NZ264237A - Cyclo-penta, -hexa and -hepta pyrazole-3-carboxaldehyde derivatives - Google Patents
Cyclo-penta, -hexa and -hepta pyrazole-3-carboxaldehyde derivativesInfo
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- NZ264237A NZ264237A NZ264237A NZ26423792A NZ264237A NZ 264237 A NZ264237 A NZ 264237A NZ 264237 A NZ264237 A NZ 264237A NZ 26423792 A NZ26423792 A NZ 26423792A NZ 264237 A NZ264237 A NZ 264237A
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Description
New Zealand Paient Spedficaiion for Paient Number £64237
264237
iSuiuy Date(v):
Complete Specification Filed:
Class; M.ccrl&.'l&V
Publication Date: 2-
6...S.EP.J995
P.O. Journal No:
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PATENTS FORM 5 PATENTS ACT 1953 COMPLETE SPECIFICATION
Number Dated
INTERMEDIATES USEFUL IN MAKING TETRAHYDROINDAZO LE, TETRAHYDROCYCLOPENTAPYRAZOLE, AND HEXAHYDROCYCLOHEPTAPYRAZOLE COMPOUNDS USEFUL AS HMG-COA REDUCTASE INHIBITORS
We, ORTHO PHARMACEUTICAL CORPORATION, of US Route #202, Raritan, New Jersey 08869-0602, United States of America, a corporation organized under the laws of the State of Delaware, United States of America do hereby declare the invention for which I/we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement.
• 1a *64237
This application is a divisional application of New Zealand Patent application No. 243575.
BACKGROUND OF THE INVENTION
Compounds which inhibit HMG-CoA reductase, the enzyme controlling the rate-limiting step in cholesterol biosynthesis, are assuming an important role in the management of certain forms of hyperlipidemia. Lovastatin, disclosed in U. S. Patent 4,231,938, has been approved for use in the treatment of primary hypercholesterolemia, a disease characterized by normal serum triglyceride levels and elevated serum levels of low density lipoprotein (LDL) cholesterol and total cholesterol. In several large clinical studies, lovastatin was found to decrease plasma LDL and total cholesterol concentrations 25% to 40% while causing small but significant increases (up to 10%) in high density lipoprotein (HDL) cholesterol concentration. When compared with cholestyramine and probucol, two drugs used in the treatment of primary hypercholesterolemia, lovastatin reduced LDL cholesterol levels to a significantly greater extent. In addition, combined administration of lovastatin with other hypolipidemic agents was found to potentiate their effects on LDL and total cholesterol concentrations.
The biochemical target for lovastatin is HMG-CoA reductase, the enzyme which catalyzes the reduction of HMG-CoA to mevalonic acid. Lovastatin, in its open dihydroxy acid form, is a reversible, competitive inhibitor of the enzyme. A number of compounds structurally related to lovastatin have been shown to be inhibitors of HMG-CoA reductase. These include simvastatin (U.S. Patent No. 4.444,784 and related compounds
2642 37
disclosed in U.S. Patent No. 4,444,784). Sankyo has reported a related compound, pravastatin (U.S. Patent No. 4,346,227). Sandoz has reported a number of HMG-CoA reductase inhibitors: indoles (U. S. Patent No. 4,739,073), pyrazoles (U.S. Patent No. 4,613,610), imidazoles (U.S. Patent No. 4,808,607), and pyrazolopyridines (U.S. Patent No. 4,822,799). Merck disclosed biphenyl-containing inhibitors in U.S. Patent No. 4,375,475. Hoechst AG disclosed non-heterocyclic HMG-CoA reductase inhibitors in Tetrahedron Letters. 1988, 29. 929. Bristol-Myers reported tetrazole-
containing compounds in UK Patent 2,202,846. Acylpyrroles are reported in U. S. Patent No. 4,681,893 by Warner-Lambert. Warner-Lambert also disclosed pyrimidines in U.S. Patent No. 4,868,185 and quinolines in U.S. Patent No. 4,761,419. Bayer AG reported tri-arylpyrroles in European Patent 287,890. Rorer reported aryl-cycloalkene and aryl-cycloalkadiene inhibitors in U.S. Patent Nos. 4,892,884 and 4,900,754. Squibb reported a number of potent compounds based on a variety of heterocycles in Journal of Medicinal Chemistry. 1990, 33. 2852. Finally, Upjohn disclosed in WO
867,357 an anti-inflammatory, anti-allergic compound genericallv described as cyclopentapyrazole.
The compounds of the NZ patent application 243575 are structurally different from the known compounds and have been shown to be potent inhibitors of HMG-CoA reductase and cholesterol biosynthesis. The compounds of the present invention are useful as intermediates for making the compounds of NZ patent application 243575.
^ C) ^ ^
SUMMARY OF THE INVENTION
Novel tetrahydroindazole, tetrahydrocyclopentapyrazole, and hexahydrocycloheptapyrazole compounds of the general formula X:
Wherein Rl5 R2, R3, Y, Z, n, and p are defined hereinafter have been found to be useful intermediates for making potent compounds for inhibiting HMG-CoA reductase and cholesterol biosynthesis and for use in the treatment or prevention of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis.
DETAILED DESCRIPTION OF THE INVENTION
New Zealand Patent Application No. 243575 is directed to compounds of the following general formula I:
Ri (CH2)p
N--N
X
Ri
(CP -2)p
N- -N
Uo 1
3 a kj 4)
wherein Ri is selected from any one of H, alkyl, aryl, or substituted aryl; wherein R2 is selected from any one of H, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, aralkenyl, or cycloalkyl;
wherein R3 is H; or wherein R2 and R3 may be taken together to form a benzo or naphtho ring system;
wherein Y is. alkyl or alkenyl;
wherein Z is selected from any one of:
II
or wherein R4 is selected from any one of H, alkyl, a protonated amine of the formula HN(Rs)3+ wherein R5 is any one of H or alkyl, or a cation;
wherein n = 0 to 3 and p = 0 to 3 and pharmaceutical^ acceptable acid salts thereof.
4
The Ri substituent may be attached either directly or indirectly to either of the ring nitrogens but' not both at the same time. Two double bonds represented by the dotted line in the nitrogen containing ring are positioned accordingly depending upon the position of the Ri substituent.
In preferred compounds Rj> R 2 ' ^ 3 > ^ and Z are as listed below.
Rj is selected from any one of H, Cj-~Cg alkyl, aryl, or substituted aryl.
Examples of suitable Ri substituents include 4-fluorophenyl and 4-chlorophenyl.
R2 is selected from any one of H, Ci-Cs alkyl, aryl, substituted aryl,
aralkyl wherein the alkyl portion is Ci-C4, substituted aralkyl wherein the alkyl portion is C1-C4, aralkenyl wherein the alkenyl portion is C2 -C4; or C3-C8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and the like. Examples of suitable R2 groups include H, 4-fluorobenzyl, 3-phenyl-2-15 propenyl, cyclohexyl, ethyl, methyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-
phenylbenzyl, benzyl, 4-chlorobenzyl, 4-isopropylbenzyl, 4-methoxybenzyl and 4-t-butylbenzyl.
2 5 MAY 19 95
R3 is H.
R2 and R3 may be taken together to form a benzo or naphtho ring system.
Y is Ci-Cs alkyl or C2 -Cg alkenyl such as CH=CH and CH=C(CH3).
Z is selected from any one of:
OH
VoWlYl or
OR4
OH OH O III
wherein R4 is H, Ci-Cs alkyl, a protonated amine of the formula
HN(R5)3+ wherein R5 is H or Ci-Cs alkyl, or a cation such as Na+, K+, Li+, Ca2+, or Mg2+.
The values for n are 0 to 3 and the values for p are 0 to 3.
The preferred compounds of formula I can be generally represented by three sub-groups of compounds represented by formulas 1(a), 1(b), and 1(c) which are set forth as follows:
1(a)
26 4 2
wherein R4 is any of Ci-Cs alkyl, and Ri, R2, R3, Y, n, and p are as defined above; or wherein R4 is H, a cation such as Na+, K+, Li+, or a protonated amine of the formula HN(Rs)3+, wherein R5 is H or Ci-Cs alkyl, and Ri, R2, R3, Y, n, and p are as defined above; or
OH
wherein Ri, R2, R3, Y, n, and p are as defined above.
Vowv^n within the scope of this invention are intermediate compounds which are useful in making the compounds of formula i. The intermediate compounds are represented by the general formula x:
Ri
(CH2)p
CHO
wherein Ri, R2 > R3 > n anc^ P are as defined on page 3a.
In preferred compounds Rj, R£ and R^ are as defined below. Rj is selected from any onfcof Cj-Cg alkyl, aryl, or substituted aryl.
R2 is selected from any one of H, Ci-Cs alkyl, aryl, substituted aryl, aralkyl wherein the alkyl portion is C1-C4, substituted aralkyl wherein the alkyl portion is C1-C4. aralkenyl wherein the alkenyl portion is c2 -C4. or C3-Cg cycloalkyl such as cycl'opropyl, cyclobutyl, cvclopentvl and the like.
R3 is H.
N.Z. PATEi'-IT OFFICE
2 5 MAY 1995
received
R2 and R3 may be taken together to form a benzo or naphtho ring svstem.
1
The term "aryl." as used herein alone or in combination with other terms, indicates aromatic hydrocarbon groups such as a phenyl or naphthvl group. The term "aralkyl" indicates a radical containing a lower Ci-Cs alkyl
8
26 4 2
group substituted with an aiyl radical or substituted aryl radical as defined above.
The aryl groups and the ring formed by R2 and R3 may be independently substituted with any of Ci-Cs alkyl, such as methyl, ethyl, propyl, isopropyl, t-butyl, and sec-butyl; alkoxy such as methoxy and t-butoxy; halo such as fluoro, chloro, bromo, and iodo; or nitro.
As used herein alkyl and alkoxy include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl, 1 -methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. The term "independently" is used with respect to aryl and ring substituents to indicate that when more than one of such substituents is possible such substituents may be the same or different from each other. Position 1 in the N-containing ring is the N atom adjacent to the ring fusion.
The compounds produced include the various individual isomers as well as the racemates thereof, e.g. the isomers arising from the various attachments on the side chain Z as well as the substituents R2 and R3.
The compounds of formula I and intermediates of formula X may be prepared according to the following general reaction scheme, which as is
9
26423
apparent contains a plurality of alternative routes depending upon starting materials and the reactions carried out.
Reaction Scheme
O O
26 4 2
VII
g
(CH2)p
N-N
CHO
R^CH2)r vra
(R = Ac)
OAc
VIII
(R = THP)
r3/V!?H2)„
xn n
OH
IX
C02Et m
C02Et
11
26 4
C02Et
VI
ch2oh r
x +
(MeO)2P
ii
O
OMe
O O
\
o xvm
Si(Me)2-t-Bu cho xvn
Kb)
1(c)
12
26 4 2
If desired, the substituted cyclic ketone VI may be obtained from commercial suppliers (Aldrich Chemical Co., Lancaster Synthesis Ltd., or Wiley Organics). Alternatively, compound VI may be prepared as shown in the reaction scheme by treatment of imine IV (Stork, G., Dowd, S. R. J. Am. Chem. Soc.. 1963, 85. 2178-80) in an inert solvent such as THF with an appropriate base such as s-BuLi or LiN(i-Pr)2 (LDA) at -78 to 0°C for 15 to 45 min under N2, followed by alkylation at 0°C to RT (room temperature) for 16 h, followed by hydrolysis of the resulting imine with 2N HC1 at RT for 5 h. Alternatively, compound VI may be prepared by treatment of the 2-carboethoxy cyclic ketone V (commercially available from Aldrich Chemical Co.) in an inert solvent such as benzene or DMF with an appropriate base such as NaH at 0 to 25 °C for 30 to 60 min under N2, followed by alkylation at 0°C to RT for 2 to 3 days, followed by hydrolysis of the ester and decarboxylation of the resulting acid with 6N HC1 at reflux for 2 to 3 days.
Compound VI can be treated with ah appropriate base, such as LDA or LiN(SiMe3)2, in an inert solvent, such as THF, at -78°C to 0°C and acylated with methyl dimethoxyacetate at 0°C to RT for 16 h to give the diketone VII. Compound VII is dissolved in an appropriate solvent, such as EtOH, and treated with a substituted hydrazine for 16 h at RT. The resulting acetal is hydrolyzed with IN HC1 at reflux to give the aldehyde X as a separable mixture of regioisomers.
Compound X can also be prepared from compound VI by several alternate routes. Thus, compound VI is treated with pyrrolidine and acetoxyacetyl chloride to give the acetoxy methyl diketone VIII (R = Ac:
13 2 6 4 2
Dolmazon, R. J. Heterocyclic Chem.. 1982, 19. 117-121). Reaction of VIII with a substituted hydrazine in a suitable solvent, such as EtOH, from RT to ) reflux for 4 to 10 h gives the regioisomeric mixture of acetoxy compounds XI, which is dissolved in an alcoholic solvent such as MeOH and hydrolyzed with IN NaOH at RT to provide the separable mixture of alcohols XII. Alternatively, the THP derivative of compound VIII (R = THP), prepared by the treatment of compound VI and ethyl (tetrahydropyranyloxy)acetate (Ireland, R. Tetrahedron Lett.. 1989, 30. 919-922) in ether with a suitable base, such as NaH or NaOEt, from 0°C to RT for 16 h, can be treated with a substituted hydrazine at reflux for 4 h, followed by hydrolysis of the THP group with IN HC1 to give the separable mixture of alcohols XII.
Alternatively, compound VI is treated with NaH and diethyl oxalate to give the 2-substituted dioxoacetate IX (Tsuboi, S. i Org. Chem. 1987, 52.
