CA2203912A1 - Indolyl neuropeptide y receptor antagonists - Google Patents
Indolyl neuropeptide y receptor antagonistsInfo
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- CA2203912A1 CA2203912A1 CA002203912A CA2203912A CA2203912A1 CA 2203912 A1 CA2203912 A1 CA 2203912A1 CA 002203912 A CA002203912 A CA 002203912A CA 2203912 A CA2203912 A CA 2203912A CA 2203912 A1 CA2203912 A1 CA 2203912A1
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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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
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- 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
- C07D401/12—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 chain containing hetero atoms as chain links
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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
- C07D401/14—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 three or more hetero rings
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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Abstract
This invention provides a series of substituted indoles which are useful in treating or preventing a condition associated with an excess of neuropeptide Y. This invention also provides the novel substituted indoles as well as pharmaceutical formulations which comprise as an active ingredient one or more of these substituted indoles.
Description
W O 97/09308 PCT~US96/14163 Title INDOLYL NEUROP~:~ llL)E Y RECEPTOR ANTAGONISTS
Priority Claim This application claims the benefit of United States Provisional Applications 60/003,150, filed September 1, 1996, and 60/021,638, filed July 12, 1996 and United Kingdom Patent Applic?/tion 9623999.2, filed November 23, 1996.
B~kFround of the Invention Neuropeptide Y is a peptide present in the central and peripheral nervous systems. The peptide co-exists with noradrenaline in many neurons and acts as a ne~ollansmitter per se or synergistically together with noradren~line. Neuropeptide Y-cont~ining fibers are numerous around arteries in the heart, but are also found around the arteries in the respiratory tract, the gastrointestinal tract, and the genitourinary tract. Neuropeptide Y is also present in the cerebrum with effects on blood pressure, feeding, and the release of different hormones. Alterations in central concentrations of neuropeptide Y have been implicated in the etiology of psychiatric disorders.
Neuropeptide Y was discovered, isolated and sequenced in 1982 from porcine brain as part of a general screening protocol to discover carboxy-terminal amidated peptides and was named neuropeptide Y due to its isolation from neural tissue and the presence of tyrosine as both the amino and carboxy terminal amino acid.
Neuropeptide Y is a member of the pancreatic f~mily of peptides and shares significant sequence homology with pancreatic polypeptide and peptide YY.
Neuropeptide Y and the other members of its family of peptides all feature a tertiary structure consisting of an N-terminal polyproline helix and an amphiphilic a-helix, connected with a ~-turn, creating a hairpin-like loop, which is sometimes referred to as the W O 97/09308 PCT~US96/1416 pancreatic polypeptide (PP) fold. The helices are kept together by hydrophobic interactions. The a_idated C-terminal end projects away from the hairpin loop.
Subsequent to its disc-Jvely neuropeptide Y was identified as 5 being the most abundant peptide in the central nervous system with widespread distribution including the cortex, brainstem, hippocampus, hypot~hl~mll~, amygdala, and t~lAmus as well as being present in the peripheral nervous system in symp~At~etic neurons and adrenal chromAf~ln cells.
Neuropeptide Y seems to fulfill the main criteria for a role as a neurotransmitter, as it is stored in synaptic granules, is released upon electrical nerve st;m~ tion, and acts at specific receptors. It is clear that neuropeptide Y is an important messenger in its own right, probably in the brain, where neuropeptide Y potently inhibits the activity of adenylate cyclase and induces an increase in the intracellular levels of calcium. Central injection of neuropeptide Y results in blood pressure changes, increased feeding, increased fat storage, elevated blood sugar and insulin, decreased locomotor activity, reduced body temperature, and catalepsy.
Neuropeptide Y (as well as its chemical relatives) acts upon membrane receptors that are dependent on guanyl-nucleotide hin~ling proteins, known as G protein-coupled receptors. G proteins are a family of memhrane proteins that become activated only after binding guanosine triphosphate. Activated G proteins in turn activate an Amplifier enzyme on the inner face of a memhrane; the enzyme then converts precursor molecules into second messengers.
Neuropeptide Y appears to interact with a family of closely related receptors. These receptors are generally ~ sified into several subtypes based upon the ability of different tissues and receptors to bind 3 o different fr~gments of neuropeptide Y and other members of the PP
family of peptides. The Y1 receptor subtype appears to be the major vascular neuropeptide Y receptor. The Y2 receptor subtypes can also occur postjunctionally on vascular smooth muscle. The as-yet-unisolated Y3 receptor subtype appears to be neuropeptide Y-specific, 3 5 not binding peptide YY. This receptor is likely to be present in the adrenal tissues, medulla, heart, and brain stem, among other areas.
[For a review of neuropeptide Y and neuropeptide Y receptors, see. e.F., ~ C. Wahlestedt and D. Reis, Annual Review of Pharmacolo~v and Toxicolo~v, 33:309-352 (1993); D. Gehlert and P. Hipskind, Current Pharmaceutical Desi~n, 1:295-304 (1995)].
In view of the wide number of clinical m~ lies associated with an excess of neuropeptide Y, the development of neuropeptide Y
receptor antagonists will serve to control these clinical conditions. The earliest such receptor antagonists, such as Patent Cooperation Treaty Patent Publication WO 91/08223, pllhli~hed June 13, 1991, and Patent Cooperation Treaty Patent Publication WO 94/00486, published January 6, 1994, were peptide del;valives. These antagonists are of limited pharmaceutical utility because of their metabolic instability.
This invention provides a class of potent non-peptide neuropeptide Y receptor antagonists. By virtue of their non-peptide nature, the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based neuropeptide Y receptor antagonists.
S~lmm~ry of the Invention This invention encompasses methods for the treatment or l,level.tion of a disorder associated with an excess of neuropeptide Y, which method co~l~lises ~-lmini~tering to a m~mm~l in need of said treatment an effective ~mount of a compound of Formula I
,R2 ,~ (CH2)s ,C~
~ (CH2)q yl X
Rb~"A (CH2)p--R
R
wherein:
Rb is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 ~lk~noyl, trifluoromethyl, hy~o~y, or halo;
R1 is hydrogen, C1-C6 alkyl, or -(CH2)V-Rla;
where v is 1 to 12, and R1a is phenyl, n~phthyl, hexamethyleneiminyl, piperazinyl, heptamethylenei_inyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, he~methyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the groups consisting of C1-C6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C1-C6 alkyl)amino, C1-C6 alkylamino, C2-C6 ~1k~noyl, C2-C6 alkanoyloxy, and C3-Cg cycloalkyl, said said phenyl, benzyl, or C3-Cg cycloalkyl, being optionally substituted with one, two, or three moieties independently selected from the group consisting of C1-C6 alkyl, halo, or C1-C6 alkoxy, or Rla may be substituted with -(CH2)~R1b, where w is 1 to 12 and R1b is piperidinyl, pyrimidyl, pyrrolidinyl, C1-C6 alkoxy, C1-C6 alkylthio, di[di(Cl-C6 alkyl)amino(C1-C6 alkylenyl)]amino, di(C1-C6 alkyl)amino(Cl-C6 alkylenyl)amino, phenyl, C3-Cg cycloalkyl, pyrrolidinyl, and acetamido, said phenyl, or C3-Cg cycloalkyl, being optionally substituted with one, two, or three moieties independently selected from the group ~ consisting of Cl-C6 alkyl, halo7 or Cl-C6 alkoxy;
-A is a bond, -(CH2)m or -C(O)-;
Al is a bond, -NRa-, -O-, -(CH2)m-, or -S(O)n-;
qisOto6;
0 pisOto6;
nis 0,1, or2;
m is O to 6;
s is O to 6;
Ra is hydrogen, Cl-C6 alkyl, or C2-C6 ~lk~nnyl;
D is a bond, C2-C4 alkenylenyl, or -C(X)(Y)-, where one of X and Y is hy~ o~y and the other is hydrogen, or both X and Y are hydrogen, or X and Y
combine to form =O, or =NORC;
Rc is hydrogen, benzyl, acetyl, benzoyl, or Cl-C6 alkyl;
one of Xl and yl is hydloxy and the other is hydrogen, or 3 o both Xl and yl are hydrogen, or Xl and yl combine to form =O, or =NORd;
Rd is hydrogen or Cl-C6 alkyl;
R2 is hydroxy, C1-C6 alkyl, Cl-C6 alkoxy, phenoxy, or a group of the formula N\
wherein R4 and R5 are independently hydrogen, Cl-C6 alkyl, phenyl, or phenyl(Cl-C6 alkylenyl)-, or R2 is a heterocyclic ring selected from the group consisting of he~Amethyleneiminyl, piperazinyl, heptamethyleneiminyl, imi~ olinyl, piperidinyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl;
any one of which hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of Cl-C6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino(C1-C6 alkylenyl)-, Cl-c6 alkylamino(cl-c6 alkylenyl)-, C2-C6 alkanoyl, carboxamido, 2-aminoacetyl, C2-C6 AlkAnOylOxy~ Cl-C6 alkoxycarbonyl-, Cl-C6 alkylAmino, C3-Cg cycloalkyl, piperidinyl, pyrrolidinyl, pyrimidyl, phenyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, piperidinyl(C1-C6 alkylenyl)-, pyrrolidinyl(C1-C6 alkylenyl)-, pyrimidyl(C1-C6 alkylenyl)-, C1-C6 alkogy, Cl-C6 alkylthio, di[di(Cl-C6 alkyl)amino(Cl-C6 alkylenyl)]amino, di(Cl-C6 alkyl)amino(C1-C6 alkylenyl)amino, and acetamido, any one of which benzyl, phenyl, piperidinyl, C3-Cg cycloaLkyl, phenyl(Cl-C6 alkylenyl)-, phenoxy(Cl-C6 alkylenyl)-, pyrrolidinyl, ~ piperidinyl(Cl-C6 alkylenyl)-, pyrrolidinyl(Cl-C6 alkylenyl)-, pyri_idyl(Cl-C6 alkylenyl)-, or pyrimidyl group may be substituted with one or more moieties selected from the group consisting of Cl-C6 alkyl, halo, trifluoromethyl, acetamido, C2-C6 alkanoyl, C2-C7 alkanoyloxy, and Cl-C6 alkoxy, or the nitrogen on said piperidinyl, pyrrolidinyl, piperidinyl(Cl-C6 alkylenyl)-, pyrrolidinyl(Cl-C6 alkylenyl)-, pyrimidyl(Cl-C6 alkylenyl)-, or pyrimidyl may be substituted with an amino-protecting group, or R2 is a group of the formula R4a I ~ R6a N\
R5a where R4a, R5a, and R6a are independently hydrogen, Cl-C6 alkyl, trifluoromethyl, or Cl-C6 alkoxy, or R4a is hydrogen, Cl-C6 alkyl, trifluoromethyl, or C1-C6 alkoxy and R5a and R6a comhine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or 2 5 heptamethyleneiminyl, or R4a is o~y~ell, and R5a and R6a combine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or 3 o heptamethyleneiminyl;
R is phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C3-Cg cycloaLkyl, pyrazinyl, allyl, CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/14163 thiazolyl, furyl, pyrimidyl, pyridinyl, quinolinyl, isoqllinolinyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethyleneiminyl, hept~methyleneiminyl, piperidinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C3-Cg cycloalkyl, pyrazinyl, thiazolyl, furyl, pyrimidyl, pyridinyl, quinolinyl, isoquinolinyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, he~methyleneiminyl~
heptamethyleneiminyl, piperidinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of C1-C12 alkyl, C2-C1o alkenyl, C2-C1o alkynyl, halo, trifluoromethyl, carbox~mido, cyano, benzyl, phenyl, di(cl-c6 alkyl)amino, C2-C6 zllk~noyl, C2-C6 alkanoyloxy, Cl-C6 alkyl~mino, oxazolyl, dihydrooxazolyl, piperidinyl(C1-C12 alkoxy)-, piperidinyl(C1-C12 alkoxy)(C1-C6 alkylenyl)-, piperidinyl(C1-C12 alkylenyl)-,phenyl(C1-C12 alkoxy)-, phenyl(C2-C12 alkylenyl)-, C3-Cg cycloalkyl, piperidinyl, pyrimidyl, C1-C6 alkoxy, C1-C6 alkylthio, a group of the formula RXRYN-G-L-(co-c6 alkylenyl)-, and acetamido, where Rx and RY are independently hydrogen, C1-C6 alkyl, phenyl, benzyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, morpholinyl, 3 o piperazinyl, or C3-Cg cycloalkyl, or where RXRYN is a ring selected from the group consisting of piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, 3 5 azetidinyl, which may be attached to G at any appropriate place on the ring, ~ G is C1-C12 alkylenyl, C2-Cl2 alkenylenyl, or'~ C2-C12 alkynylenyl, and .
L is a bond, -O-, -S-, -S(O)-, -S(0)2-, or -NH-;
with the proviso that when, Al is NRa, -O-, or -S(O)n-, and A is -CH2-, R1 is not hydrogen;
10 or a pharmaceutically acceptable salt or solvate thereof.
This invention also encompasses the novel compounds of Formula I as well as pharmaceutical formulations comprising a compound of Formula I in cnmhin~t.ion with one or more 15 pharmaceutically acceptable carriers, diluents, or excipients therefor.
Detailed Description and Plefelled Embodiments The current invention concerns the disc~v~ly that a select 2 o group of substituted indoles, those of Formula I, are useful as neuropeptide Y receptor antagonists.
"C1-C6 alkoxy" represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
Typical Cl-C6 alkoxy groups include methoxy, ethoxy, propoxy, 25 isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term aC1-C6 alkoxy" includes within its definition the terms "Cl-C4 alkoxy" and "C1-C3 alkoxy".
As used herein, the term "C1-Cl2 alkyl" refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 12 carbon 3 o atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term "Cl-Cl2 alkyl" includes within its definition the terms "Cl-C6 alkyl" and "Cl-C4 alkyl".
"C2-C7 alkanoyloxy" represents a straight or branched alkyl 3 5 chain having from one to six carbon atoms attached to a carbonyl moiety joined through an oxygen atom. Typical C2-C7 alkanoyloxy groups WO 97/09308 PCT~US96/1416 include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, t-butanoyloxy, pentanoyloxy, he~n~yloxy, 3-methylpentanoyloxy and the like.
~C3-Cg cycloalkyl" represents a saturated hydrocarbon ring structure Cont~ininF from three to eight carbon atoms. Typical C3-Cg cycloalkyl groups include cyclolJ~o~yl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
~Halo~ represents chloro, fluoro, bromo or iodo.
"C1-C1o alkylthio" represents a straight or branched alkyl chain having from one to ten carbon atoms attached to a sulfur atom.
Typical C1-C1o alkylthio groups include methylthio, ethylthio, ~o~yl~hio, isolJlo~ylll~io, butylthio and the like. The term "Cl-Clo alkylthio" includes within its definition the term ~Cl-C6 alkylthio~ and ~Cl-C3 alkylthion.
~C1-C12 alkylenyl" refers to a straight or branched, divalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl, octylenyl, 3-methyloctylenyl, decylenyl. The term Ucl-c6 alkylenyl~ is encompassed within the term ~C1-C12 alkylenyl". The term ~Co alkylenyl" or any term incorporating this design~tion, refers to a bond, for ç~m~le ~Co-C6 alkylenyl" refers to a bond or C1-C6 alkylenyl, as such is defined herein.
~C1-C1o alkyl~mino" represents a group of the formula -NH(C1-C1o alkyl) wherein a chain having from one to ten carbon atoms is attached to an amino group. Typical C1-C4 alkylamino groups include methyl~mino, ethylamino, propylamino, isol,~ol~yl~mino, butylamino, sec-butylamino and the like.
The term ~C2-Cl2 alkenyl" as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to twelve carbon atoms. Typical C2-C12 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 2,4-hexadienyl, 1-propenyl, 3 5 2-propenyl, 2-butenyl, 2-pentenyl, and the like.
The term "C2-Cl2 alkynyl" as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to ten carbon atoms with at least one triple bond. Typical C2-Cl2 alkynyl groups include ethynyl, l-~ Jyllyl, 1-butynyl, 1-hexynyl, 2-propynyl, 2-butynyl, 2-pentynyl, and the like.
The term ~C2-Cl2 alkenylenyl" as used herein represents a straight or branched, divalent, unsaturated aliphatic chain having from two to twelve carbon atoms. Typical C2-cl2 alkenylenyl groups include -CH=CH-, -CH2-CH=CH-, -cH2-c(cH3)=cH-cH2cH2-~ and the like.
The term "C2-Cl2 alkynylenyl" as used herein represents a straight or branched, d*alent, unsaturated aliphatic chain having from two to ten carbon atoms with at least one triple bond. Typical C2-Cl2 alkynylenyl groups include -C_C-, -CH2-C-C-, -CH2-C-C-CH2CH2-, and the like.
"C3-Cg cycloalkenyl" represents a hydrocarbon ring structure contPininF from three to eight carbon atoms and having at least one double bond within that ring.
~C1-C6 alkoxy" represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
Typical Cl-C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term ~C1-C6 alkoxy" includes within its definition the term "C1-C3 alkoxyn.
"C2-C6 alkanoyl" represents a straight or branched alkyl chain having from one to five carbon atoms ~tt~ched to a carbonyl moiety. Typical C2-C6 alkanoyl groups include ethanoyl, propanoyl, isopropanoyl, butanoyl, t-butanoyl, pentanoyl, hexanoyl, 3-methylpentanoyl and the like.
~C1-C6 alkoxycarbonyl" represents a straight or branched alkoxy chain having from one to six carbon atoms attached to a carbonyl moiety. Typical C1-C6 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and the like.
The term "amino-protecting group" as used in the specification refers to substituents of the amino group commonly 3 5 employed to block or protect the amino functionality while reacting other CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/14163 functional groups on the compound. F~mples of such amino-protecting groups include formyl, trityl, phthAlimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzylo~ycall,onyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzylo~ycall,onyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzylo~ycalbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzylo~ycalbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-ylo~ycall,onyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, l-methylcyclohexanylo~ycall,onyl, 2-methylcyclohe~nyloxycarbonyl, 2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)-etho~yca-lJonyl, fluorenylmethoxy-carbonyl ("FMOC"), 2-(trimethylsilyl)etho~ycall,onyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop- 1-enyloxycarbonyl, 2 0 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzylo~ycall,onyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethol~ycall)onyl, 4-(decyloxy)benzylo~ycalL.onyl, isobornylo~ycalbonyl, 1-piperidyloxycarbonyl and the' like;
benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphine oxide and like amino-protecting groups. The species of amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the intermediate molecule and can be select*ely removed at the a~ l;ate point without disl-u~ g the rçm~in-ler of the molecule including any other amino-protecting groups. Preferred amino-protecting groups are trityl, t-butoxycarbonyl (t-BoC, Boc, or t-Boc), allyloxycarbonyl and benzyloxycarbonyl. Further e~mples of groups referred to by the above terms are described by E. H~ m, "Protective Groups in Organic Chemistry", (J.G.W.
McOmie, ed., 1973), at Chapter 2; and T.W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991), at Chapter 7.
The term acarboxy-protecting group~ as used in the ~ specification refers to substituents of the carboxy group commonly employed to block or protect the carboxy functionality while rez~cting other functional groups on the compound. F,~mrles of such 5 car~oxy-protecting groups include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoxy-benzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, 10 t-Amyl, trityl, 4-metho~ylrilyl, 4,4'-dimetho~ytrityl, 4,4',4"-trimetho~ytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, 2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, ~inn~qmyl, 5 1-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. Preferred carboxy-protecting groups are allyl, benzyl and t-butyl. Further e~mrles of these groups are found in E. ~ m, supra, at Chapter 5, and T.W. Greene, et al., supra, at Chapter 5.
The term ahydroxy-protecting groups~ as used herein refers 2 o to substitents of the hyLo~y group commonly employed to block or protect the hydroxy functionality while re~ct;ng other functional groups on the compound. ~ mples of such hy~o~y-protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, 2,2-dichloro-1,1-25 difluoroethyl, tetrahyd~ yldnyl, ph~n~cyl, cyclo~ ylll~ethyl, allyl, Cl-C6 alkyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl, t-butyldimethylsilyl, levulinate, pivaloate, benzoate, dimethylsulfonate, dimethylphosphinyl, isobutyrate, ~ m~ntoate and tetrahydropyranyl.
Further ç~mples of these groups may be found in T. W. Greene and 3 o P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991) at Chapter 3.
The term aleaving group~ as used herein refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction. The term ~leaving group~ as 3 5 used in this document encompasses, but is not limited to, activating groups.
The term ~activating group~ as used herein refers a leaving group which, when taken with the carbonyl (-C=O) group to which it is attached, is more likely to take part in an acylation reaction than would be the case if the group were not present, as in the free acid. Such 5 activating groups are well-known to those skilled in the art and may be, for e~Ample, suc~.inimidoxy, pht~limidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido, or -O-CO-(C4-C7 alkyl).
The compounds of the present invention are derivatives of 10 indole which are named and numbered according to the RING INDEX, The American Chemical Society, as follows.
N
The compounds of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, those compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual 2 o isomers and comhin~tions thereof, are within the scope of the present nventlon.
The terms ~R" and ~S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
The term ~R" (rectus) refers to that configuration of a chiral center with 2 5 a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
3 o The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereo~.hçmi~try is contained in NOMENCLATURE OF ORGANIC
-W O 97/09308 PCTrUS96/14163 -COMPOUNDS: PNNCIPLES AND PRACTICE, (J.H. Fletcher, et al., eds., ~ 1974) at pages 103-120.
In addition to the (R)-(S) system, the older D-L system may ~ also be used in this docl~ment to denote absolute configuration, 5 especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix "D~ is used to represent the absolute configuration of the isomer in which the functional (detel...;.-i..g) group is on the right side of the carbon atom at the chiral center and "L", that of 0 the isomer in which it is on the left.
In order to lJlerelentially prepare one optical isomer over its enantiomer, the skilled practitioner can proceed by one of two routes.
The practitioner may first prepare the ~ e of enantiomers and then separate the two enantiomers. A commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an optically active salt or base. These diastereomers can then be separated using differential solubility, fractional crystallization, chromatography, or like methods.
Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al., ENANTIOMERS, RACEMATES, AND
RESOLUTIONS, (1991).
In addition to the schemes described above, the practitioner of this invention may also choose an enantiospecific protocol for the preparation of the compounds of Formula I. Such a protocol employs a synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation. These reaction schemes usually produce compounds in which greater than 95 percent of the title product is the desired enantiomer.
3 o As noted supra, this invention includes the pharmaceutically acceptable salts of the compounds defined by Formula I. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and 3 5 organic acids, to form a pharmaceutically acceptable salt.
J
CA 022039l2 l997-04-28 WO 97/09308 PCT~US96/14163 The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula which are subst~nti7lly non-toxic to living org~nicmq. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the 5 compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic lo acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. ~.~Amples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, 15 sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, o~lAte, malonate, succinate, suberate, sebacate, fumarate, 20 maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobçn~oAte, methylbenzoate, hyd-o~ybenzoate, methoxybenzoate, pht~lAte, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, ~-hydlo~ybuly~ate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, 25 mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Salts of amine groups may also comprise quarternary 30 ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or ~lk~line earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing 3 5 the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formulas I. Many of the Formula I compounds can comhine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the correspon~ing hydrate, methanolate, ethanolate and acetonitrilate.
This invention also encompasses the pharmaceutically acceptable prodrugs of the compounds of Formula I. A prodrug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form. This prodrug should have a different pharmacokinetic profile than the parent, enabling easier absorption across the mucosal epithelium, better salt formation or solubility, or improved systemic stability (an increase in pl~m~ half-life, for example).
Typically, such chemical modifications include:
2 5 1) ester or amide derivatives which may be cleaved by esterases or lipases;
2) peptides which may be recognized by specific or nonspecific proteases; or 3) derivatives that accumulate at a site of action through 3 o membrane selection of a prodrug form or a modified prodrug form;
or any cnmhin~tion of 1 to 3, supra. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in H, Bundgaard, Desi~n of Prodrl~s~ (1985).
The preferred compounds of the present invention are those 3 5 compounds of Formula I in which:
a) Rb is hydrogen, chloro, fluoro, methyl, ethyl, - hydlo~y, or acetyl;
b) R1 is methyl, ethyl, or Rla is phenyl, piperidinyl, pyrrolidinyl, he~methyleneiminyl, piperazinyl, and v is 1 to 6;
c) Al is a bond, -NH-, -N(CH3)-, -S-, or -O-;
d) A is -CH2- or -CH2CH2-;
e) q is 0, 1, or 2;
f) p is 0, 1, or 2;
g) s is 0, 1, 2, or 3;
h) D is a bond, -C(O)-, -CH(OH)-, or -CH2-;
i) R2 is a group of the formula -NR4R5 or -N+R4aR5aR6a;
j) R4 and R5 are independently hydrogen, methyl, ethyl, benzyl, or comhine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethylçneiminyl group;
k) R4a, R~a, R6a are independently hydrogen, methyl, ethyl, or R5a and R6a combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethyleneiminyl group; and l) R is phenyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, naphthyl, thiazolyl, furyl, quinolinyl, isoquinolinyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl, or quinuclidinyl;
i or a pharmaceutically acceptable salt or solvate thereof.
The preferred methods of the present invention are those methods employing compounds of Formula I in which a) Rb is hydrogen, chloro, fluoro, methyl, ethyl, hydroxy, or acetyl;
b) Rl is methyl, ethyl, or Rla is phenyl, piperidinyl, pyrrolidinyl, he~methyleneiminyl, piperazinyl, and v is 1 to 6;
c) Al is a bond, -NH-, -N(CH3)-, -S-, or -O-;
d) A is -cH2- or -cH2cH2-;
e) q is 0, 1, or 2;
f) p is 0, 1, or 2;
g) s is 0, 1, 2, or 3;
h) D is a bond, -C(O)-, -CH(OH)-, or -CH2-;
i) R2 is a group of the formula -NR4R5 or -N+R4aR5aR6a;
j) R4 and R5 are independently hydrogen, methyl, ethyl, benzyl, or combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethyleneiminyl group;
3 5 k) R4a, R~a~ R6a are independently hydrogen, methyl, ethyl, or R5a and R6a combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or h~x~methyleneiminyl group; and l) R is phenyl, piperidinyl, pyrrolidinyl, he~s~methyleneiminyl, heptamethyleneiminyl, naphthyl, thiazolyl, furyl, qllinolinyl, isoqllinolinyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl, or quinuclidinyl;
or a pharmaceutically acceptable salt or solvate thereof.
Especially l~lefel-ed compounds of the present invention are those compounds of Formula I in which:
a) Rb is hydrogen, fluoro, or methyl;
b) R1 is methyl, or R1a is piperidinyl, pyrrolidinyl, or hçx~methyleneiminyl, and v is 1, 2, or 3;
c) A1 is a bond, -NH-, -S-, or -0-;
d) A is -CH2- or -CH2CH2-;
e) qisOorl;
f) pisOorl;
g) sis Oorl;
h) D is a bond, or -C(O)-;
i) R2 is a group of the formula -NR4R5;
j) R4 and R5 are independently methyl, or comhine to form, together with the nitrogen to which they are attached, a piperidinyl, piperazinyl, or pyrrolidinyl t group;
k) R is optionally substituted phenyl, naphthyl, or cyclohexyl;
or a pharmaceutically acceptable salt or solvate thereof.~0 Especially preferred methods and formulations of the present invention are those methods and formulations employing especially preferred compounds.
Particularly preferred compounds are those of Formula I in which:
a) Rb is hydrogen;
b) Rl is methyl, piperidinyl(Cl-C4 alkylenyl)-, or pyrroldinyl(Cl-C4 alkylenyl)-;
c) Al is a bond or -0-;
d) A is -CH2-;
d) q is O;
e) pisOorl;
fl sis Oorl;
g) D is a bond, or -C(O)-;
h) R2 is a piperidinyl, or pyrrolidinyl group, substituted with amino, di(C1-C6 alkyl)amino, (C1-C6 alkyl)amino, piperidinyl, or pyrrolidinyl, or R2 is a piperazinyl group substituted with phenyl, cyclohexyl, or benzyl; and j) R is phenyl, substituted with one to three groups selected from C1-C6 alkyl, trifluoromethyl, and halo;
10 or a pharmaceutically acceptable salt or solvate thereof.
Especially preferred methods and formulations of the present invention are those methods and formulations employing especially preferred compounds.
A most preferred class of compounds of the present invention are those compounds of Formula I of the Formula /~D~,R
R** R*~0 where:
D1 is -C(O)~, or -CH2-;
R1 is methyl,piperidin-3-yl-CH2-CH2-, piperidin-3-yl-CH2-CH2-CH2-, piperidin-2-yl-cH2-cH2-~
piperidin-2-yl-CH2-CH2-CH2-, pyrrolidin-3-yl-CH2-CH2-, pyrrolidin-3-yl-CH2-CH2-CH2-, piperidin-4-yl-CH2-CH2-, or piperidin-4-yl-CH2-CH2-CH2-;
R2 is piperidinyl, or pyrrolidinyl group, substituted with amino, di(Cl-C6 alkyl)amino, (Cl-C6 alkyl)amino, piperidinyl, or pyrrolidinyl, or R2 is a piperazinyl group substituted with phenyl or cyclohexyl;
R* is chloro or bromo; and R** hydrogen or chloro;
10 or a pharmaceutically acceptable salt or solvate thereof.
Methods and formulations employing any of this class of most preferred compounds are also most preferred.
The compounds of Formula I may be prepared by a number of methods known to those skilled in the art. One protocol for preparing those compounds of Formula I in whch Rl is methyl, is depicted in Scheme I, infra.
Scheme I
~COOH ~_,OH
aLkylation or arylation (CH2)p-R I ~(CH2)p-R
As would be appreciated by those skilled in the art, there are numerous ways of performing each of the steps depicted supra.
Typical such methods are described infra in the general te7~r.hings and ~ the examples.
R~o~
~COOH ~ ,OH
Many of the compounds of Formula I are prepared through the reduction of 1-methyl-2-indolecarboxylic acid to the corresponding 2-hy~lro~y~ethyl-1-methylindole. This reduction may be prepared by several methods known in the art including catalytic hydrogenation. A
most ~lefelled method for this reduction is by using a reducing agent 15 such as sodium borohyd~ide, lithium borohydride, diisobutylaluminumhydride hydride, lithium triethylborohydride, borane-methyl sulfide complex in refluxing tetrahydrofuran, and triethoxysilane. Another means of reducing the carboxylic acid is by means of sodium in eth~nol, a method known as the Bouveault-Blanc 20 procedure. A most l,le~elled reducing agent employed in this procedure is lithium aluminum hydride.
Alkyla'don orArylation ~ ArOH
The coupling of the aryl group to the above alcohol may be performed using standard techniques. For those compounds of Formula I in which A is -O-, p is 0, and R is substituted phenyl, for ex~mple, a most preferred method involves a phenolic coupling using a Mitsunobu reagent. O. Mitsunobu, et al., Bulletin of the Chemical Societv of Japan. 44:3427 (1971); O. Mitsunobu, et al., Journal of the 5 American Chemical Society, 94:679 (1972). In this reaction triphenylphosphine, in comhin~tion with diethyl azodicarboxylate (DEAD), converts alcohols in situ to the corresponding alkoxyphosphonillm salts, which are useful alkylating agents.
Although this coupling can be accomplished using various 10 concentrations of the re~qct~nts and reagents, it is best to use 1 to 2 equivalents of the indole methyl alcohol, triphenylphosphine, and DEAD
per each equivalent of the substituted phenol (ArOH) used.
This reaction also is best carried out in the presence of an inert solvent such as, for ex~mple, toluene, benzene, or, preferably 15 tetrahydrofuran. The reaction is performed at temperatures from about 0~ C to about 40~ C, preferably at ambient temperature, until the desired compound is prepared. Typically, the reaction takes about 18 hours when run at aInbient temperature, but the progress of the reaction can be monitored via standard chromatographic techniques.
" ArX
An alternative method of arylating the alcohol involves nucleophilic aromatic substitution of an aryl fluoride with a preformed 25 alkoxide. This reaction is performed by first ~tltlin~ a base to the alcohol, followed by the addition of the aryl halide. An especially ~lere~,ed base is sodium hydride. Another preferred base is sodium hexamethylrli~ ide. The reaction is generally performed in a polar aprotic solvent, for example, acetonitrile, N,N-dimethylformamide, 30 N,N-dimethylphenylacetamide, dimethylsulfoxide, or hexamethylphosphoric triamide.
WO 97/0930~ PCT/US96/141~3 Alky~'don ~~ HCHO ~,,OAr Alkylation of the 1,2-disubstituted indole may be done by a variety of methods known to those skilled in the art. A preferred method of alkylating this substituted indole is by way of a ~nnich reaction. [For reviews of this reaction, see, Tramontini, Synthesis. 703-775 (1973);
House, MODERN SYNTHETIC REACTIONS, (2d ed., 1972) at pages 654-660.]
In this reaction formaldehyde (or sometimes another aldehyde) is condensed with HNR4R5, in the form of its salt, and a compound cont~ining an active hydrogen. Instead of ammonia, the reaction can be carried out with salts of primary (RNH2) or secondary amines (R2NH), or with amides (RCONH2), in which cases the product is substituted on the nitrogen with R, R2, and RCO, respectively. This reaction is generally carried out in a lower alkyl alcohol, such as methanol or et~nol, or in an acid, such as acetic acid.
One process for preparing those compounds of Formula I in which A is an alkylenyl group is by first o~ ing the alcohol to form the corresponding aldehyde.
~_,OH ~CHO
This reaction is generally performed using an oxidizing agent such as pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC) in a solvent such as methylene chloride. The resulting aldehyde is then reacted with a substituted phosphonate in the presence of a base.
ArCH2PO(OEt)2 ~Ar This Wittig-type reaction results in the formation of an aralkenyl group.
A ~lefelled base employed in this reaction is sodium hydride. This reaction generally results in a ~ ure of the (E) and (Z) stereoisomers.
The double bond is then reduced using either a reducing agent as 10 described supra or by means of catalytic hydrogenation using standard means. Preferred solvents for this reaction include dichloroethane.
Ar ~~Ar The resulting 1,2-disubstituted indole may then be substituted at the 3 position essentially as described above for the M~nnich chemistry.
A HNR4R5 ~>~
Those compounds in which Rl is a substituted alkylenyl group [(CH2)v-Rla]may be prepared as illustrated in Scheme II, infra.
W O 97/09308 PCT~US96/14163 Scheme II
a~ ~CH3 ~ h~/n ~ ~Ro,CH3 ~NTr ,CH3 ~,,OH
~) reduction ~
NTr ~ NTr ~ ,,OH ~"~
c ) ~ substitution ~> ~'Cl F~Cl f~
I NTr NTr in which Tr is a trityl group.
W O 97/09308 PCT~US96/14163 Scheme II (continued) d~ ~Cl \~CI
[~ halogenation NTr NTr N
e) 1) t-BuLi ~~
, ~ 2) CN{~N~N ~CH3 ~ CI
~NTr CH3 ~
NTr deprotection C~~ 3'CI
~,NTr ~NH
W 0 97/09308 PCT~US96/14163 For those compounds of Formula I in which L is -S-, the thio derivatives and intermediates of this invention may be transformed into the correspontling sulfoxide (-SO-) compounds upon treatment with a mild oxidizing agent, such as hydrogen peroxide in methanol, meta-chloroperbenzoic acid (MCPBA) in methylene chloride at 0~C, or an alkali metal periodate in aqueous alcohol. The corresponding sulfones (-SO2-) are prepared from the thio or sulfoxide compounds on treA~ment with a strong oxidizing agent, such as hydrogen peroxide in acetic acid or m-chloroperbenzoic acid in methylene chloride at 20~C-30~C.
Those compounds of Formula I in which the benzo ring of the indole has been substituted may be prepared by a number of ways known to those skilled in the art. For ç~Ample, those compounds of Formula I in which the 4-position of the indole ring has been substituted with methyl may be prepared as described in Scheme III, infra.
In step a), below, a Knoevenagel condensation reaction is performed, resulting (after the dehydration step of the reaction) in an olefin. This reaction is generally performed with an excess of the azide, although an eqllimolAr ll~ixlu~e of the two reagents may be employed.
The olefin product of step a) is then cyclized to form an indole ring. The usual means of this cyclization is by heating the olefin.
The progress of the cyclization may be followed by thin layer chromatography.
Scheme III
a) ~/ dd ti ~CO2Et ~"C02Et ~--C02Et b) ~ N3 cyclization NH
CH3 CH3 Br c) ~ brnminA~;~m ~CO2Et d) &~ CH3l ~ ~C02Et N alkylation N
Scheme III (continued) ~CO2Et 8ubStitution ~'~~
1~ 2)reductlon ~OH~
f) CH3 CH3 1) base Cl ~H20--H~ 2)substitution ~~~
g) CH3 CH3 \~
Cl--~Cl Scheme IV
Rb Rb 1) a. n-BuLi, CO
~_3 b t-BuLI CO2 ~_~
NH [MeOH] NH CH3 Rb Rb Nll OMI"I ~'~~CH3 Rb Tr CH3 ~OH
[THF~ ~
) r~
Tr NJ
Tr -CA 022039l2 l997-04-28 ScheIne IV (Continued) Rb ~OH l)NaH;[DMF] ~~~C
~,~ Z)HCO2H, [CH2C12]
N~
Tr H
CA 022039l2 l997-04-28 An alternative method of preparing those compounds of Formula I in which Rb is not hydrogen may be prepared as described in Scheme IV, infra.
The intermediates and other reagents necessary for the preparations fo the compounds of the present invention, are commercially available, are known in the literature, or can be prepared by known methods. In addition, those of ordinary skill in the art will recognize that variations on the methods for preparing the claimed compounds as described above may be performed without detracting from the synthesis of these compounds. For ~mrle, other esters may be employed, as may protecting groups, precursors, the direct introduction of the carboxylic acid group onto the benzo ring of the indole (Kolbe-Schmitt reaction ), etc. Moreover, certain Rb groups may be introduced directly onto the benzo ring. For e~mple, a chloro group can be introduced by treating with iodobenzene, chlorine, and pyridine [Murakami, et al.. Chem. Pharm. Bull.. 19:1696 (1971)] or N-chlorosllcrinimide in dimethylformamide [United States Patent 4,623,657, the entire contents of which are herein incorporated by 20 reference]. In addition to those described supra, other transformations, intraconversions, and deriv~ti~?.tions are either described in the F.~mples, infra, or are well known to those of ordinary skill in the art.
The following ~ mples further illustrate the compounds of the present invention and the methods for their synthesis. The 25 F.~mp~es are not intended to be limiting to the scope of the invention in any respect, and should not be so construed. All experiments were run under a positive pressure of dry nitrogen or argon. All solvents and reagents were purchased from commercial sources and used as received, unless otherwise indicated. Dry tetral,yLo~llran (THF) was 30 obtained by distillation from sodium or sodium benzophenone ketyl prior to use.
Proton nuclear m~gnetiC resonance (lH NMR) spectra were obtained on a GE QE-300 spectrometer at 300.15 MHz, a Bruker AM-500 spectrometer at 500 MHz, or a Bruker AC-200P spectrometer at 200 MHz, 35 or a like model. (Unless designated otherwise, the term "NMR" as employed herein refers to proton nuclear magnetic resonance.) Free atom bombardment mass spectroscopy (FAB) was performed on a VG
ZAB-2SE instrument. Field desorption mass spectroscopy (FDMS) was performed using either a VG 70SE or a Varian MAT 731 instrument.
~ Optical rotations were measured with a Perkin-Elmer 241 5 polarimeter. Chromatographic separation on a Waters Prep 500 LC was generally carried out using a linear gradient of the solvents indicated in the text unless otherwise specified.
The reactions were generally monitored for completion using thin layer chromatography (TLC). Thin layer chromatography 10 was performed using E. Merck Kieselgel 60 F2s4 plates, 5 cm x 10 cm, 0.26 mm thickness. Spots were detected using a comhin~ion of W and chemical detection (plates dipped in a ceric ammonium molybdate solution [76 g of ~mmonium molybdate and 4 g of cerium (IV) sulfate in 500 ml of 10% aqueous sulfuric acid] and then heated on a hot plate).
5 Preparative centrifugal thin layer chromatography was performed on a Harrison Model 7924A Chromatotron using Analtech silica gel GF
rotors.
Cation exchange chromatography was performed with Dowex~) 50X8-100 ion e~rh~nge resin. Anion e~lh~nge 20 chromatography was performed with Bio-Rad AG(~) 1-X8 anion-exchange resin (acetate form converted to hydroxide form). Flash chromatography was performed as described by Still, et al., Journal of Or~anic Chemistry, 43:2923 (1978).
Optical rotations are reported at the sodium-D-line (354 25 nm). Elemental analyses for carbon, hydrogen, and nitrogen were determined on a Control Equipment Corporation 440 Elemental Analyzer, or were performed by the Universidad Complutense Analytical Centre (Facultad de Farm~ , Madrid, Spain). Melting points were determined in open glass capillaries on a Thomas Hoover 30 capillary melting point apparatus or a Buchi melting point apparatus, and are uncorrected.
The following methods provide illustrative protocols for preparing the compounds of Formula I as depicted in the Schemes supra. Throughout the Methods and ~ mples, infra, the terms 35 "NMR~, "IR~, and "W" indicate that the proton nuclear magnetic resonance, infrared, and ultraviolet spectroscopy, respectively, were consistent with the desired title product.
Preparation 1 Preparation of (3'R) ethyl 2-(piperidin-3-yl)acetate O~CH3 J O
N
Ethyl-3-pyridylacetate (lOOg, 0.606 mol) was dissolved in ethanol (1.8 liters), treated with 5% rhodium on alumina (100 g) and hydrogenated at 60~C and 60 psi hydrogen gas overnight. The catalyst was removed by filtration and the solvent evaporated to give a brown liquid (101.4 g, 98%). The brown liquid was dissolved in ethyl acetate (600 15 1) and treated with L-(+)-m~ntlelic acid in warm ethyl acetate (600 1).
After cooling in the refrigerator for four hours, the solid was collected and the cryst~lli7~ion fluid reserved for processing to the other enantiomer, infra. The solid was again recrystallized from ethyl acetate (1.55-1.6 liters, overnight at ambient temperature) to give the desired title 20 product as white needles. Yield: 81.6 grams, 41%.
O.R. (EtOH) ~589 nm = +44.9~, ~365 nm = +173.73~. mp 118-119~C.
Prepar7~tior~ 2 25 Preparation of (3'S) ethyl 2-(piperidin-3-yl)acetate O~CH3 ~NJ
H
The crystallization fluid from Preparation 1, supra, was 30 evaporated to give a dark oil (100.3 g). This was dissolved in a cold CA 022039l2 l997-04-28 W 097/09308 PCT~US96/14163 solution of potassium carbonate (52 g, 0.377 mol) in water (260 ml) and extracted with ethyl acetate (5 X 150 ml). The extracts were comhined and dried over m~gnesium sulfate. The solvents were removed in vacuo to give a dark liquid (40.25 g). The dark liquid was treated with a warm 5 solution of D-(-)-m~n~lelic acid (36 g) in ethyl acetate (650 ml) and stirred at ambient temperatures overnight. The crystals were recrystallized twice more from ethyl acetate (1.2 liters and 1.1 liters, respectively) to give the desired title product as white needles. Yield: 48.7 g, 24.9%.
O.R. (EtOH) ~589 nm = -43.14~, ~365 nm = -164.31~. mp 115.5-117~C.
Chiral Analvtical Method Cold aqueous potassium carbonate (0.15 g in 10 ml of water) was treated with 0.3 g of the mandelic acid salt and the ~ e was 15 extracted with ethyl acetate (3 x 5 ml). The combined extracts were dried over magnesinm sulfate and the solvents were removed in vacuo. The residue was dissolved in diethyl ether (10 ml) and treated with S-(-)-a-methylbenzylisocyanate (0.12 ml). After 2.5 hours, the reaction was treated wtih 1 N hydrochloric acid (2 ml). The ether was separated and 20 then washed sequentially with bnne, a saturated aqueous sodium bicarbonate solution, and brine. The organic fraction was dried over m~gnçsium sulfate and the solvents were removed by evaporation. The residue was analyzed on a CHIRACEL OJTM high performance liquid chromatography column (4.6 x 250 mm), eluting with 5% ethanol in 25 hexanes at a flow rate of 2.5 mVminute. The slower component comes from the l-(~)-m~nrlelic acid salt and the faster from the d-(-)-m~nrlçlic acid salt. HPLC analysis of the final crystallization products of both enantiomers show less than three percent of the opposite enantiomer.
3 o Preparation 3 Preparation of (3'R) ethyl 2-[N-(t-butoxycarbonyl)piperidin-3-yl]acetate W 0 97/09308 PCT~US96/14163 ~O~CH3 J O
Boc (3'R)-Ethyl 2-(piperidin-3-yl)acetate (10.9 g, 34 mmol) as prepared in Preparation 1 was dissolved in 50 ml of a 12% sodium 5 carbonate in water solution and the resulting solution was extracted with chloroform. The extracts were dried and the solvents removed by evaporation. The residue was suspended in diethyl ether, filtered, and evaporated to give the free base (5.36 g). The liquid was dissolved in ether (50 ml) and treated d~v~wise with di-t-butyldicarbonate (7.9 g) in lo ether (10 ml). After stirring overnight, the solution was cooled in an ice water bath and treated dlolJwise with saturated aqueous citric acid (25 ml). The aqueous fraction was extracted with diethyl ether. The organic fractions were combined, washed with water, a saturated sodillm bicarbonate solution, and then brine, and then dried over 5 m~gneSium sulfate. The solvents were removed in vacuo to give the desired title product was a clear liquid. NMR was consistent with proposed title structure.
Pre~aration 4 Preparation of (3'S) ethyl 2-[N-(t-butoxycarbonyl)piperidin-3-yl]acetate ~O~CH3 J
N
Boc (3'S)-Ethyl 2-(piperidin-3-yl)acetate (48.6 g, 150 mmol), as prepared in Preparation 2, was treated with a solution of potassium carbonate (30 g, 0.217 mol) in water (220 ml) and the resulting solution was extracted with chloroform (3 x 100 ml). The extracts were dried over sodium sulfate and the solvents were removed in vacuo. The residue was mixed with diethyl ether (200 ml) and filtered to remove some suspended solids. Evaporation of the ether gave a brownish liquid (25 g, Theory = 25.7 g). The residue was dissolved in diethyl ether (200 ml), cooled in an ice water bath, and a solution of di-t-butyldicarbonate (31.8 5 g, 0.146 mol) in ether (25 ml) was added dl~wise with stirring. Cooling was removed and reaction was stirred overnight. The solution was again cooled in ice water and a solution of saturated aqueous citric acid (100 ml) was added dlo~wise. The organics were washed with brine, a saturated aqueous sodium bicarbonate solution, then brine, and then 10 dried over sodium sulfate. The solvents were removed in vacuo to give the desired title product as a clear liquid (38.6 g, ~99%). NMR was consistent with desired title structure.
Preparation 5 Preparation of ethyl 3-[pyrid-3-yl]prop-2-enoate o ~ O CH3 A solution of ethylphosphino~cetate (98.6 g, 0.44 mol) in dry tetrahyL~r~dn (1200 ml) was treated with 60% sodium hydride (17.5 g, 0.44 mol). The mixture was stirred at room tempe~al~e for two hours and was then cooled down to 0~C. To this ...iY~..e 3-pyridine carboxaldehyde (38.9 g, 0.36 mol) was added and the resulting reaction 25 n~i~ e was stirred for 1-2 hours while warming to room temperature.
The progress of the reaction was monitored by thin layer chromatography.
Water (1000 ml) was added to the reaction mixture. The organic fraction was extracted with ethyl acetate (3 x 1000 ml). The 30 organic fractions were combined, washed with water (2 x 1000 ml), brine (1 x 1000 ml), and the dried over sodium sulfate. The solvents were removed in vacuo to yield 62.5 grPms (97%) of the desired title product.
W O 97/09308 PCT~US96/14163 Preparation 6 Preparation of (RS) ethyl 3-[piperidin-3-yl]propionate o ~ ~ O CH3 A solution of ethyl 3-[pyrid-3-yl]prop-2-enoate (60 g, 0.34 mol) in ethanol (600 ml) was treated with 5% rhodium on alumina powder (17.2 g). The mixture was placed under a hydrogen atmosphere (55 psi) for five hours at 60~C. The reaction was stopped by removing the hydrogen and the reaciton mixture was filtered through a layer of CELITETM. The residue was washed with hot ethanol. The filtrate was concentrated and purified by flash chromatography to provide 39.6 grams (63%) of the desired title product.
IR, NMR, and IR were consistent with the proposed title structure.
Preparation 7 Preparation of (3'S) ethyl 3-[piperidin-3-yl]propionate mandelic acid salt O
~J''o CH3 N ~m~n~lelic acid A solution of (RS) ethyl 3-[piperidin-3-yl]propionate (52.0 g, 281 mmol) in hot ethyl acetate (300 ml) was added to the hot solution of R-(-) mandelic acid (42.7 g, 281 mmol). The resulting mixture was then filtered and the clear solution was left at room temperature overnight.
The newly formed white crystals of the salt were filtered from the solution. These crystals were recrystallized twice by dissolution in hot ethyl acetate (300 ml) and letting it cool down to room tempel al~ e each time. The final pure crystals were dried to yield 33.1 grams (70%).
NMR and IR were consistent with the desired title product. The conformation about the chiral center was confirmed by X-ray 5 crystallography.
Preparation 8 Preparation of (3'R) ethyl 3-[piperidin-3-yl]propionate mandelic acid salt o ~' \~I\o CH3 H ~m~n(lPlic acid The title compound was prepared essentially as described in Preparation 7, supra, except that S-(+) mandelic acid was employed 15 instead of the R-(-) m~ntlçlic acid employed therein.
NMR and IR were consistent with the desired title product.
Preparation 9 20 Preparation of (3'S) ethyl 3-[piperidin-3-yl]propionate ~~~0 CH3 A suspension of (3'S) ethyl 3-[piperidin-3-yl]propionate 25 mandelic acid salt (33.1 g, 98 mmol) in ethyl acetate (500 ml) was treated with a 30% aqueous solution of potassium carbonate until all the organic layer was clear. The mixture was poured into a separatory funnel and the organic fraction was extracted with ethyl acetate (3 x 300 ml). The combined organic fraction was washed with water (2 x 300 ml), then brine (1 x 300 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily product in nearly 100% yield.
NMR and IR were consistent with the desired title product.
Preparation 10 Preparation of (3'R) ethyl 3-[piperidin-3-yl]propionate o The title compound was prepared essentially as described in Preparation 9, supra, except that (3'R) ethyl 3-[piperidin-3-yl]propionate m~n~lelic acid salt was employed instead of the (3'S) ethyl 3-[piperidin-3-yl]propionate m~nllelic acid salt therein.
NMR and IR were consistent with the desired title product.
Preparation 11 Preparation of (3'S) ethyl 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propionate O
J~o CH3 BoC
A solution of (3'S) ethyl 3-[piperidin-3-yl]propionate (12.6 g, 67.5 mmol) in tetrahydrofuran:water (2:1, 335:168 ml) was treated with 25 potassium carbonate (14 g, 101 mmol) and di-tert-butyl dicarbonate (17.7 g, 81 mmol). The reaction mixture was stirred at room temperature for five hours. The mixture was then poured into water (200 ml). The organic fraction was extracted with ethyl acetate (3 x 200 ml). The WO 97/09308 PCT/US96/141~3 organic fractions were combined, washed with water (2 x 200 ml) and then brine (1 x 200 ml), and then dried over sodium sulfate. The solvents were removed in vacuo and the title product was further purified by flash chromatography. Yield: 19.1 grams (99.2~o).
5 NM~ and IR were consistent with the desired title product.
Preparation 12 Preparation of (3'R) ethyl 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propionate o N
BoC
The title product was prepared essentially as described in Preparation 11, supra, except that an eqllimol~qr amount of (3'R) ethyl 3-[piperidin-3-yl]propionate was employed instead of the (3'S) ethyl 3-[piperidin-3-yl]propionate employed therein.
Preparation 13 Preparation of (3'S) 3-[1-(t-buto~ycall)onyl)piperidin-3-yl]propanol ----OH
BoC
A solution of (3'S) ethyl 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propionate (17.1 g, 60 mmol) in dry diethyl acetate (600 ml) was cooled to 0~C. Lithium aluminum hydride powder (2.5 g, 65 mmol) was - gradually added to the mixture. The resulting mixture was stirred at 0~C and slowly warlned to room temperature within two hours. The WO 97/09308 PCT/US96/141~3 reaction was stopped by the slow addition of water (200 ml) and 15%
aqueous sodium hydroxide (50 ml). The organic fraction was extracted with diethyl ether (3 x 300 ml). The comhined layer was washed with water (2 x 200 ~nl) and then brine (1 x 200 ml) and then dried over sodium 5 sulfate. The solvents were removed in vacuo to provide 13.2 grams (90%
yield) of the title product.
NMR and IR were consistent with the desired title product.
P~Jalation 14 Preparation of (3'S) 3-[1-(t-buto~ycall,onyl)piperidin-3-yl]propanol Q.~"" OH
BoC
The title product was prepared essentially as described in Preparation 13, supra, except that an equimolar amount of (3'S) ethyl 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propionate was employed instead of the (3'R) ethyl 3-[1-(t-buto~yoa~bonyl)piperidin-3-yl]propionate employed therein.
Preparation 15 Preparation of (3'S) 3-[1-(t-buto~yca,l,onyl)piperidin-3-yl]~ yl bromide Q~ Br 2 5 BoC
To a cold (0~C) solution of triphenylphosphine (19.95 g, 76 mmol) in anhydrous methylene chloride (110 ml) was added bromine dropwise until the solution turned pale yellow. A few crystals of :
triphenylphosphine were added to the mixture to bring the color back to white. To this mixture was added a suspension of (3'S) 3-[1-(t-buto~ycalbonyl)piperidin-3-yl]propanol (13.2 g, 54.4 mmol) and pyridine (8.0 g, 76 mmol) in dry methylene chloride (110 ml). The resulting 5 mixture was stirred for five hours while warming to room temperature.
The reaction was stopped by ~rllling water (200 ml). The organic fraction was extracted with methylene chloride (3 x 200 ml).
The comhined organic layer was washed with water (2 x 200 ml), then brine (1 x 100 ml), and then dried over sodium sulfate. The solvents 10 were removed in vacuo to provide a light brownish crude product, which was further purified by flash chromatography to yield 11.6 grams (70~o) of the desired title product.
NMR and IR were consistent with the title product.
Preparation 16 Preparation of (3'R) 3-[1-(t-buto~ycall~onyl)piperidin-3-yl]plo~yl bromide [~ " \~ Br BoC
The title product was prepared essentially as described in Preparation 16, sul~ra, except that an equimolar amount of (3'R) 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propanol was employed instead of the (3'S) 3-[1-(~-butoky. a~bonyl)piperidin-3-yl]propanol employed therein.
Me~oll A
Preparation of 1-methyl-2-hydroxymethyl-lH-indole.
CA 022039l2 l997-04-28 ~OH LAH ~--OH
[THF]
In 950 ml of dry tetrahydrofuran under an argon atmosphere was added lithium aluminum hydride (18.40 g, 0.49 mol).
5 The resulting -i x~, e was placed over an ice bath. An aliquot of 1-methylindole-2-carboxylic acid (84.92 g, 0.49 mol) was dissolved in an additional 475 ml of dry tetrahydroru~an and then added slowly (over about 45-50 minutes) to the lithium aluminum hydride mixture.
The ice was removed from around the round bottom flask and warm water was added to the bath to raise the reaction temperature. The reaction mi~ e was then stirred at room tempelalu~e for 60-90 minutes. The progress of the reaction was monitored by thin layer chromatography.
Once the reaction had progressed sufficiently, the reaction vessel was placed in an ice bath and 20 ml of water were slowly added to the reaction ~ e. This was followed by the sequential addition of 20 ml of 5 N sodium hydroxide and then 60 ml of water. The organic fraction was dried using CELITETM followed by sodium sulfate. The organic solvents were then removed by vacuum to yield a white solid.
2 0 The white solid was then dissolved in toluene heated to reflux. The lm~ e was then cooled to room temperature and then permitted to remain overnight in a refrigerator. The off-white crystals were then collected, washed with cool toluene, and then dried in a vacuum oven. Yield 63.65 gr~ms (81.4%). FDMS 161.
Analysis for CloH1lNO:
Theory: C, 74.51; H, 6.88; N, 8.69.
Found: C, 74.73; H, 6.90; N, 8.76.
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-lH-indole WO 97/09308 PCT/US96tl4163 ~ ~--OH l. NaH ~--'~J~
CH3 F~Cl CH3 A one liter round bottom flask with a nitrogen atmosphere was charged with sodium hydride (9.28 grams of a 60% NaH solution in 5 mineral oil, 0.232 mol) and N,N-dimethylformamide (211 ml). To the resulting ~ u~e was slowly added 1-methyl-2-hydro~ymethyl-lH-indole (34.0 g, 0.211 mol) dissolved in 100 ml of N,N-dimethylformamide.
This addition resulted in the formation of a slight exotherm. The resulting reaction mixture was stirred at room temperature for about 10 three hours.
1-Chloro-4-fluorobenzene (30.29 g, 0.232 mmol) was then added to the above reaction mixture, after which the resulting mixture was heated to 80~C and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
15 The reaction mixture was then allowed to cool. The reaction ~ u~e was then poured into about one liter of water and stirred for about one hour. The solids were removed by filtration and washed with water.
The desired product was then recrystallized from benzene and the solvents were removed in vacuo.
20 IR, NMR, and W were consistent with the desired title compound.
FDMS 271 (M+).
Analysis for Cl6Hl4ClNO:
Theory: C, 70.72; H, 5.19; N, 5.15.
Found: C, 70.98; H, 5.18; N, 5.37.
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-(4-methylpiperidin- 1-yl)methyl- lH-indole (~x~mple 14) CA 022039l2 l997-04-28 W O 97/09308 PCTAUS96/141~3 CI Q~ CI
CH3 alkylation CH3 Under a nitrogen atmosphere 4-methylpiperidine (0.109 ml, 0.09 g, 0.92 mmol), dissolved in 2.0 ml of ethyl acetate, was added to a round bottom flask which was then placed in an ice bath. Concentrated hydrochloric acid (0.084 ml) was then added and the reaction mixture was removed from the ice bath. To the reaction ~ e were added formaldehyde (0.304 g, 1.01 mmol), sodium acetate (0.113 g, 1.38 mmol), and 1-methyl-2-(4-chlorophenoxymethyl)-lH-indole (0.250 g, 0.92 mmol).
The resulting mi~l~e was then heated to reflux and m~int~inerl at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
The solvents were removed in vacuo. The solids were then taken up in methylene chloride. The solvents were then removed in vacuo. The desired product was then recrystallized from ethyl acetate.
The desired title product was further purified by chromatography.
NMR was consistent with the proposed title structure.
FDMS 382.
Analysis for C23H27clN2o:
Theory: C, 72.14; H, 7.11; N,7.31.
Found: C, 72.33; H, 7.22; N, 7.47.
l~e~o-l B
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]-1,2-ethanedionyl]-lH-indole (~x~mple 106) ~N
~,Cl ~ Cl acylation CH3 1-Methyl-2-(4-chlorophenoxymethyl)-lH-indole (0.30 g, 1.10 mmol), dissolved in 2.0 ml of tetrahydrofuran, was placed in a round 5 bottom flask under an argon atmosphere. To this solution was added oxalyl chloride (0.294 g, 2.32 mmol). The resulting ~ e was stirred at room temperature for about 45 minutes. The solvents were removed in vacuo, leaving a dark brown oil.
The brown oil was taken up in 2.0 ml of dry tetrahydrofuran 10 and 4-(piperidin-1-yl)piperidine (1.07 g, 6.38 mmol), dissolved in about 10 ml of dry tetrahydrofuran, was added. The resulting reaction mixture was stirred at room temperature for about 30 minutes. The progress of the reaction was monitored by thin layer chromatography.
The solids were removed by filtration and the solvents in 15 filtrate were removed by evaporation. The residue from the filtrate was then taken up in methylene chloride and washed with a saturated sodium bicarbonate solution, followed by three extractions with 1.0 N
hydrochloric acid.
The aqueous fractions from the above extractions were 2 0 combined, basified with 1 N sodium hydroxide and then extracted thrice with methylene chloride. This organic fraction was dried over sodillm sulfate and the solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
NMR and IR were consistent with the proposed title structure.
2 5 FDMS (M+) 493.
Analysis for C2gH32ClN3O3:
Theory: C, 68.07; H, 6.53; N, 8.51.
W O 97/09308 PCTrUS96/141~3 Found: C, 67.97; H, 6.66; N, 8.27.
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[4-(phenyl)piperazin-1-yl]methyl-lH-indole (~ mple 20) N~3J
~CI ~0 V Cl CH3 alkylation CH3 Under a nitrogen atmosphere in a round bottom flask, phenylpiperazine (0.149 g, 0.920 mmol) was dissolved in 2.0 ml of lo dichloroethane. The reaction vessel was placed in an ice bath.
Concentrated hydrochloric acid (0.084 ml, 1.01 mmol) was added and the reaction vessel was removed from the ice bath. Paraformaldehyde (0.304 g, 1.01 mmol) and sodium acetate (0.113 g, 0.920 mmol) were then added, followed by the addition of 1-methyl-2-(4-chlorophenoxymethyl)-lH-indole (0.250 g, 0.920 mmol). The reaction mixture was then heated to reflux and maintained at this temperature for about six hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then stirred at room temperature for about three days.
The solvents were removed by vacuum and the residue was partitioned between ethyl acetate and a 10% potassium carbonate solution. The organic fraction was washed with water, followed by 1.0 N
hydrochloric acid. The acidic aqueous fraction was basified with a 10 potassium carbonate solution. The organic component was dried by dripping through sodium sulfate. The solvents were removed in vacuo.
The desired product was recrystallized from ethyl acetate.
NMR was consistent with the desired title structure.
FDMS 445 (M+).
Analysis for C27H2gClN3O:
Theory: C, 72.71; H, 6.33; N, 9.42.
~ Found:C, 73.00; H, 6.41; N, 9.51.
~ Method Cl Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-chloro-1,2-ethanedionyl]-lH-indole 0~
~,Cl ~, ~O_~,Cl CH3 acylation CH3 1-Methyl-2-(4-chlorophenoxymethyl)-lH-indole (1.00 g, 3.68 mmol), dissolved in 7.0 ml of diethyl ether in a round bottom flask under a nitrogen atmosphere. To the above solution was added oxalyl chloride (0.981 g, 7.73 mmol). The reaction mixture was stirred at room 15 tempe-a~ule for about 60 minutes. The progress of the reaction was monitored by thin layer chromatography.
The solvents were removed by decanting and the crystals were rinsed five times with cold diethyl ether. The solvents and rinses were collected, and placed in a freezer for about three days. The crystals 20 were collected and dried in a vacuum oven to yield 1.15 grams (86.3%) of the desired title product.
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-(4-methylpiperidin-1-yl)-1,2-ethanedionyl]-lH-indole (F.~Ample 102) ~CH3 G~CJCI ~\~-JCI
alkylation CH3 Under a nitrogen atmosphere, 4-methylpiperidine (0.490 ml, 0.411 g, 4.14 mmol) was dissolved in 3.0 ml of dry tetrahydrofuran in 5 a round bottom flask over an ice bath. To this reaction ~ ~e was added 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-chloro-1,2-ethanedionyl]-lH-indole (0.500 g, 1.39 mmol) and the resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
lo The solvents were removed in vacuo and the residue was partitioned between methylene chloride and 1.0 N sodium hydroxide.
The organic fraction was washed with 1.0 N sulfuric acid, followed by a wash with brine. The organic fraction was then dried over sodium sulfate and the solvents were removed in vacuo. The desired title product was recrystallized from ethyl acetate.
NMR and IR were consistent with the desired title structure.
FDMS 425 (M+).
Analysis for C24H2sclN2o3:
Theory: C,67.84; H, 5.93; N, 6.59.
Found: C, 68.04; H, 5.85; N,6.74.
Me1hod C2 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-1-[[4-25 (piperidin-1-yl)piperidin-1-yl]carbonyl]methyl]-lH-indole (~x~mple 77) W O 97/09308 PCTrUS96/141~3 QN~--O
Q ~ O
CH3 ~ reduction CH3 'Q
Cl Cl A round bottom flask under a nitrogen atmosphere was charged with 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-[4-(piperidin-1-5 yl)piperidin-1-yl]-1,2-ethanedionyl]-lH-indole (0.1414 g, 0.282 mmol) and 2.8 ml of denatured ethanol. To this mixture was added sodium borohydride (0.064 g, 1.69 mmol). The reaction _ixture was then stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
The solvents were removed by evaporation and the residue was partitioned between methylene chloride and water. The aqueous fraction was washed twice with methylene chloride. The organic fractions were comhined, washed with brine, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product 15 was further purified by chromatography.
NMR was consistent with the proposed title product.
FDMS 495 (M+).
Analysis for C2gH34ClN3O3:
Theory: C, 67.80; H, 6.91; N, 8.47.
Found: C, 67.86; H, 6.90; N, 8.45.
l~t~..d n Preparation of methyl indole-2-carboxylate.
~OH ~QOCH3 Indole-2-carboxylic acid (47.0 g, 292 mmol) was dissolved in 200 ml of methanol. To this solution was added 6 ml of concentrated sulfuric acid. The resulting mixture was heated to reflux and m~int~ined at this temperature for about 16 hours. The reaction 5 mixture was then cooled to room temperature and the solids were removed by filtration and then washed with 200 ml of methanol. The crystals were dried in a vacuum oven, yielding 39.5 grams (77%) of the desired title product as white needles. Analytical data obtained was consistent with the proposed title structure.
Preparation of methyl 1-[2-(1-tritylpiperidin-4-yl)ethyl]indole-2-carboxylate.
Q~ alkylation ~J~~CH3 ,N
Tr Under an argon atmosphere methyl indole-2-carboxylate (1.50 g, 8.56 mmol) was dissolved in 8.6 ml of N,N-dimethylformamide.
The solution was placed in an ice bath and sodillm hydride (0.377 g, 9.42 mmol) was added. The resulting mixture was stirred for 20 minutes 20 over ice and then permitted to warm to room temperature. The reaction mixture was then stirred for about 90 minutes at room tempelat~e, after which time it was placed again in an ice bath.
2-(1-Tritylpiperidin-4-yl)ethyl iodide (4.53 g, 9.42 mmol), prepared essentially as described in Preparation 15, dissolved in 15 ml of 25 N,N-dimethylformamide was then added and the resulting mixture was stirred in an ice bath for about three days. The reaction mixture was then poured over water and the solids were collected by filtration. The solids were taken up in methylene chloride and dried over magnesium sulfate. The solvents were removed in vacuo to yield 4.98 grams (>99%) ~ of the desired title product as a yellowish white foam. Analytical data obtained was consistent with the proposed title structure.
.
Preparation of methyl 1-[3-(1-~1 ;lyllJiperidin-3-yl)propyl]indole-2-carboxylate.
~ROCH3 ~OCH3 H alkylation N
~N- Tr Under an argon atmosphere methyl indole-2-carboxylate (1.00 g, 5.71 mmol) was dissolved in 5.7 ml of N,N-dimethylformamide.
The solution was placed in an ice bath and sodium hydride (0.251 g of a 60~o solution, 6.28 mmol) was added. The resulting mi~ e was stirred for 20 minutes over ice and then permitted to warm to room temperature. The reaction mixture was then stirred for about 60 minutes at room temperature, after which time it was placed again in an ice bath.
3-(1-Tritylpiperidin-3-yl)propyl iodide (3.11 g, 6.28 mmol), dissolved in 8 ml of N,N-dimethylformamide was then added and the resulting mixture was stirred in an ice bath overnight. The reaction mixture was then poured over water and the solids were collected by filtration. The solids were taken up in methylene chloride, washed with water, then brine, and then dried over sodium sulfate. The solvents were removed in vacuo to yield 3.38 grams (>99%) of the desired title 2 5 product. Analytical data obtained was consistent with the proposed title structure.
Preparation of 2-l-ydl o~ylllethyl-1-[2-( l-ll ;~,yl~ eridin-4-yl)ethyl]-lH-indole.
~R'OCH3 ~ Q~ \OH
reduction N-- N ' Tr Tr Under an argon atmosphere lithium alllminum hydride (0.325 g, 8.56 mmol) was dissolved in 8.6 ml of dry tetrahydrofuran. The resulting solution was placed in an ice bath and methyl 1-[2-(1-tritylpiperidin-4-yl)ethyl]indole-2-carboxylate (4.68 g, 8.52 mmol), 10 dissolved in about 10 ml of dry tetrahy~l~ofillan, was added. The resulting mixture was stirred overnight at room temperature.
To the reaction mixture 0.35 ml of water were crefully added, followed by the addition of 0.35 ml of 5.0 N sodium hydroxide, and then 1.0 ml of water. The solids were removed by filtration and the 15 solvents in the filtrate were removed in vacuo. The residue from the filtrate was redissolved in methylene chloride. The desired product was then dried over m~gnesium sulfate and the solvents were removed in vacuo to yield 3.96 grams (92.4~o) of the title product as a foam.
Analytical data obtained was consistent with the proposed title 2 0 structure .
Preparation of 2-hydroxymethyl-1-[3-(1-tritylpiperidin-3-yl)propyl]-lH-indole.
OCH3 ~ Q~ OH
reduction ~_~N~ T ~N~ T
Under an argon atmosphere methyl 1-[3-(1-tritylpiperidin-3-yl)~ yl]indole-2-carboxylate (3.38 g, 6.23 mmol) was dissolved in 3.1 ml 5 of dry tetrahyLorulan. The reaction vessel was then placed in an ice bath and lithium alumillulll hydride (0.236 g, 6.23 mmol) was added.
The resulting ,,,,~lule was stirred in an ice bath for about ten minutes and then at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
To the reaction mixture were added 0.24 ml water, followed by 0.24 ml of 5.0 N sodium hydroxide, followed by 0.72 ml of water. The residue was redissolved in methylene chloride. The desired product was then dried over sodium sulfate and the solvents were removed in vacuo to yield 2.89 grams (90.1~o) of the title product as a foam. Analytical data 15 obtained was consistent with the proposed title structure.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(1-tritylpiperidin-4-yl)ethyl]-lH-indole.
--\OH Q~ J~Cl alkylation ,NJ ,N--2 0 Tr Tr Under an argon atmosphere 2-hydlo~ymethyl-1-[2-(1-tritylpiperidin-4-yl)ethyl]-lH-indole (3.91 g, 7.81 mmol) was dissolved in about 10 ml of N,N-dimethylformamide. The resulting solution was then placed in an ice bath and sodium hydride (0.468 g, 11.71 mmol) was 5 added and the resulting mixture was stirred at room temperature for about 30 minutes. To the reaction ~ ule 1-chloro-4-fluoroben7.e~e (0.915 ml, 1.12 g, 8.59 mmol) was added and the resulting mixture was stirred at room temperature for about four days, protected from light.
The reaction mixture was poured into ice water and the 10 solids were collected by filtration. A~ter a w~hing with water, the solids were dried in a vacuum oven. The desired product was recrystallized from ethyl acetate and washed with cool ethyl acetate to yield 2.62 grams (54.9%). Analytical data obtained was consistent with the proposed title structure.
Preparation of 2-[(4-chlorophenoxy)methyl]- 1-[3-(1-tritylpiperidin-3-yl)lJf o~yl]-lH-indole .
--OH Q~ J~Cl alkylation l~,N~T ~N T
Under an argon atmosphere 2-hydroxymethyl-1-[3-(1-tritylpiperidin-3-yl)~lolJyl]-1H-indole (2.89 g, 5,61 mmol) was dissolved in about 11.2 ml of N,N-dimethylformamide. The resulting solution was then placed in an ice bath and sodillm hydride (0.247 g of a 60%
25 suspension in mineral oil, 6.18 mmol) was added and the resulting mixture was stirred at room temperature for about 60 minutes. To the reaction mixture 1-chloro-4-fluorobenzene (0.658 ml, 0.807 g, 6.18 mmol) W O 97/09308 PCT~US96/14163 was added and the resulting mi~ e was stirred at room temperature overnight. The reaction mixture was then heated to 80~C and maintained at this temperature for about eight hours. The reaction ~ mixture was then cooled to room temperature and stirred at this 5 temperature overnight. Another half equivalence of sodium hydride was added and the reaction ~e was stirred at room temperature overnight again. Another half equivalence of 1-chloro-4-fluorobenzene was added and the reaction ll~i~lul e was heated to 80~C.
The reaction mi~lure was poured into ice water and then lo partitioned between methylene chloride and brine. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were comhined, washed with brine, and dried over sodium sulfate. The desired product was further purified by chromatography to yield 1.0 grams (29~o). Analytical data obtained was consistent with the proposed 15 title structure.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(piperidin-4-yl)ethyl]-lH-indole (~ mple 137) ~ Cl Q~ ,CI
~_~ deprotecbon N
Tr H
Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-r2-(1-tritylpiperidin-4-yl)ethyl]-lH-indole was dissolved in 7.0 ml of methylene chloride. The reaction solution was then placed on an ice bath and formic acid (0.3383 g) was added. The resulting mixture was stirred in the ice bath for about five hours. The progress of the reaction ~ was monitored by thin layer chromatography.
The reaction mixture was partitioned between methylene chloride and 1.0 N sodium hydroxide. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in 5 vacuo to yield a foam. The desired product was further purified by chromatography to yield 0.1864 grams (68.7%).
NMR was consistent with the proposed title structure.
FDMS 368 (M+).
Analysis for C22H2sclN2o:
Theory: C,71.63; H,6.83; N, 7.59.
Found: C, 71.66; H,6.86; N, 7.87.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)~ Jyl]-lH-indole. (~ mple 139) --OH ~ ~ J~Cl deprotection ~ Tr l NH
The title compound was prepared essentially as described above for 2-[(4-chlorophenoxy)methyl]-1-[2-(piperidin-4-yl)ethyl]-lH-20 indole except that an equimolar amount of 2-[(4-chlorophenoxy)methyl]-1-[3-(1-l,~;~yll~iperidin-3-yl)propyl]-1H-indole was employed instead of the 2-[(4-chlorophenoxy)methyl]- 1-[2-(1-tritylpiperidin-4-yl)ethyl]- lH-indole employed therein.
