AU717422B2 - Indolyl neuropeptide Y receptor antagonists - Google Patents
Indolyl neuropeptide Y receptor antagonists Download PDFInfo
- Publication number
- AU717422B2 AU717422B2 AU69650/96A AU6965096A AU717422B2 AU 717422 B2 AU717422 B2 AU 717422B2 AU 69650/96 A AU69650/96 A AU 69650/96A AU 6965096 A AU6965096 A AU 6965096A AU 717422 B2 AU717422 B2 AU 717422B2
- Authority
- AU
- Australia
- Prior art keywords
- methyl
- preparation
- consistent
- indole
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D401/04—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D403/06—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Description
WO 97/09308 PCT/US96/14163 -1- Title INDOLYL NEUROPEPTIDE Y RECEPTOR ANTAGONISTS Priority Claim This application claims the benefit of United States Provisional Applications 60/003,150, filed September 1, 1995, and 60/021,638, filed July 12, 1996 and United Kingdom Patent Application 9523999.2, filed November 23, 1995.
Background 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 neurotransmitter per se or synergistically together with noradrenaline. Neuropeptide Ycontaining 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 family 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 P-turn, creating a hairpin-like loop, which is sometimes referred to as the WO 97/09308 PCT/US96/14163 -2pancreatic polypeptide (PP) fold. The helices are kept together by hydrophobic interactions. The amidated C-terminal end projects away from the hairpin loop.
Subsequent to its discovery neuropeptide Y was identified as being the most abundant peptide in the central nervous system with widespread distribution including the cortex, brainstem, hippocampus, hypotahlamus, amygdala, and thalamus as well as being present in the peripheral nervous system in sympathetic neurons and adrenal chromaffin 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 stimulation, 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 binding proteins, known as G protein-coupled receptors. G proteins are a family of membrane proteins that become activated only after binding guanosine triphosphate. Activated G proteins in turn activate an amplifier enzyme on the inner face of a membrane; 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 classified into several subtypes based upon the ability of different tissues and receptors to bind different fragments 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-yetunisolated Y3 receptor subtype appears to be neuropeptide Y-specific, not binding peptide YY. This receptor is likely to be present in the adrenal tissues, medulla, heart, and brain stem, among other areas.
WO 97/09308 PCT/US96/14163 -3- [For a review of neuropeptide Y and neuropeptide Y receptors, see. e., C. Wahlestedt and D. Reis, Annual Review of Pharmacology and Toxicology, 33:309-352 (1993); D. Gehlert and P. Hipskind, Current Pharmaceutical Design, 1:295-304 (1995)].
In view of the wide number of clinical maladies 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, published June 13, 1991, and Patent Cooperation Treaty Patent Publication WO 94/00486, published January 6, 1994, were peptide derivatives. 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.
Summary of the Invention This invention encompasses methods for the treatment or prevention of a disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I 2 D- (CH2)s-C/ (CH2)q Y1 X 1 Rb A A' i A (CH2)pR
R
1
I
wherein: Rb is a single substituent selected from the group consisting of hydrogen, C 1
I-C
6 alkyl, C 1
I-C
6 alkoxy, C 2
-C
6 alkanoyl, trifluoromethyl, hydroxy, and halo; R' is hydrogen, C I-C 6 alkyl, or -(CH 2 )v-R a; where v is I to 12, and R"I is phenyl, naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or r-norpholinyl, any one of which phenyl, naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholiniyl groups may be substituted with one or more moieties selected from the groups consisting Of C 1
-C
6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(CI-C 6 alkyl) amino,
C-
6 alyaio C 2
-C
6 alkanoyl, C 2
-C
6 alkanoyloxy, and C 3
-C
8 cycloalkyl, said said phenyl, benzyl, or C 3
-C
8 cycloalkyl, being optionally substituted with one, two, or three moieties independently selected from the group consisting Of C I-C 6 alkyl, halo, or C 1
-C
6 alkoxy, lb or R a may be substituted with -(CH 2 where w is 1 to 12 and Rlb is piperidinyl, pyrimidyl, pyrrolidinyl, C 1
-C
6 alkoxy, C 1
-C
6 alkylthio, di[di(C 1
-C
6 alkyl)amino(C 1
-C
6 al kylenyl)] amino, di(CI -C 6 alkyl)amino(C 1
-C
6 alkylenyl)amino, phenyl, C 3
-C
8 cycloalkyl, pyrrolidinyl, and acetarnido, said phenyl, or C 3
-C
8 cycloalkyl, being optionally substituted with one, two, or three [R:\LIBVV]02121 .doc:NJC moieties independently selected from the group consisting of C I-C 6 alkyl, halo, or alkoxy; A is a bond, -(CH 2 )m or-CO; A' is -NR or-S),; q is 0 to 6; p is 0 to 6; ii isO0, 1, or 2; iii is 0 to 6; s isO0 to 6; R' is hydrogen, C,-C 6 alkyl, or C 2
-C
6 alkanoyl; D is a bond, C 2
-C
4 alkenylenyl or 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 or =NOR'; R' is hydrogen, benzyl, acetyl, benzoyl, or C I-C 6 alkyl; one of XV and Y' is hydroxy and the other is hydrogen, or both XV and Y' are hydrogen, or XV and Y' combine to form or =NORd; R i is hydrogen or C,-C 6 alkyl; [R:\LIBVV]00973.doc:LMK WO 97/09308 WO 9709308PCT[US96/14163 -6-
R
2 is hydroxy, C i-C 6 alkyl, C 1
-C
6 alkoxy, phenoxy, or a group of the formula -N/R4 wherein R 4 and R 5 are independently hydrogen, C i-C 6 ailkyl, phenyl, or phenyl(C i-C 6 alkylenyl)-, or R 2 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, heptamethyleneiniinyl, imidazolinyl, piperidinyl, 2tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of C i-C 6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C i-C 6 alkyl)amino, di(C i-C 6 alkyl)amino(C i-C 6 alkylenyl)-, C i-C 6 alkylamino(Cl-C 6 alkylenyl)-, C 2
-C
6 alkanoyl, carboxamido, 2-aminoacetyl, C 2
-C
6 alkanoyloxy, C 1
-C
6 alkoxycarbonyl-, C i-C 6 alkylamino, C 3
-C
8 cycloalkyl, piperidinyl, pyrrolidinyl, pyrimidyl, phenyl(C i-C 6 alkylenyl)-, phenoxy(C 1
-C
6 alkylenyl)-, pipericlinyl(C i-C 6 alkylenyl)-, pyrrolidinyl(C i-C 6 alkylenyl)-, pyrimidyl(Cl-C 6 alkylenyl)-, C 1
-C
6 alkoxy, Cl-C 6 alkylthio, di[di(Cl-C 6 alkyl)amino(C 1
-C
6 alkylenyl)]amino, di(C i-C 6 alkyl)amino(C 1
-C
6 alkylenyl)amino, and acetanudo, any one of which benzyl, phenyl, piperidinyl,
C
3
-C
8 cycloalkyl, phenyl(C 1
-C
6 alkylenyl)-, WO 97/09308 PCT/US96/14163 -7phenoxy(Cl-C 6 alkylenyl)-, pyrrolidinyl, pipericinyl(Cl-C 6 alkylenyl)-, pyrrolidinyl(C1-
C
6 alkylenyl)-, pyrimidyl(C-C 6 alkylenyl)-, orpyrimidyl group may be substituted with one or more moieties selected from the group consisting of Ci-C 6 alkyl, halo, trifluoromethyl, acetanido, C 2
-C
6 alkanoyl, C 2
-C
7 alkanoyloxy, and C 1
-C
6 alkoxy, or the nitrogen on said piperidinyl, pyrrolidinyl, pipericinyl(Ci-C 6 alkylenyl)-, pyrrolidinyl(Ci-C 6 alkylenyl)-, pyrimidyl(Ci-C 6 alkylenyl)-, or pyrimidyl may be substituted with an amino-protecting group, or R 2 is a group of the formula 4a R6a R where R4a, R5a, and R6a are independently hydrogen, Cl-C 6 alkyl, trifluoromethyl, or Cl-C 6 alkoxy, or R4a is hydrogen, Ci-C 6 alkyl, trifluoromethyl, or Ci-C 6 alkoxy and R5a and R6a combine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or heptamethyleneiminyl, or R 4 a is oxygen, and R 5 a 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,
C
3
-C
8 cycloalkyl, pyrazinyl, allyl, WO 97/09308 WO 9709308PCT/US96/14163 -8thiazolyl, furyl, pyrimidyl, pyridinyl, quinolinyl, isoquinolinyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethyleneiininyl, heptamethyleneiminyl, piperidinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl,
C
3
-C
8 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 Cl-C 12 alkyl, C 2 -C1o ailkenyl,
C
2 -C1o alkynyl, halo, trifluoromethyl, carboxamido, cyano, benzyl, phenyl, cli(C i-C 6 alkyl)amino, C 2
-C
6 alkanoyl, C 2
-C
6 alkanoyloxy, Cl-C 6 alkylamino, oxazolyl, dihydrooxazolyl, piperidinyl(C 1
-C
12 alkoxy)-, piperidinyl(C i-C 12 alkoxy)(C i-C 6 alkylenyl)-, piperidinyl(Cl 1
-C
12 alkylenyl)-,phenyl(C 1
-C
12 alkoxy)-, phenyl(C 2
-C
12 alkylenyl)-, C 3
-C
8 cycloalkyl, piperidinyl, pyrimidyl, C 1 -C6 alkoxy, C 1
-C
6 alkylthio, a group of the formula RxRYN-G-L-(CO-C 6 alkylenyl)-, and acetamido, where Rx and RY are independently hydrogen, C i-C 6 alkyl, phenyl, benzyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, morph olinyl, piperazinyl, or C 3
-C
8 cycloalkyl, or where RxRYN is a ring selected from the group consisting of piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptainethyleneiminyl, azetidinyl, which may be attached to G at any appropriate place on the ring, 9 G is C,-C 12 alkylenyl, C 2
-C,
2 alkenylenyl, or C 2
-C
1 2 alkynylenyl, and L is a bond, -S(0) 2 or -NH-; with the proviso that when, A' is -NR a or and A is -CH 2 R' is not hydrogen; 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 combination with one or more pharmaceutically acceptable carriers, diluents, or excipients therefor. This invention also provides 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 of the invention or of a formulation of the invention and the use of a compound of the invention, for the manufacture of a medicament for the treatment of a condition associated with an excess of neuropeptide Y.
