)R

7 CN, CO 2 (CH2)mC(O)N(R 6 2 C(RI 2

N(R

7 2

C(O)N(R

6 2

NR

7

C(O)NR

7

SO

2

R

1

,,R

6 or tetrazole which is substituted or usubstitited by C 1 6 alkyl; 4B

R

9 is independently a bond, C I -I alkylene, C I -I alkenylene, C I.-I alkylidene, C I I alkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one of more OH, N(R 6 2 COOH or halogen; R, I is independently hydrogen, Ar, C 1 8 alkenyl, C 2 8 alkenyl, C 2 8 alkynyl, all of which may be substituted or unsubstituted by one or more OH, CH 2

N(R

6 2 or halogen;

R,

2 is independently hydrogen, C 1 6 alkyl, C 2 6 alkenyl, or C 2 7 alkynyl;

R

13 is independently divalent Ar, C 1 10 alkylene, CI- 10 alkylidene, C 2 10 alkenylene, all of which may be unsubstituted or substituted by one or more C0 2

R

6 OH, CH 2 OH, N(R 6 2 or halogen;

R

16 is independently C 1 6 alkyl or phenyl substituted by one or more C 1 6 alkyl, OH, I 5 alkoxy, S(O)qR 6

N(R

6 2 Br, F, 1, Cl, CF 3 or NHCOR 6 X is independently 0, NR 6 or S(O)q; X' is independently, 0, NR 6 or S(O)q; Y is independently CH 3 or X(CH2)nAr; Ar is: napthl,(a) (b) naphhylindolyl, pyridyl, thienyl, oxazolidinyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be unsubstituted or substitjuted by one or more Z, or Z 2 groups; A is independently C=O, or (C(R 6 2 )m; B is independently -CH 2 or Z, and Z 2 are independently hydrogen, XR 6

CI-

8 alkyl, (CH 2 )qCO 2

R

6

C(O)N(R

6 2

CN,

(CH

2

NO

2 F, CI, Br, 1, N(R 6 2

NHC(O)R

6

O(CH

2 )mnC(O)NRSO 2

RI

6

(CH

2 )mOC(O)NR,SORi 6, 4C

O(CH

2 )mNRaC(O)NRaSO 2

R]

6 tetrazolyl which may be substituted or unsubstituted by C 1 6 alkyl, CF 3 or C(O)R 6 m is independently 1 to 3; n is independently 0 to 6; q is independently 0, 1 or 2; provided R 3

R

4 and R 5 are not O-O(CH 2 ),Ar or 0-OR 6 or a pharmaceutically acceptable salt thereof P:\OPER\PDB\67645-96. 343 9/12/99 DETAILED DESCRIPTION OF THE INVENTION The compounds of AU 67645/96 are represented by structural Formula

P

(CH

2 S S *S S wherein is RszT Rs

N

P is tetrazol-5-yi, C0 2 R6 or C(O)N(R6)S(O)q R Ra Is independently hydrogen or C 1 6 alkyl, R 1 is independently hydrogen, Ar. C 1 6 alkyI Or C 1 -6 aikoxy;

R

2 is

Z

2

R

3 and R 5 are independently CO 2

R

6 OH, R 13 07, C,_ 8 alkoxy, S()R (62

NO

2 Br, F, I, Cl, CF 3

NHCOR

6

R

13 C0 2

R

7

-X-R

9

-X(C(R

6 2 )mOR 6

(CH

2 )mX'Rsor-X(CH2)nR 8 wherein each methylene group within -X(CH 2 may be unsubstituted or substituted by one or two -(CH 2 groups;

R

4 is independently R 1 1, OH, C 1- 5 alkoxy, S(O)qR 11, N(R 6 2 Br, F. 1, Cl or NHCOR6, wherein the C I..

5 alkoxy may be unsubstiwuted or substituted by OH, methoxy or halogen; 15 R 6 is independently hydrogen or C 1 8 alkcyI;

:R

7 is independently hydrogen. C 1 loalkyI. C 2 loalkenyl or C 2 .8alkyny1. all of which may be unsubstituted or substituted by one or more OH, N(R 6 2 C02R 12 halogen or XC I 1 0 alkyI; or R7 is (CH2)nAr;

R

8 is independently R 11, C0 2 R7, CO 2 C(R I j) 2 0(CO)XR 7 P0 3

(R

7 2 20 SO 2

NR

7 R 1 1, NR 7

SO

2 Ri 11, CONR 7

SO

2 R 1 1. SO 3 R7, S0 2

R

7 P(O)(0R 7

)R

7 CN, C0 2

(CH

2 )mC(O)N(R6)2, C(R I )2N(R 7 2

C(O)N(R

6 2

NR

7

C(O)NR'

7 S0 2 R 1 1, OR 6 or tetrazole which is substituted or unsubstituted bv C 1 6 aikyl; ;S is-, A~nAezntlu -2hnng C, 1 0 alkvlene. C i i alkenylene, C I I 0 aikylidene,

C

1 I loalkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one of more OH. N(R 6 2

COGH

or halogen; R 10 is independently C I lalkyl, N(R 6 )2 or Ar;

R

1 is Independently hydrogen. Ar. C I.

3 alkvl, Ci1 8 alkenyl. C 2 8 alkvnyi. all of which may be substituted or unsubstituted by one or more OH. CH2)OH, N(R 6 2

.I

or halogen: R 12 is independently hydrogen, C I 6 alkyl, C 2 6 alkenyi or C 2 7 aikynyl: R 13 is independently divalent Ar. C I 1 0 alkylene, C 140 I.alkylidene,

C

2 I alkenylene, all of which may be unsubstituted or substituted by one or more C0 2

R

6 OH, CH 2 0H, N(R 6 2 or halogen;

R

15 is independently hydrogen, Ar, C 1 6 alkyl, cyclopropylmethyl, cyclopropylethyl or XAr;

R

16 is independently C 1 6 alkyl or phenyl substituted by one or more C 1 6 alkyl, OH-, I Cj 5 aikoxy, S(O)qR6, N(R6) 2 Br, F, 1, Cl. CFj or NHCOR, 6 X is independently (CH)n, 0. NR 6 Or S(O)q: Xisindependently 0. NR 6 or S(O)q: Y is independently CH 3 or X(CH2)nkr;, Ar 'Is:

B

B

(b) -10 naphthyl. indolyl, pyridyl, thienyl. oxazolidinyl. thiazolyl. isothiazolyl, pyrazoiyl.

tna.zoiyl. tetrazolyl, imiudazolyl, imruidazolidinyl, thazolidinyl, isoxazolyl, oxadiazolyl. thiadiazolyl. morpholinyl. pipenidinyl, piperazinyl, pyrrolyl. or pyrimnidyl, all of which may be unsubstituted or substituted by one or more Z 1 or

Z

2 groups; A is independently C=O, or (C(R 6 2 )m; B is independently -CH 2 or

Z

1 and Z 2 are independently hydrogen, XR 6 CI-8alkyl, (CH 2 )qCO 2

R

6 C(0)N(R 6 2

CN,

(CH

2

NO

2 F, Cl, Br, 1, N(R 6 2

NIIC(O)R

6 0(CH 2 )mC(O)NRaSO 2

RI

6

(CH

2 )mOC(0)NRaSO 2

RI

6 7.