NMR was consistent with the proposed title strucuture. Single 25 compound of high purity as evidenced by chromatographic methods.
Method E
W O 97/09308 PCTrUS96/14163 Preparation of 3-bromo-2-[(4-chlorophenoxy)methyl]-1-[3-(1-tritylpiperidin-3-yl)propyl]- lH-indole.
CI ~ CI
~) halogenation ~
Under an argon atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl]-1-[3-(1-tritylpiperidin-3-yl)l~ro~yl]-lH-indole (0.992 g, 1.59 mmol) was dissolved in 4.0 ml of dry tetrahydrofuran. The 10 reaction vessel was then placed in an ice bath and N-bromosuccinimide (0.282 g, 1.587 mmol of a recently recrystallized lot), dissolved in 4.0 ml of tetrahydrofuran, was slowly added. The reaction mixture was stirred for about three hours over an ice bath.
The reaction mi~ e was poured over water in which 2.5 5 grams of sodium sulfate was dissolved, and the aqueous phase was extracted thrice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo, yielding 0.26 grams (23%) of the desired compound. The solvents were removed in vacuo from the mother liquor and the resulting residue 20 was recryst~qlli7.e(1 in ethyl acetate and he~nes to obtain an additional 0.65 grams (58~o) of the desired material. Analytical data obtained was consistent with the proposed title structure.
Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-1-[3-(1-tritylpiperidin-3-2 5 yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-lH-indole.
W O 97/09308 PCT~US96/14163 ,CI ~N ~CI
[~ H3C~
N Tr N Tr Under an argon atmosphere in a round bottom flask, 3-bromo-2-[(4-chlorophenoxy)methyl]-1-[3-( 1-tritylpiperidin-3-yl)l,l opyl]-lH-indole (0.226 g, 0.319 mmol) was dissolved in dry tetrahydrofuran.
The reaction vessel was placed in a dry ice/acetone bath. To this solution was added a solution of t-butyllithium (0.64 mmol) dropwise. The resulting 1 ,~lu.e was stirred for 36 minutes in the dry ice/acetone bath.
To this reaction mixture was added the Weinreb amide N-methyl-N-methoxy-[4-(piperidin-1-yl)piperidin-1-yl]acet~mide (0.0903 g, 0.336 mmol), which had been dissolved in 2.0 ml of tetrahydrofuran and cooled in the dry ice/acetone bath. The resulting mixture was stirred for about two hours and then poured into a saturated ammonium chloride solution. The aqueous fraction was extracted thrice with methylene chloride. the organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by chromatography. Analytical data obtained was consistent with the proposed title structure.
2 o Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-lH-indole. (F,~mple 70) W O 97/09308 PCT~US96/14163 ocl ~rCI
~> deprotection ~) ~N Tr l NH
Under an argon atmosphere (RS) 2-[(4-chlorophenoxy)methyl]- 1-[3-(1-tritylpiperidin-3-yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-lH-indole (0.0162 g, 0.0194 mmol) was dissolved in 0.2 ml methylene chloride. The reaction vessel was then placed in an ice bath and formic acid (0.073 ml, 0.194 mmol) was slowly added. The resulting mixture was stirred for about one hour over ice. The progress of the reaction was monitored by thin layer lo chromatography. The reaction ~ e was then stirred at room temperature for two additional hours and then an additional 5.0 equivalents of formic acid were added, followed by stirring at room temperature.
The reaction mixture was partitioned between 1.0 N sodium hydroxide and methylene chloride. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed by evaporation.
NMR was consistent with the proposed title structure.
Exact Mass (M+l) for C3sH48clN4o2:
Theory: 591.3476.
Found: 591.3476.
W O 97/09308 PCT~US96/14163 M~.~od F
Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[ 1-hydroxy-2-(piperidin-1-yl)ethyl]-lH-indole (~ mple 47) duction ~
CH3 Cl CH3 Cl Under an argon atmosphere a round bottom flask was charged with 2-[(4-chloropheno~y)methyl]-1-methyl-3-[1-(piperidin-1-yl)-1~2-et~nerlionyl]-lH-indole (F~ mple 100) (0.203 g, 0.493 mmol), dissolved in 2.0 ml of dry tetrahydrofuran. Lithium aluminum hydride (3.0 ml of a 1.0 M solution in tetrah~rdrorul~l) was then added. The resulting ~ e was then he~terl to reflux and maintained at this temperature for about four hours. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was then cooled to room temperature and 10 ml of a 1:1 tetrahydrofuran:methanol solution was added. To this mi~ e was then added 5 ml of a saturated Rochelle's salt solution.
The solvents were then removed in vacuo.
The residue was then partitioned between methylene chloride and a saturated Rochelle's salt solution. The organic fraction was washed with water and brine. The organic fraction was then dried with sodium sulfate and the solvents were removed in vacuo.
The desired title product was further purified by chromatography to yield 0.1112 grams (56.9%).
NMR was consistent with the proposed title structure.
FDMS 398 (M+).
Analysis for C23H27clN2o2:
Theory: C, 69.25; H, 6.82; N, 7.02.
Found: C, 69.51; H, 6.86; N, 6.81.
- Me~hod G
5 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(4-methylpiperidin-l-yl)ethyl]-lH-indole (~:x~mrle 48) and 2-[(4-chlorophçnoxy)methyl]-l-methyl-3-[2-(4-methylpiperidin-1-yl)ethyl]-lH-indole (F.x~mrle 33) ~S
,~H3 ~ O
reduct;ion+ CH3 CH3 Cl /~\ r' ~'~'13~
CH3 Cl Under a nitrogen atmosphere a round bottom flask was charged with 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-(piperidin-1-yl)-1,2-ethanedionyl]-lH-indole (Flx~mple 100) (0.305 g, 0.824 mmol). Borane-tetrahydrofuran complex (4.12 ml of a 1.0 M borane solution in THF, 4 12 mmol) was added slowly and the resulting mixture was stirred for about 30 minutes. The progress of the reaction was monitored by thin layer - chromatography. The reaction mixture was stirred a total of one hour and then quenched with methanol.
:
W O 97/09308 PCT~US96/14163 To the reaction mixture was added ethanol, sodium carbonate, and cesiu_ fluoride, and the resulting ~i~ e was heated to reflux and m~int~in~d at this tempela~e overnight. The reaction e was partitioned between 10% sodium carbonate and methylene chloride. The aqueous fraction was extracted twice more with methylene chloride. The organic fractions were comhined and dried over sodium sulfate. The solvents were removed in vacuo. The desired products were further purified by radial chromatography.
2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-methylpiperidin-1-yl)ethyl]-lH-indole (h~mrle 33) NMR was consistent with the proposed title structure.
FDMS 396 (M+).
Analysis for C24H2sclN2o:
Theory: C, 72.62; H, 7.36; N, 7.06.
Found: C, 72.40; H, 7.35; N,7.26.
2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydl o~y-2-(4-methyl-piperidin-1-yl)ethyl]-lH-indole (~.2~mrle 48) NMR was consistent with the proposed title structure.
FDMS 412 (M+).
Analysis for C24H2sclN2o2:
Theory: C, 69.80; H, 7.08; N,6.78.
Found: C, 70.02; H, 7.13; N, 7.00.
Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-[N-methyl-N-(1-methylpiperidin-4-yl)amino]ethyl]- lH-indole (~qmrle 54) and 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-N-(1-methylpiperidin-4-yl)amino]ethyl]-lH-indole (~ mple 38) ~ ~ ~
H3Ct~\ /--/
~~~
o~ N--CH3 CH3 Cl ~~ Cl reduction CH3 Cl HO; 7 N--CNCH3 ~,0~
CH3 Cl Under a nitrogen atmosphere a round bottom flask was charged with 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-5 N-(1-methylpiperidin-4-yl)amino]-1,2-ethanedionyl]-lH-indole (0.3349 g, 0.686 mmol) and placed in an ice bath Borane-tetrahydrofuran complex (4.11 ml of a 1.0 M borane solution in THF, 4.11 mmol) was added slowly and the ice bath was removed. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was 10 stirred for about one hour and then 0.33 ml of a 1:1 tetrahydlvfu~dll:methanol solution was added. Sodium hydroxide (1.74 ml of a 5.0 N solution) was then added and the resulting mixture was heated to reflux and maintained at this temperature overnight.
The aqueous fraction was extracted twice more with 5 tetrahydrofuran. The organic fractions were combined, washed twice with brine, and dried over sodium sulfate. The solvents were removed in vacuo. The desired products were further purified by radial chromatography .
W O 97/09308 PCTAJS96/141~3 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-N-( l-methylpiperidin-4-yl)amino]ethyl]-lH-indole (Fx~mple 38) NMR (CDCl3) was consistent with the proposed title structure.
FDMS 459 (M+).
Analysis for C2sH3lCl2N3O:
Theory: C, 65.21; H,6.79; N, 9.13.
Found: C, 65.07; H, 6.85; N, 9.06.
2-[(2,4-dichlorophenoxy)methyl]- 1-methyl-3-[1-hydl oky-2-[N-methyl-N-( l-methylpiperidin-4-yl)amino]ethyl]-lH-indole (Fx~mrle 54) NMR (CDCl3) was consistent with the proposed title structure.
FDMS 475 (M+).
Analysis for C2sH3lcl2N3o2:
Theory: C, 63.02; H,6.55; N, 8.82.
Found: C, 63.43; H, 6.88; N, 8.92.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[(3-dimethyl~minopropyl)amino]ethyl]-lH-indole (Fx~mple 30) and 2-[(4-chloropheno2~y)methyl]-l-methyl-3-[[[3-20 (dimethylamino)p~ o~ylamino]carbonyl]methyl]-lH-indole (Fx~mple 76) WO 97/09308 PCT/US96/1416~
N(CH3)2 HN~/
N(CH3)2 5~ 1 H~/ CH3 Cl ~~ reduction CH3 ~Cl H~/N(CH3)2 ~ ~'13~
CH3 Cl Under a nitrogen atmosphere borane-tetrahydloru~an complex (7.42 ml of a 1.0 M solution in THF, 7.42 mmol) was added to a 5 round bottom flask cont~ining 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[3-(dimethyl7.mino)propyl~mino]-1,2-etl ~ne~lionyl]-lH-indole (0.529 g, 1.24 mmol). The reaction mixture was stirred at room temperature for about one hour. The progress of the reaction was monitored by thin layer chromatography. The reaction was then quenched by the addition 10 of a 1:1 tetrafuran:methanol solution.
The solvents were removed by evaporation. The residue was taken up in a mixture of ethanol (8 ml), sodium carbonate (2.62 g, 24.72 mmol), and cesium fluoride (2.88 g, 18.94 mmol). The resulting mixture was heated to reflux and maintained at this temperature 5 overnight.
The reaction mixture was partitioned between methylene chloride and a 10% sodium bisulfate solution. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were - combined, and dried over sodium sulfate. The solvents were removed in 20 vacuo. The desired products were further purified by chromatography.
CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/14163 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[(3-dimethylaminopropyl)amino]ethyl]-lH-indole (F.~mple 30) NMR (CDCl3) was consistent with the proposed title structure.
5 FDMS 399 (M+).
Analysis for C23H30ClN3O:
Theory: C, 69.07; H, 7.56; N, 10.51.
Found: C, 69.23; H, 7.79; N, 10.52.
2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[[3-(dimethylamino)propylamino]carbonyl]methyl]-lH-indole (~x~mple 76) NMR (CDCl3) was consistent with the proposed title structure.
FDMS 413 (M+).
Analysis for C23H28clN3o2:
Theory: C, 66.74; H, 6.82; N, 10.16.
Found: C, 66.89; H, 6.96; N, 10.11.
Method H
Preparation of 3-bromo-2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indole ~\ halogenation /~,Br ~, ~~ ~~
CH3 Cl CH3 Cl Under an argon atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indole (5.0 g, 18.40 mmol) was dissolved in 46 ml of tetrahydrofuran. To this solution was added N-bromosuc~inimide (3.28 g, 18.4 mmol of a freshly recrystallized lot), dissolved in 46 ml of tetrahydrofuran. The resulting mixture was stirred over an ice bath for about 3.5 hours, after which time the reaction mixture was poured into about 500 ml of water in which 5.0 grams of sodium sulfate had been dissolved.
W 0 97/09308 PCT~US96/141~3 The aqueous fraction was extracted thrice with methylene ~ chloride. The organic fractions were combined, washed with a saturated sodium bicarbonate solution and, then washed with brine.
The organic fraction was dried over sodium sulfate and the solvents 5 were removed in vacuo.
The desired title product was recrystallized from ethyl acetate. Yield: 5.36 g (83.1%). Analytical data obtained was consistent with the proposed title structure.
10 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(1-tritylpiperidin-4-yl)ethyl]carbonyl]- lH-indole ~,0 acylation ~
CH3 Cl CH3 Cl Under an argon atmosphere in a round bottom flask, 3-bromo-2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indole (0.500 g, 1.426 mmol) was dissolved in 3.0 ml of tetrahydrofuran. The reaction vessel was then placed over a dry ice/acetone bath. To this solution was added a solution of t-butyllithium (1.68 ml, 2.85 mmol) and the Weinreb amide, 20 N-methyl-N-methoxy-[2-(1-tritylpiperidin-4-yl)ethyl]acetamide (0.631 g, 1.426 mmol). The resulting mixture was stirred over dry ice/acetone for about 30 minutes, followed by thirty minutes of stirring on a methanoVdry ice bath. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was poured into a saturated ammonium chloride solution. The aqueous fraction was extracted thrice with methylene chloride, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by chromatography and then recrystallized from ethyl acetate.
3 o Analytical data obtained was consistent with the proposed title structure.
W O 97/09308 PCTrUS96/14163 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(piperidin-4-yl)ethyl]carbonyl]-lH-indole (~ mple 67) r~ r~
O _~N--Tr O~_~NH
~''~'13~ deprotection Q~~~13~
CH3 Cl CH3 Cl Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(1-tritylpiperidin-4-yl)ethyl]carbonyl]-lH-indole (0.2723 g, 0.417 mmol) was dissolved in 2.1 ml of methylene chloride. To this solution formic acid (0.079 ml, 0.096 g, 2.084 mmol) was added and the resulting mixture was stirred at room temperature for about 2.5 hours.
The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was partitioned between methylene 15 chloride and 1.0 N sodium hydroxide. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo to yield the desired title product.
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 411 (M+1) Analysis for C24H27clN2o2:
Theory: C, 70.15; H, 6.62; N, 6.82.
Found: C, 69.87; H, 6.54; N, 6.79.
lVr~
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-carboxy-lH-indole W O 97/09308 PCT~US96/141~3 Br ~ OH
~o~ ~~
CH3 Cl CH3 Cl Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-methyl-3-carboxy-lH-indole (0.500 g, 1.426 mmol) was dissolved in 14.3 5 ml of dry tetrahydrofuran. The reaction vessel was then placed over a dry ice/acetone bath. To this solution t-butyllithium (1.72 ml of a 1.7 M
solution in pentane, 2.92 mmol) was added dropwise. The resulting mixture was stirred for about 15 minutes over the dry ice/acetone bath.
Carbon dioxide was then bubbled through the reaction _ixture for about 10 ten minutes and then the mixture was stirred for an additional ten minutes. The reaction vessel was then placed on a methanoVice/dry ice bath and carbon dioxide was bubbled through the reaction mixture for an additional ten minutes.
The reaction mixture was allowed to warm to room 5 temperature and was then poured into 100 ml of 1.0 N hydrochloric acid to which about 50 grams of dry ice had been added. The resulting mixture was stirred for about thirty minutes. The solids were collected by filtration. The desired product was triturated in methylene chloride.
Yield: 0.37 g (82%) 20 Analysis for Cl7Hl4ClNO3:
Theory: C, 64.67; H, 4.47; N, 4.44.
Found: C, 64.84; H, 4.60; N, 4.54.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[N,N-bis(3-25 dimethylaminopropyl)amino]carbonyl]-lH-indole (~x~mple 58) W O 97/09308 PCT~US96/14163 rN(CH3)2 O~
CH3 ~CI
Under an argon atmosphere 2-[(4-chlorophenoxy)methyl~-1-methyl-3-carboxy-lH-indole (0.100 g, 0.317 mmol) was dissolved in 3.2 ml 5 of N,N-dimethylformamide. To this solution were added N,N-bis(3-dimethyl~minopropyl)amine (0.074 ml, 0.0623 g, 0.332 mmol), 1-(3-dimethyl~mincplo~yl)-3-ethylcarbodiimide hydrochloride (0.091 g, 0.475 mmol), and hydlo~ybenztriazole (0.0642 g, 0.475 mmol). The resulting mixture was then heated for 6 hours and then stirred at room 10 temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was then partitioned between methylene chloride and water. The aqueous fraction was extracted thrice with methylene chloride. The organic fractions were combined 15 and dried over sodium sulfate. The solvents were removed in vacuo.
The desired title product was further purified by radial chromatography .
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 483 (M-1).
FABMS 485 (M+1) Analysis for C27H37ClN4O2:
Theory: C, 66.86; H, 7.69; N, 11.55.
Found: C, 66.91; H, 7.54; N, 11.69.
Me1hodJ
Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[2-[1-[3-(1-tritylpiperidin-3-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]- lH-indole (F,x~mple 69 B) O~--CNH ~ Tr CH3 Cl 1~ CH3 Cl Tr Under a nitrogen a 10 ml round bottom flask was charged 5 with 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[(piperidin-4-yl)ethyl]carbonyl]-lH-indole (0.091 g, 0.222 mmol~, 3-(1-tritylpiperidin-3-yl)propyl iodide (0.110 g, 0.2224 mmol), potassium carbonate (0.0450 g, 0.3255 mmol), and 1.5 ml of anh~drous N,N-dimethylformamide. The resulting mixture was stirred overnight and then poured into ice water.
10 The solids were collected by filtration and rinsed with cold water. The solids were dissolved in methylene chloride and then dried over sodium sulfate. The solvents were removed in vacuo. The desired product was further purified by chromatography. Yield: 0.1166 grams (67.3%).
FDMS 779 (M+2).
5 Analysis for CslHs6clN3o2:
Theory: C, 78.69; H, 7.25; N, 5.40.
Found: C, 78.92; H,7.41; N,5.27.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-[1-[3-20 (piperidin-3-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]-lH-indole (~ mple 69C) CH3 ~Cl deprotection ~~~~
Under a nitrogen atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl] - 1-methyl-3-[[2-[1-[3-(1-tritylpiperidin-3--W O 97/09308 PCTAJS96/141~3 yl)propyl]piperidin-4-yl]]ethyl]carbonyl]-lH-indole (0.1006 g, 0.1292 mmol) was dissolved in 0.6 ml of of methylene chloride. To this solution was added formic acid (0.0244 ml, 0.0297 g, 0.646 mmol). The resulting mixture was stirred for several hours at room temperature, protected 5 from light. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was partitioned between methylene chloride and 1.0 N sodium hydroxide. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were 10 combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 536 (M+1).
5 Analysis for C32H42clN3o2:
Theory: C,71.69; H,7.90; N, 7.84.
Found: C,71.46; H, 7.8~; N,7.61.
Me1 hod K
Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-formyl- lH-indole (F'~zlmple 236) ~Cl Under a nitrogen atmosphere a round bottom flask was charged with 0.63 ml of anhydrous N,N-dimethylformamide. The reaction vessel was placed in a -20~C bath and then phosphorous oxychloride (0.187 ml, 0.310 g, 2.02 mmol) was carefully added. The 30 resulting mixture was stirred in an ice bath for about twenty minutes and 2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indole (0.50 g, 1.84 mmol) W O 97/09308 PCT~US96/141~3 in 3.4 ml of N,N-dimethylformamide, was added. The resulting mixture was stirred at room temperature for about ninety minutes. The reaction mixture was then placed over an oil bath and heated to 55~C and - m~int~ined at this temperature for about one hour. The reaction mixture was then permitted to cool to room temperature and was then poured into water. Sodium hydroxide (10 ml of a 5.0 N solution) was added and heated to reflux. The resulting mixture was cooled and the solids were then collected by filtration.
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 299 (M+).
Analysis for Cl7Hl4ClNO2:
Theory: C, 68.12; H, 4.71; N, 4.67.
Found: C, 67.90; H, 4.66; N, 4.76.
Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[1-hyd~o~y-2-(methoxycarbonyl)ethyl]-lH-indole (F.~mple 55) CH3 ~CI Cl 2 o Under a nitrogen atmosphere a round bottom flask was charged with 6.7 ml of dry tetrahydloru~an. To this was added diisopropylamine (0.196 ml, 0.1417 g, 1.401 mmol) and the reaction vessel was placed in an ice bath. To this mixture was slowly added n-butyllithium (0.88 ml of a 1.6 M solution in hexanes, 1.401 m_ol) and the 2 5 resulting mixture was stirred in an ice bath for about l~i minutes. The reaction mixture was placed in a dry ice/acetone bath, methyl acetate was added and the reaction mixture was stirred for fifteen minutes over a dry ice/acetone bath. Starting aldehyde was added in a total of 7.0 ml of tetrahydrofuran and stirred over a dry ice/acetone bath of one hour and 3 o then placed in an ice bath for about 30 minutes. The reaction mixture WO 97/09308 PCT/US96tl4163 was poured into an ammonium chloride solution (32 g in 100 ml of water). The aqueous fraction was extracted with methylene chloride.
The organic fractions were combined and dried over sodium sulfate.
The solvents were removed in vacuo. The desired title product was 5 further by radial chromatography.
NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure. FDMS 373 (M+).
Analysis for C20H2oclNo4:
Theory: C, 64.26; H, 5.39; N,3.75.
Found: C, 64.55; H, 5.23; N, 3.79.
Preparation of 3-{2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl~prop-2-enoic acid ~ C113 ~ ~
CH3 Cl CH3 Cl Under a nitrogen atmosphere a round bottom flask is charged with 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(metho~yc~bonyl)ethyl]-1H-indole (F.~mple 55) (0.149 g, 0.398 mmol) 20 and 6.11 ml of dry tetrahydrofuran. To this solution is added 1.22 ml of a 2.0 N lithium hydroxide aqueous solution and the resulting mixture was stirred at room temperature for about two hours. The solvents were removed in vacuo and the residue is partitioned between methylene chloride and water. The aqueous fraction was extracted twice with 25 methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was triturated with diethyl ether.
Analytical data was consistent with the proposed title structure.
W O 97t09308 PCTAUS96/14163 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[[4-(dimethyl~mino)piperidin-1-yl]carbonyl]ethenyl]-lH-indole (Example 44) ~ OH ~3_N~N(CH3)2 Q~o ~ ' Q~~'13 CH3 Cl CH3 Cl Under a nitrogen atmosphere dimethyl~minnpiperidine was dissolved in 3.0 ml of methylene chloride. To this solution were added 3-~2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl}prop-2-enoic acid (0.050 g, 0.1462 mmol) and 1-(3-dimethylaminoy~yyl)-3-10 ethylcarbodiimide hydrochloride (0.0356 g, 0.278 mmol). The resultingmixture was stirred at room temperature overnight.
The reaction mixture was partitioned between a saturated sodium bicarbonate solution and methylene chloride. The aqueous fraction was basified with 1.0 N sodillm hydroxide and extracted twice 15 with methylene chloride. The organic fractions were combined, washed with 1.0 N hydrochloric acid, then with brine, and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
NMR (CDCl3) was consistent with the proposed title structure.~ 0 Exact Mass for C26H3oclN3o2:
Theory: 452.2105.
Found: 452.2099.
Me1 hod L
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(methoxycarbonyl)ethyl]- lH-indole O~ ~CH3 O~ o~CH3 reduction ~
A round bottom flask was charged with 10% p~ um on act*ated carbon (0.150 g), 20 ml of N,N-dimethylform~mitle and 2-[(4-5 chlorophenoxy)methyl]-1-methyl-3-[2-(metho~ycalbonyl)ethenyl]-1H-indole (1.44 g, 4.22 mmol). The reaction vessel was then placed under a hydrogen atomsphere for two hours. The reaction mixture was then passed through a CELITETM pad and then partitioned between water and methylene chloride. The aqueous fraction was extracted twice with lo methylene chloride. The organic fractions were combined, washed with water and then brine, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by chromatography.
15Preparation of 3-~2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl}propanoic acid O~o~CH3 O~OH
Q~ hydrolysis ~
CH3 Cl CH3 Cl 2 o Under a nitrogen atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(methoxycarbonyl)ethyl]-lH-indole (0.275 g, 0.771 mmol) was dissolved in 8 ml of dry tetrahydrofuran. To this solution was added 4.0 ml of a 2.0 N lithium hydroxide solution.
The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
The solvents were removed in vacuo and the residue was ~ partitioned between methylene chloride and 5% citric acid. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were comhined, washed with brine, and dried over sodium sulfate. The solvents were removed in vacuo to yield the desired title product. Yield 0.2984 grams (>99%).
Preparation of 2-[(4-chloropheno-xy)methyl]-1-methyl-3-[2-[[4-(dimethyl7.mino)piperidin-1-yl]carbonyl]ethyl]-lH-indole (~ mple 43).
~ o 3 CH3 CH3 Cl CH3 Cl Under a nitrogen atmosphere 3-~2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl}propanoic acid (0.286 g, 0.832 mmol) was dissolved in 6 ml of dry tetrahydrofuran. To this solution 1,1'-carbonyldiimidazole (0.141 g, 0.874 mmol) was added and the resulting mixture was stirred at room temperature for about two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction lJ~ix~llre was then heated to 65~C and m~int~ined at this temp~al~e for about 35 minutes. To this reaction mixture dimethyl~minopiperidine (0.112 g, 0.874 mmol), dissolved in about 3.6 ml of tetrahyd~or~all. This .nixl~l,e was stirred at room temperature overnight.
The reaction mixture was then heated to 60~C and m~int~in~d at this temperature for about 30 minutes. The solvents were removed in vacuo and the residue was partitioned between methylene chloride and water. The aqueous fraction was extracted with methylene chloride again. The organic fractions were combine, washed twice with water, then with brine, and then dried over sodium sulfate. The .
W O 97/09308 PCTrUS96/141~3 solvents were removed in vacuo. The desired title product was further purified by chromatography.
NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
5 FDMS 463 (M+) Analysis for C26H32clN3o2:
Theory: C, 68.78; H, 7.10; N, 9.26.
Found: C, 68.74; H, 7.04; N, 9.38.
o Method M
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[3-[4-(N,N-dimethylamino)piperidin-l-yl]l lolJyl]-lH-indole (F.~mple 41).
~N3N~CH ~N3N~CH
~ ~~3 Q~~'13 CH3 Cl CH3 Cl Under a nitrogen atmosphere around bottom flask is charged with 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[[4-(dimethyl~mino)piperidin-1-yl]carbonyl]ethyl]-1H-indole (0.194 g, 0.428 20 mmol). The flask was then placed in an ice bath and borane-tetrahydrofuran complex (1.71 ml of a 1.0 M solution in THF, 1.71 mmol) was added. The reaction mixture was then removed from the ice bath and stirred at room temperature for about 90 minutes. The progress of the reaction was monitored by thin layer chromatography. A 1:1 25 tetrahydrofuran:methanol solution (0.20 ml total) was added, followed by the addition of 2.0 ml of 5.0 N sodium hydroxide.
The resulting mixture was refluxed overnight. The solvents were removed by evaporation and the residue was partitioned between water and methylene chloride. The organic fraction was W O 97/09308 PCT~US96/14163 washed with brine and dried over sodium sulfate. The solvents were ~ removed in vacuo.
NMR (CDCl3) was consistent with the proposed title structure.
FABMS 440 (M~1) 5 IR was consistent with the desired title structure.
Analysis for C26H34ClN3O:
Theory: C, 70.97; H, 7.79; N, 9.55.
Found: C, 70.73; H,7.65; N, 9.44.
o Method N
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[3-(piperidin-3-yl)propyl]-lH-indole (h',~mrle 42) and 1,2-dimethyl-3-[3-(piperidin-3-yl)propyl]-lH-indole (F,~m~le 237) Under a nitrogen atmosphere 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[3-(piperidin-3-yl)propanoyl]-lH-indole (0.0737 g, 0.1793 20 mmol) was dissolved in 1.8 ml of dioxane and borane-dimethylsulfide complex (0.108 ml, 1.07 mmol) was added. The resulting mixture was - stirred overnight at room temperature. The progress of the reaction wasmonitored by thin layer chromatography. A 1:1 tetrahydrofuran:water mixture (0.3 ml) was then added as well as 1.5 ml of ~.0 N sodium hydroxide. The reaction mixture was heated to 86~C and maintained at this tempe~a~u~e overnight, and then briefly raised to 225~C.
The solvents were removed in vacuo and the residue was partitioned between methylene chloride and 1.0 N sodium hyLoxide.
5 The organic fraction was washed with brine and dried over sodium sulfate. The solvents were removed in vacuo. The desired title products were further purified by chromatography. Analytical data obtained was consistent with the proposed title structure (See h:~mples 42 and 237, infra).
Preparation of 2,4-dichloro-1-ethynylbenzene CH
~Cl Cl In a 500 ml round bottom flask 2,4-dichloroiodobenzene (3 ml, 22.1 mmol), triethylamine (6.16 ml, 44.2 mmol), and (trimethylsilyl)acetylene (3.12 ml, 22.1 mmol) were ~lmi~ed in acetonitrile (6.16 ml, 44.2 mmol) under a nitrogen atmosphere. The mixture was bubbled with nitrogen gas for 10 minutes. To this mixture 20 bis(triphenylphosphine)p~ lium(II) chloride (775 mg, 1.10 mmol) and cuprous iodide (105 mg, 0.552 mmol) were added and the resulting mixture was refluxed for four hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was cooled to ambient temperature and evaporated to leave an oily product.
The residue was dissolved in methanol (50 ml) and tetrahydrofuran (150 ml), and solid potassium carbonate (30.54 g, 0.221 mol) was added. The resulting mixture was stirred at ambient temperature for 19 hours. The progress of this reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between lM potassium carbonate and ethyl acetate. The aqueous fraction was back-extracted thrice with ethyl acetate. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo to yield 2.6 grams of the desired title product.
NMR was consistent with the proposed title structure.
Preparation of 2,4-dichloro-1-(2-bromoethen-1-yl)benzene , ~,Cl Cl lo In a 100 ml round bottom flask borane tetrahydrofuran complex (lM in tetrahydrofuran, 4.8 ml, 4.82 mmol) was cooled to 0~C
under a nitrogen atmosphere. To this complex 2-methylprop-2-ene (1.02 ml, 9.66 mmol) was added dropwise and the mixture was slowly warmed to ambient temperature and stirred at ambient temperature for 15 one hour. The reaction lm~l~e was diluted with he~methylphosphoramide (5 ml), tetrahydrofuran (5 ml), cupric bromide (2.15 g, 9.65 mmol), and cupric acetate (3.85 g, 19.3 mmol), followed by the addition of water (86 ,ul, 4.82 mol). The resulting mixture was stirred at ambient temperature for six hours. The progress of the 20 reaction was monitored by thin layer chromatography. The reaction mixture was diluted with brine and extracted thrice with diethyl ether.
The organic fractions were comhined and dried over sodium sulfate.
The solvents were removed in vacuo. The residue was further purified by liquid chromatography. Yield: 426 mg. NMR was consistent with 2 5 the proposed title structure.
Preparation of 4-hydroxy-N-isopropylbutylamine WO 97/09308 PCT/US96/141~3 HO'--~'~ N~CH3 To a solution of 4-aminobutanol (2.0 mg, 22.4 mmol) in 110 ml of dichloroethane were added acetone (3.3 ml, 44.8 mmol), acetic acid (5 eq.), and sodium acetoxyborohydride (11.9 g, 56.09 mmol). The cloudy mixture was stirred at ambient tempe~a~u~e for about 18 hours. The reaction was qllenched with saturated sodium bicarbonate. Sodium hydroxide (1 M) was added to adjust the pH to about 10. The aqueous layer was extracted with a ll~i~lule of isopropyl alcohol and methylene chloride (1:3). The organic fractions were combined and dried over sodium sulfate, filtered, and concentrated. The desired intermediate was further purified by bulb to bulb distillation to yield 1.4 grams as a clear oil. If desired, additional yield may be recovered by extracting the aqueous fraction with 3:1 toluene:butanol.
Preparation of N-(t-butoxycarbonyl)-4-hydroxy-N-isopropylbutyl~mine Ho~' ,N~CH3 A solution of 4-hydroxy-N-isopl~ylbutyl~min~ (3.0 g, 22.8 mmol) in dioxane:water:lN sodium hydroxide (91 ml:28 ml:28 ml) was treated with di(t-butoxycarbonyl)ether (4.98 g, 22.8 mmol). The cloudy reaction mixture was stirred for five hours. The reaction mixture was extracted with methylene chloride. The organic phase was dried, filtered, and concentrated. The desired title product was further purified by high performance liquid chromatography affording 2.6 grams (49%) of a colorless oil.
Preparation of 2-fluoro-5-chlorobenzaldehyde WO 97/09308 PCT/US96/141~3 F o ~ ~--\H
Cl Lithium diisopropylamide was prepared by ~rlmi~ing diisopropylamine (5.79 ml, 41.3 mmol) in 5 ml of tetrahyLof~llan. The 5 resulting mixture was cooled to -78~C and treated with n-butyllithium in such a manner that the temperature did not raise above 64~C. After stirring the suspension for 45 minutes, the remainder of the tetrahydrofuran was added (70 ml), followed by the d~o~wise addition of 4-chlorophenyl fluoride (4.0 ml, 37.6 mmol). After 45 minutes N,N-10 dimethylformamide was added, also in a dropwise fashion. Theresulting reaction mixture was stirred an additional ten minutes prior to quen( hing with acetic acid ( 6ml), followed by water (100 ml). The cold l~e was transferred to a separatory funnel and extracted twice with methylene chloride. The organic fractions were combined, dried over 15 sodium sulfate, and filtered. The solvents were removed by vacuum.
The residue was further purified by high performance liquid chromatography, affording 4.00 grams of a white solid. mp 41-43~C.
Preparation of 2-fluoro-5-methylbenzyl alcohol F
--\OH
A solution of 2-fluoro-5-methylbenzaldeyde (1.80 g, 12.3 mmol) in 3:1 tetrahydrofuran:methanol (82 ml total) at 0~C was treated ~ 25 with sodium borohydride (0.93 g, 24.6 mmol). The reaction was slowly W O 97t09308 PCT~US96/141~3 warmed to ~mhient temperature and stirred for about three hours. The reaction was quenched with water, transferred to a separatory funnel, and extracted with methylene chloride. The organic fraction was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue 5 was further purified by high performance liquid chromatography to yield 1.3 grams (76%) of a clear oil.
Preparation of 2-fluoro-5-chlorobenzyl alcohol F
--OH
0 Cl The title interme~ te was prepared essentially as was 2-fluoro-5-methylbenzyl alcohol, supra, except that an equimolar amount of 2-fluoro-5-chlorobenzaldehyde was employed instead of the 2-fluoro-5-15 methylbenzaldehyde employed therein.
Yield: 2.16 grams (86%) as a clear oil.
Preparation of 2-fluoro-5-chlorobenzyl bromide ~~\Br Cl A solution of 2-fluoro-5-chlorobenzyl alcohol (1.28 g, 7.97 mmol) in diethyl ether (26 ml) was treated with triphenylphosphine (2.72 g, 10.36 mmol), followed by carbon tetrabromide (3.44 g, 10.36 mmol).
25 The resultant suspension was stirred for 3.5 hours, then filtered, w~hin~ with diethyl ether. The filtrate was concentrated, then passed ~ through a plug of silica to remove triphenylphosphate. The residue was then purified by liquid chromatography affording 2.0 grams of a clear - oil.
Preparation of 4-(2-fluorobenzyloxy)-N-~t-butoxycarbonyl)-N-(isopropyl)butylamine BoC
F
~ ~ NyCH3 1~1 CH3 A solution of N-(t-butoxycarbonyl)-4-hydroxy-N-iso~lol~ylbutyl~-nine (539 mg, 2.33 mmol) in tetrahyLo~ulan (11 ml) at -40~C was treated with potassium t-butoxide (1 M in tetrahydlo~an, 2.64 ml, 2.64 mmol). After 40 minutes, the suspension was cooled to -78~C and treated with a solution of 2-fluorobenzyl bromide (400 mg, 2.12 mmol) in tetrahydrofuran (4 ml). The reaciton was slowly warmed to room temperature and stirred for about five hours. The reaction was diluted with methylene chloride and washed with 1 M potassium carbonate and brine. The organic fraction was dried over sodium 2 o sulfate, filtered, and concentrated. The crude oil was purified by liquid chromatography to yield 566 mg (77%) of the title intermediate as a clear oil.
Preparation of 4-(2-fluoro-6-chlorobenzyloxy)-N-(t-butoxycarbonyl)-N-2 5 (isopropyl)butylamine BoC
F
~\/N\/CH3 .~J CH3 Cl The title intermediate was prepared essentially as described supra for 4-(2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine, except that an equimolar amount of 2-fluoro-5-5 chlorobenzyl bromide was employed instead of the 2-fluorobenzyl bromide employed therein.
Yield 237 mg (35~o).
Preparation of 4-(2-fluorobenzyloxy)-N-(isol,~ ol~yl)butyl~qmine ~ ~o/ ~N~ CH3 The desired intermediate was prepared from the deprotection of 4-(2-fluorobenzyloxy)-N-(t-but~yc~lJonyl)-N-15 (iso~ro~yl)butyl~mine using st~n~rd techniques. The 4-(2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(iso~lo~yl)butylamine was lmi~ed with a 4:1 mixture of methylene chloride and trifluoroacetic acid. The progress of the reaction was monitored by thin layer chromatography .
Preparation of 4-(5-chloro-2-fluorobenzyloxy)-N-(isopropyl)butylamine ~~ N~CH3 1~1 CH3 Cl The desired intermediate was prepared essentially as described for the 4-(2-fluorobenzyloxy)-N-(isopropyl)butylamine above, except that an equimolar amount of 4-(5-chloro-2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(iso~l o~yl)butylamine was employed in place of the 4-W 0 97/09308 PCTAJS96/141~3 (2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine employed therein.
Yield: 138 mg (98~o).
5 Preparation of 3-(5-bromo-2-fluorobenzyloxy)-1-[1-(t-butoxycarbonyl)piperidin-2-yl]propane F BloC
~,1~~~
Br 3-[1-(t-Buto~ycalbonyl)piperidin-2-yl]propanol (800 mg, 3.29 mmol) was taken up in tetrahy~oru~an (17 ml), cooled to -40~C, and treated with potassium t-butoxide (1 M in tetrahyLoruldn, 3.62 ml, 3.62 mmol). The resulting ~lu.e was stirred at -40~C for about 35 minutes, then cooled to -78~C. To this mixture was then added 5-bromo-2-fluorobenzyl bromide (881 mg, 3.29 mmol) as a solution in tetrahydrofuran (5 ml). The resultant yellow reaction ~ lule was slowly warmed to 0~C and stirred for about four hours. The reaction mixture was diluted with methylene chloride and washed with 1 M
potassium carbonate and brine. The organic fraction was dried over 20 sodium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by high performance liquid chromatography, yielding 707 mg (50%) of the title intermediate as a clear oil.
Analysis for C20H2gBrFNO3:
Theory: C, 55.82; H,6.79; N,3.25.
Found: C,55.54; H,6.88; N,3.34.
Preparation of 3-(5-bromo-2-fluorobenzyloxy)-1-(piperidin-2-yl)propane WO 97/09308 PCT/US96/141~3 F
~~~
Br 3-(6-Bromo-2-fluorobenzyloxy)-1-[1-(t-butoxycarbonyl)piperidin-2-yl]propane (590 mg, 1.37 mmol) was 5 dissolved in methylene chloride (11 ml), cooled to 0~C, and treated with 3 ml of trifluoroacetic acid. The reaction mixture was stirred at 0~~ for 20 minutes, then warmed to ambient temperature, and stirred an additional ten minutes. The reaction mixture was diluted with methylene chloride and quenched with saturated sodium bicarbonate.
10 The pH was adjusted to about 10 with 1 N sodium hydroxide. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated. Yield: 420 mg (93%). The resulting intermediate was used without further purification.
Preparation of 2-fluoro-5-bromobenzyl bromide ~~ Br Br 2 0 A solution of 2-fluoro-5-bromobenzyl alcohol (20.0 g, 97.5 mmol) in diethyl ether (325 ml) was treated with triphenylphosphine (33.3 g, 127 mmol), followed by carbon tetrabromide (42.1 g, 127 mmol).
The mixture was stirred at ambient temperature for about four hours.
The precipitate was removed and washed with diethyl ether. The 2 5 desired title product was further purified by bulb to bulb distillation [150~C, 5 mm Hg (house vacuum)]. Yield: 24.36 grams (93~o) of a white, low melting solid.
W O 97/09308 PCTAJS96/141~3 ~ Preparation of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol) F
~OH
Br A solution of 2-fluoro-5-bromobenzyl bromide (15.6 g, 58.1 mmol) in N,N-dimethylformamide (290 ml) was added over 35 minutes to a mixture of 1,4-dihyLo~y-2-butyne (20.0 g, 232 mmol) and sodium hydride (15.6 g of a 60% solution, 58.1 mmol). The resulting mixture lo was stirred for 4.5 hours at ambient temperature. The reaction was quenched with 100 ml of a 1:1:1 brine:water:l M potassium carbonate solution. The aqueous fraction was extracted with methylene chloride (3 x 300 ml). The desired title product was further purified by chromatography to yield 8.90 grams (56%).
Preparation of 4-(2-fluoro-5-bromobenzyloxy)butanol ~0 Br A solution of 1,4-dihy~o~ylJ~l~ane (4.0 ml, 45.13 mmol) in N,N-dimethylformamide (62 ml) was treated with sodium hydride (1.98 g of a 60% solution, 49.63 mmol), and stirred for about 50 minutes at ambient temperature. The resulting mixture was cooled to 0~C and treated with 2-fluoro-5-bromobenzyl bromide (3.0 g, 11.28 mmol). The - 25 reaction mixture was then stirred for four hours at ambient temperature. The reaction was quenched with water. The aqueous W O 97/09308 PCTrUS96/141~3 fraction was extracted with methylene chloride. The organic fractions were comhined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography. Yield: 1.8 grams (58%) as a 5 clear oil. ~max = 271 nm.
Analysis for C11H14BrFO2:
Theory: C, 47.67; H, 5.09; Br, 28.83.
Found: C, 47.37; H, 5.15; Br, 28.55.
10 Preparation of N-(t-butoxycarbonyl)-4-(2-fluoro-5-bromobenzyloxy)-3,3-dimethylbutyl :~mi n ~
--O~N'B C
Br A stirred solution of 4-(t-buto~ycall)onylamino)-2,2-dimethylbutan-1-ol (1.5 g, 6.90 mmol) in tetrahydrofuran (49 ml) at -45~C
was treated with potassillm t-butoxide (1 M in tetrahyL.~rulan, 7.59 ml, 7.59 mmol). The anion was stirred for 30 minutes at -45~C, then cooled to -78~C and treated with a tetrahyLor~an solution of 2-fluoro-5-20 bromobenzyl bromide (1.85 g, 6.90 mmol). The resulting yellow mixture was slowly warmed to ambient temperature and stirred for about 18 hours. The cloudy reaction mixture was diluted wtih methylene chloride and washed with 1 M potassium carbonate. The organic fraction was dried over sodium sulfate, filtered, and the solvents were 25 removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.45 grams (52%) of the title intermediate as a colorless oil.
Preparation of N-(t-butoxycarbonyl)-4-(2-fluoro-5-bromobenzyloxy)-2,2-30 dimethylbutylamine W O 97/09308 PCTrUS96/1416 F H3C, ~CH3 ,~ ~HN
ll ~J
Br A stirred solution of 4-(t-buto~ycalLonylamino)-3,3-dimethylbutan-1-ol (1.0 g, 4.60 mmol) in tetrahydrofuran (33 ml) at -46~C
5 was treated with potassium t-butoxide (1 M in tetrahydrofuran, 5.06 ml, 5.06 mmol). The anion was stirred for 30 minutes at -45~C, then cooled to -78~C and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow n~i~lu,e was slowly warmed to 0~C and stirred for about four hours. The cloudy 10 reaction mixture was diluted wtih methylene chloride (100 ml) and washed with 1 M potassium carbonate. The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo.
The residue was further purified by preparative high performance liquid chromatography to yield 1.38 grams (74%) of the title intermediate 15 as a colorless oil.
Preparation of 2-[(t-butoxycarbonyl)amino]-5-(2-fluoro-5-bromobenzyloxy)-2-methylpentane H
~0/~ ' BoC
~ H3C CH3 Br A stirred solution of 4-(t-butoxycarbonylamino)-4,4-- dimethylbutan-1-ol (1.11 g, 5.11 mmol) in tetrahyd~or~dn (49 rnl) at -45~C was treated with potassium t-butoxide (1 M in tetrahydrofuran, 6.62 ml, 5.62 mmol). The anion was stirred for 30 minutes at -45~C, then cooled to -78~C and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow mixture was slowly warmed to 0~C and stirred for about four hours. The reaction mixture was diluted wtih methylene chloride (100 ml) and 5 washed with 1 M potassium carbonate (20 ml). The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.53 grams (74%) of the title intermediate as a colorless oil.
Preparation of trans-4-(t-butoxycarbonylamino)cycloheganol HOI~ O~N~ BoC
To a solution of trans-4-~minocyclohe~nnl (5.00 g, 33.0 mmol) in dioxane (132 ml), water (41 ml) and 1 N sodium hydroxide (41 ml) was added t-buto~yc~l)onyl anhydride (14.4 g, 66 mmol). The cloudy solution was stirred overnight. The reaction mixture was acidified to pH 3.0 with solid sodium bisulfate. The resulting ~ e was thrice 20 extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, and concentrated in vacuo. The desired title intermediate was recrystallized from he~nes/ethyl acetate to yield 6.5 grams (92~Zo).
MS 216.24 25 Analysis for CllH21N03:
Theory: C,61.37; H, 9.83; N, 6.50.
Found: C,61.16; H, 9.54; N, 6.39.
Preparation of trans- ~4-(butoxycarbonylamino)- 1-[2-fluoro-5-30 bromobenzyloxy]}cyclohegane W 097/09308 PCTAUS96/141~3 _ 99 _ F H
O~ BoC
Br A solution of trans-{4-(butoxycarbonylamino)}cyclohexanol (550 mg, 2.32 mmol) in dry tetrahy~orulan (16.6 ml) was cooled to -40~C
and treated with potassium t-butoxide (1 M in tetrahydrofuran, 2.55 ml, 2.55 mmol). The cloudy yellow reaction mixture was stirred for about thirty minutes, cooled to -78~C, and treated with 2-fluoro-5-bromobenzyl bromide (622 mg, 2.32 mmol). The resulting yellow mixture was gradually warmed to 0~C and stirred for about two hours. The reaction o mixture was diluted with methylene chloride, and washed with saturated sodillm bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The residue was purified further by high performance liquid chromatography to yield 558 mg (62%) of the desired title intermediate as a white solid.
Analysis for ClgH2sBrFNO3:
Theory: C, 53.74; H, 6.26; N, 3.48.
Found: C, 53.87; H, 6.16; N, 3.11.
Preparation of 3,3-dimethyl-1-(t-buto~yca,l)onyl)pyrrolidin-2-one O
H3C~,J~--BoC
H3C' \~
The desired intermediate was prepared essentially as described in F. Scheinm~qnn and A.V. Stachulski, Journal of Chemical 25 Research, 1993:414 (1993). A solution of 3-methyl-1-(t-butoxycarbonyl)pyrrolidin-2-one (8.63 g, 43.3 mmol) in tetrahydrofuran (48 ml) was cooled to -78~C. The solution was treated with NaN[Si(CH3)2]2 (56.3 ml, 56.3 mmol) and stirred for about 50 minutes - -CA 022039l2 l997-04-28 W O 97/09308 PCTrUS96/14163 prior to quen~hing with methyl iodide (8.1 ml, 130 mmol). The reaction mixture was slowly warmed to ambient temperature, and stirring was continued for about one hour. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with phosphate buffer, pH 7.0 (40 ml), 5 water (40 ml) and brine (40 ml). The organic fraction was dried over sodium sulfate, filtered, and concentrated in vacuo. The precipitate was collected, and further purified by flash chromatography to yield 8.49 grams (92%) of the title intermediate as a semi-solid. NMR was consistent with the title structure.
Preparation of 4-(t-butoxycarbonylamino)-2,2-dimethylbutanol HO~N~ BoC
A solution of 3,3-dimethyl-1-(t-buto~yca~l~onyl)pyrrolidin-2-one (3.35 g, 15.7 mmol) in absolute ethanol under a nitrogen atmosphere was treated with sodillm borohydride (1.79 g, 47.1 mmol). The resulting mixture was stirred at ambient tempeature for about 24 hours. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate. The aqueous fraction was back extracted twice with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo.
The residue was further purified by chromatography to yield 3.17 grams (93%) of the title intermediate as a clear oil. mp 76.5-76.5~C.
Preparation of 4-(2-fluoro-5-bromobenzyloxy)-1-methoxybut-2-yne F
- ~~o' OCH3 Br A solution of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol (1.07 g, 3.92 mmol) in tetrahydrofuran (26 ml) was cooled to -40~C
and then treated with potassillm t-butoxide (4.31 ml of a 1 M solution in tetrahydrofuran, 4.31 mmol). The resulting dark orange solution was stirred for thirty minutes, cooled to -78~C and treated with methyl iodide (0.49 ml, 7.84 mmol). The reaction was warmed to 0~C and stirred for 1.5 hours. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography to yield 790 mg (70%) as a clear oil.
Preparation of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl bromide ~~o _ ~ Br Br A solution of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol (8.9 g, 32.6 mmol) in diethyl ether (109 ml) was treated with triphenylphosphine (11.1 g, 42.4 mmol) and carbon tetrabromide (14.1 g, 42.4 mmol). The cloudy solution was stirred at ambient temperature for about 14 hours. The precipitate was removed by filtration and the filtrate was concentrated. The desired title intermediate was purified from the filtrate by flash chromatography. Yield 9.83 grams (90~o) as a clear oil.
Elemental analysis and NMR were consistent with the proposed title structure.
Preparation of N-methyl-4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl amine F
~~0 ~ ~ CH3 Br A solution of aminomethane (89 ml of a 2 M solution in tetrahydrofuran, 178 mmol3 was added to a solution of 4-(2-fluoro-5-lo bromobenzyloxy)but-2-ynyl bromide (6.0 g, 17.8 mmol) in tetrahydrofuran (89 ml). The cloudy reaction mixture was stirred for about fifteen minutes, at which time no starting material rem~ined, as deter_ined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed 15 with 1 M potassium carbonate. The aqueous phase was back-extracted thrice with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo.
The resulting oil was further purified by flash chromatography, affording 4.24 grams (83~o) of the title intermediate as a yellow oil. NMR
20 was consistent with the title structure.
Preparation of N-benzyl-4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl amine ¢f O ~ ~ ~3 Br W O 97/09308 PCTAJS96/141~3 A solution of benzylamine (0.98 ml, 8.93 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (300 mg, 0.893 mmol) in tetrahydrofuran (4.5 ml). The cloudy reaction mixture - was stirred for about twenty hours, at which time no starting material 5 remained, as determined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed with 1 M potassium carbonate. The aqueous phase was back extracted with methylene chloride (2 x 15 ml). The organic fractions were combined, and dried over sodium sulfate. The solvents lo were removed in vacuo. The resulting oil was further purified by flash chromatography, arrol lhlg 200 mg (62~) of the title intermediate.
Preparation of N-isopl o~yl-4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl amine ~~o ~ ,N~CH3 \~ CH3 Br A solution of iso~o~ylamine (0.25 ml, 2;9 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (97 mg, 0.29 mmol) in tetrahydrofuran (1.4 ml). The cloudy reaction mixture was stirred for about twenty hours, at which time no starting material remained, as determined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed with 1 M potassium carbonate. The aqueous phase was back extracted with methylene chloride (2 x 5 ml). The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by flash chromatography, affording 78 milligrams (86%) of the title intermediate.
NMR was consistent with the title structure.
WO 97/09308 PCT/US96/141~3 Preparation of N-cyclopropyl-4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl amine H
Br A solution of cyclop,o~ylamine (1.10 ml, 15.8 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (530 mg, 1.58 mmol) in tetraLyLorlllan (8 ml). The cloudy reaction mixture was stirred for about thrity minutes. The reaction mixture was 0 then cooled to 0~C, and held at this temperature for about four hours, at which time no starting material remained, as determined by thin layer chromatography. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 1 M potassium carbonate (10 ml). The organic fraction was dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by preparative high performance liquid chromatography, affording 362 mg (73~o) of the title intermediate as a clear oil.
Preparation of 4,5-dihydro-2-(2-fluoro-5-bromophenyl)oxazole Br A solution of N-(2-hydroxyethyl)-5-bromo-2-fluorobenzamide (956 mg, 3.65 mmol) in methylene chloride was treated with thionyl chloride (0.35 ml, 4.75 mmol). The resulting mixture was stirred at ambient temperature as the progress of the reaction was monitored by W 0 97/09308 PCTAJS96/141~3 thin layer chromatography. After one hour of stirring, no starting material was visible. The reaction ~ l~e was diluted with methylene chloride, and the reaction was quenched by the addition of water and 1 N
sodium hydroxide. The organic fraction was dried over sodium sulfate, 5 and concentrated to a white solid. The solid was dissolved in 80%
aqueous acetonitrile (25 ml) and an excess of potassium carbonate was added. The resulting mixture was stirred for about 72 hours at ambient temperature, heated to reflux for thirty hours, and worked up as before.
The desired title product was then further purified by liquid 10 chromatography, yielding 260 mg as a yellow oil.
Preparation of N,N-dimethyl-2-fluoro-5-bromobenzamide F O
Br A suspension of 2-fluoro-5-bromobenzoic acid (680 mg, 3.10 mmol) in methylene chloride (20 ml) was treated with oxalyl chloride (0.35 ml, 4.04 mmol), followed by four drops of ~,N-dimethylformamide.
The resulting clear solution was stirred for about three hours. The 20 solvents were removed in vacuo and the residue was redissolved in methylene chloride and treated with dimethylamine (4.6 ml, 9.3 mmol).
Stirring was continued for 18 hours. The reaction ~ re was diluted with methylene chloride, and washed with saturated sodium bicarbonate and brine. The organic fraciton was dried over sodillm 2 5 sulfate, and the solvents were removed in vacuo. The desired title product was further purified by liquid chromatography. Yield: 632 mg (83%) as a clear oil.
Preparation of 1-methoxy-4-(2-fluoro-5-bromobenzyloxy)butane F
~OCH3 Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butanol (897 mg, 3.24 mmol) in tetrahydrofuran (22 ml) was cooled to -40~C and then 5 treated with potassium t-butoxide (3.56 ml of a 1 M solution in tetrahydrofuran, 3.56 mmol). The resulting orange solution was stirred for thirty minutes, cooled to -78~C and treated with methyl iodide (0.40 ml, 6.48 mmol). The reaction was warmed to 0~C and stirred for 1.5 hours. The reaction mixture was then partitioned between methylene 10 chloride and saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography to yield 687 mg (73%) as a clear oil.
FDMS 291.99 Preparation of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide F
~~~
Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butanol (7.03 g, 26.3 mmol) in diethyl ether (88 ml) was treated with triphenylphosphine (8.97 g, 34.2 mmol) and carbon tetrabromide (11.3 g, 34.2 mmol). The cloudy solution was stirred at ambient temperature for about 30 hours.
The precipitate was removed by filtration and the filtrate was concentrated. The desired title intermediate was purified from the filtrate by bulb to bulb distillation. Yield 8.68 grams (86%) as a clear oil.
Elemental analysis and NMR were consistent with the proposed title structure.
Preparation of N,N-dimethyl-4-(2-fluoro-5-bromobenzyloxy)butylamine F
'O~N\CH
Br Diethylamine (17.6 ml, 35.3 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (1.2 g, 3.53 mmol) in lo tetrahyLor~an (18 ml). The resulting mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate.
The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography. Yield:
842 mg (79~) as a pale yellow oil.
Preparation of N-ethyl-4-(2-fluoro-5-bromobenzyloxy)butyl~mine ~0~ CH2CH3 ~ ~J
Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (500 mg, 1.47 mmol) in acetone (7.3 ml) was treated with sodium iodide - 25 (242 mg, 1.6 mmol). The resulting mixture was stirred at ambient ~ temperature. After 1.5 hours, the sodium bromide was removed by W O 97/09308 PCT~US96/141~3 filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of ethylamine (11 ml, 22.0 mmol). The resulting mixture was stirred for about 17 hours at ambient temperature. The progress of the reaction was monitored by thin layer 5 chromatography. The reaction mixture was diluted with methylene chloride, and washed with 25 mM phosphate buffer and brine. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography. Yield: 337 mg (75%) as a yellow oil. NMR was 10 consistent with the proposed title structure.
Preparation of N-isopropyl-4-(2-fluoro-5-bromobenzyloxy)butylamine F H
~ ,,,,,N,f CH3 Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (1.2 g, 3.53 mmol) in tetrahydrofuran (18 ml) was treated with sodium iodide (484 mg, 3.2 mmol). The resulting ~ lule was stirred at ambient temperature. After 1.5 hours, the sodium bromide was 20 removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of isopropylamine (3.01 ml, 35.3 mmol). The progress of the reaction was monitored by thin layer chromatography. The resulting mixture was stirred for about 18 hours at ambient temperature, after which time an additional 10 equivalents of 25 isopropylamine was added to drive the reaction. The reaction mixture was diluted with methylene chloride, and washed with 25 mM
phosphate buffer and brine. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography. Yield: 517 30 mg (46%) as a yellow oil.
Analysis for C14H21BrFNO:
W O 97/09308 PCT~US96/141~3 Theory: C, 52.84; H, 6.65; N,4.40.
Found: C,52.87; H, 6.77; N,4.64.
Preparation of N-(t-butyl)-4-(2-fluoro-5-bromobenzyloxy)butyl~mine (~/\ H XCH
Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (400 mg, 1.18 mmol) in tetrahydrofuran (6 ml) was treated with sodium 10 iodide (242 mg, 1.6 mmol). The resulting ~ e was stirred at ~mbient temperature. After 1.5 hours, the sodium bromide was removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydroru.all solution of tert-butyl~mine (1.24 ml, 11.8 mmol). The progress of the reaction was monitored by thin layer 15 chromatography. The resulting mixture was stirred for about 19 hours at ambient temperature. The reaction mixture was diluted with methylene chloride, and washed with saturated sodium bicarbonate.
The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further 20 purified by radial chromatography. Yield: 261 mg (66%) as a yellow oil.
NMR was consistent with the proposed title structure.
Preparation of l-(piperidin-1-yl)-4-(2-fluoro-5-bromobenzyloxy)butane ~0~ ~
,~
~ 25 Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (520 mg, 1.53 mmol) in tetrahydlof~dn (8 ml) was treated with piperidine (1.5 ml, 15.3 mmol). The resulting reaction mixture was 5 stirred for about 24 hours. The reaction mixture was then diluted with methylene chloride and washed with saturated sodium bicarbonate.
The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography. Yield: 399 mg (76%).
Preparation of l-(morpholin-4-yl)-4-(2-fluoro-5-bromobenzyloxy)butane ~\O
F
~0/--~ \~
Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (550 mg, 1.62 mmol) in tetrahydrofuran (8 ml) was treated with morpholine (1.4 ml, 16.2 mmol). The resulting reaction mixture was stirred for about 72 hours. The reaction mixture was then diluted with methylene chloride and washed with saturated sodium bicarbonate.
2 o The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography. Yield: 446 mg (79~o) as a clear oil.
Preparation of 1-[2-fluoro-5-bromobenzyloxy]-3-[1-(t-2 5 butoxycarbonyl)piperidin-3-yl]propane W O 97/09308 PCTrUS96/141~3 ~ BoC
Br An amount of 3-[1-(t-buto~ycall,onyl)piperidin-3-yl]l,lo~yl bromide (180 mg, 0.588 mmol) was dissolved in N,N-dimethylformamide (1.5 ml) in a 10 ml flask under a I~itrogen atmosphere. Sodium iodide (176 mg, 1.18 mmol) was added at ambient temperature, and the resulting mixture was stirred for ten minutes. The reaction mixture was treated with 2-fluoro-6-bromobenzyl alcohol (121 mg, 0.588 mmol), delivered as a solution in 0.5 ml of N,N-dimethylformamide. To this ~ l~e was then added sodium hydride (60%, 35 mg, 0.882 mmol) and the resulting mixture was stirred at ambient temperature for three hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by liquid chromatography. Yield: 0.115 g. MS (M+) 430.
Analysis for C20H2gBrFNO3:
Theory: C,55.82; H, 6.79; N,3.26.
Found: C,55.70; H,6.59; N,3.04.
Preparation of 1-[2-fluoro-5-bromobenzyloxy]-3-(piperidin-3-yl)propane F
Br .
W O 97/09308 PCT~US96/14163 In a 100 ml round bottom flask, 1-[2-fluoro-5-bromobenzyloxy]-3-[1-(t-butoxycarbonyl)piperidin-3-yl]propane (0.395 g) was dissolved in methylene chloride (4.2 ml). The solution was cooled to 0~C and trifluoroacetic acid (0.8 ml) was slowly added Lol~wise. The 5 resulting ~ e was stirred at 0~C for thirty minutes, followed by stirring at ambient temperature for thirty minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with 10 methylene chloride. The organic fractions were coInhined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography. Yield:
210 mg as a clear yellow oil.
Analysis for C16H21BrFNO:
Theory: C, 54.54; H, 6.41; N, 4.24.
Found: C, 54.32; H, 6.41 N, 4.34.
Preparation of 2-fluoro-5-bromobenzyl bromide F
~Br Br In a 250 ml round bottom flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl alcohol (5.85 g, 28.5 mmol) was dissolved in diethy ether (125 ml). To this solution triphenylphosphine 25 (9.73 g, 37.1 mmol) and carbon tetrabromide (12.30 g, 37.1 mmol) were added. The resulting mixture was stirred at ambient temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. The mixture was then stirred at ambient temperature for about 19 additional hours. The reaction mixture was 30 filtered and washed with cold diethyl ether. The filtrate was evaporated, yielding a light yellow oil. The oil was further purified by chromatography on a silica gel with hexanes. The desired fractions were purified by evaporation to yield 5.8 grams of the desired title intermediate. The material slowly crystallized upon st~nrling.
~ Analysis for C7H6Br2F:
Theory: C, 31.39; H, 1.88.
Found: C, 31.18; H, 1.91.
Preparation of N,N-dimethyl-3-(2-fluoro-5-bromobenzyloxy)~,ol,ylamine F
~ 7 ~ CH3 lo Br In a 10 ml round bottom flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl bromide (245 mg, 0.914 mmol) was dissolved in N,N-dimethylformamide (2.0 ml). To this solution sodium iodide (137 mg, 0.914 mmol) was added and the resulting mixture was stirred at ambient temperature for thirty minutes. In another 10 ml flask, under a nitrogen atmosphere, 3-(N,N-dimethylamino)propanol (0.162 ml, 1.37 mmol) was dissolved in N,N-dimethylformamide (2.0 ml).
Sodium hydride (60%, 62 mg, 1.55 mmol) was then added to the propanol solution. After thirty minutes of stirring, the benzyl bromide, sodillm iodide solution was added to the propanol ~ e. Some frothing occurred, but quickly dissipated. The resulting ~ e was stirred for two hours at ambient temperature. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired intermediate was further purified by liquid chromatography to yield 182 mg (69%) of the title intermediate. NMR, ~ IR, and MS were consistent with the proposed title structure.
Analysis for C12Hl7BrFNO:
Theory: C, 49.67; H, 5.91; N, 4.83.
Found: C, 49.46; H, 5.92; N, 4.99.
5 Preparation of 2-(2-fluoro-5-bromobenzyloxy)-1-methoxyethane ~~'o~ CH3 Br In a 10 ml flask, under a nitrogen atmosphere, 2-lo methoxyethanol (0.125 ml, 1.60 mmol) was dissolved in N,N-dimethylformamide (2 ml). Sodium hydride (60~, 72 mg, 1.81 mmol) was added and the mixture was stirred at ambient temperature for about thirty minutes. To this reaction ~i~lule was added 2-fluoro-5-bromobenzyl bromide (285 mg, 1.06 mmol) as a solution in N,N-15 dimethylformamide (2 ml). The resulting ~ .e was stirred atambient temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic 20 fractions were combined, washed with brine (7 X) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was used without further purification. Yield: 165 mg Preparation of 2-(2-fluoro-5-bromobenzyloxy)-(N,N-dimethyl)ethylamine ~"O~N'CH
Br WO 97/09308 PCT/US96tl4163 In a 50 ml flask, under a nitrogen atmosphere, 2-(N,N-dimethyl~minn)ethanol (1.319 g, 4.92 mmol) was dissolved in N,N-dimethylformamide (16 ml). Sodium hydride (60%, 335 mg, 8.37 mmol) 5 was added and the mixture was stirred at ambient temperature for about twenty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (1.319 g, 4.92 mmol) as a solution in N,N-dimethylform~mide (3 ml). The resulting mixture was stirred at ambient temperature for two hours. The progress of the reaction was lo monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic fractions were combined, washed with brine (7 X) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was 15 used without further purification. Yield: 1.023 g (75%) Preparation of N,N-dimethyl-2-fluoro-5-bromobenzylAmine ,CH3 1~ CH3 Br In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl bromide (1.264 g, 4.72 mmol) was dissolved in methanol (10 ml). Dimethyl~mine (8 M in H20, 1.77 ml, 14.2 mmol) was added as a solution in methanol (5 ml), and the resulting mixture was stirred at 25 ambient temperature for about two hours. The progress of the reaction was monitored by thin layer chromatography. The methanol was removed by evaporation. The residue was partitioned between 1 M
potassium carbonate and diethyl ether. The aqueous fraction was back - extracted with diethyl ether. The organic fractions were combined, 30 washed with brine (7 X) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was used without further purification. Yield: 0.987 g Preparation of 2-(2-fluoro-5-bromobenzyloxy)-(N-methyl)ethyl~mine F
~~0~ CH3 Br In a 50 ml flask, under a nitrogen atmosphere, 2-(2-fluoro-5-bromobenzyloxy)-(N,N-dimethyl)ethylamine (317 mg, 1.15 mmol) was 10 dissolved in dichloroethane (3.5 ml). This solution was cooled to 0~C and ACE ~ Cl (0.50 ml, 4.59 mmol) was added. The resulting mixture was warmed to ambient temperature, then heated to reflux and maintained at this temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. Methanol was added to 15 the reaction mixture and the resulting ~ e was stirred at ambient temperature for about three days. The ,..ix~.., e was then heated to reflux for thirty minutes. The solvents were removed in vacuo. The residue was taken up in methanol, heated to reflux for thirty minutes, and the solvents were then removed in vacuo. The title intermediate 20 was used without further purification. Yield: 210 mg Preparation of N-methyl-2-fluoro-5-bromobenzyl amine F
N,CH3 Br In a 25 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzylbromide (765 mg, 2.82 mmol) was dissolved in methanol (10 ml). Methylamine (0.99 ml, 14.1 mmol) was added and the mixture was stirred at ambient temperature for about three hours. The progress of 5 the reaction was monitored by thin layer chromatography. The solvents were removed by evaporation. The residue was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in lo vacuo. The title intermediate was further purified by liquid chromatography. Yield: 0.435 g NMR was consistent with the proposed title structure.
Preparation of N-methyl-3-[2-fluoro-5-bromobenzyloxy]l l c~ylamine F
--O/\~\N
Br In a 15 ml flask, under a nitrogen atmosphere, N,N-dimethyl-3-[2-fluoro-5-bromobenzyloxy]l ropyl~mine (351 mg, 1.21 mmol) 2 0 was dissolved in dichloroethane (3.5 ml). To this solution ACE ~ Cl (0.78 ml, 7.26 mmol) was added and the resulting mixture was heated to reflux and maintained at this tempe~a~ule for 18 hours. The reaction mi~lule was cooled to ambient tempeld~u~e, and the solvents were removed in vacuo. The residue was taken up in methanol and refluxed 2 5 for 1.5 hours. The methanol solution was then partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in - vacuo. The title intermediate was further purified by liquid 3 o chromatography. NMR was consistent with the proposed title structure.
Preparation Preparation of N,N-dimethyl-4-[2-fluoro-5-bromobenzyloxy]butylamine ~\ ~N~
~ J
Br In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl bromide (967 mg, 3.61 mmol) was dissolved in N,N-dimethylform~mide (3.5 ml). To this solution sodium hydride (60%, 246 mg, 6.14 mmol) was added and the resulting mixture was stirred for ten minutes. To the reaction ~e 4-(N,N-dimethylamino)butanol (633 mg, 5.41 mmol) was added and the rsulting mixture was stirred for six hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography. Yield 260 mg (24%) NMR was consistent with the proposed title structure.
Preparation Preparation of N-methyl-4-[2-fluoro-5-bromobenzyloxy]butyl~nine 2 s N~CH3 Br In a 10 ml flask, under a nitrogen atmosphere, N,N-dimethyl-4-[2-fluoro-5-bromobenzyloxy]butyl~nine (215 mg, 0.707 mmol) was dissolved in dichloroethane (2.0 ml). To this solution ACE ~ Cl (0.305 ml, 2.83 mmol) was added and the resulting mixture was heated to reflux. The reaction ~ ure was refluxed for four hours. The prgress of the reaciton was monitored by thin layer chromatography.
The mixture was refluxed for an additional 16 hours. The solvents were removed in vacuo and the residue was taken up in met~nol The methanol solution was refluxed for 1.5 hours and the solvents were removed by evaporation. The residue was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodillm sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography. Yield 108 mg. NMR was consistent with the proposed title structure.
Preparation Preparation of 5-[2-fluoro-5-bromobenzyloxy]pentyl chloride ~\~~ Cl Br In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl alcohol (2.139 g, 10.4 mmol) was dissolved in N,N-dimethylformamide (25 ml). To this solution sodium hydride (60~o, 625 mg, 15.6 mmol) was added and the resulting mixture was stirred for twenty minutes. To the reaction mixture 5-chloropentyl bromide was 3 0 added and the resulting mixture was stirred for two hours at ambient temperature. The progress of the reaction was monitored by thin layer chromatography. Sodium iodide (3.127 g, 20.9 mmol) was added and the resulting mixture was stirred at ambient temperature for three hours.
The reaction mixture was diluted with diethyl ether and washed seven times with brine. The solvents were removed in vacuo. The title 5 intermediate was further purified by silica gel. Yield 1.82 g (56%) NMR
was consistent with the proposed title structure.
Preparation 10 Preparation of N,N-dimethyl-5-[2-fluoro-5-bromobenzyloxy]pentylamine F
--'0~ IN
Br In a sealable tube, under a nitrogen atmosphere, 5-[2-fluoro-5-bromobenzyloxy]pentyl chloride (0.380 g, 1.23 mmol) was dissolved in N,N-dimethylformamide (5 1). To this solution sodium iodide (55 mg, 0.368 mmol) was added and the resulting ~ ure was cooled to -78~C. To the reaction mixture dimethylamine (precon(len~ed in anhydrous conditions) was added and the tube was sealed. The 20 mixture was warmed to 85 ~C and stirred for eight hours. The mixture was cooled to ambient temperature and stirred for another twelve hours.
The mixture was bubbled with nitrogen gas for fifteen minutes to remove excess dimethyl~mine. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous 25 fraction was back-extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, and the solvents were removed in vacuo. The title intermediate was further purified by silica gel.
Preparation W O 97/09308 PCT~US96/14163 Preparation of N-methyl-5-[2-fluoro-5-bromobenzyloxy]pentyl~mine F
~~0~NH
Br In a 25 ml flask, under a nitrogen atmosphere, N,N-dimethyl-5-[2-fluoro-5-bromobenzyloxy]pentylamine (696 mg, 1.87 mmol) was dissolved in dichloroethane (6.0 ml). To this solution ACE ~ Cl (0.305 ml, 2.83 mmol) was added and the resulting mixture was heated to reflux. The reaction mixture was refluxed for twenty hours. The progress of the reaction was monitored by thin layer chromatography.
The mixture was refluxed for an additional 16 hours. The solvents were removed in vacuo and the residue was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were c-)mhined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography. Yield 248 mg. NMR was consistent with the proposed title structure.
Analysis for C13H1gBrFNO:
Theory: C, 61.33; H, 6.30; N, 4.60.
Found: C, 51.06; H, 6.12; N, 4.49.
Preparation Preparation of 1-[2-fluoro-6-bromobenzyloxy]hexane W O 97/09308 PCT~US96/14163 --'O~CH3 Br In a 100 ml flask, under a nitrogen atmosphere, n-hexanol (1.44 ml, 11.5 mmol) was dissolved in N,N-dimethylformamide (35 ml).
5 To this solution sodium hydride (60%, 521 mg, 13.0 mmol) was added and the resulting ~ lule was stirred for ten minutes. To the reaction mixture 2-fluoro-5-bromobenzyl bromide (2.054, 7.67 mmol) was added and the resulting mixture was stirred at ambient temperature for six hours. The progress of the reaction was monitored by thin layer lo chromatography. The reaction mixture was partitioned between 1 M
potassium carbonate/brine (1/1) and diethyl ether. The organic fraction was washed with brine six times. The organic fraction was dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography. Yield 1.32 15 g. NMR was consistent with the proposed title structure.
Preparation Preparation of 1-(t-butoxycarbonyl)-3-[2-(2-fluoro-5-2 o bromobenzyloxy)ethyl]piperidine ~0~
BoC
Br In a 25 ml round bottom flask, 2-[1-(t-25 butoxycarbonyl)piperidin-3-yl]ethyl bromide (1.011 g, 3.46 mmol) was dissolved in N,N-dimethylformamide (9 ml). Sodium iodide (1.037 g, 6.92 WO 9~/09308 PCTAJS96/141~3 mmol) was added and the resulting mixture was stirred at ambient temperature for ten minutes. The 2-fluoro-5-bromobenzyl alcohol (0.852 g, 4.15 mmol) and sodium hydride (60%, 208 mg, 5.19 mmol) were then added and the resulting mixture began to froth and exotherm. After 5 thi ty minutes, the solution cooled and solidified. Three milliliters of N,N-dimethylformamide was added and the mass was slurried and stirred for three more hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between brine and diethyl ether. The organic fraction was 10 washed six times with brine, and then dried over sodium sulfate. The desired title product was further purified by liquid chromatography.