Detailed Description and Preferred Embodiments The current invention concerns the discovery that a select group of substituted indoles, those of Formula I, are useful as neuropeptide Y receptor antagonists.
alkoxy" represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C,-C 6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term "C,-C 6 20 alkoxy" includes within its definition the terms "C,-C 4 alkoxy" and "C,-C 3 alkoxy".
As used herein, the term 2 alkyl" refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term 2 alkyl" includes within its definition the terms "C,-C 6 alkyl" and "CI-C 4 alkyl".
25 "C 2
-C
7 alkanoyloxy" represents a straight or branched-alkyl chain having from one to six carbon atoms attached to a carbonyl moiety joined through an oxygen atom. Typical 5l C-C, alkanoyloxy groups a *le [R:\LIBVV]00973.doc:LMK WO 97/09308 PCT/US96/14163 include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, t-butanoyloxy, pentanoyloxy, hexanoyloxy, 3-methylpentanoyloxy and the like.
"C
3
-C
8 cycloalkyl" represents a saturated hydrocarbon ring structure containing from three to eight carbon atoms. Typical C 3
-C
8 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
"Halo" represents chloro, fluoro, bromo or iodo.
"C
1 -Clo alkylthio" represents a straight or branched alkyl chain having from one to ten carbon atoms attached to a sulfur atom.
Typical C 1 -Clo alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like. The term "C1-Clo alkylthio" includes within its definition the term "C 1
-C
6 alkylthio" and "C1-C 3 alkylthio".
"C
1
-C
12 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 "C 1
-C
6 alkylenyl" is encompassed within the term "C1-C 12 alkylenyl". The term "Co alkylenyl" or any term incorporating this designation, refers to a bond, for example "Co-Cs alkylenyl" refers to a bond or C 1
-C
6 alkylenyl, as such is defined herein.
"Ci-Clo alkylamino" represents a group of the formula
-NH(C
1 -Clo alkyl) wherein a chain having from one to ten carbon atoms is attached to an amino group. Typical C 1
-C
4 alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like.
The term "C 2
-C
12 alkenyl" as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to twelve carbon atoms. Typical C 2
-C
12 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, l-methyl-l-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 2,4-hexadienyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like.
WO 97/09308 PCT/US96/14163 -11- The term "C 2
-C
1 2 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
C
2
-C
12 alkynyl groups include ethynyl, 1-propynyl, 1-butynyl, 1-hexynyl, 2-propynyl, 2-butynyl, 2-pentynyl, and the like.
The term "C 2
-C
12 alkenylenyl" as used herein represents a straight or branched, divalent, unsaturated aliphatic chain having from two to twelve carbon atoms. Typical C 2
-C
12 alkenylenyl groups include -CH=CH-, -CH 2 -CH=CH-, -CH2-C(CH 3
)=CH-CH
2
CH
2 and the like.
The term "C 2
-C
12 alkynylenyl" as used herein represents a straight or branched, divalent, unsaturated aliphatic chain having from two to ten carbon atoms with at least one triple bond. Typical C 2
-C
12 alkynylenyl groups include -CH 2
-CH
2
-C=C-CH
2
CH
2 and the like.
"C
3 -Cs cycloalkenyl" represents a hydrocarbon ring structure containing from three to eight carbon atoms and having at least one double bond within that ring.
"C
1
-C
6 alkoxy" represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
Typical C 1
-C
6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term "C1-C 6 alkoxy" includes within its definition the term "C1-C3 alkoxy".
"C
2
-C
6 alkanoyl" represents a straight or branched alkyl chain having from one to five carbon atoms attached to a carbonyl moiety. Typical C2-C 6 alkanoyl groups include ethanoyl, propanoyl, isopropanoyl, butanoyl, t-butanoyl, pentanoyl, hexanoyl, 3-methylpentanoyl and the like.
"C
1
-C
6 alkoxycarbonyl" represents a straight or branched alkoxy chain having from one to six carbon atoms attached to a carbonyl moiety. Typical C 1
-C
6 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 employed to block or protect the amino functionality while reacting other WO 97/09308 WO 9709308PCTIUS96/14163 12functional groups on the compound. Examples of such amino-protecting groups include formyl, trityl, phthalimido, trichioroacetyl, chioroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2 ,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl, 1, 1-diphenyleth- 1-yloxycarbonyl, 1, 1-diphenylprop- 1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl )-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxy-carbonyl 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop- 1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2 ,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 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 selectively removed at the appropriate point without disrupting the remainder 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 examples of groups referred to by the above terms are described by E. Haslam, "Protective Groups in Organic Chemistry", (J.G.W.
3 5 McOmie, ed., 1973), at Chapter 2; and T.W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991), at Chapter 7.
WO 97/09308 PCT/US96/14163 -13- The term "carboxy-protecting group" as used in the specification refers to substituents of the carboxy group commonly employed to block or protect the carboxy functionality while reacting other functional groups on the compound. Examples of such carboxy-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, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, 2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. Preferred carboxy-protecting groups are allyl, benzyl and t-butyl. Further examples of these groups are found in E. Haslam, supra, at Chapter and T.W. Greene, et al., sura, at Chapter The term "hydroxy-protecting groups" as used herein refers to substitents of the hydroxy group commonly employed to block or protect the hydroxy functionality while reacting other functional groups on the compound. Examples of such hydroxy-protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, 2,2-dichloro-1,1difluoroethyl, tetrahydropyranyl, phenacyl, cyclopropylmethyl, allyl, Ci-
C
6 alkyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl, t-butyldimethylsilyl, levulinate, pivaloate, benzoate, dimethylsulfonate, dimethylphosphinyl, isobutyrate, adamantoate and tetrahydropyranyl.
Further examples of these groups may be found in T. W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991) at Chapter 3.
The term "leaving 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 used in this document encompasses, but is not limited to, activating groups.
WO 97/09308 PCT/US96/14163 -14- The term "activating group" as used herein refers a leaving group which, when taken with the carbonyl 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 activating groups are well-known to those skilled in the art and may be, for example, succinimidoxy, phthalimidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido, or
-O-CO-(C
4
-C
7 alkyl).
The compounds of the present invention are derivatives of indole which are named and numbered according to the RING INDEX, The American Chemical Society, as follows.
H
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 isomers and combinations thereof, are within the scope of the present invention.
The terms and are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
The term (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term (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.
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 stereochemistry is contained in NOMENCLATURE OF ORGANIC WO 97/09308 PCT/US96/14163 COMPOUNDS: PRINCIPLES AND PRACTICE, Fletcher, et al., eds., 1974) at pages 103-120.
In addition to the system, the older D-L system may also be used in this document to denote absolute configuration, 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 is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and that of the isomer in which it is on the left.
In order to preferentially prepare one optical isomer over its enantiomer, the skilled practitioner can proceed by one of two routes.
The practitioner may first prepare the mixture 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.
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 organic acids, to form a pharmaceutically acceptable salt.
WO 97/09308 PCT/US96/14163 -16- The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the 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 acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, y-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, 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 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 alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium WO 97/09308 PCT/US96/14163 -17carbonate, 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 combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding 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 plasma half-life, for example).
Typically, such chemical modifications include: 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 membrane selection of a prodrug form or a modified prodrug form; or any combination of 1 to 3, supra. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in H, Bundgaard, Design of Prodrugs, (1985).
The preferred compounds of the present invention are those compounds of Formula I in which: 18 a) R b is hydrogen, chioro, fluoro, methyl, ethyl, hydroxy, or acetyl; b) R' is methyl, ethyl, or is phenyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, piperazinyl, and v is I to 6; c) A' is -N(CH 3 or A is -CH 2 or -CH 2 e q is0,1, or 2; p pis0, 1, or 2; g) s is0,1, 2, or 3; h1) D is a bond, or -Hni) R 2 is a group of the formula -NR 4 R' or -N+R 4 aR5a R 6 a; R R 4 and R' are independently hydrogen, methyl, ethyl, benzyl, or combine t o ['orm, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hiexamethiyleneiminyl group; k) R 4 a, R 5 a, R 6 a are independently hydrogen, methyl, ethyl, or R 5 and R"~ I 5combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethyleneiminyl group; and 1) R is phenyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, hieptamethyleneiminyl, naphthyl, thiazolyl, furyl, quinolinyl, isoquinolinyl, [R:\LIBVV]00973.doc:LMK 19 morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl, or quinuclidinyl; or a pharmaceutically acceptable salt or solvate thereof.
The preferred methods of the present invention are those methods employing comnpounds of Formula I in which R b is hydrogen, chloro, fluoro, methyl, ethyl, hydroxy, or acetyl; b) R' is methyl, ethyl, or R I is phenyl, piperidinyl, pyrrolidinyl, hiexamethylenciminyl, piperazinyl, and v is I to 6; c) A' is or dl) A is or -CH 2
CH
2 ine) q is0, 1, or 2; 1) p is0,1, or 2; g) s is0,1, 2, or 3; 11) D is a bond, or i) is a group of the formula -NR 4 R' or -N±R 4 a R 5 aR 6 a; J) R 4 and R' are independently hydrogen, methyl, ethyl, benzyl, or combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hiexamethyleneiminyl group; k) R 4 la, R la R 6 are independently hydrogen, methyl, ethyl, or and R 6 eas combine to form, together with sees OOOSO0 0@ 00 se a [R:\L1BVV100973.doc: LMK the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethyleneiminyl group; and 1) R is phenyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, hieptamethyleneiminyl, naphthyl, thiazolyl, furyl, quinolinyl, isoquinolinyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl, or quinuclidinyl; or a pharmnaceutically acceptable salt or solvate thereof.
Especially preferred compounds of the present invention are those compounds of [ormula I in which: a) is hydrogen, fluoro, or methyl; b) R' is methyl, or is piperidinyl, pyrrolidinyl, or hexamethyleneiminyl, and v is 1, 2, or 3; c) A' is or dI) A is or -CHCH,-;, e) q is 0ori1; p is 0ori1; g) s is 0ori1; 11) D is a bond, or i) R 2 is a group of the formula -NR 4
R
5 [R:\LI BVV]00973 .doc: LM K 21 j) R 4 and R 5 are independently methyl, or combine to form, together with the nitrogen to which they are attached, a piperidinyl, piperazinyl, or pyrrolidinyl group; k) R is optionally substituted phenyl, naphthyl, or cyclohexyl; 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.
Particularly preferred compounds are those of Formula I in which: a) Rb is hydrogen; b) R' is methyl, piperidinyl(C,-C 4 alkylenyl)-, or pyrrolidinyl(C,-C 4 10 alkylenyl)-; c) A' is d) A is -CH2-; d) q is 0; e) p is 0 or l; t) s is 0 or 1; g) D is a bond, or [R:\LIBVV]00973.doc:LMK WO 9709308PCTIUS96/14163 WO 97/09308 -22h) R 2 is a piperidinyl, or pyrrolidinyl group, substituted with amino, di(Cl-C 6 alkylbamino, (C 1
-C
6 alkyl)ainino, piperidinyl, or pyrrolidinyl, or R 2 is a piperazinyl group substituted with phenyl, cyclohexyl, or benzyl; and j) R is phenyl, substituted with one to three groups selected from Cl-C 6 alkyl, trifluoromethyl, and halo; 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 where:
D
1 is or -H-
R
1 is methyl,piperilin-3-yl-CH 2
-CH
2 piperidin-3-yl-CH2-CH 2
-CH
2 piperidin-2-yl-CH 2
-CH
2 piperidin-2-yl-CH2-CH 2
-CH
2 pyrrolidin-3-yl-CH 2
-CH
2 pyrrolidin-3-yl-CH 2
-CH
2
-CH
2 pipericlin-4-yl-CH 2
-CH
2 or piperidin-4-yl-CH 2
-CH
2
-CH
2 WO 97/09308 PCT/US96/14163 -23-
R
2 is piperidinyl, or pyrrolidinyl group, substituted with amino, di(C1-C6 alkyl)amino, (C1-C 6 alkyl)amino, piperidinyl, or pyrrolidinyl, or R 2 is a piperazinyl group substituted with phenyl or cyclohexyl; R* is chloro or bromo; and hydrogen or chloro; 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 R 1 is methyl, is depicted in Scheme I, infra.
WO 97/09308 WO 9709308PCT/US96/14163 -24- Scheme I Q COOH reduction
N
CH
3
CH
3 alkylation or arylation
NRR
alkylation N (CH 2 )p-R
%CH
3 111(CH 2 )p-R
CH
8 WO 97/09308 PCT/US96/14163 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 teachings and the examples.
Reduction
.OH
COOH
H
CH
3 CH 3 Many of the compounds of Formula I are prepared through the reduction of 1-methyl-2-indolecarboxylic acid to the corresponding 2hydroxymethyl-1-methylindole. This reduction may be prepared by several methods known in the art including catalytic hydrogenation. A most preferred method for this reduction is by using a reducing agent such as sodium borohydride, 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 ethanol, a method known as the Bouveault-Blanc procedure. A most preferred reducing agent employed in this procedure is lithium aluminum hydride.
Alkylation or Arylation SArOH OH AOAr
CH
3 CH3 The coupling of the aryl group to the above alcohol may be performed using standard techniques. For those compounds of WO 97/09308 PCT/US96/14163 -26- Formula I in which A is p is 0, and R is substituted phenyl, for example, a most preferred method involves a phenolic coupling using a Mitsunobu reagent. 0. Mitsunobu, et al., Bulletin of the Chemical Society of Japan, 44:3427 (1971); 0. Mitsunobu, et al., Journal of the American Chemical Society, 94:679 (1972). In this reaction triphenylphosphine, in combination with diethyl azodicarboxylate (DEAD), converts alcohols in situ to the corresponding alkoxyphosphonium salts, which are useful alkylating agents.
Although this coupling can be accomplished using various concentrations of the reactants 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 example, toluene, benzene, or, preferably tetrahydrofuran. The reaction is performed at temperatures from about 00 C to about 400 C, preferably at ambient temperature, until the desired compound is prepared. Typically, the reaction takes about 18 hours when run at ambient temperature, but the progress of the reaction can be monitored via standard chromatographic techniques.
ArX \OH OAr
N
CH
3
CH
3 An alternative method of arylating the alcohol involves nucleophilic aromatic substitution of an aryl fluoride with a preformed alkoxide. This reaction is performed by first adding a base to the alcohol, followed by the addition of the aryl halide. An especially preferred base is sodium hydride. Another preferred base is sodium hexamethyldisilazide. The reaction is generally performed in a polar aprotic solvent, for example, acetonitrile, N,N-dimethylformamide, N,N-dimethylphenylacetamide, dimethylsulfoxide, or hexamethylphosphoric triamide.
WO 97/09308 PCT/US96/14163 -27- Alkylation
NR
4
R
HNR
4
R
OAr -HCHO OAr
CH
3 CHa 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 Mannich 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 HNR 4 R5, in the form of its salt, and a compound containing an active hydrogen. Instead of ammonia, the reaction can be carried out with salts of primary (RNH 2 or secondary amines (R 2 NH), or with amides (RCONH 2 in which cases the product is substituted on the nitrogen with R, R 2 and RCO, respectively. This reaction is generally carried out in a lower alkyl alcohol, such as methanol or ethanol, 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 oxidizing the alcohol to form the corresponding aldehyde.
OH
)\CHO
CH
3 CH3 This reaction is generally performed using an oxidizing agent such as pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC) in a WO 97/09308 PCT/US96/14163 -28solvent such as methylene chloride. The resulting aldehyde is then reacted with a substituted phosphonate in the presence of a base.
CHO
I N Ar
CHS
CH
3 This Wittig-type reaction results in the formation of an aralkenyl group.
A preferred base employed in this reaction is sodium hydride. This reaction generally results in a mixture of the and stereoisomers.
The double bond is then reduced using either a reducing agent as described supra or by means of catalytic hydrogenation using standard means. Preferred solvents for this reaction include dichloroethane.
Ar
CH
3
CH
3 The resulting 1,2-disubstituted indole may then be substituted at the 3 position essentially as described above for the Mannich chemistry.
NR
4
R
SAr
HNR
4
R
CH
3
CH
3 Those compounds in which R 1 is a substituted alkylenyl group [(CH2)v-Rla]may be prepared as illustrated in Scheme II, infra.
WO 97/09308 WO 9709308PCTIUS96/141 63 -29- Scheme II D. -CH 3 alkylation Tr '0 CH 3
.OH
reduction NTr substitution NTr .NTr in which Tr is a trityl group.
WO 97/09308 WO 9709308PCT/US96/14163 Scheme II (continued) halogenation 0
N
Cl 1) t-BuLi 2) CN-CN--QN ,OCH 3
CH
3 deprotection
IW
WO 97/09308 PCT/US96/14163 -31- For those compounds of Formula I in which L is the thio derivatives and intermediates of this invention may be transformed into the corresponding sulfoxide compounds upon treatment with a mild oxidizing agent, such as hydrogen peroxide in methanol, metachloroperbenzoic acid (MCPBA) in methylene chloride at 0°C, or an alkali metal periodate in aqueous alcohol. The corresponding sulfones
(-SO
2 are prepared from the thio or sulfoxide compounds on treatment with a strong oxidizing agent, such as hydrogen peroxide in acetic acid or m-chloroperbenzoic acid in methylene chloride at 20 0 C-30 0
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 example, 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 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 equimolar mixture 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.
WO 97/09308 WO 9709308PCT/US96/14163 -32- Scheme III NaCH 2
CO
2 Et addition Et cyclization
CH
3 N. N.CO 2 Et
N
3 bromination
ICO
2 Et O
CH
3 1
~O
2 Et alkylation
CO
2 Et
CO
2 Et
CH
3 WO 97/09308PCUS6416 PCT[US96/14163 -33- Scheme III (continued)
CO
2 Et -substitution
O
CH
3
CH
3
N
Olk&CN :CH 2
OHKII
1) hydrogenation 2) reduction OHl 3
CH
3 1) base
C'
2) substitution
CH
3 N. NC 1 0 CH3K~~ WO 97/09308 WO 9709308PCTIUS96/14163 -34- Scheme IV R b
N
H
1) a. n-BuLi, C0 2 b. t-BuLi, C0 2 2) conc. H 2 S0 4 [MeOH] Rb N "Y CH 3 H 0 R b N 3 ,CH 3 H 0 NaH [DMF] "00' NTr
~CH
3
LAH
[THF]
WO 97/09308 WO 9709308PCT/US96/14163 Scheme IV (Continued) El 1) NaH;
[DMF]
2) HCO 2 H, [CH 2 CI1] WO 97/09308 PCT/US96/14163 -36- 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 example, 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 example, a chloro group can be introduced by treating with iodobenzene, chlorine, and pyridine [Murakami, et al., Chem. Pharm. Bull., 19:1696 (1971)] or Nchlorosuccinimide in dimethylformamide [United States Patent 4,623,657, the entire contents of which are herein incorporated by reference]. In addition to those described supra, other transformations, intraconversions, and derivatizations are either described in the Examples, infra, or are well known to those of ordinary skill in the art.
The following Examples further illustrate the compounds of the present invention and the methods for their synthesis. The Examples 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 tetrahydrofuran (THF) was obtained by distillation from sodium or sodium benzophenone ketyl prior to use.
Proton nuclear magnetic resonance (1H 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, or a like model. (Unless designated otherwise, the term "NMR" as employed herein refers to proton nuclear magnetic resonance.) Free WO 97/09308 PCT/US96/14163 -37atom 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 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 was performed using E. Merck Kieselgel 60 F 2 5 4 plates, 5 cm x 10 cm, 0.25 mm thickness. Spots were detected using a combination of UV and chemical detection (plates dipped in a ceric ammonium molybdate solution [75 g of ammonium molybdate and 4 g of cerium (IV) sulfate in 500 ml of 10% aqueous sulfuric acid] and then heated on a hot plate).
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 exchange resin. Anion exchange chromatography was performed with Bio-Rad AG® 1-X8 anionexchange resin (acetate form converted to hydroxide form). Flash chromatography was performed as described by Still, et al., Journal of Organic Chemistry, 43:2923 (1978).
Optical rotations are reported at the sodium-D-line (354 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 Farmacia, Madrid, Spain). Melting points were determined in open glass capillaries on a Thomas Hoover capillary melting point apparatus or a Biichi 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 Examples, infra, the terms "NMR", and "UV" indicate that the proton nuclear magnetic WO 97/09308 PCT/US96/14163 -38resonance, infrared, and ultraviolet spectroscopy, respectively, were consistent with the desired title product.
Preparation 1 Preparation of ethyl 2-(piperidin-3-yl)acetate 0Nses 0 CH3 0
N
H
Ethyl-3-pyridylacetate (100g, 0.606 mol) was dissolved in ethanol (1.8 liters), treated with 5% rhodium on alumina (100 g) and hydrogenated at 600C and 60 psi hydrogen gas overnight. The catalyst was removed by filtration and the solvent evaporated to give a brown liquid (101.4 g, The brown liquid was dissolved in ethyl acetate (600 ml) and treated with L-(+)-mandelic acid in warm ethyl acetate (600 ml).
After cooling in the refrigerator for four hours, the solid was collected and the crystallization 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 product as white needles. Yield: 81.6 grams, 41%.
O.R. (EtOH) @589 nm @365 nm +173.730. mp 118-1190C.
Preparation 2 Preparation of ethyl 2-(piperidin-3-yl)acetate 0 CH 3
N
H
The crystallization fluid from Preparation 1, supra, was evaporated to give a dark oil (100.3 This was dissolved in a cold WO 97/09308 PCT/US96/14163 -39solution of potassium carbonate (52 g, 0.377 mol) in water (250 ml) and extracted with ethyl acetate (5 x 150 ml). The extracts were combined and dried over magnesium sulfate. The solvents were removed in vacuo to give a dark liquid (40.25 The dark liquid was treated with a warm solution of D-(-)-mandelic 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 -164.310. mp 115.5-117 0
C.
Chiral Analytical 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 mixture was extracted with ethyl acetate (3 x 5 ml). The combined extracts were dried over magnesium sulfate and the solvents were removed in vacuo. The residue was dissolved in diethyl ether (10 ml) and treated with methylbenzylisocyanate (0.12 ml). After 2.5 hours, the reaction was treated wtih 1 N hydrochloric acid (2 ml). The ether was separated and then washed sequentially with brine, a saturated aqueous sodium bicarbonate solution, and brine. The organic fraction was dried over magnesium 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 hexanes at a flow rate of 2.5 ml/minute. The slower component comes from the l-(+)-mandelic acid salt and the faster from the d-(-)-mandelic acid salt. HPLC analysis of the final crystallization products of both enantiomers show less than three percent of the opposite enantiomer.
Preparation 3 Preparation of ethyl 2 -[N-(t-butoxycarbonyl)piperidin-3-yl]acetate WO 97/09308 PCT/US96/14163 SO0 CH 3
I
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 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 The liquid was dissolved in ether (50 ml) and treated dropwise with di-t-butyldicarbonate (7.9 g) in ether (10 ml). After stirring overnight, the solution was cooled in an ice water bath and treated dropwise with saturated aqueous citric acid ml). The aqueous fraction was extracted with diethyl ether. The organic fractions were combined, washed with water, a saturated sodium bicarbonate solution, and then brine, and then dried over magnesium sulfate. The solvents were removed in vacuo to give the desired title product was a clear liquid. NMR was consistent with proposed title structure.
Preparation 4 Preparation of ethyl 2 -[N-(t-butoxycarbonyl)piperidin-3-yl]acetate 0 CH 3 0
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 WO 97/09308 PCT/US96/14163 -41was 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 The residue was dissolved in diethyl ether (200 ml), cooled in an ice water bath, and a solution of di-t-butyldicarbonate (31.8 g, 0.146 mol) in ether (25 ml) was added dropwise 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 dropwise. The organics were washed with brine, a saturated aqueous sodium bicarbonate solution, then brine, and then dried over sodium sulfate. The solvents were removed in vacuo to give the desired title product as a clear liquid (38.6 g, NMR was consistent with desired title structure.
Preparation Preparation of ethyl 3 -[pyrid-3-yl]prop-2-enoate 0 0 CH 3
N
A solution of ethylphosphinoacetate (98.6 g, 0.44 mol) in dry tetrahydrofuran (1200 ml) was treated with 60% sodium hydride (17.5 g, 0.44 mol). The mixture was stirred at room temperature for two hours and was then cooled down to 0°C. To this mixture 3-pyridine carboxaldehyde (38.9 g, 0.36 mol) was added and the resulting reaction mixture 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 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 grams of the desired title product.
WO 97/09308 PCT/US96/14163 -42- Preparation 6 Preparation of (RS) ethyl 3-[piperidin-3-yl]propionate 0 0 CH 3
N
H
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 The mixture was placed under a hydrogen atmosphere (55 psi) for five hours at 60 0 C. The reaction was stopped by removing the hydrogen and the reaciton mixture was filtered through a layer of
CELITE
TM
The residue was washed with hot ethanol. The filtrate was concentrated and purified by flash chromatography to provide 39.6 grams of the desired title product.
IR, NMR, and IR were consistent with the proposed title structure.
Preparation 7 Preparation of ethyl 3-[piperidin-3-yl]propionate mandelic acid salt 0 O0 CHs
N
H *mandelic 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 Rmandelic 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 WO 97/09308 PCT/US96/14163 -43ethyl acetate (300 ml) and letting it cool down to room temperature each time. The final pure crystals were dried to yield 33.1 grams NMR and IR were consistent with the desired title product. The conformation about the chiral center was confirmed by X-ray crystallography.
Preparation 8 Preparation of ethyl 3-[piperidin-3-yl]propionate mandelic acid salt *mandelic acid The title compound was prepared essentially as described in Preparation 7, supra, except that mandelic acid was employed instead of the mandelic acid employed therein.
NMR and IR were consistent with the desired title product.
Preparation 9 Preparation of ethyl 3-[piperidin-3-yl]propionate 0 A suspension of ethyl 3 -[piperidin-3-yl]propionate 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 WO 97/09308 PCT/US96/14163 -44brine (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 Preparation of ethyl 3-[piperidin-3-yl]propionate
O
O
CH
3
N
H
The title compound was prepared essentially as described in Preparation 9, suDra, except that ethyl 3-[piperidin-3yl]propionate mandelic acid salt was employed instead of the ethyl 3-[piperidin-3-yl]propionate mandelic acid salt therein.
NMR and IR were consistent with the desired title product.
Preparation 11 Preparation of ethyl 3-[l-(t-butoxycarbonyl)piperidin-3-yl]propionate 0 0
CH
3
N
I
BoC A solution of ethyl 3 -[piperidin-3-yl]propionate (12.5 g, 67.5 mmol) in tetrahydrofuran:water 335:168 ml) was treated with 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/US96/14163 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 NMR 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
0O CH3
N
BoC The title product was prepared essentially as described in Preparation 11, supra except that an equimolar amount of ethyl 3- [piperidin-3-yl]propionate was employed instead of the ethyl 3- [piperidin-3-yl]propionate employed therein.
Preparation 13 Preparation of 3 -[1-(t-butoxycarbonyl)piperidin-3-yl]propanol Cr- 0OH
N
I
BoC A solution of ethyl 3-[l-(t-butoxycarbonyl)piperidin-3yl]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 warmed to room temperature within two hours. The WO 97/09308 PCT/US96/14163 -46reaction was stopped by the slow addition of water (200 ml) and aqueous sodium hydroxide (50 ml). The organic fraction was extracted with diethyl ether (3 x 300 ml). The combined layer was 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 to provide 13.2 grams yield) of the title product.
NMR and IR were consistent with the desired title product.
Preparation 14 -0 Preparation of 3-[l-(t-butoxycarbonyl)piperidin-3-yl]propanol The title product was prepared essentially as described in Preparation 13, supra, except that an equimolar amount of ethyl 3- [1-(t-butoxycarbonyl)piperidin-3-yl]propionate was employed instead of the ethyl 3 -[l-(t-butoxycarbonyl)piperidin-3-yl]propionate employed therein.
Preparation Preparation of 3-[l-(t-butoxycarbonyl)piperidin-3-yl]propyl bromide BoC To a cold 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 WO 97/09308 PCT/US96/14163 -47triphenylphosphine were added to the mixture to bring the color back to white. To this mixture was added a suspension of butoxycarbonyl)piperidin-3-yl]propanol (13.2 g, 54.4 mmol) and pyridine g, 76 mmol) in dry methylene chloride (110 ml). The resulting mixture was stirred for five hours while warming to room temperature.
The reaction was stopped by adding water (200 ml). The organic fraction was extracted with methylene chloride (3 x 200 ml).
The combined organic layer was washed with water (2 x 200 ml), then brine (1 x 100 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to provide a light brownish crude product, which was further purified by flash chromatography to yield 11.6 grams of the desired title product.
NMR and IR were consistent with the title product.
Preparation 16 Preparation of 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl bromide Br BoC The title product was prepared essentially as described in Preparation 15, supra, except that an equimolar amount of butoxycarbonyl)piperidin-3-yl]propanol was employed instead of the (3'S) 3-[l-(t-butoxycarbonyl)piperidin-3-yl]propanol employed therein.
Preparation of 1-methyl-2-hydroxymethyl-lH-indole.
WO 97/09308 PCT/US96/14163 -48- 0 N V OH LAH
OH
I [THF] CH3CH 3 In 950 ml of dry tetrahydrofuran under an argon atmosphere was added lithium aluminum hydride (18.40 g, 0.49 mol).
The resulting mixture was placed over an ice bath. An aliquot of 1methylindole-2-carboxylic acid (84.92 g, 0.49 mol) was dissolved in an additional 475 ml of dry tetrahydrofuran 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 mixture was then stirred at room temperature 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 mixture. This was followed by the sequential addition of 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.
The white solid was then dissolved in toluene heated to reflux. The mixture 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 grams FDMS 161.
Analysis for CloH 11
NO:
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/US96/14163 -49- Cl OH 1. NaH
\IO
I I
CH
3 2. F Cl
CH
3 A one liter round bottom flask with a nitrogen atmosphere was charged with sodium hydride (9.28 grams of a 60% NaH solution in mineral oil, 0.232 mol) and N,N-dimethylformamide (211 ml). To the resulting mixture was slowly added 1-methyl-2-hydroxymethyl-lHindole (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 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 0 C and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was then allowed to cool. The reaction mixture 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.
IR, NMR, and UV were consistent with the desired title compound.
FDMS 271 Analysis for C 16
H
14 C1NO: 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-(4methylpiperidin-1-yl)methyl-lH-indole (Example 14) WO 97/09308 PCT/US96/14163
CH
3 Cl
CH
3 alkylation CH 3 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 mixture were added formaldehyde (0.304 g, 1.01 mmol), sodium acetate (0.113 g, 1.38 mmol), and l-methyl-2-(4-chlorophenoxymethyl)-1H-indole (0.250 g, 0.92 mmol).
The resulting mixture was then heated to reflux and maintained 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 C2 3
H
2 7 C1N 2 0: Theory: C, 72.14; H, 7.11; N, 7.31.
Found: C, 72.33; H, 7.22; N, 7.47.
Method B Preparation of l-methyl- 2 4 -chlorophenoxymethyl)-3-[2-[4-(piperidin-lyl)piperidin-l-yl]-l,2-ethanedionyl]-1H-indole (Example 106) WO 97/09308 PCT/US96/14163 -51- 0
N
I I I acylation
CH
3 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 bottom flask under an argon atmosphere. To this solution was added oxalyl chloride (0.294 g, 2.32 mmol). The resulting mixture 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 and 4-(piperidin-l-yl)piperidine (1.07 g, 6.38 mmol), dissolved in about 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 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 combined, basified with 1 N sodium hydroxide and then extracted thrice with methylene chloride. This organic fraction was dried over sodium 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.
FDMS 493.
Analysis for C 2 8
H
3 2 C1N 3 0 3 Theory: C, 68.07; H, 6.53; N, 8.51.
WO 97/09308 PCT/US96/14163 -52- Found: C, 67.97; H, 6.66; N, 8.27.
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[4- (phenyl)piperazin-l-yl]methyl-lH-indole (Example Cl SN I alkylation
CH
3 CH3 Under a nitrogen atmosphere in a round bottom flask, phenylpiperazine (0.149 g, 0.920 mmol) was dissolved in 2.0 ml of 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 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 Analysis for C 2 7
H
2 8 C1N 3 0: WO 97/09308 PCT/US96/14163 -53- Theory: C, 72.71; H, 6.33; N, 9.42.
Found: C, 73.00; H, 6.41; N, 9.51.
Method C1 Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-chloro-1,2ethanedionyl]-1H-indole d Cl o NCl I acylation CH 3 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 temperature 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 were collected and dried in a vacuum oven to yield 1.15 grams of the desired title product.
Preparation of 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-(4methylpiperidin-l-yl)-1,2-ethanedionyl]-1H-indole (Example 102) WO 97/09308 PCT/US96/14163 -54o C1 o N I alkylation CH3 CH3 0.411 g, 4.14 mmol) was dissolved in 3.0 m of dry tetrahydrofuran in N o N 0 I alkylation CH 3 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 a round bottom flask over an ice bath. To this reaction mixture was added l-methyl-2-(4-chlorophenoxymethyl)-3-[2-chloro-1,2-ethanedionyl]- 1H-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.
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 Analysis for C 2 4
H
2 5 C1N 2 0 3 Theory: C, 67.84; H, 5.93; N, 6.59.
Found: C, 68.04; H, 5.85; N, 6.74.
Method C2 Preparation of 2-[(4-chlorophenoxy)methyl]- -methyl-3-[ -hydroxy-l-[[4- (piperidin-l-yl)piperidin-l-yl]carbonyl]methyl]-lH-indole (Example 77) WO 97/09308 PCT/US96/14163
CH
3 re Cl duction CH3 O
CH
3
C
Cl A round bottom flask under a nitrogen atmosphere was charged with 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-[4-(piperidin-1yl)piperidin-l-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 mixture 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 combined, washed with brine, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by chromatography.
NMR was consistent with the proposed title product.
FDMS 495 Analysis for C 2 8H 34 C1N 3 0 3 Theory: C, 67.80; H, 6.91; N, 8.47.
Found: C, 67.86; H, 6.90; N, 8.45.
Method D Preparation of methyl indole-2-carboxylate.
Q-\OH
N
H
Q OCH 3
N
H
WO 97/09308 PCT/US96/14163 -56- 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 maintained at this temperature for about 16 hours. The reaction 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 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-2carboxylate.
0 VOCH3 h OCH3 N OCH 3 H alkylation N
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 sodium hydride (0.377 g, 9.42 mmol) was added. The resulting mixture was stirred for 20 minutes over ice and then permitted to warm to room temperature. The reaction mixture was then stirred for about 90 minutes at room temperature, 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 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 WO 97/09308 PCT/US96/14163 -57sulfate. The solvents were removed in vacuo to yield 4.98 grams 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-(l-tritylpiperidin-3-yl)propyl]indole-2carboxylate.
0
SOCH
3 OCH3 H alkylation 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 solution, 6.28 mmol) was added. The resulting mixture was stirred for 20 minutes over ice and then permitted to warm to room temperature. The reaction mixture was then stirred for about 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 of the desired title product. Analytical data obtained was consistent with the proposed title structure.
WO 97/09308 PCT/US96/14163 -58- Preparation of 2-hydroxymethyl-l-[2-(l-tritylpiperidin-4-yl)ethyl]-lHindole.
Q reduction N
N
Tr' Tr' Under an argon atmosphere lithium aluminum 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 tritylpiperidin-4-yl)ethyl]indole-2-carboxylate (4.68 g, 8.52 mmol), dissolved in about 10 ml of dry tetrahydrofuran, 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 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 magnesium sulfate and the solvents were removed in vacuo to yield 3.96 grams of the title product as a foam.
Analytical data obtained was consistent with the proposed title structure.
Preparation of 2-hydroxymethyl-l-[3-(l-tritylpiperidin-3-yl)propyl]- 1Hindole.
WO 97/09308 PCT/US96/14163 -59-
OCH
3
OH
reduction N Tr N' Tr Under an argon atmosphere methyl 1-[3-(l-tritylpiperidin-3yl)propyl]indole-2-carboxylate (3.38 g, 6.23 mmol) was dissolved in 3.1 ml of dry tetrahydrofuran. The reaction vessel was then placed in an ice bath and lithium aluminum hydride (0.236 g, 6.23 mmol) was added.
The resulting mixture 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 of the title product as a foam. Analytical data obtained was consistent with the proposed title structure.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-[2-(1-tritylpiperidin-4yl)ethyl]-lH-indole.
QyOH Oalkyla alkylation WO 97/09308 PCT/US96/14163 Under an argon atmosphere 2-hydroxymethyl-l-[2-(1tritylpiperidin-4-yl)ethyl]-1H-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 added and the resulting mixture was stirred at room temperature for about 30 minutes. To the reaction mixture l-chloro-4-fluorobenzene (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 solids were collected by filtration. After a washing 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 Analytical data obtained was consistent with the proposed title structure.
Preparation of 2 -[(4-chlorophenoxy)methyl]-1-[3-(1-tritylpiperidin-3yl)propyl]-lH-indole.
OH 0 alkylation N
N
N Tr Tr Under an argon atmosphere 2 -hydroxymethyl-l-[3-(1tritylpiperidin-3-yl)propyl]-lH-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 sodium hydride (0.247 g of a 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) WO 97/09308 PCTIUS96/14163 -61 was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then heated to 80 0 C and maintained at this temperature for about eight hours. The reaction mixture was then cooled to room temperature and stirred at this temperature overnight. Another half equivalence of sodium hydride was added and the reaction mixture was stirred at room temperature overnight again. Another half equivalence of l-chloro-4-fluorobenzene was added and the reaction mixture was heated to 80 0
C.
The reaction mixture was poured into ice water and then partitioned between methylene chloride and brine. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined, washed with brine, and dried over sodium sulfate. The desired product was further purified by chromatography to yield grams Analytical data obtained was consistent with the proposed title structure.
Preparation of 2-[(4-chlorophenoxy)methyl]- l-[2-(piperidin-4-yl)ethyl]-1Hindole (Example 137) SCl Cl N O' deprotection Nd Tr
N
r
H
Under an argon atmosphere 2 4 -chlorophenoxy)methyl]-l- 2 -(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.
WO 97/09308 PCT/US96/14163 -62- 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 vacuo to yield a foam. The desired product was further purified by chromatography to yield 0.1864 grams NMR was consistent with the proposed title structure.
FDMS 368 Analysis for C 2 2
H
25 C1N 2 0: 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]-l-[3-(piperidin-3-yl)propyl]- 1H-indole. (Example 139) \H o deprotection N
NH
N Tr The title compound was prepared essentially as described above for 2-[(4-chlorophenoxy)methyl]- l-[2-(piperidin-4-yl)ethyl]-1Hindole except that an equimolar amount of 2 -[(4-chlorophenoxy)methyl]- 1-[3-(1-tritylpiperidin-3-yl)propyl]-lH-indole was employed instead of the 2 -[(4-chlorophenoxy)methyl]- -tritylpiperidin-4-yl)ethyl]- 1H-indole employed therein.
NMR was consistent with the proposed title strucuture. Single compound of high purity as evidenced by chromatographic methods.
WO 97/09308 PCT/US96/14163 -63- Preparation of 3 -bromo-2-[(4-chlorophenoxy)methyl]-l-[3-(ltritylpiperidin-3-yl)propyl]- H-indole.
OB r C1 Cl halogenation Tr Tr Under an argon atmosphere in a round bottom flask chlorophenoxy)methyl]- 1-[3-(1-tritylpiperidin-3-yl)propyl]- 1H-indole (0.992 g, 1.59 mmol) was dissolved in 4.0 ml of dry tetrahydrofuran. The 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 mixture was poured over water in which 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 of the desired compound. The solvents were removed in vacuo from the mother liquor and the resulting residue was recrystallized in ethyl acetate and hexanes to obtain an additional 0.65 grams of the desired material. Analytical data obtained was consistent with the proposed title structure.
Preparation of (RS) 2-[(4-chlorophenoxy)methyl]-l-[3-(1-tritylpiperidin-3yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-1H-indole.
WO 97/09308 PCT/US96/14163 -64-
C
Br O Cl
N
SH
3 C\ o
H
3 CO N j- N\)
N.
Tr Under an argon atmosphere in a round bottom flask, 3bromo-2-[(4-chlorophenoxy)methyl]-1-[3-(l-tritylpiperidin-3-yl)propyl]- 1H-indole (0.225 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 mixture was stirred for 35 minutes in the dry ice/acetone bath.
To this reaction mixture was added the Weinreb amide Nmethyl-N-methoxy-[4-(piperidin-l-yl)piperidin-l-yl]acetamide (0.0903 g, 0.335 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.
Preparation of (RS) 2 -[(4-chlorophenoxy)methyl]-l-[3-(piperidin-3yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-1H-indole. (Example WO 97/09308 PCT/US96/14163 ND N 0 0 0N o 0 r deprotection Ni Tr
A
H
Under an argon atmosphere (RS) chlorophenoxy)methyl]-l1-[3-(l-tritylpiperidin-3-yl)propyl]-3-[[4- (piperidin-l-yl)piperidin-l-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 chromatography. The reaction mixture was then stirred at room temperature for two additional hours and then an additional 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 1 for C 3 5
H
48 C1N 4 0 2 Theory: 591.3476.
Found: 591.3476.
WO 97/09308 PCT/US96/14163 -66- MethodF Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2- (piperidin-1-yl)ethyl]-1H-indole (Example 47) ND HO S reduction
CH
3 Cl CH 3
C
Under an argon atmosphere a round bottom flask was charged with 2-[(4-chlorophenoxy)methyl]- -methyl-3-[l-(piperidin- -yl)- 1,2-ethanedionyl]-lH-indole (Example 100) (0.203 g, 0.493 mmol), dissolved in 2.0 ml of dry tetrahydrofuran. Lithium aluminum hydride ml of a 1.0 M solution in tetrahydrofuran) was then added. The resulting mixture was then heated 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 mixture 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 NMR was consistent with the proposed title structure.
FDMS 398 Analysis for C 2 3
H
2 7 C1N 2 0 2 Theory: C, 69.25; H, 6.82; N, 7.02.
WO 97/09308 WO 9709308PCTIUS96/14163 -67- Found: C, 69.51; H, 6.86; N, 6.81.
Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[1-hydroxy-2-(4.
methylpiperidin- 1-yl)ethylllH-indole (Example 48) and cblorophenoxy)methyl]- l-methyl-3-[2-(4-methylpiperidin-.1-yl)ethyl]- iRindole (Example 33) reduction
CH
3
CH
3 Under a nitrogen atmosphere a round bottom flask was charged with 2- [(4-chlorophenoxy)methyl]- 1-methyl-3-[ l-(piperidin- 1-yl)- 1,2ethanedionyl]-1H-indole (Example 100) (0.305 g, 0.824 mmol). Boranetetrahydrofuran 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 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.
WO 97/09308 PCT/US96/14163 -68- To the reaction mixture was added ethanol, sodium carbonate, and cesium fluoride, and the resulting mixture was heated to reflux and maintained at this temperature overnight. The reaction mixture was partitioned between 10% sodium carbonate and methylene chloride. The aqueous fraction was extracted twice more with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired products were further purified by radial chromatography.
2 4 -chlorophenoxy)methyl]-l-methyl-3-[2-(4-methylpiperidin-1-yl)ethyl]- 1H-indole (Example 33) NMR was consistent with the proposed title structure.
FDMS 396 Analysis for C 24
H
2 9 C1N 2 0: Theory: C, 72.62; H, 7.36; N, 7.06.
Found: C, 72.40; H, 7.35; N, 7.25.
2 -[(4-chlorophenoxy)methyl]- -methyl-3-[1-hydroxy-2-(4-methylpiperidin-1-yl)ethyl]-1H-indole (Example 48) NMR was consistent with the proposed title structure.
FDMS 412 Analysis for C 2 4
H
29 C1N 2 0 2 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]- -methyl-3-[ -hydroxy-2- [N-methyl-N-(l-methylpiperidin-4-yl)amino]ethyl]-1H-indole (Example 54) and 2-[(2,4-dichlorophenoxy)methyl]-l- methyl-3-[2-[NmethylN(1methylpiperidin-4-yl)amino]ethyl]-lH-indole (Example 38) WO 97/09308 PCT/US96/14163 -69-
H
3
C
HC
N-CH
3
H
3 C Cl O N-CH 3 CH 3 \0 reduction ,N OH 3 C.
CH
3 HO H N-\NCH3
CH
3
C
1 Under a nitrogen atmosphere a round bottom flask was charged with 2 -[(2,4-dichlorophenoxy)methyl]-l-methyl-3-[2-[N-methyl- N-(l-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 stirred for about one hour and then 0.33 ml of a 1:1 tetrahydrofuran: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 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.
WO 97/09308 WO 9709308PCTIUS96/1 4163 2-[(2,4-dichlorophenoxy)methyl.. -methyl-3- [2-[N-methyl-N.( 1methylpiperidin-4-yl)aminolethyl.. H-indole (Example 38) NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 459 Analysis for C 25
H
3 1 C1 2
N
3 0: 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-hydroxy-2-[N-methyl-N( 1methylpiperidin-4-yl)aniinolethyl.. H-indole (Example 54) NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 475 Analysis for C 25
H
3 1C1 2
N
3 0 2 Theory: C, 63.02; H, 6.55; N, 8.82.
Found: C, 63.43; H, 6.88; N, 8.92.
Preparation of 2 -I(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[(3dimethylarninopropyl)amnolethyl.. H-indole (Example 30) and chlorophenoxy)methyl]- 1-methyl-3-[[[3- (dimethylamino )propylaminolcarbonyllmethyl.. H-indole (Example 76) WO 97/09308 PCT/US96/14163 -71-
N(CH
3 2
H
N-1
N(CH
3 2 H CH cl IO reduction N
N(CH
3 2
CH
3 k 'C1
H
CH
3 0 Cl Under a nitrogen atmosphere borane-tetrahydrofuran complex (7.42 ml of a 1.0 M solution in THF, 7.42 mmol) was added to a round bottom flask containing 2 4 -chlorophenoxy)methyl]l--methyl-3- 2 -[3-(dimethylamino)propylamino]-1,2-ethanedionyl]-1H-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 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 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 vacuo. The desired products were further purified by chromatography.
WO 97/09308 PCT/US96/14163 -72- 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[(3dimethylaminopropyl)amino]ethyl]-lH-indole (Example NMR (CDC13) was consistent with the proposed title structure.
FDMS 399 Analysis for C 2 3
H
3 oC1N 3 0: 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 (Example 76) NMR (CDC13) was consistent with the proposed title structure.
FDMS 413 Analysis for C 23
H
2 8 C1N 3 0 2 Theory: C, 66.74; H, 6.82; N, 10.15.
Found: C, 66.89; H, 6.96; N, 10.11.
Method H Preparation of 3 -bromo-2-[(4-chlorophenoxy)methyl]-1-methyl-1H-indole halogenation Br
CH
3 s OCl CH3 OCl Under an argon atmosphere in a round bottom flask chlorophenoxy)methyl]-l-methyl-lH-indole (5.0 g, 18.40 mmol) was dissolved in 46 ml of tetrahydrofuran. To this solution was added Nbromosuccinimide (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.
WO 97/09308 PCT/US96/14163 -73- 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 were removed in vacuo.
The desired title product was recrystallized from ethyl acetate. Yield: 5.36 g Analytical data obtained was consistent with the proposed title structure.
Preparation of 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(1tritylpiperidin-4-yl)ethyl]carbonyl]-1H-indole Br Q- N- Tr _Br cylation
CH
3 Cl CH C1 Under an argon atmosphere in a round bottom flask, 3bromo-2-[(4-chlorophenoxy)methyl]-l-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, N-methyl-N-methoxy-[2-(l-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 methanol/dry 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.
Analytical data obtained was consistent with the proposed title structure.
WO 97/09308 PCT/US96/14163 -74- Preparation of 2-[(4-chlorophenoxy)methyl]- -methyl-3-[[2-(piperidin-4yl)ethyl]carbonyl]-lH-indole (Example 67) 0 N- Tr O N 0O deprotection J 0 CH3 Cl CH Under an argon atmosphere 2 4 -chlorophenoxy)methyl]-1methyl-3-[[2-(1-tritylpiperidin-4-yl)ethyl]carbonyl]-1H-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 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 (CDC13) was consistent with the proposed title structure.
FDMS411 (M+1) Analysis for C 2 4
H
2 7 C1N 2 0 2 Theory: C, 70.15; H, 6.62; N, 6.82.
Found: C, 69.87; H, 6.54; N, 6.79.
Method I Preparation of 2-[(4-chlorophenoxy)methyl]-l-methyl-3-carboxy-lHindole WO 97/09308 PCT/US96/14163 Br OH CHs C
CH
3 OCl Under an argon atmosphere 2 4 -chlorophenoxy)methyl]-1methyl-3-carboxy-1H-indole (0.500 g, 1.426 mmol) was dissolved in 14.3 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 mixture for about ten minutes and then the mixture was stirred for an additional ten minutes. The reaction vessel was then placed on a methanol/ice/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 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%) Analysis for C 17
H
14 C1NO 3 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]- -methyl-3-[[N,N-bis(3dimethylaminopropyl)amino]carbonyl]-lH-indole (Example 58) WO 97/09308 PCT/US96/14163 -76-
N(CH
3 2
N
OH N- N(CH3)2 C3 H 3
O
3 -Cl Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1methyl-3-carboxy-lH-indole (0.100 g, 0.317 mmol) was dissolved in 3.2 ml of N,N-dimethylformamide. To this solution were added N,N-bis(3dimethylaminopropyl)amine (0.074 ml, 0.0623 g, 0.332 mmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.091 g, 0.475 mmol), and hydroxybenztriazole (0.0642 g, 0.475 mmol). The resulting mixture was then heated for 6 hours and then stirred at room 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 and dried over sodium sulfate. The solvents were removed in vacuo.
The desired title product was further purified by radial chromatography.
NMR (CDC13) was consistent with the proposed title structure.
FDMS 483 FABMS 485 (M+1) Analysis for C 2 7
H
3 7 C1N 4 0 2 Theory: C, 66.86; H, 7.69; N, 11.55.
Found: C, 66.91; H, 7.54; N, 11.69.
Method J Preparation of 2 -[(4-chlorophenoxy)methyl]- -methyl-3-[[2-[ tritylpiperidin-3-yl)propyl]piperidin-4-yl]]ethyl]carbonyl]- H-indole (Example 69 B) WO 97/09308 WO 9709308PCTIUS96/14163 -77- Tr 0 NHl 0 0 N 0~ 6H 3 N#C1 N
CH
3 Tr Under a nitrogen a 10 ml round bottom flask was charged with 2 4 -chlorophenoxy)methyl-1-methyl-3-[[(piperilin.4 yl)ethyllcarbonyl]- 1H-indole (0.091 g, 0.222 mmol), l-tritylpiperidin-3yl)propyl iodide (0.110 g, 0.2224 mmol), potassium carbonate (0.0450 g, 0.3255 mmol), and 1.5 ml of anhydrous N,N-dimethylformamide. The resulting mixture was stirred overnight and then poured into ice water.
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 FDMS 779 Analysis for C 5 1
H
5 6
CIN
3 0 2 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-I[2-[ 1-[3- (piperidin-3-yl)propyllpiperidin-4-y1]]ethyllcarbonyl.. H-indole (Example 69C) Tr
H
N
N
0 N 0N I~Jdeprotection
N
6H 3 Cl
CH
3 Cl Under a nitrogen atmosphere in a round bottom flask chlorophenoxy)methyl]- 1-methyl-3-[[2-[ 1-tritylpiperidin-3- WO 97/09308 PCT/US96/14163 -78yl)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 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 combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
NMR (CDC13) was consistent with the proposed title structure.
FDMS 536 Analysis for C 32
H
4 2 C1N 3 0 2 Theory: C, 71.69; H, 7.90; N, 7.84.
Found: C, 71.45; H, 7.85; N, 7.61.
Method K Preparation of 2-[(4-chlorophenoxy)methyl]-l-methyl-3-formyl-1H-indole (Example 236) 0
H
N K CJ 6B 3 CHCl 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 0 C bath and then phosphorous oxychloride (0.187 ml, 0.310 g, 2.02 mmol) was carefully added. The resulting mixture was stirred in an ice bath for about twenty minutes and 2 -[(4-chlorophenoxy)methyl]-l-methyl-1H-indole (0.50 g, 1.84 mmol) WO 97/09308 PCT/US96/14163 -79in 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 0 C and maintained 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 (CDC13) was consistent with the proposed title structure.
FDMS 299 Analysis for C 17
H
14 C1N0 2 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]-l-methyl-3-[ -hydroxy-2- (methoxycarbonyl)ethyl]-lH-indole (Example 0
H
O
CH
3 CCH 3 O C CH3 Under a nitrogen atmosphere a round bottom flask was charged with 6.7 ml of dry tetrahydrofuran. 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 nbutyllithium (0.88 ml of a 1.6 M solution in hexanes, 1.401 mmol) and the resulting mixture was stirred in an ice bath for about 15 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 then placed in an ice bath for about 30 minutes. The reaction mixture WO 97/09308 PCT/US96/14163 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 further by radial chromatography.
NMR (CDC13) was consistent with the proposed title structure.
IR was consistent with the desired title structure. FDMS 373 Analysis for C 2 0
H
2 0 C1N0 4 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]-l-methyl-1H-indol-3yl}prop-2-enoic acid O ,CH 3 0 HO 0 OH
CH
3 0 -Cl CH3 O C1 Under a nitrogen atmosphere a round bottom flask is charged with 2-[(2,4-dichlorophenoxy)methyl]-l-methyl-3-[l-hydroxy-2- (methoxycarbonyl)ethyl]-1H-indole (Example 55) (0.149 g, 0.398 mmol) and 6.11 ml of dry tetrahydrofuran. To this solution is added 1.22 ml of a 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 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.
WO 97/09308 PCT/US96/14163 -81- Preparation of 2-[(4-chlorophenoxy)methyl]-l-methyl-3-[2-[[4- (dimethylamino)piperidin-l-yl]carbonyl]ethenyl]- H-indole (Example 44) O OH O ND-N(CH3) 2
CH
3 C cl
H
3 O C Under a nitrogen atmosphere dimethylaminopiperidine was dissolved in 3.0 ml of methylene chloride. To this solution were added 3-(2-[(4-chlorophenoxy)methyl]- -methyl-1H-indol-3-yl}prop-2enoic acid (0.050 g, 0.1462 mmol) and l-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (0.0356 g, 0.278 