O(CH

2 )mK aC(O)NRaSO2RI6 tetrazolyl which may be substituted or unsubstituted by Ci.

6 alkyl, CF 3 or C(O)R 6 m is independently I to 3; n is independently 0 to 6; q is independently 0, I or 2; provided R 3

R

4 and R 5 are not O-O(CH2)nAr or O-OR 6 or a pharmaceutically acceptable salt thereof.

All alkyl, alkenyl, alkynyl and alkoxy groups may be straight, branched or cyclic Halogen may be Br, CI, F or I.

The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All "of these compounds and their diastereoisomers are contemplated to be within the scope of the present invention.

Preferred compounds are those wherein: P is C0 2

R

6 more preferably P is CO 2

H.

RI is hydrogen.

Z

1 and Z2 are independently hydrogen. C0 2

R

6 (CH2)nOH. C -4alkyl or C 6 alkoxy, e.g. methoxy.

20 R 3 and R 5 are independently hydrogen. CO2R 6 OH, C -8alkoxy.

C 8 alkyl. N(R 6 2

NO

2 Br, F. C, I. R 1 3

CO

2 R7. X(CH2)nRg,

(CH

2 )mX'Rg. or X(C(R6)2)mOR6.

In the context of the group R3 and R 5 preferably do not represent hydrogen. In particular in the group R 3 preferably represents Br, Cl. C .galkoxy e.g. methoxy; X(CH2)nR8, wherein X preferably represents 0, n is 0, 1, or 2, and Rg is preferably selected from: C0 2

R

6 wherein R 6 is preferably hydrogen;

OR

6 wherein R 6 is preferably H; tetrazolyl optionally substituted by C l-8alkyl e.g. ethyl;

CONR

7

SO

2 R I wherein R 7 is H or C _galkyl e.g. methyl. R11 preferably is WO 97/04772 PCTIUS96/1 2581 C 1 8 alkyI methyl, isopropyl, or t-butyl) or phenyl optionally substituted by Br, Cl. F, C I .galkyl e.g. methyl; or R8 is phenyl or pyridyl substituted by one or more Br, Cl, CO 2 H, CH 2 OH; and

R

5 is C 1 8 alkoxy e.g. methoxy, or N(R 6 2 wherein R 6 preferably is H or methyl.

R

4 is hydrogen, OH, C 1 alkoxy, N(R 6 2 Br, F, Cl, 1, NHCOCH 3 or S(O)q C 1 alkyl wherein the C I 5 alkyI may be unsubstituted or substituted by OH, methoxy or halogen. R 4 is more preferably hydrogen.

R

6 is hydrogen or C I 8 alkyl e.g. methyl and ethyl.

R7is hydrogen, C 1 I alkyl, C 2 1 0 alkenyl or C 2 8 alkynyl, all of which may be unsubstituted or substituted by one or more OH. N(R 6 2 C0 2 R 12 halogen, or R 7 is (CH2)nAr. When R 7 is (CH2)nAr, n is preferably zero or 1 and Ar is preferably phenyl substituted or unsubstitued by halogen or C 1 5 alkoxy.

*R

1 is hydrogen. phenyl, pyridyl wherein the phenyl and pyridyl may be substituted or unsubstituted by one or two C 1-alcyl groups; C 1 -alkyl. C2- 8 alcenyl, S C 2 8 alkynyl, all of which may be substituted or unsubstituted by one or more OH, CH',OH. N(R6) 2 or halogen; R 1 2 is hydrogen or C 1 -alkyl.

R 13 is phenyl, pyridyl. or C 2 1 alkylene. all of which may be unsubstituted or substituted by one or more CO 2

R

6 OH, CH 2 OH, N(R 6 2 or halogen; ncri-fa.w.ki- hI4,'negsn rCr, Ik-vI o-a ethvi- i~qnnmnvi. n-butvlcyclopropylmethyl or cyclopropylethyl.

is preferably Preferred compounds are: I-n-Butyl-5-(2-(2-carboxy-6-chlorophenyi)methoxy-4-chlorophenyl1-1

IH-

pyrazol- 4 -yII-2-((5-methoxy-2,3-dihydroberlzofuran-6.yI)methyll..prop-2enoic acid; I-n-Butyl-5-(2-(2-carboxyphenyl )methoxy-4-chlorophenyl]- IH-pyrazol-4yII-2-[(5-mcthoxy-2,3-dihydrobenzofuran-6-yl)methyl J-prop-2-enoic acid; (E n-B uryl-5-[2-(2-carboxyphenyl)methoxy-4-methoxyphenyl I-I H-pyrazol-4yI j-2-15-methoxy-2,3-dihydroberizofuran-6-yI )medtiyI-prop-2-enoic acid; I1- n-BucyI-5-[2-(2-carboxy-6-chioropheriyl)methoxy-4-methoxyphenyl]- 1 Hpyrazol-4-yll-2-[(5-methoxy-2.3-dihydrobenzofuran-6&yl)methylj-prop.2.enoic acid; n-Butyl-5-(2-(2-carboxy-5-chlorophenyl)methoxy-4-methoxyphenyl..IH to pyrazol-4-yII-2-[(5-rnethoxy-2.3-dihydrobenzofuran-6-yl)methyll-prop-2..enoic acid; I- n-ButyI-5-(2-(3-carboxy-2-pyridyI)methoxy-4-methoxypheny] I Htoo pyrazol-4y]-2-(5-metoxy-2.3-dihydrobenofuran5-y)methyl..prop.2enoic acid; 210 or (E n-Butyl-5-f2-(2-carboxy-5-chlorophenyl)methoxy.4-chloropheny]. I Hpy razol -4-y1] -methoxy-2.3 -dihydrobenzofuran-6-y I)methyI] -prop- 2-eno ic acid.

The compounds of Formula may be made by methods similar to those given below.

WG 97/04772 WO 9704772PCT/US96/I 2581 Compounds of the Formula (Id): (1d) a a.

a abe.

a .a a a wherein one B is CH 2 and the other is 0 can be prepared by alkylating a ketone of Formula (2) in dirnethyl carbonate in the presence of sodium hydride to provide a b-keto ester of Formula C0 2

CH

3 11 WO'97/04772 PCTIUS96/1 2581 Condensation of a b-keto ester of Formula with dimethyl formnate dimethyl acetal in a suitable solvent such as toluene at approximately 95 OC affords a compound of Formula IN C0CH 3

CH

3 S

S.

S

S. S S. Treatment of a compound of Formula with a hydrazine derivative of the Formula

A

15 7 NH-NH 2 wherein R 15 is C 1 alkyl; in suitable solvents such as methanol and water in the presence of sodium acetate provides a pyrazole of Formula C0 2 CH 3 12- WO 97/04772 PCTIUS96/12581 Reduction of an ester of Formula with a reducing agent such as diisobutylallurninum hydride in a solvent such as dichioromethane followed by oxidation with an oxidant such as Jones reagent in acetone affords an aldehyde of Formula (7.

CHO

S.

5* 5* 0 See.