Yield: 0.540 grams. NMR was consistent with proposed title structure.
Preparation Preparation of 3-[2-(2-fluoro-5-bromobenzyloxy)ethyl]piperidine ~~~
N
Br 2 0 In a 1- ml round bottom flask 1-(t-butoxycarbonyl)-3-[2-(2-fluoro-5-bromobenzyloxy)ethyl]piperidine (0.495 g) was dissolved in methylene chloride (4 ml) under a nitrogen atmosphere. The solution was cooled to 0~C and trifluoroacetic acid (1 ml) was slowly added dlo~vise. The resulting mixture was stirred for thirty minutes at 2 5 ambient temperature. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents 3 0 were removed in vacuo. The resulting residue was used as is. Yield:
240 mg. NMR was consistent with the proposed title structure.
W O 97/09308 PCT~US96/14163 Preparation Preparation of 1-hydroxymethyl-2-[2-(2-fluoro-5-5 bromobenyloxy)methyl]cyclopropane ~/\ ~.,,,,,I~OH
Br In a 100 ml round bottom flask, 1,2-di(hydroxymethyl)cyclopropane (398 mg, 3.90 mmol) was dissolved in N,N-dimethylformamide (15 ml). Sodium hydride (60%, 171 mg, 4.29 mmol) was added and the resulting mixture was stirred at 0~C for fifteen minutes and then at ambient tempelalu,e for fifteen minutes.
The reaction solution was cooled to 0~C and 2-fluoro-5-bromobenzyl 15 bromide (348 mg, 1.30 mmol) was then added as a solution in N,N-dimetL~l~olmamide. The resulting reaction was stirred at 0~C for 1.5 hours and at ambient temperature for thirty minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction ll~i~lu~e was partitioned between brine and diethyl ether. The organic 20 fraction was washed seven times with brine, and then dried over sodium sulfate. The desired title product was further purified by liquid chromatography. Yield: 0.240 grams (21%). NMR was consistent with proposed title structure.
2 5 Preparation Preparation of 1-bromomethyl-2-[2-(2-fluoro-5-bromobenzyloxy)methyl]cyclopropane F
~3~' ~~ ~Br Br In a 50 ml flask 1-hy~)~ylllethyl-2-[2-(2-fluoro-5-bromobenzyloxy)methyl]cyclopropane (420 mg, 1.45 mmol) was dissolved 5 in diethyl ether (10 ml) under a nitrogen atmosphere. The reaction mixture was treated with triphenylphosphine (495 mg, 1.89 mmol) and carbon tetrabromide (626 mg, 1.89 mmol) stirred at ~mbient temperature for 17 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was treated wtih another 0.19 10 grams of triphenylphosphine and 0.241 grams of carbon tetrabromide.
After four additional hours of stirring at ambient tempela~ul e, the solvents were removed in vacuo. The title intermediate was further purified from the residue by liquid chromatography. Yield: 0.389 grams (76~o) as a clear oil.
Preparation Preparation of 1-[(N-methylamino)methyl]-2-[2-(2-fluoro-5-bromobenzyloxy)methyl]cyclopropane F
~~ ~~<~ ..,,,,~1~ N~ CH
Br In a 100 ml flask 1-bromomethyl-2-[2-(2-fluoro-5-bromobenzyloxy)methyl]cyclopropane (344 mg, 0.977 mmol) was 25 dissolved in dry tetrahydrofuran (5 ml) under a nitrogen atmosphere.
- The reaction mixture was treated with methylamine (2M in W 0 97/09308 PCTAUS96/141~3 tetrahydlorul~n, 1.9 ml, 3.91 mmol). The resulting mixture was stirred at ambient temperature for one hour and then additional methyl~mine (2 ml) was added. The resulting mixture was heated to reflux and maintained at this temperature for four hours. The progress of the 5 reaction was monitored by thin layer chromatography. The reaction mixture partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and then dried over sodium sulfate. The solvents were removed in vacuo. The title 10 intermediate was further purified by liquid chromatography. Yield:
0.131 grams (44%) as a light yellow oil. NMR was consistent with the proposed title structure.
Preparation Preparation of cis 4-(2-fluoro-5-bromobenzyloxy)but-2-en-1-ol OH
~0 Br In a 500 ml flask, 1,4-dihydlo2~ybut-2-ene (6.13 ml, 74.5 mmol) was dissolved in N,N-dimethylformamide (160 ml) under a nitrogen atmosphere. Sodium hydride (60~o, 2.98 g, 74.5 mmol) was added and the resulting mixture was stirred at ambient temperature for thirty minutes. The reaction mixture was cooled to 0~C and 2-fluoro-5-bromobenzyl bromide (3.99 g, 14.9 mmol) was added dropwise. The resulting mixture was warmed to ambient temperature and stirred for four hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were WO 97/09308 PCTAUS96/141~3 combined and dried over sodium sulfate. The desired title intermediate was further purified by liquid chromatography. Yield: 2.145 gr~ms (61%) as a clear oil. NMR and MS were consistent with the proposed title structure.
Preparation Preparation of cis 4-(2-fluoro-5-bromobenzyloxy)but-2-enyl bromide F Br ~3~o lo Br In a 100 ml round bottom flask 4-(2-fluoro-5-bromobenzyloxy)but-2-en-1-ol (2.145 g, 7.80 mmol) was dissolved in diethyl ether under a nitrogen atmosphere. Triphenylphosphine (2.66 g, 10.1 mmol) and then carbon tetrabromide (3.36 g, 10.1 mmol) were added to the reaction mixture. The resulting ~ e was stirred for six hours at ambient temperature. A white precipitate formed during the stirring. The progress of the reaction was monitored by thin layer chromatography. The solution was filtered and the filtrate was evaporated to give a thick oil. The desired title intermediate was further purified by liquid chromatography. Yield: 2.16 g (83%). NMR and MS
were consistent with the proposed title structure.
Preparation Preparation of cis N-methyl-4-(2-fluoro-5-bromobenzyloxy)but-2-enylamine -W O 97/09308 PCT~US96/141~3 NH
~0~~
Br In a 250 ml flask 4-(2-fluoro-5-bromobenzyloxy)but-2-enyl bromide (1.968 g, 5.89 mmol) was dissolved in dry tetrahydrofuran (40 5 ml). To this solution methylamine (29.6 ml, 58.9 mmol) was added in one portion and the resulting mixture was stirred at ambient temperature for five hours. The progress of the reaciton was monitored by thin layer chromatography. The solvents were removed in vacuo and the residue was taken up in 1 M potassium carbonate and extracted 10 thrice with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo.
The desired title intermediate was further purified by liquid chromatography. Yield: 1.199 grams (70%). NMR and MS were consistent with the proposed title structure.
Preparation Preparation of N-(t-butoxycarbonyl)-4-(2-fluoro-5-bromobenzyloxy)butylAmine ~o~ BoC
Br In a 25 ml flask 4-(t-butoxycarbonylamino)butanol was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. The W O 97/09308 PCTrUS96/14163 solution was cooled to -40~C and potassium tert-butoxide (lM in tetrahydrofuran, 2.14 ml, 2.14 mmol) was added slowly. The resulting mixture was stirred at -40~C for thirty minutes. To this reaction ufe was added 2-fluoro-5-bromobenzyl bromide (521 mg, 1.94 mmol), 5 added dropwise as a solution in tetrahydrofuran (3.5 ml). The resulting mixture was slowly warmed to 0~C and stirred at this temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction ~i~ e was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was 10 back-extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired intermediate was further purified by liquid chromatography. Yield: 335 mg (46%) as a yellow oil.
Analysis for Cl6H23BrFNO3:
Theory: C, 51.07; H, 6.16; N, 3.72.
Found: C, 51.18; H, 6.18; N, 3.80.
Preparation 20 Preparation of 4-(2-fluoro-5-bromobenylozy)butylamine ~ \o/~ , 2 In a 250 ml flask, N-(t-butoxycarbonyl)-4-(2-fluoro-5-25 bromobenzyloxy)butylamine (3.5 grams) was dissolved in methylene chloride (60 ml) under a nitrogen atmosphere. Trifluoroacetic acid (15 ml) was added to the solution at 0~C. The resulting mixture was stirred at 0~C for thirty minutes and then at ambient temperature for 15 minutes. The progress of the reaction was monitored by thin layer - 30 chromatography. The reaction mixture was partitioned between 1 M
- potassium carbonate and methylene chloride. The aqueous fraction was W O 97/09308 PCT~US96/14163 back-extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired intermediate was further purified by liquid chromatography. Yield: 1.82 g. NMR was consistent with the proposed title structure.
Preparation Preparation of 4-methyl-lH-indole-2-carboxylic acid Under an argon atmosphere 4-methylindole (0.91 g, 6.96 mmol) was dissolved in 12 ml of tetrahydrofuran. The resulting solution was cooled in a dry ice/acetone bath. To this solution n-butyllithium (1.6 M in hexanes, 4.48 ml, 7.17 mmol) was carefully added and the resulting mixture was stirred for fifty minutes. Carbon dioxide was bubbled through 26 ml of tetrahydrofuran on a dry ice/acetone bath for twenty minutes. The cold carbon dioxide/tetrahydrofuran solution was c~nn~ qted into the organolithium solution. Carbon dioxide was bubbled through the reaction mixture, and the resulting mixture was 2 0 stirred for thirty minutes over the dry ice/acetone bath. The reaction mi~ e was then stirred at room temperature for ten minutes with continued carbon dioxide bubbling. The carbon dioxide was shut off and the reaction mi~ e was stirred at room temperature for ninety minutes.
2 5 The solvents were removed in vacuo, argon was added to the reaction vessel, which was then rinsed with 5 ml of tetrahydrofuran.
The solvents were removed in vacuo. The brown solid was stored overnight at 4~C under an argon atmosphere.
The residue was then dissolved in 12 ml warm 3 0 tetrahydrofuran and the resulting solution was cooled in a dry ice/acetone bath. To this solution t-butyllithium (1.7 M in pentane, 4.22 ml, 7.17 mmol) was carefully added over fifteen minutes. The resulting mixture was allowed to stir over the dry ice/acetone bath for about seventy minutes. In a separate vessel carbon dioxide was bubbled 3 5 through 26 ml of tetrahydrofuran cooled over a dry ice/acetone bath. Thecarbon dioxide/tetrahydrofuran solution was added to the organolithium solution via c~qnnula. The carbon dioxide was bubbled directly into the reaction _ixture for an additional five minutes. The reaction mixture was stirred over dry ice/acetone for one hour and then carbon dioxide was bubbled through the reaction mixture for one half hour. One 5 milliliter of water was added to the reaction ~ e and the reaction mixture was allowed to stir at room temperature for several hours.
The reaction mi~t.lre was poured into a saturated ammonium chloride solution and extracted twice with diethyl ether.
The organic fractions were combined and the solvents were removed in 10 vacuo and recrystallized from water to obtain 0.17 grams of the desired intermediate. The aqueous fraction was acidified by adding 5% sulfuric acid and stirred for one hour at room temperature. The solids were removed by filtration to yield an additional 0.48 grams of the desired title intermediate.
15 NMR was consistent with the proposed title structure.
Preparation Preparation of methyl 4-methyl-lH-indole-2-carboxylate Under an argon atmosphere 4-methyl-lH-indole-2-carboxylic acid (0.64 g, 3.65 mmol) was dissolved in 20 ml of methanol.
Concentrated sulfuric acid (0.5 ml) was added and the resulting l~ e was heated to reflux and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
Some solvent was removed in vacuo and the resulting crystals were removed by filtration. The solids were taken up in diethyl ether, washed twice with saturated sodium bicarbonate, and then once with brine. The organic fraction was dried over magnesium sulfate and the solvents were removed in vacuo. Yield: 0.38 grams (55.1 %) Preparation Preparation of 2-[4-chlorophenoxymethyl]-3-(2-bromoacetyl)-lH-indole Under a nitrogen atmosphere bromoacetylbromide (1.31 ml, 0.015 mol) was added to a slurry of 2-[4-chlorophenoxymethyl]-lH-indole (0.81 g, 0.003 mol), and lithium carbonate (2.22 g, 0.03 mol) in diethyl ether (37.5 ml). The resulting mixture was heated to 55~C. The progress 5 of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between diethyl ether and a sodium bicarbonate solution. The organic fraction was washed with water and then brine, and then dried over sodium sulfate. The solvents were removed in vacuo. Yield: 1.34 g. NMR was consistent with the 10 proposed title structure.
Preparation Preparation of 2-[4-chloropheno~ymethyl]-3-[2-[4-(piperidin-1-15 yl)piperidin-1-yl]acetyl]-lH-indole To a slurry of 2-[4-chlorophenoxymethyl]-3-(2-bromoacetyl)-lH-indole (3 mmol) and lithium carbonate (0.47 g, 6 mmol) in tetrahy~ofu.dn (10 ml) 4-(piperidin-1-yl)piperidine (1.01 g, 6 mmol) was 20 added. The resulting mixture was stirred at room temperature for about 2.5 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was extracted thrice with 1 N hydrochloric acid. The combined acidic extracts were extracted with ethyl acetate, then basified with sodium carbonate, and then extracted 25 twice with ethyl acetate, and then twice with methylene chloride. The organic fractions were comhined and the solvents were removed in vacuo. After ~,;I ~ating with diethyl ether 0.46 grams of the desired product as crystalline material were obtained.
NMR, IR, and W were consistent with the proposed title structure.
3 o Exact Mass FAB for C28H3sclN3o2:
Theory: 480.2418 Found: 480.2411 FDMS 479 (M+) mp 144-145~C
W O 97/09308 PCT~US96/14163 - The following ~ mples were prepared essentially as described in the Schemes and Methods, supra. In the following mples, unless otherwise noted, NMR was consistent with the proposed title ~ e.
Exam~le 1 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-(amino)methyl-lH-indole C~ ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 300 (M+).
Analysis for Cl7Hl7ClN20:
Theory: C, 67.88; H,5.70; N, 9.3L
Found: C,67.64; H, 5.86; N, 9.24.
mnle 2 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(N,N-dimethylamino)methyl]-lH-indole N(CH3)2 ~ ~Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 328 (M+) Analysis for ClsH2lclN2o:
Theory: C, 69.40; H, 6.44; N,8.52.
Found: C,69.18; H, 6.73; N,8.54.
- . -W O 97/09308 PCT~US96/14163 Example 3 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(N,N-5 diethylamino)methyl]-lH-indole hydrochloride N(CH2CH3)2 H
NMR (DMS0) was consistent with the proposed title structure.
lo FDMS 366 (M+).
Analysis for C2lH2sClN2O2 ~ HCl:
Theory: C, 64.12; H, 6.66; N, 7.12.
Found: C, 64.30; H, 6.69; N, 7.18.
~mr~le 4 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(N,N,N-trimethyl~mmonium)methyl]-lH-indole iodide H3C ~ I CH3 ~ I-~~'13~
CH3 Cl NMR (DMS0) was consistent with the proposed title structure.
FDMS 343 (M+) Analysis for C2oH24clN2o ~ I:
Theory: C, 51.03; H, 5.14; N, 5.95.
Found: C, 50.80; H, 4.93; N, 6.00.
~mple 5 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-5 [(benzylamino)methyl]-lH-indole hydrochloride ~-3 HN ~HCl ~~"13~
CH3 Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 390 (M+).
Analysis for C24H23ClN2O ~ HCl:
Theory: C, 67.45; H, 5.66; N, 6.56.
Found: C, 67.63; H, 5.70; N, 6.60.
F,~mple 6 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(2-phenylethylamino)methyl]-lH-indole hydrochloride H ~HCl 0~
CH~ Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 404 (M+).
Analysis for C2sH2sClN2O ~ HCl:
Theory: C, 68.03; H, 5.94; N, 6.35.
Found: C, 68.27; H, 5.99; N, 6.60.
~?mDle 7 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(N-methyl-N-lo butylamino)methyl]-lH-indole ~--CH3 ~~ ~l3 C1 NMR (CDCl3) was consistent with the proposed title structure.
15 IR was consistent with the desired title structure.
FDMS 370 (M+).
Analysis for C22H27clN2o:
Theory: C, 71.24; H, 7.34; N, 7.55.
Found: C, 71.19; H, 7.48; N, 7.39.
~mple 8 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(N-methyl-N-benzylamino)methyl]-lH-indole hydrochloride N
~,, C~.
CH3 Cl NMR, IR and W were consistent with the desired title structure.
FDMS 404 (M+).
Analysis for C2sH2sClN2O ~ HCl:
Theory: C, 68.03; H, 5.94; N, 6.35.
Found: C, 68.30; H,5.92; N, 6.45.
F~mI)le 9 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[N-methyl-N-(3-N',N'-dimethylaminopropyl)amino]methyl]-lH-indole N(CH3)2 N
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 400 (M+l).
Analysis for C23H30ClN3O:
Theory: C, 69.07; H, 7.66; N, 10.51.
Found: C, 69.33; H, 7.34; N, 10.41.
~Pmple 10 -Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[N-methyl-N-[3-25 (N',N'-dimethylamino)-2,2-dimethylpropyl]amino]methyl]- lH-indole W O 97/09308 PCT~US96/14163 H X N(CH3)2 CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 414 (M+1) Analysis for C24H32ClN3O:
Theory: C, 69.93; H, 7.79; N, 10.15.
Found: C, 69.67; H, 7.78; N, 10.17.
~,x~m~le 11 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(pyrrolidin-1-yl)methyl]-lH-indole hydrochloride '3' CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 354 (M+).
Analysis for C2lH23ClN2O ~ HCl:
Theory: C, 64.45; H, 6.18; N, 7.16.
Found: C, 64.66; H, 6.33; N, 7.03.
m~le 12 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride W O 97/09308 PCT~US96/14163 /~
HCl N ~ O ~
CH3 ~ Cl NMR, IR and W were consistent with the desired title structure.
5 FDMS 368 (M+).
Analysis for C22H2sClN2O ~ HCl:
Theory: C, 65.19; H, 6.46; N, 6.91.
Found: C, 65.46; H, 6.52; N, 7.16.
~.x~mnle 13 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(3-methylpiperidin-1-yl)methyl]-lH-indole N ~
~-~'13~
CH3 Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 382 (M+).
Analysis for C23H27clN2o:
Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 72.38; H, 7.22; N, 7.36.
.
~x~qm}~le 14 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(4-methylpiperidin- 1 -yl )methyl] - lH-indole ~=~3~
CH3 Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 382 (M+).
Analysis for C23H27clN2o:
Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 72.33; H, 7.22; N, 7.47.
~.x~mnle 15 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[4-(N,N-dimethylamino)piperidin-1-yl]methyl]-lH-indole Q~)~ ( CH3 ) 2 CH3 Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 411 (M+).
Analysis for C24H30ClN3O:
Theory: C, 69.97; H, 7.34; N, 10.20.
Found: C, 69.74; H, 7.38; N, 10.13.
F~xarr~le 16 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[4-(piperidin- 1-25 yl)piperidin-1-yl]methyl]-lH-indole rN3N~
~"'~~~
FDMS 4~1 (M+).
Analysis for C27H34ClN30:
Theory: C, 71.74; H, 7.58; N, 9.30.
Found: C, 71.55; H, 7.44; N, 9.14.
F.~ml?le 17 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-~(4-acetamido-4-phenylpiperidin- l-yl)methyl]-lH-indole o~CH3 ~J, CH3 Cl 15 FDMS ~01 (M+).
Analysis for C30H32clN3o2:
Theory: C, 71.77; H, 6.43; N, 8.37.
Found: C, 71.79; H, 6.61; N, 8.52.
2 0 F.x~ml~le 18 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(4-methylpiperazin- 1 -yl )methyl] - lH -indol e CA 022039l2 1997-04-28 W O 97/09308 PCT~US96/14163 ~ ~' ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 383 (M+).
Analysis for C22H26ClN3O:
Theory: C, 68.83; H, 6.83; N, 10.95.
Found: C, 68.80; H, 6.71; N, 10.95.
~?.mI)le 19 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(4-isopl ol~yl~i~erazin- l-yl)methyl]- lH-indole ~ CH3 r~ N N ~
~ ~ 'H3 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 411 (M+).
Analysis for C24H30ClN3O:
Theory: C, 69.97; H, 7.34; N, 10.20.
Found: C, 69.97; H, 7.36; N, 10.02.
m~le 20 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(4-phenylpiperazin-l-yl)methyl]-lH-indole W 0 97/09308 PCTrUS96/14163 N N~
~~
NMR was consistent with the desired title structure.
FDMS 445 (M+).
Analysis for C27H2gClN3O:
Theory: C, 72.71; H,6.33; N, 9.42.
Found: C,73.00; H, 6.41; N, 9.51.
F.x~ ?le 21 Preparation of 2-[(4~chlorophenoxy)methyl]-1-methyl-3-[(4-benzylpiperazin-1-yl)methyl]-lH-indole hydrochloride N N
~/ \J
=~' NMR (DMSO) was consistent with the proposed title structure.
FDMS 459 (M+).
Exact Mass (FAB+) for C2gH3lClN3O:
Theory: 460.2155.
Found: 460.2145.
F,x~qrnple 22 .
~ Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(4-25 cyclohexylpiperazin- 1 -yl )methyl]- lH-indole CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/1416 - /~ rN N{~
~''~'13~
CH3 Cl NMR (DMSO) was consistent with the proposed title structure.
5 FDMS 451 (M+).
Analysis for C27H34ClN3O:
Theory: C, 71.74; H, 7.58; N, 9.30.
Found: C, 71.48; H, 7.53; N, 9.26.
lo ~ 9m~le 23 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[4-(~ylillnd-2-yl)piperazin-l-yl)methyl]-lH-indole CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 447 (M+).
Analysis for C2sH26ClNsO:
Theory: C, 67.03; H, 5.85; N, 15.63.
Found: C, 67.05; H, 5.93; N, 15.64.
mrle 24 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-(morpholin-4-yl)methyl]-lH-indole WO 97/09308 PCT~US96/141~3 --N O
~~
NMR was consistent with the desired title structure.
FDMS 370 (M+).
Analysis for C2lH23clN2o2:
Theory: C, 68.01; H, 6.25; N, 7.55.
Found: C, 67.84; H, 6.65; N, 7.25.
h'x~mple 25 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-(tryptolin-2-yl)methyl]-lH-indole N
C~l~ ~ C 1 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 455 (M+).
Analysis for C2gH26ClN3O:
Theory: C, 73.75; H, 5.75; N, 9.21.
Found: C, 73.99; H, 6.00; N, 9.03.
m~le 26 Preparation of 2-[(2,4-dichlorophenoxy)methyl]- 1-methyl-3-[N-( l-methylpiperidin-4-yl )-N-methylamino]methyl]- lH-indole dihydrochloride monohydrate W 0 97/09308 PCT~US96/14163 CH3 ~2 N ~ N-CH3 ~" 0~ ~ H2 ~
CH3 Cl Cl NMR was consistent with the desired title structure.
5 mp 196-197~C.
FDMS 446 (M+).
Analysis for C24H2gCl2N3O ~ 2HCl ~ H2O:
Theory: C, 53.64; H, 6.19; N, 7.82.
Found: C, 53.66; H, 5.92; N, 8.10.
F~Ample 27 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[[4-(N,N-dimethyl~mino)piperidin-1-yl]methyl]-lH-indole r~
r N ~ N(CH3)2 ~~3~
CH3 Cl Cl NMR, IR, and W were consistent with the desired title structure.
mp 105-106~C.
FDMS 445 (M+).
Analysis for C24H2gCl2N30:
Theory: C, 64.57; H, 6.55; N, 9.41.
Found: C, 64.27; H, 6.48; N, 9.49.
2 5 F.~m~le 28 Preparation of 2-[(2,4-dichlorophenoxy)methyl]- 1-methyl-3-[[4-(piperidin-1-yl)piperidin-1-yl]methyl]-lH-indole N ~ N ~
~ r ~~~3~
CH3 Cl Cl NMR, IR, and W were consistent with the desired title structure.
FDMS 485(M+).
mp 106-107~C
Analysis for C27H33Cl2N3O:
Theory: C, 66.66; H, 6.84; N, 8.64.
Found: C, 66.92; H, 7.04; N, 8.74.
F.x~mrle 29 15 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-(2-aminoethyl)-lH-indole ,~
N~--~'13~
CH3 Cl 20 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 314 (M+).
Exact Mass (FAB) for Cl8H20clN2o:
Theory: 315.1264.
Found: 315.1246.
mple 30 W O 97/09308 PCTAUS96/141~3 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[(3-dimethylAminopropyl)amino]ethyl]-lH-indole N (CH3) 2 N--~0~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 399 (M+).
Analysis for C23H30ClN3O:
Theory: C, 69.07; H, 7.56; N, 10.51.
lo Found: C, 69.23; H, 7.79; N, 10.52.
F.~Amrle 31 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-N-15 (3-dimethylaminopropyl)Amino]ethyl]-lH-indole dihydrochloride N(CH2) 3 H3C~
N
/~ /--/ ~2 HCl ~3 _ 0~3~
NMR (DMSO) was consistent with the proposed title structure.
FDMS 413 (M+).
Exact Mass (FAB) for C24H33ClN30:
Theory: 414.2312.
Found: 414.2312.
W 0 97/09308 PCT~US96/141~3 F.~mple 32 -Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(piperidin- 1-yl)ethyl]-lH-indole <~
N
~0~
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 382 (M+).
10 Analysis for C23H27ClN20:
Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 72.40; H, 7.26; N, 7.37.
F.~mr~le 33 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-methylpiperidin- l-yl )ethyl]- lH-indole ~S
NJ
'' ~0~3~
CH, C 1 ~ NMR (CDCl3) was consistent with the proposed title structure. FDMS 396 (M+).
Analysis for C24H2gClN20:
Theory: C, 72.62; H, 7.36; N, 7.06.
Found: C, 72.40; H, 7.35; N, 7.25.
F,x~rn~le 34 Prcparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-benzylpiperidin-1-yl)ethyl]-lH-indole ~~~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 472 (M~).
Analysis for C30H33ClN2O:
Theory: C, 76.17; H, 7.03; N, 5.92.
Found: C, 76.37; H, 7.15; N, 5.85.
nple 35 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[4-(N,N-dimethylamino)piperidin- 1-yl]ethyl]-lH-indole N(CH3) 2 N
~ r~ ~ Cl ~ NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass (FAB) for C2sH33ClN3O:
~ Theory: 426.2312.
Found: 426.2297.
F,~qm~le 36 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]ethyl]-lH-indole C~
~o CH3 ~ Cl FDMS 465 (M+) Analysis for C2gH36ClN3O:
Theory: C, 72.16; H, 7.79; N, 9.02.
Found: C, 72.09; H, 7.69; N, 9.09.
F,~mple 37 20 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-cyclohexylpiperazin- 1-yl )ethyl]- lH-indole WO 97/09308 PCT~US96/141~3 N ~
I~ ~ Cl NMR (CDC13) was consistent with the proposed title structure.
FDMS 465 (M+).~ Analysis for C2gH36ClN3O:
Theory: C, 72.16; H,7.79; N, 9.02.
Found: C, 72.00; H, 7.88; N, 9.05.
Fx~ le 38 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-N-( l-methylpiperidin-4-yl)]ethyl]- lH-indole H3C~
~2 ~lu~ ~Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 459 (M+).
Analysis for C2sH3lCl2N3O: ~
Theory: C, 65.21; H, 6.79; N, 9.13.
Found: C, 65.07; H, 6.85; N, 9.06.
-W O 97/09308 PCT~US96/14163 F~m~le 39 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[4-(N,N-5 dimethylamino)piperidin-1-yl]ethyl]-lH-indole N(CH3)2 ~' CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
lo Exact Mass for C25H32Cl2N3~:
Theory: 460.1922.
Found: 460.1890.
F.~mple 40 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]ethyl]-lH-indole N- ' (~ OC1 NMR (CDCl3) was consistent with the proposed title structure.
W O 97/09308 PCTrUS96/14163 Exact Mass for C2gH36Cl2N3O:
Theory: 500.2235.
Found: 500.2215.
~x~mple 41 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[3-[4-(N,N-dimethyl ~ mi no)piperidin- 1 -yl~propyl] - lH-indole r N ~ N(CH3)2 r ~o CH3 ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FABMS 440 (M+1) 15 Analysis for C26H34ClN3O:
Theory: C, 70.97; H, 7.79; N, 9.55.
Found: C, 70.73; H, 7.65; N, 9.44.
~mple 42 Preparation of (RS) 2-[(4-chloropheno~y)methyl]-1-methyl-3-[3-(piperidin-3-yl)~ yl]-lH-indole G ~
CH~ Cl WO 97/09308 PCT~US96/14163 ~ NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass for C24H30clN2o:
Theory: 397.2047.
Found: 397.2055.
F.x~mnle 43 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[[4-(dimethylamino)piperidin-1-yl]carbonyl]ethyl]-lH-indole ~ N 3 N(CH3)2 ~~'13~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 453 (M+) Analysis for C26H32clN3o2:
Theory: C, 68.78; H, 7.10; N, 9.26.
Found: C, 68.74; H, 7.04; N, 9.38.
~,x~m~le 44 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[[4-(dimethyl~qmino)piperidin-1-yl]carbonyl]ethenyl]-lH-indole o ~
~ N ~ N(CH3)2 ~ ~ ~ ~'13~
CH, Cl W O 97t09308 PCT~US96/14163 NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass (FAB) for C26H3lclN3o2:
Theory: 452.2105.
Found: 4~2.2099.
F.~qTnple 46 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[1-hyd, o~y-2-[(3-acetamido)pyrrolidin-1-yl]ethyl]-lH-indole ~, N~ C H 3 J O
H0~7 ~~'13 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 442 (M+).
Exact Mass FAB (M+1) for C24H2gClN303:
Theory: 442.1897.
Found: 442.1878.
F.~m~le 47 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(piperidin-1-yl)ethyl]-lH-indole HoyN
~~'13~
NMR (CDCl3) was consistent with the proposed title structure.
~ FDMS 398 (M+).
~ Analysis for C23H27ClN202:
Theory: C, 69.25; H, 6.82; N, 7.02.
Found: C, 69.51; H, 6.86; N, 6.81.
mple 48 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(4-methylpiperidin- 1-yl )ethyl]- lH-indole ~ ~1 CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 412, (M+).
Analysis for C24H2sclN2o2:
Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 70.02; H, 7.13; N, 7.00.
~mple 49 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(4-benzylpiperidin- 1-yl)ethyl]- lH-indole CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 488 (M+).
Analysis for C30H33clN2o2:
Theory: C, 73.67; H, 6.80; N, 5.73.
Found: C, 73.52; H, 6.87; N, 5.58.
mrle 50 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(4-dimethylaminopiperidin- 1-yl)ethyl]- lH-indole N(CH3) 2 HO
,~
0~3 NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 442 (M+).
Analysis for C2sH32clN3o2:
Theory: C, 67.94; H, 7.30; N, 9.51.
Found: C, 67.73; H, 7.52; N, 9.75.
WO 97/09308 PCT/US96/141~3 mple 51 -Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-[4-(piperidin-1-yl)piperidin-1-yl]ethyl]-lH-indole dihydrochloride N
HO~ ~ 2 HC 1 ~~'13~
CH3 C l NMR (DMSO) was consistent with the proposed title structure.
FDMS 481 (M+1).
10 Analysis for C2gH3sClN3O2 ~ 2 HCl Theory: C, 60.71; H, 6.73; N, 7.59; Cl, 19.20.
Found: C, 60.86; H, 6.90; N, 7.53; Cl, 19.19.
m~le 52 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(4-cyclohexylpiperazin-1-yl)ethyl]- lH-indole ~N
~0,3~
CH-~ Cl W O 97/09308 PCTrUS96/14163 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 482 (M+1).
Analysis for C28H36clN3o2:
Theory: C,69.76; H, 7.53; N, 8.72.
Found: C, 70.06; H, 7.61; N, 8.46.
~x~m~le 53 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-3-(piperidin-4-yl)propyl]-lH-indole NH
N ~ O
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 412 (M+).
Single compound of high purity as evidenced by chromatographic methods.
Analysis for C24H2sclN2o2:
Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 68.18; H, 7.87; N, 6.58.
h~xz~m~le 54 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-rN-methyl-N-(1-methylpiperidin-4-yl)amino]ethyl]- lH-indole CA 022039l2 l997-04-28 H3C~ ~
HO ~ N ~ NCH3 ~1'- ~Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 475 (M+).
5 Analysis for C2sH3lcl2N3o2:
Theory: C, 63.02; H, 6.55; N, 8.82.
Found: C, 63.43; H, 6.88; N, 8.92.
F.x~mple 55 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[1-hydroxy-2-(metho~ycall)onyl)ethyl]-lH-indole HO ~ ~
Q~o,3~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 373 (M+).
Analysis for C2oH2oclNo4:
20Theory: C, 64.26; H, 5.39; N, 3.75.
Found: C, 64.55; H, G.23; N, 3.79.
F,~mr!le 56 CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/14163 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-carboxy-lH-indole ~_ o~3~
CH3 Cl NMR (DMSO) was consistent with the desired title structure.
FDMS 315 (M+).
Analysis for Cl7Hl4ClNO3:
Theory: C, 64.67; H, 4.47; N, 4.44.
Found: C, 64.84; H, 4.60; N, 4.54.
~m~le 57 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[3-15 dimethylamino-2,3-dimethylpropylamino]carbonyl]- lH-indole ,CH3 H3C~ ~ N~
O ~ CH3 ~u ~Cl NMR (CDCl3) was consistent with the proposed title structure.
FAB 426 (M-l).
Analysis for C24H30ClN3O2:
Theory: C, 67.36; H, 7.07; N, 9.82.
Found: C, 67.58; H, 6.79; N, 9.64.
~ mT-le 58 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[N,N-bis(3-dimethylaminopropyl)aminn]carbonyl]- lH-indole .
~ N(CH3)2 0~ r N(CH3)2 CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 483 (M-1).
FABMS 485 (M+1) Analysis for C27H37clN4o2:
Theory: C, 66.86; H, 7.69; N, 11.55.
Found: C, 66.91; H, 7.54; N, 11.69.
nple 59 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[N-methyl-N-(1-methylpiperidin-4-yl)amino]carbonyl]-lH-indole ,CH~
CH~ Cl 20 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 427 (M+2) Analysis for C24H28clN3o2:
Theory: C, 67.67; H, 6.63; N, 9.86.
Found: C, 67.38; H, 6.90; N, 9.94.
WO 97/09308 PCT/US96/141~3 F.x~n~nle 60 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[4-(piperidin-1-5 yl)piperidin- l-yl]carbonyl]- lH-indole ~3 N 3 CH3 ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 465 (M+).
Analysis for C27H32ClN302:
Theory: C,69.59; H,6.92; N, 9.02.
Found: C,69.47; H,7.00; N, 9.22.
~ mDle 61 Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-3-yl)acetyl]-lH-indole ,~. J~.' ~'13 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 396 (M+) Analysis for C23H2sclN2o2:
Theory: C, 69.60; H,6.35; N, 7.06.
Found: C,69.71; H, 6.28; N,7.20.
W O 97/09308 PCT~US96/14163 ~.x~mrle 62 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(1-tritylpiperidin-4-yl)acetyl]-lH-indole ~ NTr O~ J
~0~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 638 (M+) Analysis for C42H3gClN202:
Theory: C, 78.92; H, 6.15; N, 4.38.
Found: C, 78.73; H, 6.15; N, 4.25.
F,x~mnle 63 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-4-yl)acetyl]-lH-indole NH
~Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 397 (M+1) Analysis for C23H2sClN202:
- Theory: C, 69.60; H, 6.35; N, 7.06.
Found: C, 69.34; H, 6.43; N, 6.86.
W 0 97/09308 PCT~US96/14163 F,~m~le 64 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[4-(piperidin-1-5 yl)piperidin-1-yl]acetyl]-lH-indole dihydrochloride ~N
N~ ~'13~
NMR (DMSO) was consistent with the proposed title structure.
FDMS 479 (M+) Analysis for C2gH34ClN3O2 ~ 2HCl:
Theory: C, 60.82; H, 6.56; N, 7.60.
Found: C, 60.67; H, 6.70; N, 7.38.
~ mple 65 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(piperidin-3-yl)ethyl]carbonyl]- lH-indole CH 1 C l NMR (CDCl3) was consistent with the proposed title structure.
FDMS 411 (M+1).
Analysis for C24H27clN2o2:
W O 97/09308 PCT~US96/14163 Theory: C, 70.15; H, 6.67; N, 6.82.
Found: C, 70.38; H, 6.39; N, 7.02.
.
F.~mple 66 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[2-( 1-tritylpiperidin-4-yl)ethyl]carbonyl]- lH-indole NTr C~' ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
C43H41ClN2O2 FDMS 652 (M+).
Single compound of high purity as evidenced by chromatographic means.
F.~mple 67 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(piperidin-4-yl)ethyl]carbonyl]-lH-indole r\
O~_~NH
~ ~~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 411 (M+l) 2 5 Analysis for C24H27clN2o2:
- Theory: C, 70.15; H, 6.62; N, 6.82.
Found: C, 69.87; H, 6.54; N, 6.79.
F,x~mnle 68 5 Preparation of 2-[(4-chlorophenoxy)methyl]-l-methyl-3-[[2-[l-[3-[(l-tritylpiperidin-4-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]-lH-indole ~_~N ~ NTr ~ '~"13~
CH3 Cl FDMS 779 (M+2) Analysis for Cs1Hs6ClN3O:
Theory: C, 78.69; H, 7.25; N, 5.40.
Found: C, 78.90; H, 7.34; N, 5.60.
h'.x~mple 69A
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-[1-[3-(piperidin-4-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]- lH-indole r~ r~
O _~N ~ NH
~~'13~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FAB 536(M+).
Exact mass FAB (M+1) for C32H43ClN3O2:
Theory: ~36.3044.
Found: 536.3044.
WO 97/09308 PCT~US96/14163 ~mple 69B
~ Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-[1-[3-(1-5 tritylpiperidin-3-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]-lH-indole r~ r O~ ~N
~-~'13~
CH~ Cl FDMS 779 (M+2).
0 Analysis for CslHs6clN3o2:
Theory: C, 78.69; H, 7.25; N, 6.40.
Found: C, 78.92; H, 7.41; N, 5.27.
~mple 69C
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-[1-[3-(piperidin-3-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]-lH indole NMR (CDCI3) was consistent with the proposed title structure.
FDMS 536 (M+1).
- Analysis for C32H42ClN302:
- Theory: C, 71.69; H, 7.90; N, 7.84.
Found: C, 71.45; H, 7.85; N, 7.61.
W O 97/09308 PCT~US96/14163 F,~mple 70 Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-lH-indole r~
N
N
NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB (M+) for C35H48ClN4~2:
Theory: 691.3466.
Found: 591.3476.
F.~mple 70A
15 Preparation of (S) 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-[[4-(piperidin- l-yl)piperidin- l-yl]acetyl]- lH-indole / \ ~\
o~M~ N ~
~_0~3~
Cl H
WO 97/09308 PCTrUS96/141~3 - NMR (CDCl3) was consistent with the proposed title structure. FABMS 691.3476 (M+).
~ Analysis for C3sH47ClN4O2:
Theory: C, 71.10; H, 8.01; N, 9.48.
Found: C, 70.82; H, 8.14; N, 9.23.
F.~m~le 70B
Preparation of (R) 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-l o yl)propyl]-3-[[4-(piperidin- l-yl)piperidin- l-yl]acetyl]- lH-indole N
Cl C' N
NMR (CDCl3) was consistent with the proposed title structure.
15 Exact Mass for C35H48ClN402:
Theory: 591.3466.
Found: 591.3458.
~mnle 71 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]-3-[[4-(piperidin- 1 -yl)piperidin- l-yl]acetyl]- lH-indole ~ 3 ~
~ ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass for C3sH48clN4o2:
Theory: 591.3466.
Found: 691.3464.
F.~,qmple 72 Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-[3-(piperidin-3-yl)propanoyl]- lH-indole o~
~ Cl H
15 NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass for C31H41ClN302:
Theory: 522.2887.
Found: 522.2905.
-F,~mrle 73 ~ Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]-3-5 [3-(piperidin-3-yl)propanoyl]-lH-indole r\ ~
\ ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
lo Exact Mass for C3lH41ClN3O2 (M+1):
Theory: 522.2887.
Found: 522.2910.
F,~m~le 74 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-[3-(piperidin-4-yl)propanoyl]-lH-indole CA 022039l2 l997-04-28 W O 97/09308 PCTrUS96/14163 - ~ NH
~ ~--~'13~
NH
IR and NMR (CDCl3) were consistent with the desired title structure.
FABMS 522 (M+1) Analysis for C3lH40ClN302:
Theory: C, 71.31; H, 7.72; N, 8.05.
Found: C, 71.04; H, 7.89; N, 7.78.
h~amrle 75 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-[3-(piperidin-4-yl)l,l ol~yl]-3-[3-(piperidin-4-yl)propanoyl]-lH-indole O ~ NH
~ 0~
~ Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 522 (M+1) Analysis for C31H40ClN3O2:
Theory: C, 71.31; H, 7.72; N, 8.05.
W 097/09308 PCT~US96/14163 Found: C, 71.10; H, 7.66; N, 7.97.
h~x~mple 76 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[[3-(dimethylamino)propylamino]carbonyl]methyl]-lH-indole H N(CH3)2 N
lo NMR (CDCl3) was consistent with the proposed title structure.
FDMS 413 (M+).
Analysis for C23H28ClN3O2:
Theory: C, 66.74; H, 6.82; N, 10.15.
Found: C, 66.89; H, 6.96; N, 10.11.
~mple 77 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[ l-hydroxy- 1-[[4-(piperidin- l-yl)piperidin- 1 -yl]carbonyl]methyl]- lH-indole Q ~ OH
Cl NMR (CDCl3) was consistent with the proposed title structure.
- FDMS 495 (M+).
~ 25 Analysis for C2gH34ClN3O3:
Theory: C, 67.80; H, 6.91; N, 8.47.
Found: C, 67.86; H, 6.90; N, 8.45.
F.~mple 78 Preparation of 2-[1-methyl-2-[(4-chlorophenoxy)methyl]indol-3-5 yl]glyoxylic acid OH
C
NMR (DMSO) was consistent with the proposed title structure.
lo FDMS 343 (M+) Analysis for C1gH14ClNO4:
Theory: C, 62.89; H, 4.11; N, 4.07.
Found: C, 63.15; H, 4.37; N, 3.92.
5F,x~qm;l?le 79 Preparation of methyl 2-[1-methyl-2-[(4-chlorophenoxy)methyl]indol-3-yl]glyoxylate ~ ~ OCH3 ~~O
Cl NMR (CDCl3) and IR were consistent with the desired title structure.
Exact Mass FAB (M+1) for ClgHl7ClNO4: -Theory: 368.0846.
Found: 368.0818.
mple 80 Preparation of phenyl 2-[1-methyl-2-[(4-chlorophenoxy)methyl]indol-3-yl]glyoxylate ~~~3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 419 (M+) 10 Analysis for C24HlgClNO4:
Theory: C, 68.66; H,4.32; N,3.34.
Found: C, 68.90; H,4.49; N, 3.33.
m~le 81 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-amino-1,2-ethanedionyl]- lH-indole ~ ~ NH2 ~o Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 342 (M+).
Analysis for C18HlsClN2O3:
Theory: C, 63.07; H,4.41; N, 8.17.
Found: C, 63.36; H,4.50; N,8.18.
.
-W O 97/09308 PCTAUS96/141~3 F.~mple 82 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-methylamino-1,2-ethanedionyl]-lH-indole C
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 357 (M+l) Analysis for C1gH17ClN2O3:
Theory: C, 63.96; H, 4.80; N,7.85.
Found: C, 63.97; H, 4.83; N, 7.82.
~Am~le 83 Preparation of 3-dimethylAminol,rol,yl 2-[1-methyl-2-[(4-chlorophenoxy)methyl]indol-3 -yl]glyoxylate N(CH3)2 Cl NMR (CDCl3) was consistent with the proposed title structure.
C23H2sClN2O4: FAB 429 (M+).
Single compound of high purity as evidenced by chromatographic methods.
~Am~le 84 WO 97/09308 PCT/US96/141~3 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[2-(dimethylamino)ethyl ~mino]- 1,2-ethanedionyl]- lH-indole hydrochloride .
O~ CH3 Cl ~HCl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 413 (M+).
10 Analysis for C22H24ClN303 ~ HCl:
Theory: C, 58.67; H, 5.59; N, 9.33.
Found: C, 58.38; H, 5.82; N, 9.48.
m~le 85 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[3-(dimethylamino)propylamino]- 1,2-ethanedionyl]-lH-indole N N(CH3)2 Cl NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB (M+1) for C23H27ClN303:
- Theory: 428.1741.
- Found: 428.1738.
m}-le 86 W O 97/09308 PCT~US96/141~3 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[3-amino~l o~Jylamino]-1,2-ethanedionyl]-lH-indole CH3 ~Q
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 399 (M+).
Analysis for C21H22ClN3O3:
lo Theory: C, 63.08; H, 5.55; N, 10.51.
Found: C, 69.53; H, 6.18; N, 11.70.
Single compound of high purity as evidenced by chromatographic methods.
~ mple 87 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[3-(t-butoxycarbonylamino)propyl~mino]-1,2-ethanedionyl]-lH-indole ~;~ H NHBoC
CH~ ~
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 499 (M+).
mp 175-176~C.
2 5 Analysis for C26H30ClN3Os:
Theory: C, 62.46; H, 6.05; N, 8.40.
Found: C, 62.19; H, 6.08; N, 8.27.
- F~mT)l e 88 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[2,2-dimethyl-3-(dimethyl~mino)propyl~mino]-1,2-ethanedionyl]-lH-indole ~ HN ~ N(CH3)2 Cl 10 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 456 (M+).
Analysis for C2sH30ClN3O3:
Theory: C, 65.85; H, 6.63; N, 9.22.
Found: C, 65.62; H, 6.76; N, 9.12.
mple 89 Preparation of 2-[(4-chloroph~no~y)methyl]-1-methyl-3-[2-[6-(dimethyl~mino)hexylamino]-1,2-ethanedionyl]-lH-indole ~ H N(CH3)2 Cl - NMR (CDCl3) was consistent with the proposed title structure.- IR was consistent with the desired title structure.
Exact Mass FAB (M+1) for C27H33ClN303:
Theory: 470.2210.
Found: 470.2196.
~IxAmrle 90 5 Prcparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-2-(dimethylamino)ethylamino]-1,2-ethanedionyl]-lH-indole N ( CH3 ) 2 CH3 ~
Cl 10 NMR, W, and IR were consistent with the desired title structure.
FDMS 427 (M+). mp 142-143~C.
Analysis for C23H26ClN3O3:
Theory: C, 64.56; H, 6.12; N, 9.82.
Found: C, 64.82; H, 6.32; N, 9.89.
h',x~m~le 91 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-3-(dimethylamino)propylamino]- 1,2-ethanedionyl]- lH-indole o CH<
N ~ N(CH3), C
NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
25 Exact Mass FAB (M+1) for C24H2gClN303:
Theory: 442.1897.
Found: 442.1904.
F.~rnple 92 Preparation of 2-[(4-chlorophçno~y)methyl]-1-methyl-3-[2-[N-methyl-3-(dimethylamino)lJI ol ylamino]- 1,2-ethanedionyl]- lH-indole hydrochloride o CH3 ~ ,~ , N(CH3)2 NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title product.
FDMS 441 (M+).
Exact Mass FAB (M+1) for C24H2gClN303:
Theory: 442.1897.
Found: 442.1895.
F.~mple 93 20 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[bis[3-(dimethylamino)propyl]amino]-1,2-ethanedionyl]-lH-indole (H3C)2N
o N(CH3)2 CH~ ~
Cl W O 97/09308 PCTAUS96/141~3 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 512 (M+) Analysis for C2gH37ClN4O3:
Theory: C, 65.55; H, 7.27; N, 10.92.
Found: C, 65.85; H, 7.46; N, 11.04.
h'.~z~mrle 94 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[N-benzyl-3-(dimethylamino)propyl~mino]-1,2-ethanedionyl]-lH-indole N(CH3)2 Cl 15 IR, NMR, and W were consistent with the desired title structure.
FDMS 517 (M+).
Analysis for C30H32ClN3O3:
Theory: C, 69.55; H, 6.23; N, 8.11.
Found: C, 69.82; H, 6.31; N, 8.13.
mrle 95 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[N-methyl-3-[1-(t-butoxycarbonyl )piperidin-3-yl]propylamino] - 1,2-ethanedionyl] - lH-25 indole WO 97/09308 PCT/US96/141~3 ' C?BOC
CH3~Q
Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 581 (M+).
Analysis for C32H40ClN3Os:
Theory: C, 66.02; H, 6.93; N, 7.22.
Found: C, 65.91; H, 7.14; N, 7.08.
F.~m~le 96 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(1-methylpiperidin-3-yl)amino]-1,2-ethanedionyl]-lH-indole GN~CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 439 (M+).
Analysis for G24H26ClN3O3:
Theory: C, 65.52; H, 5.96; N, 9.55.
Found: C, 65.80; H, 5.96; N, 9.56.
F,~mple 97 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-(1-methylpyrrolidin-3-yl)amino]-1,2-ethanedionyl]- lH-indole W O 97/09308 . PCTAUS96/14163 o IcH3 ,CH3 Cl IR, NMR, and W were consistent with the desired title structure.
5 FDMS 439 (M~).
Analysis for C24H26ClN303:
Theory: C,65.52; H, 5.96; N, 9.55.
Found: C, 65.54; H, 6.03; N,9.69.
~.x~qmnle 98 Preparation of (RS) 2-[(4-chloropheno~y)methyl]-1-methyl-3-[2-rN-methyl-(1-methylpiperidin-3-yl)amino]-1,2-ethanedionyl]-lH-indole o CH3 N~CH3 CH3 \~
Cl IR was consistent with the desired title structure. FDMS 453 (M+).
Analysis for C2sH2gClN303:
Theory: C,66.14; H, 6.22; N, 9.26.
Found: C, 65.86; H, 6.17; N, 9.29.
~.x~mple 99 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[(quinuclidin-25 3-yl )amino]- 1,2-ethanedionyl]- lH-indole WO 97/09308 PCT~US96/141C3 H
Cl NMR, W, and IR were consistent with the desired title structure.
5 FDMS 451 (M+). mp 204-205~C.
Analysis for C2sH26ClN3O3:
Theory: C, 66.44; H, 5.80; N, 9.30.
Found: C, 66.37; H, 5.88; N, 9.37.
F.~mT-le 100 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(piperidin-1-yl)-1,2-ethanedionyl]-lH-indole o ~
N
N ~ O
C
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 410 (M+).
Analysis for C23H23ClN203:
Theory: C, 67.22; H, 5.64; N, 6.82.
Found: C, 67.50; H, 5.81; N, 6.63.
F~mple 101 WO 97/09308 PCTAUS96tl4163 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[2-(dimethylaminomethyl)cyclohegylamino- 1,2-ethanedionyl]- 1H-indole hydrochloride N(CH3)2 ~N~
Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 481 (M+).
Analysis for C27H32ClN3O3 ~ HCl:
Theory: C, 62.55; H, 6.42; N, 8.10.
Found: C, 62.56; H, 6.44; N, 8.06.
mple 102 Preparation of 2-[(4-chloropheno~y)methyl]-1-methyl-3-[2-(4-methylpiperidin-1-yl)-1,2-ethanedionyl]-lH-indole N~
Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 424 (M+).
Analysis for C24H2sClN2O3:
Theory: C, 67.84; H, 5.93; N, 6.59.
W O 97/09308 PCTAJS96/141~3 Found: C, 68.04; H, 5.85; N, 6.74.
F~m~le 103 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-benzylpiperidin-1-yl)-1,2-ethanedionyl]-lH-indole N
CH3 ~Q
Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 500 (M+).
Analysis for C3oH2sclN2o3:
Theory: C, 71.92; H, 5.83; N, 5.59.
Found: C, 71.69; H, 5.74; N, 5.38.
mr)le 104 Preparation of 2-[(4-chloropheno~y)methyl]-1-methyl-3-[2-(4-20 aminocarbonylpiperidin-1-yl)-1,2-ethanedionyl]-lH-indole ~NH2 ~N
CH3 ~Q
Cl NMR, W, and IR were consistent with the desired title structure.
W O 97/09308 PCTAUS96/141~3 FDMS 453 (M+). mp 220-221~C.
Analysis for C24H24ClN3O4:
Theory: C, 63.60; H, 5.33; N, 9.26.
Found: C, 63.46; H, 5.50; N, 9.18.
F.~mrle 106 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-dimethyl~qminopiperidin-l-yl)-1,2-ethanedionyl]-lH-indole ~, N~
~ N~
N~\_ O
CH3 '1Q
Cl NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB (M+l) for C2sH29ClN3O3:
Theory: 454.1897.
Found: 464.1882.
F.~mple 106 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[4-(piperidin- 1-yl)piperidin-l-yl]-1,2-ethanedionyl]-lH-indole N
. ~ ~ N ~
~~O
CH3 ~Q
Cl NMR (CDCl3) and IR were consistent with the proposed title structure.
FDMS 493 (M+) Analysis for C2gH32ClN3O3:
Theory: C, 68.07; H, 6.53; N, 8.51.
Found: C, 67.97; H, 6.66; N, 8.27.
~.~?mnle 107 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(3-aminocarbonylpiperidin- 1-yl)- 1,2 -ethanedionyl]- lH-indole H2N>eO
o ~
~N
CH3 )Q
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 453.
mp 229-230~C
Analysis for C24H24ClN3O4:
Theory: C, 63.50; H, 5.33; N, 9.26.
Found: C, 63.53; H, 5.44; N, 9.04.
F.~qm~le 108 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(piperazin-1-5 yl)- 1 ,2-ethanedionyl]- lH-indole o 1--N J
Cl NMR (CDCl3) was consistent with the proposed title structure.
lo FDMS 411 (M+) mp 168-169~C.
Analysis for C22H22ClN3O3:
Theory: C, 64.15; H, 6.38; N, 10.20.
Found: C, 63.95; H, 5.36; N, 10.08.
F.~mT)le 109 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-isopropylpiperazin-l-yl)-1,2-ethanedionyl]-lH-indole ~N)~ CH3 , N~J
~N~--O
Cl NMR (CDCl3) was consistent with the proposed title structure.
W O 97/09308 PCT~US96/14163 ~ FDMS 453 (M+).
Analysis for C2sH2gClN3O3:
Theory: C, 66.15; H, 6.22; N, 9.26.
Found: C, 65.94; H, 6.48; N, 8.97.
F.x~mrle 110 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[4-(t-butoxycarbonyl)piperazin-1-yl]-1,2-ethanedionyl]-lH-indole BoC
N
, NJ
N ~ O
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 511 (M+).
mp 200-201~C
Analysis for C27H30ClN3Os:
Theory: C, 63.34; H, 5.91; N, 8.21.
Found: C, 63.10; H, 5.80; N, 7.98.
F.~mple 111 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-cyclohexylpiperazin-1-yl)-1,2-ethanedionyl]-lH-indole O ~
, ,NJ
N ~ O
Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
5 FDMS 493 (M+).
Analysis for C2gH32ClN3O3:
Theory: C, 68.07; H, 6.53; N, 8.50.
Found: C, 67.81; H, 6.60; N, 8.24.
F~m~le 112 Preparation of 2-[(4-chlororheno~y)methyl]-1-methyl-3-[2-[4-(2-dimethylaminoethyl)piperazin-1-yl]-1,2-ethanedionyl]-lH-indole dihydrochloride o ~ N ~ N(CH3)2 ~;; ~NJ
c1 ~2 HCl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
2 o FDMS 482 (M+).
Analysis for C26H31ClN4O3 ~ 2 HCl:
Theory: C, 56.17; H, 5.98; N, 10.07.
WO 97t09308 PCT~US96/14163 Found: C, 56.47; H, 6.07; N, 10.05.
-m~nle 113 5 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[3-aminoacetylpyrrolidin-1-yl]-1,2-ethanedionyl]-lH-indole o ~ NH2 N
Cl 10 NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 453 (M+).
Analysis for C24H24ClN3O4:
Theory: C, 63.50; H, 5.33; N, 9.26.
Found: C, 63.75; H, 5.37; N, 9.21.
F~mple 114 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-20 3-(dimethylamino)propyl~mino]-1,2-ethanedionyl]-lH-indole N ~ N~ CH3 C
- NMR (CDCl3) was consistent with the proposed title structure.
W was consistent with the desired title structure.
FDMS 475 (M+).
Analysis for C24H27Cl2N3O3:
Theory: C, 60.51; H, 5.71; N, 8.82.
Found: C, 60.69; H, 5.80; N, 8.77.
F,~7~mple 115 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-lo (l-methylpiperidin-4-yl)amino]-1,2-ethanedionyl]-lH-indole N ~ N- CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
C2sH27ClN3O3: FDMS487(M+) Single compound of high purity as evidenced by chromatographic methods.
F~Ampl e 116 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[4-(N,N-dimethylamino )piperidin- l-yl] - 1,2 -ethanedionyl] - lH-indole I~r N~ CH
CH, Cl -W 0 97/09308 PCT~US96/141~3 NMR (CDCl3) was consistent with the proposed title structure.
W was consistent with the desired title structure.
FDMS 487, 489 (M+).
Analysis for C2sH27Cl2N3O3:
Theory: C, 61.48; H, 5.57; N, 8.60.
Found: C, 61.75; H, 5.63; N, 8.59.
F.~mrle 117 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[(4-(piperidin-1-yl)piperidin-1-yl]-1,2-ethanedionyl]-lH-indole '\~ N
~, M~J
~~
CH3 ~
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 527,529 (M+).
Analysis for C2gH31Cl2N3O3:
Theory: C, 63.64; H, 5.91; N, 7.95.
Found: C, 63.82; H, 6.08; N, 7.85.
mrle 118 Preparation of 2-[(2-cyano-4-bromophenoxy)methyl]-1-methyl-3-[2-[N-25 methyl-(3-dimethylaminopropyl)amino]-1,2-ethanedionyl]-lH-indole W O 97/09308 PCTrUS96/14163 ~,N N~CH
o~N
Br IR, NMR, and W were consistent with the desired title structure.
FDMS 511, 513 (M+).~ Analysis for C2sH27BrN4O3 ~ 0.5 H2O:
Theory: C, 67.70; H, 5.42; N, 10.75.
Found: C, 57.56; H, 5.36; N, 10.60.
Exact Mass for C2sH2gBrN4O3:
Theory: 511.1332.
0 Found: 511.1345.
F'.-r~mrle 119 Preparation of 2-[(2-cyano-4-bromophçno~y)methyl]-1-methyl-3-[2-[N-15 methyl-(1-methylpiperidin-4-yl)amino]- 1,2-ethanedionyl]- lH-indole Br IR, NMR, and W were consistent with the desired title structure.
FDMS ~22, 524 (M+).
Analysis for C26H27BrN4O3:
Theory: C, 59.66; H, 5.20; N, 10.70.
Found: C, 59.38; H, 5.24; N, 10.49.
2 5 h'.~qmI-l e 120 CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/141~3 Preparation of 2-[(2-cyano-4-bromophenoxy)methyl]-1-methyl-3-[2-(4-~ dimethyl~mi nopiperidin- 1-yl)] - 1,2 -ethanedionyl]- lH-indole ~,N(CH3) 2 ~;~ N~J
~~
Br IR, NMR, and W were consistent with the desired title structure.
FDMS 622, 624 (M+).
Analysis for C26H27BrN4O3 ~ 0.6 H2O:
Theory: C, 58.65; H, 6.30; N, 10.62.
Found: C, 58.61; H, 6.21; N, 10.42.
Exact Mass for C26H2gBrN4O3:
Theory: 523.1345.
Found: 623.1365.
F.~qmrle 121 Preparation of 2-[(2-cyano-4-bromophenoxy)methyl]-l-methyl-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]]-1,2-ethanedionyl]-lH-indole ~;~ N~
Br IR, NMR, and W were consistent with the desired title structure.
FDMS 563, 565 (M+).
W O 97/09308 PCT~US96/14163 Analysis for C2gH31BrN4O3:
Theory: C, 61.81; H, 5.54; N, 9.94.
Found: C, 61.56; H, 5.62; N, 9.91.
~ m.nle 122 Preparation of 2-[(4-chlorophenoxy)methyl]-1-ethyl-3-[2-(4-dimethylaminopiperidin-1-yl)]- 1,2-ethanedionyl]- lH-indole ~,N (CH3 ) 2 ~,, N~) N~\_ O
H3C ~Q
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 467.
Analysis for C26H3OClN3O3:
Theory: C, 66.73; H, 6.46; N, 8.98.
Found: C, 66.88; H, 6.57; N, 8.90.
~mnle 123 20 Preparation of 2-[(4-chlorophenoxy)methyl]-1-ethyl-3-[2-[N-methyl-(1-methylpiperidin-4-yl)amino]-1,2-ethanedionyl]-lH-indole ~, C, H3 N ~\
H3C \~'Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 467.
Analysis for C26H3OClN3O3:
Theory: C, 66.73; H, 6.46; N, 8.98.
s Found: C, 66.90; H, 6.70; N, 9.03.
mrle 124 Preparation of 2-[(4-chlorophenoxy)methyl]-1-benzyl-3-[2-(4-0 dimethylaminopiperidin- 1-yl)]- 1,2-ethanedionyl]- lH-indole N(CH3), N
~~
~ Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 529.
Analysis for C3lH32ClN303:
Theory: C, 70.24; H, 6.08; N, 7.93.
Found: C, 70.26; H, 6.18; N, 7.73.
F.~m~le 125 Preparation of 2-[(4-chlorophenoxy)methyl]-1-(2-piperidin-1-ylethyl)-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]-1,2-ethanedionyl]-lH-indole W O 97/09308 PCT~US96/14163 O
N ~
N ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB for C34H44ClN4Os:
Theory: 591.3102.
Found: 591.3100.
F,~rnrle 126 10 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl)-3-[piperidin- 1-ylmethyl]- lH-indole ~o ~ Cl 15 NMR (CDCl3) was consistent with the proposed title structure.
Single compound of high purity as evidenced by chromatographic methods.
W O 97/09308 PCTAUS96/141~3 F.R~mrle 127 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(1-methylpiperidin-3-yl)propyl)-3-[piperidin-1-ylmethyl]-lH-indole ~ N~\--O
.~ ~
Cl N
NMR (CDCl3) was consistent with the proposed title structure.
Single compound of high purity as evidenced by chromatographic 0 methods.
m~le 128 Preparation of 2-[(4-chlorophenoxy)methyl]-1-ethyl-3-[(4-15 dimethylaminopiperidin-1-yl)methyl]-1H-indole N ( CH3 ) 2 ~~~
H3C Cl NMR and W were consistent with the desired title structure. FDMS
425 (M+). mp 115-116~C.
Analysis for C2sH32ClN3O:
Theory: C, 70.49; H, 7.67; N, 9.86.
Found: C, 70.70; H, 7.67; N, 9.80.
~mple 129 Preparation of 2-[(4-chlorophenoxy)methyl]-1-benzyl-3-[(4-10 dimethylaminQpiperidin-l-yl)methyl]-lH-indole N ( CH 3 ) 2 ~0 ~ ~ Cl NMR and W were consistent with the desired title structure. FDMS
15 488 (M+). mp 127-128~C.
Analysis for C30H34ClN3O:
Theory: C, 73.83; H, 7.02; N, 8.61.
Found: C, 73.77; H, 7.21; N, 8.66.
li'~ample 130 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(piperidin- 1-yl)ethyl]-3-[(4-dimethylaminopiperidin- l-yl)methyl]- lH-indole N(CH3)2 ~0 ~
N ~ O
< ~ ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB for C30H42ClN40:
Theory: 509.3047.
Found 509.3018.
F.~mple 131 0 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-[3-(piperidin- l-yl)l~l o~yl]-3- [(4-dimethylaminopiperidin-1-yl)methyl]-lH-indole trihydrochloride N(CH3)2 ~, ~3 HCl Cl C~
15 NMR and W were consistent with the desired title structure.
W O 97/09308 PCT~US96/14163 FDMS 523 (M+1).
mp 240-242~C.
Analysis for C31H43ClN4O ~ 3 HCl:
Theory: C, 58.86; H, 7.33; N, 8.86.
Found: C, 58.66; H, 7.09; N, 8.77.
F.~mple 132 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-10 [(4-dimethyl~minopiperidin-1-yl)methyl]-lH-indole N(CH3)2 ~0 c ~ Cl N
NMR (CDCl3) was consistent with the proposed title structure.
C31H43ClN4O: FDMS522(M+) Single compound of high purity as evidenced by chromatographic methods.
mple 133 Preparation of 2-[(4-chlorophenoxy)methyl]-1-ethyl-3-[[4-(piperidin-1-yl)piperidin- 1-yl]methyl]- lH-indole O
H3C ~ Cl NMR and W were consistent with the desired title structure. FDMS
465 (M+). mp 130-131~C.
Analysis for C2gH36ClN3O:
Theory: C, 72.16; H, 7.79; N, 9.02.
Found: C, 72.12; H, 7.78; N, 8.86.
F.~mrle 134 Preparation of 2-[(4-chlorophenoxy)methyl]-1-benzyl-3-[[4-(piperidin-1-yl)piperidin- 1-yl]methyl]- lH-indole ~ Cl NMR and W were consistent with the desired title structure.
FDMS 527 (M+).
mp 153-154~C.
Analysis for C33H3gClN3O:
Theory: C, 75.05; H, 7.25; N, 7.96.
Found: C, 75.25; H, 7.40; N, 8.08.
-Fx~mT)le 135 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(piperidin-1-yl)ethyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]methyl]-lH-indole ~ Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 548 (M+) mp 102-103~C.
Analysis for C33H4sClN4O:
lo Theory: C, 72.17; H, 8.26; N, 10.20.
Found: C, 72.12; H, 8.31; N, 10.17.
F~-nrle 136 5 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-[2-(piperidin- 1-yl )ethyl] - lH-indole ~o ~> Cl 20 IR, NMR, and W were consistent with the desired title structure.
FDMS 368 (M+). FAB 369 (M+1).
Analysis for C22H25ClN2~:
Theory: C, 71.63; H, 6.83; N, 7.59.
Found: C, 71.93; H,7.28; N,7.22.
Single compound of high purity as evidenced by chromatographic methods.
~.~?mI)le 137 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(piperidin-4-yl)ethyl]-lH-indole Q~o ~ Cl N
H
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 368 (M+).
Analysis for C22H2sclN2o:
Theory: C, 71.63; H,6.83; N,7.59.
Found: C, 71.66; H,6.86; N, 7.87.
F,~m.~le 138 20 Preparation of 2-[(phenylthio)methyl]-1-[3-(piperidin-3-yl)propyl]-lH-indole Q~s NMR (CDCl3) was consistent with the proposed title structure.
FDMS 364 (M+).
5 Analysis for C23H2gN2S:
Theory: C, 75.78; H, 7.75; N, 7.69.
Found: C, 75.70; H, 7.73; N, 7.86.
F'.~z~mrle 139 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)~rol,yl]-lH-indole ~;~~
Cl C~
N
NMR (CDCl3) was consistent with the proposed title structure.
Single compound of high purity as evidenced by chromatographic methods.
2 o F,~qmrle 140 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(1-methylpiperidin-3-~ yl)~rol yl]-lH-indole ~_-0 c~ Cl N
NMR and W were consistent with the desired title structure.
mp 97-98~C.
Analysis for C24H2gClN20:
Theory: C, 72.62; H, 7.36; N, 7.06.
Found: C, 72.59; H, 7.48; N, 7.14.
F.~mple 141 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)l,~o~yl]-15 lH-indole Q~o~
Cl NMR (CDCl3) was consistent with the proposed title structure.
~0 C23H27ClN20: FDMS 382 (M+) W O 97/09308 PCT~US96/14163 Single compound of high purity as evidenced by chromatographic methods.
F,~mrle 142 Preparation of 2-[2-(4-chlorophenyl)ethyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~HCl H3C ~
Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 366 (M+).
Analysis for C23H27ClN2 ~ HCl:
Theory: C, 68.48; H, 7.00; N, 6.94.
Found: C, 68.26; H, 6.87; N, 6.76.
F.~mr~le 143 Preparation of 2-[(4-chlorophenylamino)methyl]-1-methyl-3-[(piperidin-20 1-yl)methyl]-lH-indole ~?
H~C
Cl NMR, W, and IR were consistent with the desired title structure.
25 FDMS 367 (M+). mp 169~C.
Analysis for C22H26ClN3:
Theory: C, 71.82; H, 7.12; N, 11.42.
Found: C, 71.60; H, 7.06; N, 11.46.
F.~zml?le 146 Preparation of 2-[(2,4-dichlorophenylamino)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~N?l H3C ~
Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 401, 403 (M+).
mp 147-148~C.
Analysis for C22H2sCl2N3:
Theory: C, 65.67; H, 6.26; N, 10.44.
Found: C, 66.48; H, 6.30; N, 10.59.
mple 147 Preparation of 2-[(4-chlorophenylamino)methyl]-3-[(piperidin-1-yl)methyl]-lH-indole Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 353, 354 (M+). mp 135~C.
Analysis for C21H24ClN3:
Theory: C, 71.27; H, 6.84; N, 11.87.
Found: C, 71.90; H, 7.17; N, 12.02.
nple 148 Preparation of 2-[(2,4-dichlorophenylamino)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole --~HN c 1 CH3 ~ /
Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 401 (M+) mp 147-148~C.
Analysis for C22H2sCl2N3:
Theory: C, 65.47; H, 6.26; N, 10.44.
Found: C, 65.48; H, 6.30; N, 10.59.
nrle 149 Preparation of 2-[(cyclohexylamino)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole 6~N?
N N
NMR, W, and IR were consistent with the desired title structure.
FDMS 339 (M+).
mp 162-164~C.
Analysis for C22H33N3:
Theory: C, 77.83; H, 9.80; N, 12.38.
Found: C, 75.98; H, 9.11; N, 12.67.
Exact Mass FAB for C22H34N3:
Theory: 340.2763.
Found: 340.2770.
F.~zlmple 150 Preparation of 2-[(cyclohexylmethyl~mino)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole dihydrochloride (3~ ~ 2HCl NMR, W, and IR were consistent with the desired title structure.
FDMS 354, 390 (M+). mp 159-161~C.
Analysis for C23H3sN3 ~ 2HCl:
Theory: C, 64.78; H, 8.75; N, 9.85.
Found: C, 64.62; H, 8.82; N, 9.65.
F.~qmrle 151 Preparation of 2-t(naphth-2-yl~mino)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole W O 97/09308 PCT~US96/14163 ~;?
CH3 ~
NMR (CDCl3), IR, and W were consistent with the proposed title structure.
5 FDMS 383 (M+).
mp 144~C.
Analysis for C26H2gN3:
Theory: C, 81.42; H, 7.62; N, 10.96.
Found: C, 81.26; H, 7.49; N, 10.89.
~0 mnle 152 Preparation of 2-[[N-acetyl-N-(cyclohexylmethyl)amino~methyl]-1-methyl-3-[(piperidin- 1-yl)methyl]- lH-indole hydrochloride ~~U
CH3 ~ O ~HCl NMR, W, and IR were consistent with the desired title structure.
FDMS 395 (M+).
20 Analysis for C2sH37N3O ~ HCl:
Theory: C, 69.50; H, 8.87; N, 9.73.
Found: C, 68.87; H, 9.29; N, 9.30.
Exact Mass FAB for C2sH3gN3O:
Theory: 396.3015 Found: 396.3020 F.~mI-le 153 Preparation of 2-[[N-acetyl-N-(benzyl)~mino]methyl]-1-methyl-3-5 [(piperidin- 1-yl )methyl]- lH-indole hydrochloride A
CH, ~e o H3C ~HCl NMR, UV, and IR were consistent with the desired title structure.
10 FDMS 389 (M+). mp 148-150~C.
Analysis for C2sH31N3O ~ HCl:
Theory: C, 70.49; H, 7.57; N, 9.86.
Found: C, 70.21; H, 7.40; N, 9.73.
F.~ )le 164 Preparation of 2-[[(3-chlorophenyl)amino]carbonyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole (~ ~N~¦3~C1 NMR, W, and IR were consistent with the desired title structure.
FDMS 381, 383 (M+). mp 137-138~C.
Analysis for C22H24ClN3O:
Theory: C, 69.19; H, 6.33; N, 11.00.
Found: C, 69.39; H, 6.39; N, 11.20.
W O 97/09308 PCT~US96/14163 ~m~le 156 Preparation of 2-[[(2,4-dichlorophenyl)amino]carbonyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole r~
~ Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 417 (M+). mp 180-182~C.
Analysis for C22H23Cl2N3O:
Theory: C, 63.47; H, 5.57; N, 10.09.
Found: C, 63.27; H, 5.65; N, 10.18.
~,mnle 1~6 Preparation of 2-[[(cyclohexyl)amino]carbonyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole Q ~ H
NMR, W, and IR were consistent with the desired title structure.
FDMS 353 (M+). mp 180~C.
Exact Mass FAB for C22H32N30:
Theory: 354.2545.
2 5 Found: 354.2543.
mnle 157 Preparation of 2-[[(cyclohexylmethyl)amino]carbonyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~'-~J
NMR (CDCl3), IR, and W were consistent with the proposed title structure.
mp 126~C.
lo Analysis for C23H33N30:
Theory: C, 75.16; H, 9.05; N, 11.43.
Found: C, 75.09; H, 9.03; N, 11.25.
F.x~ nle 158 Preparation of 2-[[(naphth-2-yl)amino]carbonyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~0 NMR, W, and IR were consistent with the desired title structure.
FDMS 397 (M+). mp 187~C.
Analysis ffir C26H27N30:
Theory: C, 78.56; H, 6.86; N, 10.67.
- 25 Found: C, 78.84;H, 7.02; N, 10.78.
.
F,x~mnle 159 W O 97/09308 PCTAUS96/141~3 Preparation of 2-[phenoxymethyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride NMR, W, and IR were consistent with the desired title structure.
FDMS 334 (M+). mp 225~C.
