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WO1996034850A1 - Derives de cyclobutane et leur utilisation comme inhibiteurs de proteine farnesyl-transferase - Google Patents

Derives de cyclobutane et leur utilisation comme inhibiteurs de proteine farnesyl-transferase Download PDF

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Publication number
WO1996034850A1
WO1996034850A1 PCT/US1996/006156 US9606156W WO9634850A1 WO 1996034850 A1 WO1996034850 A1 WO 1996034850A1 US 9606156 W US9606156 W US 9606156W WO 9634850 A1 WO9634850 A1 WO 9634850A1
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WIPO (PCT)
Prior art keywords
independently selected
heterocyclic
occurrence
cyclobutane
aryl
Prior art date
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PCT/US1996/006156
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English (en)
Inventor
David L. Arendsen
Saul H. Rosenberg
Todd W. Rockway
Herman H. Stein
Anthony K. L. Fung
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Abbott Laboratories
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Priority to AU57227/96A priority Critical patent/AU5722796A/en
Publication of WO1996034850A1 publication Critical patent/WO1996034850A1/fr

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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07C233/19—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to substituted benzoic acids which are useful in inhibiting protein farnesyltransferase and the farnesylation of the oncogene protein Ras, compositions containing such compounds and to methods of using such compounds.
  • Transformed protein Ras is involved in the proliferation of cancer cells.
  • the Ras must be farnesylated before this proliferation can occur.
  • Farnesylation of Ras by farnesyl pyrophosphate (FPP) is effected by protein
  • farnesyltransferase Inhibition of protein farnesyltransferase and, thereby, of farnesylation of the Ras protein, blocks the ability of transformed cells to proliferate.
  • Ras also partially mediates smooth muscle cell proliferation (Circulation, I-3: 88 (1993). Inhibition of protein farnesyltransferase and, thereby, of farnesylation of the Ras protein, will also aid in the prevention of restenosis.
  • Transformed protein Ras is involved in the proliferation of cancer cells. The Ras, must be farnesylated before this proliferation can occur. Farnesylation of Ras by farnesyl pyrophosphate (FPP) is effected by protein
  • farnesyltransferase Inhibition of protein farnesyltransferase and, thereby, of farnesylation of the Ras protein, blocks the ability of transformed cells to proliferate.
  • Ras also partially mediates smooth muscle cell proliferation (Circulation, I-3: 88 (1993). Inhibition of protein farnesyltransferase and, thereby, of farnesylation of the Ras protein, would aid in the prevention of restenosis.
  • a 1 and A 2 are independently selected from
  • R 1 is independently selected from (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkynyl, (e) cycloalkyl, (f) cycloalkylalkyl, (g) alkoxycarbonylalkyl,
  • cycloalkylalkyl (heterocyclic)alkyl or heterocyclic-substituted cycloalkylalkyl wherein the aryl group, the aryl part of the arylalkyl group, the aryl part of the aryl-substituted
  • cycloalkylalkyl the heterocyclic group, the heterocyclic part of the (heterocyclic)alkyl group or the heterocyclic part of the heterocyclic-substituted cycloalkylalkyl group is substituted with -Y-R 3 wherein at each occurrence Y is independently selected from (i) a covalent bond, (ii) -C(O)-, (iii) -CH 2 -, (iv) -O-, (v) -S(O) m - wherein m is 0, 1 or 2, (vi) -N(R b )- wherein R b is hydrogen or loweralkyl, (vii) -CH 2 O-, (viii) -CH 2 S(O) m - wherein m is 0, 1 or 2, and (ix) -CH 2 N(R b )- wherein R b is hydrogen or loweralkyl and at each occurrence R 3 is independently selected from (i) aryl, (
  • R 2 is independently selected from
  • alkenyl (i) alkynyl, (iii) aryl, (iv) arylalkyl, (v) arylalkenyl, (vi) heterocyclic, (vii) (heterocyclic)alkyl and (viii) aryl,
  • heterocyclic, arylalkyl or (heterocyclic)alkyl wherein the aryl group, the aryl part of the arylalkyl group, the heterocyclic group or the heterocyclic part of the (heterocyclic)alkyl group is substituted with -Z-R 4 wherein at each occurrence Z is
  • R 4 is independently selected from (i) aryl, (ii) arylalkyl,
  • R 28 is hydrogen, aryl or loweralkyl
  • R 29 is selected from hydrogen and loweralkyl
  • R 29 is as defined above
  • R 31 is selected from hydrogen, loweralkyl, alkenyl, alkoxyalkyl and benzyl,
  • Q is independently selected from (a) a covalent bond, (b) alkylene,
  • arylalkyl (heterocyclic)alkyl, C 3 -C 7 -cycloalkyl,
  • Preferred compounds of the invention are compounds of formula (II):
  • a 1 , A 2 , B 1 and B 2 are defined as above;
  • Preferred compounds of the invention are compounds of formula (I) or (II) wherein A 1 and A 2 are independently selected from -C(O)-G wherein G is defined as above and B 1 and B 2 are independently selected from (a) -W-R 5 wherein W is a covalent bond or alkylene and R 5 is 5-tetrazolyl or
  • More preferred compounds of the invention are compounds of formula (I) or (II) wherein A 1 and A 2 are independently selected from -C(O)-G wherein
  • G is -N(R 1 )(R 2 ) wherein R 1 and R 2 are as defined above and B 1 and B 2 are independently selected from (a) -W-R 5 wherein W is a covalent bond or alkylene and R 5 is 5-tetrazolyl or
  • a 1 and A 2 are independently selected from -C(O)-G wherein G is -N(R 1 )(R 2 ) wherein at each occurrence R 1 is independently selected from (a) hydrogen, (b) loweralkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkoxyalkyl, (f) thioalkoxyalkyl, (g) aryl, (h) heterocyclic, (i) arylalkyl,
  • (vi) (heterocyclic)alkyl and at each occurrence R 2 is independently selected from aryl, heterocyclic, arylalkyl and (heterocyclic)alkyl wherein the aryl group, aryl part of the arylalkyl group, heterocyclic group or heterocyclic part of the (heterocyclic)alkyl group is substituted with -Z-R 4 wherein at each occurrence Z is independently selected from (i) -O-, (ii) -S(O) p - wherein p is 0, 1 or 2 and (iii) -N(R c )- wherein R c is hydrogen or loweralkyl and at each occurrence R 4 is independently selected from (i) aryl, (ii) arylalkyl,
  • B 1 and B 2 are independently selected from (a) -W-R 5 wherein W is a covalent bond or alkylene and R 5 is 5-tetrazolyl or
  • a 1 and A 2 are independently selected from -C(O)-G wherein G is -N(R 1 )(R 2 ) wherein at each occurrence R 1 is independently selected from (a) loweralkyl, (b) cycloalkyl and