0505

S

0055

S'S.

OS..

5.5.

~0 8* S

C

S. S 0* S ~5 .555..

0 Knoevenagel condensation of an aldehyde of Formula with a half acid of Formula wherein R 16 is CI1.8 alkyl

R

6 0 2 C C0 2

H

(H

13- WO 97/04772 PCTIUS96/12581 in a solvent such as benzene at reflux, in the presence of piperidinium acetate with azeotropic removal of water using a Dean-Stark apparatus to afford an ester of Formula R, R R coR,, N CO2 R 1 N CH,)n z 2

B

B- (9) Followed if necessary and desired by: 1) deprotection and alkylation and hydrolysis of the R 3 R, R R, R 15

R

16

Z

and Z 2 groups as required and; 10 2) salt formation Aldehyde condensation may be effected by heating in the presence of pyridine and acetic acid.

Conversion of an ester of formula into an acid may be carried out using conventional deprotection techniques i.e. hydrolysis.

A half acid of Formula 1 R 6 0 2 ,C COH

Z,

(CH2)n B q -B (8) 14- W6 97/04772 wherein R 16 is C1-8 alkyl and n1 is 1, may be prepared staning from 4-methoxyphenol PCTIUS96/12581 OMe

III

OH

which upon bromination affords a bromobenzene of Formula (11).

OMe

ZI

Br OH (1 Alkylation of phenol of Formula (11) with 1 .2-dichloroethane under phase transfer reaction conditions provides a compound of Formula (12).

C

(12) 15 WO 97/04772 PCT/US96/12581 Treatment of bromobenzene of Formula (12) with an organolithium reagent such n-butyllithium or metal such as magnesium in a solvent such as tetrahydrofuran affords dihydrobenzofuran of Formula (13).

Z,

(13) Bromination of a compound of Formula (13) with hexamethylenetetraamine hydrobromide perbromide in a solvent such as dichloromethane provides bromodihydrobenzofuran of Formula (14).

M

Br (14) Metal-halogen exchange of compound of Formula (14) using an organolithium reagent such n-butyllithium in a solvent such as tetrahydrofuran affords an aldehyde 15 of Formula MeO z.

OHC 16- WO 97/04772 PCT/US96/12581 Condensation of an aldehyde of Formula (15) with dialkyl malonate such as diethyl malonate in the presence of piperidine and acetic acid in a solvent such as benzene provides an ab-unsatuated ester of Formula (16).

EtOC OMe EtOKC

Z

O

(16) Treatment of an a,b-unsatuated ester of Formula (16) with sodium borohydride in ethanol followed by mono saponification with aqueous sodium hydroxide in a solvent such as ethanol affords, after acidification with aqueous hydrochloric acid, an acid of Formula whereas R16 is ethyl and n is 1.

Other compounds of Formula (Id) may be made by methods well known in the art.

The invention also is a process for preparing compounds of Formula (Id)by: reaction of a compound of Formula (II) R4 R3 oR a r 0 15 s N 1 N) 17wo 97/04772 PCTIUS96/2581 or a protected form or precursor thereof (as defined hereinafter) with a compound of Formula (8) Z 16 0 2 C CO 2

H

B((CH)n

V

2

B

-B (8) wherein one B is CH 2 and the other is 0, and Z

I

Z

2 and R 16 are as defined for Formula (Id) hereinabove; followed if necessary or desired by: conversion of one compound of Formula (Id) into a different compound of Formula (Id) e.g.

when Formula (Id) contains a group CO 2

R

6

CO

2

R

7 or CO 2

R

12 or

CO

2

R

16 wherein R 6

R

7

R

12 or R 16 is alkyl, conversion to a corresponding compound where R 6 R7, R 12 or R 16 represents hydrogen; 15 (ii) when Formula (Id) contains hydroxy group in R 3

R

4 or R 5 conversion to a different group, e.g. a group (CH 2 )Ar where Ar is optionally substituted phenyl, by method well known in the art; and/or salt formation.

It will be appreciated by those skilled in the art that the substituents R 15

R

3

R

4 and R 5 and be introduced at any appropriate stage of the synthesis, preferably at an early stage, using methods well known in the art In some of the reactions depicted above, particularly those in the early stages of the overall synthesis, one or more of the substitutents R 15

R

3

R

4 and R 5 may therefore represent a precursor for the eventual substituent. A precursor for any of the substituents R 15

R

3

R

4 and R means a group which may be derivatised or converted into the desired group R 15 18-

R

3

R

4 and R 5 It will be further appreciated that it may be necessary or desirable to protect certain of these substituents (or their precursors) at various stages in the reaction sequence. Suitable precursors and protecting groups as well known to those skilled in the art, as are methods for their conversion of removal respectively.

The present invention now provides for an intermediate of the formula (II) wherein R 15

R

3

R

4

R

5 and R a are as described for Formula Compounds of Formula (Ii) Ra Ra C* R' rN

N

A,

P CH 2 )n (Ii) ei wherein one B is CH2 and the other is O; can be prepared starting by commercially available ketones of Formula (17)

R:

R

1 0 (17) 19- W6 97/04772 WO 9704772PCTIUS96!1 2581 by reaction with diethyl oxalate of Formula 18) EtC 'jfQ" t 0 (18) in the presence of a base such as sodium ethoxide in a solvent such as ethanol to produce a diketone of Formula (19).

0 0 (19) Reaction of a diketone of Formula (19) with hydrazine derivative of Formula R

.NH

2 in a suitable solvent such as ethanol at reflux provides a pyrazole of Formula (2 1).

A

15

CO

2 Et

NN

RI (21) WO 97/04772 wo 9704772PCT/US96/1 2581 Saponification of an ester of Formula (2 1) using lithium hydroxide in a solvent such as aqueous methanol affords, after acidification an acid of the Formula (22).

4 R3 (22) 4*

*.SO

which can be subsequently converted to the corresponding N-methoxy-Nmethylarnide of Formula (23)

R

4 R3 0

N

1

NN

RI (23) 10 by treatment with methyl chloroformate followed by N,0-dimethylhyciroxylamine hydrochloride in the presence of a base such as N-methylpiperidine. Compound of Formula (23) can be treated with an organometallic reagent Ra-M wherein Ra is -21 WO 97/04772 PCT/US96/12581 C 1-6 alkyl and M is Li or MgCl, to provide a compound of Formula wherein Ra is C 1-6alkyI.

(24) Alternatively, reaction of compound wherein Ra is Cl-6alkyI, with Lawesson's reagent in a suitable solvent such as tetrahydrofuran affords a thione of Formula which can be treated with the diazoester (26) 2

R

16 R 2 (26) 22 WO 97/04772 WO 9704772PCT/US96/12581 in refluxing tetrahydrofuran to provide a thiirane of Formula (27).

R 4 A3 N N PN CH 2 )n

B

B-i (27) Treatment of a thiirane of Formula (27) with trimethyiphosphite at reflux in a solvent such as chloroform provides compounds of Formula wherein Ra is C 1 6 alkyI.

A

4 R 3 jRa N 1N PI ~CH 2 )n B2 Zj

B

B (28) 0 Saponification of an ester of Formula (28) using lidiumh hydroxide in a solveni suc.h as aqueous methanol affords, after acidification with acetic acid, an acid of the Formula wherein P is CO2H.

