IE902294A1 - Alkynyl amines that regulate cholinergic neurotransmission - Google Patents

Alkynyl amines that regulate cholinergic neurotransmission

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Publication number
IE902294A1
IE902294A1 IE229490A IE229490A IE902294A1 IE 902294 A1 IE902294 A1 IE 902294A1 IE 229490 A IE229490 A IE 229490A IE 229490 A IE229490 A IE 229490A IE 902294 A1 IE902294 A1 IE 902294A1
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mmol
hydrogen
loweralkyl
nmr
functionalized
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IE229490A
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Abbott Lab
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/46—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/44—Two oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

A compound that regulates cortical cholinergic neurotransmission of formula (I), wherein A is (1) a functionalized lactam; (2) a a functionalized azacycloalkyl group; (3) a functionalized carbonylaminomethyl group; or (4) a functionalized oxyalkyl group; and B is (1) a functionalized pyrrolidin-2-yl group; (2) a functionalized aminomethyl group; (3) a 5-membered heterocycle containing two heteroatoms; or (4) a piperidine derivative; or a pharmaceutically acceptable salt thereof.

Description

The present invention relates to compounds that regulate (stimulate or antagonize) cortical cholinerginc neurotransmission, processes for making such compounds, synthetic intermediates employed in these processes and methods for treating cognitive disorders or neurological and mental illnesses due to dysfunction of acetylcholine systems .
Alzheimer's Disease (AD) is a degenerative brain disease which affects about one in six individuals past the age of sixty. Patients with AD suffer memory loss, personality changes and symptoms of cortical disconnection . -2Although a number of brain neurochemical systems are affected (P. Davies, Med. Res. Rev. . 2., 221-236, (1983)) in AD, a consistent and profound loss (50-90%) of cholinergic neurons in the basal forebrain has been linked to cortical cholinergic deficit using presynaptic cholinergic markers in neocortex and hippocampus, such as choline acetyltransferase activity, acetylcholinesterase activity and acetylcholine synthesis (P. J. Whitehouse et. al., CRC Crit. Rev. Clin, Neurobiol., 1, 319-339, (1985).
Postsynaptic muscarinic acetylcholine receptors, however, are generally preserved in AD patients. Therefore, muscarinic cholinergic agonists capable of stimulating such sites directly are useful in correcting the cholinergic deficiency in AD and provide treatment of the memory impairment symptom of cerebral insufficiency (F. V. DeFeudis, Drugs of Today, 2Δ., (7), 473-490, (1988)).
Existing agonists, however, are therapeutically suboptimal. This is due to unfavorable pharmacokinetics (e.g., arecoline), poor potency and lack of selectivity (e.g., RS-86) or poor CNS penetration (e.g., carbachol).
In addition, known agents have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor. Peripheral side effects include miosis, lacrimation and defecation (M. Davidson, E. Hollander, Z. Zemishlany, L, J, Cohen, R. C. Mohs, and K.
Current Research in Alzheimer Therapy; E.
R. Becker, Ed.; Taylor & Francis: New York, 1988; pp 333336) .
It has also been reported that a subpopulation of muscarinic receptors reside on the presynaptic cortical L. Davis In Giacobini and -3cholinergic neurons and appear to act as autoreceptors regulating the release of endogenous acetylcholine (E. Mutschler, G. Lambrecht, TIPS Suppl: Subtypes of Muscarinic Receptors, Eds B. Hirschowitz, et. al., 1985, 39-45; R. A. North, Β. E. Slack, J. Physiol.. 368. 435452, (1985)). In addition, there is also data supporting the existance of muscarinic receptors on cortical gabaergic interneurons (D. A. McCormick, D. A. Prince, Proc.Sci. USA, £2, 6344-6348, (1985); JL· Physiol 375, 169-194, (1986)). Stimulation of these receptors may be involved in the release of the inhibitory neurotransmitter GABA. Therefore, compounds capable of antagonizing the effects resulting from the stimulation of one or both of these muscarinic receptor populations may also be useful in correcting the cholinergic deficiency in AD via more indirect mechanisms.
Summary of the Invention In accordance with the present invention, there are compounds that regulate (stimulate or antagonize) cortical cholinergic neurotransmission of the formula I: A-C=C-B (I) or a pharmaceutically acceptable salt thereof.
A is (1) a functionalized lactam; (2) a functionalized azacycloalkyl group; (3) a functionalized carbonylaminomethyl group; or -4 (4) a functionalized oxyalkyl group.
B is (1) a functionalized pyrrolidin-2-yl group; (2) a functionalized aminomethyl group; (3) a 5-membered heterocycle containing two heteroatoms; or (4) a piperidine derivative.
The term functionalized lactam as used herein includes wherein Rl is (i) -C(0)-, (ii) -S(O)2- or (iii) -(CH(R4))r- wherein R4 is independently selected at each occurrence from hydrogen, loweralkyl, phenyl and substituted phenyl and r is 1 to 3; R2 is (i) -CH2-, (ii) -0(iii) -S- or (iv) -N(R26)- wherein R26 is hydrogen, loweralkyl, -5aryl, alkanoyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or an N-protecting group; R3 is absent or -(C(Rg)(R7))3- wherein Rg and R7 are independently selected at each occurrence from hydrogen, loweralkyl, phenyl and substituted phenyl and s is 1 to 3; R21 and R22 are independently selected from hydrogen and loweralkyl; and R23 is one, two or three substituents independently selected from (A) hydrogen, (ii) loweralkyl, (iii) haloalkyl, (iv) halo, (v) aryl, (vi) - (CH2) m-Y-(CH2) p-R24 wherein m is 0 to 3, p is 0 to 3, Y is -0-, -S- or -N(R2s)- wherein R25 is hydrogen, loweralkyl, arylalkyl or an N-protecting group and R24 is hydrogen, loweralkyl, alkenyl, alkynyl, haloalkyl or aryl or (vii) -T-G-W-R24 wherein G is -C(0)- or -S(0)2~ and T and W are independently absent or independently selected from -0-, -S- and -N(R25)~ wherein R25 is defined as above and R24 is defined as above.
The term functionalized azacycloalkyl group as used herein includes rRi wherein R2 is defined as above, Re is (i) loweralkyl, (ii) alkoxy, (iii) phenyl, (iv) substituted phenyl, (v) phenoxy, (vi) substituted phenoxy, (vii) benzyloxy or (viii) substituted benzyloxy; R23 is defined as above; t is 1 to 3 and u is 1 to 3.
The term functionalized carbonylaminomethyl group as used herein includes CH2Re wherein R9 is (i) loweralkyl or -7(ii) loweralkyl substituted with a substituent selected from -OR28 wherein R28 is hydrogen, loweralkyl, aryl, alkanoyl, alkoxycarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, -SR28 wherein R28 is defined as above and -N(R26) (R27) wherein R26 is defined as above and R27 is hydrogen or loweralkyl; and RlO is (i) loweralkyl or (ii) loweralkyl substituted with a substituent selected from -OR26 wherein R26 is independently defined as above, -SR26 wherein R26 is independently defined as above and -N-(R26) (R27) wherein R26 is independently defined as above and R27 is hydrogen or loweralkyl.
The term functionalized oxyalkyl group as used herein includes R40-O-(C(R21) (R22) ) e“ wherein e is 1 to 6; R21 and R22 are defined as above; and R40 is (i) loweralkyl, (ii) alkenyl, (iii) alkynyl, (iv) haloalkyl, (v) aryl, (vi) - (CH2) a-Y- (CH2) d_R24 wherein a is 1 to 3, d is 0 to 3, Y is defined as above and R24 is defined as above or (vii) —C(0)-W-R24 wherein W and R24 are defined as above .
The term functionalized pyrrolidin-2-yl group as used herein includes wherein n is 0, 1 or 2; Ru is (i) hydrogen or (ii) loweralkyl; Rl2 is (i) absent or (ii) loweralkyl; Ri3 is (i) hydrogen or (ii) loweralkyl; Ri5 is independently selected at each occurrence from (i) hydrogen and (ii) loweralkyl; R23 is independently defined as above; and the dashed bond represents a single bond or a double bond. - 9The term functionalized aminomethyl group as used herein includes Rl8 wherein Rl6 and R17 are independently selected from (i) hydrogen, (ii) loweralkyl, (iii) alkenyl and (iv) alkynyl;or Rig and R17 taken together with the adjacent nitrogen atom represents N I R23 wherein Q is (i) absent or (ii) -L-(CH2)b“ wherein L is -CH2-, -0-, -N(R26)wherein R26 is independently defined as above, -S-, -S(0)- or -S(0)2- and b is 0 or 1; and R23 is independently defined as above; and Rl8 is (i) hydrogen or (ii) -CH2R23 wherein R23 is independently defined as above . -10The term 5- or 6-membered heterocycle containing two heteroatoms as used herein includes wherein v is 1 to 3; Z is (i) NH when the dashed bond is absent or (ii) N when the dashed bond is present; X is (i) NH, (ii) O or (iii) S; Rl9 is (i) hydrogen, (ii) -OR28 wherein R28 is independently defined as above, (iii) -SR28 wherein R28 is independently defined as above, (iv) -N(R26) (R27) wherein R26 is independently defined as above and R27 is independently defined as above; and (v) -C(O)OR20 wherein R20 is hydrogen or loweralkyl; (vi) -C(O)N(R26) (R27) wherein R26 and R27 are independently defined as above; (vii) R23 is independently defined as above; and the dashed bond represents a single bond or a double bond.
The term piperidine derivative as used herein wherein • D is (i) -O(ii) -S-, (iii) -N(R26) ~ wherein R26 is independently defined as above or (iv) -CH2-; R23 is independently defined as above; R29 is (i) hydrogen or (ii) loweralkyl; and the dashed bond represents a single bond or a double bond.
The term loweralkyl or alkyl as used herein refers to straight or branched chain radicals having from 1 to 7 carbon atoms including, but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl and the like.
The term alkenyl as used herein refers to a C2 to C12 straight or branched chain of carbon atoms which -12contains a carbon-carbon double bond including, but not limited to, allyl, propenyl, butenyl, isoprenyl and the like .
The term alkynyl as used herein refers to a C2 to C12 straight or branched chain of carbon atoms which contains a carbon-carbon triple bond including, but not limited to, propargyl, butynyl and the like.
The terms alkoxy and thioalkoxy as used herein refer to -OR30 and -SR30, respectively, wherein R30 is a loweralkyl group.
The term phenoxy as used herein refers to -OR31 wherein R31 is phenyl.
The term substituted phenoxy as used herein refers to -OR32 wherein R32 is substituted phenyl as defined herein .
The term benzyloxy as used herein refers to -OCH2R33 wherein R33 is phenyl.
The term substituted benzyloxy as used herein is -OCH2R34 wherein R34 is substituted phenyl as defined herein .
The term alkanoyl as used herein refers to -C(O)R35 wherein R35 is a loweralkyl group.
The term alkoxycarbonyl as used herein refers to -C(O)OR36 wherein R36 is a loweralkyl group.
The term alkyaminocarbonyl as used herein refers to -C(O)NHR37 wherein R37 is a loweralkyl group.
The term dialkylaminocarbonyl as used herein refers to -C(O)NR38R39 wherein R38 and R39 are independently selected from loweralkyl.
The term halo or halogen as used herein refers to fluoro, chloro , bromo, or iodo. -13The term haloalkyl as used herein refers to a loweralkyl group in which one or more hydrogen atoms are substituted by halogen including, but not limited to, chloromethyl, trifluoromethyl, difluoroethyl and the like.
The term substituted phenyl as used herein refers to a phenyl group substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, alkoxycarbonyl, nitro, haloalkyl, hydroxy, amino, alkylamino and dialkylamino.
The term aryl or aryl group as used herein refers to a mono- or polycyclic aromatic carbocyclic fused or nonfused aromatic ring systems including, but not limited to, phenyl, naphthyl, indanyl, fluorenyl, (1,2,3,4)-tetrahydronaphthyl, indenyl and isoindenyl.
Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, alkoxycarbonyl, nitro, haloalkyl, hydroxy, amino, alkylamino and dialkylamino.
The term arylalkyl as used herein refers to a loweralkyl radical to which is appended an aryl group.
The term N-protected or N-protecting group as used herein refers to those groups intended to protect the Nterminus of an amino acid or peptide or to protect an amino group against undesirable reactions during a synthetic procedure or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds and includes, but is not limited to sulfonyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzoyl or an L- or DIE 902294 -14aminoacyl residue, which may itself be N-protected similarly.
Compounds of the invention which have one or more asymmetric carbon atoms can exist as the optically active compound, a particular diastereomer, the racemic mixture or a diastereomeric mixture. In addition, some of the compounds of the invention can exist as exo and endo isomers. It is to be understood that the invention covers all such isomers and mixtures thereof.
The compounds of this invention can be prepared by a general synthetic scheme as illustrated in Scheme I. Nprotected acyclic or cyclic alpha-aminoaldehydes 1, prepared from the corresponding alpha-amino acids by the known technologies in the literature, are treated with triphenyl phosphine and carbon tetrabromide under the Corey-Fuch's conditions as described in E. J. Corey, P. L. Fuchs, Tetrahedron Lett.r 36, 3769-3772, (1972). The resulting dibromo compounds 2. are then treated with 2.05 equivalents of.n-butyllithium at -78°C under nitrogen atmosphere to give the acetylide anions 2, which could be quenched with a proton source such as methanol to give the terminal alkynes 4. or quenched with paraformaldeyde to give the propargyl alcohol derivatives 2The Mannich reaction of 4. with secondary amines 2 and a formaldehyde equivalent in the presence of Cu(I) salt affords propargyl amines £. When R is -OtBu, the 8 N-protecting group can be removed by treatment with trifluoroacetic acid (TFA). The resulting secondary amines can then be acylated to give 2 (R^^=acyl group).
The hydroxyl group in compounds 2 can be further elaborated. For example, compounds 12 are prepared from -15propargyl alcohols 2 in three steps: a Mitsunobu coupling with cyclic-imides £. to give the imides 12, which are then subjected to NaBi^/MeOH reduction to give the hydroxy lactams 11. and the subsquent treatment of 11 with Et3SiH/triflouroacetic acid proceeds to give compounds 12 (Rl2=H). Simple N-alkylation provides compounds 12 which are tertiary amines.
It will be apparent to those skilled in the art that, several methods of transforming the alcohol group in compounds £. to an amide group in 12 are also well documented in the literature. For example, conversion of the alcohol group in 2 to the mesylate, tosylate, or halide, followed by the displacement of the leaving group by the appropriate amide or lactam anion affords 12 as well.
In any of the above reactions it may be necessary and/or desirable to protect any sensitive groups in the compounds. For example, amino, carboxy, hydroxy or thiol groups may be.protected in conventional manner. Thus, suitable protecting groups for hydroxy groups include silyl groups such as trimethylsilyl or dimethyl-tbutylsilyl, and etherifying groups such as tetrahydropyranyl; and for amino groups include benzyloxycarbonyl and t-butyloxycarbonyl. Carboxy groups are preferably protected in a reduced form such as in the form of their corresponding protected alcohols, which may be subsequently oxidized to give the desired carboxy group. Thio groups may be protected by disulfide formation, either with the thiol itself or with another thiol to form a mixed disulfide. The protecting groups -16may be removed at any convenient stage in the synthesis of the desired compound according to conventional techniques.
Scheme I υγ* Ph3P, CBr< °^r8 zy* Br ^N'^^Br n~BuLi O=S8 -7B°C N O^Rg Li O^Rg .0 ς 15 Ph3P, (EtO2CN)2 ^/V* «Λ/V* O^N^O H Κθ^° / NaBH«, MeOH H,CO cuci 1. TFA (Ra=OtBu) 2. R41C1 H R8^O ^N^yNy 11 OH X I TFA, Et3SiH H R.2 ^γΝγ «Λ/» -18The following examples will serve to further illustrate preparation of the novel compounds of the invention. In the Examples, THF is tetrahydrofuran; EtOAc is ethyl acetate; and ether is diethyl ether. Thin-layer chromatography (TLC) was performed on 0.25 mm E. Merck prcoated silica gel plates (60 F-254). Flash chromatography was performed on 200-400 mesh silica gel (Merck).
EXAMPLE 1 3-(2-Qxo-l-pyrrolidinyl)-1-(2(R)-pyrrolidinyl)-1-propyne hydrogen oxalate EXAMPLE la M-tert-Butoxycarbonyl-(R)-proiinal The title compound was prepared from N-tertbutoxycarbonyl-(R)-proline via a diborane reduction as described by K. E. Rittle, C. F. Homnick, G. S.
Ponticello, Β. E. Evans, J.Qrg.Chem., Al, 3016, (1982), followed by an oxidation of the resulting alcohol with sulfur trioxide-pyridine complex as described by Y.
Hamada, T. Shioiri, Chem. Pharm. Bull., 21, (5), 1921, (1982) .
EXAMPLE lb 2(R)-(2,2-Dibromoethenyl)-N-tert-butoxycarbonylpyrrolidine To a mixture of triphenylphosphine (13.0 g, 49.54 mmol), Zn dust (2.16 g, 33.0 mmol) and carbon tetrabromide (11.0 g, 33.0 mmol) was added dicholoromethane (80 mL) at room temperature under nitrogen. After stirring for 5 -19min, a solution of N-tert-butoxycarbonyl-(R)-prolinal (3.29 g, 16.5 mmol) in dicholoromethane (25 ml) was added The reaction was slightly exothermic. After stirring for 1 hr, the reaction mixture was diluted with a mixture of EtOAc/hexane (1/1) and filtered through basic alumina (0.25 inch thick)/silica gel (0.5 inch thick, 40-60 micron). The filter cake was washed with a mixture of dicholoromethane/EtOAc/hexane (1/1/1). The filtrate was concentrated and the residue was taken up in ethyl acetate/hexane (1/1) . The resulting precipitate was filtered off. After concentration of the filtrate, the residual oil was subjected to flash chromatography using EtOAc/hexane (1:6.5 -> 1:5) as the elutant. The pure solid product was isolated in 91% yield (5.31 g). TLC Rf = 0.35 (EtOAc/hexane=l:4). [a]26D = -17.4° (c 1.15, MeOH). m.p. = 65-66°C. MS(CI) m/e 354 (M+H)+. 1H NMR (DMSO-dg, 70°C, 300MHz) 6 6.57 (d, J=8.1 Hz, IH), 4.26 (ddd, J=7.9, 7.9, 4.9 Hz, IH), 3.30 (m, 2H), 2.05-2.17 (m, IH) , 1.72-1..92 (m, 2H) , 1.60-1.71 (m, IH) , 1.40 (s, 9H) . Anal, calcd. for C^^H|7Br2NO2: C, 37.21; H, 4.83; N, 3.95; Found: C, 37.45; H, 4.85; N, 3.97.
EXAMELE...LC 3-Hydroxy-l-(2(R)-N-tert-butoxycarbonylpyrrolidinyl)-1propyne To a solution of 2(R)-(2,2-dibromoethenyl)-N-tertbutoxycarbonylpyrrolidine (1.54 g, 4.34 mmol) in anhydrous THF cooled to -78°C was added a solution of n-BuLi in hexane (5.6 mL, 1.6 M, 8.92 mmol) dropwise over a period of 5 minutes under nitrogen. After stirring at -78°C for 50 minutes, powdered paraformaldehyde was added. The -20reaction mixture was allowed to graduately warm up to ambient temperature over a period of 16 hours, then quenched with saturated aquoues NaHCOg solution.
Extraction with EtOAc (3X), dried (MgSO4/Na2SO4), concentration and flash chromatography (EtOAc/hexane = 1:3 -> 1:2) provided 486 mg (50%) of the required product as a clear oil. TLC Rf = 0.12 (EtOAc/hexane = 1:3). [a)26D = + 137.1° (c 0.62, MeOH) . MS(CI) m/e 226 (M+H) + . ^-H NMR (CD3OD, 300MHz) δ 4.49 (br s, 1H), 4.17 (br s, 2H), 3.343.45 (m, 1H), 3.22-3.30 (m, 1H), 1.85-2.15 (m, 4H) , 1.47 (s, 9H$ .
EXAMPLE Id 3- (2, 5-dioxQ-pyppolidinyl) -1- (2.(R) nylpyrrolidinyl)-1-propyne To a solution of 3-Hydroxy-l-(2(R)-N-tertbutoxycarbonylpyrrolidinyl)-1-propyne (464 mg, 2.06 mmol), succimide (306 mg, 3.09 mmol) and triphenyl phosphine (1.08 g, 4.12 .mmol) in anhydrous THF cooled to 0°C was added diethyl azodicarboxylate (718 mg, 4.12 mmol) dropwise under nitrogen. The reaction mixture was allowed to graduately warm up to ambient temperature overnight. Concentration and flash chromatography (EtOAc/hexane = 1:1) provided 574 mg (91%) of the required product as an amber viscous oil. TLC Rf = 0.21 (EtOAc/hexane = 1:1). [a]25D = +81.8° (c 0.62, MeOH). HRMS(CI) m/e calcd for C16H23N2°4< 307.1658 (M+H)+, found, 307.1661. ΧΗ NMR (CD3OD, 300MHz) δ 4.40 (br m, 1H), 4.22 (d, J= 1.8 Hz, 2H), 3.38 (m, 1H), 3.27 (m, 1H) , 2.70 (s, 4H) , 1.85-2.15 (m, 4H), 1.46 (s, 9H). -21EXAMPLE le 3_^(5-HvdrQxy-2-QXO-pyrrolidinyl) -1-(2 (R) -N-tertbutoxycarbonylpyrrolidinyl)-1-propyne To a solution of 3- (2,5-dioxo-pyrrolidinyl)-1-(2(R)-Ntert-butoxycarbonylpyrrolidinyl)-1-propyne (498 mg, 1.62 mmol) in MeOH (30 mL) cooled to -5°C (ice and brine) was added NaBH4 (492 mg, 13.0 mmol) in one portion. After stirring for 45 minutes, the reaction mixture was poured into a solution of saturated aquoues NaHCOj solution and extracted with choloroform (3X60 ml). The combined organic layers were dried (Na2SO4), concentrated and the residue was flash chromatographed (EtOAc/hexane=9:1 -> 0.1% MeOH in EtOAc) providing 277 mg (56%) of the required product (oil) as a mixture of diastereomers at the hydroxy center. TLC Rf = 0.24 (EtOAc). HRMS(FAB) m/e calcd for C16H23N2°3' 291.1709 (M-OH)+, found, 291.1711. Anal, calcd. for Cx6H24N2O4·1/4 H2O: C, 61.42; H, 7.89; N, 8.95; Found: C, 61.10; H, 7.62; N, 8.56.