  • cycloalkylalkyl and at each occurrence R 2 is independently selected from aryl and arylalkyl wherein the aryl group or aryl part of the arylalkyl group is substituted with -Z-R 4 wherein at each occurrence Z is independently selected from (i) -O- and (ii) -S- and at each occurrence R 4 is independently selected from (i) aryl, (ii) arylalkyl, (iii) cycloalkyl, (iv) cycloalkylalkyl, (v) heterocyclic and (vi) (heterocyclic)alkyl and B 1 and B 2 are independently selected from -Q-C(O)-R 6 , -W-R 5 and
  • Q and W are independently selected from a covalent bond and alkylene
  • R 6 is -OR 7 wherein R 7 is hydrogen or a carboxy- protecting group and R 5 is 5-tetrazolyl or
  • Most preferred compounds of the invention are compounds of formula (I) or (II) wherein A 1 and A 2 are independently selected from -C(O)-G wherein G is -N(R 1 )(R 2 ) wherein at each occurrence R 1 is independently selected from (a) loweralkyl, (b) cycloalkyl and (c) cycloalkylalkyl and at each occurrence R 2 is independently selected from phenyl and benzyl wherein the phenyl group or the phenyl ring of the benzyl group is substituted with -Z-R 4 wherein at each occurrence Z is independently selected from (i) -O- and (ii) -S- and at each occurrence R 4 is independently selected from (i) aryl, (ii) arylalkyl, (iii) heterocyclic and (iv) (heterocyclic)alkyl and B 1 and B 2 are independently selected from -Q-C(O)-R 6 , -W
  • Q and W are independently selected from a covalent bond and alkylene
  • R 6 is -OR 7 wherein R 7 is hydrogen or a carboxy- protecting group and R 5 is 5-tetrazolyl or
  • Most highly preferred compounds of the invention are compounds of formula (I) or (II) wherein A 1 and A 2 are independently selected from -C(O)-G wherein G is -N(R 1 )(R 2 ) wherein at each occurrence R 1 is independently selected from (a) loweralkyl, (b) cycloalkyl and (c) cycloalkylalkyl and R 2 is benzyl wherein the phenyl ring of the benzyl group is substituted with -Z-R 4 wherein at each occurrence Z is independently selected from (i) -O- and (ii) -S- and R 4 is aryl and B 1 and B 2 are independently selected from
  • Q and W are independently selected from a covalent bond and alkylene
  • R 6 is -OR 7 wherein R 7 is hydrogen or a carboxy- protecting group and R 5 is 5-tetrazolyl or
  • a 1 and A 2 are independently selected from -C(O)-G wherein G is -N(R 1 )(R 2 ) wherein at each occurrence R 1 is (a) loweralkyl, (b) cycloalkyl and (c) cycloalkylalkyl and R 2 is benzyl wherein the phenyl ring of the benzyl group is substituted with -Z-R 4 wherein at each occurrence Z is independently selected from (i) -O- and (ii) -S- and R 4 is heterocyclic and B 1 and B 2 are independently selected from -Q-C(O)-R 6 , -W-R 5 and
  • Q and W are independently selected from a covalent bond and alkylene
  • R 6 is -OR 7 wherein R 7 is hydrogen or a carboxy- protecting group and R 5 is 5-tetrazolyl or
  • Another aspect of this invention relates to the use of compounds of the formula:
  • a 1 and A 2 are independently selected from
  • R a is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl and at each occurrence
  • G is independently selected from -R 2 , -N(R 1 )(R 2 ), -OR 2 and -SR 2 wherein at each occurrence R 1 is independently selected from (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkynyl,
  • cycloalkylalkyl (heterocyclic)alkyl or heterocyclic-substituted cycloalkylalkyl wherein the aryl group, the aryl part of the arylalkyl group, the aryl part of the aryl-substituted
  • cycloalkylalkyl the heterocyclic group, the heterocyclic part of the (heterocyclic)alkyl group or the heterocyclic part of the heterocyclic-substituted cycloalkylalkyl group is substituted with -Y-R 3 wherein at each occurrence Y is independently selected from (i) a covalent bond, (ii) -C(O)-, (iii) -CH 2 -, (iv) -O-, (v) -S(O) m - wherein m is 0, 1 or 2, (vi) -N(R b )- wherein R b is hydrogen or loweralkyl, (vii) -CH 2 O-, (viii) -CH 2 S(O) m - wherein m is 0, 1 or 2, and (ix) -CH 2 N(R b )- wherein R b is hydrogen or loweralkyl and at each occurrence R 3 is independently selected from (i) aryl, (
  • R 2 is independently selected from
  • alkenyl (i) alkynyl, (iii) aryl, (iv) arylalkyl, (v) arylalkenyl, (vi) heterocyclic, (vii) (heterocyclic)alkyl and (viii) aryl,
  • heterocyclic, arylalkyl or (heterocyclic)alkyl wherein the aryl group, the aryl part of the arylalkyl group, the heterocyclic group or the heterocyclic part of the (heterocyclic)alkyl group is substituted with -Z-R 4 wherein at each occurrence Z is independently selected from (i) a covalent bond, (ii) -C(O)-, (iii) -CH 2 -, (iv) -O-, (v) -S(O) p - wherein p is 0, 1 or 2, (vi) -N(R c )- wherein R c is hydrogen or loweralkyl, (vii) -CH 2 O-,
  • B 1 and B 2 are independently selected from
  • R 5 is independently selected from
  • R 27 is -CN, -NO 2 , or -CO 2 R 28 wherein R 28 is hydrogen, aryl or loweralkyl,
  • R 29 is selected from hydrogen and loweralkyl, wherein R 29 is as defined above,
  • R 31 is selected from hydrogen, loweralkyl, alkenyl, alkoxyalkyl and benzyl,
  • Q is independently selected from (a) a covalent bond, (b) alkylene,
  • arylalkyl (heterocyclic)alkyl, C 3 -C 7 -cycloalkyl,
  • inhibitors of protein farnesyltransferase are compounds of formula (III) or (IV) wherein
  • a 1 and A 2 are independently -C(O)-NR 1 R 2
  • R 1 is independently selected from
  • heterocyclic part of the heterocyclic-substituted cycloalkylalkyl group is substituted with -Y-R 3 wherein at each occurrence Y is independently selected from (i) a covalent bond, (ii) -C(O)-, (iii) -CH 2 -, (iv) -O-, (v) -S(O) m - wherein m is 0, 1 or 2, (vi) -N(R b )- wherein R b is hydrogen or loweralkyl, (vii) -CH 2 O-, (viii) -CH 2 S(O) m - wherein m is 0, 1 or 2, and (ix) -CH 2 N(R b )- wherein R b is hydrogen or loweralkyl and at each occurrence
  • R 3 is independently selected from (i) aryl, (ii) arylalkyl,
  • R 2 is independently selected from arylalkyl
  • B 1 and B 2 are independently selected from
  • Q is independently selected from (a) a covalent bond, (b) alkylene,
  • R 6 is independently selected from (a) -OR 7 wherein R 7 is hydrogen or a carboxy-protecting group, (b) -NH 2 , (c) -NHOH, (d) -NHSO 2 CF 3 (e) an alpha-amino acid or a beta-amino acid which is bonded via the alpha- or beta- amino group and (f) a di-, tri- or tetra-peptide which is bonded via the amino terminal amino group, and (3) -C(O)-NH-S(O) 2 -R 26 wherein R 26 is aryl, heterocyclic,
  • arylalkyl (heterocyclic)alkyl, C 3 -C 7 -cycloalkyl,
  • the present invention also relates to processes for preparing the compounds of formula (I), (II), (III) or (IV) and to the synthetic
  • compositions which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier.