23 Wd 97/04772 WO 9704772PCTIUS96/1 2581 Compounds of the Formula (Ie) B (lUe) wherein one B is C- and the other is 0; can be prepared following the steps outlined in the following Scheme R 1 N 1 1 1 T M S

H

CO Ri (29) 0 N TMS

R

1 Me 3 06BF 4 CsF

A

15 C0 2 Me starting from an aryl ester of Forrmula wherein R 16 is CI1-8 ailkyl, to provide a pyrrole of Formula Compound of Formula (30) can be subsequently converted to compounds of Formula (le) following the same sequence of steps as the one 24 WO 97/04772 PCTIUS96/12581 described above for the conversions of compound and compound (21) to compounds (Id) and compound respectively.

Compounds of Formula (Ih) may be prepared starting from a boronic acid of Formula (31) R 4 5

B(OH)

2 (31) with a triazole of Formula wherein X is Cr or Br;

X*

R-N N

CO

2 Me N=N (32) o under standard Suzuki coupling conditions to provide an ester of Formula (33) R 3 R R N

CO

M e 1: NN (33) A compound of Formula (31) may be prepared by reaction of a corresponding organometallic derivative (eg lithium or Grignard) with a triaikyi borate followed by hydrolysis.

WO 97/04772 PCTIUS96/1 2581 A compound of Formula (32) may be prepared starting from dimethyl malonate with p-acetarniinobenzenesulfonyl azide in a solvent such as acetonitrile in the presence of a base such as triethyl amine to provide dimethyl diazornalonate (34).

CH 3 0-U OCH 3

N

2 (34) Treatment of diazomalonate of Formula (34) with an amnine of Formula Ri! NH2(35) followed by acidic work up provides a triazole of Formula (36) ~0

OH

R 7-N N

CO

2

MO

N=N

(36) Reaction of a compound of Formula (36) with PX 5 whereas X is Br or Cl, in the 15 presence of potassium carbonate in dimethylformamide affords a compound of Formula (32).

Compounds of Formula (Ij) may be prepared starting from an analine of Formula (37) NH 2 (37) 26 WO 97/04772 WO 9704772PCTIUS96/12581 with a diketorie of Formula of (38) C0 2

RIS

0 0 (38) in a suitable solvent such as ethyl alcohol at reflux to provide a pyrrole of Formula (39).

RIS N C0 2

R

16

S

S.

S

S

(39) A diketone of Formula of (38) can be prepared by reacting of ab-unsatuated ketone of Formula 0

R'

with a silyl enol ether of Formula (41) Me 3 SiO OSiMe 3 EtO ORt (41) in the presence of Lewis acid such as zinc chloride in a suitable solvent such as dichioromethane followed by acidic hydrolysis.

27 WO '97/04772 PCT/US96/12581 Compounds of Formula (33) and compounds of Formula (39) can be subsequently converted to compounds of Formula (Ih) and compounds of Formula (Ij), respectively, following the same sequence of steps as the one described above for the conversions of compound compound (21) and compound (30) to compounds compound (Ii) and compound respectively.

In order to use a compound of the Formula or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Compounds of Formula and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration.

Compounds of Formula and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include i magnesium stearate. terra alba, talc, gelatin, agar, pectin, acacia, stearic acid. starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums. celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a 28- WO '97/04772 PCT/US96/12581 parenterally acceptable oil. for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.

Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.

A typical suppository formulation comprises a compound of Formula or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.

Typical transdermal formulations comprise a conventional aqueous or nonaqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.

*15 Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.

Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from I mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound

S,

of Formula or a pharmaceutically acceptable salt thereof calculated as the free acid. Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to of a compound of Formula The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person. The active -29- WO 97/04772 PCT/US96/12581 ingredient may be administered from I to 6 times a day, sufficient to exhibit the desired activity.

No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.

The biological activity of the compounds of Formula are demonstrated by the following tests: I. Binding Assay A) CHO cell membrane preparation.

CHO cells stably transfected with human ETA and ETB receptors were grown in 245 mm x 245 mm tissue culture plates in Dulbecco's modified .e SEagle's medium supplemented with 10% fetal bovine serum. The confluent cells were washed with Dulbecco's phosphate-buffered saline containing a protease inhibitor cocktail (5 mM EDTA, 0.5 mM PMSF, 5 ug/ml of leupeptin and 0.1 U/ml of aprotinin) and scraped in the same buffer. After centrifugation at 800 x g, the cells were lysed by freezing in liquid nitrogen and thawing on ice followed by homogenization (30 times using a glass dounce homogenizer) in lysis buffer containing 20 mM Tris HCI, pH 7.5, and the protease inhibitor cocktail. After an initial centrifugation at 800 x g for 10 min to remove unbroken cells and nuclei, the supernatants were centrifuged at 40,000 x g for 15 min and the pellet was resuspended in 50 mM Tris HCI, pH 7.5. and 10 mM MgCl 2 and stored in small aliquots at -70*C after freezing in liquid N 2 Protein was determined by using the BCA method and BSA as the standard.

Binding studies.

125 1]ET-1 binding to membranes prepared from CHO cells was performed following the procedure of Elshourbagy et al. (1993). Briefly, the assay was initiated in a 100 ui volume by adding 25 ul Uof 1 ijT- (0.2-0.3 UM) -i 0.05% BSA to membranes in the absence (total binding) or presence (nonspecific binding) of 100 nM unlabeled ET-1. The concentrations of membrane proteins were 0.5 and 0.05 ug per assay tube for ETA and ETB receptors, respectively. The incubations (30°C. 60 min) were stopped by dilution with cold buffer (20 mM Tris WO 97/04772 PCTIUS96/12581 HCI. pH 7.6, and 10 MM MgCl2) and filtering through Whatxnan GF/C filters (Clifton, NJ) presoaked in 0. 1% BSA. The filters were washed 3 times (5 ml each time) with the same buffer by using a Brandel cell harvester and were counted by using a gamma counter at 75% efficiency.

The following examples are illustrative and are not limiting of the compounds of this invention.