EXAMPLE If 3-(2-Oxo-l-pyrrolidinyl)-1-(2(R)-pyrrolidinvl)-l-propvne hydrogen oxalate To a solution of 3-(5-hydroxy-2-oxo-l-pyrrolidinyl)-1(2(R)-N-tert-butoxycarbonylpyrrolidinyl)-1-propyne (163 mg, 0.53 mmol) and triethylsilane (154 mg, 133 mmol) in choloroform (2 mL) was added triflouroacetic acid (TFA) (1.02 mL, 13.23 mmol) at 23°C. After stirring for 2 hrs, the reaction mixture was concentrated to dryness and the residue was taken up in chloroform and washed with saturated aqueous K2CO3· The aqueous layer was extracted with chloroform (5X). The combined organic phase was -22dried (Na2SO4>, concentrated and the resulting oil was flash chromatographed using 10% MeOH-CHClg as the elutant to afford 75 mg (74%) of the required product as an oil. Addition of ethereal oxalic acid to a solution of the product in ether/MeOH gave the oxalate salt after storing in the freezer for a week. m.p. = 85-87°C. TLC Rf= 0.4 (CHCI3:MeOH:NH4OH = 9:1:0.1). [a]23D= +19.6° (c 0.28, MeOH). MS(CI) m/e 193 (M+H)+. *Η NMR (DMSO-d6, 500 MHz) δ 4.31 (tt, J=7.2, 1.8 Hz, 1H), 4.06 (s, J=1.8 Hz, 2H), 3.38 (t, J=7.0 Hz, 2H), 3.14-3.28 (m, 2H) , 2.24 (m, 3H) , 2.05-1.85 (m, 5H). Anal, calcd. for 011Η1θΝ2Ο·02Η2θ4: C, 54.96; H, 6.46; N, 9.86; Found: C, 54.76; H, 6.41; N, 9.79.
EXAMPLE 2 3-(2-Qxo-l-pyrrolidinyl)-1-(N-Methyl-2(R)-pyrrolidinyl)-1propyne hydrogen oxalate To a mixture of 3-(2-oxo-l-pyrrolidinyl)-1-(2(R)pyrrolidinyl)-1-propyne (181 mg, 0.94 mmol) and ten-fold excess each of 37% formalin and 88% formic acid was heated at reflux for 16 hours. After cooling to room temperature, the reaction mixture was acidified with 6 N HCl. The aqueous phase was extracted with ether and the phases separated. The aqueous phase was basified with K2CO3 and extracted with choloroform three time. The combined organics was dried (Na2SO4) and concentrated under vacuum to give 153 mg (79%) of the desired product as an oil. Addition of oxalic acid to a solution of the product in ether/MeOH gave the oxalate salt as an viscous oil. TLC Rf= 0.40 (10% MeOH in CHCI3) . (0t]23D= -42.7° (c 0.86, MeOH). 95°C, 300MHz) -23MS(CI) m/e 207 (M+H)+. ΧΗ NMR (DMSO-dg, 4.06 (d, J=1.6Hz, 2H), 3.62 (m, 1H), 3.39 (t, J=7.0 Hz, 2H), 2.97 (m, 1H), 2.69 (m, 1H), 2.50 (s, 3H), 2.22 (t, J=8.1 Hz, 2H), 2.15 (m, 1H), 1.97 (m, 2H) , 1.85 (m, 3H). Anal, calcd. for 0χ2Η18Ν2^‘θ·9H2O·1.3 C2H2°4 ·' c' 51.64; H, 6.65; N, 8.25; Found: C, 51.54; H, 6.26; N, 8.31.
EXAMPLE 3 1,1-Dlmethyl-2(R)-Γ3-(2-oxo-pyrroli-dinyl)-1propynyllpyrrolidinium iodide 3-(2-Oxo-l-pyrrolidinyl)-1-(N-Methyl-2(R)pyrrolidinyl)-1-propyne (50 mgs, 0.24 mmols) was taken up in anhydrous diethyl ether. An excess of iodomethane was added and the reaction stirred for 3 hours at room temperature. The white solid that formed was collected on a filter via vacuum filtration and subsequently washed with diethyl . ether. The quaternary amine (49 mgs) was isolated in 59% yield, [α]= +36.4° (c 0.45, MeOH). m.p. = 94-98°C. MS(FAB) m/e 221 6, 100°C, 500MHz) 54.79-4.76 (m, 1H), 4.28 (s, 2H), 3.803.84 (m, 1H), 3.66-3.60 (m, 1H), 3.52 (t, J=7.1 Hz, 2H), 3.26 (s, 3H), 3.14 (s, 3H), 2.62-2.60 (m, 1H), 2.35 (t, J=8.0 Hz, 2H), 2.28-2.22 (m, 3H), 2.09 (q, J=7.5 Hz, 2H). Anal, calcd. for Ci3H2iIN2O1/5 HI: C, 41.77; H, 5.72; N, 7.46; Found: C, 41.27; H, 5.58; N, 7.36. -24EXAMPLE 4 1-(2.5-Dioxo-pyrrolidinyl)-3-(2(R)-pyrrolidinyl)-1-propyne hydrogen oxalate To the product of EXAMPLE Id (136 mg, 0.44 mmol) in methylene chloride (1.5 mL) was added trifluoroacidic acid (1.5 mL) at room temperature. After stirring for 1 h, the reaction mixture was evaporated to dryness with a stream of nitrogen. Methylene chloride (2 mL) was added and the mixture was evaporated to dryness. This was repeated twice. The residual oil was taken up in methanol/ether and treated with two equivalents of oxalic acid to give 73 mg (56%) of oxalate salt after storing in the freezer for two days. m.p. 179-180°C. TLC Rf=0.5 (CHCI3:MeOH:NH4OH=9:1:0.1). [a]25D=+20 .7° (c 0.60, MeOH) MS (CI) m/e 207 (M+H) + . ^-H NMR (CD3OD, 300 MHz) 0 4.38 (tt, J=7.4, 1.8 Hz, IH), 4. 31 (d , J=1.8 Hz, 2H), 3. 33 (m, 2H), 2.73 (s, 4H), 2.32 (m, IH) , 2.21-1. . 95 (m, 3H) . Anal calcd. for C11H14N2O2C2H2O4·1/4 H2O: C, 51.91; H,5.53; N, 9.31; Found: C, 52.22; H, 5.47; N, 9.21.
EXAMPLE 5 3-(2-Qxo-pyrrolidinyl)-1-(2(S)-pyrrolidinyl)-l-pxopvna hydrogen oxalate The product was prepared from N-tert-butoxycarbonyl(S)-proline using the conditions described in EXAMPLE la through EXAMPLE If. -25EXAMPLE 6 3-(2-Qxo-pyrrolidinyl)-1-(N-methyl-2(S)-pyrrolidinyl)-1Exopyna hydrogen oxalate The compound was prepared from the product of EXAMPLE 5 using the conditions described in EXAMPLE 2.
EXAMPLE 7 1.1-Dimethyl-2(S)-f3-(2-oxo-pyrrolidinyl)-1propynyllpyrrolidinium iodide 1-[(2S)-1-Methylpyrrolidinyl]-3-(2-oxo-pyrrolidinyl)1-propyne was taken up in anhydrous diethyl ether and an excess of iodomethane was added at 0°C . The reaction was allowed to stir at 0°C for 90 minutes. The ether was stripped and the remaining material triturated with diethyl ether (X3). The material was placed on high vacuum (<5 mm) for four days netting a tan solid in 96% yield. [a]23D = -34.0° (c 0.45, MeOH). m.p. = 88-92°C. MS(FAB) m/e 221 (M)+. 1H NMR (DMSO-dg, 10 O°C, 300MHz) δ 4. 73-4.67 (m, 1H), 4.18 (d, J=1.8 Hz, 2H), 3.78-3.69 (m, 1H) , 3.60- 3.49 (m, 1H), 3.43 (t, J=6.7 Hz, 2H), 3.17 (s, 3H) , 3.05 (s, 3H), 2.57-2.47 (m, 1H), 2.26 (t, J=7.9 Hz, 2H) , 2.22- 2.12 (m, 3H), 2.00 (q, J=7.5 Hz , 2H) . Anal. calcd . for Ci3H2iIN2O-l/2 H2O: C, 43.71; H, 6.21; N, 7.84 ; Fou nd: C, 44.02; H , 6.08; N, 7.83. -2 6EXAMB.LE 8 3-(2,5-Dioxo-pyrrolidinyl))-1-(2(S)-pyrrolidinyl)-1prppyne hydrogen oxalahe The title compound was prepared from 3-(2,5-dioxopyrrolidinyl))-1-(2(S)-N-tert-butoxycarbonylpyrr olidinyl)-1-propyne using the conditions described in EXAMPLE 4. m.p. 138-139°C. [a]25D=-22.0° (c 0.60, MeOH).
EXAMELE.,-2 1-(2(R)-N-acetyl-pyrrolidinyl)-3-(N,Ndime thyl amino I.pxopynfi EXAMELE.ia 2(R)-ethyne-N-tert-butoxycarbonylpyrrolidine To the product of EXAMPLE lb (3.65 g, 10.28 mmol) in THF (20 mL) cooled to -75°C was added an 1.6 M solution of n-BuLi (13.2 mL, 21.11 mmol) in hexane dropwise over a period of 15 min under nitrogen. After stirring for 1 h, mL of MeOH was added dropwise down the sides of reaction flask. The dry ice bath was removed and saturated aqueous NaHCOg solution was added. The mixture was extracted with EtOAc (3X) and the combined organics dried (Na2SO4) and concentrated. The resulting residue was flash chromatographed (ether:hexane = 1:6 1:5) to give 1.33 g (66%) of desired product as an oil. TLC Rf= 0.21 (ether : hexane=l: 6) . (2®d= +117.6° (c 1.15, MeOH) . MS (CI) m/e 196 (M+H)+. l-H NMR (CDCI3, 300 MHz) δ 4.55-4.36 (m, 1H), 3.53-3.24 (m, 2H), 2.25-1.85 (m, 5H), 1.48 (s, 9H) . -27EXAMPLE 9b 1- (2 (R)-N-tert-butoxycarbonylpyrrolidinyl)-3-(N,Ndimethylamino)-l-propyne To a mixture of the product of EXAMPLE 9a (730 mg, 3.73 mmol), N,N,N’,N'-tetramethylethylenediamine (1.15 g, 11.22 mmol) and copper(I) chloride (19 mg, 0.19 mmol) in THF (8 mL) was heated at reflux for 5 h. Additional N,N,N',N'-tetramethylethylenediamine (1 equivalent) and copper (I) chloride (5 mol%) were added and heating was continued for 5 h. The reaction mixture was diluted with chloroform and washed with saturated aqueous K2CO3 solution. The aqueous layer was extracted with chloroform (5X) . The combined organics-were dried (Na2SC>4) and concentrated in vacuo. The residue was purified by flash chromatography (4% MeOH in CHCI3) to give 105 mg of starting material and 560 mg (59%) of desired product as an oil. TLC Rf= 0.39 (10% MeOH in CHCI3). [a]26D=+141.2° (c 0.60, MeOH). HRMS (CI) m/e calcd for C14H25N2O2, 253.1916 (M+H)+, found, 253.1918. ΣΗ NMR (CD3OD, 300 MHz) δ 4.50 (dt, J=5.1, 1.8 Hz, 1H), 3.40 (m, 1H), 3.30 (m, 1H), 3.26 (br s, 2H), 2.30 (s, 6H) , 2.15-1.90 (m, 4H), 1.47 (s, 9H).
EXAMPLE 9c 1-(2(R)-N-acetyl-pyrrolidinvl)-3-(N,Ndimethylamino)propyne To the product of EXAMPLE 9b (288 mg, 1.14 mmol) dissolved in THF (1 mL) was treated with trifluoroacidic acid (1.5 mL). The reaction mixture was stirred at ambient temperature for 1.5 h and then concentrated in vacuo to dryness. The residue was taken up in methylene -28chloride (1.5 mL) and treated with triethylamine (346 mg, 3.42 mmol) and acetic anhydride (233 mg, 2.28 mmol) at 0°C. The reaction mixture was allowed to warm to ambient temperature and continue stirring overnight. The reaction mixture was poured into saturated aqueous K2CO3 solution and extracted with chloroform (3X). The combined organics were dried over Na2SO4 and filtered. Evaporation of the volatiles in vacuo provided a residue which was chromatographed on basic alumina (1 drop of MeOH per 10 mL CHCI3) to give 216 mg (98%) of oil. TLC Rf= 0.49 (10% MeOH/CHCl3:NH4OH=9.9:0.1). [a]26D=+140.3° (C 0.58, MeOH).
HRMS (CI) m/e calcd for C11H19N2O, 195.1497 (M+H)+, found, 195.1527. 1h NMR (CD3OD, 300 MHz) 2 conformers δ 4.744.68 (m, 1H), 3.66-3.30 (m, 3H), 3.23 (d, J=2.2 Hz, 1H), 2.29 (s, 3.3H), 2.27 (s, 2.7H), 2.25-1.90 (m, 7H) .
EXAMPLE 9d 1- (2 (R) -N-acetyl-pyrrolidinyl) -3- (N.N-dimethylami.no) -1= propyne hydrogen oxalate To a solution of the product from EXAMPLE 9c in anhydrous Et2O/MeOH was added a solution of oxalic acid (2.1 equivalents) in ether. After standing at 0°C overnight, the solid deposited in flask was collected on a filter funnel. m.p,=102-103°C. [a]2θρ=+83.7° (c 0.6, MeOH). MS(CI) m/e 195 (M+H)+. ΧΗ NMR (CD3OD, 300 MHz) 2 conformers δ 4.80 (m, 0.3H), 4.71 (m, 0.7H), 4.11 (d, J=1.8 Hz, 0.6H), 4.02 (d, J=1.8 Hz, 1.4H), 3.70-3.32 (m, 2H), 2.92 (s, 1.8H), 2.91 (s, 4.2H), 2.30-1.95 (m, 7H). Anal, calcd. for Ci2HfgN2O-2 C2H2O4: C, 48.13; H, 5.92; N, 7.48; Found: C, 48.09; H, 5.95; N, 7.43. -2 9EXAMPLE IQ 1-(2 (S)-N-acetyl-pyrrolidinyl)-3-(N,N,-dimethylamino)-1propyne hydrogen oxalate The title compound was prepared from the enantiomer of EXAMPLE lb using the conditions described in EXAMPLES 9a through 9d. m.p.=109-110°C. [a]26D=-80.0° (c 0.59, MeOH).
^H NMR is same as in EXAMPLE 9d. Anal, calcd. for c11h18n2°·2 C2H2O4: C, 48.13; H, 5.92; N, 7.48; Found: C, 48.69; H, 6.07; N, 7.45.
EXAMPLE 11 3-(2-Qxo-pyrrolidinyl) -1-(2(R) -piperidinyll -1-propvne hydrogen oxalate EXAMPLE Ila 2(R)-1-tert-Butoxycarbonylpiperidinecarboxylic acid 2(R)-Piperidinecarboxylic acid (2.95 g, 22.8 mmols) and N,N-diisopropylethylamine (4.8 mis, 27.4 mmols) were combined in 90 mis of 1,4-dioxane:H2O (1:1) and cooled to OoC. To this solution was added di-tert-butyl dicarbonate (7.5 g, 34.2 mmols) and the mixture was allowed to stir at room temperature for two days. The reaction contents were then poured over saturated sodium bicarbonate solution and extracted with ethyl acetate (X2). The aqueous phase was next acidified with 10% citric acid and a small amount of 2 N HCl to pH=3. The acidified solution was then extracted with ethyl acetate (X4). The organics were combined, washed with brine (back extracted), dried over sodium sulfate and concentrated to leave a white solid (5.03 g) -30in 96% yield. TLC Rf = 0.36 (CHCI3:MeOH:NH4OH 10:4:1). [a]23D = +43.6° (c 0.96, MeOH). m.p. = 112-118°C. MS(CI) m/e 230 (M+H)+. XH NMR (DMSO-dg, 100°C, 300 MHz) δ 4.58 (dd, J=5.9, 2.4 Hz, 1H), 3.81 (dm, 1H) 2.93 (ddd, J=12.8, 12.8, 2.8 Hz, 1H), 2.07-2.04 (m, 1H), 1.63-1.56 (m, 3H), 1.38-1.22 (m, 2H), 1.39 (s, 9H). Anal, calcd. for C11H19NO4-3/10 H2O: C, 56.30; H, 8.42; N, 5.97; Found: C, 56.21; H, 8.16; N, 5.84.
EXAMPLE lib 2(R)-Hydroxymethyl-l-tert-butoxycarbonylpiperidine The product from EXAMPLE 11a (4.88 g, 21.3 mmols) was taken up in 27 mis of anhydrous tetrahydrofuran and cooled to OoC. To this stirred solution was added borane-methyl sulfide complex, 2.0 M in THF, (16.0 mis, 31.9 mmols) dropwise under N2. After complete addition the reaction was allowed to warm to room temperature and stir over night. Saturated NaHCO3 solution was added and the mixture vigorously stirred for 30 minutes and then extracted with ethyl acetate (X4). The organics were combined, washed with brine (back extracted), dried over Na2SO4 and concentrated. The crude was subjected to flash chromatography using (EtOAc/hexane 1:3->l:1->1:0) as the elutant. A white solid in 86% yield was isolated. TLC Rf = 0.37 (10% MeOH in CHCI3). [a]23D = +38.7° (c 0.98, CHCI3). m.p. = 81-83°C. MS(CI) m/e 216 (M+H)+. 3H NMR (DMSO-dg, 100°C, 500 MHz) 5 4.21 (t, J=5.5 Hz, 1H), 4.064.02 (m, 1H), 3.82-3.78 (m, 1H), 3.51 (ddd, J=10.6, 8.0, .8 Hz, 1H), 3.44 (ddd, J=10.5, 6.4, 5.3 Hz, 1H), 2.76 (ddd, J=13.5, 12.6, 3.1 Hz, 1H), 1.76 (dm, 1H), 1.57-1.46 (m, 3H), 1.44-1.36 (m, 1H), 1.39 (s, 9H) , 1.33-1.26 (m, -31IH) . Anal, calcd. for CHH21NO3: C, 61.37; H, 7.83; N, 6.50; Found: C, 61.54; H, 7.86; N, 6.47.
EXAMPLE lie 2(R)-1-tert-Butoxycarbonylpiperidinecarbaldehyde The product from EXAMPLE lib (3.18 g, 14.8 mmols) and triethylamine (6.2 mis, 44.4 mmols) were dissolved in 18.5 mis of anhydrous DMSO. To this solution was added pyridinium sulfur trioxide (7.1 g, 44.4 mmols) in 13 mis of anhydrous DMSO dropwise under N2. After complete addition the reaction was stirred for 10 minutes and then the reaction contents were poured over ice and extracted with diethyl ether (X4). The'organics were combined and washed in succession with 10% citric acid (Back extracted), water (back extracted), saturated sodium bicarbonate solution and finially dried over sodium sulfate. The solvent was removed leaving a clear oil (5.06 g) in 97% crude yield. An analytical amount was subjected to flash chromatography using (Et2O/hexane 1:12) as the elutant. TLC Rf = 0.23 (EtOAc/hexane 1:8). [a]22D = +36.8° (c 1.14, CHCI3). HRMS(CI) m/e calcd for C11H2on03, 214.1443 (M+H)+, found, 214.1440. 1HNMR (DMSO-d6, 100°C, 360 MHz) δ 9.54 (s, IH) , 4.44 (dd, J=6.0, 3.5 Hz, IH), 3.79-3.73 (m, IH), 2.98-2.88 (m, 2H), 2.12-2.05 (m, IH), 1.67-1.27 (m, 3H), 1.42 (s, 9H), 1.26-1.22 (m, IH).
EXAMPLE lid 2(R)-(2,2-Dibromoethenyl)-1-tert-butoxycarbonylpiperidine Triphenylphosphine (16.8 g, 64 mmols) and carbon tetrabromide (8.5 g, 25.6 mmols) were combined in 21 mis of anhydrous methylene chloride and stirred at room -32temperature for 20 minutes. The product from EXAMPLE 11c (2.7 g, 12.8 mmols) was then added under N2 via cannula at a steady rate. After complete addition the reaction was allowed to stir for five minutes and then the entire reaction was poured over ethyl acetate/hexane (1:1) . The slurry that resulted was filtered thru 1/4 inch basic aluminum oxide / 1/4 silica gel (40-63 m) via vacuum filtration. The filter cake was washed with ethyl acetate / hexane (1:1). The obtained filtrate was concentrated and subjected to flash chromatography (Et2O/hexane 1:19).
A white solid was isolated in 84% yield. TLC Rf = 0.13 (Et2O/hexane 1:15). [CC]23d = -31.6° (c 0.97, CHCI3) . m.p. = 108-110°C. MS(FAB) m/e 370' (M+H)+. XH NMR (DMSO-dg, 100°C, 500 MHz) δ 6.93 (d, J=8.1 Hz, 1H), 4.77 (ddd, J=8.1, 5.3, 5.0 Hz, 1H), 3.83 (m, 1H), 2.92 (ddd, J=13.5, 12.3, 3.1 Hz, 1H), 1.68-1.58 (m, 4H), 1.50-1.43 (m, 1H), 1.42 (s, 9H), 1.40-1.34 (m, 1H). Anal, calcd. for c12H19Br2NO2: C, 39.05; H, 5.19; N, 3.79; Found: C, 39.36; H, 5.39; N, 3.65.