1359-62). Treatment of compound IX in MeOH with hydrazine hydrate at RT to 60°C for 16 h gives the 3-carboethoxy compound XIII. The separable regioisomeric mixture of esters XIV is prepared by treating compound XIII with a suitable base, such as NaH, in an inert solvent, such as DMF, at 140°C for 15 min under N2, followed by the addition of the alkylating agent at 140°C. The alcohol XII is prepared by reduction of the corresponding 3-carboxylate XIV with a suitable reducing agent, such as LiAlH4, in an inert solvent, such as THF, at 0°C to RT for 2 to 3 h under N2. Oxidation of compound XII with either Mn02 in an appropriate solvent, such as benzene, or pyridinium chlorochromate in an appropriate solvent, such as methylene chloride, gives the corresponding aldehyde X.
14
26 4 2
Treatment of compound X with NaH and triethyl phosphonoacetate or triethyl phosphonopropionate in an inert solvent such as THF at 0° to RT for 16 h gives the corresponding ester XV. Reduction of the ester is accomplished by treatment of XV with (£-Bu)2A1H in an inert solvent, such as toluene or THF, for 1 to 2 h at 0°C under N2 to give the alcohol XVI. Alternatively, compound XVI can be prepared from the appropriately substituted cyclic ketone VI by treatment of said ketone with a substituted hydrazine and an appropriate base, such as NaOAc, in EtOH at reflux for 3 h to give the hydrazone. The hydrazone is then treated with a suitable base, such as LDA, at -10°C and acylated with methyl 4-tetrahydropyranyloxy-2-butenoate (Hamish, W.; Morera, E.; Ortar, G. J. Org. Chem., 1985, 50.
1990-2); the resulting intermediate is treated with 3N HC1 at reflux for 15 min, followed by reaction with pyridinium p-toluenesulfonate at reflux for 8 h under N2 to give the substituted alcohol XVI. Oxidation of alcohol XVI by treatment with Mn02 in an appropriate solvent, such as benzene, at reflux for 3 h or with Cr03 and pyridine in an appropriate solvent, such as methylene chloride, gives aldehyde XVII. Ethyl acetoacetate is treated with an appropriate base, such as LDA, or mixture of bases, such as NaH and n-BuLi, and reacted with compound XVII at 0 to -10°C for 1 to 2 h in an inert solvent such as THF. Reaction of the intermediate ester with Et3B in a solvent mixture such as 1:4 MeOH:THF at 0°C, followed by treatment with NaBH4 at -78°C to RT for 16 h, gives the dihydroxyheptenoate 1(a).
Alternatively, compound 1(a) can be prepared by the reaction of compound X with methyl 3-[(t-butyldimethylsilyl)oxy-6-(dimethoxyphos-phinyl)-5-oxohexanoate XVIII (Theisen, P. D.; Heathcock, C. H. J. Org.
Chem.. 1988, 53. 2374-81), LiCl, and DBU in an appropriate solvent, such as
26 4 2
acetonitrile, at RT under N2 for 6 h to give 3-hydroxy-5-oxoheptenoate XIX. Treatment of ester XEX with Et3B in a solvent mixture such as 1:4 MeOH:THF at 0 to -78°C, followed by reaction with NaBH4 at -78°C to RT for 16 h gives the dihydroxyheptenoate 1(a). Compound 1(a) can be hydrolyzed with aqueous NaOH or KOH and a suitable alcoholic solvent, followed optionally by neutralization with dilute aqueous HC1 and treatment with an amine base, to give the dihydroxyheptenoic acid derivative 1(b). Hydrolysis of compound 1(a) as described above to the crude acid, followed by treatment of said acid with an appropriate carbodiimide, such as 1 -cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate, in an inert solvent, such as methylene chloride, at 0°C to RT for 16 h, gives the tetrahydropyranyl compound 1(c).
The compounds of New Zealand Patent Application No. 243575 are useful as hypocholesterolimic or hypolipidemic agents by virtue of their ability to inhibit the biosynthesis of cholesterol through the inhibition of the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase). The ability of the compounds of 1
that invention to inhibit the biosynthesis of cholesterol was measured by two different tests.
HMG-CoA Reductase Isolation And Assay
Livers were harvested from male Wistar rats (250 g) following a five day feeding with powdered chow containing 2% cholestyramine.
Ammonium sulfate precipitated HMG-CoA reductase was prepared from these livers according to the method of Heller, et. al. (Heller, R. A., Shrewsbury, M.A. Journal of Biological Chemistry, 251, 1976, 3815-3822).
16
2642 37
HMG-CoA reductase activity was measured using a modification of the procedure of Edwards, et. al . (Edwards, P. A., Lemongello, D., Fogelman A. M. Journal of Lipid Research. 20, 1979. 40-46). The effects of compounds on HMG-CoA reductase activity were determined by combining the compound with the enzyme and preincubating for 10 minutes prior to addition of the substrate HMG-CoA reductase.
Cell Culture Cholesterol Biosynthesis Assay
Hep-G2 cells obtained from the American Type Culture Collection were maintained in MEM (minimal essential medium) obtained from GIBCO containing Earles salts and supplemented with 10% HI-FBS. For cholesterol biosynthesis experiments, cells were plated into T25 flasks. When the cells were 2/3 confluent, they were fed MEM containing Earles salts and delipidated serum protein (DLP) at 5mg/mL and then incubated for a period of 24 h. DLP was prepared according to the procedure of Rothblat, et. al. (Rothblat, G.H., Arrbogast, L.Y., Ouellette, L., Howard, B.V. In Vitro (Rockville). 12, 1976. 554-557). The DLP medium was then removed and
3.3 mL of media containing the drug indicated was added. Monolayers were incubated with drug for 2.5 h at which time 14C-acetate (0.2 mCi/12 mmol) was added and cells incubated for an additional 3 h. The reaction was stopped by the addition of 0.2 mL of 12 N H2SO4; 3H-cholesterol and 3H-oleic acid were added as internal recovery standards, and samples were saponified. Fatty acids were extracted and digitonin precipitable sterols were recovered according the procedure of Kanduch and Saucier (Kandutch, A. A., Saucier, S. E. Journal of Biological Chemistry, 244, 1969. 2299-2305).
To adjust for cell number per flask, the cholesterol synthesized was
17
2642 37
normalized to the fatty acids synthesized and results were expressed as percent inhibition vs. control.
i>
The activities of certain representative examples are shown in Tables 5 I-V. In the Tables, Me means methyl, Et is ethyl, Pr is propyl, Bu is butyl, c-Hex is cyclohexyl, Ph is phenyl, Nap is naphthyl, MeO is methoxy, and Biphenyl is (l,l'-biphenyl)-4-yl. Each of the compounds was tested in the form of a racemic mixture.
Each of the compounds in Tables I-V was tested in one or both of the biological assays. The symbol "nt" indicates that a particular compound was not tested.
18 Table I
26 42
3
OH OH O
Compound Number
R2
Cell Culture Cholesterol Biosynthesis IC50 (|iM)
42
43
(2-Nap)-CH2 (4-i-Pr-Ph)-CH2
0.365 0.12
Table H
Rlv N-N
Cell Culture Cholesterol Biosynthesis ic50 (M.M)
HMG-CoA
Compound Reductase
Number n Ri R2 IC50 (nM)
2
0
4-F-Ph
H
100,000
nt
3
1
4-F-Ph
(4-F-Ph)-CH2
31.000
27
4
1
4-F-Ph c-Hex
47,000
nt
1
4-F-Ph
Et
,000
nt
6
1
4-F-Ph
Me
100,000
nt
7
1
4-F-Ph
Ph-(CH2)2
nt
>10
8
1
4-F-Ph
Ph-CH=CH-CH2
3,000
nt
9
2
(4-F-Ph)-CH2
H
100,000
nt
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264237
OEt
OH OH O
Compound Number
R2
HMG-CoA Reductase IC50 (nM)
Cell Culture Cholesterol Biosynthesis ic50 (HM)
47 58 60 62 64
Ph-CH2 (3-MeO-Ph)-CH2 (4-Cl-Ph)-CH2 (4-Me-Ph)-CH2 (4-t-Bu-Ph)-CH2
120 210 nt 70 30
0.29 0.80 0.46 0.20
nt
Table V
O
Cell Culture
HMG-CoA Cholesterol
Compound Reductase Biosynthesis
Number R2 ic50 (nM) 1C50 (nM)
79 Ph-CH2 750 0.26
80 (2-EtJBu 29,000 nt
81 (2-Nap)-CH2 nt 0.39
82 (4-t-Bu-Ph)-CH2 70 0.23
83 H 9.000 nt
26 4 2 3
The pharmaceutical compositions are comprised of the compounds of NZ
application number 234575 and are pharmaceutical^ acceptable carrier in either solid or liquid form. Solid form preparations include powders, tablets, dispersible granules, capsules, etc. The earner may also be one or more substances which act as diluents, flavoring agents, solublizers, lubricants, suspending agents, binders, or tablet disintegrating agents and they may also be encapsulating materials. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, peptin, dextrin, starch, methyl cellulose, sodium 10 carboxyl methyl cellulose, and the like. Liquid form preparations include solutions which are suitable for oral or parenteral administration, or suspensions and emulsions suitable for oral administration. Sterile water solutions of the active component or sterile solutions of the active components in solvents comprising water, ethanol, or propylene glycol are 15 examples of liquid preparations suitable for parenteral administration.
Sterile solutions may be prepared by dissolving the active component in the desired solvent system, then passing the resulting solution through a membrane filter to sterilize it, or alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions. 20 Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers and thickening agents as required. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as a natural or synthetic gum, resin 25 methyl cellulose, sodium carboxy methyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
22
2 6 4 2 3
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term "unit dosage form" as used in the specification and claims herein refers to physically discrete units suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
In therapeutic use as hypolipidemic or hypocholesterolemic agents, the compounds utilized in the pharmaceutical method of this invention are administered to the patient at dosage levels of from about 0.01-100 mg/kg per day. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of optimum dosages for a particular situation is within the skill of the art.
In the following examples, Examples 13, 14, 20 and 21. Tables 8, 9A, 9B, 13A, 13B, and 14, illustrate the preparation of the final compounds I(a-c) • Examples 3 and 11, Tables 3A?
3B, and 6, illustrate the preparation of the novel intermediate of the compound of formula X. The remainder of the examples illustrate the preparations of the various intermediates according to the reaction scheme set forth previously that are made to produce the compounds of the present invention. For ease of reference, each example is keyed to a particular step in the reaction scheme. Moreover, there are specific examples of one compound for each step in the sequence and a general procedure for
23
264237
making the other compounds which are listed in the table at the end of each example.
Unless otherwise noted, materials used in the examples were obtained from commercial suppliers and were used without further purification. Tetrahydrofuran (THF) was distilled from Na/benzophenone immediately prior to use. The following chemicals were obtained from Sigma Chemical Co: digitonin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), and p-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH). The (l-14C)-acetate was obtained from both Research Biochemicals, Inc. (RBI) and New England Nuclear-Dupont (NEN). The (3-14C)-HMG-CoA was obtained from NEN, and (7-3H)-cholesterol and (7-3H)-cholesteryl oleate were obtained from Amersham. HI-FBS (heat-inactivated fetal bovine serum) and calf serum were obtained from Grand Island Biological Co. (GIBCO). Lovastatin was obtained from Merck. Lovastatin-Na was prepared from Lovastatin by reaction with sodium hydroxide. Pravastatin was obtained from Sigma, and XU-62320 was obtained from Sandoz. Diisopropylamine was distilled from CaH2 and was stored over 4A molecular sieves. l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was used without purification. Dimethylformamide (DMF) was dried over 4A sieves prior to use. Melting points were determined on a Thomas-Hoover apparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectra were measured in the indicated solvent with tetramethylsilane (TMS) as the internal standard using the following spectrometers: Bruker WP-100SY (100 MHz *H, 25 MHz 13C), General Electric QE-300 (300 MHz iH, 75 MHz i3C), Varian XL-400 (400 MHz XH, 100 MHz 13C). NMR chemical shifts are expressed in parts per million (ppm) downfield from internal TMS using the 8 scale. *H
2 6 4 2
Hertz). 13C NMR data are reported for proton-decoupled spectra and are tabulated in order. Infrared (IR) spectra were determined on a Nicolet 5DXB FT-IR spectrophotometer. Chemical ionization (DCI), electron impact (EI), and fast atom bombardment (FAB) mass spectra (MS) were determined on a Finnegan MAT 8230 spectrometer. Elemental analyses were carried out on a Perkin Elmer 240C analyzer. Analytical thin layer chromatography (TLC) was done with Merck Silica Gel 60 F254 plates (250 micron). Flash chromatography and medium pressure liquid chromatography (MPLC) were done with Merck Silica Gel 60 (230-400 mesh).