EAMPLE I I -n-B utyl-5-[2-(2-carboxy-6-chlorophenyl)methoxy-4-chlorophenyl I Hpyrazol-4-yl 1-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid a) 2-B romo-4-methoxyphenol To a solution of 4-methoxyphenol (13.00 g, 104.84 mznol) in DMIF (50 mL) was added bromine (5.40 mL, 104.84 mrnol) at 0 OC. The reaction was allowed to warm to room temperature. After stirring for 2 h the reaction was quenched with water and :extracted with ethyl acetate (3x200 rnL). The combined organic extracts were washed with brine and dried (Na 2

SO

4 Removal of the solvent under reduced pressure gave 21.28 g of the crude title compound as a dark oil: 'H NMR (250 MHz, CDC1 3 d 7.49 1H), 6.96 1H), 6.72-6.62 (in, 2H), 3.71 3H).

b) 2-Bromo- 2-chloroethoxy)-4-methoxybenzene To a solution of 2-bromo-4-methoxyphenol (20.00 g, 98.04 mmol) in 1 .2-dichloroethane (50.00 mL, 0.63 inol) was added sodium hydroxide (12.00 g, 0.29 mol) ar1%U LClzUIi IU1Uiy IVuu LULII t6IAUII1U k.7.VU Jj III VVIA&w k L-V LAL). LIIAw stirred at reflux for 24 h and extracted with ethyl acetate (3x 150 mL). The combined organic extracts were washed with brine and dried (Na 2

SO

4 After removing the solvent under reduced pressure, flash chromatography 1 diethyl ether/hexane) of 31 WO'97/04772 PCTfUS96M581 the residue gave 14.20 g (66% over two steps) of the title compound as a yellow oil: 'H NMR (250 MHz, CDCl3) d 7.09 I 6.82-6.72 (in. 2H), 4.27 2H), 3.75 3H), 3.71 3H).

c) 5-Methoxy-2,3-dihydrobenzofuran To a solution of 2-bromo- 1-(2-chloroethoxy)-4-methoxybenzene (1.38 g, 5.22 inmol) in THE was added 190 mg (7.82 rnmol) of Mg and Mel (3 The mixture was sonicated for 2. h and stirred at room temperature for additional 20 h. The reaction was quenched with 3N HCI (50 rnL) and extracted with 1: 1 hexane/ethyl acetate (3x50 ml). The combined organic extracts were washed with saturated NaHCO 3 brine and dried (Na 2

SO

4 After removing the solvent under reduced pressure, flash chromatography (3:1 hexane/ethyl acetate) of the residue gave 0.66 g of the title compound as a colorless liquid: 'H NMR (400 MHz, CDCI 3 d 6.80 IH). 6.70 18). 6.65 (dd. 1H), 4.53 2H), 3.75 38), 3.18 3H).

d) 6-Bromo-5-methoxy-2.3-dihydrobenzofuran To a solution of 5-methoxy-2.3-dihydrobenzofuran (1 .00 g, 6.66 inmol) in dichloromethane (10 ml-) was added hexamethylenetetraarnine hydrobromide perbromide (2.79g. 7.32 mxnol) at -78 OC. The reaction was allowed to warm to room temperature. After stirring for 3 h, the reaction was quenched with water and extracted with ethyl acetate (3x50 rnL). The combined organic extracts were washed with brine and dried (Na,S0 4 Removal of the solvent under reduced pressure gave 1.45 g of the title compound as a dark solid: 'H NMR (250 MHz, CDC1 3 d 7.00 18), 6.82 18), 4.57 2H), 3.81 3H), 3.15 28).

e) 5-Methoxy-2.3-dihydrobenzoftuwa-6-aI To a solution of 6-bromo-5-methoxy-2.3-dihydrobenzofuran (9.20 g, 40.35 mmol) in THF (50 miL) was dropwise added n-Butyl lithium (24.00 mL, 38.40 mmnol) at 32 WO 97/04772 PCT/US96/12581 -78 OC. After stirring for 30 min, DMF (5.00 mL, 60.53 mmol) was added and the mixture was allowed to stir at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate (3x150 mL). The combined organic extracts were dried (Na 2 SO4) and the solvent was removed under reduced pressure.

Flash chromatography (1:1 ether/hexane) of the residue afforded 5.42g of the title compound as a yellow solid: 'H NMR (250 MHz, CDC1 3 d 10.32 1H), 6.90 1H), 6.82 1H), 4.57 2H). 3.91 3H), 3.25 2H).

f) Diethyl 2-(5-methoxy-2,3-dihydrobenzofuran-6-yliden)-malonate To a solution of 5-Methoxy-2,3-dihydrobenzofuran-6-al (295 mg, 1.66 mmol) in benzene was added diethyl malonate (265 mg, 1.66 mmol), acetic acid (20 mL, 0.35 mmol) and piperidine (30 mL, 0.30 mmol). The mixture was heated at reflux for 3 h and then poured into 100 mL of water. This mixture was extracted with three mL portion of ethyl acetate. The combined organic extracts were washed with brine and dried (Na 2

SO

4 Removal of the solvent under reduced pressure gave quatitative yield of the title compound as a yellowish oil: 'H NMR (400 MHz, CDC1 3 d 8.02 1H), 6.79 1H), 6.78 1H), 4.52 2H), 4.30 4H), 3.80 3H), 3.18 (t, 2H), 1.28 6H).

g) Diethyl 2-(5-methoxy-2,3-dihydrobenzofuranyl)methyl-malonate To a solution of diethyl 2-(5-methoxy-2.3-dihydrobenzofuran-6-yliden)-malonate (1.80 g, 5.62 mmol) in ethanol (25 mL) was added sodium borohydride (0.22 g. 5.66 mmol) at room temperature. After stirring for 2 h the reaction was quenched with water and extracted with ethyl acetate (3x50 mL). The combined organic extracts were washed with brine and dried (Na 2

SO

4 After removing the solvent under reduced pressure, flash chromatography (1:1 diethyl ether/hexane) of the dark residue afforded 1.47 g of the title compound as a yellow oil: 'H NMR (250 MHz, CDC1 3 d 6.70 1H), 6.54 1H), 4.44 2H), 4.12 2H), 3.74 4H), 3.11 4H), 1.18 6H).

33 WO 97/04772PCfs6128 PCT/US96!12581 h) Ethyl, hydrogen 2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl-malonate To a solution of diethyl 2-(5-methoxy-2,3-dihydrobenzofuranyl)methyl-malonate (6.55 g, 20.34 mrnol) in ethanol (50 mnL) was added a solution of potassium hydroxide (1.35 g, 24.40 mmol) in water (10 mL). The reaction mixture was stirred at roam temperatur for 5 h. After concentrating the aqueous layer was washed with ether and acidified with concentrated HC1 to pH 1 and extracted with ethyl acetate (3 x 100 mL). The organic extracts were washed with brine and dried (Na2SO4).

Removal of the solvent under reduced pressure gave 5.26 g of the title compound as a white solid: 'H NMR (250 MHz, CDC1 3 d 11.43 1H). 6.72 (s, 1H), 6.58 1H). 4.48 2H), 4.16 2H), 3.82 IH), 3.75 3H), 3.14 (t, 3H), 1.20 3H); MS (ESI) rn/c 295.2 114- 116 OC.

i) 4-Chloro-2-hydroxyacetophenone In a 500 m.L of round bottom flask purged with argon was placed 26.00 g 153 :mol) of 3-acetoxychlorobenzene, coaled with ice bath. Then 30.00 g (0.225 rnol) of 3 was added in portions. The resulting mixture was heated to 140 oC for 2 h (caution: vigorous evolution of gas) and then coaled to QoC. treated with 15 ml- of conc. HCl in 100 mL of ice water, extracted with EtOAc (3x000 mL). The combined organic extracts were washed with brine and dried (Na 2

SO

4 Removal of the solvent gave 24.00 g of the title compound as a light yellow liquid: 'H NMR (250 MHz, CDC1 3 d 10.7 1H), 7.65 J=8.6 Hz. IH). 6.98 1.8 Hz. 1H), 6.87 (dd, J= 1. 8. 8.6 Hz. 1IH). 2.61 3 H).