EXAMPLE lie 3-Hydroxv-l-Γ 2(R)-1-tert-butoxycarbonylpiperidinvl1-1propyne The title compound was prepared by the same procedure as in EXAMPLE lc. The crude was subjected to flash chromatography using (EtOAc/hexane 1:4 to 1:2) as the elutant. A light yellow oil was isolated in quantitative yield. TLC Rf = 0.47 (EtOAc/hexane 1:2). [0(]23d = +112.0° (c 1.12, CHCI3). HRMS(CI) m/e calcd for ΟχβΗ^ΝΟβ, 240.1600 (M+H)+, found, 240.1601. NMR (DMSO-dg, 100°C, 360 MHz) δ 5.00 (br s, 1H), 4.80 (t, J=5.8 Hz, 1H), 4.11 -33(dd, J=5.8, 1.6 Hz, 2H), 3.81 (dm, 1H), 2.97 (ddd, J=13.0, 13.0, 2.6 Hz, 1H), 1.74-1.58 (m, 4H) , 1.43 (s,9H), 1.581.30 (m, 2H).
EXAMPLE Ilf 3- (2,5-Dioxo-pyrrolidinyl)-1-Γ2(R)-1-tertbutoxycarbonylpiperidinyl1-1-propyne This compound was prepared by the same procedure as in EXAMPLE Id. The crude was subjected to flash chromatography using (EtOAc/hexane 1:2->1:1) as the elutant. However, flash chromatography was not successful in removing the impurity diethyl hydrazinedicarboxylate. A yield of 70% was calculated based on the molar ratio of impurity vs product as seen from 3H NMR. An analytical amount of the above material was deprotected (see EXAMPLE 4), flash chromatographed, reprotected with di-tert-butyl dicarbonate and flash chromatographed once again to give a pure white solid. TLC Rf = 0.31 (EtOAc/hexane 1:1). [a]23D= +91.4° (c 0.98, CHC13). m.p. = 108-110°C. MS(CI) m/e 321 (M+H)+. 1H NMR (DMSO-dg, 100°C, 500 MHz) δ 4.92 (br s, 1H), 4.18 (d, J=1.8 Hz, 2H), 3.77 (dm, 1H), 2.89 (ddd, J=13.0, 13.0, 2.6 Hz, 1H), 2.67 (s, 4H), 1.68-1.51 (m, 5H), 1.40 (s, 9H), 1.32-1.26 (m, 1H). Anal, calcd. for Cf7H24N2O4: C, 63.73; H, 7.55; N, 8.74; Found: C, 63.72; H, 7.47; N, 8.67.
EXAMPLE Ila 3-(5-Hydroxy-2-oxo-pyrrolidinyl)—1— Γ 2(R)-l-t&rtbutoxycarbonylpiperidinyll-1-propvne The title compound was prepared from the product of EXAMPLE Ilf by using the same procedure as that in EXAMPLE -34le. The crude was flash chromatographed using (EtOAc/hexane 2:1) as the elutant. A white solid was isolated in 56% yield. TLC Rf = 0.38 (EtOAc). m.p. = 104106°C. HRMS(CI) m/e calculated for C17H27N2O4,323.1971 (M+H)+ , found, 323.1973. 1H NMR (DMSO-dg, 98°C, 500 MHz) .75 (dd, J=6.9, 2.4 Hz, 1H), 5.19-5.17 (m, 1H) , 4.96 (br s, 1H) , 4 .30-4 .26 (ddd, J=17 .3, 2.0, 1. 8 Hz, 1H), 3.80-3.73 (m, 2H) , 2 . 93 (ddd, J= 12.9, 10.9, 2.1 Hz, 1H) , 2.40-2.35 (m, 1H) , 2 . 22-2.12 (m, 2H), 1.79- 1.72 (m, 1H), 1.68-1.52 (m, 5H) , 1 . 41 (s, 9H), 1.37-1.27 (m, 1H). Anal calcd. forC17H26N2°4 : C, 63.33; H, 8.13; N , 8.69; Found C, 63.38; H, 8.15; N, 8.67.
EXAMPLE llh 3-(2-Qxo-pyrrolidinyl)-1-Γ2IR)-piperidinyll-1-propyne The product was prepared from the product of EXAMPLE llg using the same procedure as that described under EXAMPLE If. The crude was subjected to flash chromatography using (10% MeOH in CHCI3) as the elutant. A slightly colored oil was isolated in 88% yield. TLC Rf = 0.14 (10% MeOH in CHCI3). (a]23D = +4.7° (c 1.1, CHCI3).
HRMS(CI) m/e calcd for C12H19N2O, 207.1497 (M+H)+, found, 207.1499. 1H NMR (DMSO-dg, 100°C, 360 MHz) δ 4.03 (d, J=1.6 Hz, 2H), 3.60-3.55 (m, 1H), 3.41 (t, J=7.0 Hz, 2H), 2.93-2.89 (m, 1H), 2.61-2.53 (m, 1H), 2.23 (t, J=8.0 Hz, 2H), 1.97 (q, J=7.3 Hz, 2H), 1.74-1.65 (m, 2H), 1.481.40 (m, 4H). -35EXAMPLE Hi 3-(2-Oxo-pyrrolidinyl)-1-Γ2(R)-piperidinyll-1-propyne hydrogen oxalate The free base from EXAMPLE llh was dissovlved in anhydrous diethyl ether and stirred at room temperature.
To this solution was added 1.0 equivalents of oxalic acid in diethyl ether dropwise. The reaction was strirred for three hours and then the ether was decanted. The remaining solid was triturated with diethyl ether (X3) resulting in an 82% yield. [tt]23D = +10.9° (c 0.96, MeOH). m.p. = 778l°C. .MS(CI) m/e 207 (M+H)+. 1H NMR (DMSO-d6, 100°C, 500 MHz) δ 4.15-4.11 (m, 1H), 4.08 (d, J=1.8 Hz, 2H), 3.41 (t, J=7.0 Hz, 2H), 3.26 (ddd, J=12.5, 5.4, 4.8 Hz, 1H), 2.93 (ddd, J=12.7, 8.0, 4.4 Hz, 1H), 2.23 (t, J=8.0 Hz, 2H), 2.00-1.92 (m, 3H), 1.77- 1.69 (m, 2H), 1.68-1.62 (m, 2H), 1.57-1.50 (m, 1H). Anal, calcd. for C12H18N2°‘1·3C2H2°4: 54.24; H, 6.42; N, 8.66; Found: C, 54.53; H, 6.57; N, 8.68.
EXAMPLE 12 1-f2(R)-(1-Methylpiperidinyl)1-3-(2-Qxa-pyrrQlidinvl)-1propyne hydrogen oxalate EXAMPLE 12a 1-Γ2 (R)-(1-Methylpiperidinyl)1-3-(2-oxQ-pyrrolidinyl)-1pjopyiue The above tertiary amine was prepared in a similiar fashion as that described under EXAMPLE 2. A clear oil was isolated in 79% yield. HRMS(CI) m/e calcd for C13H21N2O 221.1654 (M+H) +, found, 221.1654. l-H NMR (DMSO-d6, 100°C, 500 MHz) δ 4.06 (d, J=1.5 Hz, 2H), 3.42 (t, J=7.0 Hz, 2H), 3.31 (br s, 1H), 2.44 (ddd, J=ll , .4, 8.5, 3.3 Hz, 1H) , 2.27-2.21 (m, 3H) , 2.20 (s, 3H), 1.97 (q, J=7.5 Hz, 2H), 1.74-1.68 (m, 1H) , 1.63-1.55 (m, 1H) , 1.54-1.42 (m, 3H), 1.41-1.38 (m, 1H) .
EXAMPLE_.12b 1— Γ 2(R)-(1-Methylpiperidinyl)1-3-(2-oxo-pyrrolidinyl)-1propyne hydrogen oxalate The salt was prepared according to a similiar procedure described under EXAMPLE Hi. A clear glass solid was obtained in 87% yield. [0C]22D = +20.4° (c 0.94, MeOH). MS(FAB) m/e 221 (M+H)+. !h NMR (DMSO-d6, 100°C, 500 MHz) δ 4.15 (s, 2H) , 3,74 (br s, 1Η), 3.48 (t, J=7.0 Hz, 2H), 2.81-2.79 (m, 1H), 2.65-2.62 (m, 1H), 2.49 (s, 3H) , 2.29 (t, J=8.1 Hz, 2H), 2.03 (q, J=7.4 Hz, 2H), 1.91-1.87 (m, 1H), 1.77-1.72 (m, 1H), 1.67-1.62 (m, 3H), 1.53-1.49 (m, 1H). Anal, calcd. for C13H20N2O·C2H2O4·3/5 H2O: C, 56.10; H, 7.28; N, 8.72; Found: C, 56.08; H, 6.89; N, 8.34· EXAMPLE 13 1,1-Dimethyl-2(R)-Γ3-(2-oxo-pyrrolidinyl)-1propynyllpiperidinium iodide The material from EXAMPLE 12a was dissolved in anhydrous diethyl ether and stirred at room temperature.
To this solution was added an excess of iodomethane and the resulting mixture was stirred for 90 minutes. The ether was evaporated and the remaining solid triturated with diethyl ether (X3). A white solid was obtained in 51% yield, m.p. = 124-126°C. [a]24D = +9.0° (c 0.56, MeOH). -37MS(FAB) m/e 235 (M)+. 1H NMR (DMSO-dg, 100°C, 500 MHz) δ 4.53 (dm, IH), 4.17 (d, J=1.5 Hz, 2H), 3.56 (ddd, J=12.7, 4.4, 4.4 Hz, IH), 3.42 (t, J=7.0 Hz, 2H), 3.35 (ddd, J=12.8, 10.5, 3.8 Hz, IH), 3.18 (s, 3H), 3.08 (s, 3H) , 2.25 (t, J=8.1 Hz, 2H) , 2.11-2.07 (m, IH), 2.02-1. 92 (m, 3H), 1.90-1.72 (m, 3H) , 1.60-1.52 (m, IH). Anal. calcd. for C34H23IN2O: C, 46. 42; H, 6.40; N, 7.73; Found: c, 46.40; H, 6.28; N, 7.66.
EXAMPLE 14 1-f 2 (R)-Piperidinyl1-3-(2,5-dioxo-pyrrolidinyl)-1-propyne The product from EXAMPLE' Ilf was deprotected using similiar conditions as that already noted under EXAMPLE 4. The residue obtained was subjected to flash chromatography using 7% MeOH in CHCl3~>10% MeOH in CHCI3 as the elutant.
A clear foam like solid was obtained in 83% yield. TLC Rf = 0.29 (10% MeOH in CHCI3). [tt]24D = +6.2° (c 1.0, CHCI3). m.p. = 144-146°C. HRMS(CI) m/e calcd for Οι2Η17Ν2θ2· 221.1290 (M+H)+, found, 221.1288. NMR (DMSO-dg, 98°C, 500 MHz) δ 4.24 (d, J=1.9 Hz, 2H), 4.20-4.17 (m, IH), 3.16 (ddd, J=12.5, 5.9, 4.3 Hz, IH), 2.95 (ddd, J=13.0, 8.0, 4.5 Hz, IH), 2.69 (s, 4H), 1.96-1.91 (m, IH), 1.751.62 (m, 4H), 1.57-1.52 (m, IH). Anal, calcd. for C12H16N2°2·Ο2Γ3ΗΟ2*i/2 H20: C' 48.98; H, 5.29; N, 8.16; Found: C, 48.95; H, 4.90; N, 8.09. -38EXAMPLE 15 1-f2 (R) -1-Me.thylpiperidinyn-3-..(2, S-diQXQ-pyrgQlidinyl) -1prppyne The title compound was prepared utilizing the same procedure as in EXAMPLE 2. The crude was subjected to flash chromatography using 5% MeOH in CHCI3 as the elutant. A clear viscous oil which solidified upon standing overnight at 4°C was isolated in 66% yield. [a]23D = +23.9° (c 0.74, CHCI3). m.p. = 88-90°C. HRMS(CI) m/e calcd for C13H19N2O2 235.1446 (M+H)+, found, 235.1444. 2H NMR (DMSO-dg, 100°C, 300 MHz) δ 4.18 (d, J=1.8 Hz, 2H), 3.24-3.21 (m, 1H), 2.66 (s, 4H), 2.46-2.38 (m, 1H), 2.24-2.16 (m, 1H), 2.16 (s, 3H), 1.71-1.62 (m, 1H), 1.591.30 (m, 5H). Anal, calcd. for C13H1QN2O2: C, 66.64; H, 7.74; N, 11.96; Found: C, 66.53; H, 7.59; N, 11.78.
EXAMPLE- 12 1,1-Dimethyl-2 (R) - Γ3-(2.5-diQXQ-pyrrolidin.yJ.) cl-. propynyllpiperidinium iodide The title compound was prepared from the product of EXAMPLE 15 using the same procedure as in EXAMPLE 13. A white solid was collected in 81% yield, [a]23^ = +11.7° (c 0.81, H2O). m.p. = 232-236°C. MS(FAB) m/e 249 (M)+. XH NMR (DMSO-dg, 100°C, 500 MHz) δ 4.56 (ddt, J=10.0, 2.0, 2.0 Hz, 1H) , 4.32 (d, J=2.0 Hz, 2H), 3.59-3.54 (m, 1H), 3.413.36 (m, 1H), 3.18 (s, 3H), 3.07 (s, 3H), 2.70 (s, 4H), 2.09-2.02 (m, 1H), 1.97-1.71 (m, 4H), 1.60-1.51 (m, 1H). -3 9Anal. calcd. for C14H21IN2O2: C, 44.69; H, 5.63; N, 7.44; Found: C, 44.88; H, 5.70; N, 7.44.
EXAMPLE 17 3-(2-Oxo-l-pyrrolidinyl)-1-Γ2(R) — (3(R)-npropylpyrrolidinyl)1-1-propyne hydrogen oxalate Example 17a Diethyl l-Acetyl-5-hydroxy-3-n-propylpyrrolidine-2.2dicarboxylate Sodium (3.48 g, 0.15 mol) was dissolved in a stirred solution of diethyl acetamidomalonate (201.6 g, 0.93 mol) in anhydrous ethanol (1200 mL) at room temperature under nitrogen. The reaction mixture was cooled to 0 °C and trans-2-hexenal (100.0 g, 1.02 mol) was then added dropwise. The resulting mixture was allowed to warm to room temperature. After stirring for 3 h at 23 °C, the reaction was quenched with 24 mL of acetic acid. The solution was concentrated in vacuo and the resulting residue was taken up in EtOAc and washed with saturated aqueous NaHCOg (2x) and brine. Dried over MgSO4, concentration and recrystallization of the residue from EtOAc/Hexane gave 271.4 g (93%) of the product as fine needles. mp 105-106 °C. TLC, Rf= 0.43 (9:1 CHClg/MeOH). MS (CI) m/e 316 (M+l)+, 298 (MH-H2O) + . 1H NMR (CD3OD, 300 MHz) δ 0.94 (t, J=7.2 Hz, 3H), 1.47-1.11 (m, 9H), 1.901.78 (m, 1H), 1.94 (dd, J=12.8, 5.2 Hz, 1H), 2.08 (dd, J=12.8, 6.4 Hz, 1H), 2.21 (s, 3H), 2.83 (m, 1H), 4.10-4.26 (m, 4H), 5.64 (d, J=5.2 Hz, 1H). IR (CDCI3) 3460, 1750, -401665 cm-!. Anal, calcd. for Cj5H25NOg: C, 57.13; H, 7.99; N, 4.44. Found: C, 57.28; H, 8.08; N, 4.42.
Example 17b Diethyl l-Acetyl-3-n-propylpyrrolidine-2,2-dicarboxylate To a solution of diethyl l-acetyl-5-hydroxy-3-npropylpyrrolidine-2,2-dicarboxylate (271.0 g, 0.86 mol) and triethylsilane (206 mL, 1.29 mol) in CH2CI2 (3 L) was added trifluoroacetic acid (663 mL, 8.6 mol) dropwise with stirring while controlling the internal temperature at 2530 °C by means of an ice bath. After stirring for 3 h at 23 °C, the solution was concentrated in vacuo and the residue was diluted with CH2C12 and washed with saturated aqueous NaHCC>3 solution until all the TFA are neutralized. The organic phase was dried (Na2SC>4) and concentrated to give 350 g of oil. The oily product containing silicon impurities was used directly in the subsequent step. An analytically pure sample was obtained as an oil after flash chromatography (1:2 -> 1:1 EtOAc/hexane). TLC, Rf= O. 55 (9:1 CHCl3/MeOH). MS(CI) m/e 300 (M+H)+. IR (CDCI3) 1745, 1655 cm-1. ^H NMR (CDCI3 300 MHz) δ 0.89-93 (t, J=7.0 Hz, 3H), 1.15-1.42 (m, 9H), 1.70-1.85 (m, 2H), 2.012.16 (m, 4H), 2.40-2.51 (m, 1H), 3.57 (ddd, J=10.7, 9.6, 6.2 Hz, 1H) , 3.76 Cdt', J=9.6, 1.1 Hz, 1H) , 4.17-4.28 (m, 4H). Anal, calcd. for CJ5H25NO5: C, 60.18; H, 8.42; N, 4.68. Found: C, 59.90; H, 8.34; N, 4.65.
Example 17c Trans- and cis-3-n-propylproline hydrochlorides The crude ester of example 17b (350 g) was suspended in N HCl (2 L) and acetic acid (500 mL) and heated at 2H)> 2 2H) , 3 -4 1reflux for 17 h. The reaction mixture was extracted with EtOAc (2x) and the aqueous phase was concentrated on a rotary evaporator. The residue was then triturated with ether to crystallize the product. The solid was collected by filtration, washed with ether and dried in a vacuum oven to give 152.3 g of the hydrochloride salt. An analytically pure sample was obtained by recrystallization from acetone/ether. mp 131-133 °C. TLC, Rf= 0.26 (10:4:1 CHCl3/MeOH/NH4OH). IR (KBr) 3420, 1735 cm-1. MS (CI) m/e 158 (free base MH+). NMR (D2O, 300 MHz) major isomer: δ 0.91 (t, J=7.2 Hz, 3H), 1.18-1.50 (m, 3H), 1.68-1.90 (m, 16-2.32 (m, IH), 2.43-2.50 (m, IH), 3.29-3.58 (m, (d, J=7.4 Hz, IH) ,-'Minor isomer: δ 0.89 (t, J=6.8 Hz, 3H), 1.18-1.50 (m, 3H), 1.68-1.90 (m, 2H), 2.162.32 (m, IH), 2.60-2.66 (m, IH), 3.29-3.58 (m, 2H), 4.32 (d, J=8.1 Hz, IH). Anal, calcd. for CgHigNO2Cl: C, 49.61; H, 8.33; N, 7.23. Found: 7.18 .
C, 49.35; H, 8.17; N, Methyl N-tert-butoxycarbonyl-3-n-propylproline The hydrochloride salt of example 17c (152.3 g) was dissolved in MeOH (1.5 L) and the solution was charged with HCl gas until it was saturated. After stirring overnight, the reaction mixture was concentrated to give an oil. This was taken up in 1 N HCl and extracted with EtOAc (2x). The aqueous layer was carefully basified with K2CO3 and extracted with CHCI3 exhaustively. The combined organic phases were dried (MgSO4), filtered and concentrated to give 122 g of oil. TLC, Rf= 0.70 (90:10:0.1 CHCl3/MeOH/NH4OH). MS (CI) m/e 272 (M+H)+. -42Partial NMR (CDClg, 300 MHz) Major isomer: δ 3.36 (d, J=6.3 Hz, 1H), 3.74 (s, 3H). Minor isomer: δ 3.72 (s, 3H), 3.83 (d, J=8.1 Hz, 1H). The oil (122 g) was taken up in MeOH (1 L) and then NaHCOg (180 g) and di-t-butyldicarbonate (171.4 g, 0.79 mol) were added slowly. After stirring overnight at 23 °C, the mixture was filtered and the filtrate concentrated. The residue was triturated with EtOAc, filtered again and concentrated to give 186.1 g of oil as a mixture of cis and trans isomers. TLC, Rf= 0.31 (1:6 EtOAc/hexane). IR (CDCI3) 1700, 1745 cm-1.