  • compositions which comprise a compound of the present invention in combination with another antihyperlipoproteinemic agent and/or with one or more other serum cholesterol lowering agents or HMG CoA reductase inhibitors and a pharmaceutically acceptable carrier.
  • compositions which comprise a compound of the present invention in combination with another chemotherapeutic agent and a pharmaceutically acceptable carrier.
  • a method for inhibiting squalene synthase in a human or lower mammal comprising administering to the patient a therapeutically effective amount of a compound of the invention.
  • a method for inhibiting or treating atherosclerosis or inhibiting or treating hyperlipidemia which would inhibit the development of atherosclerosis in a human or lower mammal, comprising administering to the patient a therapeutically effective amount of a compound of the invention alone or in combination with another cardiovascular agent.
  • a method for inhibiting or treating cancer in a human or lower mammal comprising administering to the patient a therapeutically effective amount of a compound of the invention alone or in combination with another chemotherapeutic agent
  • the compounds of the invention comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the
  • ⁇ and ⁇ are employed to describe relative orientation for ring substituents on cyclic compounds, i.e., substituted cycl ⁇ butanes in the present invention.
  • the ⁇ -side of the reference plane (the plane formed by the cyclobutane ring) is that side on which the highest ranking substituent (according to the Cahn-lngold-Prelog Sequence Rule) lies at the lowest-numbered stereogenic carbon atom. All substituents lying on the same side of the reference plane as the highest-ranking substituent are assigned an ⁇ descriptor. Those substituents lying on the opposite side of the reference plane are assigned a ⁇ descriptor. It should be
  • ⁇ -amino acid or "alpha-amino acid” refers to an ⁇ - amino acid selected from the group consisting of alanine, arginine,
  • the stereochemistry at the asymmetric center can be of the
  • ⁇ -amino acid or "beta-amino acid” refers to an amino acid wherein the amino group is ⁇ to the carboxylic acid functionality.
  • ⁇ -amino acids examples include ⁇ -alanine, ⁇ -phenylalanine and the like.
  • dipeptide refers to AA 1 -AA 2 wherein AA 1 and AA 2 are independently selected from ⁇ - and ⁇ -amino acids as described above coupled together by an amide bond (-C(O)-NH-) between the carboxy terminus of AA 1 and the amino terminus of AA 2 .
  • Examples of dipeptides include H- Glycyl-Alanine-OH,
  • tripeptide refers to AA 1 -AA 2 -AA 3 wherein AA 1 , AA 2 and AA 3 are independently selected from ⁇ - and
  • tripeptides include H-Glycyl-Alanyl-Leucine-OH, H-Glycyl- ⁇ -Alanyl-Sarcosine-OH, H-Leucyl-Glycyl-Alanine-OH and the like.
  • tetrapeptide refers to amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the same amino acids having the amino acids
  • AA 1 -AA 2 -AA 3 -AA 4 wherein AA 1 , AA 2 , AA 3 and AA 4 are independently selected from ⁇ - and ⁇ -amino acids as described above coupled together by amide bonds (-C(O)-NH-) between the carboxy terminus of AA 1 and the amino terminus of AA 2 , the carboxy terminus of AA 2 and the amino terminus of AA 3 , and the carboxy terminus of AA 3 and the amino terminus of AA 4 .
  • carboxy protecting group refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out.
  • Carboxy-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis” pp. 152-186 (1981), which is hereby incorporated herein by reference.
  • a carboxy-protecting group can be used as a prodrug whereby the carboxy-protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium
  • carboxy protecting groups are C 1 to C 8 loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such-as
  • benzoyloxymethyl benzoyloxyethyl and the like
  • arylalkylcarbonyloxyalkyl such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like
  • alkoxycarbonylalkyl or cycloalkyloxycarbonylalkyl such as
  • alkoxycarbonyloxyalkyl or cycloalkyloxycarbonyloxyalkyi such as methoxycarbonyloxy methyl, t-butyloxycarbonyloxymethyl, 1- ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and the like; aryloxycarbonyloxyalkyl, such as 2-(phenoxycarbonyloxy)ethyl, 2-(5- indanyloxycarbonyloxy)ethyl and the like; alkoxyalkylcarbonyloxyalkyl, such as 2-(1-methoxy-2-methylpropan-2-oyloxy)ethyl and like;
  • arylalkyloxycarbonyloxyalkyl such as 2-(benzyloxycarbonyloxy)ethyl and the like; arylalkenyloxycarbonyloxyalkyl, such as 2-(3-phenylpropen-2- yloxycarbonyloxy)ethyl and the like; alkoxycarbonylaminoalkyl, such as t- butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4- methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3-
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference.
  • N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, ,o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl,
  • benzenesulfonyl p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • loweralkyl refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.
  • alkoxy refers to RO- wherein R is loweralkyl as defined above.
  • Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy and the like.
  • alkoxyalkoxy refers to R 80 O-R 81 O- wherein
  • R 80 is loweralkyl as defined above and R 81 is an alkylene group.
  • alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
  • alkoxyalkyl refers to an alkoxy group as previously defined appended to an alkyl group as previously defined.
  • alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
  • alkoxycarbonyl refers to an alkoxy group as previously defined appended to the parent molecular moiety through a carbonyl group.
  • alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
  • alkoxycarbonylalkyl refers to an alkoxycarbonylalkyl
  • alkoxylcarbonyl group as previously defined appended to a loweralkyl group.