EXAMPLE 1
2-1(1, r-Biphenyl)-4-ylmethyl]cyclohexanone (Compound (hereinafter CP) 84, Reaction Scheme (hereinafter RS) Step a):
A 1.3 M solution of s-BuLi in hexanes (51.8 mmol, 39.8 mL) was added over a 15 min period to a -78 °C solution containing 9.29 g (51.8 mmol) of N-cyclohexylidine cyclohexylamine (Stork, G., Dowd, S. R. J. Am. Chem. Soc.. 1963, 85. 2178-80) in 75 mL of THF under N2. After 30 min, the cooling bath was removed and the cloudy solution was allowed to warm to 0°C. A solution of 10.0 g (49.3 mmol) of 4-(chloromethyl)biphenyl in 30 mL of THF was added and the resulting mixture was stirred at room temperature overnight. A 40 mL portion of 2 N aqueous HC1 was added and the mixture was stirred for 5 h. Et20 (200 mL) was added and the organic solution was washed successively with water, saturated NaHCOs, and brine. The organic layer was dried over Na2S04 and concentrated to give 13.1 g of an off-white solid. Recrystallization from EtOAc:hexanes afforded 9.22 g (71%) of the title compound as a white solid, m.p. 78-79 °C; *H NMR (CDCI3, 300 MHz) 1.40 (m, 1), 1.65 (m, 2), 1.83 (m, 1), 2.10 (m, 2), 2.35
26 4 2
(m, 1), 2.52 (m, 2), 2.60 (m, 1), 3.27 (dd, 1, J=5, 13.5 Hz), 7.2-7.6 (complex); IR (KBr) 1695 cm"1; MS (DCI) m/z 265 (base). Anal. Calcd. for C19H20O: C, 86.32; H, 7.63. Found: C, 86.66; H, 7.98.
General procedure for the preparation of 2-substituted cyclohexanones shown in Table 1:
Method A (RS step a): s-BuLi (50 mmol) was added under N2 to a solution of 50 mmol of the cyclohexylimine of N-cyclohexylidine cyclohexylamine in 75 mL of THF at -78 °C. The resulting cloudy solution was stirred for 30 min and was allowed to warm to 0°C. A solution of 48 mmol of the appropriate alkyl or aralkyl halide in a minimum volume of THF was added dropwise and the solution was allowed to warm to room temperature and was stirred overnight. A 50 mL portion of 2 N aqueous HCl (100 mmol) was added and the two phase mixture was stirred vigorously until TLC analysis showed that hydrolysis of the imine was complete (2-8 h). The mixture was extracted with Et20 or EtOAc and the organic layer was washed with water, saturated aqueous NaHCC>3, and brine. After drying over Na2SC>4 and concentration, the crude product was purified by either MPLC or vacuum distillation using a short path still.
Alternatively, a solution of 50 mmol of the appropriate cyclohexylimine in a minimum volume of THF was added dropwise under N2 to an ice-cold stirring solution of 52.5 mmol of lithium diisopropylamide (LDA, generated by the addition of 55 mmol of diisopropylamine in 35 mL of THF to 52.5 mmol of a 1.6 M hexanes solution of n-BuLi at 0°C). After 30-45 min, a solution of 48 mmol of the appropriate alkyl or aralkyl halide in a minimum volume of THF was added dropwise and the mixture was allowed to warm to room temperature and was stirred overnight. A 75 mL portion of 2 N
> » 2 6 4 2 3
aqueous HCl (150 mmol) was added and the two phase mixture was stirred vigorously until TLC analysis showed that hydrolysis of the imine was complete (4-24 h). The reaction mixture was worked up as described above.
Method B (RS step b): An ice-cold suspension of oil-free NaH (150 mmol) in 120 mL of a 1:1 mixture of benzene and DMF was treated,
dropwise, with ethyl 2-cyclohexanonecarboxylate (145 mmol) in 60 mL of the same solvent mixture over a 30 min period. The mixture was stirred an additional 30 min and 140 mmol of the appropriate alkyl or aralkyl halide in a minimum amount of benzene was added dropwise. After stirring at room temperature for 2-3 days, 250 mL of Et20 was added and the organic solution was washed with water (3 x 100 mL) and brine. Drying (Na2SC>4) and concentration gave the crude alkylated keto ester which was dissolved in 100 mL each of HOAc and 6 N aqueous HCl and refluxed until TLC analysis showed that the hydrolysis/decarboxylation was complete (2-3 days). Most of the solvent was removed by rotary evaporation and the residue was partitioned between water (100 mL) and Et20 (300 mL). The Et20 layer was washed with brine, dried over Na2S04, and concentrated to give the crude product which was purified as described in Method A above.
27
Table 1
26 4 2
o
Compound Number
Method
R2
bp (°C)
Mass spectrum m/z [M+H]+
85
A
(1-Nap)-CH2
oil
239
86
B
(2-Cl-Ph)-CH2
129-135 (0.4 Torr)
223
87
A
(2-Nap)-CH2
180-190 (0.6 Torr)
239
88
A
(3-MeO-Ph)-CH2
190-195 (4 Torr)
219
89
A
(3,4-di-MeO-Ph)-CH2
180-187 (1 Torr)
249
90
A
(4-Cl-Ph)-CH2
150-170 (0.1 Torr)
223
91
B
(4-F-Ph)-CH2
110-125 (0.5 Torr)
207
92
A
(4-i-Pr-Ph)-CH2
90-160 (0.1 Torr)
231
93
A
(4-Me-Ph)-CH2
oil
203
94
B
(4-MeO-Ph)-CH2
155-170 (0.6 Torr)
219
95
A
(4-t-Bu-Ph)-CH2
136-148 (0.5 Torr)
245
96
A
Ph-(CH2)2
124-130 (0.5 Torr)
203
97
A
Ph-(CH2)3
100-200 (0.8 Torr)
217
98
A
Ph-CH=CH-CH2
160-170 (0.8 Torr)
215
EXAMPLE 2
6-[(l,r-Biphenyl-4-yl)methyl]-2-(2,2-dimethoxy-l-oxoethyl)cyclohexanone (CP 99, RS step c):
Diisopropylamine (38.8 mmol, 3.93 g, 5.4 mL) was added under N2 to a -20°C solution of 1.6 M n-BuLi in hexanes (35.3 mmol, 22.0 mL) and 30 mL of THF. After 15 min, the solution was cooled to -78°C and 8.88 g (33.6 mmol) of Compound 84 in 50 mL of THF was added. After 45 min, 2.26 mL (18.5 mmol, 2.48 g) of methyl dimethoxyacetate was added and the mixture was allowed to warm slowly to room temperature and was stirred overnight. The resulting solution was cooled to 0°C and acidified to pH 3^4 with 2N aqueous HCl. The mixture was diluted with Et20 (200 mL) and washed with water and brine. After drying over Na2SC>4, the solution was concentrated to
26 4 2
give 11.5 g of a yellow oil. The crude product was purified by MPLC using a solvent gradient ranging from 1:6 to 1:5 EtOAc:hexanes to afford 5.94 g (96%) of the title compound as a waxy, white solid: *H NMR (CDCI3, 300 MHz) 1.4-2.8 (complex, 9), 3.33 (s, 3, minor tautomer), 3.37 (s, 3, minor tautomer), 3.42 (s, 6, major tautomer), 4.63 (s, 1, minor tautomer), 4.96 (s, 1, major tautomer), 7.2-7.6 (complex, 9) ; IR (KBr) 1739, 1704, 1601, 1584, 1488, 1444 cm"1: MS (DCI) m/z 335 (base), 303. Anal. Calcd. for C23H26O4: C, 75.38; H, 7.15. Found: C, 75.64; H, 7.39.
General procedure for the preparation of 6-substituted diketones shown in Table 2 (RS step c):
Diisopropylamine (57.8 mmol) was added under N2 to a -20°C solution of 52.5 mmol of a 1.6 M hexanes solution of n-BuLi and 45 mL of THF. (Alternatively, 52.5 mmol of a 1.0 M solution of LiN(SiMe3)2 in 5 THF/cyclohexane was added to 25 mL of THF under N2 at -20°C.) After 15 min, the solution was cooled to -78 °C and 50.0 mmol of the appropriately substituted cyclohexanone (from Table 1, or commercially available) in 50 mL of THF was added. After 45 min, 27.5 mmol of methyl dimethoxyacetate was added and the mixture was allowed to warm slowly to room temperature. After stirring overnight, the resulting solution was cooled to 0°C and acidified to pH 3-4 with 2N aqueous HCl. The mixture was diluted with Et20 (200 mL) and washed with water and brine. After drying over Na2SC>4, the solution was concentrated to give the crude product, which was purified by MPLC.
29
26 4 2
Table 2
o o
Compound Number
R2
mp (°C)
Mass spectrum m/z [MH-MeOH]'
100
(1-Nap)-CH2
oil
309
101
(2-Cl-Ph)-CH2
oil
293
102
(2-Et)Bu oil
225
103
(2-Nap)-CH2
oil
309
104
(3-MeO-Ph)-CH2
oil
289
105
(3,4-di-MeO-Ph)-CH2
oil
319
106
(4-Cl-Ph)-CH2
oil
293
107
(4-F-Ph)-CH2
oil
277
108
(4-i-Pr-Ph)-CH2
oil
301
109
(4-Me-Ph)-CH2
oil
273
110
(4-MeO-Ph)-CH2
oil
289
111
(4-t-Bu-Ph)-CH2
oil
315
112
c-Hex oil
251
113
Et oil
197
114
Me oil
183
115
n-Pr oil
211
116
Ph oil
245
117
Ph-CH2
oil
259
118
Ph-(CH2)2
oil
273
119
Ph-(CH2)3
oil
287
120
Ph-CH=CH-CH2
oil
285
121
s-Bu oil
225
EXAMPLE 3
7-[(l,r-Biphenyl-4-yl)methyl]-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxaldehyde (CP 122, RS step g) and 7-[(l,l'-Biphenyl-4-yl)methyl]-l-(4-fluorophenyl)-4,5,6,7-tetrahydro-lH-indazole-3-carboxaldehyde (CP 123 RS step g):
A solution of Compound 99 (20.2 mmol, 5.35 g) in 100 mL of absolute EtOH was treated with 1.91 g (23.3 mmol) of NaOAc and 3.45 g (21.2 mmol) of 4-fluorophenylhydrazine • HCl. After stirring overnight under N2, the solvent was removed by rotary evaporation and the orange residue was
26423?
dissolved in 100 mL of THF. A 50 mL portion of IN aqueous HCl was added and the mixture was stirred and refluxed gently for 4 h. Et20 (150 mL) was added after cooling and the organic layer was washed sequentially with water, saturated aqueous NaHCC>3, and brine. Drying over Na2SC>4 and concentration afforded 6.74 g of an orange foam. The crude product was purified by MPLC using 1:9 EtOAc:hexanes to give 1.90 g (23%) of the 2-(4-fluorophenyl) isomer and 1.15 g (14%) of the l-(4-fluorophenyl) isomer, each as an orange solid. The 2-(4-fluorophenyl) isomer was recrystallized from Et0Ac:Et20 to afford Compound 122 as a pale orange solid, m.p. 148-10 150°C; lH NMR (CDC13, 300 MHz) 1.6-2.0 (complex, 4), 2.72 (dd, 1,
J=10.5, 13.5 Hz), 2.75-3.0 (complex), 3.15 (m, 1), 3.56 (dd, 1, J=4, 13.5 Hz). 7.2-7.7 (complex, 13), 9.87 (s, 1): IR (KBr) 1510, 1222 cm*1; MS (DCI) m/z 411 (base). HRMS (EI) Cacld for C27H23FN2O: 410.179428. Found: 410.175457.
The l-(4-fluorophenyl) isomer was recrystallized from EtOAc:hexanes to provide analytically pure Compound 123 as an orange solid, m.p. 155-156: *H NMR (CDCI3, 300 MHz) 1.7-1.9 (complex, 4), 2.46 (dd, 1. J=10.5, 13.5 Hz), 2.61 (dd, 1, J=4, 13.5 Hz), 2.73 (dt, 1, J=16.5, 8 Hz), 3.02 (dt, 1, J=16.5, 4 Hz), 3.30 (m, 1), 6.89 (d, 2, J=8 Hz), 7.2-7.6 (complex, 11), 20 10.08 (s, 1); IR (KBr) 1691, 1512 cm'1: MS (DCI) m/z 411 (base). Anal. Calcd. for C27H23FN2O: C, 79.00: H, 5.65: N, 6.82. Found: C, 79.22; H, 5.54; N, 6.61.
General procedure for the preparation of 7-substituted 4,5,6,7-tetrahydroindazole-3-carboxaldehydes shown in Tables 3A and 3B (RS step g):
264237
A solution of 10 mmol of the appropriately substituted diketone from Table 2 in 100 mL of absolute EtOH or MeOH was treated with 11.5 mmol of a base (NaOAc, Et3N, or pyridine) and 10.5 mmol of the appropriately substituted hydrazine hydrochloride. After stirring overnight under N2, the p'Dlvent was removed by rotary evaporation and the residue was dissolved in 50 mL of THF. A 25 mL portion of IN aqueous HCl was added and the mixture was stirred and refluxed gently for 4 h. After cooling, 100 mL of Et20 was added and the organic layer was washed sequentially with water, saturated aqueous NaHCOs, and brine. Drying over Na2S04 and concentration afforded the crude product as a mixture of 2-aryl and 1-aryl isomers in ratios ranging from 1:1 to 1:3. The crude mixture was purified by re crystallization and/or MPLC; the 2-aryl isomer eluted before the 1-aryl isomer in all cases.