MS (CI) m/e 272 (M+H)+. Partial XH NMR (CDCI3, 300 MHz) Cis isomer (2 conformers): δ 0.91 (t, J=7.0 Hz, 3H), 3.71 (s, 1.8H), 3.72 (s, 1.2H), 4.23 (d, J=8.5 Hz, 0.6H), 4.32 (d, J=8.1 Hz, 0.4H). Trans isomer (2 conformers): δ 0.92 (t, J=7.0 Hz, 3H), 1.06-1.78 (m, 14H), 1.92-2.03 (m, 1H), 2.13-2.25 (m, 1H), 3.42-3.50 (m, 1H) , 3.56-3.68 (m, 1H) , (s, 1.8H), 3.74 (s, 1.2 H), 3.81 (d, J=6.2 Hz, 0.6H), 3.94 (d, J=5.5 Hz, 0.4H). Anal. 61.97; H, 9.29; N, 5.16. Found: 5.11 . calcd for C14H25NO4: C, C, 61.93; H, 9.30; N, Example 17e N-t-Boc-fcrans-3-n-propylproline and Methyl N-t-Boc-cis-3n-propylproline To a solution of the esters of example 17d (186.0 g, 0.685 mol), in MeOH (685 mL) was added 1 N NaOH (685 mL) at 23 °C. After stirring for 20 h, the solution was concentrated to remove MeOH and then extracted with EtOAc (3x). The extracts were dried (MgSO4), filtered and concentrated to give 71.4 g (38%) of cis ester. TLC, Rf= 0.54 (1:4 EtOAc/hexane). IR (CDCI3) 1745, 1700 cm-1. -43High resolution MS(CI) m/e 272 C14H26NO4' calcd 272.1862). ΤΗ isomer (2 conformers): δ 0.91 1869 ((M+H)+, for NMR (CDC13, 300 MHz) Cis (t, J=7.0 Hz, 3H), 1.07- 1.20 (m, 1H) , 1.23-1.45 (m, 12H), 1.64-1.78 (m, 1H), 1.90 2.12 (m, 1H) , 2.25-2.41 (m, 1H), 3.25-3.34 (m, 1H), 3.56- 3.68 (m, 1H) , 3.71 (s, 1 .8H), 3.72 (s, 1.2H), 4 .23 (d, J=8.5 Hz, 0. 6H), 4.32 (d , J=8.1 Hz, 0.4H). The aqueous phase was acidified with solid citric acid and extracted twice with EtOAc. The combined extract was washed with H2O and brine, dried (MgSO4), filtered and concentrated to 94.2 g (53%) of trans acid. TLC, Rf= 0.45 (9:1 CHCl3/MeOH). IR (CDCI3) 3050, 1720, 1690 cm-1. MS(CI) m/e 258 (M+H)+. ^H NMR (CDC13, 300 MHz) 2 conformers: δ 0.93 (m, 3H), 1.28-1.69 (m, 14H), 1.97-2.12 (m, 1H), 2.30 (m, 0.4H), 2.50 (m, 0.6H), 3.34-3.64 (m, 2H), 3.84 (brd, J=6.2 Hz, 0.4H), 3.98 (br d, J=4.4 Hz, 0.6H). Anal, calcd. for C13H23NO4: C, 60.68; H, 9.01; N, 5.44. Found: C, 60.66; H, 8.91; N, 5.44.
Example L7f N-tert-Butoxycarbonyl-trans-3-n-propyl-proline,—(s)methylbenzylamides To a solution of trans acid of example 17e (94.2 g, 0.37 mol), (S)- (-)methylbenzylamine (44.8 g, 0.37 mol) and 1-hydroxybenzotriazole hydrate (54.4 g, 0.40 mol) in CH2C12 (1 L) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide·HCl (76.9 g, 0.40 mol) under nitrogen at 0 °C. After stirring overnight at 23 °C, the reaction mixture was diluted with EtOAc, washed with 10% aqueous citric acid, saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated. The residue -44was dissolved in minimum amount of ether and the S-isomer (with respect to proline), preferentially crystallized upon standing (34.0 g, 90% S-isomer). The mother liquor was concentrated and the resulting residue was chromatographed on silica gel using 35% EtOAc/Hexane as elutant to give 46.5 g of the R-isomer (35%, contains <5% S-isomer) 6.9 g of mixture and 16.3 g of S-isomer (90% Sisomer). The 34.0 g of 90% pure S-isomer, 6.9 g of mixture and 16.3 g of 90% pure S-isomer were combined and recrystallized three time from ether/hexane to give a total of 40.2 g (30%) of S-isomer (99%+ pure).
Alternatively, the mixture could also be separated by HPLC with about 80% recovery. S-Isomer: mp 112-114 °C (Et2<3/hexane) . TLC, Rf=0.39 (EtOAc:hexane=l:2). [a]23D= -56.3° (c=0.75, MeOH). NMR (300 MHz, DMSO-d6, 138°C) δ 0.88 (br t, J=7.0 Hz, 3H), 1.40 (s, 9H) , 1.43 (d, J=7.1Hz, 3H), 1.25-1.55 (m, 5H), 1.97 (m, 1H), 2.14(m, 1H), 3.303.55 (m, 2H), 3.77 (d, J=5.1 Hz, 1H), 4.99 (q, J=7.1Hz, 1H), 7.65-7.15 (m, 5H). MS (CI) m/e 361 (MH+, base), 305, 261, 112. Anal. Calcd. For C21H32N2O3: C, 69.97; H, 8.95; N, 7.77. Found: C, 69.99; H, 9.05; N, 7.73. Risomer: mp 104-105 °C (Et2O/Hexane). TLC, Rf=0.45 (EtOAc:Hexane=l:2). [a]D=-65.8° (c=0.76, MeOH). NMR (300 MHz, DMSC )-d6, 138 <3C) δ 0.91 (br t, J=7.0 Hz, 3H), 1.36 (s, 9H) , 1.28-1.42 (m, 3H), 1.43 (d, J=7 . 1 Hz, 3H), 1.45-1.58 (m, 2H), 2.00 (m, 1H), 2.18 (m, 1H) , 3.33-3.51 (m, 2H), 3.79 (d, J=4.9 Hz, 1H), 4.98 (Qr J=7 . 1 Hz, 1H) , 7.60-7.17 (m, 5H). MS (CI) m/e 3 16I (MH+, base ), 305, 261, 112. Ana 1. Ca led for C 21H32N2°3: c, 69. 97; H , 8.95; N, 7.77. Found: C, 70.27; H, 9.25; N, 7.73. -45Example 17g N-t-Boc-fcrans-3-n-propyl-(L)-proline A solution of the S-isomer of example 17f (40.2 g, 0.11 mol) in 8 N HCl (870 mL) and glacial acetic acid (220 mL) was heated at reflux overnight. The solution was concentrated on a rotary evaporator and the residue taken up into H2O and extracted with ether. The aqueous phase was concentrated and azeotroped 3x with toluene to give 43.0 g of trans-3-n-propyl-(L)-proline and (s)methylbenzylamine hydrochlorides. The salts were taken up in dioxane/H20 (1:1, 400 mL) and then treated carefully with N,N—diisopropylethylamine (35.5 g, 0.275 mol) and dit-butyl dicarbonate (60.0 g, 0.275 mol) sequentially at 0 °C. After stirring overnight at 23 °C, the mixture was diluted with EtOAc and the two layers were separated. The organic layer was extracted with 0.5 N NaOH (2x). The combined aqueous phase was extracted with EtOAc once and again back-extracted EtOAc was washed with 0.5 N NaOH.
The combined basic H2O phase was cooled to 0 °C-5 °C and acidified to pH 1.0 with cold 4 N HCl and extracted immediately with EtOAc (2x). The combined EtOAc extract was washed with brine, dried (MgSOzj) and concentrated.
The residue was dried in vacuous desicator over P2O5 to give 26.1 g (92%) of desired product as a white solid, mp 88-89 °C (Hexane). TLC, Rf=0.15 (CHCI3:MeOH=9:1). [a]24D= -38.3° (c=1.0, CHCI3); [a]25D=-42.5° (c 0.095, CHCI3) . l-H NMR (360 MHz, DMSO-dg, 100 °C) δ 0.90 (t, J=7.0 Hz, 3H), 1.20-1.55 (m, 15H), 1.98 (m, 1H), 2.20 (m, 1H) , 3.30 (m, 1H), 3.40 (m, 1H), 3.67 (d, J=4.0 Hz, 1H) .
MS (CI) m/e 258 (MH)+, 219 (base), 202, 158. Anal. -4 6Calcd. for C33H23NO4: C, 60.68; H, 9.01; N, 5.44. Found: C, 60.85; H, 8.97; N, 5.44. The (+)-isomer was obtained similarly: mp 90-92 °C (Hexane). [a]24Q= +43.2° (c 1.0, CHCI3).
EXAMPLE 17h 2(R)-Hydrpxymethyl-liR)-n-propyl-l-tertbutoxycarbonylpyrrolidine The product of EXAMPLE 17g was subjected to conditions similiar to that described under EXAMPLE lib. A clear oil was isolated in 98% crude yield. TLC Rf = 0.79 (10% MeOH in CHCI3). HRMS(CI) m/e calcd for Οχ3Η26Νθ3, 244.1913 (M+H)+, found, 244.1911. 1H' NMR (DMSO-dg, 100°C, 360 MHz) δ 4.29 (t, J=5.5 Hz, IH), 3.52-3.46 (m, IH), 3.45-3.33 (m, 3H), 3.15 (ddd, J=10.6, 7.7, 6.0 Hz, IH), 2.17-2.12 (m, IH), 2.00-1.90 9H) , 0.90 (t, J=7.0 Hz, 3H) .
EXAMPLE-ILL 2(R)-Formvl-3(R)-n-propyl-l-tert-butoxycarbonylpyrrolidine The crude from EXAMPLE 17h was subjected to similiar conditions as that described under EXAMPLE 11c. A slightly colored oil was isolated in 82% crude yield. TLC Rf = 0.52 (EtOAc/hexane 1:4). HRMS(CI) m/e calcd for Ci3H24NO3, 242.1756 (M+H)+ , found, 242.1753. 1H NMR (CDCI3, 300 MHz) 2 conformers δ 9.47 (d, J=2.9 Hz, 0.3H), 9.36 (d, J=3.8 Hz, 0.7H), 3. 77-3.67 (m, IH), 3.62-3.52 (m, IH), 3.44-3.37 (m, IH), 2.17 -2.02 (m, 2H), 1.63-1.51 (m, IH), 1.50-1.30 (m, 4H), 1.48 (s, 2.7H), 1.45 (s, 6.3H), 0.92 (t, J=7.0 Hz, 3H) . -47EXAMPLE 17 j The crude from EXAMPLE 17i was subjected to similiar conditions as that described under EXAMPLE lid. The crude was flash chromatographed using Et2O/hexane (1:10) as the elutant. A waxy solid was isolated in 85% yield. TLC Rf = 0.40 (EtOAc/hexane 1:8). [a]23D = -46.4° (c 1.12, CHC13). m.p. = 35-37°C. MS(CI) m/e 398 (M+H)+. 1H NMR (DMSO-d6, 100°C, 500 MHz) δ 6.49 J=8.4 Hz, 1H) , 3.93 (dd, J=8.4, 5.5 Hz, 1H), 3.42 (ddd, J=10.8, 7.8, 4.1 Hz, 1H), 3.24 (ddd, J=10.7, 7.7, 7.1 Hz, 1H), 2.08-1.92 (m, 2H), 1.53-1.30 (m, 5H), 1.39 (s, 9H), 0.89 (t, J=7.1 Hz, 3H).
Anal, calcd. for C14H23Br2NO2: C, 42.34; H, 5.84; N, 3.53; Found: C, 42.69; H, 5.91; N, 3.55.
EXAMPLE .17k 3-Hydroxy-l-Γ 2(R)-(3(R)-n-propy1-1-tertbupoxycarbonylpyrrolidinyl)1-1-propyne The title compound was prepared from the product of EXAMPLE 17j by the same procedure as that described under EXAMPLE lc. The crude was subjected to flash chromatography using EtOAc/hexane (1:4—>1:1) as the elutant. A viscous yellow oil was isolated in 64% yield. TLC Rf = 0.12 (EtOAc/hexane 1:4). [OC]23d = +70.0° (c 1.06, CHC13). HRMS(CI) m/e calcd for Ο15Η26ΝΟ3, 268.1913 (M+H)+, found, 268.1911. 1H NMR (DMSO-d6, 100°C, 500 MHz) δ 4.73 (t, J=5.8 Hz, 1H), 4.08 (dd, J=5.7, 1.7 Hz, 2H), 4.04-4.01 (m, 1H), 3.41 (ddd, J= 10.8, 7.6, 5.7 Hz, 1H), 3.23 (ddd, J=10.7, 7.6, 6.9Hz, 1H), 2.18-2.14 (m, 1H), 2.07-2.02 (m, -481H), 1.56-1.26 (m, 5H), 1.43 (s, 9H) , 0.91 (t, J=7.1 Hz, 3H) .
EXAMPLE 171 1-f 2(R)- (3(R)-n-Propyl-l-tertbutoxycarbonylpyrrolidinyl)1-3-(2,5-dioxo-pyrrolidinyl)-1propyne The title compound was prepared from the product of EXAMPLE 17k by the same procedure as that described under EXAMPLE Id. The crude was flash chromatographed using ETOAc/hexane (1:2) as the elutant. Diethyl hydrazinedicarbonate co-eluted with product and a yield of 55% was determined via 1H NMR. An analytical amount of the title compound was purified by the same means as that described under EXAMPLE Ilf. TLC Rf = 0.40 (EtOAc/hexane 1:1). [a]23D = +68.8° (c 0.85, CHC13). m.p. = 54-58°C.
HRMS(CI) m/e calcd for C19H29N2O4, 349.2127 (M+H)+, found, 349.2131. 1H NMR (DMSO-d6, 100°C, 500 MHz) 6 4.16 (d, J=1.8 Hz, 2H), 3.95-3.91 (m, 1H), 3.39 (ddd, J=10.8, 7.8, 5.4 Hz, 1H), 3.21 (ddd, J=10.8, 7.5, 7.2 Hz, 1H), 2.66 (s, 4H), 2.17-2.09 (m, 1H), 2.03-1.96 (m, 1H), 1.53-1.25 (m, 5H), 1.41 (s, 9H), 0.90 (t, J=7.0 Hz, 3H). Anal, calcd. for 03^28^04: C, 65.49; H, 8.10; N, 8.04; Found: C, 65.57; H, 8.14; N, 7.96.
EXAMPLE 17m 3-(5-Hydroxy-2-oxo-pyrrolidinyl)-1-12(R)-f3(R)-n-PrOPVl~ltert-butoxycarbonylpyrrolidinylll-l-propvne The title compound was prepared from the product of EXAMPLE 171 in the same manner as that in EXAMPLE le. The crude was flash chromatographed using EtOAc/hexane -49(2:33:21:0) as the elutant. A light yellow oil was isolated in quantitative yield. TLC Rf = 0.40 (ETOAc). HRMS(FAB+KI) m/e calcd for C19H30KN2O4, 389.1843 (M+K)+, found, 389.1841. 1H NMR (DMSO-dg, 100°C, 500 MHz) 05.71 (dd, J=7.0, 2.0 Hz, 1H), 5.20-5.16 (m, 1H), 4.26 (dd, J=17.4, 1.4 Hz, 1H), 3.98-3.96 (m, 1H), 3.70 (dd, J=17.4, 1.0 Hz, 1H), 3.42-3.37 (m, 1H), 3.22 (ddd, J=10.6, 7.4, 7.0 Hz, 1H), 2.40-2.34 (m, 1H), 2.22-2.10 (m, 3H), 2.031.93 (m, 1H), 1.78-1.74 (m, 1H) , 1.54-1.28 (m, 5H), 1.41 (s, 9H), 0.90 (t, J=7.0 Hz, 3H).
EXAMPLE llQ 3-(2-Oxo-pyrrolidinyl)-1-(2(R)-i3(R)-npropylpyrrolidinyll)-1-propyne The title compound was prepared from the product of EXAMPLE 17m by the same procedure as that in EXAMPLE If. The crude was flash chromatographed using 10% MeOH in CHCI3 as the elutant. An amber colored oil was isolated in 85% yield. TLC Rf = 0.50 (2 drops NH4OH per lOmls of 10% MeOH in CHCI3). [a]23D = -38.0° (c 0.98, CHCI3). HRMS(CI) m/e calcd for C14H23N2O, 235.1810 (M+H)+, found, 235.1812. 1H NMR (DMSO-dg, 100°C, 300 MHz) 6 4.01 (d, J=1.9 Hz, 2H) , 3.38 (t, J=7. 1 Hz, 2H), 3.27 (dt, J=6, .8, 1.9 Hz, 1H) 2.92- -2.87 (m, 1H) , 2.79 (ddd, J=10 • 3, 8.4, 4.5 Hz, 1H) , 2.23 (t, J=8.0 Hz, 2H) , 1.99-1.88 (m, 4H) , 1.50-1 . 43 (m, 1H) , 1.42-1.32 (m, 2H) , 1.32-1.24 (m, 2H) , 0.90 (t , J=7.1 Hz, 3H). -50EXAMPLE 17q 3- (2-Oxo-l-pyrrolidinyl)-1-f2(R)- (3(R)-npropylpyrrolidinyl)1-1-propyne hydrogen oxalate The oxalate salt of EXAMPLE 17n was made in 94% yield from a similiar procedure outlined under EXAMPLE Hi. [a]23D = -29.4° (c 1.0, MeOH) NMR (DMSO-dg, 100°C, 300 MHz) 3.83 (dt, J=8.9, 2.0 Hz, 1H), (dd, J=8.5, 5.9 Hz, 2H), 2.24 (m, 2H), 2.03-1.93 (m, 2H) , 1 (m, 3H) , 0.92 (t, J=7.0 Hz, C14H22N2°·9/10 C2H2O4: C, 60.23; H, 7.73; N, MS(CI) m/e 235 (M+H)+. !h δ 4.10 (d, J=1.8 Hz, 2Η), 3.42 (t, J=6.9 Hz, 2Η), 3.20 Hz, 2H), 2.19-2.08 1.46-1.33 for 88; Found: (t, J=8.0 60-1.50 (m, 2H), 3H) . Anal. calcd.
C, 60.18; H, 7.61; N, 8 8.93. ' EXAMPLE 18 1— r 2(R)-(l-Methyl-3(R)-n-propylpyrrolidinyl)1-3-(2-oxopyrrolidinyl)-1-propyne hydrogen oxalate EXAMPLE 18a 1— r 2(R)-(l-Methyl-3(R)-n-propylpyrrolidinyl) 1 -3-(2-oxopyrrolidinyl)-1-propyne The product from EXAMPLE 17o was subjected to conditions outlined under EXAMPLE 2. The crude was flash chromatographyed using 2% MeOH in CHCI3 as the elutant. A clear oil was isolated in 82% yield. TLC Rf = 0.29 (5% MeOH in CHCI3). [a]23D = -17.8° (c 0.84, CHCI3). MS(CI) m/e 249 (M+H)+. 1H NMR (DMSO-dg, 90°C, 300 MHz) δ 4.02 (d, J=1.8 Hz, 2H), 3.38 (t, J=7.0 Hz, 2H), 2.77 (ddd, J=8.5, 8.5, 4.9 Hz, 1H), 2.68 (dt, J=7.3, 1.8 Hz, 1H), 2.32-2.23 (m, 1H), 2.25 (s, 3H) , 2.21 (t, J=8.0 Hz, 2H), -512.09-1.87 (m, 4H) , 1.50-1.41 (m, 1H), 1.40-1.21 (m, 4H), 0.88 (t, J=7.0 Hz, 3H).
EXAMPLE 18b l-Γ(R)-(l-Methyl-3(R)-n-propylpyrrolidinyl)l-3-(2-oxopyrrolidinyl)-1,-pr.agyne hydrogen oxalate The product from EXAMPLE 18a was subjected to conditions previously described under EXAMPLE lli. A white solid was isolated in 90% yield. [OC]23d = -10.2° (c 1.18, MeOH). m.p. = 105-108°C. MS(CI) m/e 249 (M+H)+. 1H NMR (DMSO-dg, 100°C, 300 MHz) δ 4.10 (d, J=1.8 Hz, 2H), 3.42 (t,·J=7.0 Hz, 2H), 3.30 (dt, J=8.5, 1.8 Hz, 1H), 3.12 (ddd, J=10.4, 8.5, 5.5 Hz, 1H) , 2.74 (ddd, J=9 .8, 9.8, 6 Hz, 1H), 2.54 (s, 3H), 2.24 (t, J=7.9 Hz, 2H), 2.23-2.17 (m, 1H), 2.13-1.95 (m, 3H) , 1.56 i-1.47 (m, 2H) , 1.42-1.31 (m, 3H), 0.91 (t, J=7. 0 Hz, 3H) . Anal, calcd. forC15H24N2°'C2H2°4,H20: C, 58 .77; H, 7.83; N, 8. 06; Found: C, 58.89; H, 7.61; N, 7.90.
EXAMPLE 19 1.l-Dimethyl-2(R)-Γ3-(2-oxo-pyrrolidinyl)-1-propynyll3(R)-n-propylpyrrolidinium iodide The product from EXAMPLE 18a was subjected to conditions described under EXAMPLE 13. An amber solid was isolated in 98% yield. [a]23D = -10.9° (c 0.65, MeOH). m.p. = 80-83°C. MS(FAB) m/e 263 (M)+. 1H NMR (DMSO-d6, 100°C, 300 MHz) δ 4.38 (dt, J=11.0, 1.8 Hz, 1H), 4.20 (d, J=l,8 Hz, 2H), 3.79-3.70 (m, 1H), 3.65-3.58 (m, 1H), 3.43 (t, J=7.0 Hz, 2H), 3.18 (s, 3H), 3.06 (s, 3H), 2.53-2.47 (m, 1H), 2.43-2.31 (m, 1H), 2.26 (t, J=7.9 Hz, 2H), 2.00 -52(q, J=7.5 Hz, 2H), 1.85-1.77 (m, IH), 1.65-1.37 (m, 4H) , 0.93 (t, J=7.3 Hz, 3H). Anal, calcd. for 016Η27IN2O·H20: C, 48.13; H, 7.07; N, 7.02; Found: C, 48.18; H, 6.89; N, 6.96.
EXAMPLE 20 1—f2R—(3(R)-n-Propylpyrrolidinyl)1-3-(2,5-dioxopyrrolidinyl) -1-propyne hydrogen oxalate EXAMPLE 2.0a 1—F2R— (3(R)-n-Propylpyrrolidinyl) 1 -3-(2,5-dioxopyrrolidinyl) -1-propyne The product from EXAMPLE' 171 was subjected to conditions described under EXAMPLE 4 to yield the title compound. The crude was flash chromatographed using 10% MeOH in CHCI3 as the elutant. A viscous amber oil was isolted in 97% yield. [α]22^ = -3θ·7° (c 0.48, CHCI3). HRMS(CI) m/e calcd for C14H21N2O2, 249.1603 (M+H)+, found, 249.1600. ^H NMR (DMSO-dg, 100°C, 300 MHz) δ 4.23 (d, J=1.8 Hz, 2H), 3.86 (dt, J=9.4, 1.8 Hz, IH), 3.23-3.18 (m, 2H), 2.68 (s, 4H), 2.17-2.07 (m, 2H), 1.61-1.47 (m, 2H), 1.42-1.30 (m, 3H), 0.89 (t, J=7.0 Hz, 3H) .