  • alkoxycarbonylalkyl include methoxycarbonylmethyl, 2- ethoxycarbonylethyl and the like.
  • alkylene denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example methylene, 1 ,2-ethylene, 1 ,1- ethylene, 1 ,3-propylene, 2,2-dimethylpropylene, and the like.
  • alkenyl refers to a branched or straight hydrocarbon chain comprising two to twenty carbon atoms which also
  • alkenyl groups include 2-propenyl (i.e., allyl), 3-methyl-2-butenyl, 3,7-dimethyl-2,6- octadienyl, 4,8-dimethyl-3,7-nonadienyl, 3,7,11-trimethyl-2,6,10-dodecatrienyl and the like.
  • alkynyl refers to a branched or straight hydrocarbon chain comprising two to twenty carbon atoms which also
  • alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
  • amino refers to -NH 2 .
  • alkylamino refers to R 51 NH- wherein R 51 is a loweralkyl group, for example, methylamino, ethylamino, butylamino, and the like.
  • dialkylamino refers to R 56 R 57 N- wherein R 56 and R 57 are independently selected from loweralkyl, for example
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
  • arylalkyl refers to a loweralkyl radical to which is appended an aryl group.
  • Representative arylalkyl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and the like.
  • arylalkenyl refers to an aryl group as
  • arylalkenyl examples include styryl (i.e., 2-phenylethenyl), 2-(1- naphthyl)ethenyl and the like.
  • aryl-substituted cycloalkylalkyl refers to a cycloalkylalkyl radical in which the alkyl portion of the radical is substituted with an aryl group.
  • aryl-substituted cycloalkylalkyl include ⁇ - (cyclopropylmethyl)benzyl,
  • carboxaldehyde refers to the group -C(O)H.
  • carboxamide refers to the group -C(O)NH 2 .
  • cycloalkyl refers to an alicyclic group comprising from 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkylalkyl refers to a loweralkyl radical to which is appended a cycloalkyl group.
  • cycloalkylalkyl include cyclopropylmethyl, cyclohexylmethyl, 2- (cyclopropyl)ethyl and the like.
  • 1 ,2,3,4-cyclobutanetetracarboxylic dianhydride refers to the (1.2/3.4) compound wherein the two anhydride rings are trans (i.e., on opposite sides of the plane formed by the cyclobutane ring) to one another.
  • halogen or halo as used herein refers to I, Br, Cl or F.
  • haloalkyl refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • the 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds.
  • the nitrogen heteroatoms can be optionally quatemized.
  • heterocyclic also includes bicyclic groups in which any of the above
  • heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl or benzothienyl and the like).
  • Heterocyclics include: azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolid
  • Heterocyclics also include compounds of the formula where X* is -CH 2 - or
  • Y* is -C(O)- or [-C(R") 2 -] v where R" is hydrogen or C 1 -C 4 -alkyl and v is 1 , 2 or 3 such as 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like.
  • nitrogen containing heterocycles can be N- protected.
  • heterocyclic alkyl refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
  • heterocyclic alkyl examples include 2-pyridylmethyl, 4-pyridylmethyl, 4- quinolinylmethyl and the like.
  • heterocyclic-substituted cycloalkylalkyl refers to a cycloalkylalkyl radical in which the alkyl portion of the radical is substituted with a heterocyclic group.
  • heterocyclic-substituted cycloalkylalkyl include ⁇ -(cyclopropylmethyl)furan-2-ylmethyl, ⁇ -(cyclobutylmethyl)thien-2- ylmethyl and the like.
  • mercapto refers to the group -SH.
  • perfluoro-C 1 -C 4 -alkyl refers to an alkyf radical of 1 to 4 carbon atoms in which all hydrogen atoms have been replaced with fluorine atoms.
  • Examples of perfluoro-C 1 -C 4 -alkyl include trifluoromethyl, pentafluoroethyl and the like.
  • tetrazolyl or “5-tetrazolyl” as used herein refers to a
  • thioalkoxy refers to R 70 S- wherein R 70 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
  • thioalkoxyalkyl refers to a thioalkoxy group as previously defined appended to a loweralkyl group as previously defined. Examples of thioalkoxyalkyl include
  • Representative compounds of the invention include:
  • (+)-(1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )-1 2-Di[N-methyl-N-((1S)-1-(4-phenoxyphenyl)- 1-ethyl)aminocarbonyl]cyclobutane-3,4-dicarboxylic acid; (+)-(1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )-1 ,2-Di[N-methyl-N-((1 R)-1-(4-phenoxyphenyl)-
  • Preferred compounds are selected from the group consisting of (1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )-1 ,2-Di[N-benzyl-N-(4-phenoxybenzyl)- aminocarbonyl]cyclobutane-3,4-dicarboxylic acid;
  • the compounds of the invention can be prepared by the processes illustrated in Schemes l-XIX.
  • reaction Scheme I 1 ,2,3,4-cyclobutanetetracarboxylic dianhydride (where the two anhydrides are trans to one another) in an inert solvent such as dimethylformamide is treated with an appropriately substituted secondary amine (HNR 1 R 2 ) in the presence of an aprotic base such as triethylamine to afford a mixture of the 1 ,2- and 1 ,3- diamides.
  • an inert solvent such as dimethylformamide
  • the dicarboxylic acid (2) can be further elaborated, if desired, to its diester 4 (wherein R 10 is loweralkyl, benzyl, a carboxy protecting group or prodrug) by treatment with an alcohol such as methanol in the presence of concentrated sulfuric acid or with diazomethane.
  • Compound 6 is activated as an acid halide (for example by treatment with thionyl chloride or phosphorus oxychloride) or activated ester including esters or anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, N- hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5- trichlorophenol and the like and then reacted with a secondary amine
  • optically active compounds of the invention is shown in Scheme III.
  • R 1 is propyl and R 2 is 4- (phenoxy)benzyl.
  • the dicarboxylic acid 2 is esterified with a chiral alcohol (such as (+) or (-) seophenethyl alcohol or (+) or (-) menthol and the like) to give a mixture of phenethyl esters (11) which are separable by silica gel chromatography to give a single diastereomer 12.
  • Catalytic hydrogenation or hydrolysis affords the optically active product 13.
  • the carboxy functionalities of compound 2 can be elaborated in a number of ways.
  • Scheme IV shows the replacement of one of the carboxy groups with tetrazolyl.
  • the dicarboxylic acid diamide 2, prepared in Scheme I is converted to a mono-ester 14 where R 30 is loweralkyl (for example, making the diester and hydrolyzing one of the esters with a stoichiometric amount of lithium hydroxide).