To a solution of 4-chloro-2-hydroxyacetophenone (22.00 g, 0. 129 mol) in DMF (200 rnL) was added K 2 C0 3 (72.00 g, 0.516 mol) and bromomnethylmethyl ether 134 mol). After stirring at 55 OC for I h, the mixture was poured into water and extracted 34 WO 97104772 WO 9704772PCT/US96/I 2581 with EtOAc (30300 mL). The combined organic extrats were washed with brine and dried (Na2SO 4 and removal of the solvent under reduced pressure gave 25.00 g of the title compound as an oil: 'H NMR (250 MHz, CDC1 3 d 7.68 J=8.3 Hz. INH). 7.22 J= 1.8 Hz. IH), 7.00 (dd. J= 1.8, 8.3 Hz, I1H), 5.28 2H), 3.53 (s.

3H), 2.62 3H).

k) Methyl 2 4 -oro-2-methoxymehoxy)benzoylacetate To a solution of 4 -Chloro-2-methoxymethoxyacetophenone 25 .00 g. 0. 116 mol) in dimethyi carbonate (15 mL) was added 7.5 g of 80% NaN (0.257 mol). After stirring for 10 min. at room temperature, the mixture was heated to 70 OC for rru. The resulting mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and washed with brine and dried (Na 2

SO

4 Removal of the solvent under reduced pressure gave 29.00 g of the title compound as an oil: MS (ESI) mlz 273 (M+H) 4 'H NMR (400 MHz, CDCI 3 d 7.82 J=8.4 Hz, IH), 7.25 J= 1.8 Hz. IN), 7.06 (dd.

1. 8, 8.4 Hz, I1H), 5.25 2H), 3.97 2H), 3.72 3H), 3.51 3 H).

1) Methyl (Z)-2-(4-chloro-2-methoxymethoxy)benzoyl.3- (dimethylaznino)propenoate A mixture of Methyl 2 4 -chloro- 2 -methoxymethoxy)benzoylacetate (24.00 g. 0. 107 mol) and NN-dimethylformamiude dimethyl acetal (25.51 g, 0.2 14 mol) was heated to 90 OC overnight. Concentration under reduced pressure gave 34.86 g (100%) of the title compound as an oil: MS (ESI) m/z 328 'H NMR (400 M&z,

CDCI

3 d 7.71 (s,1IH), 7.25 INH), 7.13 (s,I1H), 7.00 INH), 5.12 2H). 3.46 (s.

6H), 3.44 6H).

WO 97/04772 WO 9704772PCT/US96/12581 m) Methyl 1 -n-butyl-5-(4-chloro-2-methoxyrnethoxyphenyl)- I H-pyrazol-4-yI carboxylate To a mixture of Methyl (Z)-2-(4-chloro-2-methOxymethoxy)benzoyl-3- (dimnethylfamino)propenoate (34.00 g, 0. 104 mol) and n-butylhydrazine (37.00 g.

0.208 mol) in 600 m.L of MeOHIH 2 O 1) was added NaOAc (84.86 g, 0.624 mol).

The resulting mixture was stirred at room temperature overnight and then partitioned between water and CH 2

CI

2 The organic layer was separated and washed with brine and dried (Na 2

SO

4 Removal of the solvent under reduced pressure gave 35.50 g of the title compound as an oil: M4S (ESI) rn/z 353 'H NMR (400 MHz, CDCI 3 d 7.93 IH), 7.04-7.22 (mn. 3H). 5.01 (dd, J=6.8, 9.5 Hz, 2H), 3.75- 3.92 (in. 2H), 3.60 3H), 3.30 3H), 1.65 (in. 2H), 1. 12 (mn, 2H), 0.74 3H).

n) I -n-Butyl-5-(4-chloro-2-inethoxymethoxyphenyl )4-hydroxyinethylpyrazole To a solution of Methyl 1 -n-butyl-5-(4-chloro-2-inethoxymethoxyphenyl)- 1 Hpyrazol-4-yl carboxylate (10.00 g, 0.028 mol) in 200 mL of CH 2

CI

2 at 0 OC was :added 85.2 m.L of 1.5 M Dibal1-H in toluene. After stirring for I h. the reaction was quenched with MeOH (100 inL) followed by addition of 35 m.L of conc. HCl in 200 mL of water. The resulting mixture was stirred for 15 min. and extracted with CH-)CI-) (3x200 mL). The combined organic extracts were washed with brine and dried (Na-,S0 4 Removal of the solvent under reduced pressure gave 9.50 g (97%) of the title compound as a oil: MS (ESI) flhz 325 'H NMR (400 MHz.

CDC1 3 d 7.63 (s,I1H), 7.13-7.29 (in,3H), 5.09 2H), 4.36 (dd. 2H), 3.80-3-98 3.35 3H), 1.70 (in, 2H). 1. 18 (in. 2H). 0.81 3H).

o) 1 -n-Butyi-5-(4-chioro-2-inethoxymethoxyphenyi)- IHr-pyrazoi-4-yi carboxaldehyde To a solution of I1-n-Butyl-5-(4-chloro-2-methoxymethoxyphenyl)-4hydroxyinethylpyrazole (10.00 g, 30.86 mmol) in 150 mnL of acetone at 0 OC was 36- WO 97/04772 PCTIUS96/12581 added of Jones' reagent until pink color persisted (30 mL). 60 mL of isopropyl alcohol was then added and the resulting mixture was stirred at room temperature for min, diluted with 300 mL of cold water, extracted with CH 2 Cl 2 (3x200 mL).

The combined organic extracts were washed with brine and dried (Na 2

SO

4 After removing the solvent under reduced pressure, flash column chromatography of the residue with 25% EtOAc in hexane gave 5.50 g of the title compound as an oil: MS (ESI) m/z 323 'H NMR (400 MHz, CDCI 3 d 9.54 8.07 (s, 1H), 7.35 1H), 7.18 2H), 5.13 2H), 3.90-4.05 2H), 3.38 3H), 1.75 2H), 1.20 2H), 0.83 3H).

p) Ethyl -n-butyl-5-(4-chloro-2-methoxymethoxyphenyl) -IH-pyrazol-4-yl]- 2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate To a mixture of 1-n-Butyl-5-(4-chloro-2-methoxymethoxyphenyl) 1H-pyrazol-4-yl carboxaldehyde (5.50 g, 17.08 mmol) and Ethyl, hydrogen 2-(5-methoxy-2,3dihydrobenzofuran-6-yl)methyl-malonate (7.28 g, 24.70 mmol) in 50 mL of benzene was added piperidine (2.16 g, 25.41 mmol) and AcOH (0.51 g, 8.50 mmol), respectively. After heating at reflux for 3 h, the mixture was poured into water, .extracted with EtOAc (3x100 mL). The combined organic extracts were washed with brine and dried (Na2SO 4 After removing the solvent under reduced pressure.