Analysis for C22H26N2O ~ HCl:
Theory: C, 71.32; H, 7.34; N, 7.55.
Found: C, 71.45; H, 7.44; N, 7.79.
F'.~z~mple 160 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-15 yl)methyl]-lH-indole hydrochloride salt NMR, IR and W were consistent with the desired title structure.
20 FDMS 368 (M+). mp 214~C.
Analysis for C22H2sClN2O ~ HCl:
Theory: C, 65.32; H, 6.46; N, 6.91.
Found: C, 65.46; H, 6.52; N, 7.16.
~ mple 161 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]- lH-indole .
CH3 Cl NMR was consistent with the desired title structure.
5 FDMS 368 (M+).
Analysis for C22H2sclN2o:
Theory: C, 71.63; H, 6.83; N, 7.59.
Found: C, 68.39; H, 6.55; N, 6.16.
~mnle 162 Preparation of 2-[(3-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~ O ~Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 368 (M+). mp 222~C.
Analysis for C22H2sClN2O ~ HCl:
Theory: C, 65.19; H, 6.46; N, 6.91.
Found: C, 65.15; H, 6.55; N, 6.95.
~mple 163 Preparation of 2-[(2-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride - 222 - ~
~,3 CH3 C l NMR, W, and IR were consistent with the desired title structure.
FDMS 369 (M+).
Analysis for C22H2sClN2O ~ HCl:
Theory: C, 65.19; H, 6.46; N, 6.91.
Found: C, 65.48; H, 6.65; N, 6.98.
mrle 164 Preparation of 2-[(4-fluorophenoxy)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole hydrochloride ~ HC l NMR (CDCl3) was consistent with the proposed title structure.
FDMS 352 (M+).
Analysis for C22H2sFN2O ~ HCl:
Theory: C, 67.94; H, 6.74; N, 7.20.
Found: C, 67.74; H, 6.77; N, 7.16.
mple 166 Preparation of 2-[(3-fluorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride N
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 352 (M+).
5 Analysis for C22H2sFN2O ~ HCl:
Theory: C, 67.94; H, 6.74; N, 7.20.
Found: C, 65.85; H, 6.51; N, 6.68.
SIngle compound of high purity as evidenced by chromatographic methods.
F.~mrle 166 Preparation of 2-[(2-fluoropheno~y)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole hydrochloride --~;f ~HCl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 352 (M+).
20 Analysis for C22H2sFN2O ~ HCl:
Theory: C, 67.94; H, 6.74; N, 7.20.
Found: C, 67.67; H, 6.63; N, 7.40.
mrle 167 ~ 25 Preparation of 2-[(4-trifluoromethylphenoxy)methyl]-1-methyl-3-[(piperidin- 1-yl )methyl]- lH-indole hydrochloride CA 022039l2 l997-04-28 W O 97/09308 PCTrUS96/14163 Q~o?~cl NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
5 Analysis for C23H2sF3N2O ~ HCl:
Theory: C, 62.94; H, 5.97; N, 6.38.
Found: C, 63.51; H, 6.05; N, 6.41.
Single compound of high purity as evidenced by chromatographic methods.
mrle 168 Preparation of 2-[(3-trifluoromethylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride N ~ ~HCl ~ O ~ CF3 NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
20 Analysis for C23H2sF3N2O ~ HCl:
Theory: C, 62.94; H, 5.97; N, 6.38.
Found: C, 64.11; H, 6.07; N, 6.42.
Single compound of high purity as evidenced by chromatographic methods.~5 mnle 169 W O 97/09308 PCT~US96/14163 Preparation of 2-[(2-trifluoromethylph~noxy)methyl]-1-methyl-3-[(piperidin- 1-yl )methyl]- lH-indole hydrochloride ~ Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C23H2sF3N2O ~ HCl:
Theory: C, 62.94; H, 5.97; N, 6.38.
Found: C, 62.89; H, 6.02; N, 6.37.
F.xAmple 170 Preparation of 2-[(4-acetylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride r~
Q~ ~ HC 1 NMR, W, and IR were consistent with the desired title structure.
FDMS 376 (M+) Analysis for C24H2gN2O ~ HCl:
Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 69.69; H, 7.27; N, 6.72.
FxAmnle 171 WO 97/09308 PCT/US96/141~3 Preparation of 2-[(3-acetylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~
NMR, W, and IR were consistent with the desired title structure.
FDMS 376 (M+).
Analysis for C24H2gN2O2 ~ HCl:
Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 69.91; H, 7.18; N, 6.81.
F.~m~le 172 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~3, NMR and W were consistent with the desired title structure.
20 FDMS 402 (M+).
Analysis for C22H24cl2N2o:
Theory: C, 60.26; H, 5.75; N, 6.39.
Found: C, 61.61; H, 5.69; N, 6.34.
Single compound of high purity as evidenced by chromatographic 25 methods.
F.x~m;~?le 173 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride r~
~ HCl CH3 Cl Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C22H24Cl2N20 ~ HCl:
lo Theory: C, 60.08; H, 6.73; N, 6.37.
Found: C, 60.31; H, 6.00; N, 6.62.
ple 174 Preparation of 2-[(3,5-dichloroph~no~y)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~HCl CH3 Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C22H24CI2N20 ~ HCl:
Theory: C, 60.08; H, 5.73; N, 6.37.
Found: C, 58.13; H, 5.25; N, 5.99.
Single compound of high purity as evidenced by chromatographic methods.
-mnle 175 Preparation of 2-[(2,5-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole r~
,Cl CH3 Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C22H24cl2N2o:
Theory: C, 65.51; H, 6.00; N, 6.95.
Found: C, 65.71; H, 6.00; N, 6.93.
F.~m~le 176 Preparation of 2-[(2,6-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride HC l CH3 Cl NMR, UV, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C22H24Cl2N2O ~ HCl:
Theory: C, 60.08; H, 5.73; N, 6.37.
Found: C, 59.79; H, 5.43; N, 6.11.
m~e 177 W O 97/09308 PCT~US96tl4163 Preparation of 2-[(3,4-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~ HCl CH3 Cl NMR, UV, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C22H24Cl2N20 ~ HCl:
Theory: C, 60.08; H,5.73; N, 6.37.
Found: C, 59.82; H, 5.72; N, 6.21.
~.~anl;E)le 178 Preparation of 2-[(2,3-dichlorophenoxy)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole ~ ~~ ' CH3 Cl Cl NMR, UV, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C24H24cl2N2o:
Theory: C, 65.51; H, 6.00; N, 6.95.
~ Found: C, 65.23; H, 5.96; N, 6.82.
~ 25 mrle 179 W O 97/09308 PCT~US96/141~3 Preparation of 2-[(4-phenylphenoxy)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole ~,N~>
CH3 ~
NMR, W, and IR were consistent with the desired title structure.
FDMS 410 (M+).
Analysis for C28H3oN2o:
Theory: C, 81.91; H, 7.36; N, 6.82.
Found: C, 80.96; H, 7.34; N, 6.73.
Single compound of high purity as evidenced by chromatographic methods.
mrle 180 Preparation of 2-[(3-phenylI~hçnoxy)methyl]-1-methyl-3-[(piperidin-1-yl )methyl] - lH-indole hydrochloride HCl Q~, NMR, W, and IR were consistent with the desired title structure.
FDMS 410 (M~).
Analysis for C2gH30N2O ~ HCl:
Theory: C, 75.23; H, 6.99; N, 6.27.
Found: C, 74.74; H, 7.10; N, 6.23.
W 0 97/09308 PCT~US96/141~3 Single compound of high purity as evidenced by chromatographic methods.
m~le 181 s Preparation of 2-[(2-phenylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~HCl CH, ~=~
~.d NMR, W, and IR were consistent with the desired title structure.
FDMS 410 (M+).
Analysis for C2gH30N2O ~ HCl:
Theory: C, 75.23; H, 6.99; N, 6.27.
Found: C, 74.03; H, 7.10; N, 6.35.
Single compound of high purity as evidenced by chromatographic methods.
~mrle 182 Preparation of 2-[(4-methylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~--~) f ' NMR, W, and IR were consistent with the desired title structure.
W O 97/09308 PCT~US96/14163 FDMS 348 (M+).
Analysis for C23H2gN2O ~ HCl:
Theory: C, 71.76; H, 7.59; N, 7.28.
Found: C, 70.88; H, 7.70; N, 7.32.
5 Single compound of high purity as evidenced by chromatographic methods.
F',~7~rnl;~le 183 10 Preparation of 2-[(3-methylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl )methyl]- lH-indole hydrochloride ~ ~ H:l 15 NMR, W, and IR were consistent with the desired title structure.
FDMS 348 (M+).
Analysis for C23H2gN2O ~ HCl:
Theory: C, 71.76; H, 7.59; N, 7.28.
Found: C, 72.41; H, 7.78; N, 7.29.
20 Single compound of high purity as evidenced by chromatographic methods.
~m~nle 184 25 Preparation of 2-[(2-methylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl )methyl]- lH-indole hydrochloride ~ ~c 1 CH~ H C
W O 97/09308 PCT~US96/14163 NMR, W, and IR were consistent with the desired title structure.
FDMS 348 (M+).
Analysis for C23H2gN2O ~ HCl:
Theory: C, 71.76; H, 7.59; N, 7.28.
Found: C, 71.71; H, 7.64; N, 7.21.
F~x~Tnrle 186 Preparation of 2-[(4-methoxyphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride HCl NMR, W, and IR were consistent with the desired title structure.
FDMS 364 (M+).
Analysis for C23H2gN2O2 ~ HCl:
Theory: C, 68.90; H, 7.29; N, 6.99.
Found: C, 68.68; H, 7.30; N, 7.12.
F~mnle 186 Preparation of 2-[(3-methoxyphenoxy)methyl]- 1-methyl-3-[(piperidin- 1-yl )methyl]- lH-indole hydrochloride ~ HCl W O 97/09308 PCTrUS96/1416 NMR, W, and IR were consistent with the desired title structure.
FDMS 364 (M+).
Analysis for C23H2gN2O2 ~ HCl:
Theory: C, 68.90; H, 7.29; N, 6.99.
Found: C, 69.13; H, 7.38; N, 6.83.
h~rAmI)le 187 Preparation of 2-[(2-methoxyphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~
NMR, W, and IR were consistent with the desired title structure.
FDMS 364 (M+).
Analysis for C23H2gN2O2 ~ HCl:
Theory: C, 68.90; H, 7.29; N, 6.99.
Found: C, 73.45; H, 7.94; N, 6.92.
Single compound of high purity as evidenced by chromatographic methods.
~mple 188 Preparation of 2-[2-hydroxyethyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~-~ ?
- Analysis for Cl6H22N2o:
Theory: C, 74.38; H, 8.58; N, 10.84.
Found: C, 74.35; H, 8.78; N, 10.96.
mDle 189 Preparation of 2-(2-methoxyethyl)-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~ G~II
NMR was consistent with the desired title structure.
FDMS 272, 273 (M+).
Analysis for Cl7H24N2o:
Theory: C, 74.96; H, 8.88; N, 10.28.
Found: C, 73.31; H, 8.86; N, 9.97.
mrle 190 20 Preparation of 2-(2-allyloxyethyl)-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride salt ~ CH2 CH3 HCl 25 NMR, W, and IR were consistent with the desired title structure.
- FDMS 298 (M+).
Analysis for ClgH26N20 ~ HCl:
Theory: C, 68.14; H, 8.13; N, 8.37.
Found: C, 68.30; H, 8.14; N, 8.39.
le 191 5 Preparation of 2-(benzyloxymethyl)-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~ HC 1 lo IR, W, and NMR (CDCl3) were consistent with the proposed title structure.
FDMS 384 (M+) Analysis for C23H2gN2O ~ HCl:
Theory: C, 71.76; H, 7.59; N,7.28.
Found: C, 68.44; H, 7.04; N,6.36.
Single compound of high purity as evidenced by chromatographic methods.
~ qmple L92 Preparation of 2-[(3-chlorobenzyloxy)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole hydrochloride /--\ ~HCl ~'Q
CH3 Cl NMR was consistent with the desired title structure.
FDMS 382 (M+).
Analysis for C23H27ClN2O ~ HCl:
W 0 97/09308 PCTAUS96/141~3 Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 71.92; H, 7.22; N, 7.43.
.
~mple 193 Preparation of 2-[(2-chlorobenzyloxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~o~
NMR was consistent with the desired title structure.
FDMS 382 (M+). mp 82-83~C.
Analysis for C23H27clN2o:
Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 71.87; H, 7.07; N, 7.36.
rr ple 194 Preparation of 2-[(4-chlorobenzyloxy)methyl]- 1-methyl-3-[(piperidin- 1-20 yl)methyl]-lH-indole hydrochloride Q~30 CH3 ~ HCl NMR (CDCl3), IR, and W were consistent with the proposed title ~ 25 structure.
FDMS 382 (M+) - Analysis for C23H27ClN2O ~ HCl:
Theory: C, 65.87; H, 6.73; N, 6.68.
W O 97/09308 PCT~US96/14163 Found: C, 65.54; H, 6.59; N, 6.39.
F,~amrle 195 s Preparation of 2-[(naphth-1-yloxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~HCl CH3 ~
Il I
lo NMR, W, and IR were consistent with the desired title structure.
FDMS 384 (M+).
Analysis for C26H2gN2O ~ HCl:
Theory: C, 74.18; H, 6.94; N, 6.65.
Found: C, 74.47; H, 7.05; N, 6.64.
F.~m~?le 196 Preparation of 2-[(naphth-2-yloxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride~0 r~
NMR, W, and IR were consistent with the desired title structure.
FDMS 384 (M+).
25 Analysis for C26H2gN2O ~ HCl:
WO 97/09308 PCTtUS96tl4163 Theory: C, 74.18; H, 6.94; N, 6.65.
Found: C, 71.44; H, 6.93; N, 6.67.
Single compound of high purity as evidenced by chromatographic methods.
F.~mnle 197 Preparation of 2-[(thiazol-2-yl)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole ~ N
NMR was consistent with the desired title structure.
mp 175-176~C.
FDMS 341 (M+).
Analysis for ClgH23N3OS:
Theory: C, 66.83; H, 6.79; N, 12.31.
Found: C, 66.64; H, 6.82; N, 12.03.
F.~mrle 198 Preparation of 2-[(pyrazin-2-yl)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole Qf ~ 3 CH~
NMR, W, and IR were consistent with the desired title structure.
FDMS 336 (M+). mp 101~C.
Analysis for C2oH24N4o:
Theory: C, 71.40; H, 7.19; N, 16.65.
Found: C, 71.44; H, 7.33; N, 16.43.
mrle 199 Preparation of 2-[(6-chloropyrazin-2-yl)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole O ~ N ~ C
NMR, W, and IR were consistent with the desired title structure.
FDMS 370 (M+). mp 94-96~C.
15 Analysis for C2oH23clN4o:
Theory: C, 64.77; H, 6.25; N, 15.11.
Found: C, 65.04; H, 6.45; N, 15.21.
F.~ml~le 200 Preparation of 2-[(pyrimidin-2-yl)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole CH~ N
NMR, W, and IR were consistent with the desired title structure.
FDMS 337 (M+1).
mp 123-125~C.
Analysis for C2oH24N40:
Theory: C, 71.40; H, 7.19; N, 16.65.
Found: C, 71.60; H, 7.43; N, 16.59.
~:x~n~le 201 Preparation of 2-[(quinolin-2-yl)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole ~}~ ~
NMR, W, and IR were consistent with the desired title structure.
FDMS 385 (M+1).
mp 113~C.
Analysis for C2sH27N3O:
Theory: C, 77.89; H, 7.06; N, 10.90.
Found: C, 77.64; H, 7.00; N, 11.05.
F,~nlnle 202 Preparation of 2-[(6-chloropyridazin-2-yl)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole CH~ ~ ~Cl NMR, UV, and IR were consistent with the desired title structure W O 97/09308 PCT~US96/1416 - 242 - ~
FDMS 371 (M+1). mp 138-139~C.
Analysis for C20H23ClN4O:
Theory: C, 64.77; H, 6.25; N, 15.11.
Found: C, 64.84; H, 6.28; N, 15.00.
~"~ ple 203 Preparation of 2-[(5,6,7,8-tetrahydrnn~phtll-1-yl)methyl]-1-methyl-3-[(4-dimethylaminopiperidin-1-yl)methyl]-lH-indole 3 N(CH3)2 NMR was consistent with the desired title structure.
FDMS 431 (M+).
15 Analysis for C2gH37N3O:
Theory: C, 77.92; H, 8.64; N, 9.74.
Found: C, 7~.79; H, 8.74; N, 8.74.
F.~ ?le 204 Preparation of 2-[(5,6,7,8-tetrahydronaphth-2-yl)methyl]-1-methyl-3-[(4-dimethylaminopiperidin- 1-yl)methyl]- lH-indole dihydrochloride hydrate ~ 1'1 ~
2HCl W O 97/09308 PCT~US96/14163 NMR and W were consistent with the desired title structure.
FDMS 431~ 432 (M+). mp 202~C.
Analysis for C2gH37N3O ~ 2 ECl ~ H2O:
Theory: C, 64.36; H, 7.91; N, 8.04.
Found: C, 64.73; H, 7.50; N, 7.99.
~,x~m,nle 205 Preparation of 2-[phenylthiomethyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride S~3 ~HCl NMR, W, and IR were consistent with the desired title structure.
FDMS 360 (M+1).
Analysis for C22H26N2S ~ HCl:
Theory: C, 68.28; H, 7.03; N, 7.24.
Found: C, 68.03; H, 7.00; N, 7.10.
~,xam~l?le 206 Preparation of 2-[(4-chlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride G~)~ .HCl NMR, W, and IR were consistent with the desired title structure.
FDMS 384 (M+).
Analysis for C22H2sClN2S ~ HCl:
Theory: C, 62.70; H, 6.22; N, 6.65.
Found: C, 62.12; H, 6.42; N, 6.22.
Single compound of high purity as evidenced by chromatographic 5 me ' hods.
mnle 207 Preparation of 2-[(3-chlorophenylthio)methyl]- 1-methyl-3-[(piperidin- 1-10 yl)methyl]-lH-indole hydrochloride NMR, W, and IR were consistent with the desired title structure.
FDMS 384 (M+).
Analysis for C22H2sClN2S ~ HCl:
Theory: C, 62.70; H, 6.22; N, 6.65.
Found: C, 62.94; H, 6.23; N, 6.93.
~ mrle 208 Preparation of 2-[(2-chlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ) f ~ HC l CH~ Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 384 (M+).
Analysis for C22H2sClN2S ~ HCl:
Theory: C, 62.70; H, 6.22; N, 6.65.
Found: C, 62.76; H, 6.20; N, 6.67.
F.~ ple 209 Preparation of 2-[(2,4-dichlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~ HC
CH, Cl Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 418 (M+).
Analysis for C22H24Cl2N2S ~ HCl:
Theory: C, 67.96; H, ~.53; N, 6.16.
Found: C, 56.61; H, 5.70; N, 6.05.
Single compound of high purity as evidenced by chromatographic methods.
F~lnrle 210 Preparation of 2-[(2,5-dichlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride CH3 Cl NMR, W, and IR were consistent with the desired title structure.
W O 97/09308 PCT~US96/14163 FDMS 418, 420 (M+1).
Analysis for C22H24Cl2N2S ~ HCl:
Theory: C, 57.96; H, 5.53; N, 6.15.
Found: C, 57.87; H, 5.50; N, 5.99.
F.x7mple 211 Preparation of 2-[(2,6-dichlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride HC l ~J
NMR, W, and IR were consistent with the desired title structure.
FDMS 417 (M+).
15 Analysis for C22H24Cl2N2S ~ HCl:
Theory: C, 57.96; H, 5.53; N, 6.15.
Found: C, 58.16; H, 5.68; N, 6.33.
F.x~mple 212 Preparation of 2-[(3,4-dichlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride Q s~cl CH3 Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 418, 420 (M+1).
Analysis for C22H24Cl2N2S ~ HCl:
Theory: C, 57.96; H, 5.53; N, 6.15.
Found: C, 57.98; H, 5.54; N, 6.16.
~ rnple 213 Preparation of 2-[(cyclohexylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~ {
NMR (CDCl3), UV, and IR were consistent with the proposed title structure.
FDMS 356 (M+).
15 Analysis for C22H32N2S ~ HCl:
Theory: C, 67.23; H, 8.46; N, 7.13.
Found: C, 66.28; H, 9.27; N, 7.71.
Single compound of high purity as evidenced by chromatographic methods.
~mr~le 214 Preparation of 2-[(n-1~l o~yl~hio)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole hydrochloride CH-I
NMR (CDCl3), W, and IR were consistent with the proposed title structure.
FDMS 316 (M+) Analysis for ClgH2gN2S ~ HCl:
Theory: C, 64.65; H, 8.28; N, 7.94.
Found: C, 64.72; H, 8.03; N, 8.12.
F~rnrle 215 Preparation of 2-[(benzylthio)methyl]- 1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride Q ~?~ j NMR, W, and IR were consistent with the desired title structure.
FDMS 365 (M+).
Analysis for C23H2gN2S ~ HCl:
Theory: C, 68.89; H, 7.29; N, 6.99.
Found: C, 68.63; H, 7.52; N, 7.11.
~r~mrle 216 Preparation of 2-[(2-phenylethylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole NMR (CDCl3) was consistent with the proposed title structure.
C24H30N2S: FDMS 379 (M+1).
Single compound of high purity as evidenced by chromatographic methods.
~.x~m}~le 217 Preparation of 2-[(naphth-2-ylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~ ~
NMR (CDCl3), W, and IR were consistent with the proposed title structure.
FDMS 400 (M+) 15 Analysis for C26H2gN2S ~ HCl:
Theory: C, 71.45; H, 6.69; N, 6.41.
Found: C, 69.59; H, 6.67; N, 6.21.
Single compound of high purity as evidenced by chromatographic methods.~0 mple 220 Preparation of 2-phenyl-3-(piperidin-1-yl)methyl-lH-indole 2s 6~
NMR, W, and IR were consistent with the desired title structure.
W O 97/09308 PCTrUS96/14163 FDMS 290 (M+).
Analysis for C2oH22N2:
Theory: C, 82.72; H, 7.64; N, 9.65.
Found: C, 82.97; H, 7.74; N, 9.81.
~qmple 221 Preparation of 1-methyl-2-phenyl-3-(piperidin-1-yl)methyl-lH-indole NMR, W, and IR were consistent with the desired title structure.
FDMS 304,305 (M+1).
Analysis for C2lH24N2:
Theory: C, 82.85; H, 7.95; N, 9.20.
Found: C, 82.68; H, 7.92; N, 9.40.
mple 222 20 Preparation of 2-phenyl-1-methyl-3-[2-(piperidin-1-yl)-1,2-ethanedionyl]-lH-indole 25 NMR (CDCl3), IR, and W were consistent with the proposed title structure.
FDMS 346 (M+) W O 97/09308 PCT~US96/14163 Analysis for C22H22N2o2:
Theory: C, 76.28; H, 6.40; N, 8.09.
FOund: C,76.09; H,6.35; N,8.09.
F.~7lmIlle 223 Preparation of 2-phenyl-1-methyl-3-[2-[N-benzyl-N-3-(dimethylaminopropyl)amino]-1,2-ethanedionyl]-lH-indole ~ CH
IR, NMR, and W were consistent with the desired title structure.
FDMS 463 (M+).
Analysis for C2sH3lN3o2:
Theory: C, 76.79; H, 6.89; N,9.26.
Found: C, 77.06; H,7.02; N,9.45.
F.~7m~nle 224 20 Preparation of 2-phenyl-1-methyl-3-[2-(4-dimethyl~minopiperidin-1-yl)-1,2-ethanedionyl]- lH-indole O ~ ,CH~
\C
.
IR, NMR, and W were consistent with the desired title structure.
FDMS 389 (M+).
Analysis for C24H27N3o2:
Theory: C, 74.01; H, 6.99; N, 10.79.
Found: C, 73.82; H, 6.98; N, 10.75.
F.~mple 225 Preparation of 1-methyl-3-[2-[N-benzyl-N-3-(dimethylaminopropyl)amino]-1,2-ethanedionyl]-lH-indole o CH3 ' CH3 IR, NMR, and W were consistent with the desired title structure.
FDMS 377 (M~). FAB 378 (M+1).
Analysis for C23H27N302:
Theory: C, 73.18; H, 7.21; N, 11.13.
Found: C, 70.74; H, 7.14; N, 10.75.
Single compound of high purity as evidenced by chromatographic methods.
m~le 226 Preparation of 1-methyl-3-[2-(4-dimethylaminopiperidin-1-yl)-1,2-ethanedionyl]-lH-indole W O 97/09308 PCT~US96/14163 O /--\ ~CH3 Q~ )-- CH3 IR, NMR, and W were consistent with the desired title structure.
FDMS 313 (M+1).
Analysis for Cl8H23N3o2:
Theory: C, 68.98; H, 7.40; N, 13.41.
Found- C, 68.97; H, 7.59; N, 13.43.
~mrle 227 Preparation of 5-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride HCl CH3 Cl Cl NMR (CDCl3) was consistent with the proposed title structure.
mp 177-179~C.
Analysis for C22H23Cl3N2O ~ HCl:
Theory: C, 55.72; H, 5.10; N, 5.91.
Found: C, 55.70; H, 5.21; N, 6.16.
~mple 228 Preparation of 5-methoxy-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-25 [(piperidin-1-yl)methyl]-lH-indole H3CO~ ~
CH3 Cl Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 432 (M+). mp 119-121~C.
5 Analysis for C23H26cl2N2o2:
Theory: C,63.74; H,6.05; N, 6.46.
Found: C, 63.70; H, 6.12; N, 6.46.
F.x~mrle 229 Preparation of 5-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[(4-dimethylaminopiperidin- 1 -yl )methyl]- lH-indole dihydrochloride Cl ~ (CH3)2 CH3 Cl Cl NMR (CDCl3) was consistent with the proposed title structure.
Analysis for C24H2gCl3N3O ~ 2 HCl:
Theory: C,52.05; H, 5.46; N, 7.59.
Found: C, 52.05; H,5.41; N, 7.56.
F.~mple 230 Preparation of 5-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[[4-(piperidin-1-yl)piperidin-1-yl]methyl]-lH-indole dihydrochloride CA 022039l2 l997-04-28 C~
CH3 Cl Cl NMR (CDCl3) was consistent with the proposed title structure.
Analysis for C27H32Cl3N3O ~ 2 HCl:
Theory: C, 54.61; H, 5.77; N, 7.08.
Found: C, 51.53; H, 6.53; N, 7.57.
~mrle 231 10 Preparation of 5-bromo-2-[(2,4-dichloroph en o~y)methyl] - 1-methyl-3-[2-(piperidin- 1-yl)ethyl]-lH-indole Br ~ N
N ~ ~
CH3 Cl Cl 15 NMR and IR were consistent with the desired title structure.
mp 158-160~C.
Analysis for C23H2sBrcl2N2o:
Theory: C, 55.67; H, 5.08; N, 5.64.
Found: C, 55.96; H, 5.28; N, 5.69.
mnle 232 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl- lH-indole ~,o~
IR, NMR, and W were consistent with the desired title structure.
FDMS 271 (M~).
5 Analysis for Cl6H14ClNO:
Theory: C, 70.72; H, 5.19; N, 5.15.
Found: C, 70.~2; H, 5.26; N, 5.28.
F,~mFle 233 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-1H-indole 15 IR, NMR, and W were consistent with the desired title structure.
FDMS 305.
Analysis for C16Hl3Cl2NO:
Theory: C, 62.76; H, 4.28; N, 4.57.
Found: C, 63.37; H, 4.72; N, 4.37.
~mple 234 Preparation of 2-[(5~6~7~8-tetrahydronaphth-l-yloxy)methyl]-l-methyl-lH
indole W 0 97/09308 PCTrUS96/141~3 Q~"o~
NMR was consistent with the desired title structure.
FDMS 292 (M+1).
Analysis for C2oH21NO:
Theory: C,82.44; H, 7.26; N,4.81.
Found: C, 82.51; H, 7.28; N,4.80.
F.~m~le 235 Preparation of 2-[(5,6,7,8-tetrahydronaphth-2-yloxy)methyl]-1-methyl-lH-indole NMR (CDCl3) was consistent with the proposed title structure.
FDMS 291 (M+).
Analysis for C2oH2lNO:
Theory: C, 82.44; H,7.26; N,4.81.
Found: C,82.25; H,6.98; N, 4.95.
rnnle 236 Preparation of 2-[(4-chlorophenoxy)methyl]-3-formyl-1-methyl-lH-indole CA 022039l2 l997-04-28 o Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 299 (M+).
5 Analysis for C17H14ClNO2:
Theory: C, 68.12; H, 4.71; N, 4.67.
Found: C, 67.90; H, 4.93; N, 4.73.
Fx~mple 237 Preparation of (RS) 1,2-dimethyl-3-[3-(piperidin-3-yl)propyl]-lH-indole ~'~
15 NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass for C18H27N2:
Theory: 271.2174.
Found: 271.2176.
F'.x~mple 238 Preparation of 1-methyl-2-[[2-[(piperidin-1-yl)methyl]phenoxy]methyl]-lH-indole W O 97/09308 PCT~US96/14163 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 335 (M+).
Analysis for C22H26N20:
Theory: C, 7g.01; H, 7.84; N, 8.38.
Found: C, 78.78; H, 7.58; N, 8.56.
F,x~mple 239 Preparation of 1-methyl-3-[2-[(4-chlorophenoxy)methyl]piperidin-1-ylmethyl]-lH-indole Q~
Cl NMR (CDC13) was consistent with the proposed title structure.
FDMS 368 (M+).
Analysis for C22H2sClN20 ~ HCl:
T heory: C, 65.19; HJ 6.46; N, 6.91.
Found: C, 64.93; H, 6.44; N, 6.78.
F,~mple 240 Preparation of l-methyl-3-[3-[(4-chlorophenoxy)methyl]piperidin-1-ylmethyl]- lH-indole ~ N ~
CH3 ~~
Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 368 (M+).
Analysis for C22H2sclN2o:
Theory: C, 71.63; H, 6.83; N, 7.59.
Found: C, 63.74; H, 6.54; N, 6.86.
m~e 241 Preparation of l-methyl-3-[2-[2-(4-chlorophenoxy)ethyl]piperidin-1-15 ylmethyl]-lH-indole ~N~
CH~
O~
~1 NMR (CDCl3) was consistent with the proposed title structure.
2 o FDMS 382 (M+).
Analysis for C23H27ClN2O:
Theory: C, 65.87; H, 6.73; N, 6.68.
Found: C, 62.05; H, 6.36; N, 6.18.
Tnrle 243 Preparation of ethyl 3-[2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl]propanoate ~O CH3 CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 371 (M+) Single compound of high purity as evidenced by chromatographic methods.
~rnrle 244 Preparation of (RS) ethyl 2-amino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl]propanoate o r CH3 ~0 /~NH2 ~, ~~
CH3 ~ C l NMR was consistent with the desired title structure.
FDMS 386.
25 Analysis for C2lH23ClN2O3:
Theory: C, 65.20; H, 5.99; N, 7.24.
Found: C, 64.95; H, 5.95; N, 7.27.
F.~qmrle 245 5 Preparation of ethyl 2-hydroxyimino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl]propanoate O r CH3 ~0 /~ NOH
,0~
CH3 Cl Ø2 H20 10 IR, NMR, and W were consistent with the desired title structure.
FDMS 400 (M+). mp 165-166~C.
Analysis for C2lH2lClN2O4 ~ 0 2 H2O:
Theory: C, 62.36; H, 5.33; N, 6.93.
Found: C, 62.38; H, 5.38; N, 6.87.
F,~mrle 246 Preparation of (RS) methyl 2-methoxyimino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl]propanoate O~ r 3 /~NOCH3 ~~'13~
IR, NMR, and W were consistent with the desired title structure.
FDMS 414 (M+).
mp 106-107~C.
Analysis for C22H23clN2o4:
Theory: C, 63.69; H, 5.59; N, 6.75.
- Found: C, 63.95; H, 5.57; N, 7.01.
F~mrle 247 Preparation of ethyl 2-benzoxyimino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl- lH-indol-3-yl]propanoate o r CH~
CH3 Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 490 (M~). mp 96~C.
Analysis for C28H27clN2o4:
Theory: C, 68.50; H, 6.54; N, 5.71.
Found: C, 68.78; H, 5.67; N, 5.64.
F.~r~qmrle 248 20 Preparation of ethyl 2-ethanoyloxyimino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl]propanoate O ~ r 3 NO r CH3 ~Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 442 (M+).
mp 128-129~C.
Analysis for C23H23clN2os:
Theory: C, 62.37; H, 5.23; N, 6.32.
Found: C, 62.44; H,5.40; N, 6.33.
F.~qmrle 249 Preparation of ethyl 2-benzoyloxyimino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl- lH-indol-3-yl]propanoate Q~
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 504 (M+).
mp 146-147~C
Analysis for C2gH2sClN2Os:
Theory: C, 66.60; H, 4.99; N, 5.55.
Found: C, 66.88; H,5.22; N, 5.80.
F.~m,nle 250 Preparation of 2-r(4-chlorophenoxy)methyl]-3-(4-hydroxy-1-25 methylpiperidin-4-yl)-1-methyl-lH-indole CH~
HO
~;~~
Cl NMR, IR and W were consistent with the desired title structure.
FDMS 384 (M+).
5 Analysis for C22H2sclN2o2:
Theory: C, 68.65; H, 6.55; N, 7.28.
Found: C, 69.46; H, 6.44; N, 7.28.
Single compound of high purity as evidenced by chromatographic methods.
F,x~ ?le 251 Preparation of ethyl 2-hy~l~ o~yi~ o-3-[1-methyl-2-phenyl-1H-indol-3-yl]propanoate o r CH3 ~0 ~ ~ NOH
~, CH3 ~
NMR (CDCl3) was consistent with the proposed title structure.
W and IR were consistent with the proposed title structure.
2 o FDMS 322 (M+) - mp 141-142~C.
Analysis for C19H18N203:
Theory: C, 70.79; H, 5.62; N, 8.69.
Found: C, 70.64; H, 5.89; N, 8.58.
W O 97/09308 PCTrUS96/14163 F,~m~le 252 Preparation of ethyl 2-hydro~yilllino-3-[1H-indol-3-yl]propanoate O~ r CH3 ~0 NOH
HN
IR, NMR, and W were consistent with the desired title structure.
FDMS 246 (M+).
10 mp 156~C.
Analysis for C13H14N2O3 ~ 0.3 H2O:
Theory: C, 62.04; H,5.85; N, 11.13.
Found: C, 61.77; H,5.55; N, 11.07.
~mrle 253 Preparation of 6-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-(piperidin-1-yl)ethyl]-lH-indole ~ N ~
Cl~ ~o~3~
CH3 Cl Cl IR and NMR were consistent with the desired title structure. FDMS 450 (M+). mp 116.5-118.5~C.
Analysis for C23H2sCl3N2O:
Theory: C, 61.14; H,-5.58; N, 6.20.
Found: C, 61.43; H,5.67; N, 6.26.
W O 97/09308 PCT~US96/14163 F~rle 255 Preparation of 7-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-5 (piperidin- 1-yl)ethyl]- lH-indole ~ ~ ~ Cl IR and NMR were consistent with the desired title structure. mp 134-0 136~C.
Analysis for C23H2scl3N2o:
Theory: C,61.14; H,5.58; N, 6.20.
Found: C, 61.39; H, 5.71; N,6.47.
F.~qmrle 256 Preparation of 4-methyl-2-[(2,4-dichlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]- lH-indole ~ H3 ~3 0~3~
~ Cl Cl - ~ NH
~
NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB (M+l) for C24H30clN2o:
Theory: 397.2047.
Found: 397.2041.
mrle 257 Preparation of 5-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[(4-dimethylaminopiperidin- l-yl)methyl]- lH-indole dihydrochloride Cl /--\
(cC ) Cl Analysis for C24H2gCl3N3O:
Theory: C, 52.05; H, 5.46; N, 7.59.
Found: C, 52.05; H, 5.41; N, 7.56.
F.~mrle 258 Preparation of 7-methyl-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[3-(piperidin-l-yl)propyl]-lH-indole dihydrochloride H3 ~ ~
NMR (CDC13) was consistent with the proposed title structure.
mp 129-131~C.
25 Analysis for C2sH3ocl2N2o:
Theory: C, 67.41; H, 6.79; N, 6.29.
Found: C, 67.34; H, 6.80; N, 6.05.
W 0 97/09308 PCTrUS96/14163 F.~mple 259 Preparation of 1,2-dimethyl-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-lH-indole ~N3N~
NMR, IR and W were consistent with the desired title structure.
FDMS 353 (M+) 10 Analysis for C22H31N3~:
Theory: C, 74.75; H, 8.84; N, 11.89.
Found: C, 74.76; H, 8.96; N, 11.76.
F~mnle 260 Preparation of 1,2-dimethyl-3-[[4-(N,N-dimethy~mino)piperidin-1-yl]acetyl]-lH-indole O /~ CH3 ~N~ N
NMR was consistent with the desired title structure.
C1gH27N3O: FDMS 313 (M+).
F,~mrle 261 Preparation of 2-[(4-chlorophenoxy)methyl]-3-[[(4-cyclohexyl)piperazin-1-yl] acetyl]- 1 -methyl- lH-indole W O 97/09308 PCT~US96/14163 - 270 - ~
N N{~
Cl NMR was consistent with the desired title structure.
C2gH34ClN3O2: FDMS 480 (M+) F,~r~rn,nle 262 Preparation of 2-[(4-chlorophenoxy)methyl]-3-[[(4-phenyl)piperazin-1-yl]acetyl]-1-methyl-lH-indole ~,N N{~
Cl NMR was consistent for the desiredtitle structure.
C2gH2gClN3O2: FDMS 474 (M+) ~ qm,nl e 263 Preparation of 2-[(4-chlorophenoxy)methyl]-3-[[4-(N,N-dimethylamino)piperidin-1-yl]acetyl]-1-methyl-lH-indole W O 97/09308 PCT~US96/14163 O /~ ,CH3 ~'~ \~ CH3 Cl NMR, IR and W were consistent with the desired title structure.
5 MSFD 439 (M+) Analysis for C2sH3oclN3o2:
Theory: C, 68.25; H, 6.87; N, 9.55.
Found: C, 67.98; H, 6.81; N, 9.40.
~ mI)le 264 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[N-methyl-N-(3-N', N'-dimethylaminopropyl)amino]acetyl]-lH-indole O C, H3 CH3 ~,N N~CH
H3C ~
Cl NMR and IR were consistent with the desired title structure.
FDMS 428 (M+1) FAB exact mass CalculatedforC24H3lClN302: 428.2105 2 o Found: 428.2113 ~.x~mrle 26~ -Preparation of 2[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[(4-piperidin- 1-5 yl)piperidin-1-yl]acetyl]-lH-indole Cl NMR, IR and UV were consistent with the desired title structure.
MSFD 479 (M+1) FAB exact mass CalculatedforC28H3sClN302: 480.2418 Found 480.2411 ~ x&~mrlle 266 Preparation of 2-[(4-chlorophenoxy)methyl]-3-[2-[(4-piperidin-1-yl)piperidin-1-yl]acetyl]-1-[2-(N,N-dimethylpiperidin-4-ylium)ethyl]-lH-indole iodide WO 97t09308 PCTtUS96/14163 N
N+ I-NMR was consistent with the desired title structure.
Analysis for C36HsoclIN4o2 ~ H2O:
Theory: C, 57.56; H, 6.90; N, 7.46.
Found: C, 57.85; H, 6.86; N, 7.04 mple 267 2-[(4-chlorophenoxy)methyl]-1-[(2-piperidin-4-yl)ethyl]-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]acet-1-yl]-lH-indole CI
N
NMR was consistent with the desired title structure.
FABMS 577 (M+1) 5 Analysis for C34H4sClN402:
Theory: C, 70.75; H, 7.86; N, 9.71 Found: C, 70.55; H, 7.87; N, 9.52 F.~mn1e 268 2-~(4-chlorophenoxy)methyl]-3-[2-(methylaminoy~ oyyldimethylamine)acet-l-yl]-1-[(2-piperidin-3-yl)ethyl]-indole H3C~
C
O~N
Cl ~~~Cl ~NH
NMR was consistent with the desired title structure.
FABMS 525(M+l) Exact Mass for C30H42N4~2Cl:
Theory: 525.2996 Found: 525.3003 m~le 269 2-[(4-chlorophenoxy)methyl]-1-[(2-piperidin-3-yl)ethyl]-3-[2-(4-(piperidin-l-yl)piperidin-l-yl)acet-l-yl]-lH-indole N
~O~Cl \~NH
NMR was consistent with the desired title structure.
FDMS (M+l) Analysis for: C34H4sN4O2Cl:
Theory: C, 70.75; H, 7.86; N, 9.71 Found: C, 70.72; H, 7.83; N, 9.63 F.~m~le 270 2-[(4-chlorophenoxy)methyl] -3-[2-10 (methylaminop~ yldimethylamine)acet-1-yl]-1-[(2-piperidin-4-yl)ethyl]-lH-indole H3C~
CH3 ,_~N-CH3 O~N~
~ 0~ Cl 15 NMR was consistent with the desired title structure.
Exact Mass for C30H42N4O4Cl (M+1):
Theory: 525.2996 Found: 525.3013 ~mrle 271 S-2-[(4-chlorophenoxy)methyl]-3-[2-(4-(piperidin-1-yl)piperidin-1-yl)acet-1-yl]-1-[(3-piperidin-3-yl)propyl]-lH-indole W O 97/09308 PCTrUS96/14163 ' ~
O ~ N
~O~Cl ~ NH
NMR was consistent with the desired title structure.
FABMS (M+l) Analysisfor: C35H47clN4O2 Theory: C, 71.10; H, 8.01; N, 9.48 Found: C, 70.82; H, 8.14; N, 9.23 F,x~mple 272 R-2-[(4-chlorophenoxy)methyl]-3-[2-(4-(piperidin- 1-yl)piperidin- 1-yl)acet-1-yl] -1-[(3-piperidin-3-yl)propyl]-lH-indole O~N
~,0~ Cl GNH
NMR was consistent with the desired title structure.
Exact Mass for C3sH48ClN402:
Theory: 591.3466 Found: 591.3458 mple 273 cis/trans-2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(4-(piperidin- 1-yl)cyclohex-l-yl)acet-l-yl]-lH-indole N
0~
~~Cl Mixture of cis/trans isomers I & 2 NMR was consistent with the desired title structure.
- FDMS 478 (M+) - Analysisfor: C2sH3sclN2o2 Theory: C, 72.71; H, 7.36; N, 5.85 Found: C, 72.65;H, 7.61;N,5.95 ml)le 274 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-(piperidin-1-yl)cyclohex-1-yl)acet-1-yl]-lH-indole o\~
~<~Cl CH3 Isomer I
NMR was consistent with the desired title structure.
FDMS 478 (M+) Analysis for: C2gH3sclN2o2 Theory: C, 72.71; H, 7.36; N, 5.85 Found: C, 72.55; H, 7.52; N, 5.67 ~ mple 275 2-[(4-chlorophenoxy)methyl] -3-[2-(4-(piperidin- 1-yl)cyclohex-1-yl)acet-1-yl ]-1-[(2-piperidin-4-yl)ethyl]-lH-indole WO 97/09308 PCT~US96/14163 0~
~O~Cl lsomer 1 NMR was consistent with the desired title structure.
FDMS 575 (M+) 5 Analysisfor: C3sH46clN3o2 Theory: C, 72.95; H, 8.06; N, 7.29 Found: C, 72.88; H, 8.23; N, 7.53 e 276 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-(piperidin-1-yl)cyclohex-1-yl?acet-1-yl]-indole CA 022039l2 l997-04-28 ' ~
O~p ~~Cl Isomer 2 NMR was consistent with the desired title structure.
FDMS 478 (M+) 5 Analysisfor: C2sH3sclN2o2 Theory: C, 72.71; H, 7.36; N, 5.85 Found: C, 72.43; H, 7.42; N, 5.86 F~m~le 277 2-[(4-chlorophenoxy)methyl]-5-fluoro-1-methyl-3-[2-(4-(piperidin-1-yl)piperidin- lyl)acet- 1-yl]-lH-indole O~N
F~ O~Cl NMR was consistent with the desired title structure.
FABMS 498 (M+1) WO 97/09308 PCT~US96/14163 Analysis for: C28H33clFN3o2 Theory: C, 67.53; H, 6.68; N, 8.44 Found: C, 67.34; H, 6.59; N, 8.68 By substantially following the procedures described above one skilled in the art can prepare the other compounds of Formula I.
The compounds of the present invention bind to receptors specific for neuropeptide Y as well as the closely related neuropeptides.
10 [For a review of neuropeptide Y receptors, see, D. Gehlert, Life Sciences, 55:~51-562 (1994); P.A. Hipskind and D.R. Gehlert, Annual Reports in Medicinal Ch~mi.~try. 31:1 (1996)]. Receptors for neuropeptide Y and peptide YY have considerable overlap while pancreatic polypeptide appears to have its own distinct set of receptors. Many, but not all, of the 15 effects of neuropeptide Y can be replicated using peptide YY.
Two subtypes of receptors for neuropeptide Y were initially proposed on the basis of the afflnity of the 13-36 fragment of neuropeptide Y using a preparation of the sympathetic nervous system. While these are the best estqhli~hed receptors for neuropeptide Y, a substantial body 20 of evidence exists that there are additional receptor subtypes. The best estqhli~hed is a Y-3 receptor that is responsive to neuropeptide Y, but not to peptide YY. Another recently ~lçlinçqted receptor has been described that binds peptide YY with high affinity and neuropeptide Y with lower affinity. While the pharmacology of the feeding response to 25 neuropeptide Y appears to be Y-1 in nature, a separate "feeding receptor" has been proposed. Several of the receptors have been successfully cloned to date. The following paragraphs sl~mmqrize the available information on the known neuropeptide Y receptor subtypes and their potential role in physiological function.
Y-1 Receptor The Y-1 receptor is the best characterized receptor for neuropeptide Y. This receptor is generally considered to be postsynaptic and mediates many of the known actions of neuropeptide Y in the 35 periphery. Originally, this receptor was described as having poor CA 022039l2 l997-04-28 - affinity for C-terminal fr~grnents of neuropeptide Y, such as the 13-36 fr~ment, but interacts with the full length neuropeptide Y and peptide YY with equal affinity. C. Wahlestedt, et al., ReFulatory PeI?tides~
13:307-318(1986); C. Wahlestedt, et al., NEURONAL MESSENGERS IN
VASCUnl~R FUnNCTION, 231-241 (Nobin, et al., eds. 1987). Substitution of the amino acid at position 34 with a proline (Pro34) results in a protein which is specific for the Y-1 receptor. E.K. Potter, et al., European Journal of Phar-n~- lo~v~ 193:15-19(1991). This tool has been used to establish a role for the Y-1 receptor in a variety of functions. The receptor is thought to be coupled to adenylate cyclase in an inhibitory manner in cerebral cortex, vascular smooth muscle cells, and SK-N-MC
cells. [For a review, see, B.J. McDermott, et al., Cardiovascular Research. 27:893-905(1993)]. This action is prevented by application of pertussis toxin confirming the role of a G-protein coupled receptor. The Y-1 receptor mediates the mobilization of intracellular calcium in a porcine vascular smooth muscle cells and human erythroleukemia cells.
The cloned human Y-1 receptor can couple to either phosphotidylinositol hydrolysis or the inhibition of adenylate cyclase, depen~1ing on the type of cell in which the receptor is expressed. H.
Herzog, et al., Proceellin~s of the National Academy of Sciences (USA), 89:5794-5798(1992). The Y-1 receptor has been reported to couple to either second messenger system when studied using tissue preparations or cell lines naturally expressing the receptor. D. Gehlert, supra, at 553. The Y-1 receptor cannot, therefore, be distinguished solely on the basis of coupling to a single second messenger.
Modulation of a Y-1 receptor (either a typical or an atypical Y-1 receptor) is believed to influence multiple physiological conditions, including, but not limited to, obesity or appetite disorder, adult onset diabetes, bulimia nervosa, pheochromocytoma-induced hypertension, subarachnoid hemorrhage, neurogenic vascular hypertrophy, hypertension, anxiety, and anorexia nervosa. PCT Patent Publication W O 96/16542, published June 6,1996, at page 135, and the references cited therein.
Y-2 Receptor W097/09308 PCT~S96/14163 As with the Y-1 receptor, this receptor subtype was first delineated using vascular preparations. Pharmacologically, the Y-2 receptor is distinguished from Y-1 by exhibiting affinity for C-terminal fr~gments of neuropeptide Y. The receptor is most often differentiated 5 by the use of neuropeptide Y(13-36), though the 3-36 fra~ment of neuropeptide Y and peptide YY provides improved affinity and selectivity. Y. Dumont, et al., Society for Neuroscience Abstracts. 19:726 (1993). Like Y-1 rece~to,-, this receptor is coupled to the inhibition of adenylate cyclase, though in some preparations it may not be sensitive to 10 pertussis toxin. The Y-2 receptor was found to reduce the intracellular levels of calcium in the synapse by selective inhibition of N-type calcium h~nnel~. Like the Y-1 receptor, the Y-2 receptor may exhibit differential coupling to second messengers. The Y2 receptor is believed to be involved in mod~ tin~ hypertension, epileptic seizure, and 5 neurogenic vascular hypertrophy. PCT Patent Publication WO 96/16542, published June 6,1996, at page 135, and the references cited therein.
The Y-2 receptors are found in a variety of brain regions, including the hippocampus, substantia nigra-lateralis, t~ rnus, hypot~ mus, and brainstem. In the periphery, Y-2 iS found in the 20 peripheral nervous system, such as symp~t~letic, parasympathetic, and sensory neurons. In all these tissues, Y-2 receptors mediate a decrease in the release of neurotransmitters. The Y-2 receptor has been cloned using expression cloning techniques. P.M. Rose, et al., Journal of Biolo~ical Chemistry. 270:22661 (1995); C. Gerald, et al., Journal of 25 Biolo~ical Chemistry. 270:26758 (1995); D.R. Gehlert, et al., Molecular PharmacoloFy. 49:224 (1996).
Y-3 Rece~?tor This receptor has high affinity for neuropeptide Y while 3 o having lower affinity for peptide YY. While neuropeptide Y is a fully efficacious agonist at this receptor population, peptide YY is weakly efficacious. This pharmacological property is used to define this receptor. A receptor that has ~imil~r pharmacology to the Y-3 receptor has been identified in the CA3 region of the hippocampus using 3 5 electrophysiological techniques. This receptor may potentiate the excitatory response of these neurons to N-methyl-D-aspartate (NMDA).
W097/09308 PCT~S96/141 F.P. Monnet, et al., European Journal of PharmacoloFy, 182:207-208 - (1990). This receptor is believed to modulate hypertension. PCT Patent pllhli~on WO 96/16542, pllhli~hed June 6,1996, at page 135, and the references cited therein.
The presence of this receptor is best established in the rat brainstem, specifically in the nucleus tractus solitarius. Application of neuropeptide Y to this region produces a dose-dependent reduction in blood pressure and heart rate. This area of the brain also may have significant contributions from the Y-1 and Y-2 receptor. Neuropeptide Y
also inhibits the acetylcholine-induced release of catecholamines from the adrenal medulla, presumably through a Y-3 receptor. C.
Wahlestedt, ~, Life Sciences. 50:PL7-PL14 (1992).
Peptide YY Preferrin~ Rece~tor A fourth receptor has been described that exhibits a modest preference for peptide YY over neuropeptide Y. This receptor was first described in the rat small intestine as having a 5-10 fold higher affinity for peptide YY over neuropeptide Y. M. Laburthe, et al., Endocrinolo~y.
118:1910-1917 (1986). Subsequently, this receptor was found in the adipocyte and a kidney proximal tubule cell line. This receptor is coupled in an inhibitory m~nner to adenylate cyclase and is sensitive to pertussis toxin.
In the intestine, this receptor produces a potent inhibition of fluid and electrolyte secretion. The receptor is loc~li7.e~1 to the crypt cells 2 5 where intestinal chloride secretion is believed to take place. The peptideYY l,~efe~l;ng receptor in adipocytes mediates a reduction in lipolysis by way of a cyclic adenosine monophosphate (cAMP)-dependent mechanism.
"Feellin~ Receptor"
One of the earliest discovered central effects of neuropeptide Y was a profound increase in food intake that was observed following the hypothalmic ~(lmini~tration of the peptide to rats. The response was greatest when the peptide was infused into the perifornical region of the 3 5 hypothAl~mus. B.G. Stanley, et al., Brain Research. 604:304-317 (1993).
While the pharmacology of this response resembled the Y-1 receptor, the W O 97/09308 PCT~US96/14163 2-36 fr2~Frnent of neuropeptide Y was significantly more potent than neuropeptide Y. In addition, intracerebroventricular neuropeptide Y(2-36) fully stimulates feeding, but does not reduce body temperature as does full length neuropeptide Y. F.B. Jolicoeur, et al., Brain Research Bulletin. 26:309-311 (1991). Two recent patent publications describe the cloning and expression of the Y5 receptor, believed to be the "feeding receptor". Patent Cooperation Treaty Publication WO 96/16542, published June 6, 1996; and Australian Patent Publication AU 956467 A0, published November 30, 1995.
The biological activity of the compounds of the present invention was evaluated employing an initial screening assay which rapidly and accurately measured the binrling of the tested compound to known neuropeptide Y receptor sites. Assays useful for evaluating neuropeptide Y receptor antagonists are well known in the art. See. e.~
United States Patents 5,284,839, issued February 8, 1994, which is herein incorporated by reference. See P~l~o, M.W. Walker, et al., Journal of Neurosciences,8:2438-2446 (1988).
Neuropeptide Y B;ndin~ Assay The ability of the compounds of the instant invention were assessed as to their ability to bind to neuropeptide Y using a protocol essentially as described in M.W. Walker, et al., supra. In this assay the cell line SK-N-MC was employed. This cell line was received from Sloane-Kettering Memorial Hospital, New York. These cells were cultured in T-150 flasks using Dulbecco's Minim~l Essential Media (DMEM) supplemented with 5% fetal calf serum. The cells were manually removed from the flasks by scraping, pelleted, and stored at -70~C.
The pellets were resuspended using a glass homogenizer in 25 mM HEPES (pH 7.4) buffer cont~ining 2.5 mM calcium chloride, 1 mM magnesium chloride, and 2 g/L bacitracin. Incubations were performed in a final volume of 200 ~ll cont~ining 0.1 nM l25I-peptide YY
(2200 Ci/mmol) and 0.2-0.4 mg protein for about two hours at room temperature.
Nonspecific binrling was defined as the amount of - radioactivity rem~ining bound to the tissue after incubating in the presence of 1 IlM neuropeptide Y. In some experiments various concentrations of compounds were included in the incubation mixture.
Incubations were terminated by rapid filtration through glass fiber filters which had been presoaked in 0.3~o polyethylen~imine using a 96-well harvester. The filters were washed with 5 ml of 50 mM
Tris (pH 7.4) at 4~C and rapidly dried at 60~C. The filters were then treated with melt-on scint~ tion sheets and the radioactivity retained on the filters were counted. The results were analyzed using various software packages. Protein concentrations were measured using standard collm~sie protein assay reagents using bovine serum albumin as standards.
Many of the compounds prepared _upra showed significant activity as neuropeptide Y receptor antagonists (Kj = 10 ~M to 0.1 nM).
As the compounds of Formula I are effective neuropeptide Y receptor antagonists, these compounds are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of 2 0 an excess of neuropeptide Y. Thus, the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises ~iministering to a m~mm~l in need of said tre~trnent an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. The term ~physiological disorder associated with an excess of neuropeptide Y" encompasses those disorders associated with an ina~ opliate stimulation of neuropeptide Y receptors, regardless of the actual amount of neuropeptide Y present in the locale.
These physiological disorders include:
3 o disorders or diseases pert~ining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, ~ngin~, myocardial infarction, sudden cardiac death, congestive heart failure, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow 3 5 of fluid, abnormal mass transport, or renal failure;
conditions related to increased sympathetic nerve activity for e~mple, during or after coronary artery s~ely~ and operations and surgery in the gastrointestinal tract;
cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, dementia, seizure, and epilepsy;
conditions related to pain or nociception;
diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease;
abnormal drink and food intake disorders, such as obesity, anorexia, blllimi~, and metabolic disorders;
diseases related to sexual dysfunction and reproductive disorders;
conditions or disorders associated with infl~mm~tion;
respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leut.ini~ing hormone, growth hormone, insulin, and prolactin.
The compounds of Formula I are usually ~-lmini~tered in the form of pharmaceutical compositions. These compounds can be 2 5 A-1mini.~tered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intr~n~l. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a m~nner well known in the pharmaceutical art and comprise at least one active compound.
3 0 The present invention also includes methods employing pharmaceutical compositions which contain, as the active ingredient, a compound of Formula I associated with pharmaceutically acceptable carriers. In m~kin~ the compositions of the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or 3 5 enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/14163 - diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, 5 aerosols (as a solid or in a liquid medium), ointments cont~ininF for mple up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the 10 active compound to provide the a~l ~ol~l;ate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a S subst~nt~ ly uniform distribution in the formulation, e.g. about 40 mesh.
Some e~mples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum ~c~ , calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, 20 microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include:
lubricating agents such as talc, m~gnesium stearate, and mineral oil;
wetting agents; emulsifying and suspen-ling agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and 2 5 flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after ~tlmini~tration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit 3 o dosage form, each dosage cont~ining from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term aunit dosage form" refers to physically discrete units suitable as unitary dosages dosages for human subjects and other m~mm~l~, each unit cont~qining a predetermined quantity of active material calculated to 3 5 produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound is effective over a wide dosage range.
For e~mples, dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult hllm~n~, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is 5 especially preferred. However, it will be understood that the amount of the compound ~ctll~lly ~-lmini~tered will be determined by a physician, in the light of the relevant cil cumstances, including the condition to be treated, the chosen route of ~mini~tration, the actual compound Arlmini~tered, the age, weight, and response of the individual patient, 10 and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, 15 provided that such larger doses are first divided into several smaller doses for ~rlmini~tration throughout the day.
For preparing solid compositions such as tablets the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition cont~ininE a homogeneous 20 mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dipsersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid 25 ~lefo,.llulation is then subdivided into unit dosage forms of the type described above cont~ining from 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage 3 o of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the 3 5 duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for ~tlmini~tration orally or by 5 injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and simil~r pharmaceutical vehicles.
Compositions for inh~l~tion or insufflation include 0 solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or ll~i~lu~es thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are zltlmini~tered by the oral or nasal respiratory route for local or systemic 15 effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebl1li7.ing device or the nebllli7.ing device may be attached to a face mask, tent, or intermittent positive pressure breathing m~hine. Solution, suspension, or powder compsoitions may 20 be ~tlmini~tered, preferably orally or nasally, from devices which deliver the formulation in an aplJlop~iate manner.
The following examples illustrate the pharmaceutical compositions of the present invention.
Formulation Preparation 1 Hard gelatin capsules cont~ining the following ingredients are prepared:
Quantity Tnpredient (m~/capsule) Active Ingredient 30.0 Starch 3050 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin 15 capsules in 340 mg quantities.
Formulation Preparation 2 A tablet formula is prepared using the ingredients below:
Quantity Tn~redient (m~/tablet) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg.
Formulation Preparation 3 A dry powder inhaler formulation is prepared cont~ining the following components:
Tn~redient W~i~ht ~o Active Ingredient 5 Lactose 96 The active mixture is mixed with the lactose and the mixture is added to a dry powder inh~ling appliance.
Formulation Preparation 4 Tablets, each cont~ining 30 mg of active ingredient, are prepared as follows:
Quantity Tn~redient (m~/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinyll~yl 1 olidone (as 10% solution in water) 4.0 mg Sodium carboxy-methyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 m~
Total 120 mg W O 97/09308 PCT~US96/14163 The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are 5 then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60~C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine 10 to yield tablets each weighin~ 120 mg.
Formulation Preparation 5 Capsules, each cont~qining 40 mg of medicament are made 15 as follows:
Quantity InFre-lient (mF/capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 m~
Total 150.0 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 160 mg quantities.
W O 97/09308 PCT~US96/14163 Formulation Preparation 6 Suppositories, each cont~inin~ 25 mg of active ingredient are made as follows:
Tn~redient Amount Active Ingredient 26 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nomin~l 2.0 g capacity and allowed to cool.
Formulation Preparation 7 Suspensions, each cont~inin~ 50 mg of medicament per 5.0 ml dose are made as follows:
Tn~redient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v.
.
3 5 Purified water to 5.0 ml W O 97/09308 PCT~US96/14163 The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium bçn7.0~te, flavor, and 5 color are diluted with some of the water and added with stirring.
Sufficient water is then added to produce the required volume.
Formulation Preparation 8 Capsules, each conhining 15 mg of medicament, are made as follows:
Quantity Tn~redient (m~/capsule) Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 rn~
Total 425.0 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled 2 5 into hard gelatin capsules in 425 mg quantities.
Formulation Preparation 9 An intravenous formulation may be prepared as follows:
Tn~redient Quantity Act*e Ingredient 260.0 mg Isotonic saline 1000 ml Formulation Preparation 10 A topical formulation may be prepared as follows:
Tn~redient Quantitv Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20g White Soft Paraffin to 100 g The white soft paraffin is heated until molten. The liquid praffin and 25 emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
- - -W O 97/09308 PCT~US96/14163 Formulation Preparation 11 Sublingual or buccal tablets, each cont~ining 10 mg of active ingredient, may be prepared as follows:
Quantity Tn~redient Per Tablet Active Ingredient(s) 10.0 mg Glycerol 210.5 mg Water 143.0 mg Sodium Citrate 4.5 mg Polyvinyl Alcohol 26.5 mg Polyvinyl~yll olidone 15.5 rn~
Total 410.0 mg The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and m~int~inin~ the temperature at about 90~C. When the polymers have gone into solution, the solution is cooled to about 50-55~C and the 25 medicament is slowly admixed. The homogenous ~ e is poured into forms made of an inert material to produce a drug-co~t~inin~
diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
3 o Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches 3 5 for the delivery of pharmaceutical agents is well known in the art. See.
e.~., U.S. Patent ~,023,2~2, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, - or on d~m~n(l delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly.
5 Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such impl~ntable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S.
Patent 5,011,472, issued April 30, 1991, which is herein incorporated by 10 refernce.
Indirect techniques, which are generally preferred, usually involve form~ ting the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
Latentiation is generally achieved through blocking of the hydroxy, 15 carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and ~men~ble to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enh~nced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
Priority Claim This application claims the benefit of United States Provisional Applications 60/003,150, filed September 1, 1996, and 60/021,638, filed July 12, 1996 and United Kingdom Patent Applic?/tion 9623999.2, filed November 23, 1996.
B~kFround of the Invention Neuropeptide Y is a peptide present in the central and peripheral nervous systems. The peptide co-exists with noradrenaline in many neurons and acts as a ne~ollansmitter per se or synergistically together with noradren~line. Neuropeptide Y-cont~ining fibers are numerous around arteries in the heart, but are also found around the arteries in the respiratory tract, the gastrointestinal tract, and the genitourinary tract. Neuropeptide Y is also present in the cerebrum with effects on blood pressure, feeding, and the release of different hormones. Alterations in central concentrations of neuropeptide Y have been implicated in the etiology of psychiatric disorders.
Neuropeptide Y was discovered, isolated and sequenced in 1982 from porcine brain as part of a general screening protocol to discover carboxy-terminal amidated peptides and was named neuropeptide Y due to its isolation from neural tissue and the presence of tyrosine as both the amino and carboxy terminal amino acid.
Neuropeptide Y is a member of the pancreatic f~mily of peptides and shares significant sequence homology with pancreatic polypeptide and peptide YY.
Neuropeptide Y and the other members of its family of peptides all feature a tertiary structure consisting of an N-terminal polyproline helix and an amphiphilic a-helix, connected with a ~-turn, creating a hairpin-like loop, which is sometimes referred to as the W O 97/09308 PCT~US96/1416 pancreatic polypeptide (PP) fold. The helices are kept together by hydrophobic interactions. The a_idated C-terminal end projects away from the hairpin loop.
Subsequent to its disc-Jvely neuropeptide Y was identified as 5 being the most abundant peptide in the central nervous system with widespread distribution including the cortex, brainstem, hippocampus, hypot~hl~mll~, amygdala, and t~lAmus as well as being present in the peripheral nervous system in symp~At~etic neurons and adrenal chromAf~ln cells.
Neuropeptide Y seems to fulfill the main criteria for a role as a neurotransmitter, as it is stored in synaptic granules, is released upon electrical nerve st;m~ tion, and acts at specific receptors. It is clear that neuropeptide Y is an important messenger in its own right, probably in the brain, where neuropeptide Y potently inhibits the activity of adenylate cyclase and induces an increase in the intracellular levels of calcium. Central injection of neuropeptide Y results in blood pressure changes, increased feeding, increased fat storage, elevated blood sugar and insulin, decreased locomotor activity, reduced body temperature, and catalepsy.
Neuropeptide Y (as well as its chemical relatives) acts upon membrane receptors that are dependent on guanyl-nucleotide hin~ling proteins, known as G protein-coupled receptors. G proteins are a family of memhrane proteins that become activated only after binding guanosine triphosphate. Activated G proteins in turn activate an Amplifier enzyme on the inner face of a memhrane; the enzyme then converts precursor molecules into second messengers.
Neuropeptide Y appears to interact with a family of closely related receptors. These receptors are generally ~ sified into several subtypes based upon the ability of different tissues and receptors to bind 3 o different fr~gments of neuropeptide Y and other members of the PP
family of peptides. The Y1 receptor subtype appears to be the major vascular neuropeptide Y receptor. The Y2 receptor subtypes can also occur postjunctionally on vascular smooth muscle. The as-yet-unisolated Y3 receptor subtype appears to be neuropeptide Y-specific, 3 5 not binding peptide YY. This receptor is likely to be present in the adrenal tissues, medulla, heart, and brain stem, among other areas.
[For a review of neuropeptide Y and neuropeptide Y receptors, see. e.F., ~ C. Wahlestedt and D. Reis, Annual Review of Pharmacolo~v and Toxicolo~v, 33:309-352 (1993); D. Gehlert and P. Hipskind, Current Pharmaceutical Desi~n, 1:295-304 (1995)].
In view of the wide number of clinical m~ lies associated with an excess of neuropeptide Y, the development of neuropeptide Y
receptor antagonists will serve to control these clinical conditions. The earliest such receptor antagonists, such as Patent Cooperation Treaty Patent Publication WO 91/08223, pllhli~hed June 13, 1991, and Patent Cooperation Treaty Patent Publication WO 94/00486, published January 6, 1994, were peptide del;valives. These antagonists are of limited pharmaceutical utility because of their metabolic instability.
This invention provides a class of potent non-peptide neuropeptide Y receptor antagonists. By virtue of their non-peptide nature, the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based neuropeptide Y receptor antagonists.
S~lmm~ry of the Invention This invention encompasses methods for the treatment or l,level.tion of a disorder associated with an excess of neuropeptide Y, which method co~l~lises ~-lmini~tering to a m~mm~l in need of said treatment an effective ~mount of a compound of Formula I
,R2 ,~ (CH2)s ,C~
~ (CH2)q yl X
Rb~"A (CH2)p--R
R
wherein:
Rb is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 ~lk~noyl, trifluoromethyl, hy~o~y, or halo;
R1 is hydrogen, C1-C6 alkyl, or -(CH2)V-Rla;
where v is 1 to 12, and R1a is phenyl, n~phthyl, hexamethyleneiminyl, piperazinyl, heptamethylenei_inyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, he~methyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the groups consisting of C1-C6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C1-C6 alkyl)amino, C1-C6 alkylamino, C2-C6 ~1k~noyl, C2-C6 alkanoyloxy, and C3-Cg cycloalkyl, said said phenyl, benzyl, or C3-Cg cycloalkyl, being optionally substituted with one, two, or three moieties independently selected from the group consisting of C1-C6 alkyl, halo, or C1-C6 alkoxy, or Rla may be substituted with -(CH2)~R1b, where w is 1 to 12 and R1b is piperidinyl, pyrimidyl, pyrrolidinyl, C1-C6 alkoxy, C1-C6 alkylthio, di[di(Cl-C6 alkyl)amino(C1-C6 alkylenyl)]amino, di(C1-C6 alkyl)amino(Cl-C6 alkylenyl)amino, phenyl, C3-Cg cycloalkyl, pyrrolidinyl, and acetamido, said phenyl, or C3-Cg cycloalkyl, being optionally substituted with one, two, or three moieties independently selected from the group ~ consisting of Cl-C6 alkyl, halo7 or Cl-C6 alkoxy;
-A is a bond, -(CH2)m or -C(O)-;
Al is a bond, -NRa-, -O-, -(CH2)m-, or -S(O)n-;
qisOto6;
0 pisOto6;
nis 0,1, or2;
m is O to 6;
s is O to 6;
Ra is hydrogen, Cl-C6 alkyl, or C2-C6 ~lk~nnyl;
D is a bond, C2-C4 alkenylenyl, or -C(X)(Y)-, where one of X and Y is hy~ o~y and the other is hydrogen, or both X and Y are hydrogen, or X and Y
combine to form =O, or =NORC;
Rc is hydrogen, benzyl, acetyl, benzoyl, or Cl-C6 alkyl;
one of Xl and yl is hydloxy and the other is hydrogen, or 3 o both Xl and yl are hydrogen, or Xl and yl combine to form =O, or =NORd;
Rd is hydrogen or Cl-C6 alkyl;
R2 is hydroxy, C1-C6 alkyl, Cl-C6 alkoxy, phenoxy, or a group of the formula N\
wherein R4 and R5 are independently hydrogen, Cl-C6 alkyl, phenyl, or phenyl(Cl-C6 alkylenyl)-, or R2 is a heterocyclic ring selected from the group consisting of he~Amethyleneiminyl, piperazinyl, heptamethyleneiminyl, imi~ olinyl, piperidinyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl;
any one of which hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of Cl-C6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino(C1-C6 alkylenyl)-, Cl-c6 alkylamino(cl-c6 alkylenyl)-, C2-C6 alkanoyl, carboxamido, 2-aminoacetyl, C2-C6 AlkAnOylOxy~ Cl-C6 alkoxycarbonyl-, Cl-C6 alkylAmino, C3-Cg cycloalkyl, piperidinyl, pyrrolidinyl, pyrimidyl, phenyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, piperidinyl(C1-C6 alkylenyl)-, pyrrolidinyl(C1-C6 alkylenyl)-, pyrimidyl(C1-C6 alkylenyl)-, C1-C6 alkogy, Cl-C6 alkylthio, di[di(Cl-C6 alkyl)amino(Cl-C6 alkylenyl)]amino, di(Cl-C6 alkyl)amino(C1-C6 alkylenyl)amino, and acetamido, any one of which benzyl, phenyl, piperidinyl, C3-Cg cycloaLkyl, phenyl(Cl-C6 alkylenyl)-, phenoxy(Cl-C6 alkylenyl)-, pyrrolidinyl, ~ piperidinyl(Cl-C6 alkylenyl)-, pyrrolidinyl(Cl-C6 alkylenyl)-, pyri_idyl(Cl-C6 alkylenyl)-, or pyrimidyl group may be substituted with one or more moieties selected from the group consisting of Cl-C6 alkyl, halo, trifluoromethyl, acetamido, C2-C6 alkanoyl, C2-C7 alkanoyloxy, and Cl-C6 alkoxy, or the nitrogen on said piperidinyl, pyrrolidinyl, piperidinyl(Cl-C6 alkylenyl)-, pyrrolidinyl(Cl-C6 alkylenyl)-, pyrimidyl(Cl-C6 alkylenyl)-, or pyrimidyl may be substituted with an amino-protecting group, or R2 is a group of the formula R4a I ~ R6a N\
R5a where R4a, R5a, and R6a are independently hydrogen, Cl-C6 alkyl, trifluoromethyl, or Cl-C6 alkoxy, or R4a is hydrogen, Cl-C6 alkyl, trifluoromethyl, or C1-C6 alkoxy and R5a and R6a comhine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or 2 5 heptamethyleneiminyl, or R4a is o~y~ell, and R5a and R6a combine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or 3 o heptamethyleneiminyl;
R is phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C3-Cg cycloaLkyl, pyrazinyl, allyl, CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/14163 thiazolyl, furyl, pyrimidyl, pyridinyl, quinolinyl, isoqllinolinyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethyleneiminyl, hept~methyleneiminyl, piperidinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C3-Cg cycloalkyl, pyrazinyl, thiazolyl, furyl, pyrimidyl, pyridinyl, quinolinyl, isoquinolinyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, he~methyleneiminyl~
heptamethyleneiminyl, piperidinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of C1-C12 alkyl, C2-C1o alkenyl, C2-C1o alkynyl, halo, trifluoromethyl, carbox~mido, cyano, benzyl, phenyl, di(cl-c6 alkyl)amino, C2-C6 zllk~noyl, C2-C6 alkanoyloxy, Cl-C6 alkyl~mino, oxazolyl, dihydrooxazolyl, piperidinyl(C1-C12 alkoxy)-, piperidinyl(C1-C12 alkoxy)(C1-C6 alkylenyl)-, piperidinyl(C1-C12 alkylenyl)-,phenyl(C1-C12 alkoxy)-, phenyl(C2-C12 alkylenyl)-, C3-Cg cycloalkyl, piperidinyl, pyrimidyl, C1-C6 alkoxy, C1-C6 alkylthio, a group of the formula RXRYN-G-L-(co-c6 alkylenyl)-, and acetamido, where Rx and RY are independently hydrogen, C1-C6 alkyl, phenyl, benzyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, morpholinyl, 3 o piperazinyl, or C3-Cg cycloalkyl, or where RXRYN is a ring selected from the group consisting of piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, 3 5 azetidinyl, which may be attached to G at any appropriate place on the ring, ~ G is C1-C12 alkylenyl, C2-Cl2 alkenylenyl, or'~ C2-C12 alkynylenyl, and .
L is a bond, -O-, -S-, -S(O)-, -S(0)2-, or -NH-;
with the proviso that when, Al is NRa, -O-, or -S(O)n-, and A is -CH2-, R1 is not hydrogen;
10 or a pharmaceutically acceptable salt or solvate thereof.