  • R 30 is loweralkyl (for example, making the diester and hydrolyzing one of the esters with a stoichiometric amount of lithium hydroxide).
  • the remaining carboxylic acid moiety is reduced (for example, via a mixed anhydride with sodium borohydride or with BH 3 and the like) to give the hydroxymethyl compound 15.
  • the hydroxymethyl compound is oxidized (for example, using tetrapropylammonium perruthenate (TPAP) or oxalyl chloride in DMSO and the like) to give the aldehyde 16.
  • TPAP tetrapropylammonium perruthenate
  • DMSO methyl methoxysulfoxide
  • the aldehyde is reacted with hydroxylamine to give the oxime 17.
  • Treatment of the oxime 17 with trifluoroacetic anydride gives the cyano compound 18.
  • the cyano compound is reacted by standard tetrazole forming methodology (for example, sodium azide and triethylamine hydrochloride in DMF) to give the tetrazolyl compound 19.
  • Ester hydrolysis of 19 for example, lithium hydroxide in THF affords the tetrazolyl carboxylic acid 20.
  • the carboxylic acid is activated with isobutylchloroformate in the presence of 4-methylmorpholine and then reacted with diazomethane to give the diazoacetyl compound 25.
  • the carboxylic acids are activated with isobutylchloroformate in the presence of 4- methylmorpholine and then reacted with diazomethane to give the bis- diazoacetyl compound 27.
  • Scheme VI illustrates further modifications of the carboxy moiety.
  • the mono-ester 14 (wherein R 30 is loweralkyl), prepared in Scheme IV, is reacted with diphenylphosphorylazide in the presence of triethylamine followed by benzyl alcohol to give the benzyloxycarbonyl protected amine 43 (Z is benzyloxycarbonyl).
  • Catalytic hydrogenation removes the Z protecting group to give the 4-amino compound 44.
  • the amine 44 is reacted with
  • Another isomer is obtained by taking the (1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ ) isomer of diester 8, prepared in Scheme II, (wherein R 30 is loweralkyl) and epimerizing with sodium methoxide in methanol to give the (1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ ) isomer 49 (wherein J is R 30 where R 30 is lower alkyl).
  • Sodium hydroxide hydrolysis in methanol- water gives the dicarboxylic acid 50 (wherein J is hydrogen).
  • the preparation of yet another isomer is shown in Scheme IX.
  • the (1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )-isomer 36 is converted to the mono-ester 38 where R 30 is loweralkyl (for example, by converting to the dimethyl ester with diazomethane and then hydrolyzing one of the ester functionalities with a stoichiometric amount of lithium hydroxide).
  • the mono-ester 38 is epimerized with a non- nucleophilic base (for example, with sodium hexamethyldisilazide or lithium diisopropylamide and the like) to give the (1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )-isomer 39.
  • the ester is then hydrolyzed to give the dicarboxylic acid 40.
  • diphenylphosphoryl azide in an inert solvent (for example, in benzene or toluene and the like) in the presence of triethylamine followed by tert-butanol to give the bis(Boc-protected amine) 53.
  • the protecting group is removed-with trifluoroacetic acid to give the diamine 54 as its trifluoroacetate salt.
  • This diamine is reacted with an acid (R 2 COOH) 55 under amide coupling conditions (for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl, 1- hydroxybenzotriazole hydrate, and triethylamine in THF) to give the diamide 56.
  • amide coupling conditions for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl, 1- hydroxybenzotriazole hydrate, and triethylamine in THF
  • R a is loweralkyl, cycloalkyl or cycloalkylalkyl and L is a leaving group such as Cl, Br, I or a sulfonate
  • a non-nucleophilic strong base for example, NaH
  • N- deprotection provides 66.
  • Diamine 66 can be converted to 61 as described in Scheme XIII.
  • Amine 65 is prepared by the procedures outlined in the preceding schemes.
  • Compound 66 is prepared from 3,4-dihydroxy-3- cyclobutene-1 ,2-dione and benzyl alcohol in toluene using a Dean-Stark trap and a catalytic amount of p-toluenesulfonic acid.
  • Compound 65 is reacted with compound 66 in DMF with heating to give compound 67.
  • Mono-carboxylic acid 69 is prepared by the procedures described in the preceding schemes.
  • the carboxylic acid group of compound 69 is activated (for example, using N-methylmorpholine and isobutyl chloroformate) and then reacted with tert-butyl carbazate to give the protected hydrazino carbonyl compound.
  • Treatment with hydrogen chloride in dioxane affords the free hydrazino carbonyl compound 70.
  • Compound 70 is reacted with phosgene in toluene to give cyclic compound 71. Debenzylation by catalytic hydrogenation affords the desired compound 72.
  • Mono-carboxaldehyde 75 is prepared by the procedures described in the preceding schemes. 2,2,6-Trimethyl-4H-1 ,3-dioxin-4-one is treated with a base such as lithium diisopropylamide and 1 ,3-dimethyl-3,4,5,6-tetrahydro- 2(1 H)-pyrimidone and then reacted with carboxaldehyde 75 to give compound 76. Treatment with potassium carbonate in methanol gives lactone 77.
  • Diamide diacid (wherein R 1 , R 2 and Q are as previously defined herein) 79 is mono-activated (for example, using carbonyldiimidazole) in an inert solvent such as methylene chloride and treated with an alcohol (R 6 OH) to give compound 80.
  • the diacid 79 is treated with a base (for example, sodium hydride) and sodium iodide in an inert solvent such as DMF and then reacted with a prodrug group (L-R 6 ) having a leaving group L (for example, a halide or a mesylate) to give compound 80.
  • the diamide dibenzyl ester 81 is converted to the mono- carboxylic acid 82 using one equivalent of a base (for example, lithium hydroxide).
  • the mono-carboxylic acid 82 is reacted with an alcohol (R 6 OH) under coupling conditions (for example, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride and dimethylaminopyridine in DMF) to give the protected prodrug 83.
  • Catalytic hydrogenation for example, using a palladium on carbon catalyst
  • solvent such as ethyl acetate effects debenzylation to afford compound 84
  • Scheme XIX The preparation of compounds having an optically active R 2 side chain is illustrated in Scheme XIX.
  • the oxazolidinone is alkylated by treatment with NaN(Si(CH 3 ) 3 ) 2 in THF followed by addition of the activated side chain (M-L where L is a leaving group such as halide or sulfonate) to give chiral compound 88.
  • Oxazolidinone 88 is treated with 30% hydrogen peroxide followed by lithium hydroxide in THF and water to give the substituted phenyl acetic acid 89.