flash column chromatography of the residue with 25% EtOAc in hexane gave 4.50 g of the title compound as an oil: MS (ESI) m/z 555 NMR (400 MHz, CDCI 3 d 7.53 7.37 1H), 7.32 1H), 7.13 2H), 6.78 1H), 6.45 1H), 5.11 2H), 4.47 2H), 4.14 2H), 3.89 2H), 3.85 3H), 3.38 3H), 3.16 2H), 1.65 2H), 1.20(t, 3H), 1.17 2H), 0.79 3H).

q) Ethyl -n-butyl-5-(4-chloro-2-hydroxyphenyl)- IH-pyrazol-4-yl]-2-[(5methoxy-2,3-dihydrobenzofuran-6-yl)methyll-2-propenoate To a solution of Ethyl (E)-3-[1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-

IH-

pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate 37- WO 9704772PCT/US96/.12581 (4.50 g. 8. 10 mrnol) in EtOH (60 m.L) was added 0.6 m.L of conc. HCI. After heating at reflux for 3 h, the mixture was concentrated and then diluted with EtOAc. The resulting mixture was washed with 5% NaHCO 3 brine and dried (Na 2

SO

4 After removing the solvent. column chromatography of the residue with 25% EtOAc in hexane gave 2.65 g of the title compound as a solid: m.p. 158-160 OC'- MS (ES) rn/z 511 'H NMR (400 MHz, CDCI 3 d 7.58 IH), 7.47 I H), 7.02 1H), 6.78 IH), 6.62 (dd, IH), 6.59 1H). 6.48 2H), 5.50 (bs, 1H), 4.48 2H), 4.12 (in, 2H), 3.85-3.95 (mn, 4H), 3.83 3H), 3.81 3H), 3.16 2H), 1.67 (in, 2H), 1.20 3H), 1. 17 (mn, 2H), 0.80 3H).

r) Methyl 3-chloro-2-inethylbenzoate To a solution of 3-chloro-2-inethylbenzoic acid (1.00 g, 5.86 inrol) in methanol mL) was added 3 drops of sulfuric acid. The mixture was stirred at reflux for 18 h.

After concentrating the residue was dissolved in ether, washed with 10% sodium hydroxide solution, brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 0.95 g of the title compound as a white solid: 'H NMR (250 MHz, CDCI 3 d 7.62 IH), 7.41 1H), 7.05 IH), 3.82 3H), 2.55 (s, 3H).

s) 2-Chloro-6-methyl carboxylate benzylbroinide To a solution of methyl 3-chloro-2-methylbenzoate (1.30 g, 7.04 mmiol) in benzene ml) was added NES (1.50 g. 8.45 inmol) and berizoyl peroxide (0.20 g. 0.83 inxol). After stirring at reflux for 18 h, the mixture was poured into water, and the resulting mixture was extracted with ethyl acetate (3x50 inL). The combined organic were was'hed WILLh bOn=eL~ an u rid aS After Izemv"ig the soIlen under reduced pressure, flash column chromatography 1 ether/hexane) of the residue gave 1.87 g of the title compound as a dark oil: 'H NMR (250 MHz, CDC1 3 d 7.72 IH), 7.55 1H), 7.21 1H), 5.09 2H), 3.92 3H).

38- WO 97/04772 PCT/US96/1 2581 t) Ethyl I -n-butyl-5-[2-(2..methoxycarbonyl)phenYlmethoxy4-chloro-phenyI..

1 H-pyrazol- 4 -yI-2-[(5-mehoxy-2.3-dihydrobenzofuran-6-yl)methyl].2-propenoate To a solution of the ethyl (E)-[lI-n-buryl-5-(2-hydroxy-4-chlorophenyl)- IH..pyrazol.

4-yl J-2-[(5-methoxy-2.3-dihydrobenzofuran-6-yl)methylJ-2.propenoate (0.20 g, 0.39 mmol) and methyl 2-bromomethyl-3-chlorobenzoate 13 g, 0.47 mnmol) in DMIF mL) was added sodium hydride (0.02 g, 0.59 mmol) at 0 0 C. The mixture was stirred at room temperature for 4 h. After an aqueous work up, extracting with ethyl acetate (3 x 15 the combined organic extracts were washed with brine and dried (Na,7SO 4 After removing the solvent under reduced pressure, flash column chromatography 1 ethyl acetate/hexane) of the residue afforded the titde compound as an oil (0.22 g, 'H NM1R (250 MHz, CDCI 3 d 7.78 I 7.55 IH), 7.48 IH), 7.32 (in, 2H), 7.12 2H), 6.75 IH), 6.45 lH), 5.55 (dd, 10, 27.5 Hz, 2H),4.49 4. 10 2H), 3.83 3H) 3.77 2H), 3.65 3H), 3.15 2H). 1.52 (quintet, 2H), 1.20 3H), 1.05 (sextet. 2H), 0.75 3H).

u) 1 -n-Butyl-5-(2.(2-carboxy-6-chorophenyl)nethoxy4chlorophenyll.. 1Hpyrazol-4-yl]-2- [(5-inethoxy-2.3-dihydrobenzofuran-6-yl)methyl]-propen-2 -oic acid To a solution of the ethyl I-n-butyl-5-(2-[2-(methoxycarbonyl)-6c hlorophenylmethoxy]-4-chlorophenylJ- I H-pyrazol-4-y]-2-X5-methoxy-2,3dihydrobenzofuran-6-yl)methyl]-2-propenoate (0.20 g, 0.29 mxnol) in methanol rnL) was added a solution of sodium hydroxide (0.04 g, 0.87 mmrol) in water (2 iL).

The mixture was stirred at reflux for 18 h. The methanol was removed under reduced pressure and the aqueous layer was washed with ether. The aqueous layer was then acidified with concentrated HC1 to pH I and extracted with ethyl acetate (3 x rn he cobndogn wetais were washed with waier, brine and dried (Na2SO4). Removal of the solvent gave a solid. Recrystallization from methanol yielded the title compound as a light yellow solid 17 g, 9 1 I H NNM (400 MHz CDC1 3 d 7.75 1H), 7.80 1H), 7.48 (in, 2H), 7.33 IH). 7.25 1H).

7. 10 LH), 7.05 (mn, 2H), 6.65 IH), 6.35 IH), 5.49 (dd, J=10, 27.5 Hz, 2H), 39 WO 97/04772 PCT/US96i12581 4.40 2H), 3.79 5H) 3.63 2H), 3.05 2H), 1.50 (quintet, 1.30 (quintet.

1H). 0.94 (quintet. 2H). 0.60 3H); MS(ESI) rn/e 652.2 mp: 155-157 OC (methanol); Anal. (C 3 4

H

3 2 C1 2

N

2 0 7 calcd: C, 62.62; H. 4.96; N, 4.30. found: C.

62.40; H. 5.32; N, 4.19.

EXAMPLE2 .n-Butyl-5-(2-(2-carboxyphenyl)methoxy4-chorophenyl tIH-pyrazol-4ylJ-2-15-methoxy-2.3-dihydrobenofuran-6-yl)methyll-prop2-enoic acid a) Ethyl I n-Butyl-5-[2-(2-methoxycarbonyl)phenylmethoxy.4.

chiorophenyl]- IH-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6yl)methyl -2-propenoate Following the procedure of Example (it) except substituting methyl 2bromomethylbenzoate for methyl 2-bromomethyl-3-cbhlorobenzoate, the title compound was prepared in 85% yield.

b) Following the procedure of Example (lu) except substituting Ethyl In-Butyl-5-[2-(2-methuxycarbony)phenylmeLoxy-~-ciorophenylJ. 1H-pyrazol-4yl]-2- [(5-methoxy-2.3-dihydhrobenzofuan-6-yl)methyl-2-propenoate for ethyl I[ -n-butyl-5-(2.(2.(methoxycarbonyl)-6-chlorophenylmethoxy]4chlorophenyl.