This invention also encompasses the novel compounds of Formula I as well as pharmaceutical formulations comprising a compound of Formula I in cnmhin~t.ion with one or more 15 pharmaceutically acceptable carriers, diluents, or excipients therefor.
Detailed Description and Plefelled Embodiments The current invention concerns the disc~v~ly that a select 2 o group of substituted indoles, those of Formula I, are useful as neuropeptide Y receptor antagonists.
"C1-C6 alkoxy" represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
Typical Cl-C6 alkoxy groups include methoxy, ethoxy, propoxy, 25 isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term aC1-C6 alkoxy" includes within its definition the terms "Cl-C4 alkoxy" and "C1-C3 alkoxy".
As used herein, the term "C1-Cl2 alkyl" refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 12 carbon 3 o atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term "Cl-Cl2 alkyl" includes within its definition the terms "Cl-C6 alkyl" and "Cl-C4 alkyl".
"C2-C7 alkanoyloxy" represents a straight or branched alkyl 3 5 chain having from one to six carbon atoms attached to a carbonyl moiety joined through an oxygen atom. Typical C2-C7 alkanoyloxy groups WO 97/09308 PCT~US96/1416 include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, t-butanoyloxy, pentanoyloxy, he~n~yloxy, 3-methylpentanoyloxy and the like.
~C3-Cg cycloalkyl" represents a saturated hydrocarbon ring structure Cont~ininF from three to eight carbon atoms. Typical C3-Cg cycloalkyl groups include cyclolJ~o~yl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
~Halo~ represents chloro, fluoro, bromo or iodo.
"C1-C1o alkylthio" represents a straight or branched alkyl chain having from one to ten carbon atoms attached to a sulfur atom.
Typical C1-C1o alkylthio groups include methylthio, ethylthio, ~o~yl~hio, isolJlo~ylll~io, butylthio and the like. The term "Cl-Clo alkylthio" includes within its definition the term ~Cl-C6 alkylthio~ and ~Cl-C3 alkylthion.
~C1-C12 alkylenyl" refers to a straight or branched, divalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl, octylenyl, 3-methyloctylenyl, decylenyl. The term Ucl-c6 alkylenyl~ is encompassed within the term ~C1-C12 alkylenyl". The term ~Co alkylenyl" or any term incorporating this design~tion, refers to a bond, for ç~m~le ~Co-C6 alkylenyl" refers to a bond or C1-C6 alkylenyl, as such is defined herein.
~C1-C1o alkyl~mino" represents a group of the formula -NH(C1-C1o alkyl) wherein a chain having from one to ten carbon atoms is attached to an amino group. Typical C1-C4 alkylamino groups include methyl~mino, ethylamino, propylamino, isol,~ol~yl~mino, butylamino, sec-butylamino and the like.
The term ~C2-Cl2 alkenyl" as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to twelve carbon atoms. Typical C2-C12 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 2,4-hexadienyl, 1-propenyl, 3 5 2-propenyl, 2-butenyl, 2-pentenyl, and the like.
The term "C2-Cl2 alkynyl" as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to ten carbon atoms with at least one triple bond. Typical C2-Cl2 alkynyl groups include ethynyl, l-~ Jyllyl, 1-butynyl, 1-hexynyl, 2-propynyl, 2-butynyl, 2-pentynyl, and the like.
The term ~C2-Cl2 alkenylenyl" as used herein represents a straight or branched, divalent, unsaturated aliphatic chain having from two to twelve carbon atoms. Typical C2-cl2 alkenylenyl groups include -CH=CH-, -CH2-CH=CH-, -cH2-c(cH3)=cH-cH2cH2-~ and the like.
The term "C2-Cl2 alkynylenyl" as used herein represents a straight or branched, d*alent, unsaturated aliphatic chain having from two to ten carbon atoms with at least one triple bond. Typical C2-Cl2 alkynylenyl groups include -C_C-, -CH2-C-C-, -CH2-C-C-CH2CH2-, and the like.
"C3-Cg cycloalkenyl" represents a hydrocarbon ring structure contPininF from three to eight carbon atoms and having at least one double bond within that ring.
~C1-C6 alkoxy" represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
Typical Cl-C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term ~C1-C6 alkoxy" includes within its definition the term "C1-C3 alkoxyn.
"C2-C6 alkanoyl" represents a straight or branched alkyl chain having from one to five carbon atoms ~tt~ched to a carbonyl moiety. Typical C2-C6 alkanoyl groups include ethanoyl, propanoyl, isopropanoyl, butanoyl, t-butanoyl, pentanoyl, hexanoyl, 3-methylpentanoyl and the like.
~C1-C6 alkoxycarbonyl" represents a straight or branched alkoxy chain having from one to six carbon atoms attached to a carbonyl moiety. Typical C1-C6 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and the like.
The term "amino-protecting group" as used in the specification refers to substituents of the amino group commonly 3 5 employed to block or protect the amino functionality while reacting other CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/14163 functional groups on the compound. F~mples of such amino-protecting groups include formyl, trityl, phthAlimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzylo~ycall,onyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzylo~ycall,onyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzylo~ycalbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzylo~ycalbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-ylo~ycall,onyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, l-methylcyclohexanylo~ycall,onyl, 2-methylcyclohe~nyloxycarbonyl, 2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)-etho~yca-lJonyl, fluorenylmethoxy-carbonyl ("FMOC"), 2-(trimethylsilyl)etho~ycall,onyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop- 1-enyloxycarbonyl, 2 0 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzylo~ycall,onyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethol~ycall)onyl, 4-(decyloxy)benzylo~ycalL.onyl, isobornylo~ycalbonyl, 1-piperidyloxycarbonyl and the' like;
benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphine oxide and like amino-protecting groups. The species of amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the intermediate molecule and can be select*ely removed at the a~ l;ate point without disl-u~ g the rçm~in-ler of the molecule including any other amino-protecting groups. Preferred amino-protecting groups are trityl, t-butoxycarbonyl (t-BoC, Boc, or t-Boc), allyloxycarbonyl and benzyloxycarbonyl. Further e~mples of groups referred to by the above terms are described by E. H~ m, "Protective Groups in Organic Chemistry", (J.G.W.
McOmie, ed., 1973), at Chapter 2; and T.W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991), at Chapter 7.
The term acarboxy-protecting group~ as used in the ~ specification refers to substituents of the carboxy group commonly employed to block or protect the carboxy functionality while rez~cting other functional groups on the compound. F,~mrles of such 5 car~oxy-protecting groups include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoxy-benzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, 10 t-Amyl, trityl, 4-metho~ylrilyl, 4,4'-dimetho~ytrityl, 4,4',4"-trimetho~ytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, 2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, ~inn~qmyl, 5 1-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. Preferred carboxy-protecting groups are allyl, benzyl and t-butyl. Further e~mrles of these groups are found in E. ~ m, supra, at Chapter 5, and T.W. Greene, et al., supra, at Chapter 5.
The term ahydroxy-protecting groups~ as used herein refers 2 o to substitents of the hyLo~y group commonly employed to block or protect the hydroxy functionality while re~ct;ng other functional groups on the compound. ~ mples of such hy~o~y-protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, 2,2-dichloro-1,1-25 difluoroethyl, tetrahyd~ yldnyl, ph~n~cyl, cyclo~ ylll~ethyl, allyl, Cl-C6 alkyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl, t-butyldimethylsilyl, levulinate, pivaloate, benzoate, dimethylsulfonate, dimethylphosphinyl, isobutyrate, ~ m~ntoate and tetrahydropyranyl.
Further ç~mples of these groups may be found in T. W. Greene and 3 o P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991) at Chapter 3.
The term aleaving group~ as used herein refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction. The term ~leaving group~ as 3 5 used in this document encompasses, but is not limited to, activating groups.
The term ~activating group~ as used herein refers a leaving group which, when taken with the carbonyl (-C=O) group to which it is attached, is more likely to take part in an acylation reaction than would be the case if the group were not present, as in the free acid. Such 5 activating groups are well-known to those skilled in the art and may be, for e~Ample, suc~.inimidoxy, pht~limidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido, or -O-CO-(C4-C7 alkyl).
The compounds of the present invention are derivatives of 10 indole which are named and numbered according to the RING INDEX, The American Chemical Society, as follows.
N
The compounds of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, those compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual 2 o isomers and comhin~tions thereof, are within the scope of the present nventlon.
The terms ~R" and ~S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
The term ~R" (rectus) refers to that configuration of a chiral center with 2 5 a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
3 o The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereo~.hçmi~try is contained in NOMENCLATURE OF ORGANIC
-W O 97/09308 PCTrUS96/14163 -COMPOUNDS: PNNCIPLES AND PRACTICE, (J.H. Fletcher, et al., eds., ~ 1974) at pages 103-120.
In addition to the (R)-(S) system, the older D-L system may ~ also be used in this docl~ment to denote absolute configuration, 5 especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix "D~ is used to represent the absolute configuration of the isomer in which the functional (detel...;.-i..g) group is on the right side of the carbon atom at the chiral center and "L", that of 0 the isomer in which it is on the left.
In order to lJlerelentially prepare one optical isomer over its enantiomer, the skilled practitioner can proceed by one of two routes.
The practitioner may first prepare the ~ e of enantiomers and then separate the two enantiomers. A commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an optically active salt or base. These diastereomers can then be separated using differential solubility, fractional crystallization, chromatography, or like methods.
Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al., ENANTIOMERS, RACEMATES, AND
RESOLUTIONS, (1991).
In addition to the schemes described above, the practitioner of this invention may also choose an enantiospecific protocol for the preparation of the compounds of Formula I. Such a protocol employs a synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation. These reaction schemes usually produce compounds in which greater than 95 percent of the title product is the desired enantiomer.
3 o As noted supra, this invention includes the pharmaceutically acceptable salts of the compounds defined by Formula I. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and 3 5 organic acids, to form a pharmaceutically acceptable salt.
J
CA 022039l2 l997-04-28 WO 97/09308 PCT~US96/14163 The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula which are subst~nti7lly non-toxic to living org~nicmq. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the 5 compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic lo acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. ~.~Amples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, 15 sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, o~lAte, malonate, succinate, suberate, sebacate, fumarate, 20 maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobçn~oAte, methylbenzoate, hyd-o~ybenzoate, methoxybenzoate, pht~lAte, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, ~-hydlo~ybuly~ate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, 25 mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Salts of amine groups may also comprise quarternary 30 ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or ~lk~line earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing 3 5 the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formulas I. Many of the Formula I compounds can comhine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the correspon~ing hydrate, methanolate, ethanolate and acetonitrilate.
This invention also encompasses the pharmaceutically acceptable prodrugs of the compounds of Formula I. A prodrug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form. This prodrug should have a different pharmacokinetic profile than the parent, enabling easier absorption across the mucosal epithelium, better salt formation or solubility, or improved systemic stability (an increase in pl~m~ half-life, for example).
Typically, such chemical modifications include:
2 5 1) ester or amide derivatives which may be cleaved by esterases or lipases;
2) peptides which may be recognized by specific or nonspecific proteases; or 3) derivatives that accumulate at a site of action through 3 o membrane selection of a prodrug form or a modified prodrug form;
or any cnmhin~tion of 1 to 3, supra. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in H, Bundgaard, Desi~n of Prodrl~s~ (1985).
The preferred compounds of the present invention are those 3 5 compounds of Formula I in which:
a) Rb is hydrogen, chloro, fluoro, methyl, ethyl, - hydlo~y, or acetyl;
b) R1 is methyl, ethyl, or Rla is phenyl, piperidinyl, pyrrolidinyl, he~methyleneiminyl, piperazinyl, and v is 1 to 6;
c) Al is a bond, -NH-, -N(CH3)-, -S-, or -O-;
d) A is -CH2- or -CH2CH2-;
e) q is 0, 1, or 2;
f) p is 0, 1, or 2;
g) s is 0, 1, 2, or 3;
h) D is a bond, -C(O)-, -CH(OH)-, or -CH2-;
i) R2 is a group of the formula -NR4R5 or -N+R4aR5aR6a;
j) R4 and R5 are independently hydrogen, methyl, ethyl, benzyl, or comhine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethylçneiminyl group;
k) R4a, R~a, R6a are independently hydrogen, methyl, ethyl, or R5a and R6a combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethyleneiminyl group; and l) R is phenyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, naphthyl, thiazolyl, furyl, quinolinyl, isoquinolinyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl, or quinuclidinyl;
i or a pharmaceutically acceptable salt or solvate thereof.
The preferred methods of the present invention are those methods employing compounds of Formula I in which a) Rb is hydrogen, chloro, fluoro, methyl, ethyl, hydroxy, or acetyl;
b) Rl is methyl, ethyl, or Rla is phenyl, piperidinyl, pyrrolidinyl, he~methyleneiminyl, piperazinyl, and v is 1 to 6;
c) Al is a bond, -NH-, -N(CH3)-, -S-, or -O-;
d) A is -cH2- or -cH2cH2-;
e) q is 0, 1, or 2;
f) p is 0, 1, or 2;
g) s is 0, 1, 2, or 3;
h) D is a bond, -C(O)-, -CH(OH)-, or -CH2-;
i) R2 is a group of the formula -NR4R5 or -N+R4aR5aR6a;
j) R4 and R5 are independently hydrogen, methyl, ethyl, benzyl, or combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethyleneiminyl group;
3 5 k) R4a, R~a~ R6a are independently hydrogen, methyl, ethyl, or R5a and R6a combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or h~x~methyleneiminyl group; and l) R is phenyl, piperidinyl, pyrrolidinyl, he~s~methyleneiminyl, heptamethyleneiminyl, naphthyl, thiazolyl, furyl, qllinolinyl, isoqllinolinyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl, or quinuclidinyl;
or a pharmaceutically acceptable salt or solvate thereof.
Especially l~lefel-ed compounds of the present invention are those compounds of Formula I in which:
a) Rb is hydrogen, fluoro, or methyl;
b) R1 is methyl, or R1a is piperidinyl, pyrrolidinyl, or hçx~methyleneiminyl, and v is 1, 2, or 3;
c) A1 is a bond, -NH-, -S-, or -0-;
d) A is -CH2- or -CH2CH2-;
e) qisOorl;
f) pisOorl;
g) sis Oorl;
h) D is a bond, or -C(O)-;
i) R2 is a group of the formula -NR4R5;
j) R4 and R5 are independently methyl, or comhine to form, together with the nitrogen to which they are attached, a piperidinyl, piperazinyl, or pyrrolidinyl t group;
k) R is optionally substituted phenyl, naphthyl, or cyclohexyl;
or a pharmaceutically acceptable salt or solvate thereof.~0 Especially preferred methods and formulations of the present invention are those methods and formulations employing especially preferred compounds.
Particularly preferred compounds are those of Formula I in which:
a) Rb is hydrogen;
b) Rl is methyl, piperidinyl(Cl-C4 alkylenyl)-, or pyrroldinyl(Cl-C4 alkylenyl)-;
c) Al is a bond or -0-;
d) A is -CH2-;
d) q is O;
e) pisOorl;
fl sis Oorl;
g) D is a bond, or -C(O)-;
h) R2 is a piperidinyl, or pyrrolidinyl group, substituted with amino, di(C1-C6 alkyl)amino, (C1-C6 alkyl)amino, piperidinyl, or pyrrolidinyl, or R2 is a piperazinyl group substituted with phenyl, cyclohexyl, or benzyl; and j) R is phenyl, substituted with one to three groups selected from C1-C6 alkyl, trifluoromethyl, and halo;
10 or a pharmaceutically acceptable salt or solvate thereof.
Especially preferred methods and formulations of the present invention are those methods and formulations employing especially preferred compounds.
A most preferred class of compounds of the present invention are those compounds of Formula I of the Formula /~D~,R
R** R*~0 where:
D1 is -C(O)~, or -CH2-;
R1 is methyl,piperidin-3-yl-CH2-CH2-, piperidin-3-yl-CH2-CH2-CH2-, piperidin-2-yl-cH2-cH2-~
piperidin-2-yl-CH2-CH2-CH2-, pyrrolidin-3-yl-CH2-CH2-, pyrrolidin-3-yl-CH2-CH2-CH2-, piperidin-4-yl-CH2-CH2-, or piperidin-4-yl-CH2-CH2-CH2-;
R2 is piperidinyl, or pyrrolidinyl group, substituted with amino, di(Cl-C6 alkyl)amino, (Cl-C6 alkyl)amino, piperidinyl, or pyrrolidinyl, or R2 is a piperazinyl group substituted with phenyl or cyclohexyl;
R* is chloro or bromo; and R** hydrogen or chloro;
10 or a pharmaceutically acceptable salt or solvate thereof.
Methods and formulations employing any of this class of most preferred compounds are also most preferred.
The compounds of Formula I may be prepared by a number of methods known to those skilled in the art. One protocol for preparing those compounds of Formula I in whch Rl is methyl, is depicted in Scheme I, infra.
Scheme I
~COOH ~_,OH
aLkylation or arylation (CH2)p-R I ~(CH2)p-R
As would be appreciated by those skilled in the art, there are numerous ways of performing each of the steps depicted supra.
Typical such methods are described infra in the general te7~r.hings and ~ the examples.
R~o~
~COOH ~ ,OH
Many of the compounds of Formula I are prepared through the reduction of 1-methyl-2-indolecarboxylic acid to the corresponding 2-hy~lro~y~ethyl-1-methylindole. This reduction may be prepared by several methods known in the art including catalytic hydrogenation. A
most ~lefelled method for this reduction is by using a reducing agent 15 such as sodium borohyd~ide, lithium borohydride, diisobutylaluminumhydride hydride, lithium triethylborohydride, borane-methyl sulfide complex in refluxing tetrahydrofuran, and triethoxysilane. Another means of reducing the carboxylic acid is by means of sodium in eth~nol, a method known as the Bouveault-Blanc 20 procedure. A most l,le~elled reducing agent employed in this procedure is lithium aluminum hydride.
Alkyla'don orArylation ~ ArOH
The coupling of the aryl group to the above alcohol may be performed using standard techniques. For those compounds of Formula I in which A is -O-, p is 0, and R is substituted phenyl, for ex~mple, a most preferred method involves a phenolic coupling using a Mitsunobu reagent. O. Mitsunobu, et al., Bulletin of the Chemical Societv of Japan. 44:3427 (1971); O. Mitsunobu, et al., Journal of the 5 American Chemical Society, 94:679 (1972). In this reaction triphenylphosphine, in comhin~tion with diethyl azodicarboxylate (DEAD), converts alcohols in situ to the corresponding alkoxyphosphonillm salts, which are useful alkylating agents.
Although this coupling can be accomplished using various 10 concentrations of the re~qct~nts and reagents, it is best to use 1 to 2 equivalents of the indole methyl alcohol, triphenylphosphine, and DEAD
per each equivalent of the substituted phenol (ArOH) used.
This reaction also is best carried out in the presence of an inert solvent such as, for ex~mple, toluene, benzene, or, preferably 15 tetrahydrofuran. The reaction is performed at temperatures from about 0~ C to about 40~ C, preferably at ambient temperature, until the desired compound is prepared. Typically, the reaction takes about 18 hours when run at aInbient temperature, but the progress of the reaction can be monitored via standard chromatographic techniques.
" ArX
An alternative method of arylating the alcohol involves nucleophilic aromatic substitution of an aryl fluoride with a preformed 25 alkoxide. This reaction is performed by first ~tltlin~ a base to the alcohol, followed by the addition of the aryl halide. An especially ~lere~,ed base is sodium hydride. Another preferred base is sodium hexamethylrli~ ide. The reaction is generally performed in a polar aprotic solvent, for example, acetonitrile, N,N-dimethylformamide, 30 N,N-dimethylphenylacetamide, dimethylsulfoxide, or hexamethylphosphoric triamide.
WO 97/0930~ PCT/US96/141~3 Alky~'don ~~ HCHO ~,,OAr Alkylation of the 1,2-disubstituted indole may be done by a variety of methods known to those skilled in the art. A preferred method of alkylating this substituted indole is by way of a ~nnich reaction. [For reviews of this reaction, see, Tramontini, Synthesis. 703-775 (1973);
House, MODERN SYNTHETIC REACTIONS, (2d ed., 1972) at pages 654-660.]
In this reaction formaldehyde (or sometimes another aldehyde) is condensed with HNR4R5, in the form of its salt, and a compound cont~ining an active hydrogen. Instead of ammonia, the reaction can be carried out with salts of primary (RNH2) or secondary amines (R2NH), or with amides (RCONH2), in which cases the product is substituted on the nitrogen with R, R2, and RCO, respectively. This reaction is generally carried out in a lower alkyl alcohol, such as methanol or et~nol, or in an acid, such as acetic acid.
One process for preparing those compounds of Formula I in which A is an alkylenyl group is by first o~ ing the alcohol to form the corresponding aldehyde.
~_,OH ~CHO
This reaction is generally performed using an oxidizing agent such as pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC) in a solvent such as methylene chloride. The resulting aldehyde is then reacted with a substituted phosphonate in the presence of a base.
ArCH2PO(OEt)2 ~Ar This Wittig-type reaction results in the formation of an aralkenyl group.
A ~lefelled base employed in this reaction is sodium hydride. This reaction generally results in a ~ ure of the (E) and (Z) stereoisomers.
The double bond is then reduced using either a reducing agent as 10 described supra or by means of catalytic hydrogenation using standard means. Preferred solvents for this reaction include dichloroethane.
Ar ~~Ar The resulting 1,2-disubstituted indole may then be substituted at the 3 position essentially as described above for the M~nnich chemistry.
A HNR4R5 ~>~
Those compounds in which Rl is a substituted alkylenyl group [(CH2)v-Rla]may be prepared as illustrated in Scheme II, infra.
W O 97/09308 PCT~US96/14163 Scheme II
a~ ~CH3 ~ h~/n ~ ~Ro,CH3 ~NTr ,CH3 ~,,OH
~) reduction ~
NTr ~ NTr ~ ,,OH ~"~
c ) ~ substitution ~> ~'Cl F~Cl f~
I NTr NTr in which Tr is a trityl group.
W O 97/09308 PCT~US96/14163 Scheme II (continued) d~ ~Cl \~CI
[~ halogenation NTr NTr N
e) 1) t-BuLi ~~
, ~ 2) CN{~N~N ~CH3 ~ CI
~NTr CH3 ~
NTr deprotection C~~ 3'CI
~,NTr ~NH
W 0 97/09308 PCT~US96/14163 For those compounds of Formula I in which L is -S-, the thio derivatives and intermediates of this invention may be transformed into the correspontling sulfoxide (-SO-) compounds upon treatment with a mild oxidizing agent, such as hydrogen peroxide in methanol, meta-chloroperbenzoic acid (MCPBA) in methylene chloride at 0~C, or an alkali metal periodate in aqueous alcohol. The corresponding sulfones (-SO2-) are prepared from the thio or sulfoxide compounds on treA~ment with a strong oxidizing agent, such as hydrogen peroxide in acetic acid or m-chloroperbenzoic acid in methylene chloride at 20~C-30~C.
Those compounds of Formula I in which the benzo ring of the indole has been substituted may be prepared by a number of ways known to those skilled in the art. For ç~Ample, those compounds of Formula I in which the 4-position of the indole ring has been substituted with methyl may be prepared as described in Scheme III, infra.
In step a), below, a Knoevenagel condensation reaction is performed, resulting (after the dehydration step of the reaction) in an olefin. This reaction is generally performed with an excess of the azide, although an eqllimolAr ll~ixlu~e of the two reagents may be employed.
The olefin product of step a) is then cyclized to form an indole ring. The usual means of this cyclization is by heating the olefin.
The progress of the cyclization may be followed by thin layer chromatography.
Scheme III
a) ~/ dd ti ~CO2Et ~"C02Et ~--C02Et b) ~ N3 cyclization NH
CH3 CH3 Br c) ~ brnminA~;~m ~CO2Et d) &~ CH3l ~ ~C02Et N alkylation N
Scheme III (continued) ~CO2Et 8ubStitution ~'~~
1~ 2)reductlon ~OH~
f) CH3 CH3 1) base Cl ~H20--H~ 2)substitution ~~~
g) CH3 CH3 \~
Cl--~Cl Scheme IV
Rb Rb 1) a. n-BuLi, CO
~_3 b t-BuLI CO2 ~_~
NH [MeOH] NH CH3 Rb Rb Nll OMI"I ~'~~CH3 Rb Tr CH3 ~OH
[THF~ ~
) r~
Tr NJ
Tr -CA 022039l2 l997-04-28 ScheIne IV (Continued) Rb ~OH l)NaH;[DMF] ~~~C
~,~ Z)HCO2H, [CH2C12]
N~
Tr H
CA 022039l2 l997-04-28 An alternative method of preparing those compounds of Formula I in which Rb is not hydrogen may be prepared as described in Scheme IV, infra.
The intermediates and other reagents necessary for the preparations fo the compounds of the present invention, are commercially available, are known in the literature, or can be prepared by known methods. In addition, those of ordinary skill in the art will recognize that variations on the methods for preparing the claimed compounds as described above may be performed without detracting from the synthesis of these compounds. For ~mrle, other esters may be employed, as may protecting groups, precursors, the direct introduction of the carboxylic acid group onto the benzo ring of the indole (Kolbe-Schmitt reaction ), etc. Moreover, certain Rb groups may be introduced directly onto the benzo ring. For e~mple, a chloro group can be introduced by treating with iodobenzene, chlorine, and pyridine [Murakami, et al.. Chem. Pharm. Bull.. 19:1696 (1971)] or N-chlorosllcrinimide in dimethylformamide [United States Patent 4,623,657, the entire contents of which are herein incorporated by 20 reference]. In addition to those described supra, other transformations, intraconversions, and deriv~ti~?.tions are either described in the F.~mples, infra, or are well known to those of ordinary skill in the art.
The following ~ mples further illustrate the compounds of the present invention and the methods for their synthesis. The 25 F.~mp~es are not intended to be limiting to the scope of the invention in any respect, and should not be so construed. All experiments were run under a positive pressure of dry nitrogen or argon. All solvents and reagents were purchased from commercial sources and used as received, unless otherwise indicated. Dry tetral,yLo~llran (THF) was 30 obtained by distillation from sodium or sodium benzophenone ketyl prior to use.
Proton nuclear m~gnetiC resonance (lH NMR) spectra were obtained on a GE QE-300 spectrometer at 300.15 MHz, a Bruker AM-500 spectrometer at 500 MHz, or a Bruker AC-200P spectrometer at 200 MHz, 35 or a like model. (Unless designated otherwise, the term "NMR" as employed herein refers to proton nuclear magnetic resonance.) Free atom bombardment mass spectroscopy (FAB) was performed on a VG
ZAB-2SE instrument. Field desorption mass spectroscopy (FDMS) was performed using either a VG 70SE or a Varian MAT 731 instrument.
~ Optical rotations were measured with a Perkin-Elmer 241 5 polarimeter. Chromatographic separation on a Waters Prep 500 LC was generally carried out using a linear gradient of the solvents indicated in the text unless otherwise specified.
The reactions were generally monitored for completion using thin layer chromatography (TLC). Thin layer chromatography 10 was performed using E. Merck Kieselgel 60 F2s4 plates, 5 cm x 10 cm, 0.26 mm thickness. Spots were detected using a comhin~ion of W and chemical detection (plates dipped in a ceric ammonium molybdate solution [76 g of ~mmonium molybdate and 4 g of cerium (IV) sulfate in 500 ml of 10% aqueous sulfuric acid] and then heated on a hot plate).
5 Preparative centrifugal thin layer chromatography was performed on a Harrison Model 7924A Chromatotron using Analtech silica gel GF
rotors.
Cation exchange chromatography was performed with Dowex~) 50X8-100 ion e~rh~nge resin. Anion e~lh~nge 20 chromatography was performed with Bio-Rad AG(~) 1-X8 anion-exchange resin (acetate form converted to hydroxide form). Flash chromatography was performed as described by Still, et al., Journal of Or~anic Chemistry, 43:2923 (1978).
Optical rotations are reported at the sodium-D-line (354 25 nm). Elemental analyses for carbon, hydrogen, and nitrogen were determined on a Control Equipment Corporation 440 Elemental Analyzer, or were performed by the Universidad Complutense Analytical Centre (Facultad de Farm~ , Madrid, Spain). Melting points were determined in open glass capillaries on a Thomas Hoover 30 capillary melting point apparatus or a Buchi melting point apparatus, and are uncorrected.
The following methods provide illustrative protocols for preparing the compounds of Formula I as depicted in the Schemes supra. Throughout the Methods and ~ mples, infra, the terms 35 "NMR~, "IR~, and "W" indicate that the proton nuclear magnetic resonance, infrared, and ultraviolet spectroscopy, respectively, were consistent with the desired title product.
Preparation 1 Preparation of (3'R) ethyl 2-(piperidin-3-yl)acetate O~CH3 J O
N
Ethyl-3-pyridylacetate (lOOg, 0.606 mol) was dissolved in ethanol (1.8 liters), treated with 5% rhodium on alumina (100 g) and hydrogenated at 60~C and 60 psi hydrogen gas overnight. The catalyst was removed by filtration and the solvent evaporated to give a brown liquid (101.4 g, 98%). The brown liquid was dissolved in ethyl acetate (600 15 1) and treated with L-(+)-m~ntlelic acid in warm ethyl acetate (600 1).
After cooling in the refrigerator for four hours, the solid was collected and the cryst~lli7~ion fluid reserved for processing to the other enantiomer, infra. The solid was again recrystallized from ethyl acetate (1.55-1.6 liters, overnight at ambient temperature) to give the desired title 20 product as white needles. Yield: 81.6 grams, 41%.
O.R. (EtOH) ~589 nm = +44.9~, ~365 nm = +173.73~. mp 118-119~C.
Prepar7~tior~ 2 25 Preparation of (3'S) ethyl 2-(piperidin-3-yl)acetate O~CH3 ~NJ
H
The crystallization fluid from Preparation 1, supra, was 30 evaporated to give a dark oil (100.3 g). This was dissolved in a cold CA 022039l2 l997-04-28 W 097/09308 PCT~US96/14163 solution of potassium carbonate (52 g, 0.377 mol) in water (260 ml) and extracted with ethyl acetate (5 X 150 ml). The extracts were comhined and dried over m~gnesium sulfate. The solvents were removed in vacuo to give a dark liquid (40.25 g). The dark liquid was treated with a warm 5 solution of D-(-)-m~n~lelic acid (36 g) in ethyl acetate (650 ml) and stirred at ambient temperatures overnight. The crystals were recrystallized twice more from ethyl acetate (1.2 liters and 1.1 liters, respectively) to give the desired title product as white needles. Yield: 48.7 g, 24.9%.
O.R. (EtOH) ~589 nm = -43.14~, ~365 nm = -164.31~. mp 115.5-117~C.
Chiral Analvtical Method Cold aqueous potassium carbonate (0.15 g in 10 ml of water) was treated with 0.3 g of the mandelic acid salt and the ~ e was 15 extracted with ethyl acetate (3 x 5 ml). The combined extracts were dried over magnesinm sulfate and the solvents were removed in vacuo. The residue was dissolved in diethyl ether (10 ml) and treated with S-(-)-a-methylbenzylisocyanate (0.12 ml). After 2.5 hours, the reaction was treated wtih 1 N hydrochloric acid (2 ml). The ether was separated and 20 then washed sequentially with bnne, a saturated aqueous sodium bicarbonate solution, and brine. The organic fraction was dried over m~gnçsium sulfate and the solvents were removed by evaporation. The residue was analyzed on a CHIRACEL OJTM high performance liquid chromatography column (4.6 x 250 mm), eluting with 5% ethanol in 25 hexanes at a flow rate of 2.5 mVminute. The slower component comes from the l-(~)-m~nrlelic acid salt and the faster from the d-(-)-m~nrlçlic acid salt. HPLC analysis of the final crystallization products of both enantiomers show less than three percent of the opposite enantiomer.
3 o Preparation 3 Preparation of (3'R) ethyl 2-[N-(t-butoxycarbonyl)piperidin-3-yl]acetate W 0 97/09308 PCT~US96/14163 ~O~CH3 J O
Boc (3'R)-Ethyl 2-(piperidin-3-yl)acetate (10.9 g, 34 mmol) as prepared in Preparation 1 was dissolved in 50 ml of a 12% sodium 5 carbonate in water solution and the resulting solution was extracted with chloroform. The extracts were dried and the solvents removed by evaporation. The residue was suspended in diethyl ether, filtered, and evaporated to give the free base (5.36 g). The liquid was dissolved in ether (50 ml) and treated d~v~wise with di-t-butyldicarbonate (7.9 g) in lo ether (10 ml). After stirring overnight, the solution was cooled in an ice water bath and treated dlolJwise with saturated aqueous citric acid (25 ml). The aqueous fraction was extracted with diethyl ether. The organic fractions were combined, washed with water, a saturated sodillm bicarbonate solution, and then brine, and then dried over 5 m~gneSium sulfate. The solvents were removed in vacuo to give the desired title product was a clear liquid. NMR was consistent with proposed title structure.
Pre~aration 4 Preparation of (3'S) ethyl 2-[N-(t-butoxycarbonyl)piperidin-3-yl]acetate ~O~CH3 J
N
Boc (3'S)-Ethyl 2-(piperidin-3-yl)acetate (48.6 g, 150 mmol), as prepared in Preparation 2, was treated with a solution of potassium carbonate (30 g, 0.217 mol) in water (220 ml) and the resulting solution was extracted with chloroform (3 x 100 ml). The extracts were dried over sodium sulfate and the solvents were removed in vacuo. The residue was mixed with diethyl ether (200 ml) and filtered to remove some suspended solids. Evaporation of the ether gave a brownish liquid (25 g, Theory = 25.7 g). The residue was dissolved in diethyl ether (200 ml), cooled in an ice water bath, and a solution of di-t-butyldicarbonate (31.8 5 g, 0.146 mol) in ether (25 ml) was added dl~wise with stirring. Cooling was removed and reaction was stirred overnight. The solution was again cooled in ice water and a solution of saturated aqueous citric acid (100 ml) was added dlo~wise. The organics were washed with brine, a saturated aqueous sodium bicarbonate solution, then brine, and then 10 dried over sodium sulfate. The solvents were removed in vacuo to give the desired title product as a clear liquid (38.6 g, ~99%). NMR was consistent with desired title structure.
Preparation 5 Preparation of ethyl 3-[pyrid-3-yl]prop-2-enoate o ~ O CH3 A solution of ethylphosphino~cetate (98.6 g, 0.44 mol) in dry tetrahyL~r~dn (1200 ml) was treated with 60% sodium hydride (17.5 g, 0.44 mol). The mixture was stirred at room tempe~al~e for two hours and was then cooled down to 0~C. To this ...iY~..e 3-pyridine carboxaldehyde (38.9 g, 0.36 mol) was added and the resulting reaction 25 n~i~ e was stirred for 1-2 hours while warming to room temperature.
The progress of the reaction was monitored by thin layer chromatography.
Water (1000 ml) was added to the reaction mixture. The organic fraction was extracted with ethyl acetate (3 x 1000 ml). The 30 organic fractions were combined, washed with water (2 x 1000 ml), brine (1 x 1000 ml), and the dried over sodium sulfate. The solvents were removed in vacuo to yield 62.5 grPms (97%) of the desired title product.
W O 97/09308 PCT~US96/14163 Preparation 6 Preparation of (RS) ethyl 3-[piperidin-3-yl]propionate o ~ ~ O CH3 A solution of ethyl 3-[pyrid-3-yl]prop-2-enoate (60 g, 0.34 mol) in ethanol (600 ml) was treated with 5% rhodium on alumina powder (17.2 g). The mixture was placed under a hydrogen atmosphere (55 psi) for five hours at 60~C. The reaction was stopped by removing the hydrogen and the reaciton mixture was filtered through a layer of CELITETM. The residue was washed with hot ethanol. The filtrate was concentrated and purified by flash chromatography to provide 39.6 grams (63%) of the desired title product.
IR, NMR, and IR were consistent with the proposed title structure.
Preparation 7 Preparation of (3'S) ethyl 3-[piperidin-3-yl]propionate mandelic acid salt O
~J''o CH3 N ~m~n~lelic acid A solution of (RS) ethyl 3-[piperidin-3-yl]propionate (52.0 g, 281 mmol) in hot ethyl acetate (300 ml) was added to the hot solution of R-(-) mandelic acid (42.7 g, 281 mmol). The resulting mixture was then filtered and the clear solution was left at room temperature overnight.
The newly formed white crystals of the salt were filtered from the solution. These crystals were recrystallized twice by dissolution in hot ethyl acetate (300 ml) and letting it cool down to room tempel al~ e each time. The final pure crystals were dried to yield 33.1 grams (70%).
NMR and IR were consistent with the desired title product. The conformation about the chiral center was confirmed by X-ray 5 crystallography.
Preparation 8 Preparation of (3'R) ethyl 3-[piperidin-3-yl]propionate mandelic acid salt o ~' \~I\o CH3 H ~m~n(lPlic acid The title compound was prepared essentially as described in Preparation 7, supra, except that S-(+) mandelic acid was employed 15 instead of the R-(-) m~ntlçlic acid employed therein.
NMR and IR were consistent with the desired title product.
Preparation 9 20 Preparation of (3'S) ethyl 3-[piperidin-3-yl]propionate ~~~0 CH3 A suspension of (3'S) ethyl 3-[piperidin-3-yl]propionate 25 mandelic acid salt (33.1 g, 98 mmol) in ethyl acetate (500 ml) was treated with a 30% aqueous solution of potassium carbonate until all the organic layer was clear. The mixture was poured into a separatory funnel and the organic fraction was extracted with ethyl acetate (3 x 300 ml). The combined organic fraction was washed with water (2 x 300 ml), then brine (1 x 300 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily product in nearly 100% yield.
NMR and IR were consistent with the desired title product.
Preparation 10 Preparation of (3'R) ethyl 3-[piperidin-3-yl]propionate o The title compound was prepared essentially as described in Preparation 9, supra, except that (3'R) ethyl 3-[piperidin-3-yl]propionate m~n~lelic acid salt was employed instead of the (3'S) ethyl 3-[piperidin-3-yl]propionate m~nllelic acid salt therein.
NMR and IR were consistent with the desired title product.
Preparation 11 Preparation of (3'S) ethyl 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propionate O
J~o CH3 BoC
A solution of (3'S) ethyl 3-[piperidin-3-yl]propionate (12.6 g, 67.5 mmol) in tetrahydrofuran:water (2:1, 335:168 ml) was treated with 25 potassium carbonate (14 g, 101 mmol) and di-tert-butyl dicarbonate (17.7 g, 81 mmol). The reaction mixture was stirred at room temperature for five hours. The mixture was then poured into water (200 ml). The organic fraction was extracted with ethyl acetate (3 x 200 ml). The WO 97/09308 PCT/US96/141~3 organic fractions were combined, washed with water (2 x 200 ml) and then brine (1 x 200 ml), and then dried over sodium sulfate. The solvents were removed in vacuo and the title product was further purified by flash chromatography. Yield: 19.1 grams (99.2~o).
5 NM~ and IR were consistent with the desired title product.
Preparation 12 Preparation of (3'R) ethyl 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propionate o N
BoC
The title product was prepared essentially as described in Preparation 11, supra, except that an eqllimol~qr amount of (3'R) ethyl 3-[piperidin-3-yl]propionate was employed instead of the (3'S) ethyl 3-[piperidin-3-yl]propionate employed therein.
Preparation 13 Preparation of (3'S) 3-[1-(t-buto~ycall)onyl)piperidin-3-yl]propanol ----OH
BoC
A solution of (3'S) ethyl 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propionate (17.1 g, 60 mmol) in dry diethyl acetate (600 ml) was cooled to 0~C. Lithium aluminum hydride powder (2.5 g, 65 mmol) was - gradually added to the mixture. The resulting mixture was stirred at 0~C and slowly warlned to room temperature within two hours. The WO 97/09308 PCT/US96/141~3 reaction was stopped by the slow addition of water (200 ml) and 15%
aqueous sodium hydroxide (50 ml). The organic fraction was extracted with diethyl ether (3 x 300 ml). The comhined layer was washed with water (2 x 200 ~nl) and then brine (1 x 200 ml) and then dried over sodium 5 sulfate. The solvents were removed in vacuo to provide 13.2 grams (90%
yield) of the title product.
NMR and IR were consistent with the desired title product.
P~Jalation 14 Preparation of (3'S) 3-[1-(t-buto~ycall,onyl)piperidin-3-yl]propanol Q.~"" OH
BoC
The title product was prepared essentially as described in Preparation 13, supra, except that an equimolar amount of (3'S) ethyl 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propionate was employed instead of the (3'R) ethyl 3-[1-(t-buto~yoa~bonyl)piperidin-3-yl]propionate employed therein.
Preparation 15 Preparation of (3'S) 3-[1-(t-buto~yca,l,onyl)piperidin-3-yl]~ yl bromide Q~ Br 2 5 BoC
To a cold (0~C) solution of triphenylphosphine (19.95 g, 76 mmol) in anhydrous methylene chloride (110 ml) was added bromine dropwise until the solution turned pale yellow. A few crystals of :
triphenylphosphine were added to the mixture to bring the color back to white. To this mixture was added a suspension of (3'S) 3-[1-(t-buto~ycalbonyl)piperidin-3-yl]propanol (13.2 g, 54.4 mmol) and pyridine (8.0 g, 76 mmol) in dry methylene chloride (110 ml). The resulting 5 mixture was stirred for five hours while warming to room temperature.
The reaction was stopped by ~rllling water (200 ml). The organic fraction was extracted with methylene chloride (3 x 200 ml).
The comhined organic layer was washed with water (2 x 200 ml), then brine (1 x 100 ml), and then dried over sodium sulfate. The solvents 10 were removed in vacuo to provide a light brownish crude product, which was further purified by flash chromatography to yield 11.6 grams (70~o) of the desired title product.
NMR and IR were consistent with the title product.
Preparation 16 Preparation of (3'R) 3-[1-(t-buto~ycall~onyl)piperidin-3-yl]plo~yl bromide [~ " \~ Br BoC
The title product was prepared essentially as described in Preparation 16, sul~ra, except that an equimolar amount of (3'R) 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propanol was employed instead of the (3'S) 3-[1-(~-butoky. a~bonyl)piperidin-3-yl]propanol employed therein.
Me~oll A
Preparation of 1-methyl-2-hydroxymethyl-lH-indole.
CA 022039l2 l997-04-28 ~OH LAH ~--OH
[THF]
In 950 ml of dry tetrahydrofuran under an argon atmosphere was added lithium aluminum hydride (18.40 g, 0.49 mol).
5 The resulting -i x~, e was placed over an ice bath. An aliquot of 1-methylindole-2-carboxylic acid (84.92 g, 0.49 mol) was dissolved in an additional 475 ml of dry tetrahydroru~an and then added slowly (over about 45-50 minutes) to the lithium aluminum hydride mixture.
The ice was removed from around the round bottom flask and warm water was added to the bath to raise the reaction temperature. The reaction mi~ e was then stirred at room tempelalu~e for 60-90 minutes. The progress of the reaction was monitored by thin layer chromatography.
Once the reaction had progressed sufficiently, the reaction vessel was placed in an ice bath and 20 ml of water were slowly added to the reaction ~ e. This was followed by the sequential addition of 20 ml of 5 N sodium hydroxide and then 60 ml of water. The organic fraction was dried using CELITETM followed by sodium sulfate. The organic solvents were then removed by vacuum to yield a white solid.
2 0 The white solid was then dissolved in toluene heated to reflux. The lm~ e was then cooled to room temperature and then permitted to remain overnight in a refrigerator. The off-white crystals were then collected, washed with cool toluene, and then dried in a vacuum oven. Yield 63.65 gr~ms (81.4%). FDMS 161.
Analysis for CloH1lNO:
Theory: C, 74.51; H, 6.88; N, 8.69.
Found: C, 74.73; H, 6.90; N, 8.76.
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-lH-indole WO 97/09308 PCT/US96tl4163 ~ ~--OH l. NaH ~--'~J~
CH3 F~Cl CH3 A one liter round bottom flask with a nitrogen atmosphere was charged with sodium hydride (9.28 grams of a 60% NaH solution in 5 mineral oil, 0.232 mol) and N,N-dimethylformamide (211 ml). To the resulting ~ u~e was slowly added 1-methyl-2-hydro~ymethyl-lH-indole (34.0 g, 0.211 mol) dissolved in 100 ml of N,N-dimethylformamide.
This addition resulted in the formation of a slight exotherm. The resulting reaction mixture was stirred at room temperature for about 10 three hours.
1-Chloro-4-fluorobenzene (30.29 g, 0.232 mmol) was then added to the above reaction mixture, after which the resulting mixture was heated to 80~C and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
15 The reaction mixture was then allowed to cool. The reaction ~ u~e was then poured into about one liter of water and stirred for about one hour. The solids were removed by filtration and washed with water.
The desired product was then recrystallized from benzene and the solvents were removed in vacuo.
20 IR, NMR, and W were consistent with the desired title compound.
FDMS 271 (M+).
Analysis for Cl6Hl4ClNO:
Theory: C, 70.72; H, 5.19; N, 5.15.
Found: C, 70.98; H, 5.18; N, 5.37.
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-(4-methylpiperidin- 1-yl)methyl- lH-indole (~x~mple 14) CA 022039l2 l997-04-28 W O 97/09308 PCTAUS96/141~3 CI Q~ CI
CH3 alkylation CH3 Under a nitrogen atmosphere 4-methylpiperidine (0.109 ml, 0.09 g, 0.92 mmol), dissolved in 2.0 ml of ethyl acetate, was added to a round bottom flask which was then placed in an ice bath. Concentrated hydrochloric acid (0.084 ml) was then added and the reaction mixture was removed from the ice bath. To the reaction ~ e were added formaldehyde (0.304 g, 1.01 mmol), sodium acetate (0.113 g, 1.38 mmol), and 1-methyl-2-(4-chlorophenoxymethyl)-lH-indole (0.250 g, 0.92 mmol).
The resulting mi~l~e was then heated to reflux and m~int~inerl at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
The solvents were removed in vacuo. The solids were then taken up in methylene chloride. The solvents were then removed in vacuo. The desired product was then recrystallized from ethyl acetate.
The desired title product was further purified by chromatography.
NMR was consistent with the proposed title structure.
FDMS 382.
Analysis for C23H27clN2o:
Theory: C, 72.14; H, 7.11; N,7.31.
Found: C, 72.33; H, 7.22; N, 7.47.
l~e~o-l B
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]-1,2-ethanedionyl]-lH-indole (~x~mple 106) ~N
~,Cl ~ Cl acylation CH3 1-Methyl-2-(4-chlorophenoxymethyl)-lH-indole (0.30 g, 1.10 mmol), dissolved in 2.0 ml of tetrahydrofuran, was placed in a round 5 bottom flask under an argon atmosphere. To this solution was added oxalyl chloride (0.294 g, 2.32 mmol). The resulting ~ e was stirred at room temperature for about 45 minutes. The solvents were removed in vacuo, leaving a dark brown oil.
The brown oil was taken up in 2.0 ml of dry tetrahydrofuran 10 and 4-(piperidin-1-yl)piperidine (1.07 g, 6.38 mmol), dissolved in about 10 ml of dry tetrahydrofuran, was added. The resulting reaction mixture was stirred at room temperature for about 30 minutes. The progress of the reaction was monitored by thin layer chromatography.
The solids were removed by filtration and the solvents in 15 filtrate were removed by evaporation. The residue from the filtrate was then taken up in methylene chloride and washed with a saturated sodium bicarbonate solution, followed by three extractions with 1.0 N
hydrochloric acid.
The aqueous fractions from the above extractions were 2 0 combined, basified with 1 N sodium hydroxide and then extracted thrice with methylene chloride. This organic fraction was dried over sodillm sulfate and the solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
NMR and IR were consistent with the proposed title structure.
2 5 FDMS (M+) 493.
Analysis for C2gH32ClN3O3:
Theory: C, 68.07; H, 6.53; N, 8.51.
W O 97/09308 PCTrUS96/141~3 Found: C, 67.97; H, 6.66; N, 8.27.
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[4-(phenyl)piperazin-1-yl]methyl-lH-indole (~ mple 20) N~3J
~CI ~0 V Cl CH3 alkylation CH3 Under a nitrogen atmosphere in a round bottom flask, phenylpiperazine (0.149 g, 0.920 mmol) was dissolved in 2.0 ml of lo dichloroethane. The reaction vessel was placed in an ice bath.
Concentrated hydrochloric acid (0.084 ml, 1.01 mmol) was added and the reaction vessel was removed from the ice bath. Paraformaldehyde (0.304 g, 1.01 mmol) and sodium acetate (0.113 g, 0.920 mmol) were then added, followed by the addition of 1-methyl-2-(4-chlorophenoxymethyl)-lH-indole (0.250 g, 0.920 mmol). The reaction mixture was then heated to reflux and maintained at this temperature for about six hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then stirred at room temperature for about three days.
The solvents were removed by vacuum and the residue was partitioned between ethyl acetate and a 10% potassium carbonate solution. The organic fraction was washed with water, followed by 1.0 N
hydrochloric acid. The acidic aqueous fraction was basified with a 10 potassium carbonate solution. The organic component was dried by dripping through sodium sulfate. The solvents were removed in vacuo.
The desired product was recrystallized from ethyl acetate.
NMR was consistent with the desired title structure.
FDMS 445 (M+).
Analysis for C27H2gClN3O:
Theory: C, 72.71; H, 6.33; N, 9.42.
~ Found:C, 73.00; H, 6.41; N, 9.51.
~ Method Cl Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-chloro-1,2-ethanedionyl]-lH-indole 0~
~,Cl ~, ~O_~,Cl CH3 acylation CH3 1-Methyl-2-(4-chlorophenoxymethyl)-lH-indole (1.00 g, 3.68 mmol), dissolved in 7.0 ml of diethyl ether in a round bottom flask under a nitrogen atmosphere. To the above solution was added oxalyl chloride (0.981 g, 7.73 mmol). The reaction mixture was stirred at room 15 tempe-a~ule for about 60 minutes. The progress of the reaction was monitored by thin layer chromatography.
The solvents were removed by decanting and the crystals were rinsed five times with cold diethyl ether. The solvents and rinses were collected, and placed in a freezer for about three days. The crystals 20 were collected and dried in a vacuum oven to yield 1.15 grams (86.3%) of the desired title product.
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-(4-methylpiperidin-1-yl)-1,2-ethanedionyl]-lH-indole (F.~Ample 102) ~CH3 G~CJCI ~\~-JCI
alkylation CH3 Under a nitrogen atmosphere, 4-methylpiperidine (0.490 ml, 0.411 g, 4.14 mmol) was dissolved in 3.0 ml of dry tetrahydrofuran in 5 a round bottom flask over an ice bath. To this reaction ~ ~e was added 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-chloro-1,2-ethanedionyl]-lH-indole (0.500 g, 1.39 mmol) and the resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
lo The solvents were removed in vacuo and the residue was partitioned between methylene chloride and 1.0 N sodium hydroxide.
The organic fraction was washed with 1.0 N sulfuric acid, followed by a wash with brine. The organic fraction was then dried over sodium sulfate and the solvents were removed in vacuo. The desired title product was recrystallized from ethyl acetate.
NMR and IR were consistent with the desired title structure.
FDMS 425 (M+).
Analysis for C24H2sclN2o3:
Theory: C,67.84; H, 5.93; N, 6.59.
Found: C, 68.04; H, 5.85; N,6.74.
Me1hod C2 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-1-[[4-25 (piperidin-1-yl)piperidin-1-yl]carbonyl]methyl]-lH-indole (~x~mple 77) W O 97/09308 PCTrUS96/141~3 QN~--O
Q ~ O
CH3 ~ reduction CH3 'Q
Cl Cl A round bottom flask under a nitrogen atmosphere was charged with 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-[4-(piperidin-1-5 yl)piperidin-1-yl]-1,2-ethanedionyl]-lH-indole (0.1414 g, 0.282 mmol) and 2.8 ml of denatured ethanol. To this mixture was added sodium borohydride (0.064 g, 1.69 mmol). The reaction _ixture was then stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
The solvents were removed by evaporation and the residue was partitioned between methylene chloride and water. The aqueous fraction was washed twice with methylene chloride. The organic fractions were comhined, washed with brine, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product 15 was further purified by chromatography.
NMR was consistent with the proposed title product.
FDMS 495 (M+).
Analysis for C2gH34ClN3O3:
Theory: C, 67.80; H, 6.91; N, 8.47.
Found: C, 67.86; H, 6.90; N, 8.45.
l~t~..d n Preparation of methyl indole-2-carboxylate.
~OH ~QOCH3 Indole-2-carboxylic acid (47.0 g, 292 mmol) was dissolved in 200 ml of methanol. To this solution was added 6 ml of concentrated sulfuric acid. The resulting mixture was heated to reflux and m~int~ined at this temperature for about 16 hours. The reaction 5 mixture was then cooled to room temperature and the solids were removed by filtration and then washed with 200 ml of methanol. The crystals were dried in a vacuum oven, yielding 39.5 grams (77%) of the desired title product as white needles. Analytical data obtained was consistent with the proposed title structure.
Preparation of methyl 1-[2-(1-tritylpiperidin-4-yl)ethyl]indole-2-carboxylate.
Q~ alkylation ~J~~CH3 ,N
Tr Under an argon atmosphere methyl indole-2-carboxylate (1.50 g, 8.56 mmol) was dissolved in 8.6 ml of N,N-dimethylformamide.
The solution was placed in an ice bath and sodillm hydride (0.377 g, 9.42 mmol) was added. The resulting mixture was stirred for 20 minutes 20 over ice and then permitted to warm to room temperature. The reaction mixture was then stirred for about 90 minutes at room tempelat~e, after which time it was placed again in an ice bath.
2-(1-Tritylpiperidin-4-yl)ethyl iodide (4.53 g, 9.42 mmol), prepared essentially as described in Preparation 15, dissolved in 15 ml of 25 N,N-dimethylformamide was then added and the resulting mixture was stirred in an ice bath for about three days. The reaction mixture was then poured over water and the solids were collected by filtration. The solids were taken up in methylene chloride and dried over magnesium sulfate. The solvents were removed in vacuo to yield 4.98 grams (>99%) ~ of the desired title product as a yellowish white foam. Analytical data obtained was consistent with the proposed title structure.
.
Preparation of methyl 1-[3-(1-~1 ;lyllJiperidin-3-yl)propyl]indole-2-carboxylate.
~ROCH3 ~OCH3 H alkylation N
~N- Tr Under an argon atmosphere methyl indole-2-carboxylate (1.00 g, 5.71 mmol) was dissolved in 5.7 ml of N,N-dimethylformamide.
The solution was placed in an ice bath and sodium hydride (0.251 g of a 60~o solution, 6.28 mmol) was added. The resulting mi~ e was stirred for 20 minutes over ice and then permitted to warm to room temperature. The reaction mixture was then stirred for about 60 minutes at room temperature, after which time it was placed again in an ice bath.
3-(1-Tritylpiperidin-3-yl)propyl iodide (3.11 g, 6.28 mmol), dissolved in 8 ml of N,N-dimethylformamide was then added and the resulting mixture was stirred in an ice bath overnight. The reaction mixture was then poured over water and the solids were collected by filtration. The solids were taken up in methylene chloride, washed with water, then brine, and then dried over sodium sulfate. The solvents were removed in vacuo to yield 3.38 grams (>99%) of the desired title 2 5 product. Analytical data obtained was consistent with the proposed title structure.
Preparation of 2-l-ydl o~ylllethyl-1-[2-( l-ll ;~,yl~ eridin-4-yl)ethyl]-lH-indole.
~R'OCH3 ~ Q~ \OH
reduction N-- N ' Tr Tr Under an argon atmosphere lithium alllminum hydride (0.325 g, 8.56 mmol) was dissolved in 8.6 ml of dry tetrahydrofuran. The resulting solution was placed in an ice bath and methyl 1-[2-(1-tritylpiperidin-4-yl)ethyl]indole-2-carboxylate (4.68 g, 8.52 mmol), 10 dissolved in about 10 ml of dry tetrahy~l~ofillan, was added. The resulting mixture was stirred overnight at room temperature.
To the reaction mixture 0.35 ml of water were crefully added, followed by the addition of 0.35 ml of 5.0 N sodium hydroxide, and then 1.0 ml of water. The solids were removed by filtration and the 15 solvents in the filtrate were removed in vacuo. The residue from the filtrate was redissolved in methylene chloride. The desired product was then dried over m~gnesium sulfate and the solvents were removed in vacuo to yield 3.96 grams (92.4~o) of the title product as a foam.
Analytical data obtained was consistent with the proposed title 2 0 structure .
Preparation of 2-hydroxymethyl-1-[3-(1-tritylpiperidin-3-yl)propyl]-lH-indole.
OCH3 ~ Q~ OH
reduction ~_~N~ T ~N~ T
Under an argon atmosphere methyl 1-[3-(1-tritylpiperidin-3-yl)~ yl]indole-2-carboxylate (3.38 g, 6.23 mmol) was dissolved in 3.1 ml 5 of dry tetrahyLorulan. The reaction vessel was then placed in an ice bath and lithium alumillulll hydride (0.236 g, 6.23 mmol) was added.
The resulting ,,,,~lule was stirred in an ice bath for about ten minutes and then at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
To the reaction mixture were added 0.24 ml water, followed by 0.24 ml of 5.0 N sodium hydroxide, followed by 0.72 ml of water. The residue was redissolved in methylene chloride. The desired product was then dried over sodium sulfate and the solvents were removed in vacuo to yield 2.89 grams (90.1~o) of the title product as a foam. Analytical data 15 obtained was consistent with the proposed title structure.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(1-tritylpiperidin-4-yl)ethyl]-lH-indole.
--\OH Q~ J~Cl alkylation ,NJ ,N--2 0 Tr Tr Under an argon atmosphere 2-hydlo~ymethyl-1-[2-(1-tritylpiperidin-4-yl)ethyl]-lH-indole (3.91 g, 7.81 mmol) was dissolved in about 10 ml of N,N-dimethylformamide. The resulting solution was then placed in an ice bath and sodium hydride (0.468 g, 11.71 mmol) was 5 added and the resulting mixture was stirred at room temperature for about 30 minutes. To the reaction ~ ule 1-chloro-4-fluoroben7.e~e (0.915 ml, 1.12 g, 8.59 mmol) was added and the resulting mixture was stirred at room temperature for about four days, protected from light.
The reaction mixture was poured into ice water and the 10 solids were collected by filtration. A~ter a w~hing with water, the solids were dried in a vacuum oven. The desired product was recrystallized from ethyl acetate and washed with cool ethyl acetate to yield 2.62 grams (54.9%). Analytical data obtained was consistent with the proposed title structure.
Preparation of 2-[(4-chlorophenoxy)methyl]- 1-[3-(1-tritylpiperidin-3-yl)lJf o~yl]-lH-indole .
--OH Q~ J~Cl alkylation l~,N~T ~N T
Under an argon atmosphere 2-hydroxymethyl-1-[3-(1-tritylpiperidin-3-yl)~lolJyl]-1H-indole (2.89 g, 5,61 mmol) was dissolved in about 11.2 ml of N,N-dimethylformamide. The resulting solution was then placed in an ice bath and sodillm hydride (0.247 g of a 60%
25 suspension in mineral oil, 6.18 mmol) was added and the resulting mixture was stirred at room temperature for about 60 minutes. To the reaction mixture 1-chloro-4-fluorobenzene (0.658 ml, 0.807 g, 6.18 mmol) W O 97/09308 PCT~US96/14163 was added and the resulting mi~ e was stirred at room temperature overnight. The reaction mixture was then heated to 80~C and maintained at this temperature for about eight hours. The reaction ~ mixture was then cooled to room temperature and stirred at this 5 temperature overnight. Another half equivalence of sodium hydride was added and the reaction ~e was stirred at room temperature overnight again. Another half equivalence of 1-chloro-4-fluorobenzene was added and the reaction ll~i~lul e was heated to 80~C.
The reaction mi~lure was poured into ice water and then lo partitioned between methylene chloride and brine. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were comhined, washed with brine, and dried over sodium sulfate. The desired product was further purified by chromatography to yield 1.0 grams (29~o). Analytical data obtained was consistent with the proposed 15 title structure.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(piperidin-4-yl)ethyl]-lH-indole (~ mple 137) ~ Cl Q~ ,CI
~_~ deprotecbon N
Tr H
Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-r2-(1-tritylpiperidin-4-yl)ethyl]-lH-indole was dissolved in 7.0 ml of methylene chloride. The reaction solution was then placed on an ice bath and formic acid (0.3383 g) was added. The resulting mixture was stirred in the ice bath for about five hours. The progress of the reaction ~ was monitored by thin layer chromatography.
The reaction mixture was partitioned between methylene chloride and 1.0 N sodium hydroxide. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in 5 vacuo to yield a foam. The desired product was further purified by chromatography to yield 0.1864 grams (68.7%).
NMR was consistent with the proposed title structure.
FDMS 368 (M+).
Analysis for C22H2sclN2o:
Theory: C,71.63; H,6.83; N, 7.59.
Found: C, 71.66; H,6.86; N, 7.87.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)~ Jyl]-lH-indole. (~ mple 139) --OH ~ ~ J~Cl deprotection ~ Tr l NH
The title compound was prepared essentially as described above for 2-[(4-chlorophenoxy)methyl]-1-[2-(piperidin-4-yl)ethyl]-lH-20 indole except that an equimolar amount of 2-[(4-chlorophenoxy)methyl]-1-[3-(1-l,~;~yll~iperidin-3-yl)propyl]-1H-indole was employed instead of the 2-[(4-chlorophenoxy)methyl]- 1-[2-(1-tritylpiperidin-4-yl)ethyl]- lH-indole employed therein.
NMR was consistent with the proposed title strucuture. Single 25 compound of high purity as evidenced by chromatographic methods.
Method E
W O 97/09308 PCTrUS96/14163 Preparation of 3-bromo-2-[(4-chlorophenoxy)methyl]-1-[3-(1-tritylpiperidin-3-yl)propyl]- lH-indole.
CI ~ CI
~) halogenation ~
Under an argon atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl]-1-[3-(1-tritylpiperidin-3-yl)l~ro~yl]-lH-indole (0.992 g, 1.59 mmol) was dissolved in 4.0 ml of dry tetrahydrofuran. The 10 reaction vessel was then placed in an ice bath and N-bromosuccinimide (0.282 g, 1.587 mmol of a recently recrystallized lot), dissolved in 4.0 ml of tetrahydrofuran, was slowly added. The reaction mixture was stirred for about three hours over an ice bath.
The reaction mi~ e was poured over water in which 2.5 5 grams of sodium sulfate was dissolved, and the aqueous phase was extracted thrice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo, yielding 0.26 grams (23%) of the desired compound. The solvents were removed in vacuo from the mother liquor and the resulting residue 20 was recryst~qlli7.e(1 in ethyl acetate and he~nes to obtain an additional 0.65 grams (58~o) of the desired material. Analytical data obtained was consistent with the proposed title structure.
Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-1-[3-(1-tritylpiperidin-3-2 5 yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-lH-indole.
W O 97/09308 PCT~US96/14163 ,CI ~N ~CI
[~ H3C~
N Tr N Tr Under an argon atmosphere in a round bottom flask, 3-bromo-2-[(4-chlorophenoxy)methyl]-1-[3-( 1-tritylpiperidin-3-yl)l,l opyl]-lH-indole (0.226 g, 0.319 mmol) was dissolved in dry tetrahydrofuran.
The reaction vessel was placed in a dry ice/acetone bath. To this solution was added a solution of t-butyllithium (0.64 mmol) dropwise. The resulting 1 ,~lu.e was stirred for 36 minutes in the dry ice/acetone bath.
To this reaction mixture was added the Weinreb amide N-methyl-N-methoxy-[4-(piperidin-1-yl)piperidin-1-yl]acet~mide (0.0903 g, 0.336 mmol), which had been dissolved in 2.0 ml of tetrahydrofuran and cooled in the dry ice/acetone bath. The resulting mixture was stirred for about two hours and then poured into a saturated ammonium chloride solution. The aqueous fraction was extracted thrice with methylene chloride. the organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by chromatography. Analytical data obtained was consistent with the proposed title structure.
2 o Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-lH-indole. (F,~mple 70) W O 97/09308 PCT~US96/14163 ocl ~rCI
~> deprotection ~) ~N Tr l NH
Under an argon atmosphere (RS) 2-[(4-chlorophenoxy)methyl]- 1-[3-(1-tritylpiperidin-3-yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-lH-indole (0.0162 g, 0.0194 mmol) was dissolved in 0.2 ml methylene chloride. The reaction vessel was then placed in an ice bath and formic acid (0.073 ml, 0.194 mmol) was slowly added. The resulting mixture was stirred for about one hour over ice. The progress of the reaction was monitored by thin layer lo chromatography. The reaction ~ e was then stirred at room temperature for two additional hours and then an additional 5.0 equivalents of formic acid were added, followed by stirring at room temperature.
The reaction mixture was partitioned between 1.0 N sodium hydroxide and methylene chloride. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed by evaporation.
NMR was consistent with the proposed title structure.
Exact Mass (M+l) for C3sH48clN4o2:
Theory: 591.3476.
Found: 591.3476.
W O 97/09308 PCT~US96/14163 M~.~od F
Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[ 1-hydroxy-2-(piperidin-1-yl)ethyl]-lH-indole (~ mple 47) duction ~
CH3 Cl CH3 Cl Under an argon atmosphere a round bottom flask was charged with 2-[(4-chloropheno~y)methyl]-1-methyl-3-[1-(piperidin-1-yl)-1~2-et~nerlionyl]-lH-indole (F~ mple 100) (0.203 g, 0.493 mmol), dissolved in 2.0 ml of dry tetrahydrofuran. Lithium aluminum hydride (3.0 ml of a 1.0 M solution in tetrah~rdrorul~l) was then added. The resulting ~ e was then he~terl to reflux and maintained at this temperature for about four hours. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was then cooled to room temperature and 10 ml of a 1:1 tetrahydrofuran:methanol solution was added. To this mi~ e was then added 5 ml of a saturated Rochelle's salt solution.
The solvents were then removed in vacuo.
The residue was then partitioned between methylene chloride and a saturated Rochelle's salt solution. The organic fraction was washed with water and brine. The organic fraction was then dried with sodium sulfate and the solvents were removed in vacuo.
The desired title product was further purified by chromatography to yield 0.1112 grams (56.9%).
NMR was consistent with the proposed title structure.
FDMS 398 (M+).
Analysis for C23H27clN2o2:
Theory: C, 69.25; H, 6.82; N, 7.02.
Found: C, 69.51; H, 6.86; N, 6.81.
- Me~hod G
5 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(4-methylpiperidin-l-yl)ethyl]-lH-indole (~:x~mrle 48) and 2-[(4-chlorophçnoxy)methyl]-l-methyl-3-[2-(4-methylpiperidin-1-yl)ethyl]-lH-indole (F.x~mrle 33) ~S
,~H3 ~ O
reduct;ion+ CH3 CH3 Cl /~\ r' ~'~'13~
CH3 Cl Under a nitrogen atmosphere a round bottom flask was charged with 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-(piperidin-1-yl)-1,2-ethanedionyl]-lH-indole (Flx~mple 100) (0.305 g, 0.824 mmol). Borane-tetrahydrofuran complex (4.12 ml of a 1.0 M borane solution in THF, 4 12 mmol) was added slowly and the resulting mixture was stirred for about 30 minutes. The progress of the reaction was monitored by thin layer - chromatography. The reaction mixture was stirred a total of one hour and then quenched with methanol.
:
W O 97/09308 PCT~US96/14163 To the reaction mixture was added ethanol, sodium carbonate, and cesiu_ fluoride, and the resulting ~i~ e was heated to reflux and m~int~in~d at this tempela~e overnight. The reaction e was partitioned between 10% sodium carbonate and methylene chloride. The aqueous fraction was extracted twice more with methylene chloride. The organic fractions were comhined and dried over sodium sulfate. The solvents were removed in vacuo. The desired products were further purified by radial chromatography.
2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-methylpiperidin-1-yl)ethyl]-lH-indole (h~mrle 33) NMR was consistent with the proposed title structure.
FDMS 396 (M+).
Analysis for C24H2sclN2o:
Theory: C, 72.62; H, 7.36; N, 7.06.
Found: C, 72.40; H, 7.35; N,7.26.
2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydl o~y-2-(4-methyl-piperidin-1-yl)ethyl]-lH-indole (~.2~mrle 48) NMR was consistent with the proposed title structure.
FDMS 412 (M+).
Analysis for C24H2sclN2o2:
Theory: C, 69.80; H, 7.08; N,6.78.
Found: C, 70.02; H, 7.13; N, 7.00.
Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-[N-methyl-N-(1-methylpiperidin-4-yl)amino]ethyl]- lH-indole (~qmrle 54) and 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-N-(1-methylpiperidin-4-yl)amino]ethyl]-lH-indole (~ mple 38) ~ ~ ~
H3Ct~\ /--/
~~~
o~ N--CH3 CH3 Cl ~~ Cl reduction CH3 Cl HO; 7 N--CNCH3 ~,0~
CH3 Cl Under a nitrogen atmosphere a round bottom flask was charged with 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-5 N-(1-methylpiperidin-4-yl)amino]-1,2-ethanedionyl]-lH-indole (0.3349 g, 0.686 mmol) and placed in an ice bath Borane-tetrahydrofuran complex (4.11 ml of a 1.0 M borane solution in THF, 4.11 mmol) was added slowly and the ice bath was removed. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was 10 stirred for about one hour and then 0.33 ml of a 1:1 tetrahydlvfu~dll:methanol solution was added. Sodium hydroxide (1.74 ml of a 5.0 N solution) was then added and the resulting mixture was heated to reflux and maintained at this temperature overnight.
The aqueous fraction was extracted twice more with 5 tetrahydrofuran. The organic fractions were combined, washed twice with brine, and dried over sodium sulfate. The solvents were removed in vacuo. The desired products were further purified by radial chromatography .
W O 97/09308 PCTAJS96/141~3 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-N-( l-methylpiperidin-4-yl)amino]ethyl]-lH-indole (Fx~mple 38) NMR (CDCl3) was consistent with the proposed title structure.
FDMS 459 (M+).
Analysis for C2sH3lCl2N3O:
Theory: C, 65.21; H,6.79; N, 9.13.
Found: C, 65.07; H, 6.85; N, 9.06.
2-[(2,4-dichlorophenoxy)methyl]- 1-methyl-3-[1-hydl oky-2-[N-methyl-N-( l-methylpiperidin-4-yl)amino]ethyl]-lH-indole (Fx~mrle 54) NMR (CDCl3) was consistent with the proposed title structure.
FDMS 475 (M+).
Analysis for C2sH3lcl2N3o2:
Theory: C, 63.02; H,6.55; N, 8.82.
Found: C, 63.43; H, 6.88; N, 8.92.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[(3-dimethyl~minopropyl)amino]ethyl]-lH-indole (Fx~mple 30) and 2-[(4-chloropheno2~y)methyl]-l-methyl-3-[[[3-20 (dimethylamino)p~ o~ylamino]carbonyl]methyl]-lH-indole (Fx~mple 76) WO 97/09308 PCT/US96/1416~
N(CH3)2 HN~/
N(CH3)2 5~ 1 H~/ CH3 Cl ~~ reduction CH3 ~Cl H~/N(CH3)2 ~ ~'13~
CH3 Cl Under a nitrogen atmosphere borane-tetrahydloru~an complex (7.42 ml of a 1.0 M solution in THF, 7.42 mmol) was added to a 5 round bottom flask cont~ining 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[3-(dimethyl7.mino)propyl~mino]-1,2-etl ~ne~lionyl]-lH-indole (0.529 g, 1.24 mmol). The reaction mixture was stirred at room temperature for about one hour. The progress of the reaction was monitored by thin layer chromatography. The reaction was then quenched by the addition 10 of a 1:1 tetrafuran:methanol solution.
The solvents were removed by evaporation. The residue was taken up in a mixture of ethanol (8 ml), sodium carbonate (2.62 g, 24.72 mmol), and cesium fluoride (2.88 g, 18.94 mmol). The resulting mixture was heated to reflux and maintained at this temperature 5 overnight.
The reaction mixture was partitioned between methylene chloride and a 10% sodium bisulfate solution. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were - combined, and dried over sodium sulfate. The solvents were removed in 20 vacuo. The desired products were further purified by chromatography.
CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/14163 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[(3-dimethylaminopropyl)amino]ethyl]-lH-indole (F.~mple 30) NMR (CDCl3) was consistent with the proposed title structure.
5 FDMS 399 (M+).
Analysis for C23H30ClN3O:
Theory: C, 69.07; H, 7.56; N, 10.51.
Found: C, 69.23; H, 7.79; N, 10.52.
2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[[3-(dimethylamino)propylamino]carbonyl]methyl]-lH-indole (~x~mple 76) NMR (CDCl3) was consistent with the proposed title structure.
FDMS 413 (M+).
Analysis for C23H28clN3o2:
Theory: C, 66.74; H, 6.82; N, 10.16.
Found: C, 66.89; H, 6.96; N, 10.11.
Method H
Preparation of 3-bromo-2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indole ~\ halogenation /~,Br ~, ~~ ~~
CH3 Cl CH3 Cl Under an argon atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indole (5.0 g, 18.40 mmol) was dissolved in 46 ml of tetrahydrofuran. To this solution was added N-bromosuc~inimide (3.28 g, 18.4 mmol of a freshly recrystallized lot), dissolved in 46 ml of tetrahydrofuran. The resulting mixture was stirred over an ice bath for about 3.5 hours, after which time the reaction mixture was poured into about 500 ml of water in which 5.0 grams of sodium sulfate had been dissolved.
W 0 97/09308 PCT~US96/141~3 The aqueous fraction was extracted thrice with methylene ~ chloride. The organic fractions were combined, washed with a saturated sodium bicarbonate solution and, then washed with brine.
The organic fraction was dried over sodium sulfate and the solvents 5 were removed in vacuo.
The desired title product was recrystallized from ethyl acetate. Yield: 5.36 g (83.1%). Analytical data obtained was consistent with the proposed title structure.