32
2 6 4 2 3 7
Table 3A
CHO
Compound Number
Ri
R2
mp (°C)
Mass Spectrum [M+H]+
124
4-F-Ph
(1-Nap)-CH2
183-184
385
125
4-F-Ph
(2-Cl-Ph)-CH2
137-138
369
126
4-F-Ph
(2-Et)Bu
121-122
329
127
4-F-Ph
(2-Nap)-CH2
foam
385
128
4-F-Ph
(3-MeO-Ph)-CH2
93-94
365
129
4-F-Ph
(3,4-di-MeO-Ph)-CH2
117-119
395
130
4-F-Ph
(4-Cl-Ph)-CH2
134-135
369
131
4-F-Ph
(4-F-Ph)-CH2
128-131
353
132
4-F-Ph
(4-i-Pr-Ph)-CH2
112-113
377
133
4-F-Ph
(4-Me-Ph)-CH2
117-118
349
134
4-F-Ph
(4-MeO-Ph)-CH2
104-107
365
135
4-F-Ph
(4-t-Bu-Ph)-CH2
139-140
391
136
4-F-Ph c-Hex
119-121
327
137
4-F-Ph
Et
95-97
273
138
4-F-Ph
Me
124-125
259
139
4-F-Ph n-Pr oil
287
140
4-F-Ph
Ph
71-73
321
141
4-F-Ph
Ph-CH2
144-145
335
142
4-F-Ph
Ph-(CH2)2
97-99
349
143
4-F-Ph
Ph-(CH2}3
oil
363
144
4-F-Ph
Ph-CH=CH-CH2
106-108
361
145
4-F-Ph s-Bu
86-89
301
296
t-Bu
(1-Nap)-CH2
119-120
347
26 42
,Ri
N-N
Compound Number
Ri
R2
mp (°C)
Mass Spectrum [M+H]+
146
4-F-Ph
(1-Nap)-CH2
116-117
385
147
4-F-Ph
(2-Cl-Ph)-CH2
glass
369
297
4-F-Ph
(2-Et)Bu foam
329
148
4-F-Ph
(2-Nap)-CH2
122-123
385
149
4-F-Ph
(3-MeO-Ph)-CH2
foam
365
150
4-F-Ph
(3,4-di-MeO-Ph)-CH2
109-110
395
151
4-F-Ph
(4-Cl-Ph)-CH2
126-128
369
152
4-F-Ph
(4-F-Ph)-CH2
oil
353
153
4-F-Ph
(4-i-Pr-Ph)-CH2
oil
377
154
4-F-Ph
(4-Me-Ph)-CH2
foam
349
155
4-F-Ph
(4-MeO-Ph)-CH2
oil
365
156
4-F-Ph
(4-t-Bu-Ph)-CH2
124-125
391
157
4-F-Ph c-Hex oil
327
158
4-F-Ph
Et
72-74
273
159
4-F-Ph
Me
79-80
259
160
4-F-Ph n-Pr
50-53
287
161
4-F-Ph
Ph
139-140
321
162
4-F-Ph
Ph-CH2
99-100
335
163
4-F-Ph
Ph-(CH2)2
89-90
349
164
4-F-Ph
Ph-(CH2)3
100-102
363
165
4-F-Ph
Ph-CH=CH-CH2
104-105
361
166
4-F-Ph s-Bu oil
301
298
£-Bu
(1-Nap)-CH2
142-143
347
EXAMPLE 4
3-Acetoxymethyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole (CP 167, RS step h):
Et3N (0.717 mL, 0.520 g, 5.14 mmol) was added to a stirring suspension of 1.00 g (5.04 mmol) of 2-acetoxyacetylcyclohexanone (Dolmazon, R.; Gelin, S. J. Heterocyclic Chem., 1982. 19. 117-121) and
0.820 g (5.04 mmol) of 4-fluorophenylhydrazine • HCl in 20 mL of absolute EtOH. The resulting solution was stirred under N2 for 4 h at room
Table 3B
26 4 2 3 7
temperature and refluxed for 6 h. The mixture was concentrated and the residue was partitioned between 100 mL of Et20 and 50 mL of dilute aqueous HCl. The Et20 layer was washed with water, saturated aqueous NaHCC>3, and brine. After drying over Na2SC>4, the solution was concentrated to give 1.43 g of light brown solid. Recrystallization from EtOAc:hexanes afforded 0.753 g (52%) of the title compound as a white solid, m.p. 128.5-129.5 °C; *H NMR (CDC13, 400 MHz) 1.85 (m, 4), 2.07 (s, 3), 2.60 (t, 2, J=6 Hz), 2.73 (t, 2, J=6 Hz), 5.00 (s, 2), 7.15 (t, 2, J=9 Hz), 7.45 (dd, 2, J=5, 9 Hz); IR (KBr) 1740, 1220 cm"1; MS (DCI) m/z 289 (base), 228. Anal. Calcd. for Ci6Hi7FN202: C, 66.65; H, 5.94; N, 9.72.
Found; C, 66.74; H, 5.89; N, 9.61.
General procedure for the preparation of acetates shown in Table 4 (RS step h):
A mixture of 10 mmol of the appropriate 2-acetoxyacetylcycloalkanone (2-acetoxyacetylcyclopentanone, Dolmazon, R. J. Heterocyclic Chem., 1988,
. 751-7; 2-acetoxyacetylcyclohexanone, Dolmazon. R.; Gelin, S.
Heterocyclic Chem.. 1982, 19. 117-21), 10.5 mmol of Et3N, and 10 mmol of appropriately substituted hydrazine in 40 mL of absolute EtOH was stirred under N2 for 4-5 h and refluxed for 6-8 h. The solvent was evaporated and the resulting residue was partitioned between Et20 and 0.1 N HCl. The Et20 layer was washed with water, saturated aqueous NaHCOs, and brine. After drying over Na2S04, the solution was concentrated and the crude product was purified by recrystallization and/or MPLC. The 2-acetoxyacetylcyclopentanone reaction afforded a 9:1 mixture of l-aiyl:2-aryl isomers,
while the 2-acetoxyacetylcyclohexanone reaction gave only the 2-aryl isomer.
2642 37
Table 4
#
Compound Number
168
169
170
n
0
0
1
Rl
OAc
1-(4-F-Ph)
2-(4-F-Ph) 2-(4-Cl-Ph)
mp (°C)
85-86 87-88 oil
Mass Spectrum [M+H]+
275 275 305
EXAMPLE 5
2-(4-Fluorophenyl)-4,5t6f7-tetrahydro-2H-indazole-3-methanol (CP 171, RS 10 step i):
Compound 167 (24.3 mmol, 7.00 g) was dissolved in 125 mL of MeOH and stirred while 26.7 mL of IN aqueous NaOH was added. After 30 min the resulting cloudy suspension was concentrated and partitioned between 200 mL of EtOAc and 100 mL of water. The organic layer was washed with water 15 and brine and was dried over Na2S04. The solution was concentrated to give 5.85 g of orange solid. Recrystallization from EtOAc gave 4.08 g (68%) of the title compound as off-white crystals, m.p. 163-164 °C; *H NMR (CDCI3, ^ 400 MHz) 1.80 (m, 4), 2.52 (t, 1, J=5 Hz), 2.86 (t, 2, J=6 Hz), 2.71 (t, 2, J=6 Hz), 4.52 (d, 2, J=5 Hz), 7.12 (2, t, J=9 Hz), 7.58 (dd, 2, J=5, 9 Hz); 20 13c NMR (DMSO-d6, 25 MHz) 19.8, 23.0 (triple), 52.1, 115.7 (d, JC-F = 23 Hz), 116.6, 125.2 (d, JC-F = 8 Hz), 136.5, 137.9, 148.8, 160.6 (d, Jc-F = 244 Hz); IR (KBr) 3200 (broad), 1510 cm"1; MS (DCI) m/z 247 (base). Anal.
26 4 2 37
Calcd. for Ci4Hi5FN20: C, 68.28; H, 6.14; N, 11.37. Found: C, 68.47; H, 6.02; N, 11.35.
General procedure for the preparation of alcohols shown in Table 5 (RS step i):
The appropriate acetate from Table 4 (10 mmol) was dissolved in 50 mL of MeOH and stirred while 11 mmol of 1 N aqueous NaOH was added. The resulting suspension was stirred 0.5-24 h and worked up by one of two 10 methods. In the first method, the mixture was concentrated and partitioned between water and solvent. The organic phase was washed with water and brine, dried over Na2S04, and concentrated. Alternatively, the reaction mixture was filtered to remove the solids and the filtrate was treated with water to precipitate the remaining product. The combined 15 solids were dissolved in CHCI3, washed with brine, and concentrated. The crude product was purified by recrystallization or a combination of recrystallization and MPLC.
Table 5
OH
Compound Mass Spectrum
Number n Ri mp (°C) [M+H]+
172 0 l-(4-F-Ph) 85-86 233
173 0 2-(4-F-Ph) 170-171 233
174 1 2-(4-Cl-Ph) 184.5-185 263
37
26423
EXAMPLE 6
2-(4-Fluorophenyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol (CP 175, RS step e, followed by RS step k):
A solution of 2.80 g (25 mmol) of cycloheptanone and 4.71 g (25 mmol) of ethyl (tetrahydropyranyloxy)acetate (Ireland, R.E.; Wipf, P. Tetrahedron Lett.. 1989, 30. 919-22) in 20 mL of Et20 was added over the course of 1 h to an ice-cold, stirring mixture of hexane-washed NaH and 0.12 mL (2 mmol, 0.092 g) of absolute EtOH in 10 mL of Et20 under N2 . The light brown mixture was allowed to warm to room temperature and was 10 stirred overnight. MeOH (5 mL) was added and the solution was poured onto 200 mL of saturated aqueous NH4CI. After acidification to pH 2 with 1 N aqueous HCl, the mixture was extracted with Et20. The organic layer was washed with brine, dried over Na2S04, and concentrated to give 5.61 g of crude 2-[(tetrahydropyranyloxy)acetyl]cycloheptanone as a light brown oil. 15 The crude diketone was dissolved in 60 mL of absolute EtOH and combined with 3.07 mL (22 mmol, 2.23 g) of Et3N and 3.45 g (21.1 mmol) of 4-fluorophenylhydrazine • HCl. The resulting solution was stirred under N2 overnight and refluxed for 4 h. A 30 mL portion of 1 N aqueous HCl was added and the mixture was refluxed for an additional hour. The mixture was 20 cooled and extracted with 200 mL of Et20. The organic phase was washed ^ with water, saturated aqueous NaHCOs, and brine and dried over Na2S04. The solution was concentrated to give 5.50 g of a 1.2:1 mixture of l-(4-fluorophenyl)-l,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol and the title compound as a brown oil. The crude product was crystallized from 25 Et0Ac:Et20 to afford 0.97 g (18%) of the title compound as an off-white solid, m.p. 177-178 °C; XH NMR (CDCI3, 300 MHz) 1.72 (m, 4), 1.85 (m, 2), 2.60 (m, 2), 2.80 (m, 2), 4.51 (d, 2, J=5 Hz), 7.15 (m, 2), 7.60 (m, 2); IR
38
2642 ;
(KBr) 3240 (broad), 1513, 1223 cm-1; MS (DCI) m/z 261 (base). Anal.
Calcd. for Ci5H17FN20: C, 69.21; H, 6.58; N, 10.76. Found: C, 69.15; H, 6.77; N, 10.63.
EXAMPLE 7
Ethyl 2,4,5,6,7,8-hexahydrocycloheptapyrazole-3-carboxylate (CP 176, RS step f, followed by RS step 1):
Hydrazine hydrate (30.3 mmol, 1.52 g, 1.47 mL) was added dropwise under N2 to a stirring solution of ethyl a,2-dioxocycloheptaneacetate
(Tsuboi, S.; Nishiyama, E.; Furutani, H.; Utaka, M.; Takeda, A. J. Org. Chem.. 1987, 52. 1359-62) in 60 mL of MeOH. The reaction mixture, which had become warm during the addition, was allowed to cool to room temperature and was stirred overnight. The solvent was evaporated and the resulting oil was dissolved in CH2CI2 and washed with water and brine. After drying over 15 Na2S04, the solution was concentrated to give 6.36 g of pale yellow solid. Recrystallization from EtOAc:hexanes afforded 3.44 g (52%) of the title compound as a white solid, m.p. 90-92 °C; *H NMR (CDCI3, 300 MHz) 1.38 (t. 3, J=7 Hz), 1.67 (m, 4), 1.84 (m. 2), 2.80 (m, 2), 2.93 (m, 2), 4.37 (q, 2, J=7 Hz), 7.0 (broad s, 1); IR (KBr) 1719 cm"1; MS (DCI) m/z 209 (base). 20 Anal. Calcd. for CiiHi6N202: C, 63.44; H, 7.74; N, 13.45. Found: C, 63.48; H, 7.76; N, 13.64.
39 2 6 4 2 3
EXAMPLE 8
Ethyl 2-(4-fluorobenzyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole-3-carboxylate (CP 177, RS step m) and ethyl 1-(4-fluorobenzyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazole-3-carboxylate (CP 178, RS step m):
A solution of 7.90 g (37.9 mmol) of Compound 176 in 35 mL of DMF was added dropwise under N2 to a suspension of hexane-washed NaH (41.7 mol, 1.67 g of a 60% oil suspension) in 20 mL of DMF. When the addition was complete, the mixture was heated at 140°C with an oil bath for 15 min. A solution of 5.00 mL (41.7 mmol, 6.03 g) of 4-fluorobenzyl chloride in 5 mL of DMF was added and the mixture was heated for an additional 30 min.
After cooling, 400 mL of Et20 was added and the solution was poured onto 250 mL of saturated aqueous NH4CI. The aqueous layer was extracted with two 50 mL portions of Et20 and the combined organic phases were washed with three 100 mL portions of water and once with brine. The organic solution was dried over Na2SC>4 and concentrated to give 11.9 g of a 1:1 mixture of the title compounds as a yellow oil. Purification by MPLC afforded, in the earlier fractions, 3.85 g (32%) of pure 2-(4-fluorobenzyl) isomer as a colorless oil: :H NMR (CDCI3, 100 MHz) 1.31 (t, 3, J=7 Hz), 1.70 (m, 6), 2.83 (m, 4), 4.29 (q, 2, J=7 Hz), 5.58 (s, 2), 6.9-7.4 (complex. 4). The later-eluting fractions contained 4.94 g (42%) of the l-(4-fluorobenzyl) isomer as a colorless oil; *H NMR (CDCI3, 100 MHz) 1.40 (t, 3, J=7 Hz), 1.4-2.0 (complex, 6), 2.55 (m, 2), 2.95 (m, 2), 4.41 (q, 2, J=7 Hz), 5.35 (s, 2), 7.00 (m, 4).