  • the phenyl acetic acid 89 is reacted with diphenylphosphoryl azide in the presence of triethylamine followed by the addition of methanol to give carbamate 90 .
  • Compound 90 is reduced (for example, using lithium aluminum hydride) to give amine 91.
  • the amine is coupled with the carboxylic acid functionalities of compound 92 (for example, using oxalyl chloride and a catalytic amount of DMF to give the acid chlorides) to give compound 93.
  • aldehyde was prepared from 4-fluorophenol and 4-bromobenzaldehyde.
  • the foam was dissolved in 100 mL of ethyl acetate and washed successively with 50 mL 1 N H 3 PO 4 and 10% NaCl, then dried over anhydrous sodium sulfate, filtered and solvent removed in vacuo to afford 1.0 g of a white foamy solid.
  • the crude product containing both isomers was purified by silica gel chromatography eluting with 94:5:1 CHCl 3 -MeOH-HOAc.
  • the slower moving product was isolated in 14% yield and characterized as 1 ,2-di[N- cyclohexylmethyl-N-phenoxybenzyl)aminocarbonyl]cyclobutane-3,4- dicarboxylic acid.
  • the foam was dissolved in 100 mL of ethyl acetate and washed successively with 50 mL 1 N H 3 PO 4 and 10% NaCl, then dried over anhydrous sodium sulfate, filtered and solvent removed in vacuo to afford 0.5 g of a clear oil.
  • the crude product containing both isomers was purified by silica gel chromatography eluting with 94:5:1 CHCl 3 -MeOH-HOAc.
  • the slower moving product was isolated in 3% yield and characterized as 1 ,2-di[N-phenyl-N- phenoxybenzyl)aminocarbonyl]cyclobutane-3,4-dicarboxylic acid.
  • the solution was diluted with 100 mL of ethyl acetate and washed successively with 50 mL 1 N. H 3 PO 4 and 10% NaCl, then dried over anhydrous sodium sulfate, filtered and solvent removed in vacuo to afford 0.9 g of a white foamy solid.
  • the crude product containing both isomers was purified by silica gel chromatography eluting with 94:5:1 CHCl 3 - MeOH-HOAc. The slower moving product was isolated in 12%. yield and characterized as the title compound.
  • Example 37A The compound resulting from Example 37A (0.22 g, 0.2 mmol) was dissolved in 100 mL of EtOAc and hydrogenated at 4 atmospheres of hydrogen at room temperature over Pd/C (0.15 g, anhydrous) for 23 hours. The reaction mixture was filtered and solvent evaporated in vacuo to afford 0.14 g of crude product as a light yellow solid. The crude product was triturated with
  • reaction mixture was concentrated in vacuo and partitioned between 20% aqueous HCl and 3 portions of ethyl acetate.
  • the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo.
  • the residue was purified by column eluting with 1 :1 CHCl 3 -EtOAc, followed by 50:50:2:1 CHCl 3 -EtOAc-MeOH- AcOH to give 1 ,3-diamide-2,4-diacid as the first fraction (0.436 g, 42%) followed by the title compound (0.477 g, 46%).
  • Example 39B A mixture of the compound resulting from Example 39B (0.908 g, 4.0 mmol), 1,2,3,4-cyclobutanetetracarboxylic dianhydride (0.314 g, 1.6 mmol), triethylamine (0.69 mL, 4.8 mmol) and DMAP (20 mg) in acetonitrile (10 mL) were reacted, worked up and purified by the procedures described in Example 38H to give the 1 ,3-diamide-2,4-diacid as the first fraction (0.372 g, 36%) and the title compound as the second fraction (0.514 g, 49%).
  • N-(2-Methoxytethyl-N-(4-phenoxy)benzylamine A mixture of 4-phenoxybenzaldehyde (1.98 g, 10 mmol) and 2- methoxyethylamine (0.751 g, 10 mmol) in ethanol (10 mL) was stirred for 1 hour. Acetic acid (1 mL) and sodium cyanoborohydride (10 mmol) were added, and the reaction was stirred an additional 14 hours. The reaction mixture was then partitioned between ether and 10% aqueous sodium hydroxide solution. The organic layer was further washed with water and brine, dried over anhydrous potassium carbonate, filtered and concentrated in vacuo to give the title compound (2.48 g, 97%).
  • Example 40A A mixture of the compound resulting from Example 40A (1.38 g, 5.36 mmol), 1 ,2,3,4-cyclobutanetetracarboxylic dianhydride (0.421 g, 2.15 mmol), triethylamine (0.90 mL, 6.5 mmol), and DMAP (50 mg) in acetonitrile (15 mL) were reacted, worked up and purified by the procedures described in Example 38H to give the 1 ,3-diamide-2,4-diacid as the first fraction (0.468 g, 31%) and the title compound as the second fraction (0.807 g, 53%).
  • Example 41A A mixture of the compound resulting from Example 41A (0.682 g, 2.5 mmol), 1 ,2,3,4-cyclobutanetetracarboxylic dianhydride (0.196 g, 1.0 mmol), triethylamine (0.42 mL, 3.0 mmol) and DMAP (12 mg) in acetonitrile (10 mL) were reacted, worked up and purified by the procedures described in Example 38H to give the 1 ,3-diamide-2,4-diacid as the first fraction (0.214 g, 29%) and the title compound as the second fraction (0.274 g, 37%).
  • cyclopropylmethylamine (1.1 g, 15.1 mmol) were dissolved in methanol (85 mL) under nitrogen at room temperature.
  • Sodium cyanoborohydride (0.95 g, 15.1 mmol) was added, and stirring was continued for 48 hours.
  • the solvent was evaporated under reduced pressure, and the residue was suspended in ether, washed with brine, and dried over Na 2 SO 4 .
  • the ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol-methylene chloride to provide 3.0 g (78%) of the title compound as a colorless oil.
  • Example 47B Following the procedures described in Example 47B and using the amine prepared above (5.2 g, 20.0 mmol) provided the title compound as a wet foam after chromatography.
  • the foam was dissolved in acetonitrile (15 mL), triturated with water, and lyophilized to provide 2.3 g (33%) of the title
  • Example 47B Following the procedures described in Example 47B and using the amine prepared above (5.4 g, 20.0 mmol) provided the title compound as a wet foam after chromatography.
  • the foam was dissolved in acetonitrile (15 mL), triturated with water, and lyophilized to provide 2.19 g (30%) of the title compound as a white powder, m.p. 115-118 °C.
  • Example 47B Following the procedures described in Example 47B and using the amine prepared above (5.6 g, 20.0 mmol) provided the title compound as a wet foam after chromatography.
