WO2007109098A2 - HYDROXY AND KETO-SUBSTITUTED β-LACTAMYL ALKANEDIOIC ACIDS - Google Patents

HYDROXY AND KETO-SUBSTITUTED β-LACTAMYL ALKANEDIOIC ACIDS Download PDF

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WO2007109098A2
WO2007109098A2 PCT/US2007/006555 US2007006555W WO2007109098A2 WO 2007109098 A2 WO2007109098 A2 WO 2007109098A2 US 2007006555 W US2007006555 W US 2007006555W WO 2007109098 A2 WO2007109098 A2 WO 2007109098A2
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optionally substituted
alkyl
compound
cycloalkyl
substituted aryl
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PCT/US2007/006555
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French (fr)
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WO2007109098A3 (en
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Gary A. Koppel
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Azevan Pharmaceuticals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • vasopressin Structural modification of vasopressin has been reported, and these compounds act as vasopressin agonists (see, e.g. , Sawyer, Pharmacol. Reviews, 13:255 (1961)).
  • several potent and selective vasopressin peptide antagonists have been disclosed (see, Lazslo et al., Pharmacological Reviews, 43:73-108 (1991); Mah and Hofbauer, Drugs of the Future, 12:1055-1070 (1987); Manning and Sawyer, Trends in Neuroscience, 7:8-9 (1984)).
  • novel structural classes of non-peptidyl vasopressin antagonists have been disclosed (see, Yamamura et al., Science, 275:572-574 (1991); Serradiel-Le Gal et al., Journal of
  • azetidinylalkanedioic acids are potent antagonists of vasopressin receptors. Described herein are azetidin-2-on-l-ylalkanedioic acids, and derivatives thereof. In particular, 3 -hydroxy substituted and 3-keto substituted alkanedioic acids and derivatives are described herein. Such compounds are expected to be potent antagonists of vasopressin receptors, including the vasopressin Vi a ,Vib, and V2 receptors.
  • R 2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting of -CQ.R , -CONR 8 R 8 ', and -NR 8 CCOR 9 );
  • R is in each instance independently hydrogen or alkyl; and R is in each instance independently alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R and R in each instance are independently taken together with the attached nitrogen atom to form an optionally substituted heterocycle, such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally N-substitued with R 13 ;
  • R 9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R 8 R 8 N-(Ci-C 4 alkyl);
  • R 13 is in each instance independently selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aryloyl.
  • FIG. 2 shows the antagonist activity of Example 34 against AVP as evaluated in CHO cells expressing rat V n , receptor.
  • Example 34 inhibited V
  • FIG. 3 shows the activity of Example 34 against vehicle control in a seed finding assay of hamsters as a model of anxiety; (a) Vehicle, (b) Example 34 (1 mg/kg).
  • n is an integer from 0 to about 5;
  • R 1 is hydrogen or Ci-Ce alkyl
  • R is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R 3 is a nitrogen-containing heterocyclyl group attached at a nitrogen atom;
  • R 5 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(Ci-C4 alkyl), and R 6 R 7 N-(C2-C4 alkyl); where heterocyclyl is in each occurrence independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C1-C4 alkyl or optionally substituted aryl(Ci-C4 alkyl);
  • R 9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R 8 R 8 N-(Cj-C 4 alkyl);
  • R 1 is in each instance independently selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and . optionally substituted aryloyl.
  • R 1 , R 2 , R 4 , n, A, A 1 , B, and B' are as defined herein; and Ar i i •s an optionally substituted aryl group.
  • R 1 , R 2 , n, A, A', B, and B' are as defined herein; and Ar 1 and Ar 2 are each an independently selected optionally substituted aryl group.
  • compounds of formula IV are described: (IV) and pharmaceutically acceptable salts thereof; where R 1 , R 2 , n, B, and B 1 are as defined herein; Ar 1 and Ar 2 are each an independently selected optionally substituted aryl group; X and X 1 are each independently selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, and heterocyclyl, heterocyclyl-(Ci-C 4 alkyl), R 6 R 7 N-, and
  • compounds of formula V are described:
  • R 1 , R 2 , R 3 , R 4 , n, and A 1 are as defined herein.
  • alkyl refers to a straight-chain or optionally branched, saturated hydrocarbon, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl and the like.
  • alkenyl refers to a straight -chain or optionally branched, hydrocarbon that includes at least one double bond, including but not limited to vinyl or ethenyl, allyl or propenyl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, butadienyl, and the like.
  • alkynyl refers to a straight-chain or optionally branched, hydrocarbon that includes at least one triple bond, including but not limited to ethynyl, propynyl, 1-butynyl, hex-4-en-2-ynyl, and the like.
  • aryl refers to an aromatic ring or heteroaromatic ring and includes such groups as fiiryl, pyrrolyl, thienyl, pyridinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, oxadiazolyl, naphthyl, indanyl, fluorenyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzofuranyl, benzothienyl, and the like.
  • substituted refers to the replacement of one or more, preferably from one to three, hydrogen atoms with one or more substitutents.
  • Substituents include but are not limited to such groups as C1-C4 alkyl, C1-C4 alkoxy, C ⁇ -C4 alkylthio, hydroxy, nitro, halo, carboxy, cyano, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, amino, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylalkylamino, C 1-C4 alkylsulfonylamino, and the like.
  • heterocycle refers to a non-aromatic cyclic structure possessing one or more heteroatoms, such as nitrogen, oxygen, sulfur, and the like, and includes such groups as tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.
  • alkoxy refers to an alkyl or cycloalkyl subtituent attached through an oxygen, and includes such groups as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert- butoxy and the like.
  • halo means fluoro, chloro, bromo, and iodo.
  • alkanoyloxy includes such groups as formyloxy, acetoxy, n-propionoxy, n-butyroxy, pivaloyloxy, and like lower alkanoyloxy groups.
  • alkyl, cycloalkyl, or alkenyl refer to alkyl, cycloalkyl, or alkenyl, respectively, optionally substituted with a substituent as described herein, including but not limited to halo, hydroxy, protected hydroxy, alkyl, protected carboxyl, carbamoyl, benzylthio, alkylthio, and the like.
  • such groups include such as trifluoromethyl, trifluorochloroethyl, methoxyethyl, 2-(methoxyacetyl)propyl, and the like.
  • (C 1 -C 4 alkyl) refers to a saturated linear or branched divalent alkyl chain of from one to four carbons bearing for example aryl, C
  • optionally substituted heteroaryl include the corresponding aryl, phenyl, or heteroaryl radical optionally substituted with one or more substituents each os which is independently selected, such as Ci-C 4 alkyl, Cj-C 4 alkoxy, hydroxy, halo, nitro, trifluoromethyl, sulfonamido, cyano, carbamoyl, amino, mono(Ci-C 4 alkyl)amino, di(C ⁇ -G» alkyl)amino, Ci-C 4 alkylsulfonylamino, and indol-2-yl, and the like.
  • protected amino refers to amine protected by a protecting group that may be used to protect the nitrogen, such as the nitrogen in the ⁇ -lactam ring, during preparation or subsequent reactions.
  • protecting groups are benzyl, 4-methoxybenzyl, 4- methoxyphenyl, trialkylsilyl, for example trimethylsilyl, and the like.
  • protected carboxy refers to the carboxy group protected or blocked by a conventional protecting group commonly used for the temporary blocking of the acidic carboxy.
  • groups include lower alkyl, for example tert-butyl, halo-substituted lower alkyl, for example 2-iodoethyl and 2,2,2-trichloroethyl, benzyl and substituted benzyl, for example 4-methoxybenzyl and 4-nitrobenzyl, diphenylmethyl, alkenyl, for example allyl, trialkylsilyl, for example trimethylsilyl and tert-butyldiethylsilyl and like carboxy-protecting groups.
  • antagonist refers to a full or partial antagonist.
  • the partial antagonists illustratively show at least about 50% antagonist effect, or at least about 80% antagonist effect.
  • the term also includes compounds that are full antagonists of one or more vasopressin receptors. It is appreciated that illustrative methods described herein require therapeutically effective amounts of one or more vasopressin receptor antagonists; therefore, compounds exhibiting partial antagonism at vasopressin receptors may be adminstered in higher doses to exhibit sufficient antagonist activity to inhibit the effects of vasopressin or a vasopressin agonist.
  • an illustrative variation of alkyl is Ci-Ce alkyl, such as methyl, ethyl, propyl, prop-2-yl, and the like; an illustrative variation of alkenyl is C 2 -C 6 alkenyl, such as vinyl, allyl, and the like; an illustrative variation of alkynyl is C2-C6 alkynyl, such as ethynyl, propynyl, and the like; an illustrative variation of alkoxy is C 1 -C 4 alkoxy, such as methoxy, pent-3-oxy, and the like; an illustrative variation of alkylthio is Ci-C4 alkylthio, such as ethylthio, 3-methylbuty-2-ylthio, and the like; an illustrative variation of alkylcarbonyl is C 1 -C 3 alkylcarbo ⁇ y
  • compounds of compounds of formulae I-V are described, wherein R 1 is hydrogen. In another embodiment, compounds of compounds of formulae I-V are described, wherein R 2 is hydrogen. In another embodiment, compounds of formula I are described, wherein R 3 is a structure selected from:
  • R 10 and R 1 ' are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkylcarbonyloxy, diphenylmethoxy, triphenylmethoxy, and the like; and R is selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted aryloyl, and the like.
  • R 10 , R 1 ' , and R 12 are as defined herein.
  • R 10 and R 1 ' are as defined herein.
  • compounds of compounds of formulae I-V are described, wherein n is 0.
  • compounds of compounds of formulae I-V are described, wherein n is 1 or 2.
  • certain compounds of formulae I-III are described that are diacids, acid esters, or diesters, wherein A is R 5 O- and A' is R 5 O.
  • certain compounds of formulae I-III are described that are acid amides or ester amides, wherein A is R s O-or A' is R 5 O-, and the other of A and A 1 is monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen.
  • certain compounds of formulae I-III are described that are diamides, wherein both A and A' are independently selected monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen.
  • a and/or A 1 is monosubstituted amino of the formula XNH- or X 1 NH-, respectively, where X and X' are each independently selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyKCi -C 4 alkyl), R 6 R 7 N-, and R 6 R 7 N-(C 2 -C 4 alkyl), where each heterocyclyl is independently selected.
  • a and/or A 1 is disubstituted amino of the formula R XN- or R 14 X 1 N-, respectively, where R 14 and R 14 are each independently selected from hydroxy, alkyl, alkoxycarbonyl, and benzyl; and X and X' are each independently selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C,-C 4 alkyl), R 6 R 7 N-, and R 6 R 7 N-(C 2 -C 4 alkyl), where each heterocyclyl is independently selected.
  • a and/or A 1 is an independently selected optionally substituted nitrogen-containing heterocycle attached at a nitrogen.
  • nitrogen- containing heterocycles include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl; each of which is optinoally substituted.
  • a and/or A' is independently selected from pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-l-ylmethyl)pyrrolidin- 1-yl, or l,2,3,4-tetrahydroisoquinolin-2-yl, each of which is optionally substituted, and attached at a nitrogen.
  • a and/or A' is an independently selected optionally substituted piperidinyl attached at the nitrogen.
  • Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including
  • a and/or A' is an independently selected piperidinyl substituted at the 4-position and attached at the nitrogen. In another aspect, A and/or A' is an independently selected optionally substituted piperazinyl attached at a nitrogen.
  • Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C 2 -C 4 alkyloxy)>(C 2 -C 4 alkyl), R 6 R 7 N-, R 6 R 7 N-alkyl, including R 6 R 7 N-(Ci-C 4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C 4 alkyl), and piperidin-l-yl(Ci-C4 alkyl).
  • a and/or A 1 is an independently selected piperazinyl substituted at the 4-position and attached at a nitrogen.
  • a and/or A' is an independently selected optionally substituted homopiperazinyl attached at a nitrogen.
  • Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including
  • a and/or A' is an independently selected homopiperazinyl substituted at the 4-position and attached at a nitrogen
  • a and/or A' is an independently selected homopiperazinyl substituted at the 4-position with alkyl, aryl, aryl(Ci-C 4 alkyl), and attached at a nitrogen.
  • certain compounds of formulae I-III are described wherein A and/or A 1 is a monosubstituted amino, and n is 1 or 2.
  • compounds of formulae formulae I-I ⁇ are described wherein A and/or A' is a disubstituted amino, and n is 1 or 2.
  • compounds of formulae I-III are described wherein A and/or A' is an optionally substituted nitrogen-containing heterocycle attached at a nitrogen, and n is 1 or 2.
  • n is 0.
  • certain compounds of formulae I-IV are described, wherein B is hydroxy, alkoxy, such as methoxy, and the like; and B' is hydrogen. In another embodiment, certain compounds of formulae I-IV are described, wherein B and B' are taken together with the attached carbon to form a carbonyl group or a derivative thereof.
  • the carbonyl derivative is a ketal formed from an optionally substituted diol, such as ethylene glycol, propylene glycol, 1,2-propandiol, 2,3-butandiol, 2,4-pentandiol, and the like,
  • the diol is of the formula a -O-(CH2) P -O-, which may be optionally substituted, where p is 2 or 3.
  • the carbonyl derivative is an imine formed from a primary amine; an oxime formed from hydroxylamine, or a substituted hydroxylamine; a hydrazone formed from hydrazine, or a substituted hydrazine, and the like.
  • certain compounds of formulae I-IV are described, wherein B' is hydrogen; and B is hydroxy, optionally substituted alkoxy, or optionally substituted acyloxy.
  • a and/or A 1 is piperidinyl attached at the nitrogen atom, and optionally substituted at the 4-position with hydroxy, alkyl, including Ci-Ce alkyl, cycloalkyl, including C3-C8 cycloalkyl, alkoxy, including C 1 -C 4 alkoxy, alkoxycarbonyl, including (C 1 -C 4 alkoxy)carbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C2-C4 alkyloxy)HC 2 -C4 alkyl), R 6 R 7 N-, R 6 R 7 N- alkyl, including R 6 R 7 N-(Ci-C 4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C 4 alkyl), orpiperidin-l-yl(Ci-C 4 alkyl).
  • certain compounds of formulae I-IH are described, wherein A and/or A' is piperazinyl attached at a nitrogen atom, and optionally substituted at the 4-position with alkyl, including Ci-Ce alkyl, cycloalkyl, including C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, including optionally substituted aryl(Ci-C 4 alkyl), ⁇ -methylbenzyl, and the like, N-alkyl acetamid-2-yl, including N-(Ci-Cs alkyl) acetamid-2-yl, N-(cycloalkyl) acetamid-2-yl, including N-(C3-Cs cycloalkyl) acetamid-2-yl, R 6 R 7 N-, or alkoxycarbonyl, including (C 1 -C 4 alkoxy)carbonyl.
  • alkyl including Ci-Ce alkyl,
  • a and/or A 1 is pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-l-ylmethyl)pyrrolidin-l-yl, or l,2,3,4-tetrahydroisoquinolin-2-yl, each of which is optionally substituted.
  • certain compounds of formula V are described wherein A' is monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen- containing heterocycle attached at a nitrogen. In one variation, compounds of formula V are described wherein A' is an optionally substituted nitrogen-containing heterocycle attached at a nitrogen. In another embodiment, certain compounds of formula V are described wherein A 1 is monosubstituted amino, and n is 1 or 2. In another embodiment, certain compounds of formula V are described wherein A' is disubstituted amino, and n is 1 or 2. In another embodiment, certain compounds of formula V are described wherein A 1 is an optionally substituted nitrogen- containing heterocycle attached at a nitrogen, and n is 1 or 2.
  • n is 0.
  • a 1 is piperidinyl optionally substituted at the 4-position with hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, R 6 R 7 N-, R 6 R 7 N-alkyl, including R 6 R 7 N-(C 1 -C 4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), or piperidin- 1 -yl(C i -C 4 alkyl).
  • the compounds described herein possess an azetidinone core structure that includes asymmetric carbon atoms at C(3) and C(4), creating four stereoisomeric configurations, as illustrated by the following formulae: ⁇
  • R 3 when R 3 is 4-substituted oxazolidin-2-on-3-yl, the 4- position of the oxazolidinone ring is asymmetric, hi addition, when R 3 is 2,5-disubstituted oxazolidin-4-on-3-yl or 1 ,2,5-trisubstituted imidazolidin-4-on-3-yl, the 2- and 5-carbons of the imidazolidinone rings are each asymmetric. Finally, when R 3 is succinimido and one of R 10 and R 11 is hydrogen, the carbon bearing the non-hydrogen substituent is also asymmetric.
  • the formulae I, II, HI, IV, and V represent each single diastereomer, various racemic mixtures, and other mixtures of enantiomers and diastereomers collectively. While compounds possessing all combinations of stereochemical purity are contemplated by the present description, it is nonetheless appreciated that in many cases important biological activity, such as vasopressin antagonist activity may reside in a subset or all possible diastereomers, or in a single diasteromer. 61 one illustrative aspect, the compounds described herein have the (aR,3S,4R) absolute configuration or the (aS,3S,4R) absolute configuration.
  • the compounds described herein have the (aR, ⁇ R,3S,4R) absolute configuration or the (aS,$R,3S,4R) absolute configuration. In another illustrative aspect, the compounds described herein have the (aR$S,3S,4R) absolute configuration or the (aS ⁇ S,3S,4R) absolute configuration.
  • A' is R 14 X 1 N-, and R 14' is optionally substituted benzyl;
  • R 2 is C1-C2 alkyl
  • R 3 is 2-substituted imidazolidin-4-on-3-yl; R 3 is 1,2-disubstituted imidazolidin-4-on-3-yl;
  • R 4 is optionally substituted 2-aryleth-l-yl
  • the integer n is either 0, or n is 1 or 2
  • the group A' includes, but is not limited to 2-(piperidin-l-yl)ethylamino, 4-(piperidin-l-yl)piperidin-l-yl, 2- (pyrid-2-yl)ethylamino, morpholin-4-ylamino, 4-(pyrrolidin-l-yl)piperazin-l-yl, 4-(3- trifluorophenyl)piperazin-l-yl, 4-(benzyloxycarbonyl)piperazin-l-yl, 4-[2-(2- hydroxylethoxy)ethyl]piperazin-l-yl, 4-benzylpiperazin-l-yl, 4-(3,4- methylenedioxybenzyl)piperazin- 1 -yl , 4-phenylpiperazin- 1 -yl, 4-(3 -phenylprop-2- enyl)piperazin-l-l-
  • the group A' is selcted from 4-cyclohexylpiperazin-l-yl, 4- (pyrrolidin-l-yl)piperazin-l-yl, 4-ethylpiperazin-l-yl, 4-n-butylpiperazin-l-yl, and 4- isopropylpipe ⁇ azin-1-yl.
  • the group A' is selected from 3-trifluoromethylbenzylamino, morpholin-4-ylamino, 2-(dimethylamino)ethylamino, 3- (dimethylamino)propylamino, cyclohexylamino, piperidin- 1-yl, 2-methoxyethylamino, isopropylamino, isobutylamino, ethylamino, dimethylamino, and methylamino.
  • R 3 is a 4-substituted oxazolidin-2-on-3-yl or 1,4,5- trisubstituted imidazolidin-2-on-3-yl.
  • Those compounds of formulae I, ⁇ , HI, and IV requiring R 3 to be a 4-substituted oxazolidin-2-on-3-yl or 1 ,4,5-trisubstituted imidazolidin-2-on-3-yl are prepared from the corresponding (4-substituted oxazolidin-2-on-3-yl) or (1,4,5-trisubstituted imidazolidin-2-on-3-yl)acetyl halide or anhydride.
  • the imidazolidin-4-one ring is then alkylated with a haloacetic acid ester, the ester deesterified, and the resulting acetic acid converted to the desired acid halide or anhydride (i).
  • the required oxazolidinones are prepared in an analogous manner from the corresponding ⁇ -hydroxyacid, (R 1 ⁇ -CH(OH)CO 2 H.
  • R 3 is succinimido.
  • Those compounds of formulae I, ⁇ , ID, and IV requiring R 3 to be succinimido are prepared from the corresponding 2-(succinimido)acetyl halide or anhydride. The chemistry to prepare these reagents is described in U.S. Patent No. 4,734,498, hereby incorporated by reference. Briefly, these reagents are obtained from tartaric acid or, when one of R 10 and R 1 ' is hydrogen, from malic acid.
  • Tartaric acid is acylated or O-alkylated, the corresponding diacyl or di-O-alkyl tartaric acid is treated with an acid anhydride to form the succinic anhydride, and reaction of this succinic anhydride with an ester of glycine to form first the noncyclic half amide ester which is then cyclized to the 3,4-disubstituted succinimidoacetic acid ester.
  • the ester group is deesterif ⁇ ed and the resulting acid converted to the corresponding acid halide or anhydride (i).
  • the azetidinone ring may also be prepared with a deficit of substituents R 2 , R 3 , R 4 , or the R '-substituted N-alkanedioic acid or alkoxyalkanoic acid moiety, but possessing substituents capable of being elaborated through subsequent chemical transformation to such groups described for compounds of formulae 1,H, in, and IV.
  • azetidinones may be prepared via N-C(4) cyclization, such as the cyclization of acylhydroxamates iv to azetidinone intermediates v, as depicted in Synthetic Scheme IH, where n, A, A', B, C, R 1 , R 2 , R 3 , and R 4 are as defined above, according to the procedure of Mattingly et al. ⁇ nJ. Am. Chem. Soc. 1979, 101, 3983 and Accts. Chem. Res. 1986, 19, 49, the disclosures of which are incorporated herein by reference. It is appreciated that other hydroxamates, such as alkylhydroxamates, aryl hydroxamates, and the like, are suitable for carrying out the cyclization.
  • R may be the group ArCH 2 - where Ar is an optionally substituted aryl group, as in vii-a, such that oxidative elimination of HBr will provide the desired R 4 , such as a styryl group, as in vii-b.
  • R 4 such as a styryl group
  • elaboration of R to R 4 is not necessarily performed immediately subsequent to the cyclization and may be performed conveniently after other steps in the synthesis of compounds of formulae I, ⁇ , IH, and IV.
  • alternatives to the acylhydroxamates shown, such as alkylhydroxamates, aryl hydroxamates, and the like, are suitable for carrying out the cyclization.
  • the requisite carboxylic acid xii may be prepared from the corresponding ester via saponification under standard conditions by treatment with hydroxide followed by protonation of the resultant carboxylate anion.
  • R 6 is tert-butyl
  • the ester I-a may be dealkylated by treatment with trifluoroacetic acid.
  • R 6 is benzyl
  • the ester I-a may be dealkylated either by subjection to mild hydrogenolysis conditions, or by reaction with elemental sodium or lithium in liquid ammonia.
  • ester I-a may be deprotected and converted into the corresponding acid xii by treatment with a source of fluoride ion, such as tetrabutylammonium fluoride.
  • a source of fluoride ion such as tetrabutylammonium fluoride.
  • the carboxylic acid xii is converted to the corresponding amide I-b under standard conditions.
  • the acid may be first converted to the corresponding acid halide, preferably the chloride or fluoride, followed by treatment with an appropriate primary or secondary amine to provide the corresponding amide.
  • the acid may be converted under standard conditions to a mixed anhydride. This is typically accomplished by first treating the carboxylic acid with an amine, such as triethylamine, to provide the corresponding carboxylate anion. This carboxylate is then reacted with a suitable haloformate, for example benzyl chloroformate, ethyl chloroformate or isobutylchloroformate, to provide the corresponding mixed anhydride.
  • a suitable haloformate for example benzyl chloroformate, ethyl chloroformate or isobutylchloroformate
  • This anhydride may then be treated with an appropriate primary or secondary amine to provide the desired amide.
  • carboxylic acid may be treated with a typical peptide coupling reagent such as N,N'-carbonyldiimidazole (CDI), N.N'-dicyclohexylcarbodiimide (DCC) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), followed by the appropriate amine of formula R 5 XNH.
  • CDI N,N'-carbonyldiimidazole
  • DCC N.N'-dicyclohexylcarbodiimide
  • EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the carboxylic acid may alternatively be converted into the corresponding tert- butyl ester via treatment of the acid with an acid catalyst, such as concentrated sulfuric acid, and the like, and with isobutylene in a suitable solvent, such as dioxane, and the like.
  • the reaction is preferably carried out under pressure in an appropriate vessel, such as a pressure bottle, and the like. Reaction times of about 18 hours are not uncommon.
  • the desired ester may be be isolated from the organic layer after partitioning the reaction mixture between a suitable organic solvent, such as ethyl acetate, and the like, and a basic aqueous layer, such as cold IN sodium hydroxide, and the like.
  • the hydrogenation of the triple or double bond proceeds readily over a precious metal catalyst, such as palladium on carbon.
  • the hydrogenation solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethyl acetate.
  • the hydrogenation may be performed at an initial hydrogen pressure of about 20-80 p.s.i., preferably about 50-60 p.s.i., at a temperature of about 0-60 0 C, preferably within the range of from ambient temperature to about 40 0 C, for about 1 hour to about 3 days.
  • the ethynyl spacer of compound I-c may be selectively reduced to the ethenyl spacer of compound I-d using poisoned catalyts, such as Pd on BaSO-t, Lindlar's catalyst, and the like. It is appreciated that either the Z or E double bond geometry of compound I-d may be advantageously obtained by the appropriate choice of reaction conditions. Alternatively, a mixture of double bond geometries may be prepared. The analogous synthesis of compounds of formulae ⁇ , ID, and IV may be accomplished by this process.
  • Intermediate xiii may then be treated with an appropriate alkylating or acylating agent to prepare the corresponding amines or amides I-g, or alternatively intermediates xiii may be treated with an appropriate isocyanate to prepare the corresponding ureas I-h.
  • Svnthetic Scheme IX
  • the ureas I-h are prepared by treating a solution of the appropriate amine xiii in a suitable solvent, such as chloroform or dichloromethane, with an appropriate isocyanate, R NCO. If necessary, an excess of the isocyanate is employed to ensure complete reaction of the starting amine. The reactions are performed at about ambient temperature to about 45 0 C, for from about three hours to about three days. Typically, the product may be isolated by washing the reaction with water and concentrating the remaining organic components under reduced pressure. When an excess of isocyanate has been used, however, a polymer bound primary or secondary amine, such as an aminomethylated polystyrene, may be conveniently added to facilitate removal of the excess reagent. Isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
  • a suitable solvent such as chloroform or dichloromethane
  • the substituted amines and amides I-g are prepared by treating a solution of the appropriate amine xiii in a suitable solvent, such as chloroform or dichloromethane, with an appropriate acylating or alkylating agent, R I2 -C(O)Z or R I2 -Z, respectively. If necessary, an excess of the acylating or alkylating agent is employed to ensure complete reaction of the starting amine.
  • the reactions are performed at about ambient temperature to about 45 0 C, for from about three hours to about three days.
  • the product may be isolated by washing the reaction with water and concentrating the remaining organic components under reduced pressure.
  • compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient.
  • routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g., REMINGTON 'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
  • the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi -solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compounds are generally effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.01 to about 30 mg/kg of body weight.
  • the range of about 0.1 to about 15 mg/kg/day, in single or divided dose is especially preferred.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
  • the compounds described herein are useful in methods for antagonism of the vasopressin Via, Vib, and V2 receptors. Such antagonism is useful in treating a variety of disorders and diseases that have been linked to one or more of these receptors in mammals.