40
26 4 2 3
EXAMPLE 9
2-(4-Fluorobenzyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol (CP 179, RS step n):
A solution of 1.43 g (4.52 mmol) of Compound 177 in 13 mL of THF under N2 was added dropwise over a 10 min period to an ice cold suspension of 0.113 g (2.83 mmol) of LiAlH4 in 7 mL of THF. After 30 min in the cold, the suspension was allowed to warm to room temperature and was stirred for 2 h. Et20 (50 mL) was added, followed sequentially by 0.12 mL of water, 0.12 mL of 15% aqueous NaOH, and 0.36 mL of water, 10 dropwise over a 1 h period. The white suspension was stirred overnight, treated with MgS04, and stirred 30 min more. The solids were removed by filtration and were washed with CH2C12. The combined filtrates were concentrated to afford 1.24 g of a white solid, which was recrystallized to give 0.998 g (80%) of the title compound as white needles, m.p. 156-157 15 °C; 1H NMR (CDC13, 300 MHz) 1.55-1.70 (complex, 7), 1.82 (m, 2), 2.47
(m, 2). 2.74 (m, 2), 4.48 (d, 2, J=6 Hz), 5.27 (s, 2), 6.98 (t, 2, J=7 Hz), 7.12 (m, 2); IR (KBr) 3170 (broad), 1517, 1231, 1016 cm*1; MS (DCI) m/z 275 (base), 257. Anal. Calcd. for Ci6Hi9FN20: C, 70.05; H, 6.98; N. 10.21. Found: C, 69.98; H, 6.98; N, 10.28.
£ EXAMPLE 10
l-(4-Fluorobenzyl)-l,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol (CP 180, RS step n):
Following the procedure described above, 4.82 mmol (15.23 g) of 25 Compound 178 gave 4.12 g (98%) of the title compound as an amber oil,
which was used without purification; XH NMR (CDCI3, 100 MHz) 1.70 (m, 6), 2.57 (m, 4), 3.0 (broad s, 1), 4.59 (d, 2, J=6 Hz), 5.20 (s, 2), 7.00 (m, 4).
264 2
EXAMPLE 11
2-(4-Fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxaldehyde (CP 181, RS step j):
Pyridinium chlorochromate (22.0 mmol, 4.74 g) was suspended in 50 ml of CH2CI2. Compound 171 (14.8 mmol, 3.64 g) was added in small portions over a 5 min period and the resulting suspension was stirred at room temperature for 4 h. A 300 mL portion of Et20 was added and the mixture was filtered through a pad of Florisil. The tarry residue remaining in the flask was sonicated twice with 100 mL of Et20 and the organic solutions were also filtered through Florisil. The Florisil pad was washed thoroughly with Et20 and the combined organic solutions were dried over Na2SC>4 and concentrated to give 3.57 g of an off-white solid. The crude product was recrystallized from Et20:hexanes to give 1.71 g (42%) of white crystals, m.p. 80-81 °C (the mother liquors were concentrated to give 1.67 g (47%) of a white solid which was judged to be pure enough to carry on); LH NMR (CDCI3, 400 MHz) 1.85 (m, 4), 2.77 (t, 2, J=6 Hz), 2.88 (t, 2, J=6 Hz), 7.20 (m, 2). 7.45 (m, 2), 9.86 (s, 1); IR (KBr) 1670, 1575 cm"1; MS (DCI) m/z 245 (base). Anal. Calcd. for C14H13FN2O: C, 68.84; H, 5.36; N, 11.47. Found: C, 68.79; H. 5.40; N, 11.39.
General procedure for the preparation of aldehydes shown in Table 6 (RS step j):
Method A: MnC>2 (100-120 mmol) was added in one portion to a stirring suspension of 10 mmol of the alcohol from Example 10 in 60 mL of benzene. The mixture was refluxed gently under N2 until TLC analysis indicated that the starting material was completely consumed. After
42
2642
cooling, the slurry was filtered through a Celite pad and the black solids were washed with 250 mL of CH2CI2. The filtrate was concentrated and the crude product was purified by MPLC or recrystallization.
Method B: To a stirring suspension of pyridinium chlorochromate (10 mmol) in 25 mL of CH2CI2 was added, in approximately five portions, the appropriately substituted alcohol from Table 5 or Examples 5, 6, or 9, as a solid. The resulting suspension was stirred for 2-4 h at room temperature. Et20 (150 mL) was added and the mixture was sonicated for 5-10 min. The supernatant was decanted through a pad of Florisil and the remaining solids were sonicated twice with 50 mL portions of Et20, which in turn were filtered. The Florisil pad was washed thoroughly with Et20 and the combined filtrates were concentrated to give the crude product, which was purified by recrystallization.
Table 6
CHO
(CH2)n
Compound Number
Method n
Ri mp (°C)
Mass spectrum m/z [M+H]+
182
B
0
l-(4-F-Ph)
122-123
231
183
B
0
2-(4-F-Ph)
79-80
231
184
B
1
2-(4-Cl-Ph)
93-94
261
185
B
2
2-(4-F-Ph)
oil
259
186
A
2
l-(4-F-Ph-CH2)
oil
273
187
B
2
2-(4-F-Ph-CH2)
oil
273
43 26 4 2
EXAMPLE 12
Methyl (E)-7-[7-[(l,l'-Biphenyl-4-yl)methyl]-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3-hydroxy-5-oxo-6-heptenoate (CP 188,
RS step t):
Compound 122 (2.68 mmol, 1.10 g), LiCl (3.08 mmol, 0.131 g), and 1.18 g (3.08 mmol) of methyl 3-[(t-butyldimethylsilyl)oxy]-6-(dimethoxyphosphinyl)-5-oxohexanoate (Theisen, P. D.; Heathcock, C. H. i Org. Chem.. 1988, 53. 2374-81) were combined in 15 mL of CH3CN. DBU
(2.95 mmol, 0.449 g, 0.441 mL) was added and the resulting clear, orange solution was stirred under N2 for 6 h. The mixture was diluted with 100 mL of Et20 and washed successively with 50 mL of 5% aqueous NaHS04, water, and brine. After drying over Na2S04, the solution was concentrated to give 2.00 g of orange oil. The crude mixture was dissolved in 25 mL of CH3CN, treated with 2.5 mL of 48% aqueous HF, and stirred for 5 h. Et20 (100 mL) was added and the acid was quenched by careful addition of saturated aqueous NaHCOs. The ethereal solution was washed with brine, dried over Na2S04, and concentrated to give 1.54 g of orange foam. The crude product was purified by MPLC using 1:2 EtOAc:hexanes to afford 0.22 g (15%) of the title compound as a yellow solid and an additional 0.50 g (34%) as a pale yellow solid which crystallized directly from the chromatography fractions, m.p. 137-138 °C; !H NMR (CDCI3, 300 MHz) 1.4-2.1 (complex, 4), 2.56 (d, 2, J=6 Hz), 2.71 (m, 3), 2.80 (d, 2, J=6 Hz), 3.15 (m, 1), 3.47 (d, 1, J=4 Hz), 3.56 (dd, 1, J=4, 13.5 Hz), 3.71 (s, 3), 4.52 (m, 1), 6.51 (d, 1, J=16 Hz), 7.1-7.7 (complex, 14); IR (KBr) 3450 (broad), 1734, 1603, 1512 cm'1; MS (DCI) m/z 553, 451 (base). Anal. Calcd. for C34H33FN204: C, 73.89; H, 6.02; N, 5.07. Found: C, 73.94; H, 6.01; N, 5.03.
44
26 42
General procedure for the preparation of 7-substituted (E)-3-hydroxy-5-oxo-6-heptenoates shown in Table 7 (RS step t):
The appropriately substituted aldehyde (10 mmol) from Table 3A or 3B was combined with 11.5 mmol of LiCl and 11.5 mmol of methyl 3-[(t-butyldimethylsilyl)oxy]-6-(dimethoxyphosphinyl)-5-oxohexanoate in 25 mL of CH3CN. DBU (11 mmol) was added and the resulting clear solution was stirred for 4-6 h, becoming slightly cloudy during that time. The mixture was diluted with 100 mL of Et20 and washed successively with 100 mL of 5% aqueous NaHSC>4, water, and brine. After drying over Na2SC>4, the solution was concentrated to give the crude silyloxy keto ester. The crude residue was dissolved in 100 mL of CH3CN and was treated with 10 mL of 48% aqueous HF. After TLC analysis indicated complete consumption of silyloxy keto ester, 200 mL of Et20 was added and the HF was quenched by careful addition of saturated aqueous NaHCOs. The ethereal solution was washed with brine, dried over Na2S04, and concentrated to give the crude product, which was purified by MPLC.
Table 7
O OH O
Compound Number
Mass Spectrum mp (°C) m/z [M+H]+
189
190
191
192
193
194
195
1-(4-F-Ph)
2-(4-F-Ph) 2-(4-F-Ph) 2-(4-F-Ph) 2-(4-F-Ph) 2-(4-F-Ph) 2-(4-F-Ph)
Ph-(CH2)2 (1-Nap)-CH2 (2-Nap)-CH2 (4-i-Pr-Ph)-CH2 (4-t-Bu-Ph)-CH2
Ph-CH=CH-CH2
Ph oil foam foam oil foam foam oil
491 527 527 519 533 463 503
45
2^42 j
EXAMPLE 13
Methyl (E)-(3RS,5SR)-7-[7-[(l,l'-Biphenyl-4-yl)methyl]-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5-dihydroxy-6-heptenoate (CP 39, RS step u):
Compound 188 (1.21 mmol. 0.67 g) was dissolved in 1.5 mL of MeOH and 5 mL of THF and treated, dropwise, with 1.33 mL (1.33 mmol) of a 1.0 M solution of Et3B in THF. Air (5 mL) was bubbled into the solution via syringe and the resulting solution was stirred under N2 for 2 h and then cooled to -78 °C. After addition of solid NaBH4 in one portion, the mixture was allowed to warm slowly to room temperature and was stirred overnight. Et20 (100 mL) and saturated aqueous NH4CI (50 mL) were added. The ethereal solution was washed with brine, dried over Na2S04, and concentrated to give a yellow oil. The oil was dissolved in MeOH, stirred under air overnight, and concentrated to provide 0.74 g of pale yellow foam. Purification by MPLC using 45:55 EtOAc:hexanes afforded a white foam which crystallized upon addition of Et20, giving 281 mg (42%) of the title compound as a white solid, m.p. 118-119 °C (the mother liquors gave 77 mg (12%) of additional product as a white foam); :H NMR (CDCI3, 300 MHz) 1.4-2.0 (complex, 6), 2.49 (d, 2, J=6 Hz), 2.6-2.8 (complex, 3), 3.10 (m, 1), 3.56 (dt, 1, J=13.5, 3.5 Hz), 3.62 (s, 1), 3.71 (s. 3), 3.78 (s, 1), 4.28 (m, 1), 4.48 (m, 1), 6.01 (dd, 1, J=6, 16 Hz), 6.45 (d, 1, J=16 Hz); 13c NMR (CDCI3, 75 MHz) 21.6, 22.8, 27.9, 36.2, 40.3, 41.3, 42.7, 51.9, 68.3, 72.5, 115.7, 116.0 (JC-F = 23 Hz), 118.0, 127.0, 127.3 (JC-F = 8 Hz), 128.7, 129.8, 135.0, 135.3, 136.1, 138.8, 139.8, 141.1, 153.3, 161.7 (JC-f = 247 Hz), 172.9; IR (KBr) 3400 (broad), 1734, 1513 cm*1; MS (DCI) m/z 555 (base),
46
26 42 3?
537, 523. Anal. Calcd. for C34H35FN2O4: C, 73.63; H, 6.36; N, 5.05. Found: C, 73.33; H, 6.60; N, 5.06.
General procedure for the preparation of 7-substituted (E)-(3RS,5SR)-3,5-dihydroxy-6-heptenoates shown in Table 8 (RS step u):
The appropriately substituted hydroxy keto ester from Table 7 (10 mmol), dissolved in 10 mL of MeOH and 30 mL of THF, was treated with 11 mmol of a 1.0 M THF solution of Et3B. Air (about 20 mL) was bubbled into the solution via syringe and the resulting solution was stirred under N2 for 2 10 h. After cooling to -78 °C, the solution was treated with 11 mmol of solid NaBH4 in one portion, causing some gas evolution. The mixture was allowed to warm slowly to room temperature and was stirred overnight. Saturated aqueous NH4CI was added and the mixture was extracted with Et20. The organic extracts were washed with brine, dried over Na2S04, and 15 concentrated to dryness. The residue, which smelled of excess Et3B, was then dissolved in MeOH and stirred vigorously under air until TLC analysis showed complete conversion of the boron intermediates to the desired product (4-24 h). The MeOH was removed by rotary evaporation and the crude material was purified by MPLC.