  • the foam was dissolved in acetonitrile (15 mL), triturated with water, and lyophilized to provide 2.9 g (38%) of the title compound as a white powder, m.p. 133-135 °C.
  • THF (175 mL) was treated with 1 M LAH in THF (53 mL). The solution was refluxed for 2 hours then cooled to 0 °C and quenched with Na 2 SO 4 -10H 2 O.
  • the suspension was diluted with THF and filtered through a pad of celite.
  • Example 51 A Following the procedures described in Example 47A and substituting the compound resulting from Example 51 A (1.49 g, 15.1 mmol) for
  • Example 47B Following the procedures described in Example 47B and using the amine prepared above (5.6 g, 20 mmol) provided the title compound as a wet foam after chromatography.
  • the foam was dissolved in acetonitrile (15 mL), triturated with water, and lyophilized to provide 2.8 g (37%) of the the title compound as a white powder, m.p. 98-99 °C.
  • Example 52B Following the procedures described in Example 47B and using the compound resulting from Example 52B (0.25 g, 0.94 mmol) provided the title compound as a wet foam after chromatography.
  • the foam was dissolved in acetonitrile (2 mL), triturated with water, and lyophilized to provide 100 mg (29%) of the the title compound as a white powder, m.p. 94-95 °C.
  • N-(p-phenoxybenzyl)-N-(m-methoxyphenethyl)amine A solution of 4-benzoxybenzaldehyde (2.5 g, 12.6 mmol), 3- methoxyphenethyl amine (1.9 g, 12.6 mmol), a catalytic amount of p- toluenesulfonic acid monohydrate in absolute ethanol (12 mL) was stirred at 80 °C for 1.5 hours. After cooling to room temperature, NaBH 4 (0.49 g, 13.0 mmol) was added in portions. The reaction mixture was stirred at 80 °C for 1 hour, then cooled to room temperature, and the ethanol was removed in vacuo .
  • the reaction mixture was diluted with water and washed with ethyl acetate.
  • Example 62A To a solution of the compound resulting from Example 62A (0.43 g, 0.94 mmol) in dimethylformamide (1 mL) and methylene chloride (10 mL) at 0 °C, was added dicyclohexylcarbodiimide (0.19 g, 0.94 mmol). After 1 hour, N- methyl-N-(homogeranyl)amine (0.94 mmol) and triethylamine (0.39 mL, 2.8 mmol) were added. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. Ethyl acetate was added to the reaction mixture which was then washed with 1 M HCl and brine, dried over Na 2 SO 4 , and
  • Example 62 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.88 (m, 3H), 1.35 (m, 2H), 3.62- 4.61 (m, 12H), 6.89-7.35 (m, 23H). MS m/e 727 (M+H) + .
  • Example 64A To the compound resulting from Example 64A (5.0 g, 25 mmol) was added to a solution of lithium bromide (4.4 g, 51 mmol), trimethylsilyl chloride (8.2 mL, 64 mmol), and 51 mL acetonitrile. The reaction mixture was stirred at reflux for 2 hours, then was cooled to room temperature. Water (25 mL) was added, the acetonitrile was removed under reduced pressure, and the aqueous layer was extracted with ether. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO 4 ), filtered, and solvent evaporated in vacuo to afford 5.35 g clear oil.
  • Example 64B The compound resulting from Example 64B (6.7 g, 20.4 mmol), hydrazine (2.1 mL, 35 wt. % in water) and 130 mL absolute ethanol were stirred at reflux for 4 hours. After cooling to room temperature, the solid present was filtered and air dried briefly. The solid was then partitioned between 1 N KOH and methylene chloride. The layers were separated and the aqueous layer was extracted 2 more times with methylene chloride. The . combined organic layers were washed with water and brine, dried (MgSO 4 ), filtered, and evaporated in vacuo to afford the title compound (2.7 g) as a clear oil.
  • Example 62A The compound resulting from Example 62A was reacted with the compound resulting from Example 64C by the procedures described in
  • Example 62B to give the title compound.
  • Example 65A To a solution of the compound resulting from Example 65A (1.0 g, 5.0 mmol) in dry tetrahydrofuran (100 mL) at -78 °C under dry nitrogen was added n-butyl lithium (1.6 M in hexane, 3.1 mL). After 15 minutes, a suspension of 1 ,2,3,4-cyclobutanetetracarboxylic dianhydride (0.49 g, 2.5 mmol) in
  • Example 67B the compound resulting from Example 67B (0.378 g, 1.57 mmol, 2.2 eq.) and 1 ,2,3,4- cyclobutanetetracarboxylic dianhydride (0.140 g, 0.71 mmol, 1 eq.) were reacted to give 0.159 g (33%) of the title compound.
  • 1 H NMR 300 MHz,
  • Example 68A the compound resulting from Example 68A (0.566 g, 2.2 mmol, 2.2 eq.) and 0.196 g (1.0 mmol, 1.0 eq.) of 1 ,2,3,4-cyclobutanetetracarboxylic dianhydride were reacted to give 0.284 g (40%) of the title compound as an off white foam.
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ 7.02-7.37 (m, 18H), 2.92-4.68 (m, 12H), 1.5 (m. 4H), 0.61 (m, 6H).
  • Anal calcd for C 40 H 42N2 O 6 S 2 C, 67.58; H, 5.95; N, 3.94. Found: C, 65.78; H, 5.86; N, 3.62.
  • reaction mixture was then partitioned between water (50 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous phase was extracted with an additional 50 mL portion of ethyl acetate. The combined organic phases were then washed with 50 mL each of water, saturated NaHCO 3 and brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The solid residue was purified by recrystallization form ethyl acetate to give 0.418 g (59%) of the title compound as a white solid.
  • N-Propyl-N-(4-phenoxymethylbenzyl)amine hydrochloride To a stirred solution of 0.400 g (1.58 mmol, 1.0 eq.) of the compound resulting from Example 69C in 2 mL of dry THF at 0 °C was added 3.16 mL (3.16 mmol, 2 eq.) of a 1.0 M solution of LiAIH 4 in THF dropwise. The ice bath was removed and the mixture heated at reflux for 18 hours. After cooling to 0 °C, the excess hydride was carefully quenched by the sequential addition of 0.12 mL of water in 1 mL of THF, 0.12 mL of 15 % aqueous NaOH and 0.36 mL of water.
  • the resulting suspension was vigorously stirred for 10 minutes followed by the addition of ether (15 mL) and MgSO 4 (2 g) and the vigorous stirring continued for an additional 15 minutes.
  • the reaction mixture was filtered through a pad of SiO 2 (pre-wetted with ether) and the pad was washed well with ethyl acetate.
  • the filtrate was concentrated to dryness and the residue dissolved in THF and treated with a slight excess of aqueous HCl.
  • the solution was concentrated to dryness again (using toluene to remove the excess water).
  • the solid residue was purified by recrystallization from methanol-acetone to give 0.314 g (72%) of the title compound as a white crystalline solid.
  • Example 69D After 15 minutes the compound resulting from Example 69D (0.276 g, 1.0 mmol, 2.0 eq.) was added and the mixture allowed to reach room temperature and stirring continued for 66 hours. The reaction mixture was poured into 20 mL of 4 N aqueous H 2 SO 4 and extracted with 3 x 20 mL of ethyl acetate. The combined organic phases were then washed with water and brine, dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Example 70A To a stirred solution of the compound resulting from Example 70A (68 mg, 0.1 mmol, 1.0 eq.) in 1 mL of 3:1 THF-water at 0 °C was added 8 mg (0.2 mmol, 2.0 eq.) of LiOH H 2 O and stirring was continued at 0 °C for 4 hours and at room temperature for 30 minutes. The reaction was then quenched by the addition of 2 mL of 3 N aqueous HCl and then concentrated to dryness.
  • Example 72A A mixture of the compound resulting from Example 72A (0.116 g, 0.17 mmol, 1 eq.), NaN 3 (0.034 g, 0.52 mmol, 3.0 eq.) and Et 3 N ⁇ CI (0.072 g, 0.52 mmol, 3.0 eq.) in 1 mL of DMF were heated to 60 °C for 14 hours. The bath temperature was increased to 100 °C for 4 hours whereupon an additional 3.0 eq. each of NaN 3 ad Et 3 N ⁇ HCl were added. After an additional 70 hours at 100 °C, the mixture was cooled to room temperature and partitioned between water (20 mL) and ethyl acetate (20 mL).
  • the mesylate (0.284 g, 0.38 mmol, 1.0 eq.) was dissolved in 1.5 mL of DMSO and treated with 0.073 g (1.12 mmol, 3.0 eq.) of KCN. This suspension was stirred vigorously overnight at room temperature and then at 50-60 °C for 2 hours. This mixture was cooled to room temperature and poured into 25 mL of water and extracted with 3 x 10 mL of ethyl acetate. The combined organic phases were then extracted with 2 x 20 mL of water and 2 x 10 mL of brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • Example 73A To a solution of the compound resulting from Example 73A (0.170 g, 0.25 mmol, 1.0 eq.) in 1.5 mL of DMF was added 0.081 g (1.15 mmol, 5.0 eq.) of NaN 3 followed by 0.172 g (1.25 mmol, 5.0 eq.) of Et 3 N ⁇ HCl. The resulting suspension was heated at 100 °C overnight whereupon an additional 5 eq. each of NaN 3 and Et 3 N ⁇ HCl were added. After further heating at 100 °C for 24 hours, the mixture was cooled to room temperature and poured into 20 mL of dilute H 2 SO 4 and extracted with 3 x 20 mL of ethyl acetate.
  • Example 74A and 0.050 g of 10% Pd/C in 5 mL of ethyl acetate were
  • Example 76A To a stirred solution of the compound resulting from Example 76A (25 mg, 0.034 mmol, 1.0 eq.) in 1 mL of THF at 0 °C was added 9 mg (0.204 mmol, 6 eq.) of LiOH ⁇ H 2 O in 0.3 mL of water. After stirring for 1 hour at 0 °C and 2 hours at room temperature, the mixture was poured into 10 mL of 3 N aqueous HCl and extracted with 2 x 10 mL of ethyl acetate. The organic phases were then washed with brine, dried (MgSO 4 ), filtered and concentrated to give 0.025 g of product.
  • Wilkinson's catalyst (4 mg, 0.004 mmol, 0.01 eq.) in 1 mL of dry toluene was heated to 80-90 °C. After 1 hour, additional triethylsilane (0.050 mL) and Wilkinson's (4 mg) were added and heating continued for an additional 2 hours. After the mixture had cooled to room temperature, 2 mL of CH 3 OH was added and the mixture stirred for 15 minutes and filtered through a short plug of SiO 2 . The filtrate was concentrated and purified by column chromatography on SiO 2 (10 g, 1 :1 ethyl acetate-hexanes) to give 0.029 g (91%) of the title compound as a thick oil.
  • Example 77A To a stirred solution of the compound resulting from Example 77A (27 mg, 0.037 mmol, 1.0 eq.) in 1 mL of THF at 0 °C was added a solution of 8 mg (0.184 mmol, 5 eq.) of LiOH ⁇ 2 O in 0.3 mL of water. The cooling bath was removed and the mixture stirred for 6 hours and then poured into 10 mL of 3 N aqueous HCl. The aqueous phases was extracted with ethyl acetate (3 x 10 mL) and the combined organic phases were washed with saturated aqueous NaCl, dried (Na 2 SO 4 ), filtered and concentrated.
  • the mixture was poured into water and acidified by the addition of 4 N aqueous H 2 SO 4 and the phases were separated.
  • the aqueous phase was extracted with 2 x 10 mL of ethyl acetate and the combined organic phases were washed with 3 x 10 mL of 10% aqueous NaHSO 3 , dried (MgSO 4 ) filtered and concentrated to give 0.024 g (86%) of the title compound as a colorless syrup which was used directly.
  • Example 64B A solution of the compound resulting from Example 64B (200 mg (0.29 mmol) in dry tetrahydrofuran (10 mL) was cooled to -15 °C under dry nitrogen. N-Methylmorpholine (60 mg, 0.59 mmol) and isobutylchloroformate (81 mg, 0.59 mmol) were added followed by a solution of O-benzylhydroxylamine hydrochloride (94 mg, 0.59 mmol) and N-methylmorpholine (60 mg, 0.59 mmol) in dimethylformamide (2 mL). After stirring at -15 °C for 15 minutes, the mixture was stirred at ambient temperature for 3 hours.

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Abstract

Cette invention, qui porte sur un composé de la formule (I), concerne également des procédés de préparation de composés correspondants, d'intermédiaires efficaces dans le cadre de ces procédés, d'une composition pharmaceutique et de techniques d'emploi de ces composés.
PCT/US1996/006156 1995-05-03 1996-05-02 Derives de cyclobutane et leur utilisation comme inhibiteurs de proteine farnesyl-transferase WO1996034850A1 (fr)

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WO2008106692A1 (fr) 2007-03-01 2008-09-04 Novartis Vaccines And Diagnostics, Inc. Inhibiteurs de pim kinase et procédés de leur utilisation
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