EXAMPLE 20b 1-f2R-(3(R)-n-Propylpyrrolidinyl)1-3-(2,5-dioxopyrrolidinyl) -1-propyne hydrogen oxalate The oxalate salt of EXAMPLE 20a was prepared in 94% yield using a procedure already described under EXAMPLE Hi. [a]23D = -17.8°(c 0.40, MEOH). MS(CI) m/e 249 (M+H)+. 1H NMR (DMSO-dg, 100°C, 500 MHz) δ 4.25 (d, 1.6 Hz, 2H), 3.86 (dm, IH), 3.25-3.17 (m, 2H), 2.70 (s, 4H), -532.18-2.10 (m, 2H), 1.61-1.51 (m, 2H) , 1.42-1.33 (m, 3H), 0.91 (t, J=7.2 Hz, 3H). Anal, calcd. for C14H20N2O2‘1·2 C2H2O4-H2O: C, 53.91; H, 6.45; N, 7.67; Found: C, 54.10; H, 6.24; N, 7.49.
EXAMPLE 21 1-r2R- (3(R)-l-Methyl-3-n-propylpyrrolidinyl)1-3-(2.5dioxo-pyrrolidinyl)-1-propyne hydrogen oxalate EXAMPLE 21a 1—T2R—(3(R)-l-Methyl-3-n-propylpyrrolidinyl) 1 -3-(2,5dioxo-pyrrolidinyl)-1-propyne The title compound was prepared from the product of EXAMPLE 20a by using the same procedure as that outlined under EXAMPLE 2. The crude was flash chromatographed using 2% MeOH in CHCl3->5% MeOH in CHC13 as the elutant. A clear oil was isolated in 51% yield. TLC Rf = 0.48 (10% MeOH in CHC13). HRMS(CI) m/e calcd for Cf5H23N2O2, 263.1759 (M+H)+, found, 263.1762. 1H NMR (DMSO-dg, 100°C, 500 MHz) δ 4.17 (d, J=1.8 Hz, 2H), 2.77 (ddd, J=8.7, 8.7, 4.6 Hz, 1H), 2.68 (s, 3H), 2.65 (dt, J=7.1, 1.8 Hz, 1H), 2.27 (ddd, J=8.9, 6.8, 6.8 Hz, 1H), 2.26 (s, 4H), 2.07-2.00 (m, 1H) , 1.93 (dddd, J=12.3, 9.5, 8.2, 6.8 Hz, 1H), 1.50-1.43 (m, 1H), 1.39-1.23 (m, 4H), 0.88 (t, J=7.1 Hz, 3H).
EXAMPLE 21h l-f2R-(3(R)-l-Methyl-3-n-propylpyrrolidinvl)1-3-(2, 5dioxo-pyrrolidinyl)-1-propyne hydrogen oxalate The oxalate salt of EXAMPLE 21a was prepared by the same manners as that described under EXAMPLE Hi. A white solid was isolated in 95% yield. [a]24p = -8.8° (c 0.94, -54MeOH). m.p. = 160-162°C. MS(CI) m/e 263 (M+H)+. 1H NMR (DMSO-dg, 100°C, 500MHz) 84.20 (d, J=1.8 Hz, 2H), 3.18 (dt, J=8.5, 1.8 Hz, 1H), 3.04 (ddd, J=10.4, 7.9, 5.5 Hz, 1H), 2.70-2.62 (m, 1H), 2.67 (s, 3H), 2.47 (s, 4H), 2.171.96 (m, 2H), 1.52-1.42 (m, 2H), 1.39-1.28 (m, 3H), 0.88 (t, J=7.0 Hz, 3H). Anal, calcd. for C15H22N2O2'Ο2Η2Ο4: C 57.94; H, 6.86; N, 7.95; Found: C, 57.85; H, 6.84; N, 7.83.
EXAMPLE 22 1.l-Dimethyl-3(R)-n-propyl-2(R) — Γ 3—(2 f5-dioxopyrrolidinyl)-1-propynyllpyrrolidinium iodide The title compound was prepared from the product of EXAMPLE 42 using the procedure described under EXAMPLE 13 A yellow solid was isolated in 69% yield. [OC]24d = -15.3° (c 0.70, MeOH). m.p. = 68-75°C (dec.). MS(CI) m/e 277 (M)+. 3Η NMR (DMSO-dg, 100°C, 300 MHz) Hz, 2H), 4.31-4..28 4.32 (d, J=1.8 (m, 1H), 3.71 (ddd, J=12.2, 8.2, 4.0 Hz, 1H), 3.61-3.51 (m, 1H), 3.18 (s, 3H) , 3.02 (s, 3H) , 2.69 (s, 4H), 2.47-2.38 (m, 1H), 2.35-2.28 (m, 1H) , 1.781.74 (m, 1H), 1.58-1.49 (m, 1H), 1.48-1.32 (m, 3H), 0.91 (t, J=7.0 Hz, 3H). Anal, calcd. for 0]^Η25ΐΝ2θ2: C, 46.50; H, 6.34; N, 6.79; Found: C, 46.78; H, 6.02; N, 6.78. -55EXAMPLE 23 1-Γ1(S)-(l-Amino-2-ethanoll-3-(2-oxo-pyrrolidinyl)-1propyne EXAMPLE 23.a 4(S)-(2,2-Dibromoethenyl)-2,2-dimethyl-3-tertbntoxycaxhgnylQxazQlidine The title compound was prepared by following the procedure described under EXAMPLE lid. The appropriate aldehyde was synthesized by the procedure outlined in J. Org. Chem. 52, 2361-2364, (1987). The crude was subjected to flash chromatography using Et2O/hexane (1:19) as the elutant. A white solid was isolated in 79% yield. TLC R = 0.18 (ETOAc/hexane 1:10). [0t]23D = -20.6° (c 1.6, CHCI3). m.p. = 56-58°C. MS(FAB) m/e 386 (M+H)+. 1H NMR (DMSO-dg, 100°C, 500 MHz) δ 6.56 (d, J=8.1 Hz, 1H) , 4.45 (ddd, J=8.1, 6.5, 3.4 Hz, 1H), 4.11 (dd, J=9.1, 6.5 Hz, 1H), 3.73 (dd, J=9.1, 3.4 Hz, 1H), 1.50 (s, 3H) , 1.48 (s, 3H), 1.45 (s, 9.H) . Anal, calcd. for Ci2Hl9Br2NO3: C' 37.43; H, 4.97; N, 3.64; Found: C, 37.23; H, 4.84; N, 3.54 .
EXAMPLE 23b 1-Γ4(S)-2,2-Dimethyl-3-tert-butoxycarbonyloxazolidinvn-3 hydroxy-l-propyne The title compound was prepared from the product of EXAMPLE 23a by the same procedure as that described under EXAMPLE lb. The crude was flash columned using (EtOAc/hexane 1:41:2) as the elutant. A yellow oil was isolated in 59% yield. TLC Rf = 0.11 (EtOAc/hexane 1:4). (a]23D = +129.5° (c 0.75, MeOH). MS(CI) m/e 256 (M+H)+. -561H NMR (DMSO-dg, 100°C, 300 MHz) δ 4.60-4.56 (m, IH), 4.09 (d, J=1.6 Hz, 2H), 4.05 (dd, J=8.6, 6.2 Hz, IH), 3.86 (dd, J=8.6, 2.6 Hz, IH), 1.54 (s, 3H), 1.46 (s, 9H), 1.44 (s, 3H).
EXAMPLE 23c 1— r4(S)-2,2-Dimethy1-3-tert-butoxycarbonyloxazolidiny11-3(2.5-dioxo-pyrrolidinyl)-1-propyne The title compound was prepared from the product of EXAMPLE 23b by the same method as that described under EXAMPLE Ilf. The crude was flash chromatographed using ETOAc/hexane (2:3 to 1:1) as the elutant. Once again, as in previously described examples, diethyl hydrazinedicarboxylate was not removed by flash chromatography. A yield of 51% was achieved based on molar ratios obtained from IH NMR. TLC Rf = 0.68 (EtOAc). MS (CI) m/e 337 (M+H)+. 1H NMR (DMSO-dg, l00°C, 500 MHz) δ 4.534.51 (m, IH), 4.16 (d, J=1.9 Hz, 2H), 4.01 (dd, J=8.9, 6.2 Hz, IH), 3.83 (dd, J=8.7, 2.5 Hz, IH), 2.66 (s, 4H), 1.51 (s, 3H), 1.43 (s, 9H), 1.42 (s, 3H).
EXAMPLE 23d 1-Γ 4(S)-2.2-Dimethyl-3-tert-butoxycarbonyloxazolidinyll-3(5-hydroxy-2-oxo-pyrrolidinyl)-1-propyne The title compound was prepared from the product of EXAMPLE 23c by the same procedure as that described under EXAMPLE le. The crude was flash chromatographed using EtOAc/hexane (3:1 to 4:1) as the elutant. A solid in quantitative yield was isolated. TLC Rf = 0.32 (EtOAc). m.p. = 75-78°C. HRMS(FAB+KI) m/e calcd for Ci7H2gKN2O5, 377.1479 (M+K)+, found, 377.1474. NMR (DMSO-dg, 100°C, -57300 MHz) δ 5.78-5.65 (m, 1H), 5.21-5.15 (m, 1H), 4.584.54 (m, 1H), 4.28 (dd, J=17.1, 1.2 Hz, 1H), 4.10-4.01 (m, 1H), 3.89-3.84 (dm, 1H), 3.72 (dd, J=18.0, 1.5 Hz, 1H), 2.44-2.34 (m, 1H), 2.27- 2.12 (m, 2H), 1.84-1.74 (m, 1H), 1.52 (s, 3H), 1.45 (s, 9H), 1.44 (s, 3H). Anal, calcd. for 03,7¾ 6N2O5 · H20: C, 58.77; H, 7.83; N, 8.06; Found: C, 59.18; H, 7.59; N, 8.21.
EXAMPLE 23e 1- Π (S) - (l-Amino-2-ethanol) -3-(2-oxo-pyrrolidinyI) -1.propyne • The title compound was prepared from the product of EXAMPLE 23d by the same procedure as that described under EXAMPLE If. The crude was flash chromatographed using 10% MeOH in CHCl3->10% MeOH in CHCl3/l% NH4OH as the elutant.
A solid was isolated in 69% yield. TLC Rf = 0.25 (3 drops NH4OH per 10 mis 10% MEOH in CHCI3). [a]23D = +6.7° (c 0.33, MeOH). m.p. = 59-60°C. HRMS(CI) m/e calcd for C9H15N2°2' 183.1133 (M+H)+, found, 183.1136. NMR (DMSO-dg, 100°C, 500 MHz) δ 4.47-4.38 (br s, DC1exhangeable), 3.99 (d, J=2.0 Hz, 2H), 3.50-3.47 (m, 1H), 3.43-3.37 (m, 1H), 3.38 (t, J=7.0 Hz, 2H), 3.31-3.28 (m, 1H), 2.21 (t, J=8.0 Hz, 2H), 1.98-1.91 (m, 2H) , 1.66-1.58 (br s, DCl-exchangeable). Anal, calcd. for CgHf4N2O2: C, 59.32; H, 7.74; N, 15.37; Found: C, 59.33; H, 7.79; N, 15.26. -58EXAMPLE 24 1- fl (S) -(l-Dimethylamino-2-ethanol)-3- (2-oxopyrrolidinyl)-1-propyne hydrogen oxalate EXAMPLE 24a 1-fl(S)-(l-Dimethylamino-2-ethanol1-3-(2-oxo-pyrroldinyl)1-propyne The product from EXAMPLE 23e was subjected to conditions described under EXAMPLE 2. The crude was flash chromatographed using 10% MEOH in CHC13 as the elutant. A clear viscous oil was isolated in 77% yield. TLC Rf = 0.30 (10% MeOH in CHCI3). [a]23D=+30.8° (c 0.52, CHCI3).
HRMS(CI) m/e calcd for CnH^N^, 211.144 6 (M+H)+, found, 211.1449. 1H NMR (DMSO-dg, 100°C, 500 MHz) δ 4.24-4.21 (m, 1H), 4.06 (d, J=1.8 Hz, 2H), 3.53-3.38 (m, 3H), 3.43 (t, J=7.1 Hz, 2H), 2.24 (t, J=8.1 Hz, 2H), 2.18 (s, 6H), 2.00-1.91 (m, 2H) .
EXAMPLE 24b 1-fl(S)-(l-Dimethylamino-2-ethanon-3-(2-oxopyrrolidinyl)-1-propyne hydrogen oxalate The oxalate salt of EXAMPLE 24a was prepared by a similar means previously described under EXAMPLE lli. A white solid was isolated in 96% yield. [a]23p = +19.7° (c 1.1, MeOH). m.p. = 62-65°C. MS(CI) m/e 211 (M+H)+. XH NMR (DMSO-dg, 100°C, 500 MHz) δ 4.11 (d, J=2.1 Hz, 2H), 3.883.85 (m, 1H), 3.66-3.59 (m, 2H), 3.43 (t, J=7.1 Hz, 2H), 2.48 (s, 6H), 2.24 (t, J=8.1 Hz, 2H), 2.01-1.95 (m, 2H),. Anal, calcd. for C11H18N2O2·1.3 C2H2O4: C, 49.90; H, 6.34; N, 8.56; Found: C, 50.00; H, 6.37; N, 8.48. -59EXAMPLE. 25 3- (2-oxo-pyrrolidinyl)-1-Γ2 (R) - (4 (R) hydroxy)pyrrolidinyl)prop-l-yne hydrogen oxalate EXAMPLE 25a l-tert-Butoxycarbonyl-4(R)-(tert-butyldimethylsilvl)oxy2 (R ).-1. carboxaldehyde)pyrrolidine The title compound was prepared from 1-tertbutoxycarbonyl-4(R)-(tert-butyldimethylsilyl)oxy-2(R)-(hyd roxymethyl)pyrrolidine (11.86 g, 35.77 mmol; prepared as described by Rosen et al in J. Med. Chem.. 21, 1598-1611, (1988)) as described under EXAMPLE la to give 10.52 g of crude product as an oil. The compound was used directly in the next reaction without purification. MS(CI) m/e 330 (M+H) + . 1-H NMR (CDCI3, 300 MHz) shows two conformers at room temperature. •'•H NMR (DMSO-dg, 100°C, 500 MHz) δ 9.48 (d, J=2.2 Hz, 1H), 4.42 (m, 1H), 4.08 (m, 1H), 3.48 (dd, J=11.3, 4.0 Hz, 1H), 3.28 (dt, J=11.3, 1.7 Hz, 1H) , 2.29 (m, 1H), 1.88 (m, 1H), 1.41 (s, 9H) , 0.84 (s, 9H), 0.15 (s, 6H) .
EXAMPLE 25b l-tert-Butoxycarbonyl-4(R)-(tert-butyldimethvlailvl)oxv2(R)-(2.2-dibromoethenyl)pyrrolidine This was prepared as described in EXAMPLE lid but starting from triphenylphosphine (33.0 g, 125.2 mmol), carbon tetrabromide (23.73 g, 71.54 mmol) and product from EXAMPLE 25a (10.52g, 31.92 mmol). The product was purified by flash chromatography (ether/hexene 1:9) to give 11.51 g of the desired product as a clear oil (66% for the two step). TLC Rf=0.18 (EtOAc/hexane 1:9). -60[α]23D=-30.6° (c 0.58, MeOH). HRMS(CI) m/e calcd for c17H32Br2NO3si' 484.0522 (M+H)+, found, 484.0522. NMR (DMSO-d6, 300 MHz) δ 6.64 (d, J=8.5 Hz, 1H), 4.45-4.30 (m, 2H), 3.41 (dd, J=ll.2, 4.2 Hz, 1H), 3 .18 (br d, J=11.2 Hz, 1H), 2.28 (m, 1H) , 1.66 ('dd', J=13.2 , 1.8 Hz, 1H), 1.39 (s, 9H), 0.86 (s, 9H), 0.04 (s, 6H). Anal, calcd. for Cf7H3iBr2NO3Si : C, 42.07; H, 6.44; N , 2.89; Found: C, 42.51; H, 6.38; N, 2.87.
EXAMPLE 25c 3-Hydroxy-l-Γ2(R)- (l-tert-Butoxycarbonyl-4(R)-tertbutyldimethylsilyloxy)pyrrolidinyllprop-l-yne The title compound was prepared from the foregoing pyrrolidine (EXAMPLE 25b) using the method described in Example lc. The crude was purified by flash chromatography (EtOAc/hexane 1:51:3) to give 12% yield of 1-[2(R)- (l-tert-Butoxycarbonyl-4(R)-tertbutyldimethylsilyloxy)pyrrolidinyl]ethyne (TLC Rf=0.48 (EtOAc/hexane 1:5); MS(CI) m/e 326 (M+H)+) and 63% yield of the desired product as an amber oil. TLC Rf=0.07 (EtOAc/hexane 1:5). [a]24D=+56.6° (c 1.2, MeOH). MS(CI) m/e 356 (M+H)+. XH NMR (DMSO-dg, 300 mHz)) 5.06 (t, J=5.9 Hz, -OH), 4.44 (m, 1H), 4.38 (m, 1H), 4.05-3.99 (m, 2H), 3.50 (dd, J=11.0, 5.3 Hz, 1H), 3.06 ('br d', J=11.0 Hz, 1H), 2.33 (m, 1H), 1.80 ('dt', J=12.9, 3.7 Hz, 1H), 1.41 (s, 9H), 0.86 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). Anal, calcd. for CfgH33NO4Si·H20: C, 60.20; H, 9.37; N, 3.90; Found: C, 60.27; H, 9.27; N, 3.88. -61EXAMPLE 25d 3-(2.5-dioxo-pyrrolidinyl)-1-(2(R)-Γ(1-tertButoxycarbonyl-4(R)-tertbutyldimethylsilyloxy)pyrrolidinyl)l-l-propyne The title compound was prepared from the foregoing alcohol (EXAMPLE 25c) using the method described in EXAMPLE Id. Most of the byproducts were removed by precipitation in EtOAc/Hexane (1:1). The crude was then flash chromatographed (EtOAc/hexane l:2->2:3) to give a mixture of diethyl hydrazinedicarboxylate and the desired product. A yield of 78% was calculated based on the molar ratio as seen from NMR. TLC Rf=0.20 (EtOAc/hexane 2:3). MS(CI) m/e 437 (M+H)+. !h NMR (CDCI3, 300 MHz) δ 4.50-4.17 (m, 4H) , 3.50 (m, IH) , 3.23 (dd, J=ll.0, 4.0 Hz, IH), 2.72 (s, 4H) , 2.25 (m, IH) , 1.97 (m, IH), 1.46 (s, 9H), 0.89 (s, 9H) , 0.06 (s, 6H) .
EXAMPLE 25e 3-(5-Hydroxy-2-oxo-pyrrolidinyl)-1-f 2 (R) - Γ (1-tertbutoxycarbonyl-4(R)-tertbutyldimethylsilyloxy)pyrrolidinyll)-1-propyne The title compound was prepared from the foregoing succimide (EXAMPLE 25d) using the method described in EXAMPLE le. The crude was purified by flash chromatography (EtOAc/hexane 4:1 to 1:0) to give a mixture of the two desired epimeric alcohols (57%) as a clear oil. TLC Rf=0.43 (EtOAc). MS (CI) m/e 421 (M-OH)+. -62EXAMPLE 25f 3-(2-oxo-pyrrolidinyl)-1-(2(R)-(4(R)hydrQxylpyixplidinyl 1-:.1-propyae The title compound was prepared from the foregoing alcohols (EXAMPLE 25e) using the method described in EXAMPLE If. The reaction mixture was basified with aqueous K2CO3 solution and then extracted with CHC13 continuously overnight. The combined organic phase was dried (Na2SO4), concentrated and purified by flash chromatography (CHCl3/MeOH/NH4OH 90:10:0->90:10:1) to give 38%· yield of 3-[1-(2-oxo-pyrrolidinyl) ]-1-[2 (R) - (4 (R) tert-butyldimethylsilyloxy)pyrrolidinyl]-1-propyne as an oil (TLC Rf=0.44 (10% MeOH in CHC13). MS (CI) m/e 323 (M+H)+) and 47% yield of the title compound as an oil.
TLC Rf=0.08 (10% MeOH in CHC13). MS(CI) m/e 209 (M+H)+. 1h NMR (CDC13, 300 MHz) δ 4 .40 (ddd, J=8.5, 4.4, 2. 0 Hz, 1H) , 4. 11 (d, J=2.0 Hz, 2H) , 3.81 (m, 1H), 3.48 (t, J=7.2 Hz, 1H) , 3.07 (d, J=ll. 8 Hz, 1H) f 2.91 (dd, J=11.8, 4.4 Hz, 1H) , 2.43-2.28 (m, 3H + (NH & OH)), 2.05 (m, 2H) r 1.88-1.78 (m, 1H).
EXAMPLE 25g 3-(2-oxo-pyrrolidinyl)-1— Γ2(R) -(4(RLhydroxy)pyrrolidinyl!prop-l-yne hydrogen oxalate To a solution of the product from EXAMPLE 25f in MeOH/ether was added two equivalents of oxalic acid in ether. After standing in freezer for two days, the resulting solid was collected by filtration to give 55% yield of the title compound. m.p.=126-128°C. [a]24D=+20.4° (c 0.51, MeOH). MS(CI) m/e 209 (M+H)+. ΧΗ NMR (CD3OD, -63300 MHz) δ 4.55 (m, 1H) , 4.49 (m, 1H), 4.18 (d, J=1.5 Hz, 2H) , 3.54 (t, J=7.2 Hz, 2H), 3.34-3.29 (m, 2H), 2.61 (ddd, J=14.2, 9.2, 5.5 Hz, 1H), 2.36 (t, J=8.1 Hz, 2H) , 2.07 (m, 3H). Anal, calcd. for CjjHjgN2O2' C2H2O4: C, 52.35; H, 6.08; N, 9.39; Found: C, 52.46; H, 6.09; N, 9.36.