47
26 4 2 37
Table 8
OMe
OH O
Compound
R1
Mass Spectrum
Number
R2
mp (°C)
m/z [M+H]+
40
1-(4-F-Ph)
Ph-(CH2)2
foam
493
41
2-(4-F-Ph)
(1-Nap)-CH2
foam
529
42
2-(4-F-Ph)
(2-Nap)-CH2
foam
529
43
2-(4-F-Ph)
(4-i-Pr-Ph)-CH2
foam
521
44
2-(4-F-Ph)
(4-t-Bu-Ph)-CH2
foam
535
45
2-(4-F-Ph)
Ph foam
465
46
2-(4-F-Ph)
Ph-CH=CH-CH2
oil
505
EXAMPLE 14
(E)-(3RS,5SR)-7-[7-[(l,r-Biphenyl-4-yl)methyl]-2-(4-fluorophenyl)-4,5t6,7-tetrahydro-2H-indazol-3-yl]-3,5-diliydroxy-6-heptenoic acid • Sodium salt • Dthydrate (CP 1, RS step v):
Aqueous NaOH (0.25 N, 0.392 mmol, 1.57 mL) was added slowly to an ice-cold solution of Compound 39 (0.400 mmol, 222 mg) in 10 mL of MeOH. When the addition was complete, the solution was allowed to warm to room temperature and stirred for 2 h. The solution was concentrated to dryness using a rotary evaporator and the residue was dissolved in 40 mL of water. 15 The slightly cloudy solution was suction filtered through a coarse frit, frozen in a -78 °C bath, and lyophilized. The product was dried in a vacuum oven over Drierite to provide 219 mg (93%) of the title compound as a fluffy, white solid; *H NMR (DMSO-d6, 400 MHz) 1.3-2.0 (complex, 7), 2.05 (dd, 1. J=4, 15 Hz), 2.4-2.7 (complex, 4), 3.01 (m, 1), 3.40 (m, 1), 3.75 (m, 1), 20 4.26 (m, 1), 5.13 (broad s, 1), 6.07 (dd, 1, J=5, 16 Hz), 6.36 (d, 1, J=16 Hz), 7.2-7.7 (complex, 13); IR (KBr) 3400 (broad), 1577, 1513 cm*1; MS
48
26 42;
(FAB+) m/z 535, 563, 541, 167, 115 (base). Anal. Calcd. for C33H32FN2Na04 • 2 H20: C, 66.21; H, 6.06; N, 4.68. Found: C, 66.39; H, 5.67; N, 4.62.
General procedure for the preparation of 7-substituted (E)-(3RS,5SR)-3,5-dihydroxy-6-heptenoic acid sodium salts shown in Tables 9A and 9B (RS step v):
Aqueous NaOH (0.25 N, 0.98 mmol) was added slowly to an ice-cold methanolic solution (15 mL) of 1.0 mmol of the appropriately substituted 10 dihydroxy ester of Table 8, 13A, or 13B or Example 20. When the addition was complete, the solution was allowed to warm to room temperature and stir for 2 h until TLC analysis indicated that nearly all starting material had been consumed. The solution was concentrated to dryness using a rotary evaporator and the residue was dissolved in 40 mL of water. The slightly is cloudy solution was suction filtered through a coarse frit, frozen in a -78 °C bath, and lyophilized. The product was dried in a vacuum oven over Drierite to provide the desired sodium salt as a white, fluffy powder.
49
2642
Table 9A
0"Na+
OH OH O
Compound Number n
Rl
R2
Mass Spectrum m/z [M+H]+
2
3
4
6
7
8
9
0
4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph 4-F-Ph-CH2
H
(4-F-Ph)-CH2 c-Hex Et Me Ph-(CH2)2 Ph-CH=CH-CH2 H
383 505 497 425 411 501 513 425
50
26
4
2
Table 9B
Ri
N—N
R2
rYw
^.O'Na*
\ (CH2)n 1 1 2 n OH OH
[I
O
Compound
Mass Spectrum
Number n
Ri
R2
R3
Y
m/z [M+H]+
0
4-F-Ph
H
H
CH=CH
383
11
1
4-F-Ph
(1-Nap)-CH2
H
CH=CH
537
12
1
4-F-Ph
(2-Cl-Ph)-CH2
H
CH=CH
521
13
1
4-F-Ph
(2-Nap)-CH2
H
CH=CH
537
14
1
4-F-Ph
(3-MeO-Ph)-CH2
H
CH=CH
517
1
4-F-Ph
(3,4-di-MeO-Ph)-CH2
H
CH=CH
547
16
1
4-F-Ph
(4-Cl-Ph)-CH2
H
CH=CH
520
17
1
4-F-Ph
(4-F-Ph)-CH2
H
CH=CH
505
18
1
4-F-Ph
(4-i-Pr-Ph)-CH2
H
CH=CH
529
19
1
4-F-Ph
(4-Me-Ph)-CH2
H
CH=CH
501
1
4-F-Ph
(4-MeO-Ph)-CH2
H
CH=CH
517
21
1
4-F-Ph
(4-t-Bu-Ph)-CH2
H
CH=CH
543
22
1
4-F-Ph
6.7-Benzo—
CH=CH
445
23
1
4-F-Ph c-Hex
H
CH=CH
479
24
1
4-F-Ph
Et
H
CH=CH
425
1
4-F-Ph
H
H
CH=CH
397
26
1
4-Cl-Ph
H
H
CH=CH
413
27
1
4-F-Ph
H
H
CH=CMe
411
28
1
4-F-Ph
Me
H
CH=CH
411
29
1
4-F-Ph n-Pr
H
CH=CH
439
1
4-F-Ph
Ph
H
CH=CH
473
31
1
4-F-Ph
Ph-CH2
H
CH=CH
487
32
1
4-F-Ph
Ph-(CH2)2
H
CH=CH
501
33
1
4-F-Ph
Ph-(CH2)3
H
CH=CH
515
34
1
4-F-Ph
Ph-CH=CH-CH2
H
CH=CH
513
1
4-F-Ph s-Bu
H
CH=CH
453
36
2
4-F-Ph
7,8-Benzo—
CH=CH
459
37
2
4-F-Ph
H
H
CH=CH
411
38
2
4-F-Ph-CH2
H
H
CH=CH
425
EXAMPLE 15
Ethyl (E)-3-[2-(4-fluorophenyl)-7-benzyl-4,5,6,7-tetrahydro-2H-indazol-3-ylJ-2-propenoate (CP 196, RS step o):
Triethylphosphonoacetate (3.03 mmol, 0.706 g, 0.625 mL) in 2.5 mL of THF was added slowly under N2 to a stirring suspension of oil-free NaH
26423?
>
(3.09 mmol, 0.074 g) in 5 mL of THF. After 45 min, the solution was cooled in an ice bath and Compound 162 (2.75 mmol, 0.92 g) in 10 mL of THF was added dropwise. The mixture was allowed to warm to room temperature and was stirred overnight. Saturated aqueous NH4CI (50 mL) was added and the mixture was extracted with 100 mL of Et20. The organic phase was washed with brine, dried over Na2SC>4, and concentrated to give 1.29 g of amber oil. The crude product was crystallized from Et20:hexanes to give 0.598 g (54%) of the title compound as an off-white solid, m.p. 117-118 °C;
1H NMR (CDCI3, 300 MHz) 1.30 (t, 3, J=7 Hz), 1.4-2.1 (complex, 4), 1.6-1.8 (complex, 3), 3.10 (m, 1), 3.54 (dd, 1, J=4, 13.5 Hz), 4.22 (q, 2, J=7 Hz), 6.20 (d, 1, J=16 Hz), 7.1-7.4 (complex, 9), 7.48 (d, 1, J=16 Hz); IR (KBr) 1705 cm-1; MS (DCI) m/z 405 (base). Anal. Calcd. for C25H2sFN202: C, 74.24; H, 6.23; N, 6.93. Found; C, 74.31; H, 6.09; N, 6.91.
General procedure for the preparation of 3-substituted 2-propenoates shown in Tables 10A and 10B (RS step o):
A solution of 11 mmol of triethylphosphonoacetate or triethyl phosphonopropionate in 10 mL of THF was added slowly under N2 to a stirring suspension of 11.5 mmol of NaH in 15 mL of THF. After 45 min, the solution was cooled in an ice bath and the appropriately substituted aldehyde (10 mmol) from Table 3A, 3B, or 6 in THF (25 mL) was added dropwise. The mixture was allowed to warm to room temperature and was stirred overnight. Saturated aqueous NH4CI (100 mL) was added and the mixture was extracted with Et20. The organic phase was washed with brine, dried over Na2SC>4, and concentrated. The crude product was crystallized or was carried on without purification.
52
Table 10A
26
42 3 7
Compound Mass Spectrum Number n Rj R2 mp (°C) m/z [M+H]+
197
0
4-F-Ph
H
113-114
301
198
1
4-F-Ph
(4-F-Ph)-CH2
foam
411
199
1
4-F-Ph c-Hex oil
397
200
1
4-F-Ph
Et
99-100
343
201
1
4-F-Ph
Me oil
329
202
1
4-F-Ph
Ph-CH=CH-CH2
foam
431
203
2
(4-F-Ph)-CH2
H
75-76
343
26 4 2 3
Mass Spectrum mp (°C) m/z [M+H]+
204
0
4-F-Ph
H
CH=CH
94-95
301
205
1
4-F-Ph
(2-Cl-Ph)-CH2
CH=CH
oil
439
206
1
4-F-Ph
(2-Et)Bu
CH=CH
oil
399
207
1
4-F-Ph
(2-Nap)-CH2
CH=CH
154-155
455
208
1
4-F-Ph
(3-MeO-Ph)-CH2
CH=CH
135-137
435
209
1
4-F-Ph
(3,4-di-MeO-Ph)-CH2
CH=CH
foam
465
210
1
4-F-Ph
(4-Cl-Ph)-CH2
CH=CH
oil
439
211
1
4-F-Ph
(4-F-Ph)-CH2)
CH=CH
oil
411
212
1
4-F-Ph
(4-Me-Ph)-CH2
CH=CH
135-136
419
213
1
4-F-Ph
(4-MeO-Ph)-CH2
CH=CH
oil
435
214
1
4-F-Ph
(4-t-Bu-Ph)-CH2
CH=CH
oil
461
215
1
4-F-Ph c-Hex
CH=CH
oil
419
216
1
4-F-Ph
Et
CH=CH
oil
343
217
1
4-Cl-Ph
H
CH=CH
oil
331
218
1
4-F-Ph
H
CH=CH
76-77.5
315
219
1
4-F-Ph
H
CH=C(Me)
134-135
329
220
1
4-F-Ph
Me
CH=CH
oil
329
221
1
4-F-Ph n-Pr
CH=CH
oil
357
222
1
4-F-Ph
Ph-(CH2)2
CH=CH
oil
419
223
1
4-F-Ph
Ph-(CH2)3
CH=CH
oil
433
224
1
4-F-Ph
Ph-CH=CH-CH2
CH=CH
oil
431
225
1
4-F-Ph s-Bu
CH=CH
oil
371
226
2
4-F-Ph
H
CH=CH
53-55
329
227
2
4-F-Ph-CH2
H
CH=CH
oil
343
Compound Number n Ri
53
Table 10B
N-N' R2 ^ *
.ri kJCH2)n
'C02Et
R2
Y
EXAMPLE 16
(E)-3-[2-(4-Fluorophenyl)-7-benzyl-4,5,6,7-tetrahydro-2H-indazol-3-yl]2-^ propen-l-ol (CP 228, RS step p):
A 1.5 M solution of (i-Bu)2AlH in toluene (6.53 mmol, 4.35 mL) was o added under N2 to an ice cold solution of 1.10 g (6.53 mmol) of Compound 196 in 11 mL of THF. The solution was stirred for 1.5 h and was quenched with 0.5 mL of MeOH. When the initial bubbling had ceased, 35 mL of 1 N aqueous HCl was added and the mixture was extracted with 150 mL of ether.
54
26 4 237
The organic phase was washed sequentially with water, saturated aqueous NaHCC>3, and brine. After drying over Na2S04, the solvent was evaporated to give 0.89 g of an off-white solid. Recrystallization from EtOAc:hexanes afforded 0.62 g (63%) of the title compound as a white solid, m.p. 185-186 °C; 1H NMR (CDC13, 300 MHz) 1.4-2.0 (complex, 5), 2.62 (m, 3), 3.05 (m.
1), 3.54 (dd. 1, J=4, 13.5 Hz), 4.27 (t, 2, J=5 Hz), 6.16 (dt, 1. J=16, 5.5 Hz), 6.43 (d, 1, J=16 Hz), 7.1-7.5 (complex, 9); IR (KBr) 3300, 1515 cm"1; MS (DCI) m/z 363 (base), 345. Anal. Calcd. for C23H23FN20: C, 76.22; H, 6.40; N, 7.73. Found: C, 75.73: H, 6.01; N, 7.91.
General procedure for the preparation of 3-substituted 2-propen-l-ols shown in Tables 11A and 11B (RS step p):
A 1.5 M solution of (i-Bu)2AlH in toluene (24 mmol) was added under N2 to an ice cold solution of 10 mmol of the appropriately substituted ester 15 from Table 10A or 10B in 50 mL of THF. The solution was stirred for 1.5 h and was quenched with 2 mL of MeOH. When the initial bubbling had ceased, 100 mL of 1 N aqueous HCl was added and the mixture was extracted with 300 mL of ether. The organic phase was washed sequentially with water, saturated aqueous NaHCOs, and brine. After drying over Na2S04, 20 the solvent was evaporated and the crude product was purified by recrystallization or MPLC.