I H-pyrazol-4-yl]-2-[(5-methoxy-2,3.dihydrobenzofuran&yl)methyl]-2-propenoate the title compound was prepared in 90% yield as a white solid: Rf0.58 (1:1 EtOAchexane with 1% AcOH); 1 H NMR (400 MHz CDC1 3 d 8.19 1H). 7.58 1H), 7.53 1H), 7.49 1H), 7.30 2H), 7.13 3H), 6.77 1H), 6.48 (s, 1H), 5.52 (bs, 2H), 4.45 2H), 3.92 2H) 3.82 3H), 3.80 (bs, 2H), 3.12 (t, 2H), 1.65 2H), 1.12 2H), 0.76 3H); MS(ESI) Wre 618 mp: 116- 1 180C. Anal. (C 3 4

H

3 3 C1N 2 0 7 .0.5H 2 0) calcd: C, 65.22; H, 5.47; N, 4.47. found: C, 65.03; H. 5.33; N, 4.37.

wo 97/04772 PCT/US96/12581 WO 97/4772 CT/US9/1258 1 n-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-methoxyphenyl.. 1 H-pyrazol-4y 11-2 fdihydroberizofurari-5-y I)methyl I]-prop- 2-enoic acid 98-99*C EXAMPE 4 I1- n-Butyl-5-[2-(2-Carboxyphenyl)methoxy-4-methoxyphenyl]- I H--pyrazol- 4-yI]-2-[(6-methoxy-2.3-dihydrobenzofuran-5-yl )methyl]-prop-2-enoic acid 104- 106 0

C

1- n-Butyl-5-[2-(2-Carboxyphenil)methoxy-4-methoxyphenyl]- 1H-pyrazol- 4 ((5-methoxy-2,3-dihydrobenzofuran-6-yl )methyl]-prop-2-enoic acid 1 98-200 0

C

EXAML

1- n-Butyl-5-(2-(2-Carboxy-6-chlorophenyl)methoxy-4-inethoxyphenyl]- 1HpyrazolA4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methy1]-prop-2-enoic acid EAMLE 7 1- n-Bucyl-5-[2-(2-Carboxy-5-chlorophenyl)methoxy-4-methoxyphenyl1-I

I--

**pyrazol-4-y I] -methoxy- 2.3-dihydrobenzofuran.6-yi)methylIlI-prop- 2-enoic acid 122-124 0

C

I1- n-Buryl-5-(2-(2-Carboxy-4-chlorophenyl)methoxy-4-methoxyphenyl- I- Hpyrazol-4-yl]-2-[(5-methoxy-2,3-dihydroberizofuran-6-yI)rnethyll-prop-2-enoic acid 120- 122 0

C

EXAMPE9~ 1 n-Butyl-5-(2-(3-carboxy-2-pyridyl)methoxy-4-methoxyphenyl]- 1 Hpyrazol-4-y]-,2-[(5-methoxy-23-dihydrobenzofuran-5-yi)methyl]-prop-2-eioic acid -41 WO 97/04772 PCT/TJS96/12581 WO 97/0472 PEXAMPLE1 258 1 n-Butyl-5-f2-(cyciopeinyloxy)-4-methoxyphenyl]- 1 H-pyrazol-4-yI]- 2-R(5-methoxy-2.3-dihydrobenzofuran-6-yl)methyl] -prop-2-enoic acid 156- 158 0

C

EXAMeLIEI I1- n-Buryl-5-(2-(N,N-diethylarniido)methoxy-4-methoxyphenyl)- I H-pyrazol.

4-yI]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-y)methyl]-prop-2.enoic acid 178- 180 0

C

1 n-ButyI-5-[2-(5-tetrazolyl)methoxy-4-methoxyphenyl- 1 H-pyrazol-4-yI]-2- (5-rnethoxy-2.3-dihydrobenzofuran-6&yI)-methyl]-prop-2-enoic acid 128-130 0

C

EAMPLE 13 1 n-Butyl-5-[2-(2-picolyl)oxy-4-methoxylphenyl- I H-pyrazol-4-yi]-2-(5methoxy-2,3-dihydrobenzofuran-6-yl)-methyl]-pop-2-eioic acid 132-135 0

C

EAMPLE 14 1 n-ButyI-5-[2-(2-Carboxy-5-chlorophenyl)rnethoxy.4-chlorophenylI- I HpyrazolI-4-y -methoxy -2,3 -dihydrobenzofurai-6-y I)rnethylI prop- 2-enoic acid 110- 1 12 0

C

I- n-Butyl-5-[2-(4-methoxyphenoxy)-4-methoxyphenyl]- IH-pyrazol-4-yII-2- [(5-methoxy-2,3-dihydrobenzofuran-6-y)methyl-prop-2-enoic acid 91-92 0

C

1- n-Butyi-5-(2-N-ethyl-5-tetrazolyl)methoxy]-4-rnethoxyphenyl- IH-pyrazol- 4-yl]-2-[(5-methoxy-2,3-dihydrofuran-6-y)methyi]-prop-2-enoic acid 42- WO 97/04772 PCT/US96/12581 EXAMPLE 17 l-n-Butyl-5-[ 1 -N-ethyl-5-tetrazolyl)methoxyl]-4-methoxyphenyl-H 1-pyrazol- 4-yl]-2-[(5-methoxy-2,3-dihydrofuran-6-yl)methyll-prop-2-enoic acid EXAMPLE 18 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients.

Examples of such formulations are given below.

Inhalant Formulation A compound of Formula I, (1 mg to 100 mg) is aerosolized from a metered *o$0e 0% 0dose inhaler to deliver the desired amount of drug per use.

Tablets/In gredients Per Tablet o 1. Active ingredient 40 mg (Cpd of Form. I) 2. Corn Starch 20 mg 3. Alginic acid 20 mg 4. Sodium Alginate 20 mg 5. Mg stearate 1.3 mg 2.3 mg Procedure for tablets: Step 1 Blend ingredients No. 1, No. 2. No. 3 and No. 4 in a suitable mixer/blender.

Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.

Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.

Step 4 The wet granules are then dried in an oven at 140°F (60°C) until dry.

-43- Step 5 The dry granules are lubricated with ingredient No. Step 6 The lubricated granules are compressed on a suitable tablet press.

Parenteral Formulation A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur.

(to 100 mi). The solution is then steriled by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

e **6 e e e **o ooo go 44

Claims (1)

1. 2. A compound according to claim 1 substantially as hereinbefore described with 10 reference to the Examples. DATED this 14th day of March, 2002 SmithKline Beecham Corporation by DAVIES COLLISON CAVE 15 Patent Attorneys for the Applicant C*