10 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(1-tritylpiperidin-4-yl)ethyl]carbonyl]- lH-indole ~,0 acylation ~
CH3 Cl CH3 Cl Under an argon atmosphere in a round bottom flask, 3-bromo-2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indole (0.500 g, 1.426 mmol) was dissolved in 3.0 ml of tetrahydrofuran. The reaction vessel was then placed over a dry ice/acetone bath. To this solution was added a solution of t-butyllithium (1.68 ml, 2.85 mmol) and the Weinreb amide, 20 N-methyl-N-methoxy-[2-(1-tritylpiperidin-4-yl)ethyl]acetamide (0.631 g, 1.426 mmol). The resulting mixture was stirred over dry ice/acetone for about 30 minutes, followed by thirty minutes of stirring on a methanoVdry ice bath. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was poured into a saturated ammonium chloride solution. The aqueous fraction was extracted thrice with methylene chloride, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by chromatography and then recrystallized from ethyl acetate.
3 o Analytical data obtained was consistent with the proposed title structure.
W O 97/09308 PCTrUS96/14163 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(piperidin-4-yl)ethyl]carbonyl]-lH-indole (~ mple 67) r~ r~
O _~N--Tr O~_~NH
~''~'13~ deprotection Q~~~13~
CH3 Cl CH3 Cl Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(1-tritylpiperidin-4-yl)ethyl]carbonyl]-lH-indole (0.2723 g, 0.417 mmol) was dissolved in 2.1 ml of methylene chloride. To this solution formic acid (0.079 ml, 0.096 g, 2.084 mmol) was added and the resulting mixture was stirred at room temperature for about 2.5 hours.
The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was partitioned between methylene 15 chloride and 1.0 N sodium hydroxide. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo to yield the desired title product.
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 411 (M+1) Analysis for C24H27clN2o2:
Theory: C, 70.15; H, 6.62; N, 6.82.
Found: C, 69.87; H, 6.54; N, 6.79.
lVr~
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-carboxy-lH-indole W O 97/09308 PCT~US96/141~3 Br ~ OH
~o~ ~~
CH3 Cl CH3 Cl Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-methyl-3-carboxy-lH-indole (0.500 g, 1.426 mmol) was dissolved in 14.3 5 ml of dry tetrahydrofuran. The reaction vessel was then placed over a dry ice/acetone bath. To this solution t-butyllithium (1.72 ml of a 1.7 M
solution in pentane, 2.92 mmol) was added dropwise. The resulting mixture was stirred for about 15 minutes over the dry ice/acetone bath.
Carbon dioxide was then bubbled through the reaction _ixture for about 10 ten minutes and then the mixture was stirred for an additional ten minutes. The reaction vessel was then placed on a methanoVice/dry ice bath and carbon dioxide was bubbled through the reaction mixture for an additional ten minutes.
The reaction mixture was allowed to warm to room 5 temperature and was then poured into 100 ml of 1.0 N hydrochloric acid to which about 50 grams of dry ice had been added. The resulting mixture was stirred for about thirty minutes. The solids were collected by filtration. The desired product was triturated in methylene chloride.
Yield: 0.37 g (82%) 20 Analysis for Cl7Hl4ClNO3:
Theory: C, 64.67; H, 4.47; N, 4.44.
Found: C, 64.84; H, 4.60; N, 4.54.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[N,N-bis(3-25 dimethylaminopropyl)amino]carbonyl]-lH-indole (~x~mple 58) W O 97/09308 PCT~US96/14163 rN(CH3)2 O~
CH3 ~CI
Under an argon atmosphere 2-[(4-chlorophenoxy)methyl~-1-methyl-3-carboxy-lH-indole (0.100 g, 0.317 mmol) was dissolved in 3.2 ml 5 of N,N-dimethylformamide. To this solution were added N,N-bis(3-dimethyl~minopropyl)amine (0.074 ml, 0.0623 g, 0.332 mmol), 1-(3-dimethyl~mincplo~yl)-3-ethylcarbodiimide hydrochloride (0.091 g, 0.475 mmol), and hydlo~ybenztriazole (0.0642 g, 0.475 mmol). The resulting mixture was then heated for 6 hours and then stirred at room 10 temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was then partitioned between methylene chloride and water. The aqueous fraction was extracted thrice with methylene chloride. The organic fractions were combined 15 and dried over sodium sulfate. The solvents were removed in vacuo.
The desired title product was further purified by radial chromatography .
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 483 (M-1).
FABMS 485 (M+1) Analysis for C27H37ClN4O2:
Theory: C, 66.86; H, 7.69; N, 11.55.
Found: C, 66.91; H, 7.54; N, 11.69.
Me1hodJ
Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[2-[1-[3-(1-tritylpiperidin-3-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]- lH-indole (F,x~mple 69 B) O~--CNH ~ Tr CH3 Cl 1~ CH3 Cl Tr Under a nitrogen a 10 ml round bottom flask was charged 5 with 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[(piperidin-4-yl)ethyl]carbonyl]-lH-indole (0.091 g, 0.222 mmol~, 3-(1-tritylpiperidin-3-yl)propyl iodide (0.110 g, 0.2224 mmol), potassium carbonate (0.0450 g, 0.3255 mmol), and 1.5 ml of anh~drous N,N-dimethylformamide. The resulting mixture was stirred overnight and then poured into ice water.
10 The solids were collected by filtration and rinsed with cold water. The solids were dissolved in methylene chloride and then dried over sodium sulfate. The solvents were removed in vacuo. The desired product was further purified by chromatography. Yield: 0.1166 grams (67.3%).
FDMS 779 (M+2).
5 Analysis for CslHs6clN3o2:
Theory: C, 78.69; H, 7.25; N, 5.40.
Found: C, 78.92; H,7.41; N,5.27.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-[1-[3-20 (piperidin-3-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]-lH-indole (~ mple 69C) CH3 ~Cl deprotection ~~~~
Under a nitrogen atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl] - 1-methyl-3-[[2-[1-[3-(1-tritylpiperidin-3--W O 97/09308 PCTAJS96/141~3 yl)propyl]piperidin-4-yl]]ethyl]carbonyl]-lH-indole (0.1006 g, 0.1292 mmol) was dissolved in 0.6 ml of of methylene chloride. To this solution was added formic acid (0.0244 ml, 0.0297 g, 0.646 mmol). The resulting mixture was stirred for several hours at room temperature, protected 5 from light. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was partitioned between methylene chloride and 1.0 N sodium hydroxide. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were 10 combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 536 (M+1).
5 Analysis for C32H42clN3o2:
Theory: C,71.69; H,7.90; N, 7.84.
Found: C,71.46; H, 7.8~; N,7.61.
Me1 hod K
Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-formyl- lH-indole (F'~zlmple 236) ~Cl Under a nitrogen atmosphere a round bottom flask was charged with 0.63 ml of anhydrous N,N-dimethylformamide. The reaction vessel was placed in a -20~C bath and then phosphorous oxychloride (0.187 ml, 0.310 g, 2.02 mmol) was carefully added. The 30 resulting mixture was stirred in an ice bath for about twenty minutes and 2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indole (0.50 g, 1.84 mmol) W O 97/09308 PCT~US96/141~3 in 3.4 ml of N,N-dimethylformamide, was added. The resulting mixture was stirred at room temperature for about ninety minutes. The reaction mixture was then placed over an oil bath and heated to 55~C and - m~int~ined at this temperature for about one hour. The reaction mixture was then permitted to cool to room temperature and was then poured into water. Sodium hydroxide (10 ml of a 5.0 N solution) was added and heated to reflux. The resulting mixture was cooled and the solids were then collected by filtration.
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 299 (M+).
Analysis for Cl7Hl4ClNO2:
Theory: C, 68.12; H, 4.71; N, 4.67.
Found: C, 67.90; H, 4.66; N, 4.76.
Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[1-hyd~o~y-2-(methoxycarbonyl)ethyl]-lH-indole (F.~mple 55) CH3 ~CI Cl 2 o Under a nitrogen atmosphere a round bottom flask was charged with 6.7 ml of dry tetrahydloru~an. To this was added diisopropylamine (0.196 ml, 0.1417 g, 1.401 mmol) and the reaction vessel was placed in an ice bath. To this mixture was slowly added n-butyllithium (0.88 ml of a 1.6 M solution in hexanes, 1.401 m_ol) and the 2 5 resulting mixture was stirred in an ice bath for about l~i minutes. The reaction mixture was placed in a dry ice/acetone bath, methyl acetate was added and the reaction mixture was stirred for fifteen minutes over a dry ice/acetone bath. Starting aldehyde was added in a total of 7.0 ml of tetrahydrofuran and stirred over a dry ice/acetone bath of one hour and 3 o then placed in an ice bath for about 30 minutes. The reaction mixture WO 97/09308 PCT/US96tl4163 was poured into an ammonium chloride solution (32 g in 100 ml of water). The aqueous fraction was extracted with methylene chloride.
The organic fractions were combined and dried over sodium sulfate.
The solvents were removed in vacuo. The desired title product was 5 further by radial chromatography.
NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure. FDMS 373 (M+).
Analysis for C20H2oclNo4:
Theory: C, 64.26; H, 5.39; N,3.75.
Found: C, 64.55; H, 5.23; N, 3.79.
Preparation of 3-{2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl~prop-2-enoic acid ~ C113 ~ ~
CH3 Cl CH3 Cl Under a nitrogen atmosphere a round bottom flask is charged with 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(metho~yc~bonyl)ethyl]-1H-indole (F.~mple 55) (0.149 g, 0.398 mmol) 20 and 6.11 ml of dry tetrahydrofuran. To this solution is added 1.22 ml of a 2.0 N lithium hydroxide aqueous solution and the resulting mixture was stirred at room temperature for about two hours. The solvents were removed in vacuo and the residue is partitioned between methylene chloride and water. The aqueous fraction was extracted twice with 25 methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was triturated with diethyl ether.
Analytical data was consistent with the proposed title structure.
W O 97t09308 PCTAUS96/14163 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[[4-(dimethyl~mino)piperidin-1-yl]carbonyl]ethenyl]-lH-indole (Example 44) ~ OH ~3_N~N(CH3)2 Q~o ~ ' Q~~'13 CH3 Cl CH3 Cl Under a nitrogen atmosphere dimethyl~minnpiperidine was dissolved in 3.0 ml of methylene chloride. To this solution were added 3-~2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl}prop-2-enoic acid (0.050 g, 0.1462 mmol) and 1-(3-dimethylaminoy~yyl)-3-10 ethylcarbodiimide hydrochloride (0.0356 g, 0.278 mmol). The resultingmixture was stirred at room temperature overnight.
The reaction mixture was partitioned between a saturated sodium bicarbonate solution and methylene chloride. The aqueous fraction was basified with 1.0 N sodillm hydroxide and extracted twice 15 with methylene chloride. The organic fractions were combined, washed with 1.0 N hydrochloric acid, then with brine, and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
NMR (CDCl3) was consistent with the proposed title structure.~ 0 Exact Mass for C26H3oclN3o2:
Theory: 452.2105.
Found: 452.2099.
Me1 hod L
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(methoxycarbonyl)ethyl]- lH-indole O~ ~CH3 O~ o~CH3 reduction ~
A round bottom flask was charged with 10% p~ um on act*ated carbon (0.150 g), 20 ml of N,N-dimethylform~mitle and 2-[(4-5 chlorophenoxy)methyl]-1-methyl-3-[2-(metho~ycalbonyl)ethenyl]-1H-indole (1.44 g, 4.22 mmol). The reaction vessel was then placed under a hydrogen atomsphere for two hours. The reaction mixture was then passed through a CELITETM pad and then partitioned between water and methylene chloride. The aqueous fraction was extracted twice with lo methylene chloride. The organic fractions were combined, washed with water and then brine, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by chromatography.
15Preparation of 3-~2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl}propanoic acid O~o~CH3 O~OH
Q~ hydrolysis ~
CH3 Cl CH3 Cl 2 o Under a nitrogen atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(methoxycarbonyl)ethyl]-lH-indole (0.275 g, 0.771 mmol) was dissolved in 8 ml of dry tetrahydrofuran. To this solution was added 4.0 ml of a 2.0 N lithium hydroxide solution.
The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
The solvents were removed in vacuo and the residue was ~ partitioned between methylene chloride and 5% citric acid. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were comhined, washed with brine, and dried over sodium sulfate. The solvents were removed in vacuo to yield the desired title product. Yield 0.2984 grams (>99%).
Preparation of 2-[(4-chloropheno-xy)methyl]-1-methyl-3-[2-[[4-(dimethyl7.mino)piperidin-1-yl]carbonyl]ethyl]-lH-indole (~ mple 43).
~ o 3 CH3 CH3 Cl CH3 Cl Under a nitrogen atmosphere 3-~2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl}propanoic acid (0.286 g, 0.832 mmol) was dissolved in 6 ml of dry tetrahydrofuran. To this solution 1,1'-carbonyldiimidazole (0.141 g, 0.874 mmol) was added and the resulting mixture was stirred at room temperature for about two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction lJ~ix~llre was then heated to 65~C and m~int~ined at this temp~al~e for about 35 minutes. To this reaction mixture dimethyl~minopiperidine (0.112 g, 0.874 mmol), dissolved in about 3.6 ml of tetrahyd~or~all. This .nixl~l,e was stirred at room temperature overnight.
The reaction mixture was then heated to 60~C and m~int~in~d at this temperature for about 30 minutes. The solvents were removed in vacuo and the residue was partitioned between methylene chloride and water. The aqueous fraction was extracted with methylene chloride again. The organic fractions were combine, washed twice with water, then with brine, and then dried over sodium sulfate. The .
W O 97/09308 PCTrUS96/141~3 solvents were removed in vacuo. The desired title product was further purified by chromatography.
NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
5 FDMS 463 (M+) Analysis for C26H32clN3o2:
Theory: C, 68.78; H, 7.10; N, 9.26.
Found: C, 68.74; H, 7.04; N, 9.38.
o Method M
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[3-[4-(N,N-dimethylamino)piperidin-l-yl]l lolJyl]-lH-indole (F.~mple 41).
~N3N~CH ~N3N~CH
~ ~~3 Q~~'13 CH3 Cl CH3 Cl Under a nitrogen atmosphere around bottom flask is charged with 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[[4-(dimethyl~mino)piperidin-1-yl]carbonyl]ethyl]-1H-indole (0.194 g, 0.428 20 mmol). The flask was then placed in an ice bath and borane-tetrahydrofuran complex (1.71 ml of a 1.0 M solution in THF, 1.71 mmol) was added. The reaction mixture was then removed from the ice bath and stirred at room temperature for about 90 minutes. The progress of the reaction was monitored by thin layer chromatography. A 1:1 25 tetrahydrofuran:methanol solution (0.20 ml total) was added, followed by the addition of 2.0 ml of 5.0 N sodium hydroxide.
The resulting mixture was refluxed overnight. The solvents were removed by evaporation and the residue was partitioned between water and methylene chloride. The organic fraction was W O 97/09308 PCT~US96/14163 washed with brine and dried over sodium sulfate. The solvents were ~ removed in vacuo.
NMR (CDCl3) was consistent with the proposed title structure.
FABMS 440 (M~1) 5 IR was consistent with the desired title structure.
Analysis for C26H34ClN3O:
Theory: C, 70.97; H, 7.79; N, 9.55.
Found: C, 70.73; H,7.65; N, 9.44.
o Method N
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[3-(piperidin-3-yl)propyl]-lH-indole (h',~mrle 42) and 1,2-dimethyl-3-[3-(piperidin-3-yl)propyl]-lH-indole (F,~m~le 237) Under a nitrogen atmosphere 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[3-(piperidin-3-yl)propanoyl]-lH-indole (0.0737 g, 0.1793 20 mmol) was dissolved in 1.8 ml of dioxane and borane-dimethylsulfide complex (0.108 ml, 1.07 mmol) was added. The resulting mixture was - stirred overnight at room temperature. The progress of the reaction wasmonitored by thin layer chromatography. A 1:1 tetrahydrofuran:water mixture (0.3 ml) was then added as well as 1.5 ml of ~.0 N sodium hydroxide. The reaction mixture was heated to 86~C and maintained at this tempe~a~u~e overnight, and then briefly raised to 225~C.
The solvents were removed in vacuo and the residue was partitioned between methylene chloride and 1.0 N sodium hyLoxide.
5 The organic fraction was washed with brine and dried over sodium sulfate. The solvents were removed in vacuo. The desired title products were further purified by chromatography. Analytical data obtained was consistent with the proposed title structure (See h:~mples 42 and 237, infra).
Preparation of 2,4-dichloro-1-ethynylbenzene CH
~Cl Cl In a 500 ml round bottom flask 2,4-dichloroiodobenzene (3 ml, 22.1 mmol), triethylamine (6.16 ml, 44.2 mmol), and (trimethylsilyl)acetylene (3.12 ml, 22.1 mmol) were ~lmi~ed in acetonitrile (6.16 ml, 44.2 mmol) under a nitrogen atmosphere. The mixture was bubbled with nitrogen gas for 10 minutes. To this mixture 20 bis(triphenylphosphine)p~ lium(II) chloride (775 mg, 1.10 mmol) and cuprous iodide (105 mg, 0.552 mmol) were added and the resulting mixture was refluxed for four hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was cooled to ambient temperature and evaporated to leave an oily product.
The residue was dissolved in methanol (50 ml) and tetrahydrofuran (150 ml), and solid potassium carbonate (30.54 g, 0.221 mol) was added. The resulting mixture was stirred at ambient temperature for 19 hours. The progress of this reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between lM potassium carbonate and ethyl acetate. The aqueous fraction was back-extracted thrice with ethyl acetate. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo to yield 2.6 grams of the desired title product.
NMR was consistent with the proposed title structure.
Preparation of 2,4-dichloro-1-(2-bromoethen-1-yl)benzene , ~,Cl Cl lo In a 100 ml round bottom flask borane tetrahydrofuran complex (lM in tetrahydrofuran, 4.8 ml, 4.82 mmol) was cooled to 0~C
under a nitrogen atmosphere. To this complex 2-methylprop-2-ene (1.02 ml, 9.66 mmol) was added dropwise and the mixture was slowly warmed to ambient temperature and stirred at ambient temperature for 15 one hour. The reaction lm~l~e was diluted with he~methylphosphoramide (5 ml), tetrahydrofuran (5 ml), cupric bromide (2.15 g, 9.65 mmol), and cupric acetate (3.85 g, 19.3 mmol), followed by the addition of water (86 ,ul, 4.82 mol). The resulting mixture was stirred at ambient temperature for six hours. The progress of the 20 reaction was monitored by thin layer chromatography. The reaction mixture was diluted with brine and extracted thrice with diethyl ether.
The organic fractions were comhined and dried over sodium sulfate.
The solvents were removed in vacuo. The residue was further purified by liquid chromatography. Yield: 426 mg. NMR was consistent with 2 5 the proposed title structure.
Preparation of 4-hydroxy-N-isopropylbutylamine WO 97/09308 PCT/US96/141~3 HO'--~'~ N~CH3 To a solution of 4-aminobutanol (2.0 mg, 22.4 mmol) in 110 ml of dichloroethane were added acetone (3.3 ml, 44.8 mmol), acetic acid (5 eq.), and sodium acetoxyborohydride (11.9 g, 56.09 mmol). The cloudy mixture was stirred at ambient tempe~a~u~e for about 18 hours. The reaction was qllenched with saturated sodium bicarbonate. Sodium hydroxide (1 M) was added to adjust the pH to about 10. The aqueous layer was extracted with a ll~i~lule of isopropyl alcohol and methylene chloride (1:3). The organic fractions were combined and dried over sodium sulfate, filtered, and concentrated. The desired intermediate was further purified by bulb to bulb distillation to yield 1.4 grams as a clear oil. If desired, additional yield may be recovered by extracting the aqueous fraction with 3:1 toluene:butanol.
Preparation of N-(t-butoxycarbonyl)-4-hydroxy-N-isopropylbutyl~mine Ho~' ,N~CH3 A solution of 4-hydroxy-N-isopl~ylbutyl~min~ (3.0 g, 22.8 mmol) in dioxane:water:lN sodium hydroxide (91 ml:28 ml:28 ml) was treated with di(t-butoxycarbonyl)ether (4.98 g, 22.8 mmol). The cloudy reaction mixture was stirred for five hours. The reaction mixture was extracted with methylene chloride. The organic phase was dried, filtered, and concentrated. The desired title product was further purified by high performance liquid chromatography affording 2.6 grams (49%) of a colorless oil.
Preparation of 2-fluoro-5-chlorobenzaldehyde WO 97/09308 PCT/US96/141~3 F o ~ ~--\H
Cl Lithium diisopropylamide was prepared by ~rlmi~ing diisopropylamine (5.79 ml, 41.3 mmol) in 5 ml of tetrahyLof~llan. The 5 resulting mixture was cooled to -78~C and treated with n-butyllithium in such a manner that the temperature did not raise above 64~C. After stirring the suspension for 45 minutes, the remainder of the tetrahydrofuran was added (70 ml), followed by the d~o~wise addition of 4-chlorophenyl fluoride (4.0 ml, 37.6 mmol). After 45 minutes N,N-10 dimethylformamide was added, also in a dropwise fashion. Theresulting reaction mixture was stirred an additional ten minutes prior to quen( hing with acetic acid ( 6ml), followed by water (100 ml). The cold l~e was transferred to a separatory funnel and extracted twice with methylene chloride. The organic fractions were combined, dried over 15 sodium sulfate, and filtered. The solvents were removed by vacuum.
The residue was further purified by high performance liquid chromatography, affording 4.00 grams of a white solid. mp 41-43~C.
Preparation of 2-fluoro-5-methylbenzyl alcohol F
--\OH
A solution of 2-fluoro-5-methylbenzaldeyde (1.80 g, 12.3 mmol) in 3:1 tetrahydrofuran:methanol (82 ml total) at 0~C was treated ~ 25 with sodium borohydride (0.93 g, 24.6 mmol). The reaction was slowly W O 97t09308 PCT~US96/141~3 warmed to ~mhient temperature and stirred for about three hours. The reaction was quenched with water, transferred to a separatory funnel, and extracted with methylene chloride. The organic fraction was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue 5 was further purified by high performance liquid chromatography to yield 1.3 grams (76%) of a clear oil.
Preparation of 2-fluoro-5-chlorobenzyl alcohol F
--OH
0 Cl The title interme~ te was prepared essentially as was 2-fluoro-5-methylbenzyl alcohol, supra, except that an equimolar amount of 2-fluoro-5-chlorobenzaldehyde was employed instead of the 2-fluoro-5-15 methylbenzaldehyde employed therein.
Yield: 2.16 grams (86%) as a clear oil.
Preparation of 2-fluoro-5-chlorobenzyl bromide ~~\Br Cl A solution of 2-fluoro-5-chlorobenzyl alcohol (1.28 g, 7.97 mmol) in diethyl ether (26 ml) was treated with triphenylphosphine (2.72 g, 10.36 mmol), followed by carbon tetrabromide (3.44 g, 10.36 mmol).
25 The resultant suspension was stirred for 3.5 hours, then filtered, w~hin~ with diethyl ether. The filtrate was concentrated, then passed ~ through a plug of silica to remove triphenylphosphate. The residue was then purified by liquid chromatography affording 2.0 grams of a clear - oil.
Preparation of 4-(2-fluorobenzyloxy)-N-~t-butoxycarbonyl)-N-(isopropyl)butylamine BoC
F
~ ~ NyCH3 1~1 CH3 A solution of N-(t-butoxycarbonyl)-4-hydroxy-N-iso~lol~ylbutyl~-nine (539 mg, 2.33 mmol) in tetrahyLo~ulan (11 ml) at -40~C was treated with potassium t-butoxide (1 M in tetrahydlo~an, 2.64 ml, 2.64 mmol). After 40 minutes, the suspension was cooled to -78~C and treated with a solution of 2-fluorobenzyl bromide (400 mg, 2.12 mmol) in tetrahydrofuran (4 ml). The reaciton was slowly warmed to room temperature and stirred for about five hours. The reaction was diluted with methylene chloride and washed with 1 M potassium carbonate and brine. The organic fraction was dried over sodium 2 o sulfate, filtered, and concentrated. The crude oil was purified by liquid chromatography to yield 566 mg (77%) of the title intermediate as a clear oil.
Preparation of 4-(2-fluoro-6-chlorobenzyloxy)-N-(t-butoxycarbonyl)-N-2 5 (isopropyl)butylamine BoC
F
~\/N\/CH3 .~J CH3 Cl The title intermediate was prepared essentially as described supra for 4-(2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine, except that an equimolar amount of 2-fluoro-5-5 chlorobenzyl bromide was employed instead of the 2-fluorobenzyl bromide employed therein.
Yield 237 mg (35~o).
Preparation of 4-(2-fluorobenzyloxy)-N-(isol,~ ol~yl)butyl~qmine ~ ~o/ ~N~ CH3 The desired intermediate was prepared from the deprotection of 4-(2-fluorobenzyloxy)-N-(t-but~yc~lJonyl)-N-15 (iso~ro~yl)butyl~mine using st~n~rd techniques. The 4-(2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(iso~lo~yl)butylamine was lmi~ed with a 4:1 mixture of methylene chloride and trifluoroacetic acid. The progress of the reaction was monitored by thin layer chromatography .
Preparation of 4-(5-chloro-2-fluorobenzyloxy)-N-(isopropyl)butylamine ~~ N~CH3 1~1 CH3 Cl The desired intermediate was prepared essentially as described for the 4-(2-fluorobenzyloxy)-N-(isopropyl)butylamine above, except that an equimolar amount of 4-(5-chloro-2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(iso~l o~yl)butylamine was employed in place of the 4-W 0 97/09308 PCTAJS96/141~3 (2-fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine employed therein.
Yield: 138 mg (98~o).
5 Preparation of 3-(5-bromo-2-fluorobenzyloxy)-1-[1-(t-butoxycarbonyl)piperidin-2-yl]propane F BloC
~,1~~~
Br 3-[1-(t-Buto~ycalbonyl)piperidin-2-yl]propanol (800 mg, 3.29 mmol) was taken up in tetrahy~oru~an (17 ml), cooled to -40~C, and treated with potassium t-butoxide (1 M in tetrahyLoruldn, 3.62 ml, 3.62 mmol). The resulting ~lu.e was stirred at -40~C for about 35 minutes, then cooled to -78~C. To this mixture was then added 5-bromo-2-fluorobenzyl bromide (881 mg, 3.29 mmol) as a solution in tetrahydrofuran (5 ml). The resultant yellow reaction ~ lule was slowly warmed to 0~C and stirred for about four hours. The reaction mixture was diluted with methylene chloride and washed with 1 M
potassium carbonate and brine. The organic fraction was dried over 20 sodium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by high performance liquid chromatography, yielding 707 mg (50%) of the title intermediate as a clear oil.
Analysis for C20H2gBrFNO3:
Theory: C, 55.82; H,6.79; N,3.25.
Found: C,55.54; H,6.88; N,3.34.
Preparation of 3-(5-bromo-2-fluorobenzyloxy)-1-(piperidin-2-yl)propane WO 97/09308 PCT/US96/141~3 F
~~~
Br 3-(6-Bromo-2-fluorobenzyloxy)-1-[1-(t-butoxycarbonyl)piperidin-2-yl]propane (590 mg, 1.37 mmol) was 5 dissolved in methylene chloride (11 ml), cooled to 0~C, and treated with 3 ml of trifluoroacetic acid. The reaction mixture was stirred at 0~~ for 20 minutes, then warmed to ambient temperature, and stirred an additional ten minutes. The reaction mixture was diluted with methylene chloride and quenched with saturated sodium bicarbonate.
10 The pH was adjusted to about 10 with 1 N sodium hydroxide. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated. Yield: 420 mg (93%). The resulting intermediate was used without further purification.
Preparation of 2-fluoro-5-bromobenzyl bromide ~~ Br Br 2 0 A solution of 2-fluoro-5-bromobenzyl alcohol (20.0 g, 97.5 mmol) in diethyl ether (325 ml) was treated with triphenylphosphine (33.3 g, 127 mmol), followed by carbon tetrabromide (42.1 g, 127 mmol).
The mixture was stirred at ambient temperature for about four hours.
The precipitate was removed and washed with diethyl ether. The 2 5 desired title product was further purified by bulb to bulb distillation [150~C, 5 mm Hg (house vacuum)]. Yield: 24.36 grams (93~o) of a white, low melting solid.
W O 97/09308 PCTAJS96/141~3 ~ Preparation of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol) F
~OH
Br A solution of 2-fluoro-5-bromobenzyl bromide (15.6 g, 58.1 mmol) in N,N-dimethylformamide (290 ml) was added over 35 minutes to a mixture of 1,4-dihyLo~y-2-butyne (20.0 g, 232 mmol) and sodium hydride (15.6 g of a 60% solution, 58.1 mmol). The resulting mixture lo was stirred for 4.5 hours at ambient temperature. The reaction was quenched with 100 ml of a 1:1:1 brine:water:l M potassium carbonate solution. The aqueous fraction was extracted with methylene chloride (3 x 300 ml). The desired title product was further purified by chromatography to yield 8.90 grams (56%).
Preparation of 4-(2-fluoro-5-bromobenzyloxy)butanol ~0 Br A solution of 1,4-dihy~o~ylJ~l~ane (4.0 ml, 45.13 mmol) in N,N-dimethylformamide (62 ml) was treated with sodium hydride (1.98 g of a 60% solution, 49.63 mmol), and stirred for about 50 minutes at ambient temperature. The resulting mixture was cooled to 0~C and treated with 2-fluoro-5-bromobenzyl bromide (3.0 g, 11.28 mmol). The - 25 reaction mixture was then stirred for four hours at ambient temperature. The reaction was quenched with water. The aqueous W O 97/09308 PCTrUS96/141~3 fraction was extracted with methylene chloride. The organic fractions were comhined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography. Yield: 1.8 grams (58%) as a 5 clear oil. ~max = 271 nm.
Analysis for C11H14BrFO2:
Theory: C, 47.67; H, 5.09; Br, 28.83.
Found: C, 47.37; H, 5.15; Br, 28.55.
10 Preparation of N-(t-butoxycarbonyl)-4-(2-fluoro-5-bromobenzyloxy)-3,3-dimethylbutyl :~mi n ~
--O~N'B C
Br A stirred solution of 4-(t-buto~ycall)onylamino)-2,2-dimethylbutan-1-ol (1.5 g, 6.90 mmol) in tetrahydrofuran (49 ml) at -45~C
was treated with potassillm t-butoxide (1 M in tetrahyL.~rulan, 7.59 ml, 7.59 mmol). The anion was stirred for 30 minutes at -45~C, then cooled to -78~C and treated with a tetrahyLor~an solution of 2-fluoro-5-20 bromobenzyl bromide (1.85 g, 6.90 mmol). The resulting yellow mixture was slowly warmed to ambient temperature and stirred for about 18 hours. The cloudy reaction mixture was diluted wtih methylene chloride and washed with 1 M potassium carbonate. The organic fraction was dried over sodium sulfate, filtered, and the solvents were 25 removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.45 grams (52%) of the title intermediate as a colorless oil.
Preparation of N-(t-butoxycarbonyl)-4-(2-fluoro-5-bromobenzyloxy)-2,2-30 dimethylbutylamine W O 97/09308 PCTrUS96/1416 F H3C, ~CH3 ,~ ~HN
ll ~J
Br A stirred solution of 4-(t-buto~ycalLonylamino)-3,3-dimethylbutan-1-ol (1.0 g, 4.60 mmol) in tetrahydrofuran (33 ml) at -46~C
5 was treated with potassium t-butoxide (1 M in tetrahydrofuran, 5.06 ml, 5.06 mmol). The anion was stirred for 30 minutes at -45~C, then cooled to -78~C and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow n~i~lu,e was slowly warmed to 0~C and stirred for about four hours. The cloudy 10 reaction mixture was diluted wtih methylene chloride (100 ml) and washed with 1 M potassium carbonate. The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo.
The residue was further purified by preparative high performance liquid chromatography to yield 1.38 grams (74%) of the title intermediate 15 as a colorless oil.
Preparation of 2-[(t-butoxycarbonyl)amino]-5-(2-fluoro-5-bromobenzyloxy)-2-methylpentane H
~0/~ ' BoC
~ H3C CH3 Br A stirred solution of 4-(t-butoxycarbonylamino)-4,4-- dimethylbutan-1-ol (1.11 g, 5.11 mmol) in tetrahyd~or~dn (49 rnl) at -45~C was treated with potassium t-butoxide (1 M in tetrahydrofuran, 6.62 ml, 5.62 mmol). The anion was stirred for 30 minutes at -45~C, then cooled to -78~C and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow mixture was slowly warmed to 0~C and stirred for about four hours. The reaction mixture was diluted wtih methylene chloride (100 ml) and 5 washed with 1 M potassium carbonate (20 ml). The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.53 grams (74%) of the title intermediate as a colorless oil.
Preparation of trans-4-(t-butoxycarbonylamino)cycloheganol HOI~ O~N~ BoC
To a solution of trans-4-~minocyclohe~nnl (5.00 g, 33.0 mmol) in dioxane (132 ml), water (41 ml) and 1 N sodium hydroxide (41 ml) was added t-buto~yc~l)onyl anhydride (14.4 g, 66 mmol). The cloudy solution was stirred overnight. The reaction mixture was acidified to pH 3.0 with solid sodium bisulfate. The resulting ~ e was thrice 20 extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, and concentrated in vacuo. The desired title intermediate was recrystallized from he~nes/ethyl acetate to yield 6.5 grams (92~Zo).
MS 216.24 25 Analysis for CllH21N03:
Theory: C,61.37; H, 9.83; N, 6.50.
Found: C,61.16; H, 9.54; N, 6.39.
Preparation of trans- ~4-(butoxycarbonylamino)- 1-[2-fluoro-5-30 bromobenzyloxy]}cyclohegane W 097/09308 PCTAUS96/141~3 _ 99 _ F H
O~ BoC
Br A solution of trans-{4-(butoxycarbonylamino)}cyclohexanol (550 mg, 2.32 mmol) in dry tetrahy~orulan (16.6 ml) was cooled to -40~C
and treated with potassium t-butoxide (1 M in tetrahydrofuran, 2.55 ml, 2.55 mmol). The cloudy yellow reaction mixture was stirred for about thirty minutes, cooled to -78~C, and treated with 2-fluoro-5-bromobenzyl bromide (622 mg, 2.32 mmol). The resulting yellow mixture was gradually warmed to 0~C and stirred for about two hours. The reaction o mixture was diluted with methylene chloride, and washed with saturated sodillm bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The residue was purified further by high performance liquid chromatography to yield 558 mg (62%) of the desired title intermediate as a white solid.
Analysis for ClgH2sBrFNO3:
Theory: C, 53.74; H, 6.26; N, 3.48.
Found: C, 53.87; H, 6.16; N, 3.11.
Preparation of 3,3-dimethyl-1-(t-buto~yca,l)onyl)pyrrolidin-2-one O
H3C~,J~--BoC
H3C' \~
The desired intermediate was prepared essentially as described in F. Scheinm~qnn and A.V. Stachulski, Journal of Chemical 25 Research, 1993:414 (1993). A solution of 3-methyl-1-(t-butoxycarbonyl)pyrrolidin-2-one (8.63 g, 43.3 mmol) in tetrahydrofuran (48 ml) was cooled to -78~C. The solution was treated with NaN[Si(CH3)2]2 (56.3 ml, 56.3 mmol) and stirred for about 50 minutes - -CA 022039l2 l997-04-28 W O 97/09308 PCTrUS96/14163 prior to quen~hing with methyl iodide (8.1 ml, 130 mmol). The reaction mixture was slowly warmed to ambient temperature, and stirring was continued for about one hour. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with phosphate buffer, pH 7.0 (40 ml), 5 water (40 ml) and brine (40 ml). The organic fraction was dried over sodium sulfate, filtered, and concentrated in vacuo. The precipitate was collected, and further purified by flash chromatography to yield 8.49 grams (92%) of the title intermediate as a semi-solid. NMR was consistent with the title structure.
Preparation of 4-(t-butoxycarbonylamino)-2,2-dimethylbutanol HO~N~ BoC
A solution of 3,3-dimethyl-1-(t-buto~yca~l~onyl)pyrrolidin-2-one (3.35 g, 15.7 mmol) in absolute ethanol under a nitrogen atmosphere was treated with sodillm borohydride (1.79 g, 47.1 mmol). The resulting mixture was stirred at ambient tempeature for about 24 hours. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate. The aqueous fraction was back extracted twice with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo.
The residue was further purified by chromatography to yield 3.17 grams (93%) of the title intermediate as a clear oil. mp 76.5-76.5~C.
Preparation of 4-(2-fluoro-5-bromobenzyloxy)-1-methoxybut-2-yne F
- ~~o' OCH3 Br A solution of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol (1.07 g, 3.92 mmol) in tetrahydrofuran (26 ml) was cooled to -40~C
and then treated with potassillm t-butoxide (4.31 ml of a 1 M solution in tetrahydrofuran, 4.31 mmol). The resulting dark orange solution was stirred for thirty minutes, cooled to -78~C and treated with methyl iodide (0.49 ml, 7.84 mmol). The reaction was warmed to 0~C and stirred for 1.5 hours. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography to yield 790 mg (70%) as a clear oil.
Preparation of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl bromide ~~o _ ~ Br Br A solution of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol (8.9 g, 32.6 mmol) in diethyl ether (109 ml) was treated with triphenylphosphine (11.1 g, 42.4 mmol) and carbon tetrabromide (14.1 g, 42.4 mmol). The cloudy solution was stirred at ambient temperature for about 14 hours. The precipitate was removed by filtration and the filtrate was concentrated. The desired title intermediate was purified from the filtrate by flash chromatography. Yield 9.83 grams (90~o) as a clear oil.
Elemental analysis and NMR were consistent with the proposed title structure.
Preparation of N-methyl-4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl amine F
~~0 ~ ~ CH3 Br A solution of aminomethane (89 ml of a 2 M solution in tetrahydrofuran, 178 mmol3 was added to a solution of 4-(2-fluoro-5-lo bromobenzyloxy)but-2-ynyl bromide (6.0 g, 17.8 mmol) in tetrahydrofuran (89 ml). The cloudy reaction mixture was stirred for about fifteen minutes, at which time no starting material rem~ined, as deter_ined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed 15 with 1 M potassium carbonate. The aqueous phase was back-extracted thrice with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo.
The resulting oil was further purified by flash chromatography, affording 4.24 grams (83~o) of the title intermediate as a yellow oil. NMR
20 was consistent with the title structure.
Preparation of N-benzyl-4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl amine ¢f O ~ ~ ~3 Br W O 97/09308 PCTAJS96/141~3 A solution of benzylamine (0.98 ml, 8.93 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (300 mg, 0.893 mmol) in tetrahydrofuran (4.5 ml). The cloudy reaction mixture - was stirred for about twenty hours, at which time no starting material 5 remained, as determined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed with 1 M potassium carbonate. The aqueous phase was back extracted with methylene chloride (2 x 15 ml). The organic fractions were combined, and dried over sodium sulfate. The solvents lo were removed in vacuo. The resulting oil was further purified by flash chromatography, arrol lhlg 200 mg (62~) of the title intermediate.
Preparation of N-isopl o~yl-4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl amine ~~o ~ ,N~CH3 \~ CH3 Br A solution of iso~o~ylamine (0.25 ml, 2;9 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (97 mg, 0.29 mmol) in tetrahydrofuran (1.4 ml). The cloudy reaction mixture was stirred for about twenty hours, at which time no starting material remained, as determined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed with 1 M potassium carbonate. The aqueous phase was back extracted with methylene chloride (2 x 5 ml). The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by flash chromatography, affording 78 milligrams (86%) of the title intermediate.
NMR was consistent with the title structure.
WO 97/09308 PCT/US96/141~3 Preparation of N-cyclopropyl-4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl amine H
Br A solution of cyclop,o~ylamine (1.10 ml, 15.8 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (530 mg, 1.58 mmol) in tetraLyLorlllan (8 ml). The cloudy reaction mixture was stirred for about thrity minutes. The reaction mixture was 0 then cooled to 0~C, and held at this temperature for about four hours, at which time no starting material remained, as determined by thin layer chromatography. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 1 M potassium carbonate (10 ml). The organic fraction was dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by preparative high performance liquid chromatography, affording 362 mg (73~o) of the title intermediate as a clear oil.
Preparation of 4,5-dihydro-2-(2-fluoro-5-bromophenyl)oxazole Br A solution of N-(2-hydroxyethyl)-5-bromo-2-fluorobenzamide (956 mg, 3.65 mmol) in methylene chloride was treated with thionyl chloride (0.35 ml, 4.75 mmol). The resulting mixture was stirred at ambient temperature as the progress of the reaction was monitored by W 0 97/09308 PCTAJS96/141~3 thin layer chromatography. After one hour of stirring, no starting material was visible. The reaction ~ l~e was diluted with methylene chloride, and the reaction was quenched by the addition of water and 1 N
sodium hydroxide. The organic fraction was dried over sodium sulfate, 5 and concentrated to a white solid. The solid was dissolved in 80%
aqueous acetonitrile (25 ml) and an excess of potassium carbonate was added. The resulting mixture was stirred for about 72 hours at ambient temperature, heated to reflux for thirty hours, and worked up as before.
The desired title product was then further purified by liquid 10 chromatography, yielding 260 mg as a yellow oil.
Preparation of N,N-dimethyl-2-fluoro-5-bromobenzamide F O
Br A suspension of 2-fluoro-5-bromobenzoic acid (680 mg, 3.10 mmol) in methylene chloride (20 ml) was treated with oxalyl chloride (0.35 ml, 4.04 mmol), followed by four drops of ~,N-dimethylformamide.
The resulting clear solution was stirred for about three hours. The 20 solvents were removed in vacuo and the residue was redissolved in methylene chloride and treated with dimethylamine (4.6 ml, 9.3 mmol).
Stirring was continued for 18 hours. The reaction ~ re was diluted with methylene chloride, and washed with saturated sodium bicarbonate and brine. The organic fraciton was dried over sodillm 2 5 sulfate, and the solvents were removed in vacuo. The desired title product was further purified by liquid chromatography. Yield: 632 mg (83%) as a clear oil.
Preparation of 1-methoxy-4-(2-fluoro-5-bromobenzyloxy)butane F
~OCH3 Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butanol (897 mg, 3.24 mmol) in tetrahydrofuran (22 ml) was cooled to -40~C and then 5 treated with potassium t-butoxide (3.56 ml of a 1 M solution in tetrahydrofuran, 3.56 mmol). The resulting orange solution was stirred for thirty minutes, cooled to -78~C and treated with methyl iodide (0.40 ml, 6.48 mmol). The reaction was warmed to 0~C and stirred for 1.5 hours. The reaction mixture was then partitioned between methylene 10 chloride and saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography to yield 687 mg (73%) as a clear oil.
FDMS 291.99 Preparation of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide F
~~~
Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butanol (7.03 g, 26.3 mmol) in diethyl ether (88 ml) was treated with triphenylphosphine (8.97 g, 34.2 mmol) and carbon tetrabromide (11.3 g, 34.2 mmol). The cloudy solution was stirred at ambient temperature for about 30 hours.
The precipitate was removed by filtration and the filtrate was concentrated. The desired title intermediate was purified from the filtrate by bulb to bulb distillation. Yield 8.68 grams (86%) as a clear oil.
Elemental analysis and NMR were consistent with the proposed title structure.
Preparation of N,N-dimethyl-4-(2-fluoro-5-bromobenzyloxy)butylamine F
'O~N\CH
Br Diethylamine (17.6 ml, 35.3 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (1.2 g, 3.53 mmol) in lo tetrahyLor~an (18 ml). The resulting mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate.
The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography. Yield:
842 mg (79~) as a pale yellow oil.
Preparation of N-ethyl-4-(2-fluoro-5-bromobenzyloxy)butyl~mine ~0~ CH2CH3 ~ ~J
Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (500 mg, 1.47 mmol) in acetone (7.3 ml) was treated with sodium iodide - 25 (242 mg, 1.6 mmol). The resulting mixture was stirred at ambient ~ temperature. After 1.5 hours, the sodium bromide was removed by W O 97/09308 PCT~US96/141~3 filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of ethylamine (11 ml, 22.0 mmol). The resulting mixture was stirred for about 17 hours at ambient temperature. The progress of the reaction was monitored by thin layer 5 chromatography. The reaction mixture was diluted with methylene chloride, and washed with 25 mM phosphate buffer and brine. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography. Yield: 337 mg (75%) as a yellow oil. NMR was 10 consistent with the proposed title structure.
Preparation of N-isopropyl-4-(2-fluoro-5-bromobenzyloxy)butylamine F H
~ ,,,,,N,f CH3 Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (1.2 g, 3.53 mmol) in tetrahydrofuran (18 ml) was treated with sodium iodide (484 mg, 3.2 mmol). The resulting ~ lule was stirred at ambient temperature. After 1.5 hours, the sodium bromide was 20 removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of isopropylamine (3.01 ml, 35.3 mmol). The progress of the reaction was monitored by thin layer chromatography. The resulting mixture was stirred for about 18 hours at ambient temperature, after which time an additional 10 equivalents of 25 isopropylamine was added to drive the reaction. The reaction mixture was diluted with methylene chloride, and washed with 25 mM
phosphate buffer and brine. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography. Yield: 517 30 mg (46%) as a yellow oil.
Analysis for C14H21BrFNO:
W O 97/09308 PCT~US96/141~3 Theory: C, 52.84; H, 6.65; N,4.40.
Found: C,52.87; H, 6.77; N,4.64.
Preparation of N-(t-butyl)-4-(2-fluoro-5-bromobenzyloxy)butyl~mine (~/\ H XCH
Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (400 mg, 1.18 mmol) in tetrahydrofuran (6 ml) was treated with sodium 10 iodide (242 mg, 1.6 mmol). The resulting ~ e was stirred at ~mbient temperature. After 1.5 hours, the sodium bromide was removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydroru.all solution of tert-butyl~mine (1.24 ml, 11.8 mmol). The progress of the reaction was monitored by thin layer 15 chromatography. The resulting mixture was stirred for about 19 hours at ambient temperature. The reaction mixture was diluted with methylene chloride, and washed with saturated sodium bicarbonate.
The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further 20 purified by radial chromatography. Yield: 261 mg (66%) as a yellow oil.
NMR was consistent with the proposed title structure.
Preparation of l-(piperidin-1-yl)-4-(2-fluoro-5-bromobenzyloxy)butane ~0~ ~
,~
~ 25 Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (520 mg, 1.53 mmol) in tetrahydlof~dn (8 ml) was treated with piperidine (1.5 ml, 15.3 mmol). The resulting reaction mixture was 5 stirred for about 24 hours. The reaction mixture was then diluted with methylene chloride and washed with saturated sodium bicarbonate.
The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography. Yield: 399 mg (76%).
Preparation of l-(morpholin-4-yl)-4-(2-fluoro-5-bromobenzyloxy)butane ~\O
F
~0/--~ \~
Br A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (550 mg, 1.62 mmol) in tetrahydrofuran (8 ml) was treated with morpholine (1.4 ml, 16.2 mmol). The resulting reaction mixture was stirred for about 72 hours. The reaction mixture was then diluted with methylene chloride and washed with saturated sodium bicarbonate.
2 o The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography. Yield: 446 mg (79~o) as a clear oil.
Preparation of 1-[2-fluoro-5-bromobenzyloxy]-3-[1-(t-2 5 butoxycarbonyl)piperidin-3-yl]propane W O 97/09308 PCTrUS96/141~3 ~ BoC
Br An amount of 3-[1-(t-buto~ycall,onyl)piperidin-3-yl]l,lo~yl bromide (180 mg, 0.588 mmol) was dissolved in N,N-dimethylformamide (1.5 ml) in a 10 ml flask under a I~itrogen atmosphere. Sodium iodide (176 mg, 1.18 mmol) was added at ambient temperature, and the resulting mixture was stirred for ten minutes. The reaction mixture was treated with 2-fluoro-6-bromobenzyl alcohol (121 mg, 0.588 mmol), delivered as a solution in 0.5 ml of N,N-dimethylformamide. To this ~ l~e was then added sodium hydride (60%, 35 mg, 0.882 mmol) and the resulting mixture was stirred at ambient temperature for three hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by liquid chromatography. Yield: 0.115 g. MS (M+) 430.
Analysis for C20H2gBrFNO3:
Theory: C,55.82; H, 6.79; N,3.26.
Found: C,55.70; H,6.59; N,3.04.
Preparation of 1-[2-fluoro-5-bromobenzyloxy]-3-(piperidin-3-yl)propane F
Br .
W O 97/09308 PCT~US96/14163 In a 100 ml round bottom flask, 1-[2-fluoro-5-bromobenzyloxy]-3-[1-(t-butoxycarbonyl)piperidin-3-yl]propane (0.395 g) was dissolved in methylene chloride (4.2 ml). The solution was cooled to 0~C and trifluoroacetic acid (0.8 ml) was slowly added Lol~wise. The 5 resulting ~ e was stirred at 0~C for thirty minutes, followed by stirring at ambient temperature for thirty minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with 10 methylene chloride. The organic fractions were coInhined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography. Yield:
210 mg as a clear yellow oil.
Analysis for C16H21BrFNO:
Theory: C, 54.54; H, 6.41; N, 4.24.
Found: C, 54.32; H, 6.41 N, 4.34.
Preparation of 2-fluoro-5-bromobenzyl bromide F
~Br Br In a 250 ml round bottom flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl alcohol (5.85 g, 28.5 mmol) was dissolved in diethy ether (125 ml). To this solution triphenylphosphine 25 (9.73 g, 37.1 mmol) and carbon tetrabromide (12.30 g, 37.1 mmol) were added. The resulting mixture was stirred at ambient temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. The mixture was then stirred at ambient temperature for about 19 additional hours. The reaction mixture was 30 filtered and washed with cold diethyl ether. The filtrate was evaporated, yielding a light yellow oil. The oil was further purified by chromatography on a silica gel with hexanes. The desired fractions were purified by evaporation to yield 5.8 grams of the desired title intermediate. The material slowly crystallized upon st~nrling.
~ Analysis for C7H6Br2F:
Theory: C, 31.39; H, 1.88.
Found: C, 31.18; H, 1.91.
Preparation of N,N-dimethyl-3-(2-fluoro-5-bromobenzyloxy)~,ol,ylamine F
~ 7 ~ CH3 lo Br In a 10 ml round bottom flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl bromide (245 mg, 0.914 mmol) was dissolved in N,N-dimethylformamide (2.0 ml). To this solution sodium iodide (137 mg, 0.914 mmol) was added and the resulting mixture was stirred at ambient temperature for thirty minutes. In another 10 ml flask, under a nitrogen atmosphere, 3-(N,N-dimethylamino)propanol (0.162 ml, 1.37 mmol) was dissolved in N,N-dimethylformamide (2.0 ml).
Sodium hydride (60%, 62 mg, 1.55 mmol) was then added to the propanol solution. After thirty minutes of stirring, the benzyl bromide, sodillm iodide solution was added to the propanol ~ e. Some frothing occurred, but quickly dissipated. The resulting ~ e was stirred for two hours at ambient temperature. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired intermediate was further purified by liquid chromatography to yield 182 mg (69%) of the title intermediate. NMR, ~ IR, and MS were consistent with the proposed title structure.
Analysis for C12Hl7BrFNO:
Theory: C, 49.67; H, 5.91; N, 4.83.
Found: C, 49.46; H, 5.92; N, 4.99.
5 Preparation of 2-(2-fluoro-5-bromobenzyloxy)-1-methoxyethane ~~'o~ CH3 Br In a 10 ml flask, under a nitrogen atmosphere, 2-lo methoxyethanol (0.125 ml, 1.60 mmol) was dissolved in N,N-dimethylformamide (2 ml). Sodium hydride (60~, 72 mg, 1.81 mmol) was added and the mixture was stirred at ambient temperature for about thirty minutes. To this reaction ~i~lule was added 2-fluoro-5-bromobenzyl bromide (285 mg, 1.06 mmol) as a solution in N,N-15 dimethylformamide (2 ml). The resulting ~ .e was stirred atambient temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic 20 fractions were combined, washed with brine (7 X) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was used without further purification. Yield: 165 mg Preparation of 2-(2-fluoro-5-bromobenzyloxy)-(N,N-dimethyl)ethylamine ~"O~N'CH
Br WO 97/09308 PCT/US96tl4163 In a 50 ml flask, under a nitrogen atmosphere, 2-(N,N-dimethyl~minn)ethanol (1.319 g, 4.92 mmol) was dissolved in N,N-dimethylformamide (16 ml). Sodium hydride (60%, 335 mg, 8.37 mmol) 5 was added and the mixture was stirred at ambient temperature for about twenty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (1.319 g, 4.92 mmol) as a solution in N,N-dimethylform~mide (3 ml). The resulting mixture was stirred at ambient temperature for two hours. The progress of the reaction was lo monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic fractions were combined, washed with brine (7 X) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was 15 used without further purification. Yield: 1.023 g (75%) Preparation of N,N-dimethyl-2-fluoro-5-bromobenzylAmine ,CH3 1~ CH3 Br In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl bromide (1.264 g, 4.72 mmol) was dissolved in methanol (10 ml). Dimethyl~mine (8 M in H20, 1.77 ml, 14.2 mmol) was added as a solution in methanol (5 ml), and the resulting mixture was stirred at 25 ambient temperature for about two hours. The progress of the reaction was monitored by thin layer chromatography. The methanol was removed by evaporation. The residue was partitioned between 1 M
potassium carbonate and diethyl ether. The aqueous fraction was back - extracted with diethyl ether. The organic fractions were combined, 30 washed with brine (7 X) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was used without further purification. Yield: 0.987 g Preparation of 2-(2-fluoro-5-bromobenzyloxy)-(N-methyl)ethyl~mine F
~~0~ CH3 Br In a 50 ml flask, under a nitrogen atmosphere, 2-(2-fluoro-5-bromobenzyloxy)-(N,N-dimethyl)ethylamine (317 mg, 1.15 mmol) was 10 dissolved in dichloroethane (3.5 ml). This solution was cooled to 0~C and ACE ~ Cl (0.50 ml, 4.59 mmol) was added. The resulting mixture was warmed to ambient temperature, then heated to reflux and maintained at this temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. Methanol was added to 15 the reaction mixture and the resulting ~ e was stirred at ambient temperature for about three days. The ,..ix~.., e was then heated to reflux for thirty minutes. The solvents were removed in vacuo. The residue was taken up in methanol, heated to reflux for thirty minutes, and the solvents were then removed in vacuo. The title intermediate 20 was used without further purification. Yield: 210 mg Preparation of N-methyl-2-fluoro-5-bromobenzyl amine F
N,CH3 Br In a 25 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzylbromide (765 mg, 2.82 mmol) was dissolved in methanol (10 ml). Methylamine (0.99 ml, 14.1 mmol) was added and the mixture was stirred at ambient temperature for about three hours. The progress of 5 the reaction was monitored by thin layer chromatography. The solvents were removed by evaporation. The residue was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in lo vacuo. The title intermediate was further purified by liquid chromatography. Yield: 0.435 g NMR was consistent with the proposed title structure.
Preparation of N-methyl-3-[2-fluoro-5-bromobenzyloxy]l l c~ylamine F
--O/\~\N
Br In a 15 ml flask, under a nitrogen atmosphere, N,N-dimethyl-3-[2-fluoro-5-bromobenzyloxy]l ropyl~mine (351 mg, 1.21 mmol) 2 0 was dissolved in dichloroethane (3.5 ml). To this solution ACE ~ Cl (0.78 ml, 7.26 mmol) was added and the resulting mixture was heated to reflux and maintained at this tempe~a~ule for 18 hours. The reaction mi~lule was cooled to ambient tempeld~u~e, and the solvents were removed in vacuo. The residue was taken up in methanol and refluxed 2 5 for 1.5 hours. The methanol solution was then partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in - vacuo. The title intermediate was further purified by liquid 3 o chromatography. NMR was consistent with the proposed title structure.
Preparation Preparation of N,N-dimethyl-4-[2-fluoro-5-bromobenzyloxy]butylamine ~\ ~N~
~ J
Br In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl bromide (967 mg, 3.61 mmol) was dissolved in N,N-dimethylform~mide (3.5 ml). To this solution sodium hydride (60%, 246 mg, 6.14 mmol) was added and the resulting mixture was stirred for ten minutes. To the reaction ~e 4-(N,N-dimethylamino)butanol (633 mg, 5.41 mmol) was added and the rsulting mixture was stirred for six hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography. Yield 260 mg (24%) NMR was consistent with the proposed title structure.
Preparation Preparation of N-methyl-4-[2-fluoro-5-bromobenzyloxy]butyl~nine 2 s N~CH3 Br In a 10 ml flask, under a nitrogen atmosphere, N,N-dimethyl-4-[2-fluoro-5-bromobenzyloxy]butyl~nine (215 mg, 0.707 mmol) was dissolved in dichloroethane (2.0 ml). To this solution ACE ~ Cl (0.305 ml, 2.83 mmol) was added and the resulting mixture was heated to reflux. The reaction ~ ure was refluxed for four hours. The prgress of the reaciton was monitored by thin layer chromatography.
The mixture was refluxed for an additional 16 hours. The solvents were removed in vacuo and the residue was taken up in met~nol The methanol solution was refluxed for 1.5 hours and the solvents were removed by evaporation. The residue was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodillm sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography. Yield 108 mg. NMR was consistent with the proposed title structure.
Preparation Preparation of 5-[2-fluoro-5-bromobenzyloxy]pentyl chloride ~\~~ Cl Br In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl alcohol (2.139 g, 10.4 mmol) was dissolved in N,N-dimethylformamide (25 ml). To this solution sodium hydride (60~o, 625 mg, 15.6 mmol) was added and the resulting mixture was stirred for twenty minutes. To the reaction mixture 5-chloropentyl bromide was 3 0 added and the resulting mixture was stirred for two hours at ambient temperature. The progress of the reaction was monitored by thin layer chromatography. Sodium iodide (3.127 g, 20.9 mmol) was added and the resulting mixture was stirred at ambient temperature for three hours.
The reaction mixture was diluted with diethyl ether and washed seven times with brine. The solvents were removed in vacuo. The title 5 intermediate was further purified by silica gel. Yield 1.82 g (56%) NMR
was consistent with the proposed title structure.
Preparation 10 Preparation of N,N-dimethyl-5-[2-fluoro-5-bromobenzyloxy]pentylamine F
--'0~ IN
Br In a sealable tube, under a nitrogen atmosphere, 5-[2-fluoro-5-bromobenzyloxy]pentyl chloride (0.380 g, 1.23 mmol) was dissolved in N,N-dimethylformamide (5 1). To this solution sodium iodide (55 mg, 0.368 mmol) was added and the resulting ~ ure was cooled to -78~C. To the reaction mixture dimethylamine (precon(len~ed in anhydrous conditions) was added and the tube was sealed. The 20 mixture was warmed to 85 ~C and stirred for eight hours. The mixture was cooled to ambient temperature and stirred for another twelve hours.
The mixture was bubbled with nitrogen gas for fifteen minutes to remove excess dimethyl~mine. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous 25 fraction was back-extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, and the solvents were removed in vacuo. The title intermediate was further purified by silica gel.
Preparation W O 97/09308 PCT~US96/14163 Preparation of N-methyl-5-[2-fluoro-5-bromobenzyloxy]pentyl~mine F
~~0~NH
Br In a 25 ml flask, under a nitrogen atmosphere, N,N-dimethyl-5-[2-fluoro-5-bromobenzyloxy]pentylamine (696 mg, 1.87 mmol) was dissolved in dichloroethane (6.0 ml). To this solution ACE ~ Cl (0.305 ml, 2.83 mmol) was added and the resulting mixture was heated to reflux. The reaction mixture was refluxed for twenty hours. The progress of the reaction was monitored by thin layer chromatography.
The mixture was refluxed for an additional 16 hours. The solvents were removed in vacuo and the residue was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were c-)mhined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography. Yield 248 mg. NMR was consistent with the proposed title structure.
Analysis for C13H1gBrFNO:
Theory: C, 61.33; H, 6.30; N, 4.60.
Found: C, 51.06; H, 6.12; N, 4.49.
Preparation Preparation of 1-[2-fluoro-6-bromobenzyloxy]hexane W O 97/09308 PCT~US96/14163 --'O~CH3 Br In a 100 ml flask, under a nitrogen atmosphere, n-hexanol (1.44 ml, 11.5 mmol) was dissolved in N,N-dimethylformamide (35 ml).
5 To this solution sodium hydride (60%, 521 mg, 13.0 mmol) was added and the resulting ~ lule was stirred for ten minutes. To the reaction mixture 2-fluoro-5-bromobenzyl bromide (2.054, 7.67 mmol) was added and the resulting mixture was stirred at ambient temperature for six hours. The progress of the reaction was monitored by thin layer lo chromatography. The reaction mixture was partitioned between 1 M
potassium carbonate/brine (1/1) and diethyl ether. The organic fraction was washed with brine six times. The organic fraction was dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography. Yield 1.32 15 g. NMR was consistent with the proposed title structure.
Preparation Preparation of 1-(t-butoxycarbonyl)-3-[2-(2-fluoro-5-2 o bromobenzyloxy)ethyl]piperidine ~0~
BoC
Br In a 25 ml round bottom flask, 2-[1-(t-25 butoxycarbonyl)piperidin-3-yl]ethyl bromide (1.011 g, 3.46 mmol) was dissolved in N,N-dimethylformamide (9 ml). Sodium iodide (1.037 g, 6.92 WO 9~/09308 PCTAJS96/141~3 mmol) was added and the resulting mixture was stirred at ambient temperature for ten minutes. The 2-fluoro-5-bromobenzyl alcohol (0.852 g, 4.15 mmol) and sodium hydride (60%, 208 mg, 5.19 mmol) were then added and the resulting mixture began to froth and exotherm. After 5 thi ty minutes, the solution cooled and solidified. Three milliliters of N,N-dimethylformamide was added and the mass was slurried and stirred for three more hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between brine and diethyl ether. The organic fraction was 10 washed six times with brine, and then dried over sodium sulfate. The desired title product was further purified by liquid chromatography.
Yield: 0.540 grams. NMR was consistent with proposed title structure.
Preparation Preparation of 3-[2-(2-fluoro-5-bromobenzyloxy)ethyl]piperidine ~~~
N
Br 2 0 In a 1- ml round bottom flask 1-(t-butoxycarbonyl)-3-[2-(2-fluoro-5-bromobenzyloxy)ethyl]piperidine (0.495 g) was dissolved in methylene chloride (4 ml) under a nitrogen atmosphere. The solution was cooled to 0~C and trifluoroacetic acid (1 ml) was slowly added dlo~vise. The resulting mixture was stirred for thirty minutes at 2 5 ambient temperature. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents 3 0 were removed in vacuo. The resulting residue was used as is. Yield:
240 mg. NMR was consistent with the proposed title structure.
W O 97/09308 PCT~US96/14163 Preparation Preparation of 1-hydroxymethyl-2-[2-(2-fluoro-5-5 bromobenyloxy)methyl]cyclopropane ~/\ ~.,,,,,I~OH
Br In a 100 ml round bottom flask, 1,2-di(hydroxymethyl)cyclopropane (398 mg, 3.90 mmol) was dissolved in N,N-dimethylformamide (15 ml). Sodium hydride (60%, 171 mg, 4.29 mmol) was added and the resulting mixture was stirred at 0~C for fifteen minutes and then at ambient tempelalu,e for fifteen minutes.
The reaction solution was cooled to 0~C and 2-fluoro-5-bromobenzyl 15 bromide (348 mg, 1.30 mmol) was then added as a solution in N,N-dimetL~l~olmamide. The resulting reaction was stirred at 0~C for 1.5 hours and at ambient temperature for thirty minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction ll~i~lu~e was partitioned between brine and diethyl ether. The organic 20 fraction was washed seven times with brine, and then dried over sodium sulfate. The desired title product was further purified by liquid chromatography. Yield: 0.240 grams (21%). NMR was consistent with proposed title structure.
2 5 Preparation Preparation of 1-bromomethyl-2-[2-(2-fluoro-5-bromobenzyloxy)methyl]cyclopropane F
~3~' ~~ ~Br Br In a 50 ml flask 1-hy~)~ylllethyl-2-[2-(2-fluoro-5-bromobenzyloxy)methyl]cyclopropane (420 mg, 1.45 mmol) was dissolved 5 in diethyl ether (10 ml) under a nitrogen atmosphere. The reaction mixture was treated with triphenylphosphine (495 mg, 1.89 mmol) and carbon tetrabromide (626 mg, 1.89 mmol) stirred at ~mbient temperature for 17 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was treated wtih another 0.19 10 grams of triphenylphosphine and 0.241 grams of carbon tetrabromide.
After four additional hours of stirring at ambient tempela~ul e, the solvents were removed in vacuo. The title intermediate was further purified from the residue by liquid chromatography. Yield: 0.389 grams (76~o) as a clear oil.
Preparation Preparation of 1-[(N-methylamino)methyl]-2-[2-(2-fluoro-5-bromobenzyloxy)methyl]cyclopropane F
~~ ~~<~ ..,,,,~1~ N~ CH
Br In a 100 ml flask 1-bromomethyl-2-[2-(2-fluoro-5-bromobenzyloxy)methyl]cyclopropane (344 mg, 0.977 mmol) was 25 dissolved in dry tetrahydrofuran (5 ml) under a nitrogen atmosphere.
- The reaction mixture was treated with methylamine (2M in W 0 97/09308 PCTAUS96/141~3 tetrahydlorul~n, 1.9 ml, 3.91 mmol). The resulting mixture was stirred at ambient temperature for one hour and then additional methyl~mine (2 ml) was added. The resulting mixture was heated to reflux and maintained at this temperature for four hours. The progress of the 5 reaction was monitored by thin layer chromatography. The reaction mixture partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and then dried over sodium sulfate. The solvents were removed in vacuo. The title 10 intermediate was further purified by liquid chromatography. Yield:
0.131 grams (44%) as a light yellow oil. NMR was consistent with the proposed title structure.
Preparation Preparation of cis 4-(2-fluoro-5-bromobenzyloxy)but-2-en-1-ol OH
~0 Br In a 500 ml flask, 1,4-dihydlo2~ybut-2-ene (6.13 ml, 74.5 mmol) was dissolved in N,N-dimethylformamide (160 ml) under a nitrogen atmosphere. Sodium hydride (60~o, 2.98 g, 74.5 mmol) was added and the resulting mixture was stirred at ambient temperature for thirty minutes. The reaction mixture was cooled to 0~C and 2-fluoro-5-bromobenzyl bromide (3.99 g, 14.9 mmol) was added dropwise. The resulting mixture was warmed to ambient temperature and stirred for four hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were WO 97/09308 PCTAUS96/141~3 combined and dried over sodium sulfate. The desired title intermediate was further purified by liquid chromatography. Yield: 2.145 gr~ms (61%) as a clear oil. NMR and MS were consistent with the proposed title structure.
Preparation Preparation of cis 4-(2-fluoro-5-bromobenzyloxy)but-2-enyl bromide F Br ~3~o lo Br In a 100 ml round bottom flask 4-(2-fluoro-5-bromobenzyloxy)but-2-en-1-ol (2.145 g, 7.80 mmol) was dissolved in diethyl ether under a nitrogen atmosphere. Triphenylphosphine (2.66 g, 10.1 mmol) and then carbon tetrabromide (3.36 g, 10.1 mmol) were added to the reaction mixture. The resulting ~ e was stirred for six hours at ambient temperature. A white precipitate formed during the stirring. The progress of the reaction was monitored by thin layer chromatography. The solution was filtered and the filtrate was evaporated to give a thick oil. The desired title intermediate was further purified by liquid chromatography. Yield: 2.16 g (83%). NMR and MS
were consistent with the proposed title structure.
Preparation Preparation of cis N-methyl-4-(2-fluoro-5-bromobenzyloxy)but-2-enylamine -W O 97/09308 PCT~US96/141~3 NH
~0~~
Br In a 250 ml flask 4-(2-fluoro-5-bromobenzyloxy)but-2-enyl bromide (1.968 g, 5.89 mmol) was dissolved in dry tetrahydrofuran (40 5 ml). To this solution methylamine (29.6 ml, 58.9 mmol) was added in one portion and the resulting mixture was stirred at ambient temperature for five hours. The progress of the reaciton was monitored by thin layer chromatography. The solvents were removed in vacuo and the residue was taken up in 1 M potassium carbonate and extracted 10 thrice with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo.
The desired title intermediate was further purified by liquid chromatography. Yield: 1.199 grams (70%). NMR and MS were consistent with the proposed title structure.
Preparation Preparation of N-(t-butoxycarbonyl)-4-(2-fluoro-5-bromobenzyloxy)butylAmine ~o~ BoC
Br In a 25 ml flask 4-(t-butoxycarbonylamino)butanol was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. The W O 97/09308 PCTrUS96/14163 solution was cooled to -40~C and potassium tert-butoxide (lM in tetrahydrofuran, 2.14 ml, 2.14 mmol) was added slowly. The resulting mixture was stirred at -40~C for thirty minutes. To this reaction ufe was added 2-fluoro-5-bromobenzyl bromide (521 mg, 1.94 mmol), 5 added dropwise as a solution in tetrahydrofuran (3.5 ml). The resulting mixture was slowly warmed to 0~C and stirred at this temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction ~i~ e was partitioned between 1 M
potassium carbonate and methylene chloride. The aqueous fraction was 10 back-extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired intermediate was further purified by liquid chromatography. Yield: 335 mg (46%) as a yellow oil.
Analysis for Cl6H23BrFNO3:
Theory: C, 51.07; H, 6.16; N, 3.72.
Found: C, 51.18; H, 6.18; N, 3.80.
Preparation 20 Preparation of 4-(2-fluoro-5-bromobenylozy)butylamine ~ \o/~ , 2 In a 250 ml flask, N-(t-butoxycarbonyl)-4-(2-fluoro-5-25 bromobenzyloxy)butylamine (3.5 grams) was dissolved in methylene chloride (60 ml) under a nitrogen atmosphere. Trifluoroacetic acid (15 ml) was added to the solution at 0~C. The resulting mixture was stirred at 0~C for thirty minutes and then at ambient temperature for 15 minutes. The progress of the reaction was monitored by thin layer - 30 chromatography. The reaction mixture was partitioned between 1 M
- potassium carbonate and methylene chloride. The aqueous fraction was W O 97/09308 PCT~US96/14163 back-extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired intermediate was further purified by liquid chromatography. Yield: 1.82 g. NMR was consistent with the proposed title structure.
Preparation Preparation of 4-methyl-lH-indole-2-carboxylic acid Under an argon atmosphere 4-methylindole (0.91 g, 6.96 mmol) was dissolved in 12 ml of tetrahydrofuran. The resulting solution was cooled in a dry ice/acetone bath. To this solution n-butyllithium (1.6 M in hexanes, 4.48 ml, 7.17 mmol) was carefully added and the resulting mixture was stirred for fifty minutes. Carbon dioxide was bubbled through 26 ml of tetrahydrofuran on a dry ice/acetone bath for twenty minutes. The cold carbon dioxide/tetrahydrofuran solution was c~nn~ qted into the organolithium solution. Carbon dioxide was bubbled through the reaction mixture, and the resulting mixture was 2 0 stirred for thirty minutes over the dry ice/acetone bath. The reaction mi~ e was then stirred at room temperature for ten minutes with continued carbon dioxide bubbling. The carbon dioxide was shut off and the reaction mi~ e was stirred at room temperature for ninety minutes.
2 5 The solvents were removed in vacuo, argon was added to the reaction vessel, which was then rinsed with 5 ml of tetrahydrofuran.
The solvents were removed in vacuo. The brown solid was stored overnight at 4~C under an argon atmosphere.
The residue was then dissolved in 12 ml warm 3 0 tetrahydrofuran and the resulting solution was cooled in a dry ice/acetone bath. To this solution t-butyllithium (1.7 M in pentane, 4.22 ml, 7.17 mmol) was carefully added over fifteen minutes. The resulting mixture was allowed to stir over the dry ice/acetone bath for about seventy minutes. In a separate vessel carbon dioxide was bubbled 3 5 through 26 ml of tetrahydrofuran cooled over a dry ice/acetone bath. Thecarbon dioxide/tetrahydrofuran solution was added to the organolithium solution via c~qnnula. The carbon dioxide was bubbled directly into the reaction _ixture for an additional five minutes. The reaction mixture was stirred over dry ice/acetone for one hour and then carbon dioxide was bubbled through the reaction mixture for one half hour. One 5 milliliter of water was added to the reaction ~ e and the reaction mixture was allowed to stir at room temperature for several hours.
The reaction mi~t.lre was poured into a saturated ammonium chloride solution and extracted twice with diethyl ether.
The organic fractions were combined and the solvents were removed in 10 vacuo and recrystallized from water to obtain 0.17 grams of the desired intermediate. The aqueous fraction was acidified by adding 5% sulfuric acid and stirred for one hour at room temperature. The solids were removed by filtration to yield an additional 0.48 grams of the desired title intermediate.
15 NMR was consistent with the proposed title structure.
Preparation Preparation of methyl 4-methyl-lH-indole-2-carboxylate Under an argon atmosphere 4-methyl-lH-indole-2-carboxylic acid (0.64 g, 3.65 mmol) was dissolved in 20 ml of methanol.
Concentrated sulfuric acid (0.5 ml) was added and the resulting l~ e was heated to reflux and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
Some solvent was removed in vacuo and the resulting crystals were removed by filtration. The solids were taken up in diethyl ether, washed twice with saturated sodium bicarbonate, and then once with brine. The organic fraction was dried over magnesium sulfate and the solvents were removed in vacuo. Yield: 0.38 grams (55.1 %) Preparation Preparation of 2-[4-chlorophenoxymethyl]-3-(2-bromoacetyl)-lH-indole Under a nitrogen atmosphere bromoacetylbromide (1.31 ml, 0.015 mol) was added to a slurry of 2-[4-chlorophenoxymethyl]-lH-indole (0.81 g, 0.003 mol), and lithium carbonate (2.22 g, 0.03 mol) in diethyl ether (37.5 ml). The resulting mixture was heated to 55~C. The progress 5 of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between diethyl ether and a sodium bicarbonate solution. The organic fraction was washed with water and then brine, and then dried over sodium sulfate. The solvents were removed in vacuo. Yield: 1.34 g. NMR was consistent with the 10 proposed title structure.