55
Table 11A
264237
OH
Compound Number n
Ri
R2
Mass Spectrum mp (°C) m/z [M+H1+
229
0
4-F-Ph
H
135-136
259
230
1
4-F-Ph
(4-F-Ph)-CH2
171-173
381
231
1
4-F-Ph c-Hex oil
355
232
1
4-F-Ph
Et yellow foam
301
233
1
4-F-Ph
Me
115-116
287
234
1
4-F-Ph
Ph-CH=CH-CH2
oil
389
235
2
(4-F-Ph)-CH2
H
oil
301
56
Table 11B
264237
kjCH2)
ch2oh
Compound Number n
Ri
R2
Y
mp (°C)
Mass Spectrum m/z [M+H]+
236
0
4-F-Ph
H
CH=CH
144-145
259
237
1
4-F-Ph
(2-Cl-Ph)-CH2
CH=CH
177-178
397
238
1
4-F-Ph
(2-Et)Bu
CH=CH
oil
357
239
1
4-F-Ph
(2-Nap)-CH2
CH=CH
205-207
413
240
1
4-F-Ph
(3-MeO-Ph)-CH2
CH=CH
foam
393
241
1
4-F-Ph
(3,4-di-MeO-Ph)-CH2
CH=CH
183-184
423
242
1
4-F-Ph
(4-Cl-Ph)-CH2
CH=CH
204-206
397
243
1
4-F-Ph
(4-F-Ph)-CH2
CH=CH
183-185
381
244
1
4-F-Ph
(4-Me-Ph)-CH2
CH=CH
184-186
377
245
1
4-F-Ph
(4-MeO-Ph)-CH2
CH=CH
172-173
393
246
1
4-F-Ph
(4-t-Bu-Ph)-CH2
CH=CH
141-142
419
247
1
4-F-Ph c-Hex
CH=CH
oil
355
248
1
4-F-Ph
Et
CH=CH
140-142
301
249
1
4-Cl-Ph
H
CH=CH
171-173
289
250
1
4-F-Ph
H
CH=CH
145-146
273
251
1
4-F-Ph
H
CH=C(Me)
149-150
287
252
1
4-F-Ph
Me
CH=CH
139-140
287
253
1
4-F-Ph n-Pr
CH=CH
140-141
315
254
1
4-F-Ph
Ph-(CH2)2
CH=CH
116-118
377
255
1
4-F-Ph
Ph-(CH2)3
CH=CH
105-108
391
256
1
4-F-Ph
Ph-CH=CH-CH2
CH=CH
oil
389
257
1
4-F-Ph s-Bu
CH=CH
oil
329
258
2
4-F-Ph
H
CH=CH
104-105
287
259
2
(4-F-Ph)-CH2
H
CH=CH
78-79
301
EXAMPLE 17
(E)-3-[2-(4-Fluorophenyl)-2,4,5,6-tetrahydrobenzo[6,7]cyclohepta-[l,2-c]pyrazol-3-yl]-2-propen-l-ol (CP 260, RS step q):
1-Benzosuberone (25 mmol, 4.10 g, 3.74 mL) was added dropwise under N2 to a stirring suspension of 4.23 g (26 mmol) of 4-fluorophenyl-hydrazine • HCl and 2.13 g (26 mmol) of NaOAc in 15 mL of absolute EtOH. The mixture was refluxed for 3 h and allowed to stir at room temperature overnight. After concentration, the residue was partitioned between water
57
264237
and Et20. The organic phase was washed with saturated aqueous NaHC03 and brine, dried over Na2S04, and concentrated to give 6.68 g of crude hydrazone as an orange solid. The crude product was dissolved in 25 mL of THF and added dropwise under N2 to a solution of LDA (made by adding 7.34 mL (52.3 mmol, 5.29 g) of diisopropylamine in 20 mL of THF to 33.7 mL (52.3 mmol) of 1.6 M n-BuLi in hexanes) at -10°C. The resulting dark brown solution was stirred for 30 min and was treated with a solution of methyl 4-tetrahydropyranyloxy-2-butenoate (Harnish, W.; Morera, E.; Ortar, G. J. Org. Chem.. 1985, 50, 1990-2) in 5 mL of THF. After 1.5 h, 42 mL of 3
N aqueous HCl was added to the cold solution, which was then refluxed for 15 min. Et20 (150 mL) was added and the organic layer was washed -with saturated aqueous NaHCOs and brine. After drying over Na2S04, the mixture was concentrated to give 12 g of light brown oil. The crude residue was refluxed under N2 for 8 h with 0.31 g (1.25 mmol) of pyrdinium p-
toluenesulfonate in 50 mL of MeOH. The solution was concentrated and the residue was partitioned between Et20 and water. The organic phase was washed with saturated aqueous NaHC03 and brine, dried over Na2S04, and concentrated to give 9.2 g of brown oil. Purification by MPLC using 1:3 EtOAc:hexanes afforded 3.35 g of yellow solid which was recrystallized from EtOAc:hexanes to give 3.00 g (36%) of the title compound as a white solid, m.p. 127-128 °C; *H NMR (CDC13, 300 MHz) 2.15 (m, 2), 2.84 (m, 4), 4.30 (m, 2), 6.16 (dt, 1, J=16, 5 Hz), 6.44 (d, 1, J=16 Hz), 7.2 (complex, 5), 7.50 (m, 2), 8.07 (m, 1); IR (KBr) 3300 (broad), 1515, 1223 cm*1: MS (DCI) m/z 335 (base), 317. Anal. Calcd. for C2iHi9FN20: C, 75.43; H, 5.73; N, 8.38. Found: C, 75.26; H, 5.52; N, 8.24.
264237
EXAMPLE 18
(E)-3-[4,5-Dihydro-2-(4-fluorophenyl)-2H-benz[g]indazol-3-yl]-2-propen-l-ol (CP 261, RS step q):
a-Tetralone (25 mmol, 3.65 g, 3.33 mL) was added dropwise under N2 to a stirring suspension of 4.23 g (26 mmol) of 4-fluorophenylhydrazine • HCl and 2.13 g (26 mmol) of NaOAc in 15 mL of absolute EtOH. The mixture was refluxed for 2 h, cooled, and concentrated to remove the solvent. The residue was partitioned between water and Et20. The organic phase was washed with saturated aqueous NaHCOs and brine, dried over Na2S04, and concentrated to give 6.21 g of crude hydrazone as a yellow solid. The crude product was dissolved in 30 mL of THF and added drop-wise under N2 to a solution of LDA (made by adding 7.18 mL (51.2 mmol, 5.18 g) of diisopropylamine in 10 mL of THF to 33.0 mL (51.2 mmol) of 1.55 M n-BuLi in hexanes) at -10°C. The resulting dark brown solution was stirred for 30 min and was treated with a solution of methyl 4-tetrahydropyranyloxy-2-butenoate (Harnish, W.; Morera, E.; Ortar, G. J. Org. Chem.. 1985, 50. 1990-2) in 15 mL of THF. After 1.5 h, 42 mL of 3 N
aqueous HCl was added to the cold solution, which was then refluxed for 1 h. Et20 (150 mL) was added and the organic layer was washed with saturated aqueous NaHC03 and brine. After drying over Na2S04, the mixture was concentrated to give 10.2 g of a light brown oil. The crude residue was refluxed under N2 for 8 h with 0.31 g (1.25 mmol) of pyrdinium p-toluenesulfonate in 50 mL of MeOH. The solution was concentrated and the residue was partitioned between Et20 and water. The organic phase was washed with saturated aqueous NaHC03 and brine, dried over Na2S04, and concentrated to give 8.44 g of a brown oil. Purification by MPLC using 1:3 EtOAc:hexanes afforded 3.03 g of an off-white solid which was reciystallized
26 42 3
59
from EtOAc:hexanes to give 2.37 g (37%) of the title compound as an off-white solid, m.p. 149-150°C; *H NMR (CDC13, 300 MHz) 1.70 (t, 1, J=6 Hz), 2.91 (m, 2), 3.02 (m, 2), 4.31 (dt, 2, J=1.5, 4.5 Hz), 6.21 (dt, 1, J=16, 5 Hz), 6.46 (dd, 1, J=1.5, 16 Hz), 7.18 (t, 2, J=8.5 Hz), 7.25 (m, 3), 7.48 (dd, 2, J=5, 8.5 Hz), 7.92 (m, 1); IR (KBr) 3300 (broad), 1509, 1221 cm*1; MS (DCI) m/z 321 (base), 303. Anal. Calcd. for C20H17FN2O: C, 74.98; H, 5.35; N, 8.74. Found: C, 74.78; H, 5.33; N, 8.97.
EXAMPLE 19
(E)-3-[2-(4-Fluorophenyl)-7-benzyl-4,5,6,7-tetrahydro-2H-indazol-3-yIJ-2-propenal (CP 262, RS step r):
Mn02 (30 mmol, 2.20 g) was added in one portion to a stirring suspension of 0.84 g (2.32 mmol) of Compound 228 in 15 mL of benzene. The mixture was refluxed gently under N2 for 3 h. After cooling, the slurry was filtered through a Celite pad and the solids were washed with 100 mL of CH2CI2. The filtrate was concentrated to give 0.75 g of a yellow solid which was purified by MPLC (1:8 EtOAc:hexanes) to provide 0.529 g (63%) of the title compound as a pale yellow solid, m.p. 130-131°C; XH NMR (CDCI3, 300 MHz) 1.6-2.1 (complex, 4), 2.6-2.8 (complex, 3), 3.10 (m, 1), 3.54 (dd, 1, J=4, 13.5 Hz), 6.48 (dd, 1, J=7.5, 16 Hz), 7.1-7.5 (complex, 10), 9.52 (d, 1, J=7.5 Hz); IR (KBr) 1677, 1617, 1512 cm*1; MS (DCI) m/z 361 (base), 307, 269, 241, 178. Anal. Calcd. for C23H2iFN20: C, 76.65; H, 5.87; N, 7.77.
Found: C, 76.47; H, 5.61; N, 7.35.
60
26 42 3
General procedure for the preparation of 3-substituted 2-propenals shown in Tables 12A and 12B. RS step r:
Method A: Mn02 (100-120 mmol) was added in one portion to a stirring suspension of 10 mmol of the appropriately substituted alcohol from Table 11A or 11B or Example 17 or 18 in benzene (60 mL). The mixture was refluxed gently under N2 until TLC analysis indicated that the starting material was completely consumed. After cooling, the slurry was filtered through a Celite pad and the black solids were washed with 250 mL of CH2C12. The filtrate was concentrated and the crude product was purified 10 by MPLC or recrystallization.
Method B: CrC>3 (60 mmol) was added under N2 in several portions to an ice-cold solution of 120 mmol of pyridine in 100 mL of CH2C12. The mixture was stirred at room temperature for 15 min and was re-cooled to 0°C. The appropriately substituted alcohol from Table 11A or 11B was is either dissolved in a minimum amount of CH2C12 and added dropwise or, if solid, was added in 5-10 portions over a 30 min period. The slurry was stirred 30-45 min at 0°C and was allowed to stir at room temperature until TLC analysis indicated the reaction was complete. Et20 (200 mL) was added and the solvent was decanted from the tarry residue through a Celite pad. 20 The residue was sonicated with two 100 mL portions of Et20, which were also decanted through Celite. The combined filtrates were washed successively with 100 mL of 1 N aqueous HCl, 100 mL of water, two 100 mL portions of saturated aqueous NaHC03, and brine. The ethereal solution was dried (Na2SC>4), concentrated, and purified by MPLC or recrystallization.
26 42
Table 12A
Compound Number
Method n
Ri
R2
mp (°C)
Mass Spectrum m/z [M+H]+
263
B
0
4-F-Ph
H
138-139
257
264
A
1
4-F-Ph
(4-F-Ph)-CH2
133-136
379
265
A
1
4-F-Ph c-Hex foam
353
266
A
1
4-F-Ph
Et
118-121
299
267
A
1
4-F-Ph
Me oil
285
268
A
1
4-F-Ph
Ph-CH=CH-CH2
foam
387
269
A
2
(4-F-Ph)-CH2
H
oil
299
62
Table 12B
264 2
«•»
R2
N-N''
R,
*CHO
R-A^CH2)n
Compound Number
Method n
Ri
Ba
R3
Y
mp (°C)
Mass Spectrum m/z [M+H]+
270
B
0
4-F-Ph
H
H
CH=CH
127-128
257
271
A
1
4-F-Ph
(2-Cl-Ph)-CH2
H
CH=CH
184-185
395
272
A
1
4-F-Ph
(2-Et)Bu
H
CH=CH
98-100
355
273
A
1
4-F-Ph
(2-Nap)-CH2
H
CH=CH
174-175
411
274
A
1
4-F-Ph
(3-MeO-Ph)-CH2
H
CH=CH
97-99
391
275
A
1
4-F-Ph
(3,4-di-MeO-Ph)-CH2
H
CH=CH
foam
421
276
A
1
4-F-Ph
(4-Cl-Ph)-CH2
H
CH=CH
144-145
395
277
A
1
4-F-Ph
(4-F-Ph)-CH2
H
CH=CH
oil
379
278
A
1
4-F-Ph
(4-Me-Ph)-CH2
H
CH=CH
160-162
375
279
A
1
4-F-Ph
(4-MeO-Ph)-CH2
H
CH=CH
141-142
391
280
A
1
4-F-Ph
(4-t-Bu-Ph)-CH2
H
CH=CH
145-148
417
281
A
1
4-F-Ph
6,7-Benzo
CH=CH
foam
319
282
A
1
4-F-Ph c-Hex
H
CH=CH
oil
353
283
A
1
4-F-Ph
Et
H
CH=CH
99-101
299
284
B
1
4-Cl-Ph
H
H
CH=CH
133-134
287
285
B
1
4-F-Ph
H
H
CH=CH
122-123
271
286
A
1
4-F-Ph
H
H
CH=C(Me)
172-173
285
287
A
1
4-F-Ph
Me
H
CH=CH
145-146
285
288
A
1
4-F-Ph n-Pr
H
CH=CH
92-93
313
289
A
1
4-F-Ph
Ph-(CH2)2
H
CH=CH
132-134
375
290
A
1
4-F-Ph
Ph-(CH2)3
H
CH=CH
oil
389
291
A
1
4-F-Ph
Ph-CH=CH-CH2
H
CH=CH
foam
387
292
A
1
4-F-Ph s-Bu
H
CH=CH
oil
327
293
A
2
4-F-Ph
7,8-Benzo
CH=CH
208-210
333
294
A
2
4-F-Ph
H
H
CH=CH
92-93
285
295
A
2
(4-F-Ph)-CH2
H
H
CH=CH
oil
299
)
EXAMPLE 20
Ethyl (E)-(3RS,5SR)-7-[7-benzyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5-dihydroxy-6-heptenoate (CP 47, RS step s):
A solution of 1.11 mL of ethyl acetoacetate (8.72 mmol, 1.13 g) in 10 mL of THF was added dropwise under N2 to a stirring suspension of 0.220 g (9.16 mmol) of oil-free NaH in 10 mL of THF. The mixture was stirred for 30 min and cooled to -10°C in an ice/acetone bath. n-BuLi in hexanes (1.6
> 264237
M, 8.72 mmol, 5.45 mL) was added slowly, producing a pale yellow solution. After 30 min, a solution of 2.86 g (7.93 mmol) of Compound 262 in 25 mL of THF was added and the resulting yellow solution was stirred for 45 min. Saturated aqueous NH4CI (50 mL) was added and the mixture was extracted with 100 mL of Et20. The organic solution was washed with brine, dried over Na2SC>4, and concentrated to give 3.84 g of crude hydroxy keto ester as an orange oil.
The crude intermediate was dissolved in 8 mL of MeOH and 25 mL of THF. A 1.0 M solution of Et3B in THF (8.60 mmol, 8.60 mL) was added and 20 mL of air was bubbled into the solution via syringe. The solution was stirred under N2 for 2 h and was cooled to -78 °C. NaBH4 (8.60 mmol, 0.33 g) was added in one portion. The mixture was allowed to warm slowly to room temperature and was stirred overnight. Saturated aqueous NH4CI (100 mL) was added and the mixture was extracted with 150 mL of Et20. The organic solution was washed with brine, dried over Na2S04, and concentrated to give an oil which was dissolved in 50 mL of MeOH and stirred vigorously under air overnight. The solution was concentrated to give 3.86 g of a yellow oil. Purification by MPLC using 2:3 EtOAc:hexanes yielded 1.83 g (47%) of the title compound as a white foam; !H NMR (CDCI3, 300 MHz) 1.27 (t, 3, J=7 Hz), 1.3-2.0 (complex, 6), 2.48 (d. 2, J=6 Hz), 2.60 (m, 3), 3.03 (m, 1), 3.55 (m, 1), 3.63 (s, 1), 3.78 (s, 1), 4.17 (q, 2, J=7 Hz), 4.30 (m, 1), 4.50 (m, 1), 6.00 (dd, 1, J=6, 16 Hz), 6.44 (d, 1, J=16 Hz), 7.1-7.5 (complex, 9); 13c NMR (CDCI3, 75 MHz) 14.2, 21.6, 22.8, 27.8, 36.2, 40.7, 41.5, 42.7, 60.9, 68.4, 72.5, 115.7, 116.0 (JC-f = 23 Hz), 117.9, 125.9, 127.3 (Jc-f = 8 Hz), 128.2, 129.3, 135.0, 135.4, 136.2, 140.6, 153.3, 161.8 (JC-f = 247 Hz), 172.5: IR (KBr) 3400 (broad), 1732, 1514 cm-i; MS
64
26423
(DCI) m/z 493, 457, 401, 333, 241, 91 (base). Anal. Calcd. for C29H33FN2O4: C, 70.71; H, 6.75; N, 5.69. Found: C, 70.90; H, 7.04; N, 5.67.
General procedure for the preparation of 7-substituted (E)-(3RS,5SR)-3,5-dihydroxy-6-heptenoates shown in Tables 13A and 13B (RS step s):
A solution of 11 mmol of ethyl acetoacetate in 10 mL of THF was added dropwise under N2 to a stirring suspension of 11.5 mmol of oil-free NaH in 15 mL of THF. The mixture was stirred for 30 min and cooled to -10°C in an ice/acetone bath. n-BuLi in hexanes (11 mmol of a 1.6 M solution) was added slowly, producing a pale yellow solution. After 30 min, a solution of 10 mmol of the appropriately substituted aldehyde from Table 12A or 12B in 30 mL of THF was added and the resulting yellow solution was stirred for about 1 h. Saturated aqueous NH4CI (75 mL) was added and the mixture was extracted with 150 mL of Et20. The organic solution was washed with brine, dried over Na2S04, and concentrated to give the crude hydroxy keto ester which was carried on without purification.
The crude intermediate was dissolved in 10 mL of MeOH and 30 mL of THF. A 1.0 M solution of Et3B in THF (11 mmol) was added and 20 mL of air was bubbled into the solution via syringe. The solution was stirred under N2 for 2 h and was cooled to -78 °C. NaBH4 (11 mmol) was added in one portion, causing some gas evolution. The mixture was allowed to warm slowly to room temperature and was stirred overnight. Saturated aqueous NH4CI (150 mL) was added and the mixture was extracted with 200 mL of Et20. The organic solution was washed with brine, dried over Na2S04, and concentrated. The residue, which smelled of excess Et3B, was then dissolved in MeOH and stirred vigorously under air until TLC analysis showed complete conversion of the boron intermediates to the desired
*042 37
65
product (4-24 h). The MeOH was removed by rotary evaporation and the crude material was purified by MPLC.
Table 13A
k^5H2)n OH OH O
Compound Mass Spectrum Number n Ri R2 m/z [M+H]+
48 0 4-F-Ph H 389
49 1 4-F-Ph (4-F-Ph)-CH2 511
50 1 4-F-Ph c-Hex 485
51 1 4-F-Ph Et 431
52 1 4-F-Ph Me 417
53 1 4-F-Ph Ph-CH=CH-CH2 515
54 2 (4-F-Ph)-CH2 H 431
*
.OEt
OH OH O
ipound mber n
Hi
R2
R3
Y
Mass Spectrum m/z [M+H)+
55
0
4-F-Ph
H
H
CH=CH
389
56
1
4-F-Ph
(2-Cl-Ph)-CH2
H
CH=CH
528
57
1
4-F-Ph
(2-Et)Bu
H
CH=CH
487
58
1
4-F-Ph
(3-MeO-Ph)-CH2
H
CH=CH
523
59
1
4-F-Ph
(3,4-dl-MeO-Ph) -CH2
H
CH=CH
553
60
1
4-F-Ph
(4-Cl-Ph)-CH2
H
CH=CH
528
61
1
4-F-Ph
(4-F-Ph)-CH2
H
CH=CH
511
62
1
4-F-Ph
(4-Me-Ph)-CH2
H
CH=CH
507
63
1
4-F-Ph
(4-MeO-Ph)-CH2
H
CH=CH
523
64
1
4-F-Ph
(4-t-Bu-Ph)-CH2
H
CH=CH
549
65
1
4-F-Ph
6,7-Benzo
CH=CH
451
66
1
4-F-Ph c-Hex
H
CH=CH
485
67
1
4-F-Ph
Et
H
CH=CH
431
68
1
4-CI-Ph
H
H
CH=CH
419
69
1
4-F-Ph
H
H
CH=CH
403
70
1
4-F-Ph
H
H
CH=CMe
417
71
1
4-F-Ph
Me
H
CH=CH
417
72
1
4-F-Ph n-Pr
H
CH=CH
445
73
4-F-Ph
Ph-(CH2)2
H
CH=CH
507
74
1
4-F-Ph
Ph-(CH2)3
H
CH=CH
521
75
1
4-F-Ph s-Bu
H
CH=CH
459
76
2
4-F-Ph
7,8-Benzo
CH=CH
465
77
2
4-F-Ph
H
H
CH=CH
417
78
2
(4-F-Ph)-CH2
H
H
CH=CH
431
EXAMPLE 21
(E)-(4RS,6SR)-6-[2-[7-Benzyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyTan-2-one (CP 79, RS step w):
A 5.0 mL (1.25 mmol) portion of 0.25 N aqueous NaOH was added slowly to an ice-cold solution of 0.500 g (1.02 mmol) of Compound 47 in 15 mL of methanol. After 15 min, the solution was allowed to warm to room
67
26423?
temperature and was stirred for 1 h. The solution was concentrated to dryness using a rotary evaporator and was mixed with 50 mL of water and 100 mL of CH2CI2. The mixture was acidified to pH 2-3 with aqueous 1 N HCl. The aqueous layer was extracted with 50 mL of CH2CI2 and the 5 combined organic layers were washed with brine, dried over Na2SC>4, and concentrated. The crude dihydroxy acid (0.49 g) was dissolved in 12 mL of CH2Cl2 and cooled in an ice bath. l-Cyclohexyl-3-(2-morpholinoethyl)-carbodiimide metho-p-toluenesulfonate (1.07 mmol, 0.455 g) was added in one portion and the mixture was allowed to warm slowly to room temperature and was stirred overnight. EtOAc (100 mL) was added and the white solids were removed by suction filtration. The solids were washed with more EtOAc and the combined filtrates were washed with water and brine and dried (Na2S04). The solution was concentrated to give 0.60 g of crude product which was purified by MPLC (1:1 EtOAc:hexanes) to provide 5 0.29 g (64%) of the title compound as a white solid, m.p. 185-187 °C; :H NMR (CDCI3, 300 MHz) 1.4-2.1 (complex, 6), 2.21 (d, 1, J=2.5 Hz), 2.62
^ (m, 4), 2.74 (dd. 1, J=4.5, 18 Hz), 3.06 (m, 1), 3.53 (dt, 1, J=13.5, 3.5), 4.40 (m, 1), 5.25 (m, 1), 6.01 (dd, 1, J=6.5, 16 Hz), 6.49 (d, 1, J=16 Hz), 7.1-7.5 (complex, 9); IR (KBr) 3300 (broad), 1741, 1513 cm"1; MS (DCI) 0 m/z 447, 429, 385 (base), 359. Anal. Calcd. for C27H27FN203: C, 72.63; H, ) 6.09; N. 6.27. Found: C, 72.61; H, 6.10; N, 5.97.
General procedure for the preparation of 6-substituted (E)-(4RS,6SR)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyTan-2-ones shown in Table 14, RS step w:
A 5.0 mL (1.25 mmol) portion of 0.25 N aqueous NaOH was added slowly to an ice-cold solution of 1.02 mmol of the appropriately substituted ester from Table 8, 13A, or 13B in methanol (15 mL). After 15 min, the
68
264237
solution was allowed to warm to room temperature and was stirred for 1 h. The solution was concentrated to dryness using a rotary evaporator and was mixed with 50 mL of water and 100 mL of CH2CI2. The mixture was acidified to pH 2-3 with aqueous 1 N HCL The aqueous layer was extracted with 50 mL of CH2CI2 and the combined organic layers were washed with brine, dried over Na2S04, and concentrated. The crude dihydroxy acid was dissolved in 12 mL of CH2C12 and cooled in an ice bath. l-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (1.1 mmol) was added in one portion and the mixture was allowed to warm slowly to room temperature and was stirred overnight. EtOAc (100 mL) was added and the white solids were removed by suction filtration. The solids were washed with more EtOAc and the combined filtrates were washed with water and brine and dried (Na2S04). The solution was concentrated and the crude product was purified by MPLC.
Table 14
o
Compound Number mp (°C)
Mass Spectrum m/z |M+H]+
80
81
82
83
(2-Et)Bu (2-Nap)-CH2 (4-t-Bu-Ph)-CH2 H
foam foam foam foam
441 497 503 357
Z(oU3l
Claims (2)
- WHAT WE CLAIM IS: I. The compound of Formula X N- -N CHO X wherein Rt is selected from any one of H, alkyl, aryl, or substituted aryl; wherein R2 is selected from any one of H, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, aralkenyl or cycloalkyl; wherein R3 is H; or wherein R2 and R3 may be taken together to form a benzo or naphtho ring system; wherein n = 0 to 3 and p = 0 to 3 and pharmaceutically acceptable acid salts thereof.
- 2. The compound of claim 1 wherein Rx is selected from any one of H, C1-C8 alkyl, aryl, or substituted aryl; wherein R2 is selected from any one of H, C1-C8 alkyl, aryl, substituted aryl, aralkyl wherein the alkyl portion is Q-C4, substituted aralkyl wherein the alkyl portion is Q-C4 aralkenyl wherein the alkenyl portion is C2-C4, or C3-C8 cycloalkyl; wherein R3 is H; or wherein R2 and R3 may be taken together to form a benzo or naphtho ring system. 4. A method of preparing a compound of claim 1, substantially as herein before described with reference to Examples 3 and 11 and to Tables 3A, 3B and 6. WEST-WALKER, McCABE per ATTORNEYS FOR THE APPLICANT
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US07/742,788 US5134155A (en) | 1991-08-08 | 1991-08-08 | Tetrahydroindazole, tetrahydrocyclopentapyrazole, and hexahydrocycloheptapyrazole compounds and their use as HMG-coA reductase inhibitors |
NZ243575A NZ243575A (en) | 1991-08-08 | 1992-07-15 | Indazole, cyclopentapyrazole and cycloheptapyrazole derivatives and pharmaceutical compositions |
Publications (1)
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NZ264237A true NZ264237A (en) | 1995-09-26 |
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ID=26651094
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NZ264237A NZ264237A (en) | 1991-08-08 | 1992-07-15 | Cyclo-penta, -hexa and -hepta pyrazole-3-carboxaldehyde derivatives |
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Country | Link |
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NZ (1) | NZ264237A (en) |
-
1992
- 1992-07-15 NZ NZ264237A patent/NZ264237A/en not_active IP Right Cessation
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