  • the mammal to be treated by the administration of compounds described herein is human.
  • compounds are also described herein that cross the blood brain barrier. It is appreciated that compounds that cross the blood brain barrier may have wider application in treating various disease states that are responsive to vasopressin receptor antagonism. For example, it is to be understood that there are currently recognized distinct receptor subtypes within depressive illness.
  • patients can be selectively treated with the compounds and methods described herein for disease states that do not include cardiovascular disorders. Because patients that have otherwise healthy cardiovascular physiology are not affected by moderate changes in AVP, it is appreciated that those same patients may be treated for other disease states that are responsive to the compounds described herein without the onset of concommitant dysregulation of vasopressin mediated cardiovascular physiology., blood pressure, cardiac contractility, and coronary blood flow. It is appreciated that antagonism of the Vu, receptor at levels capable of blocking this vasopressin receptor subtype that mediates elevated pituitary ACTH secretion under chronic stress may have significant clinical potential as a treatment for certain types of depression and stress-related affective disorders.
  • Example 1 Methyl (4(S)-phenyloxazolidin-2-on-3-yl)acetate.
  • Example 2 Methyl 2-(4(S)-phenyloxazolidin-2-on-3-yl)propanoate.
  • a solution of methyl (4(S)-phenyloxazolidin-2-on-3-yl)acetate (1 g, 4.25 mmol) in 10 mL of anhydrous THF at -78 0 C was treated with 4.68 mL (4.68 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF.
  • the reaction mixture was stirred for 1 h. at about -70 0 C before adding MeI (1.59 mL, 25.51 mmol).
  • reaction Upon complete conversion of the azetidinone, the reaction was quenched with saturated aqueous NH4CI and partitioned between EtOAc and water. The organic layer was washed sequentially with saturated aqueous sodium bisulfite, and saturated aqueous NaCl.
  • Example 4 2-(4(S)-Phenyloxazolidin-2-on-3-yl)propanoyl chloride.
  • a solution of 1 equivalent of Example 3 and 1.3 equivalent of oxalyl chloride in 200 mL CH2CI2 (150 mL / g of propanoic acid derivative) was treated with a catalytic amount of anhydrous DMF (85 ⁇ L / mmole of propanoic acid derivative) resulting in vigorous gas evolution. After 45 min., all gas evolution had ceased and the reaction mixture was concentrated under reduced pressure to provide the title compound as an off-white solid after drying for 2 h. under vacuum.
  • Example 5 General procedure for amide formation from an activated ester derivative.
  • N-Benzyloxycarbonyl-L-aspartic acid ⁇ -t -butyl ester ⁇ -(3- trifluoromethyl)benzylamide A solution of N-benzyloxycarbonyl-L-aspartic acid ⁇ -/-butyl ester ⁇ -N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was treated with 0.68 mL (4.74 mmol) of 3-(trifluoromethyl)benzyl amine.
  • Examples 6-8 were prepared according to the procedure of Example 5, except that N-benzyloxycarbonyl-L-aspartic acid ⁇ -f-butyl ester ⁇ -N-hydroxysuccinimide ester was replaced by the appropriate amino acid derivative, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine.
  • Example 6 N-Benzyloxycarbonyl-L-aspartic acid ⁇ -/ -butyl ester ⁇ -[4-(2- phenylethyl)]piperazinamide.
  • Example 10 O-(Benzyl)-D- ⁇ erine /-Butyl ester.
  • Example 9 (0.620 g, 1.31 mmol) in dichloromethane (5 mL) was treated with tris(2-aminoethyl)amine (2.75 mL) for 5 h.
  • N-Benzyloxycarbonyl-D-aspartic acid ⁇ -/-butyl ester ⁇ -(3- trifluoromethyl)benzylamide A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D- aspartic acid ⁇ -t-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of l-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of l-[3-
  • Examples 12-17 were prepared according to the procedure of Example 11, except that N-benzyloxycarbonyl-D-aspartic acid ⁇ -/-butyl ester monohydrate was replaced by the appropriate amino acid derivative, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine.
  • Example 12 N-Benzyloxycarbonyl-D-glutamic acid ⁇ -/-butyl ester ⁇ -(3- trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-glutamic acid ⁇ -f-butyl ester ( 1.14 g, 3.37 mmol) and 0.53 mL (3.70 mmol, Novabiochem) of 3-(trifluoromethyl)benzylamine gave 1.67 g (quantitative yield) of Example 12 as an off-white solid.
  • Example 18 General procedure for hydrogenation of a benzyloxycarbonyl amine. L-aspartic acid ⁇ -f-butyl ester ⁇ -(3-trifluoromethyI)benzylamide. A suspension of 2.23 g (4.64 ⁇ unol) of N-benzyloxycarbonyl-L-aspartic acid ⁇ -/-butyl ester ⁇ -(3- trifluoromethyl)benzylamide and palladium (5% wt. on activated carbon, 0.642 g) in 30 mL of methanol was held under an atmosphere of hydrogen until complete conversion as determined - by thin layer chromatography (95:5 dichloromethane/methanol eluent).
  • Example 22 L-glutamic acid ⁇ -f-butyl ester ⁇ -[4-(2- phenylethyl)]piperazinamide. N-benzyloxycarbonyl-L-glutamic acid ⁇ -/-butyl ester ⁇ -[4-(2- phenylethyl)]piperazinamide (5.86 g, 11.50 mmol) gave 4.28 g (99%) of Example 22 as an off- white oil; 1 H NMR (CDCl 3 ) ⁇ 1.39 (s, 9H); 2.00-2.08 (m, IH); 2.38-2.46 (m, IH); 2.55-2.90 (m, 9H); 3.61-3.82 (m, 4H); 4.48-4.56 (m, IH); 7.17-7.26 (m, 5H).
  • Example 27 D-aspartic acid ⁇ -f -butyl ester ⁇ -[(R)- ⁇ -methylbenzyl]amide. N- benzyloxycarbonyl-D-aspartic acid ⁇ -f-butyl ester ⁇ -[(R)- ⁇ -methylbenzyl]amide (0.273 g, 0.64 mmol) gave 0.187 g (quantitative yield) of Example 27 as an off-white oil; 1 H NMR (CDCl 3 ) ⁇
  • Example 33 4-(Piperidin-l-yl)-piperidin-l-yl 3(R)-[3(S)-(4(S)- phenyloxazolidin-2-on-3-yl)-3-methyl-4(R)-(styr-2-yl)azetidin-2-on-l-yl]-3-[(3- trifluoromethyl)phenylmethylaminocarbonyl]propanoic acid.
  • Method Example 1 Human vasopressin V la receptor binding assay.
  • a cell line expressing the human Via receptor in CHO cells (henceforth referred to as the hV
  • a cDNA sequence is described by Thibonnier et al., Journal of Biological Chemistry, 269:3304- 3310 (1994), and the expression method was the same as described by Morel et al. (1992).
  • the hV i a cell line was grown in alpha-MEM with 10% fetal bovine serum and 250ug/ml G418 (Gibco, Grand Island, NY, USA).
  • Example 33 was tested according to Method Example 1, and exhibited an IC 50 in human Vl 8 of 5 nM.
  • Method Example 2. Inhibition of phosphatidylinositol turnover.
  • the physiological effects of vasopressin are mediated through specific G-protein coupled receptors.
  • the vasopressin Vu receptor is coupled to the G q /Gi i family of G proteins and mediates phosphatidylinositol turnover.
  • the agonist or antagonist character of the compounds of the invention may be determined by their ability to inhibit vasopressin-mediated turnover of phosphatidylinositol by the procedure described in the following paragraphs.
  • BioRad Poly-Prep Econo-Columns were packed with 0.3 mL of AG 1 X-8 100-200 formate form resin. Resin was mixed 1:1 with water and 0.6 mL added to each column. Columns were then washed with 10 mL water. Scintillation vials (2OmL) were placed under each column. For each well, the contents were transferred to a minicolumn, after which the well was washed with 0.5 mL distilled water, which was also added to the minicolumn. The columns were then washed twice with 5 mL of 5 mM myo-inositol to elute free inositol.
  • citrate/heparin solution 85 mM sodium citrate, 64 mM citric acid, 111 mM glucose, 5 units/mL heparin
  • PRP was then centrifuged (150 x g) and the pellet resuspended in a physiologic buffer solution (10 mM HEPES, 135 mM sodium chloride, 5 mM potassium chloride, and 1 mM magnesium chloride) containing 10 ⁇ M indomethicin.
  • a physiologic buffer solution 10 mM HEPES, 135 mM sodium chloride, 5 mM potassium chloride, and 1 mM magnesium chloride
  • Obsessive -compulsive disease appears in a great variety of degrees and symptoms, generally linked by the victim's uncontrollable urge to perform needless, ritualistic acts. Acts of acquiring, ordering, cleansing and the like, beyond any rational need or rationale, are the outward characteristic of the disease. A badly afflicted subject may be unable to do anything but carry out the rituals required by the disease. Obsessive-compulsive disease, in all its variations, is a preferred target of treatment with the present adjunctive therapy method and compositions. The utility of the compounds of formulae I, ⁇ , and HI in the treatment of obsessive-compulsive disorder was demonstrated as described in the following assay.
  • flank marking behavior In golden hamsters, a particular stereotypy, flank marking behavior, can be induced by microinjections of vasopressin (10-100 nL, 1-100 ⁇ M) into the anterior hypothalamus (Ferris et al., Science, 224:521-523 (1984); Albers and ⁇ ems, Regulatory Peptides, 12:257-260 (1985); Ferris et al., European Journal of Pharmacology, 154: 153-159 (1988)). Following the releasing stimulus, the behavior is initiated by grooming, licking and combing of the large sebaceous glands on the dorsolateral flanks. Bouts of flank gland grooming may be so intense that the flank region is left matted and soaked in saliva.
  • flank marking behavior a type of scent marking involved in olfactory communication (Johnston, Physio. Behav. , 51 :437-448 (1985); Ferris et al., Physio. Behav., 40:661-664 (1987)), by arching the back and rubbing the flank glands vigorously against any vertical surface.
  • Vasopressin-induced flank marking is usually induced within a minute after the microinjection (Ferris et al., Science, 224: 521-523 (1984)).
  • vasopressin As micro- injections of other neuropeptides, excitatory amino acids, and catecholamines do not elicit flank marking (Ferris et al., Science, 224:521-523 (1984); Albers and Ferris, Regulatory Peptides, 12:257-260 (1985)).
  • flank marking is specific to the vasopressin V) receptor, as the behavior is selectively inhibited by Vi receptor antagonists and activated by Vi receptor agonists (Ferris et al., t ⁇ euroscience Letters, 55:239-243 (1985); Albers et al., Journal of Neuroscience, 6:2085-2089 (1986); Ferris et al., European Journal of Pharmacology, 154:153-159 (1988)).
  • Stereotaxic surgery was performed under pentobarbital anesthesia.
  • the stereotaxic coordinates were: 1.1 mm anterior to the bregma, 1.8 mm lateral to the midsagittal suture at an 8° angle from the verticle line, and 4.5 mm below the dura.
  • the nose bar was placed at the level of the interaural line.
  • An unilateral 26-gauge guide cannula was lowered to the site and secured to the skull with dental cement.
  • the guide cannulae were closed with a 33- gauge obturator extending 1 mm beyond the guide.
  • the innercanulae used for the microinjections extended 3.0 mm beyond the guide to reach the anterior hypothalamus.
  • the hamsters were microinjected with 1 ⁇ M vasopressin in a volume of 150 nL.
  • vasopressin was given as a cocktail with 200 mM, 20 mM, 2 mM of the test compound or alone, in the vehicle, dimethylsulfoxide. Both the vasopressin and the test compound were dissolved in 100% dimethylsulfoxide. AU injections were aimed at the anterior hypothalamus. Animals were scored for flank marking for a period of 10 minutes in a clean cage. Another aspect of this invention is the use of compounds of formulae I, II, and
  • Compounds useful as serotonin reuptake inhibitors include but are not limited to:
  • Fluoxetine N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, is marketed in the hydrochloride salt form, and as the racemic mixture of its two enantiomers.
  • U.S. Patent No. 4,314,081 is an early reference on the compound. Robertson et al., J. Med. Chem., 31:1412 (1988), taught the separation of the R and S enantiomers of fluoxetine and showed that their activity as serotonin uptake inhibitors is similar to each other.
  • the word "fluoxetine” will be used to mean any acid addition salt or the free base, and to include either the racemic mixture or either of the R and S enantiomers;
  • Duloxetine N-methyl-3-(l-naphthalenyloxy)-3-(2-thieny])propanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Patent No. 4,956,388, which shows its high potency. The word “duloxetine” will be used here to refer to any acid addition salt or the free base of the molecule; Venlafaxine is known in the literature, and its method of synthesis and its activity as an inhibitor of serotonin and norepinephrine uptake are taught by U.S. Patent No. 4,761,501. Venlafaxine is identified as compound A in that patent;
  • the adjunctive therapy of this aspect of the present invention is carried out by administering a vasopressin V la antagonist together with a serotonin reuptake inhibitor in any manner that provides effective levels of the compounds in the body at the same time.
  • All of the compounds concerned are orally available and are normally administered orally, and so oral administration of the adjunctive combination is preferred. They may be administered together, in a single dosage form, or may be administered separately.
  • This aspect of the present invention provides a potentiation of the decrease in the concentration of vasopressin observed as an effect of administration of a vasopressin V, a antagonist by administration of a serotonin reuptake inhibitor.
  • This aspect of the present invention is particularly suited for use in the treatment of depression and obsessive compulsive disorder. Such disorders may often be resistant to treatment with a serotonin reuptake inhibitor alone.
  • Method Example 3 Human oxytocin binding and functional assay.
  • Oxytocin preparations and a number of oxytocin agonists are commercially available for therapeutic use.
  • oxytocin antagonists with antiuterotonic activity have been developed and evaluated for their potential use in the treatment of preterm labor and dysmenorrhyea (Pavo et al, J. Med. Chem., 37:255-259 (1994); Akerlund et al, Br. J. Obstet. Gynaecol, 94: 1040-1044 (1987); Akerlund et al., Br. J. Obstet. Gynaecol, 86:484-487 (1979)).
  • the oxytocin antagonist atosiban has been studied clinically and resulted in a more significant inhibition of preterm contractions than did placebo (Goodwin et al, Am. J. Obstet. Gynecol. , 170:474 (1994)).
  • the human oxytocin receptor has been cloned and expressed (Kimura et al, Nature, 356: 526-529 ( 1992)), it is identified under the accession number X64878.
  • binding studies were performed using a cell line expressing the human oxytocin receptor in 293 cells (henceforth referred to as the OTR cell line) substantially by the procedure described by Morel et al. ⁇ Nature, 356: 523-526 (1992)).
  • the 293 cell line is a permanent line of primary human embryonal kidney cells transformed by sheared human adenovirus type 5 DNA. It is identified as ATCC CRL- 1533.
  • the OTR cell line was grown in DMEM (Delbecco's Modified Essential Medium, Sigma, St. Louis, MO, USA) with 10% fetal bovine serum, 2 mM L-glutamine, 200 ⁇ g hygromycin (Sigma, St. Louis, MO, USA) and 250 ⁇ g/ml G418 (Gibco, Grand Island, NY, USA).
  • DMEM Delbecco's Modified Essential Medium
  • 2 mM L-glutamine 200 ⁇ g hygromycin
  • 250 ⁇ g/ml G418 Gibco, Grand Island, NY, USA
  • the pellet was resuspended in 40 mL of Tris-HCl (tris[hydroxymethyl]aminomethane hydrochloride) buffer (50 mM, pH 7.4) and homogenized for 1 minute with a Tekmar Tissumizer (Cincinnatti, OH USA). The suspension was centrifuged at 40,000 x g for 10 minutes. The pellet was resuspended and centrifuged as above. The final pellet was suspended in 80 mL of Tris 7.4 buffer and stored in 4 mL aliquots at -80 0 C. For assay, aliquots were resuspended in assay buffer and diluted to 375 ⁇ g protein per mL.
  • Tris-HCl tris[hydroxymethyl]aminomethane hydrochloride
  • Protein concentration was determined by BCA assay (Pierce, Rockford, IL, USA).
  • Assay buffer was 50 mM Tris-HCl (tris[hydroxymethyl]aminomethane hydrochloride), 5 mM MgCb, and 0.1% bovine serum albumin at pH 7.4.
  • the radioligand for binding assays was [ 3 H]oxytocin ([tyrosyl-2,6- 3 H]oxytocin, 48.5 Ci/mmol, DuPont NEN, Boston, MA, USA).
  • the order of additions was 195 ⁇ L assay buffer, 200 ⁇ L OTR membranes (75 ⁇ g protein) in assay buffer, 5 ⁇ L of test agent in dimethylsulfoxide (DMSO) or DMSO alone, and 100 ⁇ L [ 3 H]oxytocin in assay buffer (final concentration 1.0 nM). Incubations were for one hour at room temperature. Bound radioligand was separated from free by filtration on a Brandel cell harvester (Gaithersburg, MD, USA) through Whatman GF/B glass-fiber filters that had been soaked for 2 hours in 0.3% polyethylenimine.
  • the filters were washed with ice-cold 50 mM Tris-HCl (pH 7.7 at 25 0 C) and the filter circles were placed in scintillation vials, to which were then added 5 mL Ready Protein PlusTM scintillation fluid, and counted in a liquid scintillation counter. All incubations were in triplicate, and dose-inhibition curves consisted of total binding, nonspecific binding (100 ⁇ M oxytocin, Sigma, St. Louis, MO, USA), and 6 or 7 concentrations of test agent encompassing the IC 50 . Total binding was typically about 1,000 cpm and nonspecific binding about 200 cpm. IC so values were calculated by nonlinear least- squares curve-fitting to a 4-parameter logistic model. Certain compounds of formula I have shown affinity for the oxytocin receptor.
  • Buffer/Assay Bath The buffer used is Munsicks. This buffer contains 0.5 mM Mg 2+ . The buffer is gassed continuously with 95% oxygen/5% carbon dioxide giving a pH of 7.4. The temperature of the assay bath is 37 0 C. A lO mL assay bath is used that contains a water jacket for maintaining the temperature and inlet and outlet spikets for adding and removing buffer.
  • Polygraph/transducer The piece of uterine tissue used for the assay is anchored at one end and connected to a Statham Strain Gauge Force Transducer at the other end which in turn is attached to a Grass Polygraph Model 79 for monitoring the contractions. 4. Assay Protocol:
  • a cumulative dose response curve is then done with oxytocin and a concentration of oxytocin equivalent to approximately 80% of the maximum is used for estimating the pA 2 of the antagonist.
  • the tissue is exposed to oxytocin (Calbiochemical, San Diego, CA) for one minute and washed out. There is a three minute interval before addition of the next dose of agonist or antagonist. When the antagonist is tested, it is given five minutes before the agonist. The agonist is given for one minute. All responses are integrated using a 7P10 Grass Integrator. A single concentration of oxytocin, equal to 80% of the maximum response, is used to test the antagonist.
  • Oxytocin agonists are useful clinically to induce lactation; induce or augment labor; control postpartum uterine atony and hemmorhage; cause uterine contraction after cesarean section or during other uterine surgery; and to induce therapeutic abortion.
  • Oxytocin, acting as a neurotransmitter in the central nervous system also plays an important role in the expression of central functions such as maternal behavior, sexual behavior (including penile erection, lordosis and copulatory behavior), yawning, tolerance and dependance mechanisms, feeding, grooming, cardiovascular regulation and thermoregulation (Argiolas and Gessa, Neuroscience and Biobehavioral Reviews, 15:217-231 (1991)).
  • Oxytocin antagonists find therapeutic utility as agents for the delay or prevention of premature labor; or to slow or arrest delivery for brief periods in order to undertake other therapeutic measures.
  • Tachykinin receptor binding assay Compounds of the present invention are believed to be tachykinin agents.
  • Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.
  • neurokinin A also known as substance K, neuromedin 1, and neurokinin ⁇
  • neurokinin B also known as neuromedin K and neurokinin ⁇ . See, J.E. Maggio, Peptides, 6 (Supplement 3): 237-243 (1985) for a review of these discoveries.
  • Tachykinins are widely distributed in both the central and peripheral nervous systems. When released from nerves, they exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues. The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-I, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
  • Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
  • tachykinin receptor antagonists In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions.
  • the earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
  • Recent publications have described novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists.
  • NK-I Receptor Binding Assay Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan et al. Journal of Immunology. 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1 x 10 6 cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM l25 I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4 0 C.
  • the IM9 cell line is a well-characterized cell line which is readily available to the public. See, e.g., Annals of the New York Academy of Science, 190:221-234 (1972); Nature (London), 251:443-444 (1974); Proceedings of the National Academy of Sciences (USA), 71 :84-88 ( 1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 ⁇ g/mL gentamicin sulfate and 10% fetal calf serum.
  • NK-2 Receptor Binding Assay The CHO-hNK-2R cells, a
  • CHO-derived cell line transformed with the human NK-2 receptor expressing about 400,000 such receptors per cell, were grown in 75 cm 2 flasks or roller bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum.
  • minimal essential medium alpha modification
  • fetal bovine serum 10% fetal bovine serum.
  • Membranes were prepared by homogenization of the cell pellets in 300 mL 50 mM Tris buffer, pH 7.4 with a Tekmar® homogenizer for 10-15 seconds, followed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckman JA- 14 ® rotor. The pellets were washed once using the above procedure, and the final pellets were resuspended in 100-120 mL 50 mM Tris buffer, pH IA, and 4 ml aliquots stored frozen at -70 0 C. The protein concentration of this preparation was 2 mg/mL.
  • CHO-hNK-2R membrane preparation For the receptor binding assay, one 4-mL aliquot of the CHO-hNK-2R membrane preparation was suspended in 40 mL of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 ⁇ g/mL chymostatin. A 200 ⁇ L volume of the homogenate (40 ⁇ g protein) was used per sample.
  • the radioactive ligand was [ l2S I]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci/mmol.
  • the ligand was prepared in assay buffer at 20 nCi per 100 ⁇ L; the final concentration in the assay was 20 pM. Non-specific binding was determined using 1 ⁇ M eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration- response curve.
  • Tachykinin receptor antagonists are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin.
  • These clinical conditions may include disorders of the central nervous system such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, AEDS-associated dementia, and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as peripheral neuropathy, such as diabetic and chemotherapy-induced neuropathy, and post-herpetic and other neuralgias; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis; disorders of
  • NK-I antagonists are useful in the treatment of pain, especially chronic pain, such as neuropathic pain, post-operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.
  • chronic pain such as neuropathic pain, post-operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post partum pain, angina pain, and
  • NK-I antagonists are especially useful in the treatment and prevention of urinary incontinence; irritative symptoms of benign prostatic hypertrophy; motility disorders of the gastrointestinal tract, such as irritable bowel syndrome; acute and chronic obstructive airway diseases, such as bronchospasm, bronchopneumonia, asthma, and adult respiratory distress syndrome; artherosclerosis; inflammatory conditions, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenic inflammation, allergies, rhinitis, cough, dermatitis, urticaria, psoriasis, conjunctivitis, emesis, irritation-induced miosis; tissue transplant rejection; plasma extravasation resulting from cytokine chemotherapy and the like; spinal cord trauma; stroke; cerebral stroke (ischemia); Alzheimer's disease; Parkinson's disease; multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety; and depression.
  • NK-2 antagonists are useful in the treatment of urinary incontinence, bronchospasm, asthma, adult respiratory distress syndrome, motility disorders of the gastrointestinal tract, such as irritable bowel syndrome, and pain.
  • the compounds of the invention may be useful in the treatment of emesis, including acute, delayed, or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure.
  • the compounds of formulae I, II, and EU are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy.
  • chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl sulfonates, and other compounds with an alkylating action, such as nitrosoureas, cisplatin, and dacarbazine; antimetabolites, for example, folic acid, purine, or pyrimidine antagonists; mitotic inhibitors, for example vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
  • alkylating agents for example, nitrogen mustards, ethyleneimine compounds, alkyl sulfonates, and other compounds with an alkylating action, such as nitrosoureas, cisplatin, and dacarbazine
  • antimetabolites for example, folic acid, purine, or pyrimidine antagonists
  • mitotic inhibitors for example vinca alkaloids and derivatives of podophyllotoxin
  • cytotoxic antibiotics include cytotoxic antibiotics.
  • chemotherapeutic agents are described, for instance, by D.J. Stewart in NAUSEA AND VOMITING: RECENT RESEARCH AND CLINICAL ADVANCES, (J.
  • chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin, daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, and chlorambucil.
  • DTIC dacarbazine
  • dactinomycin mechlorethamine (nitrogen mustard)
  • streptozocin cyclophosphamide
  • BCNU carmustine
  • CCNU lomustine
  • doxorubicin daunorubicin
  • procarbazine mitomycin
  • cytarabine etoposide
  • methotrexate 5-fluorouracil
  • the compounds of formulae I, II, and EQ may also be of use in the treatment of emesis induced by radiation, including radiation therapy such as in the treatment of cancer, or radiation sickness; and in the treatment of post-operaive nausea and vomiting.
  • Method Example 7 Premenstrual Dysmenorrhoea Dysphoria.
  • Antagonism of vasopressin V] 3 receptor has also been shown to alleviate or prevent the symptoms of premenstrual dysmenorrhoea dysphoria (PMDD) and premenstrual dysmenorrhoea (PMD).
  • PMDD premenstrual dysmenorrhoea dysphoria
  • PMD premenstrual dysmenorrhoea
  • Treatment is illustratively given shortly before the onset of menstruation as a preventative treatment of dysmenorrhoea.
  • An illustrative assay of vasopressin V )a antagonists described herein includes a double-blind, randomised, placebo-controlled, cross-over trial in complete block design (such as including three periods and three treatments).
  • Illustrative treatment groups include women ages 18-35 years suffering from primary dysmenorrhoea.
  • Daily dosing is made of either placebo or drug, where the drug dosing is illustratively about 100 mg to about 300 mg of a compound as described herein. The dosing is given in the window from about 4 hours to about three days prior to the onset of bleeding and/or menstrual pain. Alternatively, patients may also be treated with a second daily dose.
  • Success outcomes include self-reporting of menstrual pain intensity by means of a visual analogue scale, self-rating of symptoms of dysmenorrhoea (including back and pelvic pain) in relation to functional capacity (using a Sultan score), and self-assessment of menstrual blood loss in a menstrual diary record.
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • the active ingredient, starch, and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50- 60 0 C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • the medicament, sucrose, and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled " into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows:
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture is then cooled until solid.

Abstract

3-Hydroxy and 3-keto substituted 2-(azetidin-2-on-l-yl)alkanedioic acids, and analogs and derivatives thereof are described. Methods for using 3-hydroxy and 3-keto substituted 2-(azetidin-2-on-l-yl)alkanedioic acids, and analogs and derivatives thereof, in the treatment of disease states responsive to antagonism of vasopressin receptors are also described.

Description

HYDROXY AND KETO-SUBSTITUTED β-LACTAMYL ALKANEDIOIC ACIDS
TECHNICAL FIELD
The present invention relates to azetidin-2-on-l-ylalkanedioic acids, and analogs and derivatives thereof. In particular, the present invention relates to 3-hydroxy substituted and 3-keto substituted azetidin-2-on-l-ylalkanedioic acids, and analogs and derivatives thereof. The present invention also relates to methods for treating mammals in need of relief from disease states associated with and responsive to the antagonism of one or more vasopressin receptors.
BACKGROUND Arginine vasopressin (AVP) is a neurohypophyseal neuropeptide produced in the hypothalamus, and is involved in many biological processes in the circulatory system, the peripheral nervous system (PNS), and the central nervous system (CNS). In particular, AVP acts as a neurotransmitter in the brain. Several pharmacologically significant vasopressin receptor subtypes, including vasopressin Via, Vib, and V2, have been identified. Such vasopressin receptors are involved in several psychiatric, psychological, and behavioral disease states including depression, anxiety, affective disorders, and stress, as well as non-opioid mediation of tolerance for pain. Vasopressin receptors are also involved in a number of metabolic processes including water metabolism homeostasis, renal function, mediation of cardiovascular function, and regulation of temperature in mammals. For example, AVP plays an important role in the onset of depression, one of the most common of the serious CNS disorders. Among the potential targets for treating depression is the hypothalamic-pituitary-adrenal-axis (HPA axis), which is perturbed in many depressed patients, as well as in stress-related affective disorders {see, Scott and Dinan, 1998; Serradiel-Le Gal et al., 2002, the disclosures of which are incorporated herein by reference). Normalization of HPA axis function appears to be a prerequisite for sustained remission of depressive symptoms when medication is used (see, Steckler, et al., 1999, the disclosure of which is incorporated herein by reference).
One of the signs of major depression is an elevated level of Cortisol and ACTH associated with dysregulation of the HPA axis (see, Owens and Nemeroff, 1993; Plotsky et al. 1998, the disclosures of which are incorporated herein by reference). Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are the two main ACTH secretagogues, and recent preclinical and clinical studies have shown that AVP is important in mediating ACTH release during chronic psychological stress (see, Scott and Dinan, 1997, 1998, the disclosures of which are incorporated herein by reference). AVP is made in neurons localized to the paraventricular nucleus of the hypothalamus, and activation of these neurons causes the release of AVP into the portal circulation of the median eminence. However, the Cortisol response to psychological stress appears to be regulated by AVP, and not by CRH in anxious healthy human volunteers {see, Boudarene et al., 1999, the disclosure of which is incorporated herein by reference). Chronic psychological stress accompanied by dysregulation of the HPA axis may contribute to the etiology of affective disorders. It has been found that many patients with major depression show elevated levels of AVP that decline as the mental illness improves (see, van Londen et al., 1997 & 2000, the disclosures of which are incorporated herein by reference). AVP is also transported to the anterior pituitary where it can stimulate ACTH release by interacting with aVib receptor on the cell membranes of corticotrophs. For example, rats selectively bred for high anxiety-related behavior show dysregulation in this HPA axis. Treatment with a Vib receptor antagonist can abolish CRH-stimulated ACTH secretion, demonstrating a shift in ACTH regulation from CRH to AVP (see, Keck et al., 1999, the disclosures of which are incorporated herein by reference). The presence of Vib receptors in several regions of the rat CNS and mouse CNS has also been demonstrated. It is therefore believed that Vib antagonists that penetrate the CNS may have greater therapeutic potential for stress-related affective disorders. Currently there are no vasopressin antagonists that are able to cross the blood brain barrier (Serradeil-Le Gal et al. 2002). There is also preclincial and clinical evidence that vasopressin, acting through a Vn, receptor, contributes to a subtype of major depression associated with chronic stress and dysregulation of the HPA axis (see, Boudarene et al., 1999; Griebel et al., 2002; Scott and Dinan, 1997, 1998, the disclosures of which are incorporated herein by reference).
Further, it has been reported that cardiovascular disease accounts for the largest cause of hospitalizations in individuals aged 65 years and older. It has been demonstrated that AVP contributes to the pathophysiology and progression of heart disease, including congestive heart failure (see, Schrier & Abraham "Hormones and hemodynamics in heart failure," N. Engl. J. Med. 341:577-585 (1999); Thibonnier "Vasopressin receptor antagonists in heart failure," Curr. Op. Pharmacology 3:683-687 (2003); Lee et al., "Vasopressin: A new target for the treatment of heart failure," Am. Heart J. 146:9-18 (2003), the disclosures of which are incorporated herein by reference). In addition, the coordinated physiology of the renal/cardiovascular systems contributes to normal cardiac performance and homeostasis. Thus, AVP also plays an important role in water and electrolytic balance, regulation of blood volume, vascular smooth muscle tone, and cardiac contractility and metabolism. Each of these are major factors affecting the performance of the heart and its ability to meet the demands of the body. AVP affects all of these factors, in particular through activation of Vu and V2 receptors. Vasopressin V]a receptors are localized to vascular smooth muscle and cardiomyocytes, promoting vasoconstriction and myocardial cell protein synthesis and growth, respectively. Vasopressin V2 receptors are localized to the collecting ducts of nephrons in the kidney promoting free water reabsorption. Small changes in plasma osmolality are sensed by receptors in the hypothalamus, which regulates the neurosecretory release of AVP from the pituitary gland. With osmotic stimulation, plasma AVP levels can rise from a basal level of 3- 4 pg/ml to 9-10 pg/ml. These modest changes in AVP neurohormone level, in concert with the renin-angiotensin-aldosterone system, regulate the day-to-day water and electrolyte balance in healthy subjects.
However, it has been reported that the role of AVP in the cardiovascular physiology of healthy subjects is minimal, and for those persons, supraphysiological doses of neurohormone are needed to affect blood pressure, cardiac contractility, and coronary blood flow. In contrast, AVP plays a substantive role in patients with heart failure. For example, it has been observed that basal plasma levels of AVP are elevated in patients with heart failure as compared to healthy controls, particularly those that also present with hyponatremia {see, Goldsmith, "Congestive heart failure: potential role of arginine vasopressin antagonists in the therapy of heart failure," Congest. Heart Fail. 8:251-6 (2002); Schrier and Ecder, (2001 X the disclosures of which are incorporated herein by reference). Further, the impaired water diuresis in congestive heart failure (CHF) patients leading to increased blood volume, hyponatremia, edema, and weight gain, is linked to AVP. With heart failure, elevations in plasma AVP lead to increased peripheral vascular resistance and pulmonary capillary wedge pressure while reducing cardiac output and stroke volume. Further, additional evidence suggests that AVP contributes to the hypertrophic myocardium characteristic of the failing heart (see, Nakamura et al., "Hypertrophic growth of cultured neonatal rat heart cells mediated by vasopressin Via receptor," Eur J Pharmacol 391:39-48 (2000); Bird et al., "Significant reduction in cardiac fibrosis and hypertrophy in spontaneously hypertensive rats (SHR) treated with a V]a receptor antagonist," (abstract) Circulation 104: 186 (2001), the disclosures of which are incorporated herein by reference), and cell/molecular studies have demonstrated that it also triggers a signaling cascade that promotes the myocardial fibrosis typically seen with progression of the disease.
Structural modification of vasopressin has been reported, and these compounds act as vasopressin agonists (see, e.g. , Sawyer, Pharmacol. Reviews, 13:255 (1961)). hi addition, several potent and selective vasopressin peptide antagonists have been disclosed (see, Lazslo et al., Pharmacological Reviews, 43:73-108 (1991); Mah and Hofbauer, Drugs of the Future, 12:1055-1070 (1987); Manning and Sawyer, Trends in Neuroscience, 7:8-9 (1984)). Further, novel structural classes of non-peptidyl vasopressin antagonists have been disclosed (see, Yamamura et al., Science, 275:572-574 (1991); Serradiel-Le Gal et al., Journal of
Clinical Investigation, 92:224-231 (1993); Serradiel-Le Gal et al., Biochemical Pharmacology, 47(4):633-641 (1994)). Finally, the general structural class of substituted 2-(azetidin-2-on-l- yl)acetic acid esters and amides are known as synthetic intermediates for the preparation of β- lactam antibiotics (see, U.S. Patent No. 4,751,299).
SUMMARY OF THE INVENTION
It has been discovered that certain compounds within the general class of azetidinylalkanedioic acids, and derivatives thereof, are potent antagonists of vasopressin receptors. Described herein are azetidin-2-on-l-ylalkanedioic acids, and derivatives thereof. In particular, 3 -hydroxy substituted and 3-keto substituted alkanedioic acids and derivatives are described herein. Such compounds are expected to be potent antagonists of vasopressin receptors, including the vasopressin Via,Vib, and V2 receptors. Illustratively, the azetidin-2-on- 1 -ylalkanedioic acids and derivatives described herein are substituted alkanedioic acid analogs of 2-aminoglutaric acid, 2-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid, 2- aminoazelaic acid, and the like, and derivatives thereof, including but not limited to ester and amide derivatives. In particular, such analogs of 2-aminoglutaric acid, 2-aminoadipic acid, 2- aminopimelic acid, 2-aminosuberic acid, 2-aminoazelaic acid, and the like, and derivatives thereof, are 3-substituted with hydroxy, bis hydroxy, or keto, each of which is optionally protected or derivatized, such as in the form of the corresponding alkoxy, acyloxy, ketal, oxime, hydrazone, imine, and the like. Also described herein are pharmaceutical compositions that include therapeutically effective amounts of azetidin-2-on-l-ylalkanedioic acids and derivatives. Also described herein are methods useful for treating diseases and disease states that are associated with vasopressin dysfunction, and that are responsive to antagonism of a vasopressin receptor, such as the Via, Vib, or V2 receptors, or a combination thereof, in a mammal. In one variation, such methods include the step of administering one or more of the azetidin-2-on-l- ylalkanedioic acids, or derivatives thereof, in an amount effective to alleviate the treatable disease or disease state, or alleviate symptoms associated with such diseases or disease states. In another variation, such methods include the step of administering a composition containing one or more of the azetidin-2-on-l-yIalkanedioic acids, or derivatives thereof, in an amount effective to alleviate the treatable disease or disease state, or alleviate symptoms associated with such diseases or disease states, in combination with one or more carriers, diluents, and/or excipients. Also described herein are processes for preparing azetidin-2-on-l-ylalkanedioic acids and derivatives.
In one illustrative embodiment of the invention, compounds of formula (I) are described:
Figure imgf000006_0001
and pharmaceutically acceptable salts thereof; wherein: n is an integer from 0 to about 5;
A is R5O-, monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen;
A' is R5 O-, monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen; B is hydroxy or a derivative thereof, optionally substituted alkoxy, optionally substituted acyloxy, or optionally substituted aroyloxy, and B' is hydrogen, hydroxy or a derivative thereof, optionally substituted alkoxy, optionally substituted acyloxy, or optionally substituted aroyloxy; or B and B' are taken together with the attached carbon to form a carboπyl group, or a derivative thereof; R1 is hydrogen or Ci-Cβ alkyl;
R2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting of -CQ.R , -CONR8R8', and -NR8CCOR9);
R3 is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R3 is a nitrogen-containing heterocyclyl group attached at a nitrogen atom;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl; Rs is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(Cι-C4 alkyl), and R6R7N-(C2-C4 alkyl); where heterocyclyl is in each occurrence independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C1-C4 alkyl or optionally substituted aryl(Ci-C4 alkyl);
R5' is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(Ci-C4 alkyl), and R6R7N-(C2-C4 alkyl); where heterocyclyl is in each occurrence independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with CrC4 alkyl or optionally substituted aryl(Ci-C4 alkyl);
R is in each instance independently hydrogen or alkyl; and R is in each instance independently alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R and R in each instance are independently taken together with the attached nitrogen atom to form an optionally substituted heterocycle, such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally N-substitued with R13;
R8 and R8 are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R8 and R8' are taken together with the attached nitrogen atom to form an heterocycle, such as optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl;
R9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R8R8N-(Ci-C4 alkyl);
R13 is in each instance independently selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aryloyl.
In another illustrative embodiment, compounds of formula II are described:
Figure imgf000008_0001
and pharmaceutically acceptable salts thereof; where R1, R2, R4, n, A, A', B, and B' are as defined herein; and Ar1 is an optionally substituted aryl group.
In another illustrative embodiment, compounds of formula HI are described:
Figure imgf000008_0002
and pharmaceutically acceptable salts thereof; where R1, R2, n, A, A', B, and B' are as defined herein; and Ar1 and Ar2 are each an independently selected optionally substituted aryl group. In another illustrative embodiment, compounds of formula IV are described:
Figure imgf000008_0003
and pharmaceutically acceptable salts thereof; where R1, R2, n, B, and B' are as defined herein; Ar1 and Ar2 are each an independently selected optionally substituted aryl group; X and X* are each independently selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, and heterocyclyl, heterocyclyl-(Ci-C4 alkyl), R6R7N-, and R6R7N-(C2-C4 alkyl), where in each occurrence heterocyclyl is independently selected; and R14 and R14 are each independently selected from hydroxy, alkyl, alkoxycarbonyl, and benzyl; or X and R14 and/or X' and R14' are each independently taken together with the attached nitrogen to form an independently selected heterocyclic ring. In another illustrative embodiment, compounds of formula V are described:
Figure imgf000009_0001
and pharmaceutically acceptable salts thereof; where R1, R2, R3, R4, n, and A', are as defined herein. It is to be understood that the compounds of each of formulae (I)-(V) may be in the form of pharmaceutically acceptable salts. In addition, many of the functional groups on the compounds of each of formulae (I)-(V) may form complexes with water, to form hydrate forms, or with other solvents, to form solvate forms. It is appreciated that such hydrate and solvate forms of the compounds of formulae (I)-(V) may form spontaneously during isolation from the processes for preparing these compounds, including those processes described herein. Accordingly, as used herein each reference to any of the compounds of any of formulae (I)-(V) is intended to refer to the free base or free acid forms, any and all pharmaceutically acceptable salt forms thereof, and/or any and all hydrate and solvate forms thereof, both individually and collectively. It is also to be understood that in each of formulae (I)-(V), the selections recited for the various groups R1 to R14 , n, A, A1, B, and B1, are each made independently. Therefore, any and all combinations of groups are contemplated and described herein. Illustratively, in one aspect of each of formulae (I)-(V), A and/or A1 is an independently selected monosubstituted amino. In another aspect, A and/or A' is an independently selected disubstituted amino. In another aspect, A and/or A' is an independently selected optionally substituted heterocyclyl. In another aspect, A or A' is monosubstituted amino, and the other of A or A' is optionally substituted heterocyclyl. In another aspect, n is 0. In another aspect, n is 1 or 2. In another aspect, n is 1 or 2 and A and/or A1 is an independently selected heterocyclyl. In another aspect, n is 1 or 2, A is monosubstituted amino, and A' is heterocyclyl. Other selections are contemplated herein, and other combinations of selections are contemplated herein.
In another illustrative embodiment, processes for preparing compounds of formulae I-V are described. In one illustrative variation, a process is described for preparing compounds of formulae I-IV that includes the step of reacting a compound of formula A with a compound of formula B
Figure imgf000010_0001
where n, A, A', B, B', R1, R2, R3, and R4 are as defined herein.
In another illustrative variation, a process is described for preparing compounds of formula IV that includes the step of reacting a compound of formula C:
with a compound of formula D:
Figure imgf000010_0002
where n, B, B1, R1, R2, X, X1, R14, R14', Ar1, and Ar2 are as defined herein.
In another illustrative variation, a process for preparing compounds of formula V is described that includes the step of reacting a compound of formula (E):
Figure imgf000010_0003
(E) where A is -OH, B is -OH, and B1 is hydrogen, and R1, R2, R3, R4, n, and A' are as defined herein, with an amide coupling reagent, such as NjN'-dicyclohexylcarbodiimide (DCC), N,N'- carbonyldiimidazole (CDI), benzenesulfonyl chloride in pyridine, and the like.
In another illustrative embodiment, pharmaceutical compositions are described, where the pharmaceutical compositions include one or more of the compounds of formulae I, π, IH, IV, and/or V. The pharmaceutical compositions described herein also include one or more pharmaceutically acceptable carriers, diluents, and/or excipients. In one illustrative aspect, pharmaceutical compositions are described that exhibit oral activity and/or oral bioavailability. In another illustrative aspect, pharmaceutical compositions are described that include compounds of formulae I, π, III, IV, and V, and derivatives thereof that are adapted to cross the blood brain barrier.
In another illustrative embodiment, methods for treating disease states responsive to the antagonism of one or more vasopressin Vu.Vib, and/or V2 receptors, in a mammal in need of such treatment are described. The methods comprise the step of administering to the mammal a pharmaceutically effective amount of one or more of the compounds described herein, including the compounds of formulae I, π, ID, IV, and V. In another embodiment, the methods comprise the step of administering to the mammal a composition containing a pharmaceutically effective amount of one or more of the compounds described herein, including the compounds of formulae I, II, III, IV, and V, and a pharmaceutically acceptable carrier, diluent, and/or excipient.
Illustrative disease states that are responsive to the antagonism of one or more of the vasopressin Vi a, V|b, and/or V2 receptors, and treatable by the methods described herein, include various stress-related mental illnesses, depression, anxiety, affective disorders, obsessive-compulsive disease, impulsivity, aggressive disorders, and the like; diseases affecting water homeostasis, renal function, inhibition of phosphatidyl inositol turnover, temperature regulation, and the like; diseases associated with nausea, emesis, and pain; and various cardiovascular diseases, including congestive heart failure, disorders or conditions associated with platelet aggregation, and the like. In addition, methods for treating other disease states and conditions treatable by, for example, oxytocin receptor antagonism, tachykinin receptor antagonism, neurokinin 1 receptor antagonism, neurokinin 2 receptor antagonism, and the like are described herein, where the method includes the step of administering to a patient in need of relief from such a disease state or condition an effective amount of one or more compounds described herein, including the compounds of formulae I, II, in, IV, and V; or the method includes the step of administering to a patient in need of relief from such a disease state or condition a composition described herein, where the composition includes an effective amount of one or more compounds described herein, including the compounds of formulae I, II, HI, IV, and V, and and a pharmaceutically acceptable carrier, diluent, and/or excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the human Vib binding affinity (Ki = 32 nM) of Example 34 through a competitive binding assay conducted in CHO cells transfected with human V|b receptor.
FIG. 2 shows the antagonist activity of Example 34 against AVP as evaluated in CHO cells expressing rat Vn, receptor. Example 34 inhibited V|b mediated phosphatidyl inositol turnover with a Kj value at 59 nM.
FIG. 3 shows the activity of Example 34 against vehicle control in a seed finding assay of hamsters as a model of anxiety; (a) Vehicle, (b) Example 34 (1 mg/kg).
FIG. 4 shows the activity of Example 34 against vehicle control in a biochemical marker assay measuring plasma testosterone as a model of stress in hamsters, where low testosterone in the control group indicates stress; (a) Vehicle, (b) Example 34 (1 mg/kg).
FIG. 5 shows the activity of Example 34 against vehicle control in a biochemical marker assay measuring plasma Cortisol as a model of stress in hamsters, where high Cortisol in the control group indicates stress; (a) Vehicle, (b) Example 34 (1 mg/kg).
DETAILED DESCRIPTION
In one illustrative embodiment of the invention, compounds of formula (T) are described:
Figure imgf000012_0001
and pharmaceutically acceptable salts thereof; wherein: n is an integer from 0 to about 5;
A is R O-, monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen; A' is R5 O-, monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen;
B is hydroxy or a derivative thereof, optionally substituted alkoxy, optionally substituted acyloxy, or optionally substituted aroyloxy, and B' is hydrogen, hydroxy or a derivative thereof, optionally substituted alkoxy, optionally substituted acyloxy, or optionally substituted aroyloxy; or B and B1 are taken together with the attached carbon to form a carbonyl group, or a derivative thereof;
R1 is hydrogen or Ci-Ce alkyl;
R2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting of -CO2R8 , -CONR8R8', and -NR8CCOR9);
R is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R3 is a nitrogen-containing heterocyclyl group attached at a nitrogen atom;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl;
R5 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(Ci-C4 alkyl), and R6R7N-(C2-C4 alkyl); where heterocyclyl is in each occurrence independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C1-C4 alkyl or optionally substituted aryl(Ci-C4 alkyl);
R5 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(Cι-C4 alkyl), and R6R7N-(C2^ alkyl); where heterocyclyl is in each occurrence independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C1-C4 alkyl or optionally substituted aryl(Cι-C4 alkyl); R6 is in each instance independently hydrogen or alkyl; and R7 is in each instance independently alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R6 and R7 in each instance are independently taken together with the attached nitrogen atom to form an optionally substituted heterocycle, such as pyrrolidinyl, piperidinyl, moφholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally N-substitued with R ;
R8 and R8 are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R8 and R8 are taken together with the attached nitrogen atom to form an heterocycle, such as optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl;
R9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R8R8N-(Cj-C4 alkyl); R1 is in each instance independently selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and . optionally substituted aryloyl.
In another illustrative embodiment, compounds of formula π are described:
Figure imgf000014_0001
and pharmaceutically acceptable salts thereof; where R1, R2, R4, n, A, A1, B, and B' are as defined herein; and Ar i i •s an optionally substituted aryl group.
In another illustrative embodiment, compounds of formula El are described:
Figure imgf000014_0002
and pharmaceutically acceptable salts thereof; where R1, R2, n, A, A', B, and B' are as defined herein; and Ar1 and Ar2 are each an independently selected optionally substituted aryl group. In another illustrative embodiment, compounds of formula IV are described:
Figure imgf000015_0001
(IV) and pharmaceutically acceptable salts thereof; where R1, R2, n, B, and B1 are as defined herein; Ar1 and Ar2 are each an independently selected optionally substituted aryl group; X and X1 are each independently selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, and heterocyclyl, heterocyclyl-(Ci-C4 alkyl), R6R7N-, and
R6R7N-(C2-C4 alkyl), where in each occurrence heterocyclyl is independently selected; and R14 and R14' are each independently selected from hydroxy, alkyl, alkoxycarbonyl, and benzyl; or X and R14 and/or X' and R14 are each independently taken together with the attached nitrogen to form an independently selected heterocyclic ring. In another illustrative embodiment, compounds of formula V are described:
Figure imgf000015_0002
and pharmaceutically acceptable salts thereof; where R1, R2, R3, R4, n, and A1, are as defined herein.
The general chemical terms used in the formulae described herein have their usual ordinary meanings. For example, the term "alkyl" refers to a straight-chain or optionally branched, saturated hydrocarbon, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl and the like.
The term "cycloalkyl" refers to a straight-chain or optionally branched, saturated hydrocarbon, at least a portion of which forms a ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term "alkenyl" refers to a straight -chain or optionally branched, hydrocarbon that includes at least one double bond, including but not limited to vinyl or ethenyl, allyl or propenyl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, butadienyl, and the like.
The term "alkynyl" refers to a straight-chain or optionally branched, hydrocarbon that includes at least one triple bond, including but not limited to ethynyl, propynyl, 1-butynyl, hex-4-en-2-ynyl, and the like.
The term "aryl" refers to an aromatic ring or heteroaromatic ring and includes such groups as fiiryl, pyrrolyl, thienyl, pyridinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, oxadiazolyl, naphthyl, indanyl, fluorenyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzofuranyl, benzothienyl, and the like.
The term "optionally substituted" refers to the replacement of one or more, preferably from one to three, hydrogen atoms with one or more substitutents. Substituents include but are not limited to such groups as C1-C4 alkyl, C1-C4 alkoxy, Cι-C4 alkylthio, hydroxy, nitro, halo, carboxy, cyano, Ci-C4 haloalkyl, Ci-C4 haloalkoxy, amino, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylalkylamino, C 1-C4 alkylsulfonylamino, and the like.
The term "heterocycle" refers to a non-aromatic cyclic structure possessing one or more heteroatoms, such as nitrogen, oxygen, sulfur, and the like, and includes such groups as tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.
The term "alkoxy" refers to an alkyl or cycloalkyl subtituent attached through an oxygen, and includes such groups as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert- butoxy and the like.
The terms "acyl," "alkanoyl," and "aroyl" refer to alkyl, alkenyl, aryl, and the like attached through a carbonyl group, and include such groups as formyl, acetyl, propanoyl, butanoyl, pentanoyl, cyclohexanoyl, optionally substituted benzoyl, and the like.
The term "halo" means fluoro, chloro, bromo, and iodo.
The term "alkanoyloxy" includes such groups as formyloxy, acetoxy, n-propionoxy, n-butyroxy, pivaloyloxy, and like lower alkanoyloxy groups. The terms "optionally substituted C1-C4 alkyl," "optionally substituted C3-C8 cycloalkyl," and "optionally substituted C2-C4 alkenyl" refer to alkyl, cycloalkyl, or alkenyl, respectively, optionally substituted with a substituent as described herein, including but not limited to halo, hydroxy, protected hydroxy, alkyl, protected carboxyl, carbamoyl, benzylthio, alkylthio, and the like. Illustratively, such groups include such as trifluoromethyl, trifluorochloroethyl, methoxyethyl, 2-(methoxyacetyl)propyl, and the like.
The term "(C1-C4 alkyl)" as used in for example "aryl(CrC4 alkyl)", "(Ci-C4 alkoxy)-(Cι-C4 alkyl)", and the like, refers to a saturated linear or branched divalent alkyl chain of from one to four carbons bearing for example aryl, C |-C4 alkoxy, and the like, as a substituent and includes such groups as for example benzyl, phenethyl, phenpropyl, α- methylbenzyl, methoxymethyl, ethoxyethyl, and the like.
The terms "optionally substituted aryl," "optionally substituted phenyl," and
"optionally substituted heteroaryl" include the corresponding aryl, phenyl, or heteroaryl radical optionally substituted with one or more substituents each os which is independently selected, such as Ci-C4 alkyl, Cj-C4 alkoxy, hydroxy, halo, nitro, trifluoromethyl, sulfonamido, cyano, carbamoyl, amino, mono(Ci-C4 alkyl)amino, di(Cι-G» alkyl)amino, Ci-C4 alkylsulfonylamino, and indol-2-yl, and the like.
The term "protected amino" refers to amine protected by a protecting group that may be used to protect the nitrogen, such as the nitrogen in the β-lactam ring, during preparation or subsequent reactions. Examples of such groups are benzyl, 4-methoxybenzyl, 4- methoxyphenyl, trialkylsilyl, for example trimethylsilyl, and the like.
The term "protected carboxy" refers to the carboxy group protected or blocked by a conventional protecting group commonly used for the temporary blocking of the acidic carboxy. Examples of such groups include lower alkyl, for example tert-butyl, halo-substituted lower alkyl, for example 2-iodoethyl and 2,2,2-trichloroethyl, benzyl and substituted benzyl, for example 4-methoxybenzyl and 4-nitrobenzyl, diphenylmethyl, alkenyl, for example allyl, trialkylsilyl, for example trimethylsilyl and tert-butyldiethylsilyl and like carboxy-protecting groups. The term "antagonist," as used herein, refers to a full or partial antagonist.
While a partial antagonist of any intrinsic activity may be useful, the partial antagonists illustratively show at least about 50% antagonist effect, or at least about 80% antagonist effect.
The term also includes compounds that are full antagonists of one or more vasopressin receptors. It is appreciated that illustrative methods described herein require therapeutically effective amounts of one or more vasopressin receptor antagonists; therefore, compounds exhibiting partial antagonism at vasopressin receptors may be adminstered in higher doses to exhibit sufficient antagonist activity to inhibit the effects of vasopressin or a vasopressin agonist. It is to be understood that in the embodiments described herein, an illustrative variation of alkyl is Ci-Ce alkyl, such as methyl, ethyl, propyl, prop-2-yl, and the like; an illustrative variation of alkenyl is C2-C6 alkenyl, such as vinyl, allyl, and the like; an illustrative variation of alkynyl is C2-C6 alkynyl, such as ethynyl, propynyl, and the like; an illustrative variation of alkoxy is C1-C4 alkoxy, such as methoxy, pent-3-oxy, and the like; an illustrative variation of alkylthio is Ci-C4 alkylthio, such as ethylthio, 3-methylbuty-2-ylthio, and the like; an illustrative variation of alkylcarbonyl is C1-C3 alkylcarboπyl, such as acetyl, propanoyl, and the like; an illustrative variation of cycloalkyl is C3-C8 cycloalkyl; an illustrative variation of cycloalkenyl is C3-C9 cycloalkenyl, such as limonenyl, pinenyl, and the like; an illustrative variation of optionally substituted arylalkyl is optionally substituted aryl(Ci-C4 alkyl); an illustrative variation of optionally substituted arylalkenyl is optionally substituted aryl(C2-C4 alkenyl); an illustrative variation of optionally substituted arylalkynyl is optionally substituted aryl(C2-C4 alkynyl); an illustrative variation of alkoxyalkyl is (C1-C4 alkoxy)-(Ci-C4 alkyl); an illustrative variation of optionally substituted heteroarylalkyl is optionally substituted heteroaryl(Cι-C4 alkyl); and an illustrative variation of alkoxycarbonyl is C1-C4 alkoxycarbonyl.
In another embodiment, compounds of compounds of formulae I-V are described, wherein R1 is hydrogen. In another embodiment, compounds of compounds of formulae I-V are described, wherein R2 is hydrogen. In another embodiment, compounds of formula I are described, wherein R3 is a structure selected from:
Figure imgf000018_0001
where R10 and R1 ' are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkylcarbonyloxy, diphenylmethoxy, triphenylmethoxy, and the like; and R is selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted aryloyl, and the like.
In one variation, certain compounds of compounds of formulae I and V are described, wherein R is a structure selected from:
Figure imgf000019_0001
Figure imgf000019_0002
where R10, R1 ' , and R12 are as defined herein.
In another variation, certain compounds of compounds of formula I and V are described, wherein R3 is a struct uurree sseelleecctteedd f frroomm::
Figure imgf000019_0003
where R10, R1 ' , and R12 are as defined herein.
In another variation, certain compounds of compounds of formula I and V are described, wherein R3 is of the formula (F):
Figure imgf000019_0004
where R10 and R1 ' are as defined herein. In another embodiment, compounds of compounds of formulae I-V are described, wherein n is 0. In another embodiment, compounds of compounds of formulae I-V are described, wherein n is 1 or 2.
In another embodiment, certain compounds of formulae I-III are described that are diacids, acid esters, or diesters, wherein A is R5O- and A' is R5 O. In another embodiment, certain compounds of formulae I-III are described that are acid amides or ester amides, wherein A is RsO-or A' is R5O-, and the other of A and A1 is monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen. In another embodiment, certain compounds of formulae I-III are described that are diamides, wherein both A and A' are independently selected monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen.
In one aspect, A and/or A1 is monosubstituted amino of the formula XNH- or X1NH-, respectively, where X and X' are each independently selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyKCi -C4 alkyl), R6R7N-, and R6R7N-(C2-C4 alkyl), where each heterocyclyl is independently selected.
In another aspect, A and/or A1 is disubstituted amino of the formula R XN- or R14X1N-, respectively, where R14 and R14 are each independently selected from hydroxy, alkyl, alkoxycarbonyl, and benzyl; and X and X' are each independently selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C,-C4 alkyl), R6R7N-, and R6R7N-(C2-C4 alkyl), where each heterocyclyl is independently selected.
In another aspect, A and/or A1 is an independently selected optionally substituted nitrogen-containing heterocycle attached at a nitrogen. Illustrative nitrogen- containing heterocycles include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl; each of which is optinoally substituted. Such optional substitutions include the groups R , R12, R6R7N-, and R6R7N-(Ci-C4 alkyl) as defined herein. In one variation, A and/or A' is independently selected from pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-l-ylmethyl)pyrrolidin- 1-yl, or l,2,3,4-tetrahydroisoquinolin-2-yl, each of which is optionally substituted, and attached at a nitrogen.
In another aspect, A and/or A' is an independently selected optionally substituted piperidinyl attached at the nitrogen. Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including
(hydroxy(C2-C4 alkyloxy)>(C2-C4 alkyl), R6R7N-, R6R7N-alkyl, including R6R7N-(Ci-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), and piperidin-1 -yl(Ci-C4 alkyl). In one variation, A and/or A' is an independently selected piperidinyl substituted at the 4-position and attached at the nitrogen. In another aspect, A and/or A' is an independently selected optionally substituted piperazinyl attached at a nitrogen. Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C2-C4 alkyloxy)>(C2-C4 alkyl), R6R7N-, R6R7N-alkyl, including R6R7N-(Ci-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), and piperidin-l-yl(Ci-C4 alkyl). In one variation, A and/or A1 is an independently selected piperazinyl substituted at the 4-position and attached at a nitrogen.
In another aspect, A and/or A' is an independently selected optionally substituted homopiperazinyl attached at a nitrogen. Illustrative optional substitutions include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including
CiVdTOXy(C2-C4 alkyloxy)>(C2-C4 alkyl), R6R7N-, R6R7N-alkyl, including R6R7N-(C1-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), and piperidin-l-yl(Ci-C4 alkyl). In one variation, A and/or A' is an independently selected homopiperazinyl substituted at the 4-position and attached at a nitrogen, hi another variation, A and/or A' is an independently selected homopiperazinyl substituted at the 4-position with alkyl, aryl, aryl(Ci-C4 alkyl), and attached at a nitrogen.
In another embodiment, certain compounds of formulae I-III are described wherein A and/or A1 is a monosubstituted amino, and n is 1 or 2. hi another embodiment, compounds of formulae formulae I-Iϋ are described wherein A and/or A' is a disubstituted amino, and n is 1 or 2. In another embodiment, compounds of formulae I-III are described wherein A and/or A' is an optionally substituted nitrogen-containing heterocycle attached at a nitrogen, and n is 1 or 2. hi one variation of each of these embodiments, n is 0.
In another embodiment, certain compounds of formulae I-IV are described, wherein B is hydroxy, alkoxy, such as methoxy, and the like; and B' is hydrogen. In another embodiment, certain compounds of formulae I-IV are described, wherein B and B' are taken together with the attached carbon to form a carbonyl group or a derivative thereof. In one aspect, the carbonyl derivative is a ketal formed from an optionally substituted diol, such as ethylene glycol, propylene glycol, 1,2-propandiol, 2,3-butandiol, 2,4-pentandiol, and the like, hi one variation, the diol is of the formula a -O-(CH2)P-O-, which may be optionally substituted, where p is 2 or 3. hi another aspect, the carbonyl derivative is an imine formed from a primary amine; an oxime formed from hydroxylamine, or a substituted hydroxylamine; a hydrazone formed from hydrazine, or a substituted hydrazine, and the like. In another embodiment, certain compounds of formulae I-IV are described, wherein B' is hydrogen; and B is hydroxy, optionally substituted alkoxy, or optionally substituted acyloxy.
In another embodiment, certain compounds of formulae I- III are described, wherein A and/or A1 is piperidinyl attached at the nitrogen atom, and optionally substituted at the 4-position with hydroxy, alkyl, including Ci-Ce alkyl, cycloalkyl, including C3-C8 cycloalkyl, alkoxy, including C1-C4 alkoxy, alkoxycarbonyl, including (C1-C4 alkoxy)carbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C2-C4 alkyloxy)HC2-C4 alkyl), R6R7N-, R6R7N- alkyl, including R6R7N-(Ci-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), orpiperidin-l-yl(Ci-C4 alkyl).
In another embodiment, certain compounds of formulae I-IH are described, wherein A and/or A' is piperazinyl attached at a nitrogen atom, and optionally substituted at the 4-position with alkyl, including Ci-Ce alkyl, cycloalkyl, including C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, including optionally substituted aryl(Ci-C4 alkyl), α-methylbenzyl, and the like, N-alkyl acetamid-2-yl, including N-(Ci-Cs alkyl) acetamid-2-yl, N-(cycloalkyl) acetamid-2-yl, including N-(C3-Cs cycloalkyl) acetamid-2-yl, R6R7N-, or alkoxycarbonyl, including (C1-C4 alkoxy)carbonyl.
In another embodiment, certain compounds of formulae I-III are described, wherein A and/or A' is homopiperazinyl attached at a nitrogen atom, and optionally substituted in the 4-position with alkyl, including C1-C4 alkyl, aryl, or arylalkyl, including (C1-C4 alkyl).
In another embodiment, certain compounds of formulae I-III are described, wherein A and/or A1 is pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-l-ylmethyl)pyrrolidin-l-yl, or l,2,3,4-tetrahydroisoquinolin-2-yl, each of which is optionally substituted.
In another embodiment, certain compounds of formula V are described wherein A' is monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen- containing heterocycle attached at a nitrogen. In one variation, compounds of formula V are described wherein A' is an optionally substituted nitrogen-containing heterocycle attached at a nitrogen. In another embodiment, certain compounds of formula V are described wherein A1 is monosubstituted amino, and n is 1 or 2. In another embodiment, certain compounds of formula V are described wherein A' is disubstituted amino, and n is 1 or 2. In another embodiment, certain compounds of formula V are described wherein A1 is an optionally substituted nitrogen- containing heterocycle attached at a nitrogen, and n is 1 or 2. In one variation of each of these embodiments, n is 0. In another embodiment, certain compounds of formula V are described wherein A1 is piperidinyl optionally substituted at the 4-position with hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, R6R7N-, R6R7N-alkyl, including R6R7N-(C1-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), or piperidin- 1 -yl(C i -C4 alkyl).
In another embodiment, certain compounds of formula V are described wherein A' is piperazinyl optionally substituted at the 4-position with alkyl, cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, α-methylbenzyl, and the like, N- alkylacetamid-2-yl, including N-(C1-C5 alkyl)acetamid-2-yl, N-(cycloalkyl)acetamid-2-yl, including N-(C3-Cg cycloalkyl)acetamid-2-yl, R R N-, or alkoxycarbonyl, including (Ci-C4 alkoxy)carbonyl .
In another embodiment, certain compounds of formula V are described wherein A1 is homopiperazinyl optionally substituted in the 4-position with alkyl, aryl, or arylalkyl.
In another embodiment, certain compounds of formula V are described wherein A' is a heterocycle selected from pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-l- ylmethyl)pyrrolidin-l-yl, or l,2,3,4-tetrahydroisoquinolin-2-yl, and attached at a nitrogen atom.
It is to be understood that the various illustrative embodiments and aspects of the invention described herein may be combined in all possible ways to define additional embodiments and aspects. For example, in another embodiment, compounds of formulae I-iπ are described wherein R and R are both hydrogen; R is of the formula (F); n is 1 or 2; A is monosubstituted amino; and A' is an optionally substituted nitrogen-containing heterocycle attached at a nitrogen. In another illustrative embodiment, compounds of formulae I-iπ are described wherein R1 and R2 are both hydrogen; R3 is of the formula (F); n is 0; A is an optionally substituted nitrogen-containing heterocycle attached at a nitrogen; and A1 is monosubstituted amino. These and other particular selections for the groups recited in formulae I-V are contemplated herein.
The compounds described herein possess an azetidinone core structure that includes asymmetric carbon atoms at C(3) and C(4), creating four stereoisomeric configurations, as illustrated by the following formulae: ^
Figure imgf000024_0001
The compounds described herein may, therefore, exist as single diastereomers, as a racemic mixture, or as a mixture of various diastereomers. It is appreciated that in some applications, certain stereoisomers or mixtures of stereoisomers may be included in the various embodiments of the invention, while in other applications, other stereoisomers or mixtures of stereoisomers may be included. One illustrative mixture is a racemic mixture of two isomers that is substantially or completely free of any other diastereomers. In other applications a single stereoisomer may be included in the various embodiments of the invention, hi one aspect, certain chiral centers are stereochemical^ pure in the compounds described herein, such as for example a single enantiomer of the azetidinone core structure corresponding to the (35.4J?)- diastereomeric configuration is described, hi one variation, other chiral centers included in the compounds of this embodiment are epimeric, such that equal amounts of each stereoconfiguration are present, hi another variation, some or all other chiral centers in the compound are optically pure. It is also understood that the α-carbon bearing R1 is also chiral. Further, except when B and B' are the same, or when B and B' are taken together with the attached carbon to form a carbonyl group or derivative thereof, the β-carbon bearing B and B' is also chiral. Further, the radicals selected for groups such as R1, R2, R3, R4, A, A1, B, and B' may also include chiral centers. For example, when R3 is 4-substituted oxazolidin-2-on-3-yl, the 4- position of the oxazolidinone ring is asymmetric, hi addition, when R3 is 2,5-disubstituted oxazolidin-4-on-3-yl or 1 ,2,5-trisubstituted imidazolidin-4-on-3-yl, the 2- and 5-carbons of the imidazolidinone rings are each asymmetric. Finally, when R3 is succinimido and one of R10 and R11 is hydrogen, the carbon bearing the non-hydrogen substituent is also asymmetric. Therefore, it is to be understood that the formulae I, II, HI, IV, and V represent each single diastereomer, various racemic mixtures, and other mixtures of enantiomers and diastereomers collectively. While compounds possessing all combinations of stereochemical purity are contemplated by the present description, it is nonetheless appreciated that in many cases important biological activity, such as vasopressin antagonist activity may reside in a subset or all possible diastereomers, or in a single diasteromer. 61 one illustrative aspect, the compounds described herein have the (aR,3S,4R) absolute configuration or the (aS,3S,4R) absolute configuration. In another illustrative aspect, the compounds described herein have the (aR,βR,3S,4R) absolute configuration or the (aS,$R,3S,4R) absolute configuration. In another illustrative aspect, the compounds described herein have the (aR$S,3S,4R) absolute configuration or the (aSβS,3S,4R) absolute configuration.
Illustrative embodiments of the compounds described herein include compounds having the formulae I-IH where:
A is R5O-; A is R5O-, and R5 is Ci-C6 alkyl;
A is R5O-, and R5 is optionally substituted aryl(CrC4 alkyl);
A1 is R5O-;
A* is R5O-, and R5" is Ci -C6 alkyl ;
A' is R5O-, and Ry is optionally substituted aryl(C|-C4 alkyl); A is a monosubstituted amino of the formula XNH-;
A is a disubstituted amino having the formula R14XN-;
A' is a monosubstituted amino having the formula X1NH-;
A' is a disubstituted amino having the formula R14XN-;
A is XNH- or R14XN, and X is optionally substituted aryl(Cι-C4 alkyl); A is XNH- or R14XN, and X is R6R7N-(C1-C4 alkyl);
A is XNH- or R14XN-, X is optionally substituted aryl(Ci-C4 alkyl), and aryl is optionally substituted phenyl;
A is XNH- or R14XN, and X is R6R7N-(Ci-C4 alkyl), where R6 and R7 are taken together with the attached nitrogen atom to form a heterocycle; A is a nitrogen-containing heterocyclyl attached at a nitrogen atom;
A is a nitrogen-containing heterocyclyl optionally substituted with an optionally substituted aryl(Ci-C4 alkyl), heterocyclyl, or C3-C8 cycloalkyl, and attached at a nitrogen atom;
A1 is XNH- or R14XN-, and X is optionally substituted aryl(CrC4 alkyl);
A1 is XTSfH- or R14X1N-, and X1 is R6R7N-(Ci-C4 alkyl); A1 is X1NH- or R14X1N-, and X' is R61R7N-;
A1 is X1NH- or R14X1N-, X is R6R7N-, and R6 is Ci-C6 alkyl;
A1 is X1NH- or R14X1N-, X1 is R6R7N-, and R7 is C1-C6 alkyl;
A' is R14X1N-, and R14' is optionally substituted benzyl;
A' is X'NH- or R14X1N-, and X1 is a heterocyclyl; A1 is X1NH- or R1 X1N-, X is R6R7N-, and R6 and R7 are taken together with the attached nitrogen atom to form a heterocycle;
A is XNH- or R14XN-, X is R6R7N-, and R6 and R7 are the same and are CpC6 alkyl; A1 is X1NH- or R14X1N-, X is R6R7N-, and R6 and R7 are taken together with the attached nitrogen to form pyrrolidinyl, piperidinyl, piperazinyl; where said pyrrolidinyl, piperidinyl, or piperazinyl is optionally substituted with a heterocycle or with R6R7N-(CpC4 alkyl);
A1 is X1NH- or R141X1N-, X is R6R7N-, and R6 and R7 are taken together with the attached nitrogen to form piperidinyl optionally substituted at the 4-position with hydroxy, Cp C6 alkyl, C3-C8 cycloalkyl, CpC4 alkoxy, (CpC4 alkoxy)carbonyl, (hydroxy^-Q alkyloxy))- (CpC4 alkyl). R6R7N-, R6R7N-(CpC4 alkyl), phenyl, phenyl(CrC4 alkyl), optionally substituted phenyl(Ci -C4 alkyl), ftiryl(Ci-C4 alkyl), pyridinyKCi-Gt alkyl), thienyl(Ci-C4 alkyl), or piperidin-l-yl(CpC4 alkyl); A1 is X1NH- or R14X1N-, X is R6R7N-, and R6 and R7 are taken together with the attached nitrogen to form piperazinyl optionally substituted at the 4-position with Cj -Ce alkyl, C3-C8 cycloalkyl, optionally substituted phenyl, optionally substituted phenyl(Ci-C4 alkyl), N- (CpC5 alkyl) acetamid-2-yl, N-(C3-C8 cycloalkyl) acetamid-2-yl, R6R7N-, or (CpC4 alkoxy)carbonyl; and A1 is X1NH- or R14X1N-, X is R6R7N-, and R6 and R7 are taken together with the attached nitrogen to form homopiperazinyl optionally substituted in the 4-position with Ci-C4 alkyl, phenyl, or phenyl(CpC4 alkyl).
R1 is hydrogen;
R1 is CpC6 alkyl; R1 is C1-C2 alkyl;
R2 is hydrogen;
R2 is C1-C2 alkyl;
R2 is cyano;
R2 is formyl; R1 and R2 are both hydrogen;
R3 is 4-substituted oxazolidin-2-on-3-yl;
R3 is 4,5-disubstituted oxazolidin-2-on-3-yl;
R3 is 2-substituted oxazolidin-4-on-3-yl;
R3 is 2-substituted imidazolidin-4-on-3-yl; R3 is 1,2-disubstituted imidazolidin-4-on-3-yl;
R3 is 5-substituted imidazolidin-2-on-l-yl;
R3 is 4,5-disubstituted imidazolidin-4-on-l-yl;
R4 is optionally substituted 2-aryleth-l-yl;
R4 is optionally substituted 2-arylethen-l-yl;
It is appreciated that the classes of compounds described above maybe combined to form additional illustrative classes. An example of such a combination of classes may be a class of compounds wherein A is a monosubstituted amino having the formula XNH-, where X is optionally substitued aryl(Ci-C4 alkyl), and A1 is a disubstituted amino having the formula R14XTSf-, where R14 and X1 are taken together with the attached nitrogen atom to form an heterocycle, such as piperidine, piperazine, and the like. Further combinations of the classes of compounds described above are contemplated in the present invention.
In another illustrative embodiment of the invention, compounds of the formulae:
Figure imgf000027_0001
are described, where n, A', B, B\ R1, and R2 are as described above. It is understood that, except when B and B1 form a symmetrical ketal or are taken together with the attached carbon to form a carbonyl group, the above formulae each represent 32 different stereoisomer^ configurations. It is appreciated that certain stereoisomers may be more biologically active than others. Therefore, the above formulae, and other formulae described herein, are intended to represent each of the possible stereoisomers, as well as various mixtures of each stereoisomer, collectively. Illustratively, the following pair of diastereomers:
Figure imgf000027_0002
is described, where the sterochemistry at the "α" carbon is either (R) or (S). It is appreciated that similar diastereomeric pairs may be contemplated from the formulae described herein. In one aspect, the group A1 includes, but is not limited to 2-(piperidin-l- yl)ethylamino, 4-(piperidin-l-yl)piperidin-l-yl, 4-(phenylethyl)piperazin-l-yl, fiir-2- yimethylamino, 4-(pyτrolidin-l-yl)piperazin-l-yl, 4-(3-trifluoromethylphenyl)piperazin-l-yl, 4- (benzyloxycarbonyl)piperazin- 1 -yl , 4-[2 -(2-hydroxyethoxy)ethyl]piperazin -1 -yl, 4- benzylpiperazin- 1 -yl, 4-(3,4-methylenedioxybenzyl)piperazin- 1 -yl, 4-phenylpiperazin- 1 -yl, 4- (3-phenylprop-2-enyl)piperazin-l-yl, 4-ethylpiperazin-l-yl, 2-(dimethylamino)ethylamino, 4- (pyrrolidin- 1 -ylcarbonylmethyl)piperazin- 1 -yl, 4-( 1 -methylpiperidin-4-yl)piperazin- 1 -yl, 4- butylpiperazin-l-yl,4-isopropylpiperazin-l-yl, 4-pyridylmethylamino, 3- (dimethylamino)propylamino, l-benzylpiperidin-4-ylamino, N-benzyl-2- (dimethylamino)ethylamino , 3-pyridylmethylamino, 4-(cyclohexyl)piperazin- 1 -yl, 4-(2- cyclohexylethyl)piperazin- 1 -yl, 4-[2-(morpholin-4-yl)ethyl]piperazin- 1 -yl, 4-(4-/ert- butylbenzyl)piperazin-l-yl, 4-[2-(piperidin-l-yl)ethyl]piperazin-l-yl, 4-[3-(piperidin-l- yl)propyl]piperazin-l-yl, 4-[2-(fcLM-dipropylamino)ethyl]piperazin-l-yl, 4-[3-(N.N- diethylamino)propyl]piperazin-l-yl,4-[2-(dimethylamino)ethyl]piperazin-l-yl, 4-[3-(pyτrolidin- 1 -yl)piopyl]piperazin- 1 -yl, 4-(cyclohexylmethyl)piperazin- 1 -yl, 4-cyclopentylpiperazin- 1 -yl, 4- [2-(pyrrolidin-l-yl)ethyl]piperazin-l-yl, 4-[2-(thien-2-yl)ethyl]piperazin-l-yl, 4-(3- phenylpropyl)piperazin- 1 -yl, 4-[2-(fcJ,N-diethylammo)ethyl]piperazin- 1 -yl, 4- benzylhomopiperazin- 1 -yl, 4-(bisphenylmethyl)piperazin-l -yl, 3-(4-methylpiperazin- 1 - yl)propylamino, (+)-3(5}-l-benzylpyrrolidin-3-ylamino, 2-pyridylmethylamino, and 4-[2- (piperidin-l-yl)ethyl]piperidin-l-yl.
In another aspect, the integer n is either 0, or n is 1 or 2, and the group A' includes, but is not limited to 2-(piperidin-l-yl)ethylamino, 4-(piperidin-l-yl)piperidin-l-yl, 2- (pyrid-2-yl)ethylamino, morpholin-4-ylamino, 4-(pyrrolidin-l-yl)piperazin-l-yl, 4-(3- trifluorophenyl)piperazin-l-yl, 4-(benzyloxycarbonyl)piperazin-l-yl, 4-[2-(2- hydroxylethoxy)ethyl]piperazin-l-yl, 4-benzylpiperazin-l-yl, 4-(3,4- methylenedioxybenzyl)piperazin- 1 -yl , 4-phenylpiperazin- 1 -yl, 4-(3 -phenylprop-2- enyl)piperazin-l-yl, 4-ethylpiperazin-l-yl, 2-(dimethylamino)ethylamino, 4-(pyrrolidin-l- ylcarbonylmethyl)piperazin- 1 -yl, 4-(l -methylpiperidin-4-yl)piperazin- 1 -yl, 4-butylpiperazin- 1 - yl, 4-isopropylpiperazin-l-yl, 4-pyridylmethylamino, 3-(dimethylamino)propylamino, 1- benzylpiperidin-4-ylamino, N-benzyl-2-(dimethylamino)ethylamino, 3-pyridylmethylamino, 4- cyclohexylpiperazin- 1 -yl, 4-(2-cyclohexylethyl)piperazin- 1 -yl, 4-[2-(moφholin-4- yl)ethyl]piperazin-l -yl, 4-(4-terf-butylbenzyl)piperazin-l -yl, 4-[2-(piperidin-l- yl)ethyl]piperazin-l-yl, 4-[3-(piρeridin-l-yl)proρyl]piperazin-l-yl, 4-[2- (diisopropylamino)ethyl]piperazin- 1 -yl, 4-[3-(diethylamino)propyl]piperazin- 1 -yl, 4-(2- dimethylaminoethyl)piperazm- 1 -yl, 4-[3-(pyrrolidin- 1 -yl)propyl]piperazin- 1 -yl, 4- (cyclohexylmethyl)piperazin- 1 -yl, 4-[2 -(piperidin- 1 -yl)ethyl]piperidin- 1 -yl, 4-propyl-piperazin- 1-yl, 4-[N-(isopropyl)acetamid-2-yl]piperazin-l-yl, and 3-benzyl-hexahydro-(lH)-l,3-diazepin- 1-yl.
In one aspect, the group A' includes, but is not limited to benzylamino, (2- methylbenzyl)amino, (3-methylbenzyl)amino, (4-methylbenzyl)amino, (α-methylbenzyl)amino, H-benzyl-N-methylamino, N-benzyl-N-(/-butyl)amino, N-benzyl-N-butylamino, (3,5- dimethylbenzyl)amino, (2-phenylethyl)amino, dimethylamino, (3- trifluoromethoxybenzyl)amino, (3,4-dichlorobenzyl)amino, (3,5-dichlotobenzyl)amino, (2,5- dichlorobenzyl)amino, (2,3 -dichlorobenzyl)amino, (2-fluoro-5-trifluoromethylbenzyl)amino, (4-fluoro-3-trifluoromethylbenzyl)amino, (3-fluoro-5-trif1uoromethylben2yl)amino, (2-fluoro- 3-trifluorornethylbenzyl)amino, (4-chloro-3-trifluoromethylbenzyl)amino, indan-1-ylamino, 4- (2-hydroxybenzimidazol- 1 -yl)-piperidin- 1 -yl, 3(S)-(ter/-butylarninocarbonyl)- 1 ,2,3,4- tetrahydroisoquinolin-2-yl, (3,3-dimethylbutyl)amino, 4-hydroxy-4-phenylpiperidin- 1 -yl, (cyclohexylmeithyl)amino, (2-phenoxyethyl)amino, 3,4-methylenedioxybenzylamino, 4- benzylpiperidin-1-yl, and (3-trifluoromethylphenyl)amino.
In one varaition, the group A' is selcted from 4-cyclohexylpiperazin-l-yl, 4- (pyrrolidin-l-yl)piperazin-l-yl, 4-ethylpiperazin-l-yl, 4-n-butylpiperazin-l-yl, and 4- isopropylpipeτazin-1-yl. In another variation, the group A' is selected from 3-trifluoromethylbenzylamino, morpholin-4-ylamino, 2-(dimethylamino)ethylamino, 3- (dimethylamino)propylamino, cyclohexylamino, piperidin- 1-yl, 2-methoxyethylamino, isopropylamino, isobutylamino, ethylamino, dimethylamino, and methylamino.
In another illustrative embodiment of the invention, compounds of the formula:
Figure imgf000029_0001
are described, where n, B, B1, R1, and R2 are as described above; and W is either carbon or ntrogen, each optionally substituted with a carbocyclyl or carbocyclylalkyl substituent, such as cyclopentyl, cyclohexyl, cyclohexylethyl, and the like, an heterocyclyl or heterocyclylalkyl substituent, such as pyrrolidinyl, piperidinyl, piperidinylethyl, and the like, or an aryl or arylalkyl substituent such as benzyl, phenethyl, and the like. In one variation, the sterochemistry at the "α" carbon is (R); in another variation, the sterochemistry at the "α" carbon is (S). In one aspect, when n is 0, W as defined above is a carbon atom substituted with piperidin-l-yl. In one aspect, when n is 1, W as defined above is a carbon atom substituted with piperidin-l-yl. In another aspect, when n is 2, W as defined above is a nitrogen atom substituted with cyclohexyl. The following compounds:
Figure imgf000030_0001
are illustrative of this embodiment. It is to be understood that other diastereomers and mixtures of diastereomers of these formulae are contemplated herein.
In one variation of the above formulae, R1 is hydrogen. In another variation of the above formulae, R1 is alkyl, such as methyl. In another variation of the above formulae, R2 is selected from alkyl such as methyl, haloalkyl such as trifluoromethyl, alkylthio such as methylthio, alkoxy such as methoxy, cyano, halo such as fluoro, and acyl such as formyl. In another variation of the above formulae, the group A1 is selected from optionally substituted 4- piperidin-1-ylpiperidinyl, optionally substituted 4-arylalkylpiperazinyl, and optionally substituted 4-cycloalkylpiperazinyl.
In another illustrative embodiment of the invention, compounds having the formula:
Figure imgf000031_0001
are described, where n, A', B,'C, R1, and R2 are as described above. It is understood that, except when B and B' form a symmetrical ketal are taken together with the attached carbon to form a carbonyl group, the above formula represents 64 different stereoisomers configurations. It is appreciated that certain stereoisomers may be more biologically active than others. Therefore, the above formula contemplates herein all possible stereoisomers, as well as various mixtures of each stereoisomer. Illustratively, the following pair of enantiomers:
Figure imgf000031_0002
is described, where the sterochemistry at the "α" carbon is either (R) or (JS). In another illustrative embodiment of the invention, compounds of the formula:
Figure imgf000031_0003
are described, where n, B, B1, R , 1 , R r»2 , and W are as described above. The following compounds:
Figure imgf000032_0001
are illustrative of this embodiment, where R2 is methyl, methoxy, methylthio, trifluoromethyl, cyano, or fluoro.
In another illustrative embodiment of the invention, compounds having the following formula:
Figure imgf000032_0002
are described, where n, A, B, B1, R1, and R2 are as described above. It is understood that as described above, each of the 32 different stereoisomeric configurations are individually and collectively represented by the formulae. In one aspect, the group A includes, but is not limited to (3- trifluoromethoxybenzyl)amino, (3,4-dichlorobenzyl)amino, (3,5-dichlorobenzyl)amino, (2,5- dichlorobenzyl)amino, (2,3-dichlorobenzyl)amino, ^-fluoro-S-trifluoromethylbenzyOamino, (4-fluoro-3-tτifluoromethylbenzyl)amino, (3 -fluoro-5-trifluoromethylbenzyl)amino, (2-fluoro- 3-trifluoromethylbenzyl)amino, (4-chloro-3-trifluoromethylbenzyl)amino, (2- trifluoromethylbenzyl)amino, (3-methoxybenzyl)amino, (3-fluorobenzyl)amino, (3,5- difluorobenzyl)amino, (3-chloro-4-fluorobenzyl)amino, (3-chlorobenzyl)amino, [3,5- bis(trifluoromethyl)benzyl]amino, (3-nitrobenzyl)amino, (3-bromobenzyl)amino, benzylamino, (2-methylbenzyl)amino, (3-methylbenzyl)amino, (4-methylbenzyl)amino, (α- methylbenzyl)amino, (M-methylbenzyl)amino, (M-*erf-butylbenzyl)amino, (M- butylbenzyl)amino, (3,5-dimethylbenzyl)amino, (2-phenylethyl)amino, (3,5- dimethoxybenzyl)amino, (lR)-(3-methoxyphenyl)ethylamino, (lS)-(3- methoxyphenyl)ethylammo, (α,α-dimethylbenzyl)amino, N-methyl-N-(3- trifluoromethylbenzyl)amino, [(S)-α-methylbenzyl]amino, (l-phenylcycloprop-lyl)amino, (pyridin-2-ylmethyl)amino, (pyridin-3-ylmethyl)amino, (pyridin-4-ylmethyl)amino, (fur-2- ylmethyl)amino, [(5-methylfur-2-yl)methyl]amino, (thien-2-ylmethyl)amino, [(S)- 1,2,3 ,4- tetrahydro- 1 -naphth- 1 -yl]amino, [(R) -1 ,2,3 ,4-tetrahydro- 1 -naphth- 1 -yl]amino, (indan- 1 - yl)amino, (l-phenylcyclopent-l-yl)amino, (α,α-dimethyl-3,5-dimethoxybenzyl)amino, (2,5- dimethoxybenzyl)amino, (2-methoxybenzyl)amino, and (α,α,2-trimethylbenzyl)amino. In one aspect, the group A includes, but is not limited to 2-(piperidin-l - yl)ethylamino, 4-(piperidin-l-yl)piperidin-l-yl, 4-(phenylethyl)piperazin-l-yl, fur-2- ylmethylamino, 4-(pyrrolidin-l-yl)piperazin-l-yl, 4-(3-trifluoromethylphenyl)piperazin-l-yl, 4- (benzyloxycarbonyl)piperazin- 1 -yl, 4-[2 -(2-hydroxyethoxy)ethyl]piperazin -1 -yl, 4- benzylpiperazin-1-yl, 4-(3,4-methylenedioxybenzyl)piperazin-l-yl, 4-phenylpiperazin-l-yl, 4- (3-phenylprop-2-enyl)piperazin- 1 -yl, 4-ethylpiperazin- 1 -yl, 2-(dimethylamino)ethylamino, 4- (pyrrolidin- 1 -ylcarbonylmethy^piperazin- 1 -yl, 4-( 1 -τnethylpiperidin-4-yl)piperazin- 1 -yl , 4- butylpiperazin-l-yl,4-isopropylpiperazin-l-yl, 4-pyridylmethylamino, 3- (dimethylamino)propylamino, l-benzylpiperidin-4-ylamino, N-benzyl-2- (dimethylamino)ethylamino, 3-pyridylmethylamino, 4-(cyclohexyl)piperazin-l-yl, 4-(2- cyclohexylethyl)piperazin-l-yl, 4-[2-(morpholin-4-yl)ethyl]piperazin-l-yl, 4-(4-tert- butylbenzyl)piperazin- 1 -yl, 4-[2-(piperidin- 1 -yl)ethyl]piperazin- 1 -yl, 4-[3-(piperidin- 1 - yl)propyl]piperazin- 1 -yl, 4-[2-(N,N-dipropylamino)ethyl]piperazin- 1 -yl, 4-[3-(N,N- diethylamino)propyl]piperazin- 1 -yl,4-[2-(dimethylamino)ethyl]piperazin- 1 -yl, 4-[3-(pyrrolidin- l-yl)propyl]piperazin-l-yl, 4-(cyclohexylmethyl)piperazin-l-yl, 4-cyclopentylpiperazin-l-yl, 4- [2-(pyrrolidin- 1 -yl)ethyl]piperazin- 1 -yl, 4-[2-(thien-2-yl)ethyl]piperazin- 1 -yl, 4-(3- phenylpropyl)piperazin- 1 -yl, 4-[2-(&N.-diethylamino)ethyl]piperazin- 1 -yl, 4- benzylhomopiperazin- 1 -yl, 4-(bisphenylmethyl)piperazin-l -yl, 3-(4-methylpiperazin- 1 - yl)propylamino, (+)-3(5)-l-benzylpyirolidin-3-ylamino, 2-pyridylmethylamino, and 4-[2- (piperidin-l-yl)ethyl]piperidin-l-yl.
In another aspect, the integer n is 0, or the the integer n is 1 or 2, and the group A includes, but is not limited to 2-(piperidin-l-yl)ethylamino, 4-(piperidin-l-yl)piperidin-l-yl, 2-(pyrid-2-yl)ethylamino, morpholin-4-ylamino, 4-(pyrrolidin-l-yl)piperazin-l-yl, 4-(3- trifluorophenyl)piperazin- 1 -yl, 4-(benzyloxycarbonyl)piperazin- 1 -yl, 4-[2-(2- hydroxylethoxy)ethyl]piperazin-l-yl, 4-benzylpiperazin-l-yl, 4-(3,4- methylenedioxybenzyl)piperazin- 1 -yl, 4-phenylpiperazin- 1 -yl, 4-(3-phenylprop-2- enyl)piperazin-l-yl, 4-ethylpiperazin-l-yl, 2-(dimethylamino)ethylamino, 4-(pyrrolidin-l- ylcarbonylmethyl)piperazin- 1 -yl, 4-( 1 -methylpiperidin-4-yI)piperazin- 1 -yl, 4-butylpiperazin- 1 - yl, 4-isopropylpiperazin-l-yl, 4-pyridylmethylamino, 3-(dimethylamino)propylamino, 1- benzylpiperidin-4-ylamino, N-benzyl-2-(dimethylamino)ethylamino, 3-pyridylmethylamino, 4- cyclohexylpiperazin- 1 -yl, 4-(2-cyclohexylethyl)piperazin- 1 -yl, 4-[2-(morpholin-4- yl)ethyl]piperazin- 1 -yl, 4-(4-terf-butylbenzyl)piperazin- 1 -yl, 4-[2-(piperidin- 1 - yl)ethyl]piperazin- 1 -yl, 4-[3-(piperidin- 1 -yl)propyl]piperazin- 1 -yl, 4-[2- (diisopropylamino)ethyl]piperazin- 1 -yl, 4-[3-(diethylamino)propyl]piperazin- 1 -yl, 4-(2- dimethylaminoethyl)piperazin- 1 -yl, 4-[3-(pyrrolidin- 1 -yl)propyl]piperazin- 1 -yl, 4-
(cyclohexylmethyl)piperazin- 1 -yl, 4-[2 -(piperidin- 1 -yl)ethyl]piperidin- 1 -yl, 4-propyl-piperazin- 1-yl, 4~[N-(isopropyl)acetaraid-2-yl]piperazin-l-yl, and 3-benzyl-hexahydro-{lH)-l,3-diazepm- 1-yl.
In another illustrative embodiment of the invention, the compounds described herein include a basic amino group. Such amines are capable of forming salts with a variety of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. It is appreciated that in cases where compounds of the formulae described herein are oils rather than solids, those compounds capable of forming addition salts that are solid will ease the handling and administration of the compounds described herein. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, sυberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid, trifluoroacetic acid, maleic acid or fumaric acid. Generally, the 2-(azetidinon-l-yl)-3-(hydroxy)-substituted and 2-(azetidinon-l- yl)-3-(keto)-substituted alkanedioic acid esters and amides of formulae I, H, III, and FV, and the analogs and derivatives thereof described herein, maybe prepared by syntheses known in the art, as well as by the new methods described herein. As illustrated for compounds of formula I, the 2-(azetidinon-l-yl)alkanedioic acid esters described herein are obtainable by the 2+2 cycloaddition of an appropriately substituted acetic acid derivative (i), and an imine ester (ii) upon treatment with a base in an appropriately selected solvent, as described in Synthetic Scheme I, where Z is a leaving group, and the integer n, and the moieties A, A', B, C, R1, R2, R3, and R4 are as previously described. The term "leaving group" as used hereinafter refers to a subsitutent, such as halo, acyloxy, benzoyloxy and the like, present on an activated carbon atom that may be replaced by a nucleophile. The chemistry described in Synthetic Scheme I is applicable to imines (ii) bearing ester, thioester, or amide moieties.
Synthetic Scheme I
Figure imgf000035_0001
The preparation of the appropriate imines (ii), preparation of representative examples of the required acetyl halides or anhydrides (i), and the cycloaddition procedure, are generally described in U.S. Patent Nos. 4,665,171 and 4,751,299, the disclosures of which are hereby incorporated by reference. The analogous synthesis of compounds of formulae H, III, and IV may be accomplished by this process using the appropriate alkoxy-βubstituted amino acid imines.
In one illustrative variation, R3 is a 4-substituted oxazolidin-2-on-3-yl or 1,4,5- trisubstituted imidazolidin-2-on-3-yl. Those compounds of formulae I, π, HI, and IV requiring R3 to be a 4-substituted oxazolidin-2-on-3-yl or 1 ,4,5-trisubstituted imidazolidin-2-on-3-yl are prepared from the corresponding (4-substituted oxazolidin-2-on-3-yl) or (1,4,5-trisubstituted imidazolidin-2-on-3-yl)acetyl halide or anhydride. The acid halide or anhydride is available from an appropriately substituted glycine. The glycine is first converted to the carbamate and then reduced to provide the corresponding alcohol. The alcohol is then cyclized to the 4-substituted oxazolidin-2-one, which is subsequently N-alkylated with a haloacetic acid ester. The ester is hydrolyzed, and the resulting acid is converted to the acetyl halide or anhydride (i). Illustrative of the oxazolidinones that are included in this synthetic route, and subesequent synthetic routes described herein, include the following commercially available compounds:
Figure imgf000036_0001
Figure imgf000036_0003
Figure imgf000036_0002
Illustrative of the imidazolidinones and imidazolidindiones that are included in this synthetic route, and subsequent synthetic routes described herein, include the following commercially available compounds:
Figure imgf000037_0001
Figure imgf000037_0003
Figure imgf000037_0004
Figure imgf000037_0002
Figure imgf000037_0005
In another illustrative variation, R is a 2,5-disubstituted oxazolidin-4-on-3-yl or
1,2,5-trisubstituted imidazolidin-4-on-3-yl. Those compounds of formulae I, II, ID, and IV requiring R3 to be 2,5-disubstituted oxazolidin-4-on-3-yl or 1,2,5-trisubstituted imidazolidin-4- on-3-yl are prepared from the corresponding (2,5-disubstituted oxazolidin-4-on-3-yl) or (1,2,5- trisubstituted imidazolidin-4-on-3-yl)acetyl chlorides or anhydrides respectively. The chemistry to prepare these reagents is described in U.S. Patent No. 4,772,694, hereby incorporated by reference. Briefly, the required oxazolidinone or imidazolidinone is obtained from an α-hydroxyacid or an α-aminoacid, respectively. The imidazolones are prepared by converting the α-aminoacid, (R1^-CH(NH2)CO2H, to an amino-protected amide and then condensing the amide with an aldehyde, (RIO)-CHO, in the presence of an acid to form the 3- protected imidazolidin-4-one, where R10 and R1 ' are as defined above. The 1 -position may be functionalized with an appropriate reagent to introduce R12 and the 3-position deprotected, where R is as defined above. The imidazolidin-4-one ring is then alkylated with a haloacetic acid ester, the ester deesterified, and the resulting acetic acid converted to the desired acid halide or anhydride (i). The required oxazolidinones are prepared in an analogous manner from the corresponding α-hydroxyacid, (R1 ^-CH(OH)CO2H.
In another illustrative variation, R3 is succinimido. Those compounds of formulae I, π, ID, and IV requiring R3 to be succinimido are prepared from the corresponding 2-(succinimido)acetyl halide or anhydride. The chemistry to prepare these reagents is described in U.S. Patent No. 4,734,498, hereby incorporated by reference. Briefly, these reagents are obtained from tartaric acid or, when one of R10 and R1 ' is hydrogen, from malic acid. Tartaric acid is acylated or O-alkylated, the corresponding diacyl or di-O-alkyl tartaric acid is treated with an acid anhydride to form the succinic anhydride, and reaction of this succinic anhydride with an ester of glycine to form first the noncyclic half amide ester which is then cyclized to the 3,4-disubstituted succinimidoacetic acid ester. The ester group is deesterifϊed and the resulting acid converted to the corresponding acid halide or anhydride (i). The mono-substituted succinimidoacetyl halide or anhydride is obtained with malic acid via succinic anhydride formation followed by succinimide formation as described above. In another illustrative variation, R3 is an N-substituted amine or an N'- substituted urea. Those compounds of formulae I, II, DI7 and IV requiring R3 to be an N- substituted amine or an N'-substituted urea may be prepared from the corresponding phthalimido protected 3-amino analogs. The phthalimide protecting group may be removed using conventional procedures, such as by treatment with hydrazine, and the like. Once liberated, the amine may be alkylated with any one of a variety of alkyl and cycloalkyl halides and sulfates, such as methyl iodide, isopropylbromide, diethyl sulfate, cyclopropylmethylbromide, cyclopentyliodide, and the like. Such amines may also be acylated with acid halides, acid anhydrides, isocyanates, isothiocyanates, such as acetyl chloride, propionic anhydride, methylisocyanate, 3-trifluoromethylphenylisothiocyanate, and the like. The bases to be used in Synthetic Scheme I include, among others, aliphatic tertiary amines, such as trimethylamine and triethylamine, cyclic tertiary amines, such as N- methylpiperidine and N-methylmorpholine, aromatic amines, such as pyridine and lutidine, and other organic bases such as l,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
The solvents useful for reactions described in Synthetic Scheme I include, among others, dioxane, tetrahydrofuran, diethyl ether, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, acetonitrile, dimethyl sulfoxide and N,N- dimethylformamide.
Alternatively, the compounds of formulae I, II, III, and IV may be prepared via N-C(4) cyclization, as illustrated for compounds of formula I in Synthetic Scheme II, via cyclization of β-hydroxy amides iii, where n, A, A', B, C, R1, R2, R3, and R4 are as defined previously, according to the procedure of Townsend and Nguyen in /. Am. Chem. Soc. 1981, 103, 4582, and Miller and Mattingly in Tetra. 1983, 39, 2563, the disclosures of which are incorporated herein by reference. The analogous synthesis of compounds of formulae F-, III, and IV may be accomplished by cyclizatoin of β-hydroxy amides of alkoxy-substituted amino acids.
Synthetic Scheme II
Figure imgf000039_0001
The azetidinone ring may also be prepared with a deficit of substituents R2, R3, R4, or the R '-substituted N-alkanedioic acid or alkoxyalkanoic acid moiety, but possessing substituents capable of being elaborated through subsequent chemical transformation to such groups described for compounds of formulae 1,H, in, and IV. In general, azetidinones may be prepared via N-C(4) cyclization, such as the cyclization of acylhydroxamates iv to azetidinone intermediates v, as depicted in Synthetic Scheme IH, where n, A, A', B, C, R1, R2, R3, and R4 are as defined above, according to the procedure of Mattingly et al. \nJ. Am. Chem. Soc. 1979, 101, 3983 and Accts. Chem. Res. 1986, 19, 49, the disclosures of which are incorporated herein by reference. It is appreciated that other hydroxamates, such as alkylhydroxamates, aryl hydroxamates, and the like, are suitable for carrying out the cyclization.
Synthetic Scheme ID
Figure imgf000039_0002
w v
Subsequent chemical transformation of the acyloxyazetidinone v to introduce for example an R1 -substituted alkanedioic acid moiety using conventional procedures will illustratively provide compounds of formula I. The analogous synthesis of compounds of formulae II, III, and IV may be accomplished by this process using an appropriate R'-substituted alkoxyalkanoic acid.
An alternative cyclization to form intermediate azetidinones, which may be further elaborated to compounds of formulae I, II, III, and FV may occur by oxidative cyclization of acylhydroxamates vi to intermediate azetidinones vii, as illustrated in Synthetic Scheme IV, where R2 and R3 are as defined above and L is a leaving group such as halide, according to the procedure of Rajendra and Miller in J. Org. Chem. 1987, 52, 447 '1 and Tetrahedron Lett. 1985, 26, 5385, the disclosures of which are incorporated herein by reference. The group R in Scheme IV represents an alkyl or aryl moiety selected to provide R4, as defined above, upon subsequent transformation. For example, R may be the group ArCH2- where Ar is an optionally substituted aryl group, as in vii-a, such that oxidative elimination of HBr will provide the desired R4, such as a styryl group, as in vii-b. It is appreciated that elaboration of R to R4 is not necessarily performed immediately subsequent to the cyclization and may be performed conveniently after other steps in the synthesis of compounds of formulae I, π, IH, and IV. It is further appreciated that alternatives to the acylhydroxamates shown, such as alkylhydroxamates, aryl hydroxamates, and the like, are suitable for carrying out the cyclization.
Synthetic Scheme IV
Figure imgf000040_0001
vii-a va Other useful intermediates, such as the azetidinone-4-carboxaldehyde viii illustrated in Synthetic Scheme V for preparing compounds of formulae I, π, III or IV may be further elaborated to 4-(R4)-substituted azetidinones via an olefination reaction. The groups R1, R2, and R3 are as defined above, and the group R in Scheme V is selected such that upon successful olefination of the carboxaldehyde the resulting group R-CHCH- corresponds to the desired alkyl or aryl moiety R4, as defined above. Such olefination reactions may be accomplished by any of the variety of known procedures, such as by Wittig olefination, Peterson olefination, and the like. Synthetic Scheme V illustrates the corresponding Wittig olefination with phosphorane ix. The analogous synthesis of compounds of formulae II, IQ, and IV may be accomplished by this process using an appropriate alkoxy-substituted azetidinone-4-carboxaldehyde derivative .
Synthetic Scheme V
Figure imgf000041_0001
viii ix
Still other useful intermediates, such as the azetidinonyl acetic acid derivatives x, may be converted into compounds of formulae I, π, III, and IV as illustrated for the synthesis of compounds of formula I in Synthetic Scheme VI, where n, A, A', B, C, R1 , R2, R3, R4, and n are as defined above. Introduction of the R1 moiety, and a carboxylic acid derivative A'-C(O)-(CH2)n- for compounds of formula I, may be accomplished by alkylation of the anion ofx.
Synthetic Scheme VI
Figure imgf000041_0002
xt-b Acetic acid derivative x is deprotonated and subsequently alkylated with an alkyl halide corresponding to R '-Z, where Z is a leaving group, to provide intermediate xi-a. Illustratively, the anion of xi-a may be alkylated with a compound ZI-C(O)-(CH2)nCOAl, where Z' is a leaving group, to provide compounds of formula I1 where B and C are taken together with the attached carbon to form a carbonyl group.
Alternatively, acetic acid derivative x is deprotonated and subsequently alkylated with a compound Z'-C(O)-(CH2)nCOA', where Z1 is a leaving group, to provide intermediate xi-b, where B and C are taken together with the attached carbon to form a carbonyl group. Illustratively, the anion of xi-b may be alkylated with an alkyl halide corresponding to R'-Z, where Z is a leaving group, to provide compounds of formula I. It is appreciated that the order of introduction of either the substituent R1 or the acid derivative - C(O)-(CH2)nCOA', may be dictated by steric or electronic considerations, synthetic convenience, or the availability of certain starting materials, and such order of introduction may be different for each compound of formulae I, II, III or IV. A solution of the 2-(3,4-disubstituted azetidin-2-on-l-yl)acetic acid derivative x or xi in an appropriate solvent, such as tetrahydrofuran, dioxane, or diethyl ether, is treated with a non-nucleophilic base to generate the anion of x or xi, respectively. Suitable bases for this transformation include lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidinamide, or lithium bis(trimethylsilyl)amide. The anion is then reacted with an appropriate electrophile to provide the desired compounds. Illustrative electrophiles represented by the formulae R'-Z, R5XN-C(O)-(CH2)H-C(O)Z', or R6O-C(OHCH2)n-C(O)-Z' provide the corresponding compounds xi or I, respectively. The analogous synthesis of compounds of formulae π, HI, and IV may be accomplished by this process by using the appropriate electrophile.
As discussed above, the compounds prepared as described in Synthetic Schemes I, π, III, IV, V, and VI may be pure diastereomers, mixtures of diastereomers, or racemates. The actual stereochemical composition of the compound will be dictated by the specific reaction conditions, combination of substituents, and stereochemistry or optical activity of the reactants employed. It is appreciated that diasteromeric mixtures may be separated by chromatography or fractional crystallization to provide single diastereomers if desired, using standard methods. Particularly, the reactions described in Synthetic Schemes ID, IV, and VI create a new chiral center at the carbon bearing R1.
Compounds of formula I which are 2-(3,4-disubstituted azetidin-2-on-l- yl)alkanedioic acid half-esters, such as compounds I-a where A' is R6 O-, while useful vasopressin V Ia agents in their own right, may also be converted to the corresponding half- carboxylic acids xii, where the integer n and the groups B, C, R1, R2, R3, R4, R5, R6 , A, and X1 are as previously defined, as illustrated in Synthetic Scheme VII. These intermediates are useful for the preparation of other compounds of the invention, such as I-b where A' is R5XN-. It is appreciated that the transformation illustrated in Synthetic Scheme VII is equally applicable for the preparation of compounds I where A1 is X1NH- or where a different R6O- is desired.
Synthetic Scheme VII
Figure imgf000043_0001
The requisite carboxylic acid xii may be prepared from the corresponding ester via saponification under standard conditions by treatment with hydroxide followed by protonation of the resultant carboxylate anion. Where R6 is tert-butyl, the ester I-a may be dealkylated by treatment with trifluoroacetic acid. Where R6 is benzyl, the ester I-a may be dealkylated either by subjection to mild hydrogenolysis conditions, or by reaction with elemental sodium or lithium in liquid ammonia. Finally, where R6' is 2-(trimethylsilyl)ethyl, the ester I-a may be deprotected and converted into the corresponding acid xii by treatment with a source of fluoride ion, such as tetrabutylammonium fluoride. The choice of conditions is dependent upon the nature of the R6 moiety and the compatability of other functionality in the molecule with the reaction conditions.
The carboxylic acid xii is converted to the corresponding amide I-b under standard conditions. The acid may be first converted to the corresponding acid halide, preferably the chloride or fluoride, followed by treatment with an appropriate primary or secondary amine to provide the corresponding amide. Alternatively, the acid may be converted under standard conditions to a mixed anhydride. This is typically accomplished by first treating the carboxylic acid with an amine, such as triethylamine, to provide the corresponding carboxylate anion. This carboxylate is then reacted with a suitable haloformate, for example benzyl chloroformate, ethyl chloroformate or isobutylchloroformate, to provide the corresponding mixed anhydride. This anhydride may then be treated with an appropriate primary or secondary amine to provide the desired amide. Finally, the carboxylic acid may be treated with a typical peptide coupling reagent such as N,N'-carbonyldiimidazole (CDI), N.N'-dicyclohexylcarbodiimide (DCC) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), followed by the appropriate amine of formula R5XNH. A polymer- supported form of EDC has been described in Tetrahedron Letters, 34(48):7685 (1993), the disclosure of which is incorporated herein by reference, and is useful for the preparation of the compounds of the present invention. It is appreciated that substituting an appropriate amine with an appropriate alcohol in the synthethic scheme presented above will provide the esters of the invention, e.g. analogs of I-a with a different ester R6O-. The carboxylic acid may alternatively be converted into the corresponding tert- butyl ester via treatment of the acid with an acid catalyst, such as concentrated sulfuric acid, and the like, and with isobutylene in a suitable solvent, such as dioxane, and the like. The reaction is preferably carried out under pressure in an appropriate vessel, such as a pressure bottle, and the like. Reaction times of about 18 hours are not uncommon. The desired ester may be be isolated from the organic layer after partitioning the reaction mixture between a suitable organic solvent, such as ethyl acetate, and the like, and a basic aqueous layer, such as cold IN sodium hydroxide, and the like.
It is appreciated that the transformation illustrated in Synthetic Scheme VII may also be used to convert in an analogous fashion, the half-ester I where A is R6O- to the corresponding acid and subsequently into derivatives I where A is XNH-, R5XN-, or a different R O-. Finally, it is appreciated that the general synthetic strategy represented by the transformation in Synthetic Scheme VII is equally applicable to changing the carboxylic acid derivatives in compounds of formulae π, III and IV.
Compounds of formulae I, II, m, and IV where R4 includes an ethenyl or ethynyl spacer, such as for example, compounds I-c and I-d, respectively, may be converted into the corresponding arylethyl derivatives, compounds I-e, via reduction, as illustrated for compounds of formula I in Synthetic Scheme VIII. Conversion is accomplished by catalytic hydrogenation, and other like reductions, where the integer n and the groups A, A', B, C, R1, R2, and R3 are as previously defined. The corresponding compounds of formulae π, III,and IVmay also be converted from ethyne and ethene precursors in an analogous fashion. The moiety R depicted in Scheme VIII is chosen such that the substituent R-CC-, R-CHCH-, or R-CH2CH2- corresponds to the desired R4 of formulae \ II, III or IV as defined above. Svnthetic Scheme VHI
Figure imgf000045_0001
The hydrogenation of the triple or double bond proceeds readily over a precious metal catalyst, such as palladium on carbon. The hydrogenation solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethyl acetate. The hydrogenation may be performed at an initial hydrogen pressure of about 20-80 p.s.i., preferably about 50-60 p.s.i., at a temperature of about 0-60 0C, preferably within the range of from ambient temperature to about 40 0C, for about 1 hour to about 3 days. Alternatively, the ethynyl spacer of compound I-c may be selectively reduced to the ethenyl spacer of compound I-d using poisoned catalyts, such as Pd on BaSO-t, Lindlar's catalyst, and the like. It is appreciated that either the Z or E double bond geometry of compound I-d may be advantageously obtained by the appropriate choice of reaction conditions. Alternatively, a mixture of double bond geometries may be prepared. The analogous synthesis of compounds of formulae π, ID, and IV may be accomplished by this process.
Compounds of formula I where R is phthalimido are conveniently treated with hydrazine or a hydrazine derivative, for example methylhydrazine, to prepare the corresponding 2-(3-amino-4-substituted azetidin-2-on-l-yl)alkanedioic acid derivatives xiii, as illustrated in Synthetic Scheme EX for compounds of formula I, where the integer n, and the groups A, A', B, C, R1, R2, R4, R12, are as previously defined. Intermediate xiii may then be treated with an appropriate alkylating or acylating agent to prepare the corresponding amines or amides I-g, or alternatively intermediates xiii may be treated with an appropriate isocyanate to prepare the corresponding ureas I-h. Svnthetic Scheme IX
Figure imgf000046_0001
The ureas I-h are prepared by treating a solution of the appropriate amine xiii in a suitable solvent, such as chloroform or dichloromethane, with an appropriate isocyanate, R NCO. If necessary, an excess of the isocyanate is employed to ensure complete reaction of the starting amine. The reactions are performed at about ambient temperature to about 45 0C, for from about three hours to about three days. Typically, the product may be isolated by washing the reaction with water and concentrating the remaining organic components under reduced pressure. When an excess of isocyanate has been used, however, a polymer bound primary or secondary amine, such as an aminomethylated polystyrene, may be conveniently added to facilitate removal of the excess reagent. Isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
The substituted amines and amides I-g are prepared by treating a solution of the appropriate amine xiii in a suitable solvent, such as chloroform or dichloromethane, with an appropriate acylating or alkylating agent, RI2-C(O)Z or RI2-Z, respectively. If necessary, an excess of the acylating or alkylating agent is employed to ensure complete reaction of the starting amine. The reactions are performed at about ambient temperature to about 45 0C, for from about three hours to about three days. Typically, the product may be isolated by washing the reaction with water and concentrating the remaining organic components under reduced pressure. When an excess of the acylating or alkylating agent has been used, however, a polymer bound primary or secondary amine, such as an aminomethylated polystyrene, may be conveniently added to facilitate removal of the excess reagent. Isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure. While it is possible to administer a compound employed in the methods of this invention directly without any formulation, the compounds are usually administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient. These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g., REMINGTON 'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
In making the compositions employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi -solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compounds are generally effective over a wide dosage range. For examples, dosages per day normally fall within the range of about 0.01 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
The compounds described herein are useful in methods for antagonism of the vasopressin Via, Vib, and V2 receptors. Such antagonism is useful in treating a variety of disorders and diseases that have been linked to one or more of these receptors in mammals. Illustratively, the mammal to be treated by the administration of compounds described herein is human.
In another illustrative embodiment of the invention, compounds are also described herein that cross the blood brain barrier. It is appreciated that compounds that cross the blood brain barrier may have wider application in treating various disease states that are responsive to vasopressin receptor antagonism. For example, it is to be understood that there are currently recognized distinct receptor subtypes within depressive illness.
It is appreciated that patients can be selectively treated with the compounds and methods described herein for disease states that do not include cardiovascular disorders. Because patients that have otherwise healthy cardiovascular physiology are not affected by moderate changes in AVP, it is appreciated that those same patients may be treated for other disease states that are responsive to the compounds described herein without the onset of concommitant dysregulation of vasopressin mediated cardiovascular physiology., blood pressure, cardiac contractility, and coronary blood flow. It is appreciated that antagonism of the Vu, receptor at levels capable of blocking this vasopressin receptor subtype that mediates elevated pituitary ACTH secretion under chronic stress may have significant clinical potential as a treatment for certain types of depression and stress-related affective disorders.
The following preparations and examples further illustrate the synthesis of the compounds described herein and are not intended to limit the scope of the invention in any way. Unless otherwise indicated, all reactions were performed at ambient temperature, and all evaporations were performed in vacuo. All of the compounds described below were characterized by standard analytical techniques, including nuclear magnetic resonance spectroscopy (1H NMR) and mass spectral analysis (MS).
EXAMPLES
Example 1. Methyl (4(S)-phenyloxazolidin-2-on-3-yl)acetate. A solution of (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (1 g, 4.52 mmol) (prepared according to Evans in U.S. Patent No. 4,665,171) in 20 mL of anhydrous methanol was treated hourly with 5 equivalents of acetyl chloride, for a total of 20 equivalents. The resulting solution was stirred overnight. The residue obtained after evaporation of the MeOH was redissolved in 30 mL of CH2CI2 and treated with 50 mL of saturated aqueous Na2CO3. The organic layer was evaporated and dried (MgSO4) to yield the title compound as a colorless oil (1.00 Ig, 94%); 1H NMR (CDCl3) δ 3.37 (d, J = 18.0 Hz, IH), 3.69 (s, 3H), 4.13 (t, J = 8.3 Hz, IH), 4.28 (d, J = 18.0 Hz, IH), 4.69 (t, J = 8.8 Hz, IH), 5.04 (t, J = 8.4 Hz, IH), 7.26-7.29 (m, 2H), 7.36-7.42 (m, 3H).
Example 2. Methyl 2-(4(S)-phenyloxazolidin-2-on-3-yl)propanoate. A solution of methyl (4(S)-phenyloxazolidin-2-on-3-yl)acetate (1 g, 4.25 mmol) in 10 mL of anhydrous THF at -78 0C was treated with 4.68 mL (4.68 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF. The reaction mixture was stirred for 1 h. at about -70 0C before adding MeI (1.59 mL, 25.51 mmol). Upon complete conversion of the azetidinone, the reaction was quenched with saturated aqueous NH4CI and partitioned between EtOAc and water. The organic layer was washed sequentially with saturated aqueous sodium bisulfite, and saturated aqueous NaCl. The resulting organic layer was dried (MgSO4) and evaporated to afFord the title compound (a mixture of diasteromers) as a white solid (l.Oόg, 93%); 1H NMR (CDCl3) δ 1.07/1.53 (d/d, J = 7.5 Hz, 3H), 3.59/3.74 (s/s, 3H), 3.85/4.48 (q/q, J = 7.5 Hz, IH), 4.10-4.14 (m, IH), 4.60-4.64/4.65-4.69 (m/m, IH), 4.88-4.92/4.98-5.02 (m/m, IH), 7.24-7.40 (m, 5H). Example 3. 2-(4(S)-Phenyloxazolidin-2-on-3-yl)piOpanoic acid. To a solution of methyl 2-(4(S)-phenyloxazolidin-2-on-3-yl)propanoate (I g, 4.01 mmol) in 35 mL of MeOH was added, at 00C, 14.3 mL (12.04 mmol) of a 0.84 M solution of LiOH in water. The reaction mixture was then stirred for 3 h. at ambient temperature. Upon complete hydrolysis of the azetidinone, the MeOH was removed by evaporation, the crude residue dissolved in CH2Cl2 and treated with saturated aqueous NaCl. The resulting organic layer was dried (MgSO-;) and evaporated to afford the title compound (racemic mixture) as a white solid (0.906g, 96%); 1H NMR (CDCl3) δ 1.13/1.57 (d/d, J = 7.5 Hz, 3H), 3.75/4.50 (q/q, J = 7.5 Hz, IH), 4.10-4.16 (m, IH), 4.62-4.72 (m, IH), 4.92-5.03 (m, IH), 7.32-7.43 (m, 5H).
Example 4. 2-(4(S)-Phenyloxazolidin-2-on-3-yl)propanoyl chloride. A solution of 1 equivalent of Example 3 and 1.3 equivalent of oxalyl chloride in 200 mL CH2CI2 (150 mL / g of propanoic acid derivative) was treated with a catalytic amount of anhydrous DMF (85 μL / mmole of propanoic acid derivative) resulting in vigorous gas evolution. After 45 min., all gas evolution had ceased and the reaction mixture was concentrated under reduced pressure to provide the title compound as an off-white solid after drying for 2 h. under vacuum. Example 5. General procedure for amide formation from an activated ester derivative.
N-Benzyloxycarbonyl-L-aspartic acid β-t -butyl ester α-(3- trifluoromethyl)benzylamide. A solution of N-benzyloxycarbonyl-L-aspartic acid β-/-butyl ester α-N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 mL of dry tetrahydrofuran was treated with 0.68 mL (4.74 mmol) of 3-(trifluoromethyl)benzyl amine. Upon completion (TLC, 60:40 hexanes/ethyl acetate), the mixture was evaporated, and the resulting oil was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic laer was evaporated to give 2.23 g (quantitative yield) of the title compound as a white solid; 1H NMR (CDCl3) δ 1.39 (s, 9H), 2.61 (dd, J = 6.5 Hz, J = 17.2 Hz, IH), 2.98 (dd, J = 3.7 Hz, J = 17.0 Hz, IH), 4.41 (dd, J = 5.9 Hz, J = 15.3 Hz, IH), 4.50- 4.57 (m, 2H), 5.15 (s, 2H), 5.96-5.99 (m, IH), 6.95 (s, IH), 7.29-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 2H). Examples 6-8 were prepared according to the procedure of Example 5, except that N-benzyloxycarbonyl-L-aspartic acid β-f-butyl ester α-N-hydroxysuccinimide ester was replaced by the appropriate amino acid derivative, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine. Example 6. N-Benzyloxycarbonyl-L-aspartic acid β-/ -butyl ester α-[4-(2- phenylethyl)]piperazinamide. N-benzyloxycarbonyl-L-aspartic acid β-/-butyl ester α-N- hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.27 mL (11.9 mmol) gave 5.89 g (quantitative yield) of the title compound as an off-white oil; 1H NMR (CDCl3) δ 1.40 (s, 9H), 2.45-2.80 (m,10H), 3.50-3.80 (m, 4H), 4.87-4.91 (m, IH), 5.08 (s, 2H), 5.62-5.66 (m, IH), 7.17-7.33 (m, 10H).
Example 7. N-Benzyloxycarbonyl-L-glutamic acid γ-/-butyl ester α-(3- trifluoromethyl)benzylamide. N-benzyloxycarbonyl-L-glutamic acid β-f-butyl ester α-N- hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced ChemTech) and 3- (trifluoromethyl)benzylamine) 1.63 mL (11.4 mmol) gave 5.41 g (98%) of the title compound as an off-white solid; 1H NMR (CDCl3) δ 1.40 (s, 9H), 1.88-1.99 (m, IH), 2.03-2.13 (m, IH), 2.23-2.33 (m, IH), 2.38-2.47 (m,lH), 4.19-4.25 (s, IH), 4.46-4.48 (m, 2H), 5.05-5.08 (m, 2H), 5.67-5.72 (m, IH), 7.27-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 2H).
Example 8. N-Benzyloxycarbonyl-L-glutamic acid γ-t-butyl ester α-[4-(2- phenylethyl)]piperazinamide. N-benzyloxycarbonyl-L-glutamic acid γ-*-butyl ester α-N- hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-
(phenylethyl)piperazine 2.19 mL (11.5 mmol) gave 5.87 g (quantitative yield) of the title compound as an off-white oil; 1HNMR (CDCl3) δ 1.43 (s, 9H); 1.64-1.73 (m,lH);1.93-2.01 (m, IH); 2.23-2.40 (m, 2H); 2.42-2.68 (m, 6H); 2.75-2.85 (m, 2H); 3.61-3.74 (m, 4H); 4.66- 4.73 (m, IH); 5.03-5.12 (m, 2H); 5.69-5.72 (m, IH); 7.16-7.34 (m, 10H). Example 9. N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine t-
Butyl ester. N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine (0.710 g, 1.70 mmole) in dichloromethane (8 mL) was treated with /-butyl acetate (3 mL) and concentrated sulfuric acid (40 μL) in a sealed flask at 0 0C. Upon completion (TLC), the reaction was quenched with of dichloromethane (10 mL) and saturated aqueous potassium bicarbonate (15 mL). The organic layer was washed with distilled water, and evaporated. The resulting residue was purified by flash column chromatography (98:2 dichloromethane/methanol) to yield the title compound as a colorless oil (0.292 g, 77%); 1H NMR (CDCl3) δ 1.44 (s, 9H); 3.68 (dd, J = 2.9 Hz, J = 9.3 Hz, IH); 3.87 (dd, J = 2.9 Hz, J = 9.3 Hz, IH); 4.22 (t, J = 7.1 Hz, IH); 4.30- 4.60 (m, 5H); 5.64-5.67 (m, IH); 7.25-7.39 (m, 9H); 7.58-7.61 (m, 2H); 7.73-7.76 (m, 2H).
Example 10. O-(Benzyl)-D-βerine /-Butyl ester. Example 9 (0.620 g, 1.31 mmol) in dichloromethane (5 mL) was treated with tris(2-aminoethyl)amine (2.75 mL) for 5 h. The resulting mixture was washed twice with a phosphate buffer (pH = 5.5), once with saturated aqueous potassium bicarbonate, and evaporated to give 0.329 g (quantitative yield) of the title compound as an off-white solid; 1H NMR (CD3OD) δ 1.44 (s, 9H); 3.48 (dd, J = J1 = 4.2 Hz, IH); 3.61 (dd, J = 4.0 Hz, J = 9.2 Hz, IH); 3.72 (dd, J = 4.6 Hz, J = 9.2 Hz, IH); 4.47 (d, J = 12.0 Hz, IH); 4.55 (d, J = 12.0 Hz, IH); 7.26-7.33 (m, 5H). Example 11. General procedure for amide formation from a carboxylic acid.
N-Benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-(3- trifluoromethyl)benzylamide. A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D- aspartic acid β-t-butyl ester monohydrate (Novabiochem) in 3-4 mL of dichloromethane was treated by sequential addition of 0.46 mL (3.21 mmol) of 3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of l-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of l-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until complete as determined by thin layer chromatography (95:5 dichloromethane/methanol eluent), the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution and with distilled water. The organic layer was evaporated to give 1.41 g (quantitative yield) of the title compound as an off-white solid; 1H NMR (CDCl3) δ 1.39 (s, 9H); 2.61 (dd, J = 6.5 Hz, J = 17.2 Hz, IH); 2.98 (dd, J = 4.2 Hz, J = 17.2 Hz, IH); 4.41 (dd, J == 5.9 Hz, J = 15.3 Hz, IH); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96- 6.01 (m, IH); 6.91-7.00 (m, IH); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H). Examples 12-17 were prepared according to the procedure of Example 11, except that N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate was replaced by the appropriate amino acid derivative, and 3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine.
Example 12. N-Benzyloxycarbonyl-D-glutamic acid γ-/-butyl ester α-(3- trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-glutamic acid γ-f-butyl ester ( 1.14 g, 3.37 mmol) and 0.53 mL (3.70 mmol, Novabiochem) of 3-(trifluoromethyl)benzylamine gave 1.67 g (quantitative yield) of Example 12 as an off-white solid.
Example 13. N-Benzyloxycarbonyl-L-glutamic acid a-t -butyl ester γ-(4- cyclohexyl)piperazinamide. N-benzyloxycarbonyl-L -glutamic acid α-f-butyl ester (1.36 g, 4.03 mmol) and 0.746g (4.43 mmol) of 1-cyclohexylpiperazine gave 1.93 g (98%) of Example 13 as an off-white solid; 1H NMR (CDCl3) δ 1.02-1.12 (m, 5H); 1.43 (s, 9H), 1.60-1.64 (m, IH); 1.80-1.93 (m, 5H); 2.18-2.52 (m, 8H); 3.38-3.60 (m,4H); 4.20-4.24 (m, IH); 5.03-5.13 (m, 2H); 5.53-5.57 (m, IH); 7.28-7.34 (m, 5H). Example 14. N-Benzyloxycarbonyl-D-aspartic acid β-f-butyl ester α-(2-fluoro-
3-trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.12 mL of (2-fluoro-3- trifluoromethyl)benzylamine gave 0.365 g (quantitative yield) of Example 14 as an off-white solid; 1H NMR (CDCl3) δ 1.38 (s, 9H); 2.59 (dd, J = 6.5 Hz, J = 17.0 Hz, IH); 2.95 (dd, J = 4.3 Hz, J = 17.0 Hz, IH); 4.46-4.56 (m, 3H); 5.11 (s, 2H); 5.94-5.96 (m, IH); 7.15 (t, J = 8.0 Hz, IH); 7.30-7.36 (m, 5H); 7.47-7.52 (m, 2H).
Example 15. N-Benzyloxycarbonyl-D-aspartic acid β-f-butyl ester α-[(S)-α- methylbenzyl]amide. N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL of (S>α-methylbenzylamine gave 0.281 g (90%) of Example 15 as an off-white solid; 1H NMR (CDCl3) δ 1.41 (s, 9H); 1.44 (d, J = 7.0 Hz, 3H); 2.61 (dd, J = 7.0 Hz, J = 17.0 Hz, IH); 2.93 (dd, J = 4.0 Hz, J = 17.5 Hz, IH); 4.50- 4.54 (m, IH); 5.04-5.14 (m, 3H); 5.94-5.96 (m, IH); 6.76-6.80 (m, IH); 7.21-7.37 (m, 10H). Example 16. N-Benzyloxycarbonyl-D-aspartic acid β-f-butyl ester α-[(R)-α- methylbenzyl]amide. N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL of (R)-α-methylbenzylamine gave 0.281 g (90%) of Example 16 as an off-white solid; 1H NMR (CDCl3) δ 1.38 (s, 9H); 1.43 (d, J = 6.9 Hz, 3H); 2.54 (dd, J = 7.3 Hz, J = 17.2 Hz, IH); 2.87 (dd, J = 4.1 Hz, J = 17.3 Hz, IH); 4.46- 4.50 (m, IH); 4.99-5.15 (m, 3H); 5.92-5.96 (m, IH); 6.78-6.82 (m, IH); 7.21-7.33 (m, 10H).
Example 17. N-Benzyloxycarbonyl-D-aspartic acid γ-/-butyl ester α-[N-methyl- N-(3-trifluoromethylbenzyl)]amide. N-benzyloxycarbonyl-D-aspartic acid γ-M>utyl ester (0.303 g, 0.89 mmol, Novabiochem) and 0.168 g (0.89 mmol,) of N-methyl-N-(3- trifluoromethylbenzyl)amine gave 0.287 g (65%) of Example 17 as an off- white solid; 1H NMR (CDCl3) δ 1.40 (s, 9H); 2.55 (dd, J = 5.8 Hz, J = 15.8 Hz, IH); 2.81 (dd, J = 7.8 Hz, J = 15.8 Hz, IH); 3.10 (s, 3H); 4.25 (d, J = 15.0 Hz, IH); 4.80 (d, J = 15.5 Hz, IH); 5.01-5.13 (m, 3H); 5.52-5.55 (m, IH); 7.25-7.52 (m, 10H).
Example 18. General procedure for hydrogenation of a benzyloxycarbonyl amine. L-aspartic acid β-f-butyl ester α-(3-trifluoromethyI)benzylamide. A suspension of 2.23 g (4.64 πunol) of N-benzyloxycarbonyl-L-aspartic acid β-/-butyl ester α-(3- trifluoromethyl)benzylamide and palladium (5% wt. on activated carbon, 0.642 g) in 30 mL of methanol was held under an atmosphere of hydrogen until complete conversion as determined - by thin layer chromatography (95:5 dichloromethane/methanol eluent). The reaction was filtered to remove the palladium over carbon and the filtrate was evaporated to give 1.52 g (96%) of the title compound as an oil; 1H NMR (CDCl3) δ 1.42 (s, 9H); 2.26 (brs, 2H); 2.63- 2.71 (m, IH); 2.82-2.87 (m, IH); 3.75-3.77 (m, IH); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.90 (brs, IH). Examples 19-28 were prepared according to the procedure of Example 18, except that N-benzyloxycarbonyl-L-aspartic acid β-f-butyl ester α-(3- trifluoromethyl)benzylamide was replaced by the appropriate amino acid derivative.
Example 19. L-aspartic acid β-f-butyl ester α-[4-(2- phenylethyl)]piperazinamide. N-benzyloxycarbonyl-L-aspartic acid β-/-butyl ester α-[4-(2- phenylethyl)]piperazinamide (5.89 g, 11.9 mmol) gave 4.24 g (98%) of Example 19 as an off- white oil; 1H NMR (CDCl3): δ 1.42 (s, 9H); 2.61-2.95 (m, 10H); 3.60-3.90 (m, 4H); 4.35-4.45 (m, IH); 7.17-7.29 (m, 5H).
Example 20. D-aspartic acid β-/-butyl ester α-(3-trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-aspartic acid β-f-butyl ester α-(3-trifluoromethyl)benzylamide (1.41 g, 2.93 mmol) gave 0.973 g (96%) of Example 20 as an off-white oil; 1H NMR (CDCl3): δ 1.42 (s, 9H); 2.21 (brs, 2H); 2.67 (dd, J = 7.1 Hz, J = 16.8 Hz, IH); 2.84 (dd, J = 3.6 Hz, J = 16.7 Hz, IH); 3.73-3.77 (m, IH); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.83-7.87 (m, IH).
Example 21. L-glutamic acid γ-f-butyl ester α-(3-trifluorornethyl)benzylamide. N-benzyloxycarbonyl-L-glutamic acid γ-/-butyl ester α-(3-trifluoromethyl)benzylamide (5.41 g, 10.9 mmol) gave 3.94 g (quantitative yield) of Example 21 as an off-white oil; 1H NMR
(CDCl3): δ 1.41 (s, 9H); 1.73-1.89 (m, 3H); 2.05-2.16 (m, IH); 2.32-2.38 (m, 2H); 3.47 (dd, J = 5.0 Hz, J = 7.5 Hz, IH); 4.47-4.49 (m, 2H); 7.36-7.54 (m, 4H); 7.69-7.77 (m, IH).
Example 22. L-glutamic acid γ-f-butyl ester α-[4-(2- phenylethyl)]piperazinamide. N-benzyloxycarbonyl-L-glutamic acidγ-/-butyl ester α-[4-(2- phenylethyl)]piperazinamide (5.86 g, 11.50 mmol) gave 4.28 g (99%) of Example 22 as an off- white oil; 1H NMR (CDCl3) δ 1.39 (s, 9H); 2.00-2.08 (m, IH); 2.38-2.46 (m, IH); 2.55-2.90 (m, 9H); 3.61-3.82 (m, 4H); 4.48-4.56 (m, IH); 7.17-7.26 (m, 5H). Example 23. D-glutamic acid γ-/-butyl ester α-(3-trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-glutamic acid γ-f-butyl ester α-(3-trifluoromethyl)benzylamide (1.667 g, 3.37 mmol) gave 1.15 g (94%) of Example 23 as an off-white oil; 1H NMR (CDCl3) δ 1.41 (s, 9H); 1.80-2.20 (m, 4H); 2.31-2.40 (m, 2H); 3.51-3.59 (m, IH); 4.47-4.49 (m, 2H); 7.39-7.52 (m, 4H); 7.71-7.79 (m, IH).
Example 24. L-glutamic acid α-/-butyl ester γ-(4-cyclohexyl)piperazinamide. N-Benzyloxycarbonyl-L-glutamic acid α-f-butyl ester γ-(4-cyclohexyl)piperazinamide (1.93 g, 3.96 mmol) gave 1.30 g (93%) of Example 24 as an off-white oil; 1H NMR (CDCh) δ 1.02- 1.25 (m, 5H); 1.41 (s, 9H); 1.45-1.50 (m, IH); 1.56-1.60 (m, IH); 1.69-1.80 (m, 6H); 3.30 (dd, J = 4.8 Hz, J = 8.5 Hz, IH); 3.44 (t, J = 9.9 Hz, 2H); 3.56 (t, J = 9.9 Hz, 2H).
Example 25. D-aspartic acid β-f-butyl ester α-(2-fluoro-3- trifluoromethyl)benzylamide. N-benzyloxycarbonyl-D-aspartic acid β-/-butyl ester α-(2- fluoro-3-trifluoromethyl)benzylarnide (0.36 g, 0.72 mmol) gave 0.256 g (92%) of Example 25 as an off-white oil; 1H NMR (CDCl3) δ 1.39 (s, 9H); 2.50 (brs, 2H); 2.74 (dd, J = 7.0 Hz, J = 16.5 Hz, IH); 2.86 (dd, J = 4.8 Hz, J = 16.8 Hz, IH); 3.89 (brs, 2H); 4.47-4.57 (m, 2H); 7.16 (t, J = 7.8 Hz, IH); 7.48 (t, J = 7.3 Hz, IH); 7.56 (t, J = 7.3 Hz, IH); 7.97-8.02 (m, IH).
Example 26. D-aspartic acid β-t -butyl ester α-[(S)-α-methyl]benzylamide. N- benzyloxycarbonyl-D-aspartic acid β-f-butyl ester α-[(S)-α-methylbenzyl]amide (0.275 g, 0.65 mmol) gave 0.17 g (90%) of Example 26 as an off-white oil; 1H NMR (CDCl3) δ 1.40 (s, 9H); 1.47 (d, J = 6.9 Hz, 3H); 1.98 (brs, 2H); 2.49 (dd, J = 7.9 Hz, J = 17.7 Hz, IH); 2.83 (dd, J = 3.6 Hz, J = 16.7 Hz, IH); 3.69 (brs, IH); 4.99-5.10 (m, IH); 7.19-7.33 (m, 5H); 7.65-7.68 (m, IH).
Example 27. D-aspartic acid β-f -butyl ester α-[(R)-α-methylbenzyl]amide. N- benzyloxycarbonyl-D-aspartic acid β-f-butyl ester α-[(R)-α-methylbenzyl]amide (0.273 g, 0.64 mmol) gave 0.187 g (quantitative yield) of Example 27 as an off-white oil; 1H NMR (CDCl3) δ
1.38 (s, 9H); 1.46 (d, J = 6.9 Hz, 3H); 1.79 (brs, 2H); 2.51 (dd, J = 7.8 Hz, J = 17.5 Hz, IH);
2.87 (dd, J = 3.6 Hz, J = 16.9 Hz, IH); 4.19 (brs, IH); 4.99-5.11 (m, IH); 7.18-7.34 (m, 5H);
7.86-7.90 (m, IH).
Example 28. D-aspartic acid β-f -butyl ester α-[N-methyl-N-(3- trifluoromethylbenzyl)]amide. N-benzyloxycarbonyl-D-aspartic acid β-r-butyl ester α-[N- methyl-N-(3-trifluoromethylbenzyl)]amide (0.282 g, 0.57 mmol) gave 0.195 g (95%) of
Example 28 as an off-white oil. Example 29. General procedure for formation of a 2-azetidinone from an imine and an acetyl chloride.
Step 1 : General procedure for formation of an imine from an amino acid derivative. A solution of 1 equivalent of an α-amino acid ester or amide in dichloromethane is treated sequentially with 1 equivalent of an appropriate aldehyde, and a dessicating agent, such as magnesium sulfate or silica gel, in the amount of about 2 grams of dessicating agent per gram of starting α-amino acid ester or amide. The reaction is stirred at ambient temperature until all of the reactants are consumed as measured by thin layer chromatography (TLC). The reactions are typically complete within an hour. The reaction mixture is then filtered, the filter cake is washed with dichloromethane, and the filtrate concentrated under reduced pressure to provide the desired imine that is used as is in the subsequent step.
Step 2: General procedure for the 2+2 cycloaddition of an imine and an acetyl chloride. A dichloromethane solution of the imine (10 mL dichloromethane/ 1 gram imine) is cooled to 00C. To this cooled solution is added 1.5 equivalents of an appropriate amine, typically triethylamine, followed by the dropwise addition of a dichloromethane solution of 1.1 equivalents of an appropriate acetyl chloride, such as that described in Example 1 (10 mL dichloromethane/1 gm appropriate acetyl chloride). The reaction mixture is allowed to warm to ambient temperature over 1 h and is then quenched by the addition of a saturated aqueous solution of ammonium chloride. The resulting mixture is partitioned between water and dichloromethane. The layers are separated and the organic layer is washed successively with IN hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue may be used directly for further reactions, or purified by chromatography or by crystallization from an appropriate solvent system if desired. Example 30. General procedure for hydrolysis of a terf -butyl ester. A solution of terf -butyl ester derivative in formic acid, typically 1 g in 10 mL, is stirred at ambient temperature until no more ester is detected by thin layer chromatography (dichloromethane 95% / methanol 5%), a typical reaction time being around 3 hours. The formic acid is evaporated under reduced pressure; the resulting solid residue is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer is evaporated to give an off-white solid that may be used directly for further reactions, or recrystallized from an appropriate solvent system if desired.
Example 31. /erf-Butyl 3(R)-[3(S>(4(S)-phenyloxazolidin-2-on-3-yl)-3-methyl- 4(R)-(styr-2-yl)azetidin-2-on- 1 -yl]-3-[(3- trifluoromethyl)phenylmethylaminocarbonyl]propanoate. Using the general method of Example 29, the imine prepared from 0.307 g (0.89 mmol) of D-aspartic acid β-f-butyl esterα- (3-trifluoromethyl)benzyIamide (Example 20) and cinnamaldehyde was combined with 2- (4(S)-phenyloxazolidin-2-on-3-yl)propanoyl chloride (Example 4) to give 120 mg (20%) of the title compound after flash column chromatography purification (hexanes 70% / EtOAc 30%); 1H NMR (CDCl3) δ 1.25 (s, 3H), 1.38 (s, 9H); 3.09 (dd, J = 3.0 Hz, J = 18.0 Hz, IH); 3.33 (dd, J = 12.5 Hz, J = 18.0 Hz, IH); 4.01 (dd, J = 3.0 Hz, J = 11.5 Hz, IH); 4.04 (dd, J = 3.5 Hz, J = 8.8 Hz, IH); 4.42 (d, J = 9.0 Hz, IH); 4.45-4.51 (m, 3H); 4.61-4.66 (m, IH); 4.75 (dd, J = 3.5 Hz, J = 8.5 Hz, IH); 6.23 (dd, J = 9.0 Hz, J = 15.5 Hz, IH); 6.78 (d, J = 15.5 Hz, IH); 7.23- 7.53 (m, 13H); 7.64 (s, IH).
Example 32. 3(R)-[3(S>(4(S)-Phenyloxazolidin-2-on-3-yl)-3-methyl-4(R)- (styr-2-yl)azetidin-2-on-l-yl]-3-[(3-trifluoromethyl)phenylmethylaminocarbonyl]propanoic acid. Using the general method of Example 30, 120 mg (0.18 mmol) of Example 31 was hydrolyzed to give 108 mg (98%) of the title compound as an off-white solid; 1H NMR (CDCl3) δ 1.22 (s, 3H); 3.25 (dd, J = 3.5 Hz, J = 18.0 Hz, IH); 3.36 (dd, J = 10.8 Hz, J = 18.2 Hz, IH); 4.01 (dd, J = 4.0 Hz, J = 10.5 Hz, IH); 4.05 (dd, J = 3.8 Hz, J = 8.8 Hz, IH); 4.33 (d, J = 9.0 Hz, IH); 4.44-4.51 (m, 3H); 4.61-4.66 (m, IH); 4.73 (dd, J = 3.8 Hz, J = 8.8 Hz, IH); 6.19 (dd, J = 9.0 Hz, J = 16.0 Hz, IH); 6.74 (d, J = 16.0 Hz, IH); 7.22-7.54 (m, 13H); 7.65 (s, IH). Example 33. 4-(Piperidin-l-yl)-piperidin-l-yl 3(R)-[3(S)-(4(S)- phenyloxazolidin-2-on-3-yl)-3-methyl-4(R)-(styr-2-yl)azetidin-2-on-l-yl]-3-[(3- trifluoromethyl)phenylmethylaminocarbonyl]propanoic acid. Using the procedure of Example 11, except thatNj-benzyloxycarbonyl-D-aspartic acid β-/ -butyl ester monohydrate was replaced with the carboxylic acid of Example 33 and 3-(trifluoromethyl)benzyl amine was replaced with 4-(piperidin-l-yl)piperidine, the title compound was prepared in quantitative yield; MS (m+H)+ 772.
Example 34. 4-cyclohexylpiperazin-l-yl 4(S)-[3(S)-(4(S)-phenyloxazolidin-2- on-3-yl)-4(R)-(styr-2-yl)azetidin-2-on-l-yl]-4-[(R)-l,2,3,4-tetrahydronaphth-l- yl]aminocarbonyl]butanoic acid. Similar to the foregoing Examples, the other compounds described herein may be prepared by replacing the corresponding starting materials. Illustratively, the compound of Example 34 was prepared; MS (m+H)+ 744.
Method Example 1. Human vasopressin Vla receptor binding assay. A cell line expressing the human Via receptor in CHO cells (henceforth referred to as the hV|a cell line) was obtained from Dr. Michael Brownstein, NIMH, Bethesda, MD, USA. The hV|a cDNA sequence is described by Thibonnier et al., Journal of Biological Chemistry, 269:3304- 3310 (1994), and the expression method was the same as described by Morel et al. (1992). The hV ia cell line was grown in alpha-MEM with 10% fetal bovine serum and 250ug/ml G418 (Gibco, Grand Island, NY, USA). For competitive binding assay, hVla cells were plated into 6-well culture plate at 1: 10 dilution from a confluency flask, and maintained in culture for at least two days. Culture medium was then removed, cells were washed with 2ml binding buffer (25mM Hepes, 0.25% BSA, Ix DMEM, PH = 7.0). To each well, 990 μl binding buffer containing InM 3H- A VP was added, and followed by 10 μl series diluted Example compounds dissolved in DMSO. All incubations were in triplicate, and dose-inhibition curves consisted of total binding (DMSO) and 5 concentrations (0.1, 1.0, 10, 100, and 1000 nM) of test agents encompassing the ICso- 100 nM cold AVP (Sigma) was used to assess non-specific binding. Cells were incubated for 45 minutes at 37 0C, assay mixture was removed and each well was washed three times with PBS (pH = 7.4). 1ml 2% SDS was added per well and plates were let sit for 30 minutes. The whole content in a well was transferred to a scintillation vial. Each well was rinsed with 0.5ml PBS which was then added to the corresponding vial. Scintillation fluid (Ecoscint, National Diagnostics, Atlanta, Georgia) was then added at 3ml per vial. Samples were counted in a liquid scintillation counter (Beckman LS3801). IC50 values were calculated by Prism Curve fitting software. Example 33 was tested according to Method Example 1, and exhibited an IC50 in human Vl8 of 5 nM. Method Example 2. Inhibition of phosphatidylinositol turnover. The physiological effects of vasopressin are mediated through specific G-protein coupled receptors. The vasopressin Vu receptor is coupled to the Gq/Gi i family of G proteins and mediates phosphatidylinositol turnover. The agonist or antagonist character of the compounds of the invention may be determined by their ability to inhibit vasopressin-mediated turnover of phosphatidylinositol by the procedure described in the following paragraphs.
Cell culture and labeling of cells. Three days prior to the assay, near-confluent cultures of hVla cells were dissociated and seeded in 6-well tissue culture plates, about 100 wells being seeded from each 75 cm2 flask (equivalent to 12: 1 split ratio). Each well contained 1 mL of growth medium with 2 μCi of [3H]myo-inositol (American Radiolabeled Chemicals, St. Louis, MO, USA).
Incubations. All assays were in triplicate except for basal and 10 nM AVP (both n = 6). AVP ((arginine vasopressin), Peninsula Labs, Belmont, CA, USA (#8103)) was dissolved in 0.1N acetic acid. Test agents were dissolved in DMSO and diluted in DMSO to 200 times the final test concentration. Test agents and AVP (or corresponding volumes of DMSO) were added separately as 5 μL in DMSO to 12x75 mm glass tubes containing 1 mL of assay buffer (Tyrode's balanced salt solution containing 50 mM glucose, 10 mM LiCl, 15 mM HEPES pH 7.4, 10 μM phosphoramidon, and 100 μM bacitracin). The order of incubations was randomized. Incubations were initiated by removing the prelabeling medium, washing the monolayer once with 1 mL of 0.9% NaCl, and transferring the contents of the assay tubes to corresponding wells. The plates were incubated for 1 hour at 37 0C. Incubations were terminated by removing the incubation medium and adding 500 μL of ice cold 5% (w/v) trichloroacetic acid and allowing the wells to stand for 15 min.
Measurement of [3H]inositol phosphates. BioRad Poly-Prep Econo-Columns were packed with 0.3 mL of AG 1 X-8 100-200 formate form resin. Resin was mixed 1:1 with water and 0.6 mL added to each column. Columns were then washed with 10 mL water. Scintillation vials (2OmL) were placed under each column. For each well, the contents were transferred to a minicolumn, after which the well was washed with 0.5 mL distilled water, which was also added to the minicolumn. The columns were then washed twice with 5 mL of 5 mM myo-inositol to elute free inositol. Aliquots (1 mL) were transferred to 20 mL scintillation vials and 10 mL of Beckman Ready Protein Plus added. After the myo-inositol wash was complete, empty scintillation vials were placed under the columns, and [3H]inositol phosphates were eluted with three additions of 1 mL 0.5 M ammonium formate containing 0.1 N formic acid. Elution conditions were optimized to recover inositol mono-, bis-, and trisphosphates, without eluting the more metabolically inert tetrakis-, pentakis-, and hexakis- phosphates. To each sample was added 10 mL of a high salt capacity scintillation fluid such as Tru-Count High Salt Capacity or Packard Hionic-Fluor. Inositol lipids were measured by adding 1 mL of 2% sodium dodecyl sulfate (SDS) to each well, allowing the wells to stand for at least 30 min., and transferring the solution to 20 mL scintillation vials, to which 10 mL Beckman Ready Protein Plus scintillation fluid was then added. Samples were counted in a
Beckman LS 3801 liquid scintillation counter for 10 min. Total inositol incorporation for each well was calculated as the sum of free inositol, inositol phosphates, and inositol lipids.
Data analysis: concentration-inhibition experiments. Concentration-response curves for AVP and concentration -inhibition curves for test agents versus 10 nM AVP were analyzed by nonlinear least-squares curve-fitting to a 4-parameter logistic function. Parameters for basal and maximal inositol phosphates, EC 50 or ICso, and Hill coefficient were varied to achieve the best fit. The curve-fitting was weighted under the assumption that the standard deviation was proportional to dpm of radioactivity. Full concentration-response curves for AVP were run in each experiment, and IC50 values were converted to Kj values by application of the Cheng-Prusoff equation, based on the EC50 for AVP in the same experiment. Inositol phosphates were expressed as dpm per 106 dpm of total inositol incorporation.
Data analysis: competitivity experiments. Experiments to test for competitivity of test agents consisted of concentration-response curves for AVP in the absence and presence of two or more concentrations of test agent. Data were fit to the following competitive logistic equation:
M X {A / [E + (D / K)]Γ
Y = B +
1 + {A / [E + (D / K)]}Q where Y is dpm of inositol phosphates, B is concentration of basal inositol phosphates, M is the maximal increase in concentration of inositol phosphates, A is the concentration of agonist (AVP), E is the EC50 for agonist, D is the concentration of the antagonist, K is the Kj for antagonist, and Q is the cooperativity (Hill coefficient).
Vasopressin V)a receptors are also known to mediate platelet aggregation. Vasopressin Vu receptor agonists cause platelet aggregation, while vasopressin Vi a receptor antagonists inhibit the platelet aggregation precipitated by vasopressin or vasopressin Vi3 agonists. The degree of antagonist activity of the compounds of the invention may be determined by the assay described in the following paragraphs.
Blood from healthy, human volunteers was collected by venipuncture and mixed with heparin (60 mL of blood added to 0.4 mL of heparanized saline solution (4 mg heparin/mL saline)). Platelet-rich plasma (PRP) was prepared by centrifiiging whole blood (150 x g), and indomethacin (3 μM) was added to PRP to block the thromboxane-mediated release reaction. PRP was continuously stirred at 37 °C and change in optical density was followed after the addition of arginine vasopressin (AVP) (30 nM) to initiate aggregation. Compounds were dissolved in 50% dimethylsulfoxide (DMSO) and added (10 μL/415 μL PRP) before the addition of AVP. The percent inhibition of AVP-induced aggregation was measured and an IC50 calculated.
In studies using washed platelets, 50 mL of whole blood was mixed with 10 mL of citrate/heparin solution (85 mM sodium citrate, 64 mM citric acid, 111 mM glucose, 5 units/mL heparin) and PRP isolated as described above. PRP was then centrifuged (150 x g) and the pellet resuspended in a physiologic buffer solution (10 mM HEPES, 135 mM sodium chloride, 5 mM potassium chloride, and 1 mM magnesium chloride) containing 10 μM indomethicin. Human fibrinogen (0.2 mg/mL) and calcium chloride (1 mM) were added to stirred platelets before initiating aggregation with AVP (30 nM) as previously described. The activity of compounds of formulae I, II, and HI in the antagonism of the vasopressin Vi3 receptor provides a method of antagonizing the vasopressin Vi8 receptor comprising administering to a subject in need of such treatment an effective amount of a compound of that formula. It is known that numerous physiological and therapeutic benefits are obtained through the administration of drugs that antagonize the vasopressin Vu receptor. These activities may be catagorized as peripheral and central. Peripheral utilities include administration of vasopressin Vla antagonists of formula I as adjuncts in heart failure or as antithrombotic agents. Central effects include administration of vasopressin Vi a antagonists of formulae I, II, and III in the treatment of obsessive-compulsive disorder, aggressive disorders, depression and anxiety.
Obsessive -compulsive disease appears in a great variety of degrees and symptoms, generally linked by the victim's uncontrollable urge to perform needless, ritualistic acts. Acts of acquiring, ordering, cleansing and the like, beyond any rational need or rationale, are the outward characteristic of the disease. A badly afflicted subject may be unable to do anything but carry out the rituals required by the disease. Obsessive-compulsive disease, in all its variations, is a preferred target of treatment with the present adjunctive therapy method and compositions. The utility of the compounds of formulae I, π, and HI in the treatment of obsessive-compulsive disorder was demonstrated as described in the following assay.
In golden hamsters, a particular stereotypy, flank marking behavior, can be induced by microinjections of vasopressin (10-100 nL, 1-100 μM) into the anterior hypothalamus (Ferris et al., Science, 224:521-523 (1984); Albers and ¥ ems, Regulatory Peptides, 12:257-260 (1985); Ferris et al., European Journal of Pharmacology, 154: 153-159 (1988)). Following the releasing stimulus, the behavior is initiated by grooming, licking and combing of the large sebaceous glands on the dorsolateral flanks. Bouts of flank gland grooming may be so intense that the flank region is left matted and soaked in saliva. After grooming, the hamsters display flank marking behavior, a type of scent marking involved in olfactory communication (Johnston, Physio. Behav. , 51 :437-448 (1985); Ferris et al., Physio. Behav., 40:661-664 (1987)), by arching the back and rubbing the flank glands vigorously against any vertical surface. Vasopressin-induced flank marking is usually induced within a minute after the microinjection (Ferris et al., Science, 224: 521-523 (1984)). The behavior is specific to vasopressin, as micro- injections of other neuropeptides, excitatory amino acids, and catecholamines do not elicit flank marking (Ferris et al., Science, 224:521-523 (1984); Albers and Ferris, Regulatory Peptides, 12:257-260 (1985)). Furthermore, flank marking is specific to the vasopressin V) receptor, as the behavior is selectively inhibited by Vi receptor antagonists and activated by Vi receptor agonists (Ferris et al., tϊeuroscience Letters, 55:239-243 (1985); Albers et al., Journal of Neuroscience, 6:2085-2089 (1986); Ferris et al., European Journal of Pharmacology, 154:153-159 (1988)).
All animals were adult male golden hamsters (Mesocricetus auratus) weighing approximately 160 gm. The animals underwent stereotaxic surgery, and were allowed to recover before behavioral testing. The hamsters were kept on a reverse light cycle (14 hr light, 10 hr dark, lights on at 19:00) in Plexiglas™ cages, and received food and water ad libitum.
Stereotaxic surgery was performed under pentobarbital anesthesia. The stereotaxic coordinates were: 1.1 mm anterior to the bregma, 1.8 mm lateral to the midsagittal suture at an 8° angle from the verticle line, and 4.5 mm below the dura. The nose bar was placed at the level of the interaural line. An unilateral 26-gauge guide cannula was lowered to the site and secured to the skull with dental cement. The guide cannulae were closed with a 33- gauge obturator extending 1 mm beyond the guide. The innercanulae used for the microinjections extended 3.0 mm beyond the guide to reach the anterior hypothalamus. The hamsters were microinjected with 1 μM vasopressin in a volume of 150 nL.
The vasopressin was given as a cocktail with 200 mM, 20 mM, 2 mM of the test compound or alone, in the vehicle, dimethylsulfoxide. Both the vasopressin and the test compound were dissolved in 100% dimethylsulfoxide. AU injections were aimed at the anterior hypothalamus. Animals were scored for flank marking for a period of 10 minutes in a clean cage. Another aspect of this invention is the use of compounds of formulae I, II, and
HI in combination with a serotonin reuptake inhibitor for use in the treatment of obsessive- compulsive disease, aggressive disorder, or depression. Compounds useful as serotonin reuptake inhibitors include but are not limited to:
Fluoxetine, N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, is marketed in the hydrochloride salt form, and as the racemic mixture of its two enantiomers. U.S. Patent No. 4,314,081 is an early reference on the compound. Robertson et al., J. Med. Chem., 31:1412 (1988), taught the separation of the R and S enantiomers of fluoxetine and showed that their activity as serotonin uptake inhibitors is similar to each other. In this document, the word "fluoxetine" will be used to mean any acid addition salt or the free base, and to include either the racemic mixture or either of the R and S enantiomers;
Duloxetine, N-methyl-3-(l-naphthalenyloxy)-3-(2-thieny])propanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Patent No. 4,956,388, which shows its high potency. The word "duloxetine" will be used here to refer to any acid addition salt or the free base of the molecule; Venlafaxine is known in the literature, and its method of synthesis and its activity as an inhibitor of serotonin and norepinephrine uptake are taught by U.S. Patent No. 4,761,501. Venlafaxine is identified as compound A in that patent;
Milnacipran (N,N-diethyl-2-aminomethyl- 1 -phenyl cyclopropanecarboxamide) is taught by U.S. Patent No. 4,478,836, which prepared milnacipran as its Example 4. The patent describes its compounds as antidepressants. Moret et al., Neuropharmacology, 24:1211-19 (1985), describe its pharmacological activities as an inhibitor of serotonin and norepinephrine reuptake;
Citalopram, l-[3-(dimethylamino)propyl]-l-(4-fluorophenyl)-l,3-dihydro-5- isobenzofurancarbonitrile, is disclosed in U.S. Patent No.4,136,193 as a serotonin reuptake inhibitor. Its pharmacology was disclosed by Christensen et al., Eur. J. Pharmacol., 41:153 (1977), and reports of its clinical effectiveness in depression maybe found in Dufour et al., Int. Clin. Psychopharmacol., 2:225 (1987), and Timmerman et al., ibid., 239;
Fluvoxamine, 5-methoxy-l-[4-(trifluoromethyl)phenyl]-l-pentanone O-(2- aminoethyl)oxime, is taught by U.S. Patent No. 4,085,225. Scientific articles about the drug have been published by Claassen et al., Brit. J. Pharmacol, 60:505 (1977); and De Wilde et al., J. Affective Disord., 4:249 (1982); and Benfield et al., Drugs, 32:313 (1986);
Paroxetine, trans-(-)-3-[( 1 ,3 -benzodioxol -5-yloxy)methyl] -4-(4- fluorophenyl)piperidine, may be found in U.S. Patent Nos. 3,912,743 and 4,007,196. Reports of the drug's activity are in Lassen, Eur. J. Pharmacol, 47:351 (1978); Hassan et al, Brit. J. Clin. Pharmacol, 19:705 (1985); Laursen et al, Acta Psychiat. Scand., 71:249 (1985); and Battegay et al, Neuropsychobiology, 13:31 (1985); and
Sertraline, (1 S-cis)-4-(3,4-dichlorophenyl)- 1 ,2,3,4-tetrahydro-N-methyl-l- naphthylamine hydrochloride, a serotonin reuptake inhibitor disclosed in U.S. Patent No. 4,536,518, is marketed as an antidepressant.
All of the above-referenced patents are hereby incorporated by reference.
The adjunctive therapy of this aspect of the present invention is carried out by administering a vasopressin Vla antagonist together with a serotonin reuptake inhibitor in any manner that provides effective levels of the compounds in the body at the same time. All of the compounds concerned are orally available and are normally administered orally, and so oral administration of the adjunctive combination is preferred. They may be administered together, in a single dosage form, or may be administered separately.
This aspect of the present invention provides a potentiation of the decrease in the concentration of vasopressin observed as an effect of administration of a vasopressin V,a antagonist by administration of a serotonin reuptake inhibitor. This aspect of the present invention is particularly suited for use in the treatment of depression and obsessive compulsive disorder. Such disorders may often be resistant to treatment with a serotonin reuptake inhibitor alone. Method Example 3. Human oxytocin binding and functional assay.
Compounds of the present invention are believed to be oxytocin agents. Oxytocin preparations and a number of oxytocin agonists are commercially available for therapeutic use. In recent years, oxytocin antagonists with antiuterotonic activity have been developed and evaluated for their potential use in the treatment of preterm labor and dysmenorrhyea (Pavo et al, J. Med. Chem., 37:255-259 (1994); Akerlund et al, Br. J. Obstet. Gynaecol, 94: 1040-1044 (1987); Akerlund et al., Br. J. Obstet. Gynaecol, 86:484-487 (1979)). The oxytocin antagonist atosiban has been studied clinically and resulted in a more significant inhibition of preterm contractions than did placebo (Goodwin et al, Am. J. Obstet. Gynecol. , 170:474 (1994)).
The human oxytocin receptor has been cloned and expressed (Kimura et al, Nature, 356: 526-529 ( 1992)), it is identified under the accession number X64878. To demonstrate the affinity of the compounds of the present invention for the human oxytocin receptor, binding studies were performed using a cell line expressing the human oxytocin receptor in 293 cells (henceforth referred to as the OTR cell line) substantially by the procedure described by Morel et al. {Nature, 356: 523-526 (1992)). The 293 cell line is a permanent line of primary human embryonal kidney cells transformed by sheared human adenovirus type 5 DNA. It is identified as ATCC CRL- 1533.
The OTR cell line was grown in DMEM (Delbecco's Modified Essential Medium, Sigma, St. Louis, MO, USA) with 10% fetal bovine serum, 2 mM L-glutamine, 200 μg hygromycin (Sigma, St. Louis, MO, USA) and 250 μg/ml G418 (Gibco, Grand Island, NY, USA). To prepare membranes, OTR cells were grown to confluency in 20 roller bottles. Cells were dissociated with enzyme-free cell dissociation medium (Specialty Media, Lavallette, NJ, USA) and centrifuged at 3200 rpm for 15 minutes. The pellet was resuspended in 40 mL of Tris-HCl (tris[hydroxymethyl]aminomethane hydrochloride) buffer (50 mM, pH 7.4) and homogenized for 1 minute with a Tekmar Tissumizer (Cincinnatti, OH USA). The suspension was centrifuged at 40,000 x g for 10 minutes. The pellet was resuspended and centrifuged as above. The final pellet was suspended in 80 mL of Tris 7.4 buffer and stored in 4 mL aliquots at -800C. For assay, aliquots were resuspended in assay buffer and diluted to 375 μg protein per mL. Protein concentration was determined by BCA assay (Pierce, Rockford, IL, USA). Assay buffer was 50 mM Tris-HCl (tris[hydroxymethyl]aminomethane hydrochloride), 5 mM MgCb, and 0.1% bovine serum albumin at pH 7.4. The radioligand for binding assays was [3H]oxytocin ([tyrosyl-2,6-3H]oxytocin, 48.5 Ci/mmol, DuPont NEN, Boston, MA, USA). The order of additions was 195 μL assay buffer, 200 μL OTR membranes (75 μg protein) in assay buffer, 5 μL of test agent in dimethylsulfoxide (DMSO) or DMSO alone, and 100 μL [3H]oxytocin in assay buffer (final concentration 1.0 nM). Incubations were for one hour at room temperature. Bound radioligand was separated from free by filtration on a Brandel cell harvester (Gaithersburg, MD, USA) through Whatman GF/B glass-fiber filters that had been soaked for 2 hours in 0.3% polyethylenimine. The filters were washed with ice-cold 50 mM Tris-HCl (pH 7.7 at 25 0C) and the filter circles were placed in scintillation vials, to which were then added 5 mL Ready Protein Plus™ scintillation fluid, and counted in a liquid scintillation counter. All incubations were in triplicate, and dose-inhibition curves consisted of total binding, nonspecific binding (100 μM oxytocin, Sigma, St. Louis, MO, USA), and 6 or 7 concentrations of test agent encompassing the IC50. Total binding was typically about 1,000 cpm and nonspecific binding about 200 cpm. IC so values were calculated by nonlinear least- squares curve-fitting to a 4-parameter logistic model. Certain compounds of formula I have shown affinity for the oxytocin receptor.
Several bioassays are available to determine the agonist or antagonist character of compounds exhibiting affinity at the oxytocin receptor. One such assay is described in U.S. Patent No. 5,373,089, hereby incorporated by reference. Said bioassay is derived from procedures described in a paper by Sawyer et al. {Endocrinology, 106:81 (1980)), which in turn was based on a report of Holton (Brit. J. Pharmacol., 3:328 (1948)). The assay calculations for pA∑ estimates are described by Schild (Brit. J. Pharmacol, 2: 189 (1947)). Assay Method: 1. Animals: a 1.5 cm piece of uterus from a virgin rat (Holtzman) in natural estrus is used for the assay.
2. Buffer/Assay Bath: The buffer used is Munsicks. This buffer contains 0.5 mM Mg2+. The buffer is gassed continuously with 95% oxygen/5% carbon dioxide giving a pH of 7.4. The temperature of the assay bath is 37 0C. A lO mL assay bath is used that contains a water jacket for maintaining the temperature and inlet and outlet spikets for adding and removing buffer.
3. Polygraph/transducer: The piece of uterine tissue used for the assay is anchored at one end and connected to a Statham Strain Gauge Force Transducer at the other end which in turn is attached to a Grass Polygraph Model 79 for monitoring the contractions. 4. Assay Protocol:
(a) The tissue is equilibrated in the assay bath for one hour with washing with new buffer every 15 minutes. One gram of tension is kept on the tissue at all times.
(b) The tissue is stimulated initially with oxytocin at 10 nM to acclimate the tissue and with 4 mM potassium chloride (KCl) to determine the maximum contractile response.
(c) A cumulative dose response curve is then done with oxytocin and a concentration of oxytocin equivalent to approximately 80% of the maximum is used for estimating the pA2 of the antagonist. (d) The tissue is exposed to oxytocin (Calbiochemical, San Diego, CA) for one minute and washed out. There is a three minute interval before addition of the next dose of agonist or antagonist. When the antagonist is tested, it is given five minutes before the agonist. The agonist is given for one minute. All responses are integrated using a 7P10 Grass Integrator. A single concentration of oxytocin, equal to 80% of the maximum response, is used to test the antagonist. Three different concentrations of antagonists are used, two that will reduce the response to the agonist by less than 50% and one that will reduce the response greater than 50% (ideally this relation would be 25%, 50% and 75%). This is repeated three times for each dose of antagonist for a three point assay.
(e) Calculations for pA2-The dose-response (DR) ratios are calculated for antagonist and a Schild's Plot is performed by plotting the Log (DR-I) vs. Log of antagonist concentration. The line plotted is calculated by least-squares regression analysis. The pA2 is the concentration of antagonist at the point where the regression line crosses the 0 point of the Log (DR-I) ordinate. The pA^ is the negative Log of the concentration of antagonist that will reduce the response to the agonist by one-half. Oxytocin is known for its hormonal role in parturition and lactation. Oxytocin agonists are useful clinically to induce lactation; induce or augment labor; control postpartum uterine atony and hemmorhage; cause uterine contraction after cesarean section or during other uterine surgery; and to induce therapeutic abortion. Oxytocin, acting as a neurotransmitter in the central nervous system, also plays an important role in the expression of central functions such as maternal behavior, sexual behavior (including penile erection, lordosis and copulatory behavior), yawning, tolerance and dependance mechanisms, feeding, grooming, cardiovascular regulation and thermoregulation (Argiolas and Gessa, Neuroscience and Biobehavioral Reviews, 15:217-231 (1991)). Oxytocin antagonists find therapeutic utility as agents for the delay or prevention of premature labor; or to slow or arrest delivery for brief periods in order to undertake other therapeutic measures.
Method Example 4. Tachykinin receptor binding assay. Compounds of the present invention are believed to be tachykinin agents. Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's. Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin 1, and neurokinin α), and neurokinin B (also known as neuromedin K and neurokinin β). See, J.E. Maggio, Peptides, 6 (Supplement 3): 237-243 (1985) for a review of these discoveries.
Tachykinins are widely distributed in both the central and peripheral nervous systems. When released from nerves, they exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues. The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-I, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability. Recent publications have described novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non- peptidyl tachykinin receptor antagonists are found in European Patent Publication 591,040 Al, published April 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published January 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published March 3, 1994; Patent Cooperation Treaty publication WO 93/011609, published January 21, 1993, Patent Cooperation Treaty publication WO 94/26735, published November 24, 1994. Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See, e.g., J. Jukic et al, Life Sciences, 49: 1463-1469 (1991); N. Kucharczyk et al. Journal of Medicinal Chemistry, 36: 1654-1661 (1993); N. Rouissi et al., Biochemical and Biophysical Research Communications, 176:894-901 (1991).
Method Example 5. NK-I Receptor Binding Assay. Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan et al. Journal of Immunology. 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1 x 106 cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM l25I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4 0C.
The IM9 cell line is a well-characterized cell line which is readily available to the public. See, e.g., Annals of the New York Academy of Science, 190:221-234 (1972); Nature (London), 251:443-444 (1974); Proceedings of the National Academy of Sciences (USA), 71 :84-88 ( 1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 μg/mL gentamicin sulfate and 10% fetal calf serum.
The reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Specific binding of labeled substance P was determined in the presence of 20 nM unlabeled ligand. Method Example 6. NK-2 Receptor Binding Assay. The CHO-hNK-2R cells, a
CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm2 flasks or roller bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum. The gene sequence of the human NK-2 receptor is given in N.P. Gerard et al., Journal of Biological Chemistry, 265:20455-20462 (1990).
For preparation of membranes, 30 confluent roller bottle cultures were dissociated by washing each roller bottle with 10 ml of Dulbecco's phosphate buffered saline (PBS) without calcium and magnesium, followed by addition of 10 ml of enzyme-free cell dissociation solution (PBS-based, from Specialty Media, Inc.). After an additional 15 minutes, the dissociated cells were pooled and centrifuged at 1,000 RPM for 10 minutes in a clinical centrifuge. Membranes were prepared by homogenization of the cell pellets in 300 mL 50 mM Tris buffer, pH 7.4 with a Tekmar® homogenizer for 10-15 seconds, followed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckman JA- 14® rotor. The pellets were washed once using the above procedure, and the final pellets were resuspended in 100-120 mL 50 mM Tris buffer, pH IA, and 4 ml aliquots stored frozen at -700C. The protein concentration of this preparation was 2 mg/mL.
For the receptor binding assay, one 4-mL aliquot of the CHO-hNK-2R membrane preparation was suspended in 40 mL of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 μg/mL chymostatin. A 200 μL volume of the homogenate (40 μg protein) was used per sample. The radioactive ligand was [l2SI]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci/mmol. The ligand was prepared in assay buffer at 20 nCi per 100 μL; the final concentration in the assay was 20 pM. Non-specific binding was determined using 1 μM eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration- response curve.
All samples and standards were added to the incubation in 10 μL dimethylsulfoxide (DMSO) for screening (single dose) or in 5 μL DMSO for IC so determinations. The order of additions for incubation was 190 or 195 μL assay buffer, 200 μL homogenate, 10 or 5 μL sample in DMSO, 100 μL radioactive ligand. The samples were incubated 1 hr at room temperature and then filtered on a cell harvester through filters which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 mL of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 x 75 mm polystyrene tubes and counted in a gamma counter.
Tachykinin receptor antagonists are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin. These clinical conditions may include disorders of the central nervous system such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, AEDS-associated dementia, and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as peripheral neuropathy, such as diabetic and chemotherapy-induced neuropathy, and post-herpetic and other neuralgias; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis; disorders of the musculoskeletal system, such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy, ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatites; addiction disorders such as alcoholism; stress-related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal disorders or diseases associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease, emesis, and irritable bowel syndrome; disorders of bladder function such as bladder detrusor hyper-reflexia and incontinence; artherosclerosis; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; irritative symptoms of benign prostatic hypertrophy; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine, and Raynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine.
NK-I antagonists are useful in the treatment of pain, especially chronic pain, such as neuropathic pain, post-operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.
In addition to pain, NK-I antagonists are especially useful in the treatment and prevention of urinary incontinence; irritative symptoms of benign prostatic hypertrophy; motility disorders of the gastrointestinal tract, such as irritable bowel syndrome; acute and chronic obstructive airway diseases, such as bronchospasm, bronchopneumonia, asthma, and adult respiratory distress syndrome; artherosclerosis; inflammatory conditions, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenic inflammation, allergies, rhinitis, cough, dermatitis, urticaria, psoriasis, conjunctivitis, emesis, irritation-induced miosis; tissue transplant rejection; plasma extravasation resulting from cytokine chemotherapy and the like; spinal cord trauma; stroke; cerebral stroke (ischemia); Alzheimer's disease; Parkinson's disease; multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety; and depression.
NK-2 antagonists are useful in the treatment of urinary incontinence, bronchospasm, asthma, adult respiratory distress syndrome, motility disorders of the gastrointestinal tract, such as irritable bowel syndrome, and pain. In addition to the above indications the compounds of the invention may be useful in the treatment of emesis, including acute, delayed, or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formulae I, II, and EU are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy.
Examples of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl sulfonates, and other compounds with an alkylating action, such as nitrosoureas, cisplatin, and dacarbazine; antimetabolites, for example, folic acid, purine, or pyrimidine antagonists; mitotic inhibitors, for example vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D.J. Stewart in NAUSEA AND VOMITING: RECENT RESEARCH AND CLINICAL ADVANCES, (J.
Kucharczyk et al., eds., 1991), at pages 177-203. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin, daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, and chlorambucil. R.J. Gralla et al.. Cancer Treatment Reports, 68: 163-172 (1984). The compounds of formulae I, II, and EQ may also be of use in the treatment of emesis induced by radiation, including radiation therapy such as in the treatment of cancer, or radiation sickness; and in the treatment of post-operaive nausea and vomiting.
Method Example 7. Premenstrual Dysmenorrhoea Dysphoria. Antagonism of vasopressin V]3 receptor has also been shown to alleviate or prevent the symptoms of premenstrual dysmenorrhoea dysphoria (PMDD) and premenstrual dysmenorrhoea (PMD). See generally, Brouard et al, in BJOG 107:614-19 (May 2000). Treatment is illustratively given shortly before the onset of menstruation as a preventative treatment of dysmenorrhoea.
An illustrative assay of vasopressin V)a antagonists described herein includes a double-blind, randomised, placebo-controlled, cross-over trial in complete block design (such as including three periods and three treatments). Illustrative treatment groups include women ages 18-35 years suffering from primary dysmenorrhoea. Daily dosing is made of either placebo or drug, where the drug dosing is illustratively about 100 mg to about 300 mg of a compound as described herein. The dosing is given in the window from about 4 hours to about three days prior to the onset of bleeding and/or menstrual pain. Alternatively, patients may also be treated with a second daily dose.
Success outcomes include self-reporting of menstrual pain intensity by means of a visual analogue scale, self-rating of symptoms of dysmenorrhoea (including back and pelvic pain) in relation to functional capacity (using a Sultan score), and self-assessment of menstrual blood loss in a menstrual diary record.
Formulation Example 1. Hard gelatin capsules containing the following ingredients are prepared:
Figure imgf000072_0001
The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities. Formulation Example 2. A tablet formula is prepared using the ingredients below:
Figure imgf000072_0002
The components are blended and compressed to form tablets, each weighing 240 mg. Formulation Example 3. A dry powder inhaler formulation is prepared containing the following components:
Figure imgf000072_0003
The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
Formulation Example 4. Tablets, each containing 30 mg of active ingredient, are prepared as follows:
Figure imgf000073_0001
The active ingredient, starch, and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50- 60 0C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
Formulation Example 5. Capsules, each containing 40 mg of medicament are made as follows:
Figure imgf000073_0002
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
Formulation Example 6. Suppositories, each containing 25 mg of active ingredient are made as follows:
Figure imgf000073_0003
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Formulation Example 7. Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows:
Figure imgf000074_0001
The medicament, sucrose, and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
Formulation Example 8. Capsules, each containing 15 mg of medicament, are made as follows:
Figure imgf000074_0002
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled "into hard gelatin capsules in 425 mg quantities.
Formulation Example 9. An intravenous formulation may be prepared as follows:
Figure imgf000075_0001
Formulation Example 10. A topical formulation may be prepared as follows:
Figure imgf000075_0002
The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
Formulation Example 11. Sublingual or buccal tablets, each containing 10 mg of active ingredient, maybe prepared as follows:
Figure imgf000075_0003
The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90 0C. When the polymers have gone into solution, the resulting solution is cooled to about 50-55 0C and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size. Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent No. 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood- brain barrier. One such implantable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, which is herein incorporated by reference.
Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions that can transiently open the blood-brain barrier.
The type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient. While the invention has been illustrated and described in detail in the foregoing description, such an illustration and description is to be considered as exemplary and not restrictive in character, it being understood that only the illustrative embodiments have been shown and described and that all changes and modifications that come within the spirit of the invention are contemplated as further embodiments.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula
Figure imgf000077_0001
and pharmaceutically acceptable salts thereof; wherein: S n is an integer from 0 to about 5;
A is R5O-, monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen;
A1 is R5 O-, monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen; 0 B is hydroxy or a derivative thereof, optionally substituted alkoxy, optionally substituted acyloxy, or optionally substituted aroyloxy, and B' is hydrogen, hydroxy or a derivative thereof, optionally substituted alkoxy, optionally substituted acyloxy, or optionally substituted aroyloxy; or B and B' are taken together with the attached carbon to form a carbonyl group, or a derivative thereof; 5 R1 is hydrogen or C i -Ce alkyl;
R2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting of -CO∑R8, -CONR8R8', and -NR8CCOR9);
R3 is an amino, amido, acylamido, or ureido group, which is optionally 0 substituted; or R3 is a nitrogen-containing heterocyclyl group attached at a nitrogen atom;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl; 5 R5 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(Ci-C4 alkyl), and R6R7N-(C2-C4 alkyl); where heterocyclyl is in each occurrence independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said moφholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinυclidinyl is optionally N-substituted with C1-C4 alkyl or optionally substituted aryl(Ci-C4 alkyl);
R5 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(Ci-C4 alkyl), and R6R7N-(C2-C4 alkyl); where heterocyclyl is in each occurrence independently selected from tetrahydrofiiryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally N-substituted with C 1-C4 alkyl or optionally substituted aryl(Ci-C4 alkyl);
R6 is in each instance independently hydrogen or alkyl; and R7 is in each instance independently alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R6 and R7 in each instance are independently taken together with the attached nitrogen atom to form an optionally substituted heterocycle, such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally N-substitued with R13; R8 and R8 are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R8 and R8' are taken together with the attached nitrogen atom to form an heterocycle, such as optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl;
R9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R8R8N-(Ci-C4 alkyl);
R13 is in each instance independently selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aryloyl.
2. The compound of claim 1 of the formula
Figure imgf000078_0001
and pharmaceutically acceptable salts thereof; where Ar is an optionally substituted aryl group.
3. The compound of claim 1 of the formula
Figure imgf000079_0001
and pharmaceutically acceptable salts thereof; where Ar1 and Ar are each an independently selected optionally substituted aryl group.
4. The compound of claim 1 of the formula
Figure imgf000079_0002
and pharmaceutically acceptable salts thereof; where Ar1 and Ar2 are each an independently selected optionally substituted aryl group; X and X1 are each independently selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, and heterocyclyl, heterocyclyl-(CrC4 alkyl), R6R7N-, and R6R7N-(C2-C4 alkyl), where in each occurrence heterocyclyl is independently selected; and R14 and R14 are each independently selected from hydroxy, alkyl, alkoxycarbonyl, and benzyl; or X and R14 and/or X1 and R14' are each independently taken together with the attached nitrogen to form an independently selected heterocyclic ring.
5. A compound of the formula
Figure imgf000079_0003
and pharmaceutically acceptable salts thereof; where R1, R2, R3, R4, n, and A', are as defined in claim 1.
6. The compound of any one of claims 1 to 5 wherein A is monosubstituted amino.
7. The compound of any one of claims 1 to 5 wherein A is disubstituted amino.
8. The compound of any one of claims 1 to 5 wherein A is optionally substituted nitrogen-containing heterocycle attached at a nitrogen amino.
9. The compound of any one of claims 1 to 5 wherein A' is monosubstituted amino.
10. The compound of any one of claims 1 to 5 wherein A' is disubstituted amino.
11. The compound of any one of claims 1 to 5 wherein A' is optionally substituted nitrogen-containing heterocycle attached at a nitrogen amino.
12. The compound of any one of claims 1 to 5 wherein A is monosubstituted amino of the formula XNH-, where X is selected from the group consisting OfCi-C6 alkyl, C3- Ce cycloalkyl, (C1-C4 alkoxy)-(Ci-C4 alkyl), optionally substituted aryl, optionally substituted aryl(C]-C4 alkyl), optionally substituted aryl(C3-C7 cycloalkyl), optionally substituted indan-1- yl, optionally substituted indan-2-yl, optionally substituted 1 ,2,3,44etrahydronaphth-l-yl, optionally substituted l,2,3,4-tetrahydronaphth-2-yl, Y, Y-(C1-C4 alkyl), R6R7N-, and R6R7N- (C2-C4 alkyl).
13. The compound of any one of claims 1 to 5 wherein A is disubstituted amino of the formula R14XN-; where R14 is selected from the group consisting of hydroxy, Ci- C6 alkyl, CpC4 alkoxycarbonyl, and benzyl; and where X is selected from the group consisting of Ci-Ce alkyl, C3-C8 cycloalkyl, (C1-C4 alkoxy)-(Ci-C4 alkyl), optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), optionally substituted aryl(C3-C7 cycloalkyl), optionally substituted indan-1-yl, optionally substituted indan-2-yl, optionally substituted
1,2,3,4-tetrahydronaphth-l-yl, optionally substituted l,2,3,4-tetrahydronaphth-2-yl, Y, Y-<Ci- C4 alkyl), R6R7N-, and R6R7N-(C2-C4 alkyl).
14. The compound of any one of claims 1 to 5 wherein A is an optionally substituted nitrogen-containing heterocycle attached at a nitrogen selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-l-ylmethyl)pyrrolidin-l-yl, and l,2,3,4-tetrahydroisoquinolin-2-yl.
15. The compound of claim 14 wherein the optionally substituted heterocycle is substituted with a substituent selected from the group consisting of optionally substituted C, -C6 alkyl, optionally substituted C3-C8 cycloalkyl, Ci-C4 alkoxycarbonyl, CrCs alkylcarbonyloxy, optionally substituted aryl, optionally substituted aryl(C|-C4 alkyl), optionally substituted aryl(Ci-C4 alkyloxy), optionally substituted aryl(Ci-C4 alkylcarbonyloxy), R6R7N-, and R6R7N-(C1-C4 alkyl).
16. The compound of claim 14 wherein the optionally substituted heterocycle is piperidinyl optionally substituted at the 4-position with hydroxy, Cj -C6 alkyl, C3- Ce cycloalkyl, C1-C4 alkoxy, (C1-C4 alkoxy)carbonyl, (hydroxy(C2-C4 alkyloxy))-(C2-C4 alkyl), R6R7N-, R6R7N-(Ci-C4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), orpiperidin-l-yl(Cι-C4 alkyl).
17. The compound of claim 14 wherein the optionally substituted heterocycle is piperazinyl optionally substituted at the 4-position with CpC6 alkyl, C3-Cg cycloalkyl, optionally substituted aryl, optionally substituted aryl(Cι-C4 alkyl), α-methyibenzyl, N-(Ci-C5 alkyl) acetamid-2-yl, N-(C3-Cβ cycloalkyl) acetamid-2-yl, R6R7N-, or (C1-C4 alkoxy)carbonyl .
18. The compound of claim 14 wherein the optionally substituted heterocycle is homopiperazinyl optionally substituted in the 4-position with C]-C4 alkyl, aryl, or aryl(Ci-C4 alkyl).
19. The compound of any one of claims 1 to 5 wherein A' is monosubstituted amino of the formula XNH-, where X is selected from the group consisting of Ci-C6 alkyl, C3-C8 cycloalkyl, (Ci-C4 alkoxy)-(C,-C4 alkyl), optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), optionally substituted aryl(C3-C7 cycloalkyl), optionally substituted indan-1-yl, optionally substituted indan-2-yl, optionally substituted 1,2,3,4-tetrahydronaphth-l-yl, optionally substituted l,2,3,4-tetrahydronaphth-2-yl, Y, Y<Ci- C4 alkyl), R6R7N-, and R6R7N-(C2-C4 alkyl).
20. The compound of any one of claims 1 to 5 wherein A' is disubstituted amino of the formula R14XN-; where R14 is selected from the group consisting of hydroxy, Q-
Cg alkyl, C]-C4 alkoxycarbonyl, and benzyl; and where X is selected from the group consisting OfCi-C6 alkyl, C3-C8 cycloalkyl, (CrC4 alkoxy)-(d-C4 alkyl), optionally substituted aryl, optionally substituted 3TyI(CpC4 alkyl), optionally substituted 8IyI(C3-C7 cycloalkyl), optionally substituted indan-1-yl, optionally substituted indan-2-yl, optionally substituted 1,2,3,4-tetrahydronaphth-l-yl, optionally substituted l,2,3,4-tetrahydroπaphth-2-yl, Y, Y<Ci - C4 alkyl), R6R7N-, and R6R7N-(C2-C4 alkyl).
21. The compound of any one of claims 1 to 5 wherein A1 is an optionally substituted nitrogen-containing heterocycle attached at a nitrogen selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-l-ylmethyl)pyrrolidin-l-yl, and l,2,3,4-tetrahydroisoquinolin-2-yl.
22. The compound of claim 21 wherein the optionally substituted heterocycle is substituted with a substituent selected from the group consisting of optionally substituted CpC6 alkyl, optionally substituted C3-Cg cycloalkyl, CrC4 alkoxycarbonyl, CrCs alkylcarbonyloxy, optionally substituted aryl, optionally substituted aτyl(Ci-C4 alkyl), optionally substituted aryl(Ci-C4 alkyloxy), optionally substituted aryl(Ci-C4 alkylcarbonyloxy), R6R7N-, and R6R7N-(Ci-C4 alkyl).
23. The compound of claim 21 wherein the optionally substituted heterocycle is piperidinyl optionally substituted at the 4-position with hydroxy, Cj-Ce alkyl, C3- C8 cycloalkyl, C]-C4 alkoxy, (Q -C4 alkoxy)carbonyl, (hydroxy(C2-C4 alkyloxy)HC2-C4 alkyl), R6R7N-, R6R7N-(CpC4 alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(Ci-G» alkyl), or piperidin-l-yl(Cι-C4 alkyl).
24. The compound of claim 21 wherein the optionally substituted heterocycle is piperazinyl optionally substituted at the 4-position with Ci-Ce alkyl, C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted aryl(Ci-C4 alkyl), α-methylbenzyl, N-(Ci-C5 alkyl) acetamid-2-yl, N-(C3-C8 cycloalkyl) acetamid-2-yl, R6R7N-, or (C1-C4 alkoxy)carbonyl .
25. The compound of claim 21 wherein the optionally substituted heterocycle is homopiperazinyl optionally substituted in the 4-position with Ci-C4 alkyl, aryl, or aryl(CrC4 alkyl).
26. The compound of any one of claims 1 to 5 wherein B and B1 are taken together with the attached carbon to form a carbonyl group.
27. The compound of any one of claims 1 to 5 wherein B is -OH, and B1 is hydrogen.
28. The compound of any one of claims 1 to S wherein R is a structure selected from the group consisting of
Figure imgf000083_0001
Figure imgf000083_0002
where R10 and R1 ' are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkylcarbonyloxy, diphenylmethoxy, triphenylmethoxy, and the like; and R12 is selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted aryloyl, and the like.
29. The compound of claim 28 wherein R3 is a structure selected from the group consisting of
Figure imgf000083_0003
Figure imgf000083_0004
30. The compound of claim 28 wherein R3 is a structure selected from the group consisting of
Figure imgf000083_0005
31. The compound of claim 28 wherein R3 is a structure selected from the group consisting of
Figure imgf000084_0001
Figure imgf000084_0002
32. The compound of claim 28 wherein R3 is
Figure imgf000084_0003
33. The compound of any one of claims 1 to 5 wherein n is 0, or n is 1 or 2.
34. The compound of any one of claims 1 to 5 wherein R4 is optionally substituted aryl(Ci-C4 alkyl), optionally substituted aryl(C2-C4 alkenyl), or optionally substituted aryl(C2-C4 alkynyl).
35. The compound of any one of claims 1 to 5 wherein R4 is optionally substituted aryl(C2-C4 alkenyl).
36. The compound of claim 28 wherein R10 is optionally substituted phenyl.
37. The compound of any one of claims 1 to 5 wherein A is optionally substituted aryl(C,-C4 alkyl).
38. ' The compound of any one of claims 1 to 5 wherein A1 is optionally substituted piperidinyl or optionally substituted piperazinyl.
39. A pharmaceutical composition comprising the compound of any one of the preceding claims, and a pharmaceutically acceptable carrier, diluent, or excipient, where the compound is present in an amount effective to treat a disease state responsive to antagonism of one or more vasopressin receptors in a mammal in need of such treatment
40. A method for treating a disease state responsive to antagonism of one or more vasopressin receptors in a mammal in need of such treatment, comprising the step of administering to the mammal a pharmaceutically effective amount of the compound of any one of claims 1 to 38 or the pharmaceutical composition of claim 39.
41. The method of claim 40 wherein the disease state is a stress-related affective illness.
42. The method of claim 40 wherein the disease state is selected from the group consisting of anxiety, depression, obsesive-compulsive disorder, and impulsivity.
43. The method of claim 40 wherein the disease state is emesis.
44. The method of claim 40 wherein the disease state is a cardiovascular disorder.
45. The method of claim 44 wherein the cardiovascular disorder includes platelet aggregation.
46. The method of claim 44 wherein the cardiovascular disorder is congestive heart failure.
47. The method of claim 40 wherein the disease state is treated in conjunction with a serotonin reuptake inhibitor.
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WO2012043791A1 (en) 2010-10-01 2012-04-05 大正製薬株式会社 1,2,4-triazolone derivative
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CN117649950A (en) * 2024-01-29 2024-03-05 北京大学第三医院（北京大学第三临床医学院） Oxytocin pharmacokinetics model, and construction method and application thereof

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