EXAMPLE 26 3(4'-Dimethylamino-2'-butynyl)-oxazolidine-4-one Hydrogen Oxalate EXAMPLE 26a 2- (tert-Butyloxycarbonyl)hydroxy)-acetic Acid To a solution of ethyl glycolate (3.47 g, 33.3 mmol) and 4-dimethylaminopyridine (10 mg, 0.1 mmol) in CH2CI2 (40 ml) at 0°C was added di-tert-butyl dicarbonate (7.3 g, mmol). The reaction was stirred for 1.5 h as it warmed to ambient temperature. The reaction mixture was concentrated in vacuo and then the residue was dissolved in ethanol (35 ml) to which was added 2 N KOH (17 ml). After standing at room temperature for 2 h, the reaction mixture was concentrated in vacuo and the residue diluted with ethyl acetate (60 ml) and 2 N HCl (20 ml). The organic phase was separated, dried (Na2SO4), and the solvent evaporated in vacuo to afford 4.89 g (76%) of the product as a yellow oil; MS(CI) m/e 194 (M+NH4)+. 1H NMR (CDCI3, 300 MHz) δ 1.51 (s, 9H) , 4.63 (s, 2H), 9.25 (s, 1H) . -64EXAMPLE 26b 2-r(tert-Butyloxycarbonyl)hydroxyl-N-proparyl Acetamide To a solution of EXAMPLE 26a (3.07 g, 17.4 mmol), propargyl amine (1.10 g, 20 mmol), 4-dimethylaminopyridine (100 mg, 0.8 mmol) in CH2CI2 (30 ml) was added 1-(3dimethylaminopropyl)-3-ethylcarbodiimide-HCl (3.63 g, 19.0 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then washed with 1 N HCl (15 ml) followed by saturated aqueous NaHCOg-brine (15 ml). The organic phase was dried (Na2SO4), and then concentrated in vacuo to afford 2.42 g (65%) of a yellow oil which solidified on standing; mp: 54-57°C. MS (CI) m/e 214 (M+H)+, 231 (M+NH4)4·. 1H NMR (CDCI3, 300 MHz) δ 1.51 (s, 9H) , 2.26 (dd, J=2.6, 2.6 Hz, 1H), 4.12 (d, J=2.6 Hz, 1H) , 4.14 (d, J=2.6 Hz, 1H) , 4.57 (s,2H), 6.47 (br s,lH).
EXAMPLE 26c l-Dimethylamino-4-f(2-tert-Butyloxycarbonyl)hydroxyacetamidol-but-2-yne To a solution of EXAMPLE 26b (1.07 g, 5.04 mmol) in THF (10 ml) was added Ν,Ν,Ν^,Ν1- tetramethyldiaminomethane (1.53 g, 15 mmol) and copper (I) chloride (25 mg). The reaction mixture was stirred at reflux under an atmosphere of nitrogen for 2 h and then concentrated in vacuo. The residue was partitioned between CH2CI2 (25 ml) and saturated aqueous Na2CO3 (15 ml). The organic phase was dried (Na2SO4), then concentrated in vacuo to give a light brown oil. Purification by column chromatography on silica gel (CH2CI2/CH3OH 7:1) afforded 530 mg (39%) of -65the product as a light yellow oil; MS(CI) m/e 271 (M+H)+. χΗ NMR (CDC13, 300 MHz) 8 1.50 (s, 9H), 2.29 (s, 6H) , 3.22 (t, J=2.2Hz, 2H), 4.14 (t, J=2.2 Hz, 1H), 4.16 (t, J=2.2Hz, 1H), 4.56 (s, 2H), 6.46 (br s, 1H).
EXAMPLE 26d 3(41-Dimethylamino-21-butynyl)-oxazolidine-4-one Hydrogen Qxalata To a solution of EXAMPLE 26c (183 mg, 0.68 mmol) in CH3CN (8 ml) was added TsOH-H20 (167 mg, 0.88 mmol) and the reaction mixture was heated to reflux for 15 min. Diethoxymethane (excess) was then added to the reaction mixture and it was stirred at reflux overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo and then the residue was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic phase was dried (Na2SO4), and concentrated in vacuo to give a yellow oil which was purified by column chromatography on silica gel (CH2CI2/CH3OH 7:1). The purified free base was isolated in 28% yield (34.6 mg) as a colorless oil to which was added oxalic acid (25 mg, 0.28 mmol). The mixture was suspended in a small volume of EtOH and sonicated to afford a white ppt which was then diluted with ether and collected by suction filtration.; mp: 112-114°C. MS(CI) m/e 183 (M+H)+. 1H NMR (D20, 300 MHz) δ 2.94 (s, 6H), 4.06 (m, 2H), 4.28 (m, 2H), 4.37 (m, 2H), 5.23 (m, 2H). Anal, calcd. for C11H16N20gΌ.25 H20: C, 47.72; H, 6.01; N, 10.12. Found: C, 47.84; H, 5.83; N, 9.96. -66EXAMPLE 27 3(4'-Dimethylamino-2'-butynyl)-2-methyl-oxazolidine-4-one Hydrogen Oxalate To a solution of EXAMPLE 26c (202 mg, 0.75 mmol) in CH3CN (7 ml) was added TsOH-H2O (156 mg, 0. 82 mmol) and the reaction mixture was heated to reflux for 15 min. Acetal ( 1ml) was added to the mixture and stirring at reflux was continued. Approximately 1.5 h later, additi'onal acetal (1 ml) was added and stirring at reflux was continued overnight. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo and the the residue was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic phase was dried(Na2SO4), concentrated in vacuo, and the residue was purified by silica gel column chromatography (CH2CI2/CH3OH 7:1). The purified free base was isolated in 27% yield (40 mg) as an orange oil. The oil was dissolved small volume of ethanol and then oxalic acid (27 mg, 0.34 mmol) was added. The mixture was diluted with ether to precipitate a tan color solid which was collected by suction filtration; mp 117-119 °C; MS(CI) m/e 197 (M+H)+. ΧΗ NMR (CDCI3/CD3OD, 300 MHz) δ 1.51 (d, J=5.2Hz, 3H), 2.84 (s, 6H) , 3.92 (CD3OH), 3.93 (masked s, 2H), 3.99 (dt, J=18 , 1 .8 Hz, 1H), 4.25 (dd , J=14, 1.5 Hz, 1H), 4.33 (dd, J=14 , 1 .5 Hz, 1H) , 4.43 (dt , J=18, 1.8 Hz, 1H), 5.36 (qt, J=5 . 2, 1.8 Hz , 1H) . Anal. calcd. forC12H18N2°6 : C , 50. 33; H, 6. 34; N, 9.79. Found: : C, 50.48; H, 6.37; N, 9.43. -67EXAMPLE 28 3(41-Dimethylamino-2'-butynyl)-2-phenyl-oxazolidine-4-one Hydrogen Oxalate EXAMPLE 28a 3-Propargyl-2-phenyl-oxazolidine-5-one The product of EXAMPLE 26b (509 mg, 2.9 mmol) was dissolved in trifluoroacetic acid (2 ml) and the solution was kept at ambient temperature for 25 min. The reaction mixture was diluted with toluene (4 ml), then heated to 95 °C for 1.3 h. Benzaldehyde dimethyl acetal (470 mg, 3.1 mmol) and TsOH-H2O (50 mg, 0.26 mmol) were added and stirring at 95 oC was continued for 6 h with additional benzaldehyde dimethyl acetal being added periodically.
The reaction mixture was cooled to ambient temperature and the concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic phase was dried (Na2SO4), concentrated in vacuo, and the residue purified by silica gel column chromatography (ethyl acetate/hexane 1:1) to afford 175.5 mg (31%) of the product as a yellow solid; mp 109-lll°C; MS(CI) m/e 202 (M+H)+. XH NMR (CDCI3, 300 MHz) δ 2.20 (t, J=2.6 Hz, 1H), 3.24 (ddd, J=17.6, 2.6, 0.9 Hz, 1H), 4.41 (dd, J=14, 1.4 Hz, 1H)), 4.52-4.58 (m, 2H), 6.10 (dd, J=2.2, 2.2Hz, 1H), 7.41-7.46 (m, 5H) . -68EXAMPLE 28b 3- (.4 ' -DimethylaminQ-2 ' -butynyl)-2-phenyl-oxazolidine-4-one Hydrogen Oxalate To a solution of the product of EXAMPLE 28a (60 mg, 0.30 mmol) in THF (2.5 ml) was added a large excess of N,N,N1,N1-tetramethyldiaminomethane and copper (I) chloride (5 mg). The reaction mixture was stirred at reflux under an atmosphere of nitrogen for 1 h, cooled to ambient temperature, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2CI2/CH3OH 8:1) to give 66 mg (85%) of the free base as a pale yellow oil. The product was dissolved in a small volume of ethanol and then oxalic acid (37 mg, 0.41 mmol) was added. Dilution of the solution with ether precipitated the product salt as a white solid; mp 87-89 °C. MS(CI) m/e 259 (M+H)+. XH NMR (D2O, 300 MHz) δ 2.80 (s, 6H), 3.90 (t, J=1.8 Hz, 1H), 3.97 (dt, J=18.4, 1.8 Hz, 1H), 4.24 (dt, J=18.4, 1.8 Hz, 1H) ) , 4.53 (dd, J=14.3, 1.8 Hz, 1H) > 4.67 (dd, J=14.3, 1.8 Hz, 1H) ) , 6.22 (t, J=1.8 Hz, 1H), 7.53-7.60 (m, 5H). Anal, calcd. for c17H20N2°6‘0·1 h20: 58.31; H, 5.81; N, 8.00. Found: C, 58.19 H, 5.79; N, 7.91.
EXAMPLE 22 3-(4'-Dimethylamino-2'-butynyl)oxazolidine-2.4-dione Hydrogen Oxalate EXAMPLE 29a 2-Hydroxy-(4'-dimethylamino-2’-butynvl)acetamide To a solution of the product of EXAMPLE 26c (525 mg, 1.94 mmol) in CH2CI2 (3 ml) at 0 °C was added -69trifluoroacetic acid (3 ml) and the reaction mixture was maintained at 0 oC for 2 h. The mixture was concentrated in vacuo to give 270 mg of a yellow oil which was partitioned between ethyl acetate and saturated aqueous Na2CC»3 . The organic phase was dried (Na2SO4) and the solvent evaporated in vacuo leaving an oily residue.
EXAMELE-.2 9b Γ41-Dimethylamino-2'-butynyl)-oxazolidine-2,4-dione Hydrogen Oxalate The product of EXAMPLE 29a (72.6 mg, 0.52 mmol) was dissolved in dioxane (2 ml) to which was added carbonyldiimidazole (101 mg,'0.62 mmol). The reaction mixture was stirred at 70 °C for 4 h. The solvent was evaporated in vacuo, the residue dissolved in ethyl acetate, and the solution washed with saturated aqueous Na2CO3. The organic phase was dried (Na2SO4), and then concentrated in vacuo to afford an oily residue which was purified by silica gel chromatography (CH2C12/CH3OH 7:1). The product was isolated in 67% yield (68 mg) as a colorless oil. The oil was dissolved in a small volume of ethanol to which was added oxalic acid (50 mg, 0.55 mmol), and then the product salt was precipitated by dilution of the mixture with ether with the white solid the being collected by suction filtration; mp 142-145 °C; MS (CI) m/e 197 (M+H)+. XH NMR (D2O, 300 MHz) δ 2.94 (s, 6H), 4.04 (m, 2H), 4.48 (m, 2H), 4.91 (s, 2H). Anal, calcd. for C9H12N2O3·1.2(C2O4H2): C, 45.01; H, 4.77; N, 9.21. Found: C, 45.02; H, 4.62; N, 9.45. -70EXAMPLE 3Q Γ4'-Dimethylamino-21-butynyll-5(S)-methyl-oxazolidine-4one Hydrogen Oxalate EXAMPLE 30a (S)-Hydroxy-N-propargyl Propionamide To a solution of L-lactic acid (510 mg, 5.6 mmol), propargyl amine (551 mg, 10 mmol), and 4dimethylaminopyridine (50 mg, 0.41 mmol) in CH2CI2 (20 ml) and ether (10 ml) was added dicyclohexylcarbodiimide (1.2 g, 5.7 mmol). The reaction was stirred at ambient temperature for 6 h. Concentration in vacuo, followed by trituration with ethyl acetate and removal of the solids by filtration through paper, gave a clear supernatent which was washed with saturated aqueous Na2CO3, 1 N HCl, and then brine. The organic phase was dried (Na2SO4), concentrated in vacuo, and the residue purified by silica gel column chromatography (ethyl acetate/hexane 4:1) to yield 187 mg (26%) of the product as a pale yellow oil; MS(CI) m/e 128 (M+H)+, 145 (M+NH4)+. XH NMR (CDCI3, 300 MHz) δ 1.48 (br s, J=7 Hz, 3H), 2.25 (t, J=2.6 Hz, 1H), 2.38 (br s, 1H), 4.09 (m, 2H), 4.29 (br q, J=7 Hz, 1H), 6.71 (br s, 1H).
EXAMPLE 30b 3- (2’-propynyl)-5(S)-methyl-oxazolidine-4-one A solution of the product of EXAMPLE 30a (183 mg, 1.4 mmol) and diethoxymethane (179 mg, 1.72 mmol) in trifluoroacetic acid (2 ml) was heated to 75 °C for 4 h. -71The reaction was cooled to room temperature and the concentrated in vacuo. The residue was dissolved in ethyl acetate (20 ml) and washed successively with saturated aqueous Na2CC>3, 1 N HCl, and then brine. The organic phase was dried (Na2SO4), concentrated in vacuo, and the residue purified by silica gel column chromatography (ethyl acetate/hexane 2:1) to yield 57 mg (28%) of the product as a colorless oil; MS(CI) m/e 140 (M+H)+, 157 (M+NH4)+. XH NMR (CDCI3, 300 MHz) δ 1.43 (t, J=7 Hz, 3H), 2.29 (t, J=2.6 Hz, 1H), 4.15 (d, J=2.6 Hz, 2H), 4.36 (m, 1H) , 5'.11 (m, 2 H) .
EXAMPLE 3Qc Γ41-Dimethylamino-2'-butynyl!-5(S)-methyl-oxazolidine-4one Hydrogen Oxalate To a solution of the product of EXAMPLE 30b (55.5 mg, 0.40 mmol) in THF (2 ml) was added N,N,NX,NXtetramethyldiaminomethane (163 mg, 1.6 mmol) and copper (I) chloride (8 mg). The reaction mixture was stirred at reflux for 1 h. The reaction mixture was concentrated in vacuo and then the residue was dissolved in ethyl acetate (20 ml) and washed with saturated aqueous Na2CO3 (10 ml). The organic phase was dried (Na2SO4), then concentrated in vacuo leaving an amber color oil. Purification of the oil by silica gel column chromatography (CH2CI2/CH3OH 7:1) afforded 40 mg (51%) of the product as a colorless oil.
The oil was dissolved in ether to which was added an ethereal solution of oxalic acid (37 mg, 0.41 mmol). The resulting white precipitate was collected by suction filtration; mp 100-101 °C; MS(CI) m/e 197 (M+H)+. XH NMR (D2O, 300 MHz) δ 1.38 (t, J=7.0 Hz, 3H), 2.94 (s, 6H), -724.06 (m, 2H), 4.27 (m, 2H), 4.54 (m, 1H), 5.15 (m, 1H), 5.21 (m, 2H). Anal, calcd. for ^2Κΐ8Ν2θ6 ' θ · 3 H2O: C, 49.41; H, 6.43; N, 9.60. Found: C, 49.31; H, 6.17; N, 9.47 .
EXAMPLE .21 1-(2-Qxo-4(S)-acetoxy-l-pyrrolidinyl)-4-dimethylamino-but2-yne Hydrogen Oxalate EXAMELE ,21a 1—(2,4—Qxo—3(S)-acetoxy-l-pyrrolidinyl)-but-2-yne Using a modification of the procedure of Chamberlin et. al. (J. 7km. Chem Soc. , 105, 3653, (1983)), L-malic acid (4.26 g, 37.8 mmol) was refluxed in a solution of acetyl chloride (16 ml) for 2.5 h. The mixture was concentrated in vacuo, then propargyl amine (3.1 g, 57 mmol) and triethylamine (11.5 g, 113.4 mmol) were added. After stirring the reaction mixture at ambient temperature for 1 h, the mixture was concentrated in vacuo. The residue was dissolved in aqueous saturated NaHCC>3 and then washed with ethyl acetate. The aqueous phase was made acidic (pH=l) by the addition of 0.5 N HCl. The solution was saturated by the addition of solid NaCl and then it was extracted with ethyl acetate (3x) followed by CH2CI2 (xl). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in acetyl chloride (20 ml) and the stirred at reflux for 2 h. After concentration in vacuo, the residue was dissolved in ethyl acetate and the washed with saturated aqueous NaHCC>3 followed by brine. The organic phase was dried (Na2SO4), concentrated in vacuo, and the residue -73purified by silica gel column chromatography (ethyl acetate/ hexane 2:1) to afford 3.38 g (46%) of the product as a colorless oil; [a] 22D=-26.0° (C 1.5, CH2CI2) , MS(CI) m/e 196 (M+H) + . 1H NMR (CDCI3, 300 MHz) δ 2.18 (s, 3H) , 2.24 (t, J=2.6 Hz, 1H), 2.72 (dd, J=18.4, 4.8 Hz, 1H), 3.23 (dd, J=18.4, 8.8 Hz, 1H), 4.32 (d, J=2.6 Hz, 2H) 5.48 (dd, J=8.8, 4.8 Hz, 1H).
EXAMPLE 31b 1-(2-QXO-4(S)-acetoxy-5-hydroxy-l-pyrrolidinyl)-prop-2-yne To a solution of the product of EXAMPLE 31a (2.32 g, 8.53 mmol) in CH3OH at -10 °C was added sodium borohydride (0.97 g, 25.6 mmol). The reaction mixture was stirred at room temperature for 0.5 h after which time it was quenched by pouring into a solution of saturated aqueous NaHCOg. The mixture was extracted with CH2Cl2(x2), the extracts dried (Na2SO4), and then concentrated in vacuo to give 823 mg (49%) of a colorless oil; MS (CI), m/e 198 (M+H)+.
EXAMPLE-^ lc 1-(2-0ΧΟ-4(S)-acetoxy-l-pyrrolidinyl)-prop-2-yne To a solution of the product of EXAMPLE 31b (823 mg, 4.18 mmol) in CHCI3 (20 ml) was added triethylsilane (970 mg, 8.35 mmol) and trifluoroacetic acid (9.5 g, 83.6 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was concentrated in vacuo and the residue partitioned between CHClgand saturated aqueous Na2CO3. The organic phase was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography -74(ethyl acetate/hexane 4:1) to give 89 mg (12%) of the product as a pale yellow oil; MS (CI) m/e 182 (M+H)+, 199 (M+NH4)+.
EXAMPLE 3Id 1-(2-Qxo-4(S)-acetoxy-l-pyrrolidinyl)-4-dimethylamino-but2-yne Hydrogen Oxalate A solution of the product of EXAMPLE 31c (46.8 mg, 0.25 mmol), copper (I) chloride (2 mg), and N, N, N1, N^·tetramethyldiaminomethane (167 mg, 1.8 mmol) in THF (2 ml) was heated to reflux under an atmosphere of nitrogen for 0.5 h. The reaction mixture'was cooled to room temperature, diluted with ethyl acetate, and then washed with saturated aqueous Na2CC>3. The organic phase was dried (Na2SO4), concentrated in vacuo, and the residue purified by silica gel column chromatography (CH2C12/CH3OH 7:1) to yield 25.8 mg (43%) of the free base as a colorless oil. The oil was dissolved in ether to which was added an ethereal solution of oxalic acid (14 mg, 0.16 mmol). The resulting precipitate was collected by suction filtration; mp 53-55 °C; MS(CI) m/e 197 (M+H)+. 1r NMR (D2O, 300 MHz) 6 2.09 (s, 3H) , 2.55 (dd, J=18.2, 1.6 Hz, IH)), 2.94 (s, 6H), 2.95 (dd, J=18.3, 7 Hz, IH) , 3.63 (dd, J=12, 1.6 Hz , IH)), 3.97 (dd, J= 12, 5.9 Hz, IH) , 4.05 (m, 2H), 4.23 (m, 2H), 5.38 (m, IH) . Anal, calcd. for C^4H2qN2O7·0.4 H20: C, 50.12; H, 6.25; N, 8.35. Found: C, 50.08; H, 5.97; N, 8.28. -75EXAMPLE 32 3-r 4’-Dimethylamino-2'-butynyl!-5(R)-phenyl-oxazolidine-4one Hydrogen Oxalate EXAMPLE 32a 2(R)-Hydroxy-N-propargyl Phenylacetamide To a solution of (R)-mandelic acid (680 mg, 4.5 mmol), propargyl amine (275 mg, 5.0 mmol), and diisopropylethylamine (646 mg, 5.0 mmol) in THF (8 ml) at 0 °C was added diphenylphosphoryl azide (1.38 g, 5.0 mmol). The reaction mixture was stirred overnight letting warm slowly to room temperature. The mixture was concentrated in vacuo and then the oily residue was dissolved in ethyl acetate. The organic phase was dried (Na2SO4), concentrated in vacuo, and the residue was the purified by silica gel colum chromatography (ethyl acetate/hexane 3:1) to yield 739 mg (87%) of a pale yellow oil which solidified on standing; mp 87-88°C; MS(CI) m/e 190 (M+H)+. ΧΗ NMR (CDCI3, 300 MHz) δ 2.24 (t, 1H, J=2.6 Hz), 3.29 (d, 1H, J=3.5 Hz), 4.04 (ddd, 1H, J=16.4, 5.1, 2.6 Hz), 4.10 (ddd, 1H, J=16.4, 5.1, 2.6 Hz), 5.08 (d, 1H, J=3.5 Hz), 6.38 (br s, 1H), 7.31-7.45 (m, 5H) .
EXAMPLE 32b 3-(2'-propynyl)-5(R)-phenyl-oxazolidine-4-one A solution of EXAMPLE 32a (373 mg, 2.0 mmol) and diethoxymethane (420 mg, 4.0 mmol) in acetonitrile was added TsOH-H2O (38 mg, 0.2 mmol) and the reaction mixture was stirred at 80 °C for 6h. The reaction was cooled to -7 6ambient temperature and the concentrated in vacuo. The residue, which was a mixture of ethoxymethyl ether and oxazolidinone product, was dissolved in trifluoroacetic acid and heated to 75 °C for lh. After cooling, the reaction was concentrated in vacuo and the residue purified by silica gel column chromatography (ethyl acetate/hexane 1:1) to afford 147 mg (36%) of the product as a colorless oil; MS(CI) m/e 202 (M+H)+. XH NMR (CDCI3, 300 MHz) δ 2.25 (dd, 1H, J=2.6, 2.6 Hz), 4.06 (ddd, 1H, J=17.6, 5.5, 2.6 Hz), 4.13 (ddd, 1H, J=17.6, 5.5, 2.6 Hz) 4.68 (', 1H, J=7 Hz), 4.76 (d, 1H, J=7 Hz), 5.11 (s, 1H) , 7.29-7.45 (m, 5H).
EXAMPLE 3.2G Γ4'-Dimethylamino-2’-butynyl1-5(R)-phenyl-oxazolidine-4· one Hydrogen Oxalate EXAMPLE 32b (117.2 mg, 0.58 mmol) was reacted in a similar fashion to that described in EXAMPLE 30c. Purification of the residue by silica gel column chromatography (CH2CI2/CH3OH 8:1) gave 88 mg (58%)of the product as a colorless oil. The oil was dissolved in a small volume of ethanol and the an ethereal solution of oxalic acid (46 mg, 0.51 mmol) was added. The resulting precipitate was collected by suction filtration. XH NMR (D2O, 300 MHz) δ 2.80 (s, 6H), 3.97 (m, 2H), 4.09 (m, 2H), 4.78 (d, 1H, J=7.4 Hz), 4.83 (d, 1H, J=7.4 Hz), 5.15 (s, 1H), 7.46 (S, 5H). -7 7EXAMPLE 33 2-Methoxy-4-dimethylamino-pent-3-yne Hydrochloride To a solution of 3-butyn-2-ol (1.17 g, 16.7 mmol) in THF (10 ml) at 0 °C under nitrogen was added sodium hydride (530 mg, 22 mmol). After several minutes the mixture was allowed to warm to ambient temperature and was stirred an additional 15 min. Methyl iodide (2.5 g, 16.7 mmol) was the added and stirring was continued overnight. The reaction was diluted with ether (50 ml) and the organic phase was washed with brine. After drying (Na^SO,}), N, N, N1,N^-tetramethyldiaminomethane (3 g, 29 mmol), copper (I) chloride (50 mg) and THF (10 ml) were added and this mixture was heated to 60 °C with the ether solvent being allowed to boil off over the course of approximately lh. The mixture was allowed to cool to room temperature, then it was diluted with ethyl acetate and washed with saturated aqueous Na2CC>3. The organic phase was dried (Na2SO4>, the concentrated in vacuo leaving an oily residue which was purified by silica gel column chromatography (CH2CI2/CH3OH 8:1). The product was dissolved in a small volume of ethanol and a saturated solution of HCl-ether was added. The resulting white precipitate was collected by suction filtration and dried at room temperature under vacuum to yield 318 mg (10%) of the product; mp 93-95 °C; MS(CI) m/e 142 (M+H)+. 1H NMR (D2O, 300 MHz) δ 1.46 (d, 3H, J=7 Hz), 2.97 (s, 6H), 3.44 (s, 3H), 4.10 (d, 2H, J=1.5 Hz), 4.35 (qt, 1H, J=6.6, 1.5 Hz). Anal, calcd. for ΟθΗ16Ο1ΝΟ: C, 54.08; H, 9.08; N, 7.88. Found: C, 53.81; H, 9.06; N, 7.65. -78EXAMPLE 34 l-Methoxy-5-dimethylamino-pent-3-yne Hydrogen Oxalate 3-Butyn-l-ol (1.16 g, 16.55 mmol) was treated in a similar fashion to that described in example 33. The oil was purified by silica gel column chromatography (CH2C12, CH3OH 8:1). The purified product was dissolved in ether and an ether solution of oxalic acid (1.30 g, 14.4 mmol) was added to precipitate the product. The resulting white solid was collected by suction filtration and dried at room temperature under vacuum to yield 346 mg (9%) of the product; mp 96-97 °C; MS(CI) m/e 142 (M+H)+. XH NMR (D2O, 300 MHz) δ 2.59 (tt,2H, J=6.1, 2.2 Hz), 2.93 (s, 6H), 3.38 (s, 3H), 3.61 (t, 2H, J=6.1 Hz), 3.98 (t, 2H, J=2.2 Hz) . Anal, calcd. for Cjoh17n<35: C, 51.94; H, 7.41; N, 6.06. Found: C, 51.75; H, 7.31; N, 5.97.
EXAMPLE 35 3-(2-Qxo-pyrrolidinyl)—1— Γ 2(S)-piperidinyl!-1-propyne hydrogen oxalate (S)-1-tert-Butcxycarbonylpiperidinylcarboxylic acid 2(S)-Piperidinecarboxylic acid (3.96 g, 30.6 mmol), N,N-diisopropylethylamine (6.4 ml, 36.8 mmol) and ditert-butyl dicarbonate (10.0 g, 46.0 mmol) were combined in a similar fashion as that described in EXAMPLE 11a.
The title compound was isolated as a white solid in 88% yield following flash chromatography, [a]23d = -43.4° (c 1.0, MeOH). m.p. = 114-118°C. MS and XH NMR are similar to those in EXAMPLE 11a. Anal, calcd. for C11H19NO4: C, 57.63; H, 8.35; N, 6.11; Found: C, 57.24; H, 8.42; N, 6.01. -7 9EXAMPLE 35b 2(S)-Hydroxymethyl-l-tert-butoxycarbonylpiperidine The product from EXAMPLE 35a (6.06 g, 26.4 mmol) and borane-methyl sulfide complex, 2.0 M in THF, (19.8 ml, 39.7 mmol) were combined in a similar fashion as that described in EXAMPLE lib. The title compound was isolated in 88% yield following flash chromatography. [a]23D = -38.8° (c 1.18, CHC13). m.p. = 82-84°C. MS and ^H NMR are similar to those in EXAMPLE lib. Anal, calcd. for C11H21NO3: C, 61.37; H, 9.83; N, 6.50; Found: C, 61.52; H, 9.99; N, 6.50.
EXAMPLE 35c 2(S)-1-tert-Butoxycarbonylpiperidinecarbaldehyde The product from EXAMPLE 35b (4.93 g, 22.9 mmol), triethylamine (9.6 ml, 68.7 mmol) and pyridinium sulfur trioxide (10.9 g, 68.7 mmol) were combined in a similar fashion as that. described in EXAMPLE 11c. An oil in 72% crude yield was realized. A small amount of material was purified via flash chromatography for analytical purposes. [a]23D ---41.3° (c 1.45, CHCI3) . MS and XH NMR are similar to those described in EXAMPLE 11c.
EXAMPLE 35d 2(S)-(2.2-Dibromoethenyl)-1-tertbutoxycarbonylpiperidine The crude product from EXAMPLE 35c (3.22 g, 15.1 mmol), triphenylphosphine (19.8 g, 75.6 mmol) and carbon tetrabromide (10.0 g, 30.2 mmol) were combined in a similar fashion as that described in EXAMPLE lid. A -80white solid was isolated in 64% yield following flash chromatography. [CC]22d = +30.3° (c 1.0, CHCI3). m.p. = 109-lll°C. MS and 1H NMR are similar to those described in EXAMPLE lid. Anal, calcd. for C12Hi9Br2NO2: C, 39.05; H, 5.19; N, 3.79; Found: C, 39.52; H, 5.12; N, 3.78.
EXAMPLE 35e 3-Hydroxy-l-Γ2(S)-l-tert-butoxycarbonylpiperidinyll-1propyne The title compound was prepared by the same procedure as in EXAMPLE lc, also see EXAMPLE lie. The product from EXAMPLE lid (3.53 g, 9.56 mmol), nbutyllithium, 2.5 M in hexanes, (7.9 ml, 19.6 mmol) and paraformaldehyde (860 mg, 28.7 mmol) were combined to give the propargyl alcohol as a yellow oil in 87% yield following flash chromatography. [22d = -120.4° (c 1.20, CHCI3). MS and 1H NMR are similar to those in EXAMPLE He.· EXAMPLE 35f 3-(2.5-Dioxo-pyrrolidinyl) —1— Γ2 (S) -1-tertbutoxycarbonylpiperidinyl1-1-propyne The product from EXAMPLE 35e (1.84 g, 7.71 mmol), triphenylphosphine (2.42 g, 9.25 mmol), diethyl azodicarboxylate (1.45 ml, 9.25 mmol) and succinimide (840 mg, 8.48 mmol) were combined in a similar fashion as that described in EXAMPLE Id. A yield, based on molar ratios as seen from ^-H NMR, of 53% was realized. A small amount of material was purified following the procedure described in EXAMPLE Ilf for analytical -81purposes. [CC]23d = -93.1° (c 1.0, CHCI3) . m.p. = 109111°C. MS and NMR are the same as those described in EXAMPLE Ilf. Anal, calcd. for C17H24N2O4: C, 63.73; H, 7.55; N, 8.74; Found: C, 63.75; H, 7.76; N, 8.82.
EXAMPLE 35a 3-(5-Hydroxy-2-oxo-pyrrolidinyl)-1-f2(S)-1-tertbutoxycarbonylpiperidinyl1-1-propyne The title compound was prepared using the same procedure as that described in EXAMPLE le. A white solid was isolated in good yield following flash chromatography, m.p. = 103105°C. MS and ^-H NMR are similar to those described in EXAMPLE llg. Anal, calcd. for C17H2gN2O4: Cf 63.33,. H, 8.13; N, 8.69; Found: C, 63.08; H, 8.19; N, 8.56.
EXAMPLE 35h 3-(2-Qxo-pyrrolidinyl)-1-Γ2(S)-piperidinyll-1-propyne The product from EXAMPLE 35g (1.17 g, 3.62 mmol), triethylsilane (1.5 ml, 9.04 mmol) and trifluoroacetic acid (7.0 ml, 90,5 mmol) were combined in a manner previously described in EXAMPLE If to give the title compound as a clear oil in 96% yield following flash chromatography. [a]23p = -7.0° (c 1.0, CHCI3) . MS and 1H NMR are similar to those described in EXAMPLE llh.
EXAMPLE 35i 3-(2-Oxo-pyrrolidinyl)—1— Γ 2(S)-piperidinyll-1-propyne hydrogen oxalate The title compound was prepared by combining the product from EXAMPLE 35h (335 mg, 1.62 mmol) and oxalic -82acid (146 mg, 1.62 mmol) in the same manner as that described in EXAMPLE lli. A hygroscopic foam-like solid was isolated in 75% yield. [a]23p = -9.6° (c 0.90, MeOH). MS and 1H NMR are similar to those in EXAMPLE lli. Anal, calcd. for Ci4H2qN2O5 · 1/5 H20: C, 56.07; H, 6.86; N, 9.34; Found: C, 56.06; H, 7.00; N, 9.30.
EXAMPLE 36 1— Γ 2(S)-(1-Methylpiperidinyl))-3-(2-oxo-pyrrolidinyl)-1propyne hydrogen oxalate EXAMPLE 36a 1-f 2(S) - (1-Methylpiperidinyl') 1 -3- (2-oxo-pyrrolidinyl) -1propyne The product from EXAMPLE 35h (268 mg, 1.30 mmol) was subjected to conditions previously described in EXAMPLE 2. The title compound was isolated as a clear oil in 69% yield following flash chromatography. MS and ^-H NMR are similar to those in EXAMPLE 12a.
EXAMPLE 36b 1-Γ2(S)-(1-Methylpiperidinyl)1-3-(2-oxo-pyrrolidinyl)-1propyne hydrogen oxalate The product from EXAMPLE 36a (80.2 mg, 0.364 mmol) and oxalic acid (33.0 mg, 0.364 mmol) were combined in a similar fashion to that described in EXAMPLE lli. A hygroscopic glass-like solid was isolated in 95% yield. [a]23D = -27.1° (c 0.50, MeOH). MS and 1H NMR are similar to those in EXAMPLE 12b. Anal, calcd. for -83C15H22N2°5 ’ 1/2C2H2°4: C, 54.04; H, 6.60; N, 8.15; Found: C, 54.08; H, 6.52; N, 7.88.
EXAMPLE 37 1,l-Dimethyl-2(S)-Γ3-(2-oxo-pyrrolidinyl)-1propynyllpiperidinium iodide The product from EXAMPLE 36a (92.2 mg, 0.418 mmol) and an excess of iodomethane were combined in a similar fashion as that described in EXAMPLE 13 to give a white solid in 79% yield. [a] 23£> = -8.7° (c 0.63, MeOH) . MS and l-Η NME are similar to those in EXAMPLE 13. Anal, calcd. for ¢^^231^0 · 1/5H2O: C, 45.96; H, 6.45; N, 7.66; Found: C, 45.81; Η, 6.18; N, 7.61.
EXAMPLE 38 1-Γ2(S)-Piperidinyl)-3-(2,5-dioxo-pyrrolidinyl)-1propyne hydrogen oxalate EXAMPLE 38a 1-f2(S)-Piperidinyll-3-(2,5-dioxo-pyrrolidinyl)-1propyne The product, still containing the impurity diethylhydrazinedicarboxylate, from EXAMPLE 35f was subjected to conditions previously described in EXAMPLE 4. A foam-like solid was isolated in good yield following flash chromatography. MS and ^H NMR are similar to those in EXAMPLE 14. -84EXAMPLE 38b L-f2,i^),.-Piperidinyl1 -3-(2,5-diQXQ-pyrrQlidinyl) -1pcopyne hydrogen oxalate The product from EXAMPLE 38a (125 mg, 0.568 mmol) was taken up in anhydrous acetone and oxalic acid (56 mg, 0.625 mmol) in acetone was added dropwise to the reaction vessel at room temperature. The reaction was allowed to stir for ~3 hours after which the acetone was stripped and the remaining white solid triturated with cold acetone (XI) and room temperature ether (X4) to give the title compound in 7R% yield. [α]23g = -9.5° (c 0.98, H20) . MS(CI) m/e 221 (M+H)+. XH NMR (DMSO-dg, 100°C, 300 MHz) 5 4.24 (d, J=1.83 Hz, 2H), 4.09-4.06 (m, 1H), 3.14-3.08 (m, 1H), 2.93-2.87 (m, 1H), 2.70 (s, 4H), 1.92-1.87 (m, 1H), 1.75-1.50 (m, 5H). Anal, calcd. for C14H18N2°6: c' 54.19; H, 5.85; N, 9.03; Found: C, 54.04; H, 5.96; N, 8.89.
EXAMPLE 39 1— Γ 2(S)-l-Methylpiperidinyl)-3-(2,5-dioxo-pyrrolidinyl)1-propyne The product from EXAMPLE 38a (326 mg, 0.975 mmol) was subjected to conditions previously described in EXAMPLE 2, also see EXAMPLE 15. A solid was isolated in 64% yield following flash chromatography, [a]23^ = 25.7° (c 0.75, CHCI3). m.p. = 92-94°C. MS and XH NMR are similar to those in EXAMPLE 15. Anal, calcd. for -85c13h18n2°2 ’ 1/5h2O: c< 65.63; H, 7.80; N, 11.78; Found: C, 65.65v H, 7.78; N, 11.57.
EXAMPLE ,.40. 1,1-Dimethyl-2(S)-(3-(2,5-dioxo-pyrrolidinyl)-1propynyllpiperidinium iodide The product from EXAMPLE 39 (61 mg, 0.260 mmol) and iodomethane were combined using the same procedure as in EXAMPLE 13 to give a white solid in 80% yield. [a]23p = -11.7° (c 0.82, H2O). m.p. = 229-238°C dec. MS and XH NMR are similar to those described in EXAMPLE 16. Anal, calcd. for C14H2lIN2O2: C, 44.69; H, 5.62; N, 7.44; Found: C, 44.74; H, 5.73; Ν,'7.42.
EXAMPLE 41 1-(2(R)-l-Methylpyrrolidinyll-3-(2.5-dioxopyrrolidinyl) -1-propyne hydrogen, oxalate EXAMPLE 4.1a 1-Γ2(R)-l-Methylpyrrolidinyll -3-(2,5-dioxQpyrroIidinyL) -l-propyna 3- (2,5-Dioxo-pyrrolidinyl)-1-(2(R)-pyrrolidinyl)-1propyne (1.61 g, 7.81 mmol) was subjected to conditions previously described in EXAMPLE 2 to give an oil in 38% yield following flash chromatography (10% MeOH in CHCI3 used as the elutant). [CC]23d = +86-6° (c 1.0, CHCI3) .
MS(CI) m/e 221 XH NMR (DMSO-dg, 100°C, 300 MHz) 84.17 (d, J=1.38 Hz, 2H), 3.13-3.08 (m, 1H), 2.72-2.66 (m, 1H), 2.68 (s, 4H), 2.35-2.27 (m, 1H), 2.26 (s, 3H), 2.05-1.94 (m, 1H), 1.80-1.62 (m, 3H). -86EXAMPLE 41b L·- F2.LR) .r-1-MethylpyrrQlidiny.l·] -2r (2,5-dipxopyrrolidinyl)-1-propyne hydrogen oxalate The product from EXAMPLE 41a (298 mg, 1.35 mmol) was taken up in anhydrous ether and cooled to 0°C. Oxalic acid (134 mg, 1.49 mmol) dissolved in ether was added dropwise to the reaction vessel and the reaction was stirred for ~2 hours at 0°C. The ether was then stripped and the remaining white solid triturated with ether '(X3) to give a hygroscopic white solid in 85% yield. [a]23D = +36.9° (c 0.88, MeOH). MS(CI) m/e 221 (M+H)+. 1H NMR (DMSO-dg, 100°C, 300 MHz) 8 4.22 (d, J=1.76 Hz, 2H), 3.61-3.56 (m, IH), 3.01-2.93 (m, IH), 2.73-2.63 (m, IH), 2.69 (s, 4H), 2.48 (s, 3H), 2.17-2.10 (m, IH), 1.90-1.77 (m, 3H). Anal, calcd. for ^14^18^2^6 *C2H2O4*3/5H2O: 0, 46.74; H, 5.20; N, 6.81; Found: C, 46.82; H, 5.20; N, 7.05.
EXAMPLE.42 1,l-Dimethyl-2(R)-Γ3-(2,5-dioxo-pyrrolidinyl)-1propynyl1pyrrolidinium iodide The product from EXAMPLE 41a (286 mg, 1.30 mmol) and iodomethane were combined in ether at 0°C. The reaction was allowed to stir for ~2 hours after which the solvent was stripped and the remaining solid triturated with ether (X3) to give the title compound as a white solid in 26% yield. [a]23D = +41.1° (c 1.1, H2O) . m.p. = 209215°C dec. MS(FAB) m/e 235 (M)+.1H NMR (DMSO-dg, 100°C, 300 MHz) δ 4.67-4.60 (m, IH) , 4.33 (d, J=1.76 Hz, 2H), -873.75-3.67 (m, 1H), 3.57-3.47 (m, 1H) , 3.15 (s, 3H) , 3.03 (s, 3H), 2.70 (s, 4H), 2.50-2.44 (m, 1H), 2.21-2.05 (m, 3H). Anal, calcd. for C13H19IN2O2: C, 43.11; H, 5.29; N, 7.73; Found: C, 43.14; H, 5.25; N, 7.67.
EXAMPLE 43 1-Γ2(S)-l-Methylpyrrolidinyll-3-(2.5-dioxopyrrolidinyl)-1-propyne hydrogen oxalate EXAMPLE 43a 1-Γ2(S)-1-Methylpyrrolidinyll-3-(2, 5-dioxopyrrolidinyl)-1-propyne 3- (2,5-Dioxo-pyrrolidinyl)-1-(2(S)-pyrrolidinyl)-1propyne (1.80 g, 8.73 mmol) was subjected to conditions previously described in EXAMPLE 2 to give a clear oil in 32% yield following flash chromatography. [OC]23p = 84.2° (c 1.2, CHCI3). MS and NMR are similar to those in EXAMPLE 41a.
EXAMPLE 43b 1-f 2 (SI-L-Methylpyrralidinyll-3-(2, 5-dioxQpyrrolidinyl)-1-propyne hydrogen oxalate The product from EXAMPLE 43a (219 mg, 0.994 mmol) was combined with oxalic acid (98.0 mg, 1.09 mmol) in a similar fashion to that described in EXAMPLE 41b. A foam-like hygroscopic solid was isolated in 93% yield. [a]23D = -39.4° (c 0.80, MeOH). MS and ^-H NMR are similar to those in EXAMPLE 41b. Anal, calcd. for c14h18n2°6*1/2h2O: 52.66; H, 6.00; N, 8.77; Found: C, 52.52; H, 5.90; N, 8.48. -88EXAMPLE 44 1.l-Dimethyl-2(S)-(3- (2,5-dioxo-pyrrolidinyl) -1propynyllpyrrolidinium iodide The product from EXAMPLE 43a (261 mg, 1.18 mmol) and iodomethane were combined in a similar fashion as that described in EXAMPLE 42 to give a white solid in 26% yield. [a]23D = -37.9° (c 1.2, H2O). m.p. = 213-218°C dec. MS and NMR are similar to those in EXAMPLE 42. Anal, calcd. for Ci3Hi9IN2O2: C, 43.11; H, 5.29; N, 7.73; Found: C, 43.33; H, 5.34; N, 7.73.
EXAMPLE 45 ((4s)-2-Amino-oxazolinyll-3-(2-oxo-l-pyrrolidinyl)-1propyne The title compound was prepared using the procedure outlined in J. Med. Chem. 1973, 16, 510-512. Example 23e (159 mg, 0.873 mmol) and anhydrous sodium acetate (161 mg, li96 mmol) were combined in anhydrous methanol (3 ml). Cyanogen bromide (97.0 mg, 0.916 mmol) in anhydrous methanol (13 ml) was added dropwise under N2 via a cannula to the reaction vessel with stirring continuous overnight. Solid K2CO3 was then added and allowed to dissolve with stirring for an additional 24 hrs. The solvent was removed and the remaining residue subjected column chromatography using (5% MeOH in CHCl3/l% NH4OH & 10% MeOH in CHCI3 1% NH4OH) as the elutant to give a solid (130 mg, 0.627 mmol) in 72% yield. An analytical amount was recrystallized out of CHCl3/hexane ~(1:1) to give clear prism. TLC Rf=0.30 (3 drops NH4OH per 10 ml 10% MeOH in CHCI3). [a]23d=-65.7° -89(c 0.51, CHCI3). m.p.=126-128°C MS (Cl) m/e 208 (M+H)+. XH NMR (CDCI3/D2O exchange, 300 MHz) 4.76-4.69 (m,1H), 4.44 (dd, J=9.2, 7.7 Hz, 1H), 4.22-4.05 (m,3H), 3.48 (t,J=7.7 Hz, 2H), 2.39 (t, J=8.0 Hz, 2H), 2.05 (q,J=7.7 Hz, 2H) . Analysis calculated for C3.0H13N3O2: C 57.96; H 6.32; N 20.28; Found: C 57.63; H 6.27; N 20.16.
EXAMPLE 46 1-(2-Qxo-4-phenyl-l-pyrrolidinyl)-4-dimethylamino-but-2yne Hydrogen Chloride EXAMPLE 46a 2-.Cxq-4.-pheny L-pyr rolidine 2-Oxo-3-carboxy-4-phenyl-pyrrolidine (1.0 g, 4.87 mmol) in ethanol (20 ml) was heated to reflux overnight. The reaction mixture was concentrated in vacuo leaving 860 mg (99%) of orange gummy residue; MS (CI) m/e 162 (M+H)+, 179 (M+NH4)+. 1H NMR (CDCI3, 300 MHz) δ 2.53 (dd, J=16.9, 8.8 Hz, 1H), 2.76 (dd, J=16.9, 8.8 Hz, 1H) , 3.44 (dd, J=9.2, 7.4 Hz, 1H) , 3.5-4.15 (m, 3H), 6.48 (br s, 0.66H), 6.80 (br s, 0.34 H), 7.7-7.4 (m, 5H), EXAMPLE 46b 1-(2-Qxo-4-phenyl-l-pyrrolidinyi)-prop-2-yne To a solution of the product of EXAMPLE 46a (236.5 mg, 1.47 mmol) in THF (10 ml) was added tetrabutylammonium bromide (509 mg, 1.58 mmol), propargyl bromide (176 mg, 1.48 mmol) and powdered potassium hydroxide (89 mg, 1.58 mmol). The reaction mixture was stirred vigorously at room temperature for 8 -90h after which time it was concentrated in vacuo. The residue was partioned between ethyl acetate and IN HCl then the organic phase was washed with saturated aqueous NaHCO3 followed by brine. The organic phase was dried (Na2SC>4) and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane 2:1) to give 67 mg (23%) of a colorless oil; MS(CI) m/e 200 (M+H)+. 1H NMR (CDCI3, 300 MHz) δ 2.25 (t, J=2.6 Hz, 1H), 2.60 (dd, J=17.3, 8.6 Hz, 1H), 2.83 (dd, J=17.3, 8.6 Hz, 1H) , 3.53 (dd, J=9.0, 7.8 Hz, 1H), 3.63 (m,1H), 3.87 (dd, J=9.0, 7.8 Hz, 1H), 4.18 (t, J=2.6 Hz, 2H), 7.2-7.4 (m, 5H).
EXAMPLE 46c 1-(2-Qxo-4-phenyl-l-pyrrolidinyl)4-dimethylamino-but-2yne Hydrogen Chloride A solution of the product of EXAMPLE 46b (65 mg, 0.33 mmol), copper (I) chloride (10 mg) and Ν,Ν,Ν',Ν'tetramethyldiaminomethane (excess) in THF (4 ml) was heated to reflux under an atmosphere of nitrogen for lh. The reaction mixture was concentrated in vacuo, then the residue was dissolved in ethyl acetate and washed with saturated aqueous Na2CO3. The organic phase was dried (Na2SO4) , concentrated in vacuo, and the residue purified by silica gel column chromatography (CH2CI2/CH3OH 8:1) to yield 54.3 mg (67%) of the free base as a slightly yellow oil. The oil was dissolved in CH3OH and diluted with ether. An ethereal solution of HCl was added and the white solid collected by suction filtration; mp 141-142°C; MS (CI) m/e 257 (M+H)+. Ή NMR (D2O, 300 MHz) δ 2.64 (dd, J=17.1, 7.0 Hz, 1H), 2.90 -91(s, 6H), 2.96 (dd, J=17.1, 8.8 Hz, 1H), 3.60 (dd, J=9.9, .9 Hz, 1H), 3.76 (m, 1H), 4.03 (dd, J=9.9, 8.1 Hz, 1H), 4.04 (m, 3H), 4.20 (dd, J=18, 1.8 Hz, 1H), 4.35 (dd, J=18, 1.8 Hz, 1H), 7.3-7.5 (m, 5H). Anal, calcd. for C16H21CI N20 · 0.2 H2O: C, 64.83; H, 7.28; N, 9.45.
Found: C, 64.99; H, 7.37; N, 9.40.
EXAMPLE 47 1-(2-Qxo-pyrrolidinyl)-4-Γ1-(3(R)-amino)pyrrolidinyl1 but-2-yne Hydrogen Oxalate EXAMPLE 47a 3(S)-Tert-butyloxyamino-l-benzylpyrrolidine 3(S)-Azido-l-benzylpyrrolidine (364.5 mg, 1.8 mmol) [T. Rosen et al., J. Med. Chem.. 31, 1586 (1988)], methanol (100 ml) and 5% Pt/C 40 mg was placed under 4 atm of hydrogen at room temperature for 4 h. The catalyst was removed by filtration through paper and the filtrate was concentrated in vacuo to afford 305 mg of a pale yellow oil. This material was dissolved in dichloromethone (5 ml) and di-tert-butyl dicarbonate (453 mg, 2.0 mmol was added. The reaction mixture was allowed to stand at room temperature overnight then it was concentrated in vacuo and the residue purified by silica gel column chromatography (CH2C12/CH3OH 10:1) to afford 315.7 mg (63%) of a colorless oil. [a]23D=+7.3° (C=1.5, CH2C12). MS(CI) m/e 277 (M+H)+. ΧΗ NMR (CDCI3, 300 MH2) δ 1.43 (s, 9H) , 1.61 (m, 1H), 2.19-2.37 (m, 2H), 2.5-2.68 (m, 2H), 2.7 (m, 1H) , 3.61 (s, 2H) , 4.19 (m, 1H), 4.89 (brs, 1H), 7.21-7.33 (m, 5H). -92EXAMPLE 47b 3(S)-Tert-butyloxyamino-pyrrolidine EXAMPLE 47a (315 mg, 1.14 mmol), methanol (-100 ml), and 20% Pd/C was placed under 4 atm of hydrogen overnight. The catalyst was removed by filtration through paper and the filtrate was concentrated in vacuo to afford 220 mg (-100%) of a greenish brown solid; MS (CI) m/e 187 (M+H)+. XH NMR (CDC13, 300 MHz) δ 1.44 (s, 9H), 1.65 (m, 1H), 2.21 (m, 1H), 2.47) (m, 1H), 2.6 3.35 (m, 4H) , 4.18 (m, 0.66 H), 4.3 (m, 0.34 H) , 5.01 (br s, 0, , 66 H) , 5.52 (br s, 0.34 H) .
EXAMPLE 47c 1-(2-Qxo-pyrrolidinyl)-4-(1-(3(R)-tert-butyloxyamino)pyrrolidinyllbut-2-yne N-Propargyl-2-pyrrolidone (32 mg, 0.26 mmol) [A. Bebbington and D. Shakeshaft, J, Med, Chem., 2, 274 (1965)], EXAMPLE 47b (41 mg, 0.22 mmol), paraformaldehyde (10 mg, 0.33 mmol), and copper I chloride (2 mg) in 1,4 dioxane were heated to reflux under an atmosphere of nitrogen for 40 min. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The residue was partioned between ethyl acetate and saturated aqueous Na2CO3. The organic phase was dried (Na2SOzi) , concentrated in vacuo, and the residue purified by column silica gel chromatography (CH2CI2/CH3OH 12:1) to afford 21 mg (33%) of a pale yellow oil; MS(CI) m/e 322 (M+H)+, XH NMR (CDCI3, 300 MHz) δ 1.44 (s, 9H) , 1.61 (m, 2H), 2.03 (m, 2H), 2.25 (m, 1H), 2.38 (dd, J=7.5, 7.5 Hz, 2H), 2.42 (m, 1H), 2.57 (m, 1H), 2.73 (m, 1H), 2.83 (m, 1H), 3.39 -gait, J=1.5 Hz, 2H), 3.48 (dd, J=7.5, 7.5 Hz, 2H), 4.11 (t, J= 1.5 Hz, 2H) , 4.17 (m, 1H).
EXAMPLE 47d 1-(2-Oxo-pyrrolidinyl)-4-fl-(3(R)-amino) pyrrolidinyl! butr2-yne Hydrogen Oxalate To a solution of EXAMPLE 47c (21 mg, 0.06 mmol) in CH2CI2 (1 ml) at 0°C was added trifluoroacetic acid (1 ml). The reaction mixture was maintained at 0°C for 2.5 h then it was diluted with additional CH2CI2 and washed with saturated aqueous Na2CC>3. The organic phase was dried (Na2SC>4) , then concentrated in vacuo. The residue was purified by silica gel column chromatography to afford 6 mg (42%) of a pale yellow oil. The oil was dissolved in a small volume of ethanol and then diluted with ether. An ethereal solution of oxalic acid (6 mg, 0.7 mmol) was added and the resulting white solid collected by suction filtration; m.p. 117-119°C; MS(CI) m/e 222 (M+H)+. Anal, calcd. for C1.2H19N3O· 2.5 (C2H2O4)-0.5 H20: C, 44.84; H, 5.53; N, 9.23. Found: C, 44.73; H, 5.49; N, 9.31.
The compounds of formula I are useful for the treatment of disorders of cholinergic neurotransmission in mammals, especially humans. The compounds of formula I regulate (stimulate or antagonize) cortical cholinergic neurotransmission and, therefore, are useful in treatment of cognitive disorders or neurological and mental illnesses due to dysfunction of acetylcholine systems.
Such diseases include presenile and senile dementia, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania and Tourette Syndrome. The compounds of this invention are also useful analgesic agents and are -94therefore useful in the treatment of severe painful conditions such as rheumatism, arthritis, and terminal illness .
The ability of the compounds of the invention to interact with muscarinic receptors and to act as muscarinic agonists and/or antagonists can be demonstrated in vitro using the following protocols.
Protocols For Determination of Muscarinic Receptor Binding Potencies of Agonists The potencies of agonist binding at central Ml and M2 muscarinic binding sites were determined by analysis of competition with specific muscarinic receptor radioligands. The cerebral cortical Ml receptor was identified with [3H]pirenzepine. The muscarinic receptors of the pons-medulla are M2 in nature and were identified with [3H]quinuclidinyl benzilate (QNB). Adult rat frontoparietal cortex and pons-medulla were dissected free on an ice-block and homogenized (1:200 w/v) in 50 mM sodiumpotassium phosphate buffer (pH 7.4) with a polytron. Competition between various concentrations of agonist molecules and 6 nm [3H]pirenzepine (with 0.5 mg/ml cortical membranes) or 0.2 nM [3H]QNB (with 0.5 mg/ml pons-medulla membranes) was performed at 25 deg in an assay volume of 1 ml. After 60-75 min the bound radioligand was separated by vacuum filtration on Whatman GF/B glass fiber filters. Non-specific binding was defined as radioactivity remaining in the presence of 10 urn atropine. Competition curves were analyzed with a four-parameter logistic program on a computer. The Ki value for the the IC50 value agonist was determined after correction of for the presence of the radioligand. Table 1 COMPOUND Ki (urn) (3 Ml RECEPTOR Ki (uM) 0 M2 RECEPTOR Example 1 1.8 0.3 Example 2 5.2 4.3 Example 3 3.6 2.5 Example 4 1.7 1.9 Example 5 40.3 7.0 Example 6 13.2 8.4 Example 8 47.8 67.5 Example 9 7.7 15.1 Example 10 23.5 62.7 Example 11 1.4 0.5 Example 12 1.1 3.8 Example 13 1.8 2.6 Example 14 2.6 2.2 Example 16 1.4 1.5 Example 17 4.2 16.0 Example 18 19.0 71.0 Example 19 10.2 40.0 Example 20 2.1 11.6 Example 21 46.4 69.4 Example 22 72.2 77.1 Example 24 59.3 32.8 Example 26 157 3.4 Example 27 12.6 22.1 Example 28 15.0 46.6 Example 29 115 21.7 Example 30 97 36 Example 31 80 1000 Example 33 232 47.5 Example 34 89 30 .' Example 35 27.6 15.8 Example 36 6.3 11.6 Example 37 3.7 6.2 Example 38 36.3 43.7 Example 39 21.2 40.7 Example 40 6.0 8.5 Example 41 4.2 6.1 Exampl'e 4 2 2.7 3.5 Example 43 21.6 38.9 Example 44 3.4 4.8 Example 45 1 . 6 0.82 Example 46 53.1 49.0 Example 47 8.0 7.7 These results indicate that compounds of the invention bind to Ml and M2 muscarinic receptors.
Protocol for the Determination of Agonist Intrinsic Activity at Central Muscarinic Receptor-Effector Systems To show that the novel molecules were indeed muscarinic agonists in brain tissue, a pharmacological response assay employing rat striatum was employed. Rat striatal muscarinic receptors are couple to the inhibition of cyclic AMP levels. This method is described in detail in D. J. Anderson and M. McKinney, Brain Res. 475:28-34, 1988. The ATP stores in dissociated rat striatum was labeled with [3H]adenine and [3H]cyclic AMP levels were elevated with 10 um forskolin. Muscarinic receptor -97activation with the agonist carbachol inhibits forskolinactivated levels of [3H] cyclic AMP by about 40%. Most agonists stimulate this receptor-effector system with EC50 values in the range of 0.1-10 um. Intrinsic activities (maximal responses relative to that of the full agonist carbachol) can thus be measured at 100 um. Agonist activation of this biochemical response is expressed as per cent activity measured at 100 um relative to that of 100 um carbachol. All responses were shown to be fully blocked by the selective muscarinic antagonist atropine.
Table 2 COMPOUND INTRINSIC ACTIVITY (% relative to carbacol) Example 1 87 Example 2 44 Example 3 74 Example 4 43 Example 5 66 Example 6 28 Example 11 100 Example 13 11 Example 14 75 Example 16 12 Example 25 19 Example 26 86 Example 29 43 Example 35 54 Example 38 17 Example 39 11 -98Example 44 30 These results indicate that compounds of the invention are central muscarinic receptor agonists.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydtobromide, hydroiodide, 2hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by -99reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
Example of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases .
The pharmaceutically acceptable salts of the acids of « formula I are also readily prepared by conventional procedures such as treating an acid of formula I with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium lithium, calcium, or magnesium, or an organic base such as an amine, e.g·., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like .
The present invention includes one or more of the compounds of Formula (I) formulated into compositions together with one or more non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles which are collectively referred to herein as carriers, for parenteral injection, for oral administration in solid or liquid form, for rectal administration, and the like. -100In order to reduce unwanted peripherally mediated side-effects, it is advantageous, to incorporate into the composition a peripherally acting anti-cholinergic or anti-muscarinic agent such as N-methylscopolamine, Nmethylatropine, propantheline, methantheline, or glycopyrrolate.
The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powders, ointments or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particule size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and -101the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin .
If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of steile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol -102monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycos, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycos, and the like .
• Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and others well known in this art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes .
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the abovementioned excipients.
Liquid dosage forms for oral administrat in include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, -103propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oili, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents .
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include powders, sprays and inhalants. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservative, buffers or propellants as may be required. Ophthalmic formulations, eye ointments, powders and -104solutions are also contemplated as being within the scope of this invention.
The present compounds can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposones can be used. The present compositions in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the lik. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic .
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976), p 33 et seq.
Actual dosage levels of active ingredient in the compositions of the invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular compostion and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors.
Total daily dose of the compounds of this invention administered to a host in single or divided doses may be in amounts, for example, of from about 0.001 to 100 mg/kg body weight daily and preferably 0.01 to 10 mg/kg/day. -105Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims (13)

What is claimed is:
1. A compound of the formula: A-C=C-B wherein A is (1) a functionalized lactam;
2. (2) a functionalized azacycloalkyl group;
3. (3) a functionalized carbonylaminomethyl group; or (4) a functionalized oxyalkyl group; and B is (1) a functionalized pyrrolidin-2-yl group; (2) a functionalized aminomethyl group; (3) a 5-membered heterocycle containing two heteroatoms; or (4) a piperidine derivative; or a pharmaceutically acceptable salt thereof. 2. The compound of Claim 1 wherein A is a functionalized lactam and B is a functionalized pyrrolidin-2-yl group or a functionalized aminomethyl group . -1073. A compound of the formula A-C=^=C-B wherein A is wherein Rl is (i) -C(0)-, (ii) -S(0)2“ or (iii) -(CH(R 4 )) r - wherein R 4 is independentlyselected at each occurrence from hydrogen, loweralkyl, phenyl and substituted phenyl and r is 1 to 3; R2 is (i) -CH 2 -, (ii) -0(iii) -S- or (iv) -N(R26) - wherein R26 is hydrogen, loweralkyl, aryl, alkanoyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or an N-protecting group; R3 is -(C(Rg)(R 7 )) s - wherein Rg and R 7 are independently selected at each occurrence from hydrogen, loweralkyl, phenyl and substituted phenyl and s is 1 to 3; -108R21 and R22 are independently selected from hydrogen and loweralkyl; and R23 is one, two or three substituents independently selected from (i) hydrogen, (ii) loweralkyl, (iii) haloalkyl, (iv) halo, (v) aryl, (vi) - (CH2) m -Y “ (CH2) p—R24 wherein m is 0 to 3, p is 0 to 3, Y is -0-, -S- or -N(R25)- wherein R25 is hydrogen, loweralkyl, arylalkyl or an N-protecting group and R24 is hydrogen, loweralkyl, alkenyl, alkynyl, haloalkyl or aryl or (vii) -T-G-W-R24 wherein G is -C(0)- or -S(0)2 - and T and W are independently absent or independently selected from -0-, -S- and -N(R2s)~ wherein R25 is defined as above and R24 is defined as above; and B is (1) wherein n is 0, 1 or 2; Rll is (i) hydrogen or -109(ii) loweralkyl; Rl2 is (i) absent or (ii) loweralkyl; Rl3 is (i) hydrogen or (ii) loweralkyl; Rl5 is independently selected at each occurrence from (i) hydrogen and (ii) loweralkyl; R23 is independently defined as above; and the dashed bond represents a single bond or a double bond; or (2) wherein Rig and R17 are independently selected from (i) hydrogen, (ii) loweralkyl, (iii) alkenyl and (iv) alkynyl;or Rl6 and R17 taken together with the adjacent nitrogen atom represents R23 -110wherein Q is (i) absent or (ii) -L-(CH2)b~ wherein L is -CH 2 -, -Ο-, -N(R 2 6) “ wherein R 2 6 is independently defined as above, -S-, -S(0)- or —S(0)2 — and b is 0 or 1; and R 2 3 is independently defined as above; and Rl8 is (i) hydrogen or (ii) -CH 2 R 2 3 wherein R 2 3 is independently defined as above .
4. A compound of the formula:
A-C=C-B wherein A is -1115. A method for regulating cortical cholinergic neurotransmission comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1.
6. A method for treating a disorder caused by a malfunction of the acetylcholine or muscarine system comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1.
7. A pharmaceutical composition for regulating cortical cholinergic neurotr'ansmission comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
8. A pharmaceutical composition for regulating cortical cholinergic neurotransmission comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1 in combination with a therapeutically effective amount of a peripheral cholinergic antagonist.
9. A pharmaceutical composition for treating a disorder caused by a malfunction of the acetylcholine or muscarine system comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
10. A compound of the formula given and defined in claim 1, or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.
11. A pharmaceutical composition according to claim 8 or 9, substantially as hereinbefore described.
12. A process for preparing a compound of the formula given and defined in claim 1, or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified. - 112
13. A compound of the formula given and defined in claim 1, or a pharmaceutically acceptable salt thereof, whenever prepared by a process claimed in claim 12.
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