Preparation Preparation of 2-[4-chloropheno~ymethyl]-3-[2-[4-(piperidin-1-15 yl)piperidin-1-yl]acetyl]-lH-indole To a slurry of 2-[4-chlorophenoxymethyl]-3-(2-bromoacetyl)-lH-indole (3 mmol) and lithium carbonate (0.47 g, 6 mmol) in tetrahy~ofu.dn (10 ml) 4-(piperidin-1-yl)piperidine (1.01 g, 6 mmol) was 20 added. The resulting mixture was stirred at room temperature for about 2.5 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was extracted thrice with 1 N hydrochloric acid. The combined acidic extracts were extracted with ethyl acetate, then basified with sodium carbonate, and then extracted 25 twice with ethyl acetate, and then twice with methylene chloride. The organic fractions were comhined and the solvents were removed in vacuo. After ~,;I ~ating with diethyl ether 0.46 grams of the desired product as crystalline material were obtained.
NMR, IR, and W were consistent with the proposed title structure.
3 o Exact Mass FAB for C28H3sclN3o2:
Theory: 480.2418 Found: 480.2411 FDMS 479 (M+) mp 144-145~C
W O 97/09308 PCT~US96/14163 - The following ~ mples were prepared essentially as described in the Schemes and Methods, supra. In the following mples, unless otherwise noted, NMR was consistent with the proposed title ~ e.
Exam~le 1 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-(amino)methyl-lH-indole C~ ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 300 (M+).
Analysis for Cl7Hl7ClN20:
Theory: C, 67.88; H,5.70; N, 9.3L
Found: C,67.64; H, 5.86; N, 9.24.
mnle 2 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(N,N-dimethylamino)methyl]-lH-indole N(CH3)2 ~ ~Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 328 (M+) Analysis for ClsH2lclN2o:
Theory: C, 69.40; H, 6.44; N,8.52.
Found: C,69.18; H, 6.73; N,8.54.
- . -W O 97/09308 PCT~US96/14163 Example 3 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(N,N-5 diethylamino)methyl]-lH-indole hydrochloride N(CH2CH3)2 H
NMR (DMS0) was consistent with the proposed title structure.
lo FDMS 366 (M+).
Analysis for C2lH2sClN2O2 ~ HCl:
Theory: C, 64.12; H, 6.66; N, 7.12.
Found: C, 64.30; H, 6.69; N, 7.18.
~mr~le 4 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(N,N,N-trimethyl~mmonium)methyl]-lH-indole iodide H3C ~ I CH3 ~ I-~~'13~
CH3 Cl NMR (DMS0) was consistent with the proposed title structure.
FDMS 343 (M+) Analysis for C2oH24clN2o ~ I:
Theory: C, 51.03; H, 5.14; N, 5.95.
Found: C, 50.80; H, 4.93; N, 6.00.
~mple 5 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-5 [(benzylamino)methyl]-lH-indole hydrochloride ~-3 HN ~HCl ~~"13~
CH3 Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 390 (M+).
Analysis for C24H23ClN2O ~ HCl:
Theory: C, 67.45; H, 5.66; N, 6.56.
Found: C, 67.63; H, 5.70; N, 6.60.
F,~mple 6 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(2-phenylethylamino)methyl]-lH-indole hydrochloride H ~HCl 0~
CH~ Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 404 (M+).
Analysis for C2sH2sClN2O ~ HCl:
Theory: C, 68.03; H, 5.94; N, 6.35.
Found: C, 68.27; H, 5.99; N, 6.60.
~?mDle 7 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(N-methyl-N-lo butylamino)methyl]-lH-indole ~--CH3 ~~ ~l3 C1 NMR (CDCl3) was consistent with the proposed title structure.
15 IR was consistent with the desired title structure.
FDMS 370 (M+).
Analysis for C22H27clN2o:
Theory: C, 71.24; H, 7.34; N, 7.55.
Found: C, 71.19; H, 7.48; N, 7.39.
~mple 8 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(N-methyl-N-benzylamino)methyl]-lH-indole hydrochloride N
~,, C~.
CH3 Cl NMR, IR and W were consistent with the desired title structure.
FDMS 404 (M+).
Analysis for C2sH2sClN2O ~ HCl:
Theory: C, 68.03; H, 5.94; N, 6.35.
Found: C, 68.30; H,5.92; N, 6.45.
F~mI)le 9 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[N-methyl-N-(3-N',N'-dimethylaminopropyl)amino]methyl]-lH-indole N(CH3)2 N
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 400 (M+l).
Analysis for C23H30ClN3O:
Theory: C, 69.07; H, 7.66; N, 10.51.
Found: C, 69.33; H, 7.34; N, 10.41.
~Pmple 10 -Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[N-methyl-N-[3-25 (N',N'-dimethylamino)-2,2-dimethylpropyl]amino]methyl]- lH-indole W O 97/09308 PCT~US96/14163 H X N(CH3)2 CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 414 (M+1) Analysis for C24H32ClN3O:
Theory: C, 69.93; H, 7.79; N, 10.15.
Found: C, 69.67; H, 7.78; N, 10.17.
~,x~m~le 11 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(pyrrolidin-1-yl)methyl]-lH-indole hydrochloride '3' CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 354 (M+).
Analysis for C2lH23ClN2O ~ HCl:
Theory: C, 64.45; H, 6.18; N, 7.16.
Found: C, 64.66; H, 6.33; N, 7.03.
m~le 12 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride W O 97/09308 PCT~US96/14163 /~
HCl N ~ O ~
CH3 ~ Cl NMR, IR and W were consistent with the desired title structure.
5 FDMS 368 (M+).
Analysis for C22H2sClN2O ~ HCl:
Theory: C, 65.19; H, 6.46; N, 6.91.
Found: C, 65.46; H, 6.52; N, 7.16.
~.x~mnle 13 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(3-methylpiperidin-1-yl)methyl]-lH-indole N ~
~-~'13~
CH3 Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 382 (M+).
Analysis for C23H27clN2o:
Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 72.38; H, 7.22; N, 7.36.
.
~x~qm}~le 14 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(4-methylpiperidin- 1 -yl )methyl] - lH-indole ~=~3~
CH3 Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 382 (M+).
Analysis for C23H27clN2o:
Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 72.33; H, 7.22; N, 7.47.
~.x~mnle 15 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[4-(N,N-dimethylamino)piperidin-1-yl]methyl]-lH-indole Q~)~ ( CH3 ) 2 CH3 Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 411 (M+).
Analysis for C24H30ClN3O:
Theory: C, 69.97; H, 7.34; N, 10.20.
Found: C, 69.74; H, 7.38; N, 10.13.
F~xarr~le 16 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[4-(piperidin- 1-25 yl)piperidin-1-yl]methyl]-lH-indole rN3N~
~"'~~~
FDMS 4~1 (M+).
Analysis for C27H34ClN30:
Theory: C, 71.74; H, 7.58; N, 9.30.
Found: C, 71.55; H, 7.44; N, 9.14.
F.~ml?le 17 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-~(4-acetamido-4-phenylpiperidin- l-yl)methyl]-lH-indole o~CH3 ~J, CH3 Cl 15 FDMS ~01 (M+).
Analysis for C30H32clN3o2:
Theory: C, 71.77; H, 6.43; N, 8.37.
Found: C, 71.79; H, 6.61; N, 8.52.
2 0 F.x~ml~le 18 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(4-methylpiperazin- 1 -yl )methyl] - lH -indol e CA 022039l2 1997-04-28 W O 97/09308 PCT~US96/14163 ~ ~' ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 383 (M+).
Analysis for C22H26ClN3O:
Theory: C, 68.83; H, 6.83; N, 10.95.
Found: C, 68.80; H, 6.71; N, 10.95.
~?.mI)le 19 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(4-isopl ol~yl~i~erazin- l-yl)methyl]- lH-indole ~ CH3 r~ N N ~
~ ~ 'H3 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 411 (M+).
Analysis for C24H30ClN3O:
Theory: C, 69.97; H, 7.34; N, 10.20.
Found: C, 69.97; H, 7.36; N, 10.02.
m~le 20 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(4-phenylpiperazin-l-yl)methyl]-lH-indole W 0 97/09308 PCTrUS96/14163 N N~
~~
NMR was consistent with the desired title structure.
FDMS 445 (M+).
Analysis for C27H2gClN3O:
Theory: C, 72.71; H,6.33; N, 9.42.
Found: C,73.00; H, 6.41; N, 9.51.
F.x~ ?le 21 Preparation of 2-[(4~chlorophenoxy)methyl]-1-methyl-3-[(4-benzylpiperazin-1-yl)methyl]-lH-indole hydrochloride N N
~/ \J
=~' NMR (DMSO) was consistent with the proposed title structure.
FDMS 459 (M+).
Exact Mass (FAB+) for C2gH3lClN3O:
Theory: 460.2155.
Found: 460.2145.
F,x~qrnple 22 .
~ Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(4-25 cyclohexylpiperazin- 1 -yl )methyl]- lH-indole CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/1416 - /~ rN N{~
~''~'13~
CH3 Cl NMR (DMSO) was consistent with the proposed title structure.
5 FDMS 451 (M+).
Analysis for C27H34ClN3O:
Theory: C, 71.74; H, 7.58; N, 9.30.
Found: C, 71.48; H, 7.53; N, 9.26.
lo ~ 9m~le 23 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[4-(~ylillnd-2-yl)piperazin-l-yl)methyl]-lH-indole CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 447 (M+).
Analysis for C2sH26ClNsO:
Theory: C, 67.03; H, 5.85; N, 15.63.
Found: C, 67.05; H, 5.93; N, 15.64.
mrle 24 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-(morpholin-4-yl)methyl]-lH-indole WO 97/09308 PCT~US96/141~3 --N O
~~
NMR was consistent with the desired title structure.
FDMS 370 (M+).
Analysis for C2lH23clN2o2:
Theory: C, 68.01; H, 6.25; N, 7.55.
Found: C, 67.84; H, 6.65; N, 7.25.
h'x~mple 25 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-(tryptolin-2-yl)methyl]-lH-indole N
C~l~ ~ C 1 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 455 (M+).
Analysis for C2gH26ClN3O:
Theory: C, 73.75; H, 5.75; N, 9.21.
Found: C, 73.99; H, 6.00; N, 9.03.
m~le 26 Preparation of 2-[(2,4-dichlorophenoxy)methyl]- 1-methyl-3-[N-( l-methylpiperidin-4-yl )-N-methylamino]methyl]- lH-indole dihydrochloride monohydrate W 0 97/09308 PCT~US96/14163 CH3 ~2 N ~ N-CH3 ~" 0~ ~ H2 ~
CH3 Cl Cl NMR was consistent with the desired title structure.
5 mp 196-197~C.
FDMS 446 (M+).
Analysis for C24H2gCl2N3O ~ 2HCl ~ H2O:
Theory: C, 53.64; H, 6.19; N, 7.82.
Found: C, 53.66; H, 5.92; N, 8.10.
F~Ample 27 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[[4-(N,N-dimethyl~mino)piperidin-1-yl]methyl]-lH-indole r~
r N ~ N(CH3)2 ~~3~
CH3 Cl Cl NMR, IR, and W were consistent with the desired title structure.
mp 105-106~C.
FDMS 445 (M+).
Analysis for C24H2gCl2N30:
Theory: C, 64.57; H, 6.55; N, 9.41.
Found: C, 64.27; H, 6.48; N, 9.49.
2 5 F.~m~le 28 Preparation of 2-[(2,4-dichlorophenoxy)methyl]- 1-methyl-3-[[4-(piperidin-1-yl)piperidin-1-yl]methyl]-lH-indole N ~ N ~
~ r ~~~3~
CH3 Cl Cl NMR, IR, and W were consistent with the desired title structure.
FDMS 485(M+).
mp 106-107~C
Analysis for C27H33Cl2N3O:
Theory: C, 66.66; H, 6.84; N, 8.64.
Found: C, 66.92; H, 7.04; N, 8.74.
F.x~mrle 29 15 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-(2-aminoethyl)-lH-indole ,~
N~--~'13~
CH3 Cl 20 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 314 (M+).
Exact Mass (FAB) for Cl8H20clN2o:
Theory: 315.1264.
Found: 315.1246.
mple 30 W O 97/09308 PCTAUS96/141~3 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[(3-dimethylAminopropyl)amino]ethyl]-lH-indole N (CH3) 2 N--~0~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 399 (M+).
Analysis for C23H30ClN3O:
Theory: C, 69.07; H, 7.56; N, 10.51.
lo Found: C, 69.23; H, 7.79; N, 10.52.
F.~Amrle 31 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-N-15 (3-dimethylaminopropyl)Amino]ethyl]-lH-indole dihydrochloride N(CH2) 3 H3C~
N
/~ /--/ ~2 HCl ~3 _ 0~3~
NMR (DMSO) was consistent with the proposed title structure.
FDMS 413 (M+).
Exact Mass (FAB) for C24H33ClN30:
Theory: 414.2312.
Found: 414.2312.
W 0 97/09308 PCT~US96/141~3 F.~mple 32 -Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(piperidin- 1-yl)ethyl]-lH-indole <~
N
~0~
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 382 (M+).
10 Analysis for C23H27ClN20:
Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 72.40; H, 7.26; N, 7.37.
F.~mr~le 33 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-methylpiperidin- l-yl )ethyl]- lH-indole ~S
NJ
'' ~0~3~
CH, C 1 ~ NMR (CDCl3) was consistent with the proposed title structure. FDMS 396 (M+).
Analysis for C24H2gClN20:
Theory: C, 72.62; H, 7.36; N, 7.06.
Found: C, 72.40; H, 7.35; N, 7.25.
F,x~rn~le 34 Prcparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-benzylpiperidin-1-yl)ethyl]-lH-indole ~~~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 472 (M~).
Analysis for C30H33ClN2O:
Theory: C, 76.17; H, 7.03; N, 5.92.
Found: C, 76.37; H, 7.15; N, 5.85.
nple 35 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[4-(N,N-dimethylamino)piperidin- 1-yl]ethyl]-lH-indole N(CH3) 2 N
~ r~ ~ Cl ~ NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass (FAB) for C2sH33ClN3O:
~ Theory: 426.2312.
Found: 426.2297.
F,~qm~le 36 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]ethyl]-lH-indole C~
~o CH3 ~ Cl FDMS 465 (M+) Analysis for C2gH36ClN3O:
Theory: C, 72.16; H, 7.79; N, 9.02.
Found: C, 72.09; H, 7.69; N, 9.09.
F,~mple 37 20 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-cyclohexylpiperazin- 1-yl )ethyl]- lH-indole WO 97/09308 PCT~US96/141~3 N ~
I~ ~ Cl NMR (CDC13) was consistent with the proposed title structure.
FDMS 465 (M+).~ Analysis for C2gH36ClN3O:
Theory: C, 72.16; H,7.79; N, 9.02.
Found: C, 72.00; H, 7.88; N, 9.05.
Fx~ le 38 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-N-( l-methylpiperidin-4-yl)]ethyl]- lH-indole H3C~
~2 ~lu~ ~Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 459 (M+).
Analysis for C2sH3lCl2N3O: ~
Theory: C, 65.21; H, 6.79; N, 9.13.
Found: C, 65.07; H, 6.85; N, 9.06.
-W O 97/09308 PCT~US96/14163 F~m~le 39 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[4-(N,N-5 dimethylamino)piperidin-1-yl]ethyl]-lH-indole N(CH3)2 ~' CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
lo Exact Mass for C25H32Cl2N3~:
Theory: 460.1922.
Found: 460.1890.
F.~mple 40 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]ethyl]-lH-indole N- ' (~ OC1 NMR (CDCl3) was consistent with the proposed title structure.
W O 97/09308 PCTrUS96/14163 Exact Mass for C2gH36Cl2N3O:
Theory: 500.2235.
Found: 500.2215.
~x~mple 41 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[3-[4-(N,N-dimethyl ~ mi no)piperidin- 1 -yl~propyl] - lH-indole r N ~ N(CH3)2 r ~o CH3 ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FABMS 440 (M+1) 15 Analysis for C26H34ClN3O:
Theory: C, 70.97; H, 7.79; N, 9.55.
Found: C, 70.73; H, 7.65; N, 9.44.
~mple 42 Preparation of (RS) 2-[(4-chloropheno~y)methyl]-1-methyl-3-[3-(piperidin-3-yl)~ yl]-lH-indole G ~
CH~ Cl WO 97/09308 PCT~US96/14163 ~ NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass for C24H30clN2o:
Theory: 397.2047.
Found: 397.2055.
F.x~mnle 43 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[[4-(dimethylamino)piperidin-1-yl]carbonyl]ethyl]-lH-indole ~ N 3 N(CH3)2 ~~'13~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 453 (M+) Analysis for C26H32clN3o2:
Theory: C, 68.78; H, 7.10; N, 9.26.
Found: C, 68.74; H, 7.04; N, 9.38.
~,x~m~le 44 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[[4-(dimethyl~qmino)piperidin-1-yl]carbonyl]ethenyl]-lH-indole o ~
~ N ~ N(CH3)2 ~ ~ ~ ~'13~
CH, Cl W O 97t09308 PCT~US96/14163 NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass (FAB) for C26H3lclN3o2:
Theory: 452.2105.
Found: 4~2.2099.
F.~qTnple 46 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[1-hyd, o~y-2-[(3-acetamido)pyrrolidin-1-yl]ethyl]-lH-indole ~, N~ C H 3 J O
H0~7 ~~'13 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 442 (M+).
Exact Mass FAB (M+1) for C24H2gClN303:
Theory: 442.1897.
Found: 442.1878.
F.~m~le 47 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(piperidin-1-yl)ethyl]-lH-indole HoyN
~~'13~
NMR (CDCl3) was consistent with the proposed title structure.
~ FDMS 398 (M+).
~ Analysis for C23H27ClN202:
Theory: C, 69.25; H, 6.82; N, 7.02.
Found: C, 69.51; H, 6.86; N, 6.81.
mple 48 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(4-methylpiperidin- 1-yl )ethyl]- lH-indole ~ ~1 CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 412, (M+).
Analysis for C24H2sclN2o2:
Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 70.02; H, 7.13; N, 7.00.
~mple 49 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(4-benzylpiperidin- 1-yl)ethyl]- lH-indole CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 488 (M+).
Analysis for C30H33clN2o2:
Theory: C, 73.67; H, 6.80; N, 5.73.
Found: C, 73.52; H, 6.87; N, 5.58.
mrle 50 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(4-dimethylaminopiperidin- 1-yl)ethyl]- lH-indole N(CH3) 2 HO
,~
0~3 NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 442 (M+).
Analysis for C2sH32clN3o2:
Theory: C, 67.94; H, 7.30; N, 9.51.
Found: C, 67.73; H, 7.52; N, 9.75.
WO 97/09308 PCT/US96/141~3 mple 51 -Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-[4-(piperidin-1-yl)piperidin-1-yl]ethyl]-lH-indole dihydrochloride N
HO~ ~ 2 HC 1 ~~'13~
CH3 C l NMR (DMSO) was consistent with the proposed title structure.
FDMS 481 (M+1).
10 Analysis for C2gH3sClN3O2 ~ 2 HCl Theory: C, 60.71; H, 6.73; N, 7.59; Cl, 19.20.
Found: C, 60.86; H, 6.90; N, 7.53; Cl, 19.19.
m~le 52 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(4-cyclohexylpiperazin-1-yl)ethyl]- lH-indole ~N
~0,3~
CH-~ Cl W O 97/09308 PCTrUS96/14163 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 482 (M+1).
Analysis for C28H36clN3o2:
Theory: C,69.76; H, 7.53; N, 8.72.
Found: C, 70.06; H, 7.61; N, 8.46.
~x~m~le 53 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-3-(piperidin-4-yl)propyl]-lH-indole NH
N ~ O
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 412 (M+).
Single compound of high purity as evidenced by chromatographic methods.
Analysis for C24H2sclN2o2:
Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 68.18; H, 7.87; N, 6.58.
h~xz~m~le 54 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-rN-methyl-N-(1-methylpiperidin-4-yl)amino]ethyl]- lH-indole CA 022039l2 l997-04-28 H3C~ ~
HO ~ N ~ NCH3 ~1'- ~Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 475 (M+).
5 Analysis for C2sH3lcl2N3o2:
Theory: C, 63.02; H, 6.55; N, 8.82.
Found: C, 63.43; H, 6.88; N, 8.92.
F.x~mple 55 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[1-hydroxy-2-(metho~ycall)onyl)ethyl]-lH-indole HO ~ ~
Q~o,3~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 373 (M+).
Analysis for C2oH2oclNo4:
20Theory: C, 64.26; H, 5.39; N, 3.75.
Found: C, 64.55; H, G.23; N, 3.79.
F,~mr!le 56 CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/14163 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-carboxy-lH-indole ~_ o~3~
CH3 Cl NMR (DMSO) was consistent with the desired title structure.
FDMS 315 (M+).
Analysis for Cl7Hl4ClNO3:
Theory: C, 64.67; H, 4.47; N, 4.44.
Found: C, 64.84; H, 4.60; N, 4.54.
~m~le 57 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[3-15 dimethylamino-2,3-dimethylpropylamino]carbonyl]- lH-indole ,CH3 H3C~ ~ N~
O ~ CH3 ~u ~Cl NMR (CDCl3) was consistent with the proposed title structure.
FAB 426 (M-l).
Analysis for C24H30ClN3O2:
Theory: C, 67.36; H, 7.07; N, 9.82.
Found: C, 67.58; H, 6.79; N, 9.64.
~ mT-le 58 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[N,N-bis(3-dimethylaminopropyl)aminn]carbonyl]- lH-indole .
~ N(CH3)2 0~ r N(CH3)2 CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 483 (M-1).
FABMS 485 (M+1) Analysis for C27H37clN4o2:
Theory: C, 66.86; H, 7.69; N, 11.55.
Found: C, 66.91; H, 7.54; N, 11.69.
nple 59 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[N-methyl-N-(1-methylpiperidin-4-yl)amino]carbonyl]-lH-indole ,CH~
CH~ Cl 20 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 427 (M+2) Analysis for C24H28clN3o2:
Theory: C, 67.67; H, 6.63; N, 9.86.
Found: C, 67.38; H, 6.90; N, 9.94.
WO 97/09308 PCT/US96/141~3 F.x~n~nle 60 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[4-(piperidin-1-5 yl)piperidin- l-yl]carbonyl]- lH-indole ~3 N 3 CH3 ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 465 (M+).
Analysis for C27H32ClN302:
Theory: C,69.59; H,6.92; N, 9.02.
Found: C,69.47; H,7.00; N, 9.22.
~ mDle 61 Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-3-yl)acetyl]-lH-indole ,~. J~.' ~'13 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 396 (M+) Analysis for C23H2sclN2o2:
Theory: C, 69.60; H,6.35; N, 7.06.
Found: C,69.71; H, 6.28; N,7.20.
W O 97/09308 PCT~US96/14163 ~.x~mrle 62 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(1-tritylpiperidin-4-yl)acetyl]-lH-indole ~ NTr O~ J
~0~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 638 (M+) Analysis for C42H3gClN202:
Theory: C, 78.92; H, 6.15; N, 4.38.
Found: C, 78.73; H, 6.15; N, 4.25.
F,x~mnle 63 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-4-yl)acetyl]-lH-indole NH
~Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 397 (M+1) Analysis for C23H2sClN202:
- Theory: C, 69.60; H, 6.35; N, 7.06.
Found: C, 69.34; H, 6.43; N, 6.86.
W 0 97/09308 PCT~US96/14163 F,~m~le 64 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[4-(piperidin-1-5 yl)piperidin-1-yl]acetyl]-lH-indole dihydrochloride ~N
N~ ~'13~
NMR (DMSO) was consistent with the proposed title structure.
FDMS 479 (M+) Analysis for C2gH34ClN3O2 ~ 2HCl:
Theory: C, 60.82; H, 6.56; N, 7.60.
Found: C, 60.67; H, 6.70; N, 7.38.
~ mple 65 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(piperidin-3-yl)ethyl]carbonyl]- lH-indole CH 1 C l NMR (CDCl3) was consistent with the proposed title structure.
FDMS 411 (M+1).
Analysis for C24H27clN2o2:
W O 97/09308 PCT~US96/14163 Theory: C, 70.15; H, 6.67; N, 6.82.
Found: C, 70.38; H, 6.39; N, 7.02.
.
F.~mple 66 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[2-( 1-tritylpiperidin-4-yl)ethyl]carbonyl]- lH-indole NTr C~' ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
C43H41ClN2O2 FDMS 652 (M+).
Single compound of high purity as evidenced by chromatographic means.
F.~mple 67 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(piperidin-4-yl)ethyl]carbonyl]-lH-indole r\
O~_~NH
~ ~~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 411 (M+l) 2 5 Analysis for C24H27clN2o2:
- Theory: C, 70.15; H, 6.62; N, 6.82.
Found: C, 69.87; H, 6.54; N, 6.79.
F,x~mnle 68 5 Preparation of 2-[(4-chlorophenoxy)methyl]-l-methyl-3-[[2-[l-[3-[(l-tritylpiperidin-4-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]-lH-indole ~_~N ~ NTr ~ '~"13~
CH3 Cl FDMS 779 (M+2) Analysis for Cs1Hs6ClN3O:
Theory: C, 78.69; H, 7.25; N, 5.40.
Found: C, 78.90; H, 7.34; N, 5.60.
h'.x~mple 69A
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-[1-[3-(piperidin-4-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]- lH-indole r~ r~
O _~N ~ NH
~~'13~
CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FAB 536(M+).
Exact mass FAB (M+1) for C32H43ClN3O2:
Theory: ~36.3044.
Found: 536.3044.
WO 97/09308 PCT~US96/14163 ~mple 69B
~ Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-[1-[3-(1-5 tritylpiperidin-3-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]-lH-indole r~ r O~ ~N
~-~'13~
CH~ Cl FDMS 779 (M+2).
0 Analysis for CslHs6clN3o2:
Theory: C, 78.69; H, 7.25; N, 6.40.
Found: C, 78.92; H, 7.41; N, 5.27.
~mple 69C
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-[1-[3-(piperidin-3-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]-lH indole NMR (CDCI3) was consistent with the proposed title structure.
FDMS 536 (M+1).
- Analysis for C32H42ClN302:
- Theory: C, 71.69; H, 7.90; N, 7.84.
Found: C, 71.45; H, 7.85; N, 7.61.
W O 97/09308 PCT~US96/14163 F,~mple 70 Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-lH-indole r~
N
N
NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB (M+) for C35H48ClN4~2:
Theory: 691.3466.
Found: 591.3476.
F.~mple 70A
15 Preparation of (S) 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-[[4-(piperidin- l-yl)piperidin- l-yl]acetyl]- lH-indole / \ ~\
o~M~ N ~
~_0~3~
Cl H
WO 97/09308 PCTrUS96/141~3 - NMR (CDCl3) was consistent with the proposed title structure. FABMS 691.3476 (M+).
~ Analysis for C3sH47ClN4O2:
Theory: C, 71.10; H, 8.01; N, 9.48.
Found: C, 70.82; H, 8.14; N, 9.23.
F.~m~le 70B
Preparation of (R) 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-l o yl)propyl]-3-[[4-(piperidin- l-yl)piperidin- l-yl]acetyl]- lH-indole N
Cl C' N
NMR (CDCl3) was consistent with the proposed title structure.
15 Exact Mass for C35H48ClN402:
Theory: 591.3466.
Found: 591.3458.
~mnle 71 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]-3-[[4-(piperidin- 1 -yl)piperidin- l-yl]acetyl]- lH-indole ~ 3 ~
~ ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass for C3sH48clN4o2:
Theory: 591.3466.
Found: 691.3464.
F.~,qmple 72 Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-[3-(piperidin-3-yl)propanoyl]- lH-indole o~
~ Cl H
15 NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass for C31H41ClN302:
Theory: 522.2887.
Found: 522.2905.
-F,~mrle 73 ~ Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]-3-5 [3-(piperidin-3-yl)propanoyl]-lH-indole r\ ~
\ ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
lo Exact Mass for C3lH41ClN3O2 (M+1):
Theory: 522.2887.
Found: 522.2910.
F,~m~le 74 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-[3-(piperidin-4-yl)propanoyl]-lH-indole CA 022039l2 l997-04-28 W O 97/09308 PCTrUS96/14163 - ~ NH
~ ~--~'13~
NH
IR and NMR (CDCl3) were consistent with the desired title structure.
FABMS 522 (M+1) Analysis for C3lH40ClN302:
Theory: C, 71.31; H, 7.72; N, 8.05.
Found: C, 71.04; H, 7.89; N, 7.78.
h~amrle 75 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-[3-(piperidin-4-yl)l,l ol~yl]-3-[3-(piperidin-4-yl)propanoyl]-lH-indole O ~ NH
~ 0~
~ Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 522 (M+1) Analysis for C31H40ClN3O2:
Theory: C, 71.31; H, 7.72; N, 8.05.
W 097/09308 PCT~US96/14163 Found: C, 71.10; H, 7.66; N, 7.97.
h~x~mple 76 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[[3-(dimethylamino)propylamino]carbonyl]methyl]-lH-indole H N(CH3)2 N
lo NMR (CDCl3) was consistent with the proposed title structure.
FDMS 413 (M+).
Analysis for C23H28ClN3O2:
Theory: C, 66.74; H, 6.82; N, 10.15.
Found: C, 66.89; H, 6.96; N, 10.11.
~mple 77 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[ l-hydroxy- 1-[[4-(piperidin- l-yl)piperidin- 1 -yl]carbonyl]methyl]- lH-indole Q ~ OH
Cl NMR (CDCl3) was consistent with the proposed title structure.
- FDMS 495 (M+).
~ 25 Analysis for C2gH34ClN3O3:
Theory: C, 67.80; H, 6.91; N, 8.47.
Found: C, 67.86; H, 6.90; N, 8.45.
F.~mple 78 Preparation of 2-[1-methyl-2-[(4-chlorophenoxy)methyl]indol-3-5 yl]glyoxylic acid OH
C
NMR (DMSO) was consistent with the proposed title structure.
lo FDMS 343 (M+) Analysis for C1gH14ClNO4:
Theory: C, 62.89; H, 4.11; N, 4.07.
Found: C, 63.15; H, 4.37; N, 3.92.
5F,x~qm;l?le 79 Preparation of methyl 2-[1-methyl-2-[(4-chlorophenoxy)methyl]indol-3-yl]glyoxylate ~ ~ OCH3 ~~O
Cl NMR (CDCl3) and IR were consistent with the desired title structure.
Exact Mass FAB (M+1) for ClgHl7ClNO4: -Theory: 368.0846.
Found: 368.0818.
mple 80 Preparation of phenyl 2-[1-methyl-2-[(4-chlorophenoxy)methyl]indol-3-yl]glyoxylate ~~~3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 419 (M+) 10 Analysis for C24HlgClNO4:
Theory: C, 68.66; H,4.32; N,3.34.
Found: C, 68.90; H,4.49; N, 3.33.
m~le 81 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-amino-1,2-ethanedionyl]- lH-indole ~ ~ NH2 ~o Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 342 (M+).
Analysis for C18HlsClN2O3:
Theory: C, 63.07; H,4.41; N, 8.17.
Found: C, 63.36; H,4.50; N,8.18.
.
-W O 97/09308 PCTAUS96/141~3 F.~mple 82 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-methylamino-1,2-ethanedionyl]-lH-indole C
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 357 (M+l) Analysis for C1gH17ClN2O3:
Theory: C, 63.96; H, 4.80; N,7.85.
Found: C, 63.97; H, 4.83; N, 7.82.
~Am~le 83 Preparation of 3-dimethylAminol,rol,yl 2-[1-methyl-2-[(4-chlorophenoxy)methyl]indol-3 -yl]glyoxylate N(CH3)2 Cl NMR (CDCl3) was consistent with the proposed title structure.
C23H2sClN2O4: FAB 429 (M+).
Single compound of high purity as evidenced by chromatographic methods.
~Am~le 84 WO 97/09308 PCT/US96/141~3 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[2-(dimethylamino)ethyl ~mino]- 1,2-ethanedionyl]- lH-indole hydrochloride .
O~ CH3 Cl ~HCl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 413 (M+).
10 Analysis for C22H24ClN303 ~ HCl:
Theory: C, 58.67; H, 5.59; N, 9.33.
Found: C, 58.38; H, 5.82; N, 9.48.
m~le 85 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[3-(dimethylamino)propylamino]- 1,2-ethanedionyl]-lH-indole N N(CH3)2 Cl NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB (M+1) for C23H27ClN303:
- Theory: 428.1741.
- Found: 428.1738.
m}-le 86 W O 97/09308 PCT~US96/141~3 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[3-amino~l o~Jylamino]-1,2-ethanedionyl]-lH-indole CH3 ~Q
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 399 (M+).
Analysis for C21H22ClN3O3:
lo Theory: C, 63.08; H, 5.55; N, 10.51.
Found: C, 69.53; H, 6.18; N, 11.70.
Single compound of high purity as evidenced by chromatographic methods.
~ mple 87 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[3-(t-butoxycarbonylamino)propyl~mino]-1,2-ethanedionyl]-lH-indole ~;~ H NHBoC
CH~ ~
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 499 (M+).
mp 175-176~C.
2 5 Analysis for C26H30ClN3Os:
Theory: C, 62.46; H, 6.05; N, 8.40.
Found: C, 62.19; H, 6.08; N, 8.27.
- F~mT)l e 88 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[2,2-dimethyl-3-(dimethyl~mino)propyl~mino]-1,2-ethanedionyl]-lH-indole ~ HN ~ N(CH3)2 Cl 10 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 456 (M+).
Analysis for C2sH30ClN3O3:
Theory: C, 65.85; H, 6.63; N, 9.22.
Found: C, 65.62; H, 6.76; N, 9.12.
mple 89 Preparation of 2-[(4-chloroph~no~y)methyl]-1-methyl-3-[2-[6-(dimethyl~mino)hexylamino]-1,2-ethanedionyl]-lH-indole ~ H N(CH3)2 Cl - NMR (CDCl3) was consistent with the proposed title structure.- IR was consistent with the desired title structure.
Exact Mass FAB (M+1) for C27H33ClN303:
Theory: 470.2210.
Found: 470.2196.
~IxAmrle 90 5 Prcparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-2-(dimethylamino)ethylamino]-1,2-ethanedionyl]-lH-indole N ( CH3 ) 2 CH3 ~
Cl 10 NMR, W, and IR were consistent with the desired title structure.
FDMS 427 (M+). mp 142-143~C.
Analysis for C23H26ClN3O3:
Theory: C, 64.56; H, 6.12; N, 9.82.
Found: C, 64.82; H, 6.32; N, 9.89.
h',x~m~le 91 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-3-(dimethylamino)propylamino]- 1,2-ethanedionyl]- lH-indole o CH<
N ~ N(CH3), C
NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
25 Exact Mass FAB (M+1) for C24H2gClN303:
Theory: 442.1897.
Found: 442.1904.
F.~rnple 92 Preparation of 2-[(4-chlorophçno~y)methyl]-1-methyl-3-[2-[N-methyl-3-(dimethylamino)lJI ol ylamino]- 1,2-ethanedionyl]- lH-indole hydrochloride o CH3 ~ ,~ , N(CH3)2 NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title product.
FDMS 441 (M+).
Exact Mass FAB (M+1) for C24H2gClN303:
Theory: 442.1897.
Found: 442.1895.
F.~mple 93 20 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[bis[3-(dimethylamino)propyl]amino]-1,2-ethanedionyl]-lH-indole (H3C)2N
o N(CH3)2 CH~ ~
Cl W O 97/09308 PCTAUS96/141~3 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 512 (M+) Analysis for C2gH37ClN4O3:
Theory: C, 65.55; H, 7.27; N, 10.92.
Found: C, 65.85; H, 7.46; N, 11.04.
h'.~z~mrle 94 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[N-benzyl-3-(dimethylamino)propyl~mino]-1,2-ethanedionyl]-lH-indole N(CH3)2 Cl 15 IR, NMR, and W were consistent with the desired title structure.
FDMS 517 (M+).
Analysis for C30H32ClN3O3:
Theory: C, 69.55; H, 6.23; N, 8.11.
Found: C, 69.82; H, 6.31; N, 8.13.
mrle 95 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[N-methyl-3-[1-(t-butoxycarbonyl )piperidin-3-yl]propylamino] - 1,2-ethanedionyl] - lH-25 indole WO 97/09308 PCT/US96/141~3 ' C?BOC
CH3~Q
Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 581 (M+).
Analysis for C32H40ClN3Os:
Theory: C, 66.02; H, 6.93; N, 7.22.
Found: C, 65.91; H, 7.14; N, 7.08.
F.~m~le 96 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(1-methylpiperidin-3-yl)amino]-1,2-ethanedionyl]-lH-indole GN~CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 439 (M+).
Analysis for G24H26ClN3O3:
Theory: C, 65.52; H, 5.96; N, 9.55.
Found: C, 65.80; H, 5.96; N, 9.56.
F,~mple 97 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-(1-methylpyrrolidin-3-yl)amino]-1,2-ethanedionyl]- lH-indole W O 97/09308 . PCTAUS96/14163 o IcH3 ,CH3 Cl IR, NMR, and W were consistent with the desired title structure.
5 FDMS 439 (M~).
Analysis for C24H26ClN303:
Theory: C,65.52; H, 5.96; N, 9.55.
Found: C, 65.54; H, 6.03; N,9.69.
~.x~qmnle 98 Preparation of (RS) 2-[(4-chloropheno~y)methyl]-1-methyl-3-[2-rN-methyl-(1-methylpiperidin-3-yl)amino]-1,2-ethanedionyl]-lH-indole o CH3 N~CH3 CH3 \~
Cl IR was consistent with the desired title structure. FDMS 453 (M+).
Analysis for C2sH2gClN303:
Theory: C,66.14; H, 6.22; N, 9.26.
Found: C, 65.86; H, 6.17; N, 9.29.
~.x~mple 99 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[(quinuclidin-25 3-yl )amino]- 1,2-ethanedionyl]- lH-indole WO 97/09308 PCT~US96/141C3 H
Cl NMR, W, and IR were consistent with the desired title structure.
5 FDMS 451 (M+). mp 204-205~C.
Analysis for C2sH26ClN3O3:
Theory: C, 66.44; H, 5.80; N, 9.30.
Found: C, 66.37; H, 5.88; N, 9.37.
F.~mT-le 100 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(piperidin-1-yl)-1,2-ethanedionyl]-lH-indole o ~
N
N ~ O
C
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 410 (M+).
Analysis for C23H23ClN203:
Theory: C, 67.22; H, 5.64; N, 6.82.
Found: C, 67.50; H, 5.81; N, 6.63.
F~mple 101 WO 97/09308 PCTAUS96tl4163 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[2-(dimethylaminomethyl)cyclohegylamino- 1,2-ethanedionyl]- 1H-indole hydrochloride N(CH3)2 ~N~
Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 481 (M+).
Analysis for C27H32ClN3O3 ~ HCl:
Theory: C, 62.55; H, 6.42; N, 8.10.
Found: C, 62.56; H, 6.44; N, 8.06.
mple 102 Preparation of 2-[(4-chloropheno~y)methyl]-1-methyl-3-[2-(4-methylpiperidin-1-yl)-1,2-ethanedionyl]-lH-indole N~
Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 424 (M+).
Analysis for C24H2sClN2O3:
Theory: C, 67.84; H, 5.93; N, 6.59.
W O 97/09308 PCTAJS96/141~3 Found: C, 68.04; H, 5.85; N, 6.74.
F~m~le 103 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-benzylpiperidin-1-yl)-1,2-ethanedionyl]-lH-indole N
CH3 ~Q
Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 500 (M+).
Analysis for C3oH2sclN2o3:
Theory: C, 71.92; H, 5.83; N, 5.59.
Found: C, 71.69; H, 5.74; N, 5.38.
mr)le 104 Preparation of 2-[(4-chloropheno~y)methyl]-1-methyl-3-[2-(4-20 aminocarbonylpiperidin-1-yl)-1,2-ethanedionyl]-lH-indole ~NH2 ~N
CH3 ~Q
Cl NMR, W, and IR were consistent with the desired title structure.
W O 97/09308 PCTAUS96/141~3 FDMS 453 (M+). mp 220-221~C.
Analysis for C24H24ClN3O4:
Theory: C, 63.60; H, 5.33; N, 9.26.
Found: C, 63.46; H, 5.50; N, 9.18.
F.~mrle 106 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-dimethyl~qminopiperidin-l-yl)-1,2-ethanedionyl]-lH-indole ~, N~
~ N~
N~\_ O
CH3 '1Q
Cl NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB (M+l) for C2sH29ClN3O3:
Theory: 454.1897.
Found: 464.1882.
F.~mple 106 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[4-(piperidin- 1-yl)piperidin-l-yl]-1,2-ethanedionyl]-lH-indole N
. ~ ~ N ~
~~O
CH3 ~Q
Cl NMR (CDCl3) and IR were consistent with the proposed title structure.
FDMS 493 (M+) Analysis for C2gH32ClN3O3:
Theory: C, 68.07; H, 6.53; N, 8.51.
Found: C, 67.97; H, 6.66; N, 8.27.
~.~?mnle 107 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(3-aminocarbonylpiperidin- 1-yl)- 1,2 -ethanedionyl]- lH-indole H2N>eO
o ~
~N
CH3 )Q
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 453.
mp 229-230~C
Analysis for C24H24ClN3O4:
Theory: C, 63.50; H, 5.33; N, 9.26.
Found: C, 63.53; H, 5.44; N, 9.04.
F.~qm~le 108 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(piperazin-1-5 yl)- 1 ,2-ethanedionyl]- lH-indole o 1--N J
Cl NMR (CDCl3) was consistent with the proposed title structure.
lo FDMS 411 (M+) mp 168-169~C.
Analysis for C22H22ClN3O3:
Theory: C, 64.15; H, 6.38; N, 10.20.
Found: C, 63.95; H, 5.36; N, 10.08.
F.~mT)le 109 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-isopropylpiperazin-l-yl)-1,2-ethanedionyl]-lH-indole ~N)~ CH3 , N~J
~N~--O
Cl NMR (CDCl3) was consistent with the proposed title structure.
W O 97/09308 PCT~US96/14163 ~ FDMS 453 (M+).
Analysis for C2sH2gClN3O3:
Theory: C, 66.15; H, 6.22; N, 9.26.
Found: C, 65.94; H, 6.48; N, 8.97.
F.x~mrle 110 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[4-(t-butoxycarbonyl)piperazin-1-yl]-1,2-ethanedionyl]-lH-indole BoC
N
, NJ
N ~ O
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 511 (M+).
mp 200-201~C
Analysis for C27H30ClN3Os:
Theory: C, 63.34; H, 5.91; N, 8.21.
Found: C, 63.10; H, 5.80; N, 7.98.
F.~mple 111 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-cyclohexylpiperazin-1-yl)-1,2-ethanedionyl]-lH-indole O ~
, ,NJ
N ~ O
Cl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
5 FDMS 493 (M+).
Analysis for C2gH32ClN3O3:
Theory: C, 68.07; H, 6.53; N, 8.50.
Found: C, 67.81; H, 6.60; N, 8.24.
F~m~le 112 Preparation of 2-[(4-chlororheno~y)methyl]-1-methyl-3-[2-[4-(2-dimethylaminoethyl)piperazin-1-yl]-1,2-ethanedionyl]-lH-indole dihydrochloride o ~ N ~ N(CH3)2 ~;; ~NJ
c1 ~2 HCl NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
2 o FDMS 482 (M+).
Analysis for C26H31ClN4O3 ~ 2 HCl:
Theory: C, 56.17; H, 5.98; N, 10.07.
WO 97t09308 PCT~US96/14163 Found: C, 56.47; H, 6.07; N, 10.05.
-m~nle 113 5 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-[3-aminoacetylpyrrolidin-1-yl]-1,2-ethanedionyl]-lH-indole o ~ NH2 N
Cl 10 NMR (CDCl3) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 453 (M+).
Analysis for C24H24ClN3O4:
Theory: C, 63.50; H, 5.33; N, 9.26.
Found: C, 63.75; H, 5.37; N, 9.21.
F~mple 114 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-20 3-(dimethylamino)propyl~mino]-1,2-ethanedionyl]-lH-indole N ~ N~ CH3 C
- NMR (CDCl3) was consistent with the proposed title structure.
W was consistent with the desired title structure.
FDMS 475 (M+).
Analysis for C24H27Cl2N3O3:
Theory: C, 60.51; H, 5.71; N, 8.82.
Found: C, 60.69; H, 5.80; N, 8.77.
F,~7~mple 115 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-lo (l-methylpiperidin-4-yl)amino]-1,2-ethanedionyl]-lH-indole N ~ N- CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
C2sH27ClN3O3: FDMS487(M+) Single compound of high purity as evidenced by chromatographic methods.
F~Ampl e 116 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[4-(N,N-dimethylamino )piperidin- l-yl] - 1,2 -ethanedionyl] - lH-indole I~r N~ CH
CH, Cl -W 0 97/09308 PCT~US96/141~3 NMR (CDCl3) was consistent with the proposed title structure.
W was consistent with the desired title structure.
FDMS 487, 489 (M+).
Analysis for C2sH27Cl2N3O3:
Theory: C, 61.48; H, 5.57; N, 8.60.
Found: C, 61.75; H, 5.63; N, 8.59.
F.~mrle 117 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[(4-(piperidin-1-yl)piperidin-1-yl]-1,2-ethanedionyl]-lH-indole '\~ N
~, M~J
~~
CH3 ~
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 527,529 (M+).
Analysis for C2gH31Cl2N3O3:
Theory: C, 63.64; H, 5.91; N, 7.95.
Found: C, 63.82; H, 6.08; N, 7.85.
mrle 118 Preparation of 2-[(2-cyano-4-bromophenoxy)methyl]-1-methyl-3-[2-[N-25 methyl-(3-dimethylaminopropyl)amino]-1,2-ethanedionyl]-lH-indole W O 97/09308 PCTrUS96/14163 ~,N N~CH
o~N
Br IR, NMR, and W were consistent with the desired title structure.
FDMS 511, 513 (M+).~ Analysis for C2sH27BrN4O3 ~ 0.5 H2O:
Theory: C, 67.70; H, 5.42; N, 10.75.
Found: C, 57.56; H, 5.36; N, 10.60.
Exact Mass for C2sH2gBrN4O3:
Theory: 511.1332.
0 Found: 511.1345.
F'.-r~mrle 119 Preparation of 2-[(2-cyano-4-bromophçno~y)methyl]-1-methyl-3-[2-[N-15 methyl-(1-methylpiperidin-4-yl)amino]- 1,2-ethanedionyl]- lH-indole Br IR, NMR, and W were consistent with the desired title structure.
FDMS ~22, 524 (M+).
Analysis for C26H27BrN4O3:
Theory: C, 59.66; H, 5.20; N, 10.70.
Found: C, 59.38; H, 5.24; N, 10.49.
2 5 h'.~qmI-l e 120 CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/141~3 Preparation of 2-[(2-cyano-4-bromophenoxy)methyl]-1-methyl-3-[2-(4-~ dimethyl~mi nopiperidin- 1-yl)] - 1,2 -ethanedionyl]- lH-indole ~,N(CH3) 2 ~;~ N~J
~~
Br IR, NMR, and W were consistent with the desired title structure.
FDMS 622, 624 (M+).
Analysis for C26H27BrN4O3 ~ 0.6 H2O:
Theory: C, 58.65; H, 6.30; N, 10.62.
Found: C, 58.61; H, 6.21; N, 10.42.
Exact Mass for C26H2gBrN4O3:
Theory: 523.1345.
Found: 623.1365.
F.~qmrle 121 Preparation of 2-[(2-cyano-4-bromophenoxy)methyl]-l-methyl-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]]-1,2-ethanedionyl]-lH-indole ~;~ N~
Br IR, NMR, and W were consistent with the desired title structure.
FDMS 563, 565 (M+).
W O 97/09308 PCT~US96/14163 Analysis for C2gH31BrN4O3:
Theory: C, 61.81; H, 5.54; N, 9.94.
Found: C, 61.56; H, 5.62; N, 9.91.
~ m.nle 122 Preparation of 2-[(4-chlorophenoxy)methyl]-1-ethyl-3-[2-(4-dimethylaminopiperidin-1-yl)]- 1,2-ethanedionyl]- lH-indole ~,N (CH3 ) 2 ~,, N~) N~\_ O
H3C ~Q
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 467.
Analysis for C26H3OClN3O3:
Theory: C, 66.73; H, 6.46; N, 8.98.
Found: C, 66.88; H, 6.57; N, 8.90.
~mnle 123 20 Preparation of 2-[(4-chlorophenoxy)methyl]-1-ethyl-3-[2-[N-methyl-(1-methylpiperidin-4-yl)amino]-1,2-ethanedionyl]-lH-indole ~, C, H3 N ~\
H3C \~'Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 467.
Analysis for C26H3OClN3O3:
Theory: C, 66.73; H, 6.46; N, 8.98.
s Found: C, 66.90; H, 6.70; N, 9.03.
mrle 124 Preparation of 2-[(4-chlorophenoxy)methyl]-1-benzyl-3-[2-(4-0 dimethylaminopiperidin- 1-yl)]- 1,2-ethanedionyl]- lH-indole N(CH3), N
~~
~ Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 529.
Analysis for C3lH32ClN303:
Theory: C, 70.24; H, 6.08; N, 7.93.
Found: C, 70.26; H, 6.18; N, 7.73.
F.~m~le 125 Preparation of 2-[(4-chlorophenoxy)methyl]-1-(2-piperidin-1-ylethyl)-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]-1,2-ethanedionyl]-lH-indole W O 97/09308 PCT~US96/14163 O
N ~
N ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB for C34H44ClN4Os:
Theory: 591.3102.
Found: 591.3100.
F,~rnrle 126 10 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl)-3-[piperidin- 1-ylmethyl]- lH-indole ~o ~ Cl 15 NMR (CDCl3) was consistent with the proposed title structure.
Single compound of high purity as evidenced by chromatographic methods.
W O 97/09308 PCTAUS96/141~3 F.R~mrle 127 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(1-methylpiperidin-3-yl)propyl)-3-[piperidin-1-ylmethyl]-lH-indole ~ N~\--O
.~ ~
Cl N
NMR (CDCl3) was consistent with the proposed title structure.
Single compound of high purity as evidenced by chromatographic 0 methods.
m~le 128 Preparation of 2-[(4-chlorophenoxy)methyl]-1-ethyl-3-[(4-15 dimethylaminopiperidin-1-yl)methyl]-1H-indole N ( CH3 ) 2 ~~~
H3C Cl NMR and W were consistent with the desired title structure. FDMS
425 (M+). mp 115-116~C.
Analysis for C2sH32ClN3O:
Theory: C, 70.49; H, 7.67; N, 9.86.
Found: C, 70.70; H, 7.67; N, 9.80.
~mple 129 Preparation of 2-[(4-chlorophenoxy)methyl]-1-benzyl-3-[(4-10 dimethylaminQpiperidin-l-yl)methyl]-lH-indole N ( CH 3 ) 2 ~0 ~ ~ Cl NMR and W were consistent with the desired title structure. FDMS
15 488 (M+). mp 127-128~C.
Analysis for C30H34ClN3O:
Theory: C, 73.83; H, 7.02; N, 8.61.
Found: C, 73.77; H, 7.21; N, 8.66.
li'~ample 130 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(piperidin- 1-yl)ethyl]-3-[(4-dimethylaminopiperidin- l-yl)methyl]- lH-indole N(CH3)2 ~0 ~
N ~ O
< ~ ~ Cl NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB for C30H42ClN40:
Theory: 509.3047.
Found 509.3018.
F.~mple 131 0 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-[3-(piperidin- l-yl)l~l o~yl]-3- [(4-dimethylaminopiperidin-1-yl)methyl]-lH-indole trihydrochloride N(CH3)2 ~, ~3 HCl Cl C~
15 NMR and W were consistent with the desired title structure.
W O 97/09308 PCT~US96/14163 FDMS 523 (M+1).
mp 240-242~C.
Analysis for C31H43ClN4O ~ 3 HCl:
Theory: C, 58.86; H, 7.33; N, 8.86.
Found: C, 58.66; H, 7.09; N, 8.77.
F.~mple 132 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]-3-10 [(4-dimethyl~minopiperidin-1-yl)methyl]-lH-indole N(CH3)2 ~0 c ~ Cl N
NMR (CDCl3) was consistent with the proposed title structure.
C31H43ClN4O: FDMS522(M+) Single compound of high purity as evidenced by chromatographic methods.
mple 133 Preparation of 2-[(4-chlorophenoxy)methyl]-1-ethyl-3-[[4-(piperidin-1-yl)piperidin- 1-yl]methyl]- lH-indole O
H3C ~ Cl NMR and W were consistent with the desired title structure. FDMS
465 (M+). mp 130-131~C.
Analysis for C2gH36ClN3O:
Theory: C, 72.16; H, 7.79; N, 9.02.
Found: C, 72.12; H, 7.78; N, 8.86.
F.~mrle 134 Preparation of 2-[(4-chlorophenoxy)methyl]-1-benzyl-3-[[4-(piperidin-1-yl)piperidin- 1-yl]methyl]- lH-indole ~ Cl NMR and W were consistent with the desired title structure.
FDMS 527 (M+).
mp 153-154~C.
Analysis for C33H3gClN3O:
Theory: C, 75.05; H, 7.25; N, 7.96.
Found: C, 75.25; H, 7.40; N, 8.08.
-Fx~mT)le 135 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(piperidin-1-yl)ethyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]methyl]-lH-indole ~ Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 548 (M+) mp 102-103~C.
Analysis for C33H4sClN4O:
lo Theory: C, 72.17; H, 8.26; N, 10.20.
Found: C, 72.12; H, 8.31; N, 10.17.
F~-nrle 136 5 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-[2-(piperidin- 1-yl )ethyl] - lH-indole ~o ~> Cl 20 IR, NMR, and W were consistent with the desired title structure.
FDMS 368 (M+). FAB 369 (M+1).
Analysis for C22H25ClN2~:
Theory: C, 71.63; H, 6.83; N, 7.59.
Found: C, 71.93; H,7.28; N,7.22.
Single compound of high purity as evidenced by chromatographic methods.
~.~?mI)le 137 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(piperidin-4-yl)ethyl]-lH-indole Q~o ~ Cl N
H
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 368 (M+).
Analysis for C22H2sclN2o:
Theory: C, 71.63; H,6.83; N,7.59.
Found: C, 71.66; H,6.86; N, 7.87.
F,~m.~le 138 20 Preparation of 2-[(phenylthio)methyl]-1-[3-(piperidin-3-yl)propyl]-lH-indole Q~s NMR (CDCl3) was consistent with the proposed title structure.
FDMS 364 (M+).
5 Analysis for C23H2gN2S:
Theory: C, 75.78; H, 7.75; N, 7.69.
Found: C, 75.70; H, 7.73; N, 7.86.
F'.~z~mrle 139 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-3-yl)~rol,yl]-lH-indole ~;~~
Cl C~
N
NMR (CDCl3) was consistent with the proposed title structure.
Single compound of high purity as evidenced by chromatographic methods.
2 o F,~qmrle 140 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(1-methylpiperidin-3-~ yl)~rol yl]-lH-indole ~_-0 c~ Cl N
NMR and W were consistent with the desired title structure.
mp 97-98~C.
Analysis for C24H2gClN20:
Theory: C, 72.62; H, 7.36; N, 7.06.
Found: C, 72.59; H, 7.48; N, 7.14.
F.~mple 141 Preparation of 2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)l,~o~yl]-15 lH-indole Q~o~
Cl NMR (CDCl3) was consistent with the proposed title structure.
~0 C23H27ClN20: FDMS 382 (M+) W O 97/09308 PCT~US96/14163 Single compound of high purity as evidenced by chromatographic methods.
F,~mrle 142 Preparation of 2-[2-(4-chlorophenyl)ethyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~HCl H3C ~
Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 366 (M+).
Analysis for C23H27ClN2 ~ HCl:
Theory: C, 68.48; H, 7.00; N, 6.94.
Found: C, 68.26; H, 6.87; N, 6.76.
F.~mr~le 143 Preparation of 2-[(4-chlorophenylamino)methyl]-1-methyl-3-[(piperidin-20 1-yl)methyl]-lH-indole ~?
H~C
Cl NMR, W, and IR were consistent with the desired title structure.
25 FDMS 367 (M+). mp 169~C.
Analysis for C22H26ClN3:
Theory: C, 71.82; H, 7.12; N, 11.42.
Found: C, 71.60; H, 7.06; N, 11.46.
F.~zml?le 146 Preparation of 2-[(2,4-dichlorophenylamino)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~N?l H3C ~
Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 401, 403 (M+).
mp 147-148~C.
Analysis for C22H2sCl2N3:
Theory: C, 65.67; H, 6.26; N, 10.44.
Found: C, 66.48; H, 6.30; N, 10.59.
mple 147 Preparation of 2-[(4-chlorophenylamino)methyl]-3-[(piperidin-1-yl)methyl]-lH-indole Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 353, 354 (M+). mp 135~C.
Analysis for C21H24ClN3:
Theory: C, 71.27; H, 6.84; N, 11.87.
Found: C, 71.90; H, 7.17; N, 12.02.
nple 148 Preparation of 2-[(2,4-dichlorophenylamino)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole --~HN c 1 CH3 ~ /
Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 401 (M+) mp 147-148~C.
Analysis for C22H2sCl2N3:
Theory: C, 65.47; H, 6.26; N, 10.44.
Found: C, 65.48; H, 6.30; N, 10.59.
nrle 149 Preparation of 2-[(cyclohexylamino)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole 6~N?
N N
NMR, W, and IR were consistent with the desired title structure.
FDMS 339 (M+).
mp 162-164~C.
Analysis for C22H33N3:
Theory: C, 77.83; H, 9.80; N, 12.38.
Found: C, 75.98; H, 9.11; N, 12.67.
Exact Mass FAB for C22H34N3:
Theory: 340.2763.
Found: 340.2770.
F.~zlmple 150 Preparation of 2-[(cyclohexylmethyl~mino)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole dihydrochloride (3~ ~ 2HCl NMR, W, and IR were consistent with the desired title structure.
FDMS 354, 390 (M+). mp 159-161~C.
Analysis for C23H3sN3 ~ 2HCl:
Theory: C, 64.78; H, 8.75; N, 9.85.
Found: C, 64.62; H, 8.82; N, 9.65.
F.~qmrle 151 Preparation of 2-t(naphth-2-yl~mino)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole W O 97/09308 PCT~US96/14163 ~;?
CH3 ~
NMR (CDCl3), IR, and W were consistent with the proposed title structure.
5 FDMS 383 (M+).
mp 144~C.
Analysis for C26H2gN3:
Theory: C, 81.42; H, 7.62; N, 10.96.
Found: C, 81.26; H, 7.49; N, 10.89.
~0 mnle 152 Preparation of 2-[[N-acetyl-N-(cyclohexylmethyl)amino~methyl]-1-methyl-3-[(piperidin- 1-yl)methyl]- lH-indole hydrochloride ~~U
CH3 ~ O ~HCl NMR, W, and IR were consistent with the desired title structure.
FDMS 395 (M+).
20 Analysis for C2sH37N3O ~ HCl:
Theory: C, 69.50; H, 8.87; N, 9.73.
Found: C, 68.87; H, 9.29; N, 9.30.
Exact Mass FAB for C2sH3gN3O:
Theory: 396.3015 Found: 396.3020 F.~mI-le 153 Preparation of 2-[[N-acetyl-N-(benzyl)~mino]methyl]-1-methyl-3-5 [(piperidin- 1-yl )methyl]- lH-indole hydrochloride A
CH, ~e o H3C ~HCl NMR, UV, and IR were consistent with the desired title structure.
10 FDMS 389 (M+). mp 148-150~C.
Analysis for C2sH31N3O ~ HCl:
Theory: C, 70.49; H, 7.57; N, 9.86.
Found: C, 70.21; H, 7.40; N, 9.73.
F.~ )le 164 Preparation of 2-[[(3-chlorophenyl)amino]carbonyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole (~ ~N~¦3~C1 NMR, W, and IR were consistent with the desired title structure.
FDMS 381, 383 (M+). mp 137-138~C.
Analysis for C22H24ClN3O:
Theory: C, 69.19; H, 6.33; N, 11.00.
Found: C, 69.39; H, 6.39; N, 11.20.
W O 97/09308 PCT~US96/14163 ~m~le 156 Preparation of 2-[[(2,4-dichlorophenyl)amino]carbonyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole r~
~ Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 417 (M+). mp 180-182~C.
Analysis for C22H23Cl2N3O:
Theory: C, 63.47; H, 5.57; N, 10.09.
Found: C, 63.27; H, 5.65; N, 10.18.
~,mnle 1~6 Preparation of 2-[[(cyclohexyl)amino]carbonyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole Q ~ H
NMR, W, and IR were consistent with the desired title structure.
FDMS 353 (M+). mp 180~C.
Exact Mass FAB for C22H32N30:
Theory: 354.2545.
2 5 Found: 354.2543.
mnle 157 Preparation of 2-[[(cyclohexylmethyl)amino]carbonyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~'-~J
NMR (CDCl3), IR, and W were consistent with the proposed title structure.
mp 126~C.
lo Analysis for C23H33N30:
Theory: C, 75.16; H, 9.05; N, 11.43.
Found: C, 75.09; H, 9.03; N, 11.25.
F.x~ nle 158 Preparation of 2-[[(naphth-2-yl)amino]carbonyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~0 NMR, W, and IR were consistent with the desired title structure.
FDMS 397 (M+). mp 187~C.
Analysis ffir C26H27N30:
Theory: C, 78.56; H, 6.86; N, 10.67.
- 25 Found: C, 78.84;H, 7.02; N, 10.78.
.
F,x~mnle 159 W O 97/09308 PCTAUS96/141~3 Preparation of 2-[phenoxymethyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride NMR, W, and IR were consistent with the desired title structure.
FDMS 334 (M+). mp 225~C.
Analysis for C22H26N2O ~ HCl:
Theory: C, 71.32; H, 7.34; N, 7.55.
Found: C, 71.45; H, 7.44; N, 7.79.
F'.~z~mple 160 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-15 yl)methyl]-lH-indole hydrochloride salt NMR, IR and W were consistent with the desired title structure.
20 FDMS 368 (M+). mp 214~C.
Analysis for C22H2sClN2O ~ HCl:
Theory: C, 65.32; H, 6.46; N, 6.91.
Found: C, 65.46; H, 6.52; N, 7.16.
~ mple 161 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]- lH-indole .
CH3 Cl NMR was consistent with the desired title structure.
5 FDMS 368 (M+).
Analysis for C22H2sclN2o:
Theory: C, 71.63; H, 6.83; N, 7.59.
Found: C, 68.39; H, 6.55; N, 6.16.
~mnle 162 Preparation of 2-[(3-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~ O ~Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 368 (M+). mp 222~C.
Analysis for C22H2sClN2O ~ HCl:
Theory: C, 65.19; H, 6.46; N, 6.91.
Found: C, 65.15; H, 6.55; N, 6.95.
~mple 163 Preparation of 2-[(2-chlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride - 222 - ~
~,3 CH3 C l NMR, W, and IR were consistent with the desired title structure.
FDMS 369 (M+).
Analysis for C22H2sClN2O ~ HCl:
Theory: C, 65.19; H, 6.46; N, 6.91.
Found: C, 65.48; H, 6.65; N, 6.98.
mrle 164 Preparation of 2-[(4-fluorophenoxy)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole hydrochloride ~ HC l NMR (CDCl3) was consistent with the proposed title structure.
FDMS 352 (M+).
Analysis for C22H2sFN2O ~ HCl:
Theory: C, 67.94; H, 6.74; N, 7.20.
Found: C, 67.74; H, 6.77; N, 7.16.
mple 166 Preparation of 2-[(3-fluorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride N
NMR (CDCl3) was consistent with the proposed title structure.
FDMS 352 (M+).
5 Analysis for C22H2sFN2O ~ HCl:
Theory: C, 67.94; H, 6.74; N, 7.20.
Found: C, 65.85; H, 6.51; N, 6.68.
SIngle compound of high purity as evidenced by chromatographic methods.
F.~mrle 166 Preparation of 2-[(2-fluoropheno~y)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole hydrochloride --~;f ~HCl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 352 (M+).
20 Analysis for C22H2sFN2O ~ HCl:
Theory: C, 67.94; H, 6.74; N, 7.20.
Found: C, 67.67; H, 6.63; N, 7.40.
mrle 167 ~ 25 Preparation of 2-[(4-trifluoromethylphenoxy)methyl]-1-methyl-3-[(piperidin- 1-yl )methyl]- lH-indole hydrochloride CA 022039l2 l997-04-28 W O 97/09308 PCTrUS96/14163 Q~o?~cl NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
5 Analysis for C23H2sF3N2O ~ HCl:
Theory: C, 62.94; H, 5.97; N, 6.38.
Found: C, 63.51; H, 6.05; N, 6.41.
Single compound of high purity as evidenced by chromatographic methods.
mrle 168 Preparation of 2-[(3-trifluoromethylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride N ~ ~HCl ~ O ~ CF3 NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
20 Analysis for C23H2sF3N2O ~ HCl:
Theory: C, 62.94; H, 5.97; N, 6.38.
Found: C, 64.11; H, 6.07; N, 6.42.
Single compound of high purity as evidenced by chromatographic methods.~5 mnle 169 W O 97/09308 PCT~US96/14163 Preparation of 2-[(2-trifluoromethylph~noxy)methyl]-1-methyl-3-[(piperidin- 1-yl )methyl]- lH-indole hydrochloride ~ Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C23H2sF3N2O ~ HCl:
Theory: C, 62.94; H, 5.97; N, 6.38.
Found: C, 62.89; H, 6.02; N, 6.37.
F.xAmple 170 Preparation of 2-[(4-acetylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride r~
Q~ ~ HC 1 NMR, W, and IR were consistent with the desired title structure.
FDMS 376 (M+) Analysis for C24H2gN2O ~ HCl:
Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 69.69; H, 7.27; N, 6.72.
FxAmnle 171 WO 97/09308 PCT/US96/141~3 Preparation of 2-[(3-acetylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~
NMR, W, and IR were consistent with the desired title structure.
FDMS 376 (M+).
Analysis for C24H2gN2O2 ~ HCl:
Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 69.91; H, 7.18; N, 6.81.
F.~m~le 172 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~3, NMR and W were consistent with the desired title structure.
20 FDMS 402 (M+).
Analysis for C22H24cl2N2o:
Theory: C, 60.26; H, 5.75; N, 6.39.
Found: C, 61.61; H, 5.69; N, 6.34.
Single compound of high purity as evidenced by chromatographic 25 methods.
F.x~m;~?le 173 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride r~
~ HCl CH3 Cl Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C22H24Cl2N20 ~ HCl:
lo Theory: C, 60.08; H, 6.73; N, 6.37.
Found: C, 60.31; H, 6.00; N, 6.62.
ple 174 Preparation of 2-[(3,5-dichloroph~no~y)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~HCl CH3 Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C22H24CI2N20 ~ HCl:
Theory: C, 60.08; H, 5.73; N, 6.37.
Found: C, 58.13; H, 5.25; N, 5.99.
Single compound of high purity as evidenced by chromatographic methods.
-mnle 175 Preparation of 2-[(2,5-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole r~
,Cl CH3 Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C22H24cl2N2o:
Theory: C, 65.51; H, 6.00; N, 6.95.
Found: C, 65.71; H, 6.00; N, 6.93.
F.~m~le 176 Preparation of 2-[(2,6-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride HC l CH3 Cl NMR, UV, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C22H24Cl2N2O ~ HCl:
Theory: C, 60.08; H, 5.73; N, 6.37.
Found: C, 59.79; H, 5.43; N, 6.11.
m~e 177 W O 97/09308 PCT~US96tl4163 Preparation of 2-[(3,4-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~ HCl CH3 Cl NMR, UV, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C22H24Cl2N20 ~ HCl:
Theory: C, 60.08; H,5.73; N, 6.37.
Found: C, 59.82; H, 5.72; N, 6.21.
~.~anl;E)le 178 Preparation of 2-[(2,3-dichlorophenoxy)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole ~ ~~ ' CH3 Cl Cl NMR, UV, and IR were consistent with the desired title structure.
FDMS 402 (M+).
Analysis for C24H24cl2N2o:
Theory: C, 65.51; H, 6.00; N, 6.95.
~ Found: C, 65.23; H, 5.96; N, 6.82.
~ 25 mrle 179 W O 97/09308 PCT~US96/141~3 Preparation of 2-[(4-phenylphenoxy)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole ~,N~>
CH3 ~
NMR, W, and IR were consistent with the desired title structure.
FDMS 410 (M+).
Analysis for C28H3oN2o:
Theory: C, 81.91; H, 7.36; N, 6.82.
Found: C, 80.96; H, 7.34; N, 6.73.
Single compound of high purity as evidenced by chromatographic methods.
mrle 180 Preparation of 2-[(3-phenylI~hçnoxy)methyl]-1-methyl-3-[(piperidin-1-yl )methyl] - lH-indole hydrochloride HCl Q~, NMR, W, and IR were consistent with the desired title structure.
FDMS 410 (M~).
Analysis for C2gH30N2O ~ HCl:
Theory: C, 75.23; H, 6.99; N, 6.27.
Found: C, 74.74; H, 7.10; N, 6.23.
W 0 97/09308 PCT~US96/141~3 Single compound of high purity as evidenced by chromatographic methods.
m~le 181 s Preparation of 2-[(2-phenylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~HCl CH, ~=~
~.d NMR, W, and IR were consistent with the desired title structure.
FDMS 410 (M+).
Analysis for C2gH30N2O ~ HCl:
Theory: C, 75.23; H, 6.99; N, 6.27.
Found: C, 74.03; H, 7.10; N, 6.35.
Single compound of high purity as evidenced by chromatographic methods.
~mrle 182 Preparation of 2-[(4-methylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~--~) f ' NMR, W, and IR were consistent with the desired title structure.
W O 97/09308 PCT~US96/14163 FDMS 348 (M+).
Analysis for C23H2gN2O ~ HCl:
Theory: C, 71.76; H, 7.59; N, 7.28.
Found: C, 70.88; H, 7.70; N, 7.32.
5 Single compound of high purity as evidenced by chromatographic methods.
F',~7~rnl;~le 183 10 Preparation of 2-[(3-methylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl )methyl]- lH-indole hydrochloride ~ ~ H:l 15 NMR, W, and IR were consistent with the desired title structure.
FDMS 348 (M+).
Analysis for C23H2gN2O ~ HCl:
Theory: C, 71.76; H, 7.59; N, 7.28.
Found: C, 72.41; H, 7.78; N, 7.29.
20 Single compound of high purity as evidenced by chromatographic methods.
~m~nle 184 25 Preparation of 2-[(2-methylphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl )methyl]- lH-indole hydrochloride ~ ~c 1 CH~ H C
W O 97/09308 PCT~US96/14163 NMR, W, and IR were consistent with the desired title structure.
FDMS 348 (M+).
Analysis for C23H2gN2O ~ HCl:
Theory: C, 71.76; H, 7.59; N, 7.28.
Found: C, 71.71; H, 7.64; N, 7.21.
F~x~Tnrle 186 Preparation of 2-[(4-methoxyphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride HCl NMR, W, and IR were consistent with the desired title structure.
FDMS 364 (M+).
Analysis for C23H2gN2O2 ~ HCl:
Theory: C, 68.90; H, 7.29; N, 6.99.
Found: C, 68.68; H, 7.30; N, 7.12.
F~mnle 186 Preparation of 2-[(3-methoxyphenoxy)methyl]- 1-methyl-3-[(piperidin- 1-yl )methyl]- lH-indole hydrochloride ~ HCl W O 97/09308 PCTrUS96/1416 NMR, W, and IR were consistent with the desired title structure.
FDMS 364 (M+).
Analysis for C23H2gN2O2 ~ HCl:
Theory: C, 68.90; H, 7.29; N, 6.99.
Found: C, 69.13; H, 7.38; N, 6.83.
h~rAmI)le 187 Preparation of 2-[(2-methoxyphenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~
NMR, W, and IR were consistent with the desired title structure.
FDMS 364 (M+).
Analysis for C23H2gN2O2 ~ HCl:
Theory: C, 68.90; H, 7.29; N, 6.99.
Found: C, 73.45; H, 7.94; N, 6.92.
Single compound of high purity as evidenced by chromatographic methods.
~mple 188 Preparation of 2-[2-hydroxyethyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~-~ ?
- Analysis for Cl6H22N2o:
Theory: C, 74.38; H, 8.58; N, 10.84.
Found: C, 74.35; H, 8.78; N, 10.96.
mDle 189 Preparation of 2-(2-methoxyethyl)-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~ G~II
NMR was consistent with the desired title structure.
FDMS 272, 273 (M+).
Analysis for Cl7H24N2o:
Theory: C, 74.96; H, 8.88; N, 10.28.
Found: C, 73.31; H, 8.86; N, 9.97.
mrle 190 20 Preparation of 2-(2-allyloxyethyl)-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride salt ~ CH2 CH3 HCl 25 NMR, W, and IR were consistent with the desired title structure.
- FDMS 298 (M+).
Analysis for ClgH26N20 ~ HCl:
Theory: C, 68.14; H, 8.13; N, 8.37.
Found: C, 68.30; H, 8.14; N, 8.39.
le 191 5 Preparation of 2-(benzyloxymethyl)-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~ HC 1 lo IR, W, and NMR (CDCl3) were consistent with the proposed title structure.
FDMS 384 (M+) Analysis for C23H2gN2O ~ HCl:
Theory: C, 71.76; H, 7.59; N,7.28.
Found: C, 68.44; H, 7.04; N,6.36.
Single compound of high purity as evidenced by chromatographic methods.
~ qmple L92 Preparation of 2-[(3-chlorobenzyloxy)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole hydrochloride /--\ ~HCl ~'Q
CH3 Cl NMR was consistent with the desired title structure.
FDMS 382 (M+).
Analysis for C23H27ClN2O ~ HCl:
W 0 97/09308 PCTAUS96/141~3 Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 71.92; H, 7.22; N, 7.43.
.
~mple 193 Preparation of 2-[(2-chlorobenzyloxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~o~
NMR was consistent with the desired title structure.
FDMS 382 (M+). mp 82-83~C.
Analysis for C23H27clN2o:
Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 71.87; H, 7.07; N, 7.36.
rr ple 194 Preparation of 2-[(4-chlorobenzyloxy)methyl]- 1-methyl-3-[(piperidin- 1-20 yl)methyl]-lH-indole hydrochloride Q~30 CH3 ~ HCl NMR (CDCl3), IR, and W were consistent with the proposed title ~ 25 structure.
FDMS 382 (M+) - Analysis for C23H27ClN2O ~ HCl:
Theory: C, 65.87; H, 6.73; N, 6.68.
W O 97/09308 PCT~US96/14163 Found: C, 65.54; H, 6.59; N, 6.39.
F,~amrle 195 s Preparation of 2-[(naphth-1-yloxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~HCl CH3 ~
Il I
lo NMR, W, and IR were consistent with the desired title structure.
FDMS 384 (M+).
Analysis for C26H2gN2O ~ HCl:
Theory: C, 74.18; H, 6.94; N, 6.65.
Found: C, 74.47; H, 7.05; N, 6.64.
F.~m~?le 196 Preparation of 2-[(naphth-2-yloxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride~0 r~
NMR, W, and IR were consistent with the desired title structure.
FDMS 384 (M+).
25 Analysis for C26H2gN2O ~ HCl:
WO 97/09308 PCTtUS96tl4163 Theory: C, 74.18; H, 6.94; N, 6.65.
Found: C, 71.44; H, 6.93; N, 6.67.
Single compound of high purity as evidenced by chromatographic methods.
F.~mnle 197 Preparation of 2-[(thiazol-2-yl)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole ~ N
NMR was consistent with the desired title structure.
mp 175-176~C.
FDMS 341 (M+).
Analysis for ClgH23N3OS:
Theory: C, 66.83; H, 6.79; N, 12.31.
Found: C, 66.64; H, 6.82; N, 12.03.
F.~mrle 198 Preparation of 2-[(pyrazin-2-yl)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole Qf ~ 3 CH~
NMR, W, and IR were consistent with the desired title structure.
FDMS 336 (M+). mp 101~C.
Analysis for C2oH24N4o:
Theory: C, 71.40; H, 7.19; N, 16.65.
Found: C, 71.44; H, 7.33; N, 16.43.
mrle 199 Preparation of 2-[(6-chloropyrazin-2-yl)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole O ~ N ~ C
NMR, W, and IR were consistent with the desired title structure.
FDMS 370 (M+). mp 94-96~C.
15 Analysis for C2oH23clN4o:
Theory: C, 64.77; H, 6.25; N, 15.11.
Found: C, 65.04; H, 6.45; N, 15.21.
F.~ml~le 200 Preparation of 2-[(pyrimidin-2-yl)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole CH~ N
NMR, W, and IR were consistent with the desired title structure.
FDMS 337 (M+1).
mp 123-125~C.
Analysis for C2oH24N40:
Theory: C, 71.40; H, 7.19; N, 16.65.
Found: C, 71.60; H, 7.43; N, 16.59.
~:x~n~le 201 Preparation of 2-[(quinolin-2-yl)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole ~}~ ~
NMR, W, and IR were consistent with the desired title structure.
FDMS 385 (M+1).
mp 113~C.
Analysis for C2sH27N3O:
Theory: C, 77.89; H, 7.06; N, 10.90.
Found: C, 77.64; H, 7.00; N, 11.05.
F,~nlnle 202 Preparation of 2-[(6-chloropyridazin-2-yl)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]- lH-indole CH~ ~ ~Cl NMR, UV, and IR were consistent with the desired title structure W O 97/09308 PCT~US96/1416 - 242 - ~
FDMS 371 (M+1). mp 138-139~C.
Analysis for C20H23ClN4O:
Theory: C, 64.77; H, 6.25; N, 15.11.
Found: C, 64.84; H, 6.28; N, 15.00.
~"~ ple 203 Preparation of 2-[(5,6,7,8-tetrahydrnn~phtll-1-yl)methyl]-1-methyl-3-[(4-dimethylaminopiperidin-1-yl)methyl]-lH-indole 3 N(CH3)2 NMR was consistent with the desired title structure.
FDMS 431 (M+).
15 Analysis for C2gH37N3O:
Theory: C, 77.92; H, 8.64; N, 9.74.
Found: C, 7~.79; H, 8.74; N, 8.74.
F.~ ?le 204 Preparation of 2-[(5,6,7,8-tetrahydronaphth-2-yl)methyl]-1-methyl-3-[(4-dimethylaminopiperidin- 1-yl)methyl]- lH-indole dihydrochloride hydrate ~ 1'1 ~
2HCl W O 97/09308 PCT~US96/14163 NMR and W were consistent with the desired title structure.
FDMS 431~ 432 (M+). mp 202~C.
Analysis for C2gH37N3O ~ 2 ECl ~ H2O:
Theory: C, 64.36; H, 7.91; N, 8.04.
Found: C, 64.73; H, 7.50; N, 7.99.
~,x~m,nle 205 Preparation of 2-[phenylthiomethyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride S~3 ~HCl NMR, W, and IR were consistent with the desired title structure.
FDMS 360 (M+1).
Analysis for C22H26N2S ~ HCl:
Theory: C, 68.28; H, 7.03; N, 7.24.
Found: C, 68.03; H, 7.00; N, 7.10.
~,xam~l?le 206 Preparation of 2-[(4-chlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride G~)~ .HCl NMR, W, and IR were consistent with the desired title structure.
FDMS 384 (M+).
Analysis for C22H2sClN2S ~ HCl:
Theory: C, 62.70; H, 6.22; N, 6.65.
Found: C, 62.12; H, 6.42; N, 6.22.
Single compound of high purity as evidenced by chromatographic 5 me ' hods.
mnle 207 Preparation of 2-[(3-chlorophenylthio)methyl]- 1-methyl-3-[(piperidin- 1-10 yl)methyl]-lH-indole hydrochloride NMR, W, and IR were consistent with the desired title structure.
FDMS 384 (M+).
Analysis for C22H2sClN2S ~ HCl:
Theory: C, 62.70; H, 6.22; N, 6.65.
Found: C, 62.94; H, 6.23; N, 6.93.
~ mrle 208 Preparation of 2-[(2-chlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ) f ~ HC l CH~ Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 384 (M+).
Analysis for C22H2sClN2S ~ HCl:
Theory: C, 62.70; H, 6.22; N, 6.65.
Found: C, 62.76; H, 6.20; N, 6.67.
F.~ ple 209 Preparation of 2-[(2,4-dichlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~ HC
CH, Cl Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 418 (M+).
Analysis for C22H24Cl2N2S ~ HCl:
Theory: C, 67.96; H, ~.53; N, 6.16.
Found: C, 56.61; H, 5.70; N, 6.05.
Single compound of high purity as evidenced by chromatographic methods.
F~lnrle 210 Preparation of 2-[(2,5-dichlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride CH3 Cl NMR, W, and IR were consistent with the desired title structure.
W O 97/09308 PCT~US96/14163 FDMS 418, 420 (M+1).
Analysis for C22H24Cl2N2S ~ HCl:
Theory: C, 57.96; H, 5.53; N, 6.15.
Found: C, 57.87; H, 5.50; N, 5.99.
F.x7mple 211 Preparation of 2-[(2,6-dichlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride HC l ~J
NMR, W, and IR were consistent with the desired title structure.
FDMS 417 (M+).
15 Analysis for C22H24Cl2N2S ~ HCl:
Theory: C, 57.96; H, 5.53; N, 6.15.
Found: C, 58.16; H, 5.68; N, 6.33.
F.x~mple 212 Preparation of 2-[(3,4-dichlorophenylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride Q s~cl CH3 Cl NMR, W, and IR were consistent with the desired title structure.
FDMS 418, 420 (M+1).
Analysis for C22H24Cl2N2S ~ HCl:
Theory: C, 57.96; H, 5.53; N, 6.15.
Found: C, 57.98; H, 5.54; N, 6.16.
~ rnple 213 Preparation of 2-[(cyclohexylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride ~ {
NMR (CDCl3), UV, and IR were consistent with the proposed title structure.
FDMS 356 (M+).
15 Analysis for C22H32N2S ~ HCl:
Theory: C, 67.23; H, 8.46; N, 7.13.
Found: C, 66.28; H, 9.27; N, 7.71.
Single compound of high purity as evidenced by chromatographic methods.
~mr~le 214 Preparation of 2-[(n-1~l o~yl~hio)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole hydrochloride CH-I
NMR (CDCl3), W, and IR were consistent with the proposed title structure.
FDMS 316 (M+) Analysis for ClgH2gN2S ~ HCl:
Theory: C, 64.65; H, 8.28; N, 7.94.
Found: C, 64.72; H, 8.03; N, 8.12.
F~rnrle 215 Preparation of 2-[(benzylthio)methyl]- 1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride Q ~?~ j NMR, W, and IR were consistent with the desired title structure.
FDMS 365 (M+).
Analysis for C23H2gN2S ~ HCl:
Theory: C, 68.89; H, 7.29; N, 6.99.
Found: C, 68.63; H, 7.52; N, 7.11.
~r~mrle 216 Preparation of 2-[(2-phenylethylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole NMR (CDCl3) was consistent with the proposed title structure.
C24H30N2S: FDMS 379 (M+1).
Single compound of high purity as evidenced by chromatographic methods.
~.x~m}~le 217 Preparation of 2-[(naphth-2-ylthio)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole ~ ~
NMR (CDCl3), W, and IR were consistent with the proposed title structure.
FDMS 400 (M+) 15 Analysis for C26H2gN2S ~ HCl:
Theory: C, 71.45; H, 6.69; N, 6.41.
Found: C, 69.59; H, 6.67; N, 6.21.
Single compound of high purity as evidenced by chromatographic methods.~0 mple 220 Preparation of 2-phenyl-3-(piperidin-1-yl)methyl-lH-indole 2s 6~
NMR, W, and IR were consistent with the desired title structure.
W O 97/09308 PCTrUS96/14163 FDMS 290 (M+).
Analysis for C2oH22N2:
Theory: C, 82.72; H, 7.64; N, 9.65.
Found: C, 82.97; H, 7.74; N, 9.81.
~qmple 221 Preparation of 1-methyl-2-phenyl-3-(piperidin-1-yl)methyl-lH-indole NMR, W, and IR were consistent with the desired title structure.
FDMS 304,305 (M+1).
Analysis for C2lH24N2:
Theory: C, 82.85; H, 7.95; N, 9.20.
Found: C, 82.68; H, 7.92; N, 9.40.
mple 222 20 Preparation of 2-phenyl-1-methyl-3-[2-(piperidin-1-yl)-1,2-ethanedionyl]-lH-indole 25 NMR (CDCl3), IR, and W were consistent with the proposed title structure.
FDMS 346 (M+) W O 97/09308 PCT~US96/14163 Analysis for C22H22N2o2:
Theory: C, 76.28; H, 6.40; N, 8.09.
FOund: C,76.09; H,6.35; N,8.09.
F.~7lmIlle 223 Preparation of 2-phenyl-1-methyl-3-[2-[N-benzyl-N-3-(dimethylaminopropyl)amino]-1,2-ethanedionyl]-lH-indole ~ CH
IR, NMR, and W were consistent with the desired title structure.
FDMS 463 (M+).
Analysis for C2sH3lN3o2:
Theory: C, 76.79; H, 6.89; N,9.26.
Found: C, 77.06; H,7.02; N,9.45.
F.~7m~nle 224 20 Preparation of 2-phenyl-1-methyl-3-[2-(4-dimethyl~minopiperidin-1-yl)-1,2-ethanedionyl]- lH-indole O ~ ,CH~
\C
.
IR, NMR, and W were consistent with the desired title structure.
FDMS 389 (M+).
Analysis for C24H27N3o2:
Theory: C, 74.01; H, 6.99; N, 10.79.
Found: C, 73.82; H, 6.98; N, 10.75.
F.~mple 225 Preparation of 1-methyl-3-[2-[N-benzyl-N-3-(dimethylaminopropyl)amino]-1,2-ethanedionyl]-lH-indole o CH3 ' CH3 IR, NMR, and W were consistent with the desired title structure.
FDMS 377 (M~). FAB 378 (M+1).
Analysis for C23H27N302:
Theory: C, 73.18; H, 7.21; N, 11.13.
Found: C, 70.74; H, 7.14; N, 10.75.
Single compound of high purity as evidenced by chromatographic methods.
m~le 226 Preparation of 1-methyl-3-[2-(4-dimethylaminopiperidin-1-yl)-1,2-ethanedionyl]-lH-indole W O 97/09308 PCT~US96/14163 O /--\ ~CH3 Q~ )-- CH3 IR, NMR, and W were consistent with the desired title structure.
FDMS 313 (M+1).
Analysis for Cl8H23N3o2:
Theory: C, 68.98; H, 7.40; N, 13.41.
Found- C, 68.97; H, 7.59; N, 13.43.
~mrle 227 Preparation of 5-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[(piperidin-1-yl)methyl]-lH-indole hydrochloride HCl CH3 Cl Cl NMR (CDCl3) was consistent with the proposed title structure.
mp 177-179~C.
Analysis for C22H23Cl3N2O ~ HCl:
Theory: C, 55.72; H, 5.10; N, 5.91.
Found: C, 55.70; H, 5.21; N, 6.16.
~mple 228 Preparation of 5-methoxy-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-25 [(piperidin-1-yl)methyl]-lH-indole H3CO~ ~
CH3 Cl Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 432 (M+). mp 119-121~C.
5 Analysis for C23H26cl2N2o2:
Theory: C,63.74; H,6.05; N, 6.46.
Found: C, 63.70; H, 6.12; N, 6.46.
F.x~mrle 229 Preparation of 5-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[(4-dimethylaminopiperidin- 1 -yl )methyl]- lH-indole dihydrochloride Cl ~ (CH3)2 CH3 Cl Cl NMR (CDCl3) was consistent with the proposed title structure.
Analysis for C24H2gCl3N3O ~ 2 HCl:
Theory: C,52.05; H, 5.46; N, 7.59.
Found: C, 52.05; H,5.41; N, 7.56.
F.~mple 230 Preparation of 5-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[[4-(piperidin-1-yl)piperidin-1-yl]methyl]-lH-indole dihydrochloride CA 022039l2 l997-04-28 C~
CH3 Cl Cl NMR (CDCl3) was consistent with the proposed title structure.
Analysis for C27H32Cl3N3O ~ 2 HCl:
Theory: C, 54.61; H, 5.77; N, 7.08.
Found: C, 51.53; H, 6.53; N, 7.57.
~mrle 231 10 Preparation of 5-bromo-2-[(2,4-dichloroph en o~y)methyl] - 1-methyl-3-[2-(piperidin- 1-yl)ethyl]-lH-indole Br ~ N
N ~ ~
CH3 Cl Cl 15 NMR and IR were consistent with the desired title structure.
mp 158-160~C.
Analysis for C23H2sBrcl2N2o:
Theory: C, 55.67; H, 5.08; N, 5.64.
Found: C, 55.96; H, 5.28; N, 5.69.
mnle 232 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl- lH-indole ~,o~
IR, NMR, and W were consistent with the desired title structure.
FDMS 271 (M~).
5 Analysis for Cl6H14ClNO:
Theory: C, 70.72; H, 5.19; N, 5.15.
Found: C, 70.~2; H, 5.26; N, 5.28.
F,~mFle 233 Preparation of 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-1H-indole 15 IR, NMR, and W were consistent with the desired title structure.
FDMS 305.
Analysis for C16Hl3Cl2NO:
Theory: C, 62.76; H, 4.28; N, 4.57.
Found: C, 63.37; H, 4.72; N, 4.37.
~mple 234 Preparation of 2-[(5~6~7~8-tetrahydronaphth-l-yloxy)methyl]-l-methyl-lH
indole W 0 97/09308 PCTrUS96/141~3 Q~"o~
NMR was consistent with the desired title structure.
FDMS 292 (M+1).
Analysis for C2oH21NO:
Theory: C,82.44; H, 7.26; N,4.81.
Found: C, 82.51; H, 7.28; N,4.80.
F.~m~le 235 Preparation of 2-[(5,6,7,8-tetrahydronaphth-2-yloxy)methyl]-1-methyl-lH-indole NMR (CDCl3) was consistent with the proposed title structure.
FDMS 291 (M+).
Analysis for C2oH2lNO:
Theory: C, 82.44; H,7.26; N,4.81.
Found: C,82.25; H,6.98; N, 4.95.
rnnle 236 Preparation of 2-[(4-chlorophenoxy)methyl]-3-formyl-1-methyl-lH-indole CA 022039l2 l997-04-28 o Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 299 (M+).
5 Analysis for C17H14ClNO2:
Theory: C, 68.12; H, 4.71; N, 4.67.
Found: C, 67.90; H, 4.93; N, 4.73.
Fx~mple 237 Preparation of (RS) 1,2-dimethyl-3-[3-(piperidin-3-yl)propyl]-lH-indole ~'~
15 NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass for C18H27N2:
Theory: 271.2174.
Found: 271.2176.
F'.x~mple 238 Preparation of 1-methyl-2-[[2-[(piperidin-1-yl)methyl]phenoxy]methyl]-lH-indole W O 97/09308 PCT~US96/14163 NMR (CDCl3) was consistent with the proposed title structure.
FDMS 335 (M+).
Analysis for C22H26N20:
Theory: C, 7g.01; H, 7.84; N, 8.38.
Found: C, 78.78; H, 7.58; N, 8.56.
F,x~mple 239 Preparation of 1-methyl-3-[2-[(4-chlorophenoxy)methyl]piperidin-1-ylmethyl]-lH-indole Q~
Cl NMR (CDC13) was consistent with the proposed title structure.
FDMS 368 (M+).
Analysis for C22H2sClN20 ~ HCl:
T heory: C, 65.19; HJ 6.46; N, 6.91.
Found: C, 64.93; H, 6.44; N, 6.78.
F,~mple 240 Preparation of l-methyl-3-[3-[(4-chlorophenoxy)methyl]piperidin-1-ylmethyl]- lH-indole ~ N ~
CH3 ~~
Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 368 (M+).
Analysis for C22H2sclN2o:
Theory: C, 71.63; H, 6.83; N, 7.59.
Found: C, 63.74; H, 6.54; N, 6.86.
m~e 241 Preparation of l-methyl-3-[2-[2-(4-chlorophenoxy)ethyl]piperidin-1-15 ylmethyl]-lH-indole ~N~
CH~
O~
~1 NMR (CDCl3) was consistent with the proposed title structure.
2 o FDMS 382 (M+).
Analysis for C23H27ClN2O:
Theory: C, 65.87; H, 6.73; N, 6.68.
Found: C, 62.05; H, 6.36; N, 6.18.
Tnrle 243 Preparation of ethyl 3-[2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl]propanoate ~O CH3 CH3 Cl NMR (CDCl3) was consistent with the proposed title structure.
FDMS 371 (M+) Single compound of high purity as evidenced by chromatographic methods.
~rnrle 244 Preparation of (RS) ethyl 2-amino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl]propanoate o r CH3 ~0 /~NH2 ~, ~~
CH3 ~ C l NMR was consistent with the desired title structure.
FDMS 386.
25 Analysis for C2lH23ClN2O3:
Theory: C, 65.20; H, 5.99; N, 7.24.
Found: C, 64.95; H, 5.95; N, 7.27.
F.~qmrle 245 5 Preparation of ethyl 2-hydroxyimino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl]propanoate O r CH3 ~0 /~ NOH
,0~
CH3 Cl Ø2 H20 10 IR, NMR, and W were consistent with the desired title structure.
FDMS 400 (M+). mp 165-166~C.
Analysis for C2lH2lClN2O4 ~ 0 2 H2O:
Theory: C, 62.36; H, 5.33; N, 6.93.
Found: C, 62.38; H, 5.38; N, 6.87.
F,~mrle 246 Preparation of (RS) methyl 2-methoxyimino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl]propanoate O~ r 3 /~NOCH3 ~~'13~
IR, NMR, and W were consistent with the desired title structure.
FDMS 414 (M+).
mp 106-107~C.
Analysis for C22H23clN2o4:
Theory: C, 63.69; H, 5.59; N, 6.75.
- Found: C, 63.95; H, 5.57; N, 7.01.
F~mrle 247 Preparation of ethyl 2-benzoxyimino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl- lH-indol-3-yl]propanoate o r CH~
CH3 Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 490 (M~). mp 96~C.
Analysis for C28H27clN2o4:
Theory: C, 68.50; H, 6.54; N, 5.71.
Found: C, 68.78; H, 5.67; N, 5.64.
F.~r~qmrle 248 20 Preparation of ethyl 2-ethanoyloxyimino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl-lH-indol-3-yl]propanoate O ~ r 3 NO r CH3 ~Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 442 (M+).
mp 128-129~C.
Analysis for C23H23clN2os:
Theory: C, 62.37; H, 5.23; N, 6.32.
Found: C, 62.44; H,5.40; N, 6.33.
F.~qmrle 249 Preparation of ethyl 2-benzoyloxyimino-3-[2-[(4-chlorophenoxy)methyl]-1-methyl- lH-indol-3-yl]propanoate Q~
Cl IR, NMR, and W were consistent with the desired title structure.
FDMS 504 (M+).
mp 146-147~C
Analysis for C2gH2sClN2Os:
Theory: C, 66.60; H, 4.99; N, 5.55.
Found: C, 66.88; H,5.22; N, 5.80.
F.~m,nle 250 Preparation of 2-r(4-chlorophenoxy)methyl]-3-(4-hydroxy-1-25 methylpiperidin-4-yl)-1-methyl-lH-indole CH~
HO
~;~~
Cl NMR, IR and W were consistent with the desired title structure.
FDMS 384 (M+).
5 Analysis for C22H2sclN2o2:
Theory: C, 68.65; H, 6.55; N, 7.28.
Found: C, 69.46; H, 6.44; N, 7.28.
Single compound of high purity as evidenced by chromatographic methods.
F,x~ ?le 251 Preparation of ethyl 2-hy~l~ o~yi~ o-3-[1-methyl-2-phenyl-1H-indol-3-yl]propanoate o r CH3 ~0 ~ ~ NOH
~, CH3 ~
NMR (CDCl3) was consistent with the proposed title structure.
W and IR were consistent with the proposed title structure.
2 o FDMS 322 (M+) - mp 141-142~C.
Analysis for C19H18N203:
Theory: C, 70.79; H, 5.62; N, 8.69.
Found: C, 70.64; H, 5.89; N, 8.58.
W O 97/09308 PCTrUS96/14163 F,~m~le 252 Preparation of ethyl 2-hydro~yilllino-3-[1H-indol-3-yl]propanoate O~ r CH3 ~0 NOH
HN
IR, NMR, and W were consistent with the desired title structure.
FDMS 246 (M+).
10 mp 156~C.
Analysis for C13H14N2O3 ~ 0.3 H2O:
Theory: C, 62.04; H,5.85; N, 11.13.
Found: C, 61.77; H,5.55; N, 11.07.
~mrle 253 Preparation of 6-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-(piperidin-1-yl)ethyl]-lH-indole ~ N ~
Cl~ ~o~3~
CH3 Cl Cl IR and NMR were consistent with the desired title structure. FDMS 450 (M+). mp 116.5-118.5~C.
Analysis for C23H2sCl3N2O:
Theory: C, 61.14; H,-5.58; N, 6.20.
Found: C, 61.43; H,5.67; N, 6.26.
W O 97/09308 PCT~US96/14163 F~rle 255 Preparation of 7-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-5 (piperidin- 1-yl)ethyl]- lH-indole ~ ~ ~ Cl IR and NMR were consistent with the desired title structure. mp 134-0 136~C.
Analysis for C23H2scl3N2o:
Theory: C,61.14; H,5.58; N, 6.20.
Found: C, 61.39; H, 5.71; N,6.47.
F.~qmrle 256 Preparation of 4-methyl-2-[(2,4-dichlorophenoxy)methyl]-1-[3-(piperidin-3-yl)propyl]- lH-indole ~ H3 ~3 0~3~
~ Cl Cl - ~ NH
~
NMR (CDCl3) was consistent with the proposed title structure.
Exact Mass FAB (M+l) for C24H30clN2o:
Theory: 397.2047.
Found: 397.2041.
mrle 257 Preparation of 5-chloro-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[(4-dimethylaminopiperidin- l-yl)methyl]- lH-indole dihydrochloride Cl /--\
(cC ) Cl Analysis for C24H2gCl3N3O:
Theory: C, 52.05; H, 5.46; N, 7.59.
Found: C, 52.05; H, 5.41; N, 7.56.
F.~mrle 258 Preparation of 7-methyl-2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[3-(piperidin-l-yl)propyl]-lH-indole dihydrochloride H3 ~ ~
NMR (CDC13) was consistent with the proposed title structure.
mp 129-131~C.
25 Analysis for C2sH3ocl2N2o:
Theory: C, 67.41; H, 6.79; N, 6.29.
Found: C, 67.34; H, 6.80; N, 6.05.
W 0 97/09308 PCTrUS96/14163 F.~mple 259 Preparation of 1,2-dimethyl-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-lH-indole ~N3N~
NMR, IR and W were consistent with the desired title structure.
FDMS 353 (M+) 10 Analysis for C22H31N3~:
Theory: C, 74.75; H, 8.84; N, 11.89.
Found: C, 74.76; H, 8.96; N, 11.76.
F~mnle 260 Preparation of 1,2-dimethyl-3-[[4-(N,N-dimethy~mino)piperidin-1-yl]acetyl]-lH-indole O /~ CH3 ~N~ N
NMR was consistent with the desired title structure.
C1gH27N3O: FDMS 313 (M+).
F,~mrle 261 Preparation of 2-[(4-chlorophenoxy)methyl]-3-[[(4-cyclohexyl)piperazin-1-yl] acetyl]- 1 -methyl- lH-indole W O 97/09308 PCT~US96/14163 - 270 - ~
N N{~
Cl NMR was consistent with the desired title structure.
C2gH34ClN3O2: FDMS 480 (M+) F,~r~rn,nle 262 Preparation of 2-[(4-chlorophenoxy)methyl]-3-[[(4-phenyl)piperazin-1-yl]acetyl]-1-methyl-lH-indole ~,N N{~
Cl NMR was consistent for the desiredtitle structure.
C2gH2gClN3O2: FDMS 474 (M+) ~ qm,nl e 263 Preparation of 2-[(4-chlorophenoxy)methyl]-3-[[4-(N,N-dimethylamino)piperidin-1-yl]acetyl]-1-methyl-lH-indole W O 97/09308 PCT~US96/14163 O /~ ,CH3 ~'~ \~ CH3 Cl NMR, IR and W were consistent with the desired title structure.
5 MSFD 439 (M+) Analysis for C2sH3oclN3o2:
Theory: C, 68.25; H, 6.87; N, 9.55.
Found: C, 67.98; H, 6.81; N, 9.40.
~ mI)le 264 Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[N-methyl-N-(3-N', N'-dimethylaminopropyl)amino]acetyl]-lH-indole O C, H3 CH3 ~,N N~CH
H3C ~
Cl NMR and IR were consistent with the desired title structure.
FDMS 428 (M+1) FAB exact mass CalculatedforC24H3lClN302: 428.2105 2 o Found: 428.2113 ~.x~mrle 26~ -Preparation of 2[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[(4-piperidin- 1-5 yl)piperidin-1-yl]acetyl]-lH-indole Cl NMR, IR and UV were consistent with the desired title structure.
MSFD 479 (M+1) FAB exact mass CalculatedforC28H3sClN302: 480.2418 Found 480.2411 ~ x&~mrlle 266 Preparation of 2-[(4-chlorophenoxy)methyl]-3-[2-[(4-piperidin-1-yl)piperidin-1-yl]acetyl]-1-[2-(N,N-dimethylpiperidin-4-ylium)ethyl]-lH-indole iodide WO 97t09308 PCTtUS96/14163 N
N+ I-NMR was consistent with the desired title structure.
Analysis for C36HsoclIN4o2 ~ H2O:
Theory: C, 57.56; H, 6.90; N, 7.46.
Found: C, 57.85; H, 6.86; N, 7.04 mple 267 2-[(4-chlorophenoxy)methyl]-1-[(2-piperidin-4-yl)ethyl]-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]acet-1-yl]-lH-indole CI
N
NMR was consistent with the desired title structure.
FABMS 577 (M+1) 5 Analysis for C34H4sClN402:
Theory: C, 70.75; H, 7.86; N, 9.71 Found: C, 70.55; H, 7.87; N, 9.52 F.~mn1e 268 2-~(4-chlorophenoxy)methyl]-3-[2-(methylaminoy~ oyyldimethylamine)acet-l-yl]-1-[(2-piperidin-3-yl)ethyl]-indole H3C~
C
O~N
Cl ~~~Cl ~NH
NMR was consistent with the desired title structure.
FABMS 525(M+l) Exact Mass for C30H42N4~2Cl:
Theory: 525.2996 Found: 525.3003 m~le 269 2-[(4-chlorophenoxy)methyl]-1-[(2-piperidin-3-yl)ethyl]-3-[2-(4-(piperidin-l-yl)piperidin-l-yl)acet-l-yl]-lH-indole N
~O~Cl \~NH
NMR was consistent with the desired title structure.
FDMS (M+l) Analysis for: C34H4sN4O2Cl:
Theory: C, 70.75; H, 7.86; N, 9.71 Found: C, 70.72; H, 7.83; N, 9.63 F.~m~le 270 2-[(4-chlorophenoxy)methyl] -3-[2-10 (methylaminop~ yldimethylamine)acet-1-yl]-1-[(2-piperidin-4-yl)ethyl]-lH-indole H3C~
CH3 ,_~N-CH3 O~N~
~ 0~ Cl 15 NMR was consistent with the desired title structure.
Exact Mass for C30H42N4O4Cl (M+1):
Theory: 525.2996 Found: 525.3013 ~mrle 271 S-2-[(4-chlorophenoxy)methyl]-3-[2-(4-(piperidin-1-yl)piperidin-1-yl)acet-1-yl]-1-[(3-piperidin-3-yl)propyl]-lH-indole W O 97/09308 PCTrUS96/14163 ' ~
O ~ N
~O~Cl ~ NH
NMR was consistent with the desired title structure.
FABMS (M+l) Analysisfor: C35H47clN4O2 Theory: C, 71.10; H, 8.01; N, 9.48 Found: C, 70.82; H, 8.14; N, 9.23 F,x~mple 272 R-2-[(4-chlorophenoxy)methyl]-3-[2-(4-(piperidin- 1-yl)piperidin- 1-yl)acet-1-yl] -1-[(3-piperidin-3-yl)propyl]-lH-indole O~N
~,0~ Cl GNH
NMR was consistent with the desired title structure.
Exact Mass for C3sH48ClN402:
Theory: 591.3466 Found: 591.3458 mple 273 cis/trans-2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(4-(piperidin- 1-yl)cyclohex-l-yl)acet-l-yl]-lH-indole N
0~
~~Cl Mixture of cis/trans isomers I & 2 NMR was consistent with the desired title structure.
- FDMS 478 (M+) - Analysisfor: C2sH3sclN2o2 Theory: C, 72.71; H, 7.36; N, 5.85 Found: C, 72.65;H, 7.61;N,5.95 ml)le 274 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-(piperidin-1-yl)cyclohex-1-yl)acet-1-yl]-lH-indole o\~
~<~Cl CH3 Isomer I
NMR was consistent with the desired title structure.
FDMS 478 (M+) Analysis for: C2gH3sclN2o2 Theory: C, 72.71; H, 7.36; N, 5.85 Found: C, 72.55; H, 7.52; N, 5.67 ~ mple 275 2-[(4-chlorophenoxy)methyl] -3-[2-(4-(piperidin- 1-yl)cyclohex-1-yl)acet-1-yl ]-1-[(2-piperidin-4-yl)ethyl]-lH-indole WO 97/09308 PCT~US96/14163 0~
~O~Cl lsomer 1 NMR was consistent with the desired title structure.
FDMS 575 (M+) 5 Analysisfor: C3sH46clN3o2 Theory: C, 72.95; H, 8.06; N, 7.29 Found: C, 72.88; H, 8.23; N, 7.53 e 276 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[2-(4-(piperidin-1-yl)cyclohex-1-yl?acet-1-yl]-indole CA 022039l2 l997-04-28 ' ~
O~p ~~Cl Isomer 2 NMR was consistent with the desired title structure.
FDMS 478 (M+) 5 Analysisfor: C2sH3sclN2o2 Theory: C, 72.71; H, 7.36; N, 5.85 Found: C, 72.43; H, 7.42; N, 5.86 F~m~le 277 2-[(4-chlorophenoxy)methyl]-5-fluoro-1-methyl-3-[2-(4-(piperidin-1-yl)piperidin- lyl)acet- 1-yl]-lH-indole O~N
F~ O~Cl NMR was consistent with the desired title structure.
FABMS 498 (M+1) WO 97/09308 PCT~US96/14163 Analysis for: C28H33clFN3o2 Theory: C, 67.53; H, 6.68; N, 8.44 Found: C, 67.34; H, 6.59; N, 8.68 By substantially following the procedures described above one skilled in the art can prepare the other compounds of Formula I.
The compounds of the present invention bind to receptors specific for neuropeptide Y as well as the closely related neuropeptides.
10 [For a review of neuropeptide Y receptors, see, D. Gehlert, Life Sciences, 55:~51-562 (1994); P.A. Hipskind and D.R. Gehlert, Annual Reports in Medicinal Ch~mi.~try. 31:1 (1996)]. Receptors for neuropeptide Y and peptide YY have considerable overlap while pancreatic polypeptide appears to have its own distinct set of receptors. Many, but not all, of the 15 effects of neuropeptide Y can be replicated using peptide YY.
Two subtypes of receptors for neuropeptide Y were initially proposed on the basis of the afflnity of the 13-36 fragment of neuropeptide Y using a preparation of the sympathetic nervous system. While these are the best estqhli~hed receptors for neuropeptide Y, a substantial body 20 of evidence exists that there are additional receptor subtypes. The best estqhli~hed is a Y-3 receptor that is responsive to neuropeptide Y, but not to peptide YY. Another recently ~lçlinçqted receptor has been described that binds peptide YY with high affinity and neuropeptide Y with lower affinity. While the pharmacology of the feeding response to 25 neuropeptide Y appears to be Y-1 in nature, a separate "feeding receptor" has been proposed. Several of the receptors have been successfully cloned to date. The following paragraphs sl~mmqrize the available information on the known neuropeptide Y receptor subtypes and their potential role in physiological function.
Y-1 Receptor The Y-1 receptor is the best characterized receptor for neuropeptide Y. This receptor is generally considered to be postsynaptic and mediates many of the known actions of neuropeptide Y in the 35 periphery. Originally, this receptor was described as having poor CA 022039l2 l997-04-28 - affinity for C-terminal fr~grnents of neuropeptide Y, such as the 13-36 fr~ment, but interacts with the full length neuropeptide Y and peptide YY with equal affinity. C. Wahlestedt, et al., ReFulatory PeI?tides~
13:307-318(1986); C. Wahlestedt, et al., NEURONAL MESSENGERS IN
VASCUnl~R FUnNCTION, 231-241 (Nobin, et al., eds. 1987). Substitution of the amino acid at position 34 with a proline (Pro34) results in a protein which is specific for the Y-1 receptor. E.K. Potter, et al., European Journal of Phar-n~- lo~v~ 193:15-19(1991). This tool has been used to establish a role for the Y-1 receptor in a variety of functions. The receptor is thought to be coupled to adenylate cyclase in an inhibitory manner in cerebral cortex, vascular smooth muscle cells, and SK-N-MC
cells. [For a review, see, B.J. McDermott, et al., Cardiovascular Research. 27:893-905(1993)]. This action is prevented by application of pertussis toxin confirming the role of a G-protein coupled receptor. The Y-1 receptor mediates the mobilization of intracellular calcium in a porcine vascular smooth muscle cells and human erythroleukemia cells.
The cloned human Y-1 receptor can couple to either phosphotidylinositol hydrolysis or the inhibition of adenylate cyclase, depen~1ing on the type of cell in which the receptor is expressed. H.
Herzog, et al., Proceellin~s of the National Academy of Sciences (USA), 89:5794-5798(1992). The Y-1 receptor has been reported to couple to either second messenger system when studied using tissue preparations or cell lines naturally expressing the receptor. D. Gehlert, supra, at 553. The Y-1 receptor cannot, therefore, be distinguished solely on the basis of coupling to a single second messenger.
Modulation of a Y-1 receptor (either a typical or an atypical Y-1 receptor) is believed to influence multiple physiological conditions, including, but not limited to, obesity or appetite disorder, adult onset diabetes, bulimia nervosa, pheochromocytoma-induced hypertension, subarachnoid hemorrhage, neurogenic vascular hypertrophy, hypertension, anxiety, and anorexia nervosa. PCT Patent Publication W O 96/16542, published June 6,1996, at page 135, and the references cited therein.
Y-2 Receptor W097/09308 PCT~S96/14163 As with the Y-1 receptor, this receptor subtype was first delineated using vascular preparations. Pharmacologically, the Y-2 receptor is distinguished from Y-1 by exhibiting affinity for C-terminal fr~gments of neuropeptide Y. The receptor is most often differentiated 5 by the use of neuropeptide Y(13-36), though the 3-36 fra~ment of neuropeptide Y and peptide YY provides improved affinity and selectivity. Y. Dumont, et al., Society for Neuroscience Abstracts. 19:726 (1993). Like Y-1 rece~to,-, this receptor is coupled to the inhibition of adenylate cyclase, though in some preparations it may not be sensitive to 10 pertussis toxin. The Y-2 receptor was found to reduce the intracellular levels of calcium in the synapse by selective inhibition of N-type calcium h~nnel~. Like the Y-1 receptor, the Y-2 receptor may exhibit differential coupling to second messengers. The Y2 receptor is believed to be involved in mod~ tin~ hypertension, epileptic seizure, and 5 neurogenic vascular hypertrophy. PCT Patent Publication WO 96/16542, published June 6,1996, at page 135, and the references cited therein.
The Y-2 receptors are found in a variety of brain regions, including the hippocampus, substantia nigra-lateralis, t~ rnus, hypot~ mus, and brainstem. In the periphery, Y-2 iS found in the 20 peripheral nervous system, such as symp~t~letic, parasympathetic, and sensory neurons. In all these tissues, Y-2 receptors mediate a decrease in the release of neurotransmitters. The Y-2 receptor has been cloned using expression cloning techniques. P.M. Rose, et al., Journal of Biolo~ical Chemistry. 270:22661 (1995); C. Gerald, et al., Journal of 25 Biolo~ical Chemistry. 270:26758 (1995); D.R. Gehlert, et al., Molecular PharmacoloFy. 49:224 (1996).
Y-3 Rece~?tor This receptor has high affinity for neuropeptide Y while 3 o having lower affinity for peptide YY. While neuropeptide Y is a fully efficacious agonist at this receptor population, peptide YY is weakly efficacious. This pharmacological property is used to define this receptor. A receptor that has ~imil~r pharmacology to the Y-3 receptor has been identified in the CA3 region of the hippocampus using 3 5 electrophysiological techniques. This receptor may potentiate the excitatory response of these neurons to N-methyl-D-aspartate (NMDA).
W097/09308 PCT~S96/141 F.P. Monnet, et al., European Journal of PharmacoloFy, 182:207-208 - (1990). This receptor is believed to modulate hypertension. PCT Patent pllhli~on WO 96/16542, pllhli~hed June 6,1996, at page 135, and the references cited therein.
The presence of this receptor is best established in the rat brainstem, specifically in the nucleus tractus solitarius. Application of neuropeptide Y to this region produces a dose-dependent reduction in blood pressure and heart rate. This area of the brain also may have significant contributions from the Y-1 and Y-2 receptor. Neuropeptide Y
also inhibits the acetylcholine-induced release of catecholamines from the adrenal medulla, presumably through a Y-3 receptor. C.
Wahlestedt, ~, Life Sciences. 50:PL7-PL14 (1992).
Peptide YY Preferrin~ Rece~tor A fourth receptor has been described that exhibits a modest preference for peptide YY over neuropeptide Y. This receptor was first described in the rat small intestine as having a 5-10 fold higher affinity for peptide YY over neuropeptide Y. M. Laburthe, et al., Endocrinolo~y.
118:1910-1917 (1986). Subsequently, this receptor was found in the adipocyte and a kidney proximal tubule cell line. This receptor is coupled in an inhibitory m~nner to adenylate cyclase and is sensitive to pertussis toxin.
In the intestine, this receptor produces a potent inhibition of fluid and electrolyte secretion. The receptor is loc~li7.e~1 to the crypt cells 2 5 where intestinal chloride secretion is believed to take place. The peptideYY l,~efe~l;ng receptor in adipocytes mediates a reduction in lipolysis by way of a cyclic adenosine monophosphate (cAMP)-dependent mechanism.
"Feellin~ Receptor"
One of the earliest discovered central effects of neuropeptide Y was a profound increase in food intake that was observed following the hypothalmic ~(lmini~tration of the peptide to rats. The response was greatest when the peptide was infused into the perifornical region of the 3 5 hypothAl~mus. B.G. Stanley, et al., Brain Research. 604:304-317 (1993).
While the pharmacology of this response resembled the Y-1 receptor, the W O 97/09308 PCT~US96/14163 2-36 fr2~Frnent of neuropeptide Y was significantly more potent than neuropeptide Y. In addition, intracerebroventricular neuropeptide Y(2-36) fully stimulates feeding, but does not reduce body temperature as does full length neuropeptide Y. F.B. Jolicoeur, et al., Brain Research Bulletin. 26:309-311 (1991). Two recent patent publications describe the cloning and expression of the Y5 receptor, believed to be the "feeding receptor". Patent Cooperation Treaty Publication WO 96/16542, published June 6, 1996; and Australian Patent Publication AU 956467 A0, published November 30, 1995.
The biological activity of the compounds of the present invention was evaluated employing an initial screening assay which rapidly and accurately measured the binrling of the tested compound to known neuropeptide Y receptor sites. Assays useful for evaluating neuropeptide Y receptor antagonists are well known in the art. See. e.~
United States Patents 5,284,839, issued February 8, 1994, which is herein incorporated by reference. See P~l~o, M.W. Walker, et al., Journal of Neurosciences,8:2438-2446 (1988).
Neuropeptide Y B;ndin~ Assay The ability of the compounds of the instant invention were assessed as to their ability to bind to neuropeptide Y using a protocol essentially as described in M.W. Walker, et al., supra. In this assay the cell line SK-N-MC was employed. This cell line was received from Sloane-Kettering Memorial Hospital, New York. These cells were cultured in T-150 flasks using Dulbecco's Minim~l Essential Media (DMEM) supplemented with 5% fetal calf serum. The cells were manually removed from the flasks by scraping, pelleted, and stored at -70~C.
The pellets were resuspended using a glass homogenizer in 25 mM HEPES (pH 7.4) buffer cont~ining 2.5 mM calcium chloride, 1 mM magnesium chloride, and 2 g/L bacitracin. Incubations were performed in a final volume of 200 ~ll cont~ining 0.1 nM l25I-peptide YY
(2200 Ci/mmol) and 0.2-0.4 mg protein for about two hours at room temperature.
Nonspecific binrling was defined as the amount of - radioactivity rem~ining bound to the tissue after incubating in the presence of 1 IlM neuropeptide Y. In some experiments various concentrations of compounds were included in the incubation mixture.
Incubations were terminated by rapid filtration through glass fiber filters which had been presoaked in 0.3~o polyethylen~imine using a 96-well harvester. The filters were washed with 5 ml of 50 mM
Tris (pH 7.4) at 4~C and rapidly dried at 60~C. The filters were then treated with melt-on scint~ tion sheets and the radioactivity retained on the filters were counted. The results were analyzed using various software packages. Protein concentrations were measured using standard collm~sie protein assay reagents using bovine serum albumin as standards.
Many of the compounds prepared _upra showed significant activity as neuropeptide Y receptor antagonists (Kj = 10 ~M to 0.1 nM).
As the compounds of Formula I are effective neuropeptide Y receptor antagonists, these compounds are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of 2 0 an excess of neuropeptide Y. Thus, the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises ~iministering to a m~mm~l in need of said tre~trnent an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. The term ~physiological disorder associated with an excess of neuropeptide Y" encompasses those disorders associated with an ina~ opliate stimulation of neuropeptide Y receptors, regardless of the actual amount of neuropeptide Y present in the locale.
These physiological disorders include:
3 o disorders or diseases pert~ining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, ~ngin~, myocardial infarction, sudden cardiac death, congestive heart failure, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow 3 5 of fluid, abnormal mass transport, or renal failure;
conditions related to increased sympathetic nerve activity for e~mple, during or after coronary artery s~ely~ and operations and surgery in the gastrointestinal tract;
cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, dementia, seizure, and epilepsy;
conditions related to pain or nociception;
diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease;
abnormal drink and food intake disorders, such as obesity, anorexia, blllimi~, and metabolic disorders;
diseases related to sexual dysfunction and reproductive disorders;
conditions or disorders associated with infl~mm~tion;
respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leut.ini~ing hormone, growth hormone, insulin, and prolactin.
The compounds of Formula I are usually ~-lmini~tered in the form of pharmaceutical compositions. These compounds can be 2 5 A-1mini.~tered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intr~n~l. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a m~nner well known in the pharmaceutical art and comprise at least one active compound.
3 0 The present invention also includes methods employing pharmaceutical compositions which contain, as the active ingredient, a compound of Formula I associated with pharmaceutically acceptable carriers. In m~kin~ the compositions of the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or 3 5 enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a CA 022039l2 l997-04-28 W O 97/09308 PCT~US96/14163 - diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, 5 aerosols (as a solid or in a liquid medium), ointments cont~ininF for mple up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the 10 active compound to provide the a~l ~ol~l;ate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a S subst~nt~ ly uniform distribution in the formulation, e.g. about 40 mesh.
Some e~mples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum ~c~ , calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, 20 microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include:
lubricating agents such as talc, m~gnesium stearate, and mineral oil;
wetting agents; emulsifying and suspen-ling agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and 2 5 flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after ~tlmini~tration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit 3 o dosage form, each dosage cont~ining from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term aunit dosage form" refers to physically discrete units suitable as unitary dosages dosages for human subjects and other m~mm~l~, each unit cont~qining a predetermined quantity of active material calculated to 3 5 produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound is effective over a wide dosage range.
For e~mples, dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult hllm~n~, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is 5 especially preferred. However, it will be understood that the amount of the compound ~ctll~lly ~-lmini~tered will be determined by a physician, in the light of the relevant cil cumstances, including the condition to be treated, the chosen route of ~mini~tration, the actual compound Arlmini~tered, the age, weight, and response of the individual patient, 10 and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, 15 provided that such larger doses are first divided into several smaller doses for ~rlmini~tration throughout the day.
For preparing solid compositions such as tablets the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition cont~ininE a homogeneous 20 mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dipsersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid 25 ~lefo,.llulation is then subdivided into unit dosage forms of the type described above cont~ining from 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage 3 o of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the 3 5 duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for ~tlmini~tration orally or by 5 injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and simil~r pharmaceutical vehicles.
Compositions for inh~l~tion or insufflation include 0 solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or ll~i~lu~es thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are zltlmini~tered by the oral or nasal respiratory route for local or systemic 15 effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebl1li7.ing device or the nebllli7.ing device may be attached to a face mask, tent, or intermittent positive pressure breathing m~hine. Solution, suspension, or powder compsoitions may 20 be ~tlmini~tered, preferably orally or nasally, from devices which deliver the formulation in an aplJlop~iate manner.
The following examples illustrate the pharmaceutical compositions of the present invention.
Formulation Preparation 1 Hard gelatin capsules cont~ining the following ingredients are prepared:
Quantity Tnpredient (m~/capsule) Active Ingredient 30.0 Starch 3050 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin 15 capsules in 340 mg quantities.
Formulation Preparation 2 A tablet formula is prepared using the ingredients below:
Quantity Tn~redient (m~/tablet) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg.
Formulation Preparation 3 A dry powder inhaler formulation is prepared cont~ining the following components:
Tn~redient W~i~ht ~o Active Ingredient 5 Lactose 96 The active mixture is mixed with the lactose and the mixture is added to a dry powder inh~ling appliance.
Formulation Preparation 4 Tablets, each cont~ining 30 mg of active ingredient, are prepared as follows:
Quantity Tn~redient (m~/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinyll~yl 1 olidone (as 10% solution in water) 4.0 mg Sodium carboxy-methyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 m~
Total 120 mg W O 97/09308 PCT~US96/14163 The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are 5 then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60~C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine 10 to yield tablets each weighin~ 120 mg.
Formulation Preparation 5 Capsules, each cont~qining 40 mg of medicament are made 15 as follows:
Quantity InFre-lient (mF/capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 m~
Total 150.0 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 160 mg quantities.
W O 97/09308 PCT~US96/14163 Formulation Preparation 6 Suppositories, each cont~inin~ 25 mg of active ingredient are made as follows:
Tn~redient Amount Active Ingredient 26 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nomin~l 2.0 g capacity and allowed to cool.
Formulation Preparation 7 Suspensions, each cont~inin~ 50 mg of medicament per 5.0 ml dose are made as follows:
Tn~redient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v.
.
3 5 Purified water to 5.0 ml W O 97/09308 PCT~US96/14163 The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium bçn7.0~te, flavor, and 5 color are diluted with some of the water and added with stirring.
Sufficient water is then added to produce the required volume.
Formulation Preparation 8 Capsules, each conhining 15 mg of medicament, are made as follows:
Quantity Tn~redient (m~/capsule) Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 rn~
Total 425.0 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled 2 5 into hard gelatin capsules in 425 mg quantities.
Formulation Preparation 9 An intravenous formulation may be prepared as follows:
Tn~redient Quantity Act*e Ingredient 260.0 mg Isotonic saline 1000 ml Formulation Preparation 10 A topical formulation may be prepared as follows:
Tn~redient Quantitv Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20g White Soft Paraffin to 100 g The white soft paraffin is heated until molten. The liquid praffin and 25 emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
- - -W O 97/09308 PCT~US96/14163 Formulation Preparation 11 Sublingual or buccal tablets, each cont~ining 10 mg of active ingredient, may be prepared as follows:
Quantity Tn~redient Per Tablet Active Ingredient(s) 10.0 mg Glycerol 210.5 mg Water 143.0 mg Sodium Citrate 4.5 mg Polyvinyl Alcohol 26.5 mg Polyvinyl~yll olidone 15.5 rn~
Total 410.0 mg The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and m~int~inin~ the temperature at about 90~C. When the polymers have gone into solution, the solution is cooled to about 50-55~C and the 25 medicament is slowly admixed. The homogenous ~ e is poured into forms made of an inert material to produce a drug-co~t~inin~
diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
3 o Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches 3 5 for the delivery of pharmaceutical agents is well known in the art. See.
e.~., U.S. Patent ~,023,2~2, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, - or on d~m~n(l delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly.
5 Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such impl~ntable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S.
Patent 5,011,472, issued April 30, 1991, which is herein incorporated by 10 refernce.
Indirect techniques, which are generally preferred, usually involve form~ ting the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
Latentiation is generally achieved through blocking of the hydroxy, 15 carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and ~men~ble to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enh~nced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
Claims (15)
1. A compound of the formula wherein:
Rb is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoyl, trifluoromethyl, hydroxy, or halo;
R1 is hydrogen, C1-C6 alkyl, or -(CH2)v-R1a;
where v is 1 to 12, and R1a is phenyl, naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the groups consisting of C1-C6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C1-C6 alkyl)amino, C1-C6 alkylamino, C2-C6 alkanoyl, C2-C6 alkanoyloxy, and C3-C8 cycloalkyl, said said phenyl, benzyl, or C3-C8 cycloalkyl, being optionally substituted with one, two, or three moieties independently selected from the group consisting of C1-C6 alkyl, halo, or C1-C6 alkoxy, or R1a may be substituted with -(CH2)W-R1b, where w is 1 to 12 and R1b is piperidinyl, pyrimidyl, pyrrolidinyl, C1-C6 alkoxy, C1-C6 alkylthio, di[di(C1-C6 alkyl)amino(C1-C6 alkylenyl)]amino, di(C1-C6 alkyl)amino(C1-C6 alkylenyl)amino, phenyl, C3-C8 cycloalkyl, pyrrolidinyl, and acetamido, said phenyl, or C3-C8 cycloalkyl, being optionally substituted with one, two, or three moieties independently selected from the group consisting of C1-C6 alkyl, halo, or C1-C6 alkoxy;
A is a bond, -(CH2)m or -C(O)-;
A1 is a bond, NRa, -O-, -(CH2)m-, or -S(O)n-;
q is 0 to 6;
p is 0 to 6;
n is 0, 1, or 2;
m is 0 to 6;
s is 0 to 6;
Ra is hydrogen, C1-C6 alkyl, or C2-C6 alkanoyl;
D is a bond, C2-C4 alkenylenyl, or -C(X)(Y)-, where one of X and Y is hydroxy and the other is hydrogen, or both X and Y are hydrogen, or X and Y
combine to form =O, or =NORc;
Rc is hydrogen, benzyl, acetyl, benzoyl, or C1-C6 alkyl;
one of X1 and Y1 is hydroxy and the other is hydrogen, or both X1 and Y1 are hydrogen, or X1 and Y1 combine to form =O, or =NORd;
Rd is hydrogen or C1-C6 alkyl;
R2 is hydroxy, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, or a group of the formula wherein R4 and R5 are independently hydrogen, C1-C6 alkyl, phenyl, or phenyl(C1-C6 alkylenyl)-, or R2 is a heterocyclic ring selected from the group consisting of hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl;
any one of which hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of C1-C6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino(C1-C6 alkylenyl)-, C1-C6 alkylamino(C1-C6 alkylenyl)-, C2-C6 alkanoyl, carboxamido, 2-aminoacetyl, C2-C6 alkanoyloxy, C1-C6 alkoxycarbonyl-, C1-C6 alkylamino, C3-C8 cycloalkyl, piperidinyl, pyrrolidinyl, pyrimidyl, phenyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, piperidinyl(C1-C6 alkylenyl)-, pyrrolidinyl(C1-C6 alkylenyl)-, pyrimidyl(C1-C6 alkylenyl)-, C1-C6 alkoxy, C1-C6 alkylthio, di[di(C1-C6 alkyl)amino(C1-C6 alkylenyl)]amino, di(C1-C6 alkyl)amino(C1-C6 alkylenyl)amino, and acetamido, any one of which benzyl, phenyl, piperidinyl, C3-C6 cycloalkyl, phenyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, pyrrolidinyl, piperidinyl(C1-C6 alkylenyl)-, pyrrolidinyl(C1-C6 alkylenyl)-, pyrimidyl(C1-C6 alkylenyl)-, or pyrimidyl group may be substituted with one or more moieties selected from the group consisting of C1-C6 alkyl, halo, trifluoromethyl, acetamido, C2-C6 alkanoyl, C2-C7 alkanoyloxy, and C1-C6 alkoxy, or the nitrogen on said piperidinyl, pyrrolidinyl, piperidinyl(C1-C6 alkylenyl)-, pyrrolidinyl(C1-C6 alkylenyl)-, pyrimidyl(C1-C6 alkylenyl)-, or pyrimidyl may be substituted with an amino-protecting group, or R~ is a group of the formula where R4a, R5a, and R6a are independently hydrogen, C1-C6 alkyl, trifluoromethyl, or C1-C6 alkoxy, or R4a is hydrogen, C1-C6 alkyl, trifluoromethyl, or C1-C6 alkoxy and R5a and R6a combine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or heptamethyleneiminyl, or R4a is oxygen, and R5a and R6a combine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or heptamethyleneiminyl;
R is phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C3-C8 cycloalkyl, pyrazinyl, allyl, thiazolyl, furyl, pyrimidyl, pyridinyl, quinolinyl, isoquinolinyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethyleneiminyl, heptamethyleneiminyl, piperidinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C3-C8 cycloalkyl, pyrazinyl, thiazolyl, furyl, pyrimidyl, pyridinyl, quinolinyl, isoquinolinyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethyleneiminyl, heptamethyleneiminyl, piperidinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of C1-C12 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, trifluoromethyl, carboxamido, cyano, benzyl, phenyl, di(C1-C6 alkyl)amino, C2-C6 alkanoyl, C2-C6 alkanoyloxy, C1-C6 alkylamino, oxazolyl, dihydrooxazolyl, piperidinyl(C1-C12 alkoxy)-, piperidinyl(C1-C12 alkoxy)(C1-C6 alkylenyl)-, piperidinyl(C1-C12 alkylenyl)-,phenyl(C1-C12 alkoxy)-, phenyl(C2-C12 alkylenyl)-, C3-Cg cycloalkyl, piperidinyl, pyrimidyl, C1-C6 alkoxy, C1-C6 alkylthio, a group of the formula RxRyN-G-L-(C0-C6 alkylenyl)-, and acetamido, where Rx and Ry are independently hydrogen, C1-C6 alkyl, phenyl, benzyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, morpholinyl, piperazinyl, or C3-C8 cycloalkyl, or where RxRyN is a ring selected from the group consisting of piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, azetidinyl, which may be attached to G at any appropriate place on the ring, G is C1-C12 alkylenyl, C2-C12 alkenylenyl, or C2-C12 alkynylenyl, and L is a bond, -O-, -S-, -S(O)-, -S(O)2-, or -NH-;
with the proviso that when, A1 is -NRa-, -O-, or -S(O)n-, and A is -CH2-, R1 is not hydrogen;
or a pharmaceutically acceptable salt or solvate thereof.
Rb is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoyl, trifluoromethyl, hydroxy, or halo;
R1 is hydrogen, C1-C6 alkyl, or -(CH2)v-R1a;
where v is 1 to 12, and R1a is phenyl, naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the groups consisting of C1-C6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C1-C6 alkyl)amino, C1-C6 alkylamino, C2-C6 alkanoyl, C2-C6 alkanoyloxy, and C3-C8 cycloalkyl, said said phenyl, benzyl, or C3-C8 cycloalkyl, being optionally substituted with one, two, or three moieties independently selected from the group consisting of C1-C6 alkyl, halo, or C1-C6 alkoxy, or R1a may be substituted with -(CH2)W-R1b, where w is 1 to 12 and R1b is piperidinyl, pyrimidyl, pyrrolidinyl, C1-C6 alkoxy, C1-C6 alkylthio, di[di(C1-C6 alkyl)amino(C1-C6 alkylenyl)]amino, di(C1-C6 alkyl)amino(C1-C6 alkylenyl)amino, phenyl, C3-C8 cycloalkyl, pyrrolidinyl, and acetamido, said phenyl, or C3-C8 cycloalkyl, being optionally substituted with one, two, or three moieties independently selected from the group consisting of C1-C6 alkyl, halo, or C1-C6 alkoxy;
A is a bond, -(CH2)m or -C(O)-;
A1 is a bond, NRa, -O-, -(CH2)m-, or -S(O)n-;
q is 0 to 6;
p is 0 to 6;
n is 0, 1, or 2;
m is 0 to 6;
s is 0 to 6;
Ra is hydrogen, C1-C6 alkyl, or C2-C6 alkanoyl;
D is a bond, C2-C4 alkenylenyl, or -C(X)(Y)-, where one of X and Y is hydroxy and the other is hydrogen, or both X and Y are hydrogen, or X and Y
combine to form =O, or =NORc;
Rc is hydrogen, benzyl, acetyl, benzoyl, or C1-C6 alkyl;
one of X1 and Y1 is hydroxy and the other is hydrogen, or both X1 and Y1 are hydrogen, or X1 and Y1 combine to form =O, or =NORd;
Rd is hydrogen or C1-C6 alkyl;
R2 is hydroxy, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, or a group of the formula wherein R4 and R5 are independently hydrogen, C1-C6 alkyl, phenyl, or phenyl(C1-C6 alkylenyl)-, or R2 is a heterocyclic ring selected from the group consisting of hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl;
any one of which hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of C1-C6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino(C1-C6 alkylenyl)-, C1-C6 alkylamino(C1-C6 alkylenyl)-, C2-C6 alkanoyl, carboxamido, 2-aminoacetyl, C2-C6 alkanoyloxy, C1-C6 alkoxycarbonyl-, C1-C6 alkylamino, C3-C8 cycloalkyl, piperidinyl, pyrrolidinyl, pyrimidyl, phenyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, piperidinyl(C1-C6 alkylenyl)-, pyrrolidinyl(C1-C6 alkylenyl)-, pyrimidyl(C1-C6 alkylenyl)-, C1-C6 alkoxy, C1-C6 alkylthio, di[di(C1-C6 alkyl)amino(C1-C6 alkylenyl)]amino, di(C1-C6 alkyl)amino(C1-C6 alkylenyl)amino, and acetamido, any one of which benzyl, phenyl, piperidinyl, C3-C6 cycloalkyl, phenyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, pyrrolidinyl, piperidinyl(C1-C6 alkylenyl)-, pyrrolidinyl(C1-C6 alkylenyl)-, pyrimidyl(C1-C6 alkylenyl)-, or pyrimidyl group may be substituted with one or more moieties selected from the group consisting of C1-C6 alkyl, halo, trifluoromethyl, acetamido, C2-C6 alkanoyl, C2-C7 alkanoyloxy, and C1-C6 alkoxy, or the nitrogen on said piperidinyl, pyrrolidinyl, piperidinyl(C1-C6 alkylenyl)-, pyrrolidinyl(C1-C6 alkylenyl)-, pyrimidyl(C1-C6 alkylenyl)-, or pyrimidyl may be substituted with an amino-protecting group, or R~ is a group of the formula where R4a, R5a, and R6a are independently hydrogen, C1-C6 alkyl, trifluoromethyl, or C1-C6 alkoxy, or R4a is hydrogen, C1-C6 alkyl, trifluoromethyl, or C1-C6 alkoxy and R5a and R6a combine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or heptamethyleneiminyl, or R4a is oxygen, and R5a and R6a combine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or heptamethyleneiminyl;
R is phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C3-C8 cycloalkyl, pyrazinyl, allyl, thiazolyl, furyl, pyrimidyl, pyridinyl, quinolinyl, isoquinolinyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethyleneiminyl, heptamethyleneiminyl, piperidinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C3-C8 cycloalkyl, pyrazinyl, thiazolyl, furyl, pyrimidyl, pyridinyl, quinolinyl, isoquinolinyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethyleneiminyl, heptamethyleneiminyl, piperidinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of C1-C12 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, trifluoromethyl, carboxamido, cyano, benzyl, phenyl, di(C1-C6 alkyl)amino, C2-C6 alkanoyl, C2-C6 alkanoyloxy, C1-C6 alkylamino, oxazolyl, dihydrooxazolyl, piperidinyl(C1-C12 alkoxy)-, piperidinyl(C1-C12 alkoxy)(C1-C6 alkylenyl)-, piperidinyl(C1-C12 alkylenyl)-,phenyl(C1-C12 alkoxy)-, phenyl(C2-C12 alkylenyl)-, C3-Cg cycloalkyl, piperidinyl, pyrimidyl, C1-C6 alkoxy, C1-C6 alkylthio, a group of the formula RxRyN-G-L-(C0-C6 alkylenyl)-, and acetamido, where Rx and Ry are independently hydrogen, C1-C6 alkyl, phenyl, benzyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, morpholinyl, piperazinyl, or C3-C8 cycloalkyl, or where RxRyN is a ring selected from the group consisting of piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, azetidinyl, which may be attached to G at any appropriate place on the ring, G is C1-C12 alkylenyl, C2-C12 alkenylenyl, or C2-C12 alkynylenyl, and L is a bond, -O-, -S-, -S(O)-, -S(O)2-, or -NH-;
with the proviso that when, A1 is -NRa-, -O-, or -S(O)n-, and A is -CH2-, R1 is not hydrogen;
or a pharmaceutically acceptable salt or solvate thereof.
2. A compound as claimed in Claim 1 wherein R1 is hydrogen, or methyl or R1a is piperidinyl, pyrrolidinyl, piperazinyl, or quinuclidinyl, or a pharmaceutically acceptable salt or solvate thereof.
3. A compound as claimed in Claim 2 wherein R1a is piperidin-3-yl, piperidin-2-yl, pyrroldin-3-yl, or pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, pyrroldin-1-yl, or pyrrolidin-4-yl, phenyl, or apharmaceutically acceptable salt or solvate thereof.
4. A compound as claimed in Claim 3 wherein A1 is a bond or -O-, or a pharmaceutically acceptable salt or solvate thereof.
5. A compound as claimed in Claim 4 wherein -(CH2)q-D-(CH2)s- is a bond, methylene, ethylene, or -C(O)-, or a pharmaceutically acceptable salt or solvate thereof.
6. A compound as claimed in Claim 5 wherein both X1 and y1 are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.
7. A compound as claimed in Claim 6 wherein R2 is a piperidinyl group substituted with amino, di(C1-C6 alkyl)amino, C1-C6 alkylamino, or piperidinyl, or R2 is a pyrroldinyl group substituted with amino, di(C1-C6 alkyl)amino, C1-C6 alkylamino, or pyrroldinyl, or R2 is a piperazinyl group substituted with phenyl or cyclohexyl, or a pharmaceutically acceptable salt or solvate thereof.
8. A compound as claimed in Claim 7 wherein -A-A1-(CH2)p- is -CH2-O-, -CH2-NH-, or -CH2-S-, or a pharmaceutically acceptable salt or solvate thereof.
9. A compound as claimed in Claim 8 wherein R is naphthyl, phenyl, piperidinyl, pyrrolidinyl, or cyclohexyl, or a pharmaceutically acceptable salt or solvate thereof.
10. A compound as claimed in Claim 9 wherein R is phenyl optionally independently substituted at the 4-position and at the 2-position with halo, or a pharmaceutically acceptable salt or solvate thereof.
11. A pharmaceutical formulation, comprising, as an active ingredient, a compound as claimed in any one of Claims 1 to 10, in combination with one or more pahramceutically acceptable carriers, diluents, or excipients, therefor.
12. A compound as claimed in any one of Claims 1 to 10, for use in treating a condition associated with an excess of neuropeptide Y, or a related peptide.
13. A method of treating a condition associated with an excess of neuropeptide Y, which comprises administering to a mammal in need thereof an effective amount of a compound as claimed in any one of Claims 1 to 10.
14. The use of a compound as claimed in any one of Claims 1 to 10, for the manufacture of a medicament for the treatment of a condition associated with an excess of neuropeptide Y.
15. A pharmaceutical formulation adapted for the treatment of a condition associated with an excess of neuropeptide Y, comprising a compound as claimed in any one of Claims 1 to 10.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US315095P | 1995-09-01 | 1995-09-01 | |
| GB9523999.2 | 1995-11-23 | ||
| GBGB9523999.2A GB9523999D0 (en) | 1995-11-23 | 1995-11-23 | Indolyl neuropeptide y receptor antagonists |
| US2163896P | 1996-07-12 | 1996-07-12 | |
| US60/003,150 | 1996-07-12 | ||
| US60/021,638 | 1996-07-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2203912A1 true CA2203912A1 (en) | 1997-03-13 |
Family
ID=27267993
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002203912A Abandoned CA2203912A1 (en) | 1995-09-01 | 1996-08-30 | Indolyl neuropeptide y receptor antagonists |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0789688A4 (en) |
| CN (1) | CN1173867A (en) |
| AU (1) | AU717422B2 (en) |
| BR (1) | BR9606619A (en) |
| CA (1) | CA2203912A1 (en) |
| CZ (1) | CZ132897A3 (en) |
| HU (1) | HUP9701714A3 (en) |
| IL (1) | IL120724A0 (en) |
| MX (1) | MX9703186A (en) |
| NO (1) | NO308296B1 (en) |
| NZ (1) | NZ318228A (en) |
| PL (1) | PL320010A1 (en) |
| TR (1) | TR199700334T1 (en) |
| WO (1) | WO1997009308A1 (en) |
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| ES2325071T3 (en) | 2002-12-10 | 2009-08-25 | Wyeth | DERIVATIVES OF INDOL-OXO-ACETILAMINOACETIC ACID REPLACED AS INHIBITORS OF THE PLASMINOGEN-1 ACTIVATOR INHIBITOR (PAI-1). |
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| US7446201B2 (en) | 2003-09-25 | 2008-11-04 | Wyeth | Substituted heteroaryl benzofuran acids |
| US7351726B2 (en) | 2003-09-25 | 2008-04-01 | Wyeth | Substituted oxadiazolidinediones |
| US7342039B2 (en) | 2003-09-25 | 2008-03-11 | Wyeth | Substituted indole oximes |
| US7442805B2 (en) | 2003-09-25 | 2008-10-28 | Wyeth | Substituted sulfonamide-indoles |
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| US7265148B2 (en) | 2003-09-25 | 2007-09-04 | Wyeth | Substituted pyrrole-indoles |
| AU2004290499C1 (en) | 2003-11-03 | 2011-02-24 | Probiodrug Ag | Combinations useful for the treatment of neuronal disorders |
| BRPI0507485A (en) | 2004-02-05 | 2007-07-10 | Probiodrug Ag | new glutaminyl cyclase inhibitors |
| CA2577857A1 (en) | 2004-08-23 | 2006-03-02 | Wyeth | Oxazolo-naphthyl acids as plaminogen activator inhibtor type-1 (pai-1) modulators useful in the treatment of thrombosis and cardiovascular diseases |
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| EP2089383B1 (en) | 2006-11-09 | 2015-09-16 | Probiodrug AG | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
| JP5523107B2 (en) | 2006-11-30 | 2014-06-18 | プロビオドルグ エージー | Novel inhibitors of glutaminyl cyclase |
| ZA200905537B (en) | 2007-03-01 | 2010-10-27 | Probiodrug Ag | New use of glutaminyl cyclase inhibitors |
| ES2533484T3 (en) | 2007-04-18 | 2015-04-10 | Probiodrug Ag | Thiourea derivatives as glutaminyl cyclase inhibitors |
| MY160771A (en) | 2008-06-19 | 2017-03-15 | Takeda Pharmaceuticals Co | Heterocyclic compound and use thereof |
| DK2475428T3 (en) | 2009-09-11 | 2015-09-28 | Probiodrug Ag | Heterocyclic derivatives as glutaminylcyklaseinhibitorer |
| WO2011107530A2 (en) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Novel inhibitors |
| CN102791704B (en) | 2010-03-10 | 2015-11-25 | 前体生物药物股份公司 | The heterocycle inhibitor of glutaminyl cyclase (QC, EC 2.3.2.5) |
| JP5945532B2 (en) | 2010-04-21 | 2016-07-05 | プロビオドルグ エージー | Benzimidazole derivatives as inhibitors of glutaminyl cyclase |
| ES2570167T3 (en) | 2011-03-16 | 2016-05-17 | Probiodrug Ag | Benzimidazole derivatives as glutaminyl cyclase inhibitors |
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| WO2012168697A1 (en) | 2011-06-06 | 2012-12-13 | Imperial Innovations Limited | Methods to predict binding affinity of tspo imaging agents to tspo |
| CN104829465B (en) | 2015-02-13 | 2018-04-27 | 普济生物科技（台州）有限公司 | A kind of preparation method of 4- isopropylaminos-n-butyl alcohol |
| CN105949135A (en) * | 2016-05-10 | 2016-09-21 | 湖南欧亚生物有限公司 | Synthetic method of selexipag |
| EP3461819B1 (en) | 2017-09-29 | 2020-05-27 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
| CN111377821A (en) * | 2018-12-28 | 2020-07-07 | 南京艾德凯腾生物医药有限责任公司 | Method for synthesizing 4-isopropylamino-1-butanol |
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| DE2931323A1 (en) * | 1979-08-02 | 1981-02-26 | Kali Chemie Pharma Gmbh | NEW N-AMINOALKYLINDOL DERIVATIVES AND THEIR SALTS |
| US5264420A (en) * | 1990-09-27 | 1993-11-23 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
| US5206382A (en) * | 1991-06-27 | 1993-04-27 | Fidia Georgetown Institute For The Neurosciences | Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders |
| WO1993023374A1 (en) * | 1992-05-08 | 1993-11-25 | Otsuka Pharmaceutical Factory, Inc. | Indole derivative |
| TW270114B (en) * | 1993-10-22 | 1996-02-11 | Hoffmann La Roche | |
| WO1996012489A1 (en) * | 1994-10-20 | 1996-05-02 | Eli Lilly And Company | Bicyclic neuropeptide y receptor antagonists |
-
1996
- 1996-08-30 HU HU9701714A patent/HUP9701714A3/en unknown
- 1996-08-30 WO PCT/US1996/014163 patent/WO1997009308A1/en not_active Application Discontinuation
- 1996-08-30 BR BR9606619A patent/BR9606619A/en unknown
- 1996-08-30 EP EP96930691A patent/EP0789688A4/en not_active Withdrawn
- 1996-08-30 CN CN96191324A patent/CN1173867A/en active Pending
- 1996-08-30 MX MX9703186A patent/MX9703186A/en unknown
- 1996-08-30 IL IL12072496A patent/IL120724A0/en unknown
- 1996-08-30 NZ NZ318228A patent/NZ318228A/en unknown
- 1996-08-30 PL PL96320010A patent/PL320010A1/en unknown
- 1996-08-30 TR TR97/00334T patent/TR199700334T1/en unknown
- 1996-08-30 CZ CZ971328A patent/CZ132897A3/en unknown
- 1996-08-30 AU AU69650/96A patent/AU717422B2/en not_active Ceased
- 1996-08-30 CA CA002203912A patent/CA2203912A1/en not_active Abandoned
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1997
- 1997-04-30 NO NO972016A patent/NO308296B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| HUP9701714A2 (en) | 1999-06-28 |
| NZ318228A (en) | 1999-07-29 |
| EP0789688A4 (en) | 1997-11-19 |
| TR199700334T1 (en) | 1997-08-21 |
| NO972016L (en) | 1997-06-17 |
| NO308296B1 (en) | 2000-08-28 |
| WO1997009308A1 (en) | 1997-03-13 |
| CN1173867A (en) | 1998-02-18 |
| EP0789688A1 (en) | 1997-08-20 |
| PL320010A1 (en) | 1997-09-01 |
| NO972016D0 (en) | 1997-04-30 |
| AU717422B2 (en) | 2000-03-23 |
| MX9703186A (en) | 1997-07-31 |
| AU6965096A (en) | 1997-03-27 |
| BR9606619A (en) | 1997-12-23 |
| IL120724A0 (en) | 1997-08-14 |
| HUP9701714A3 (en) | 2000-03-28 |
| CZ132897A3 (en) | 1997-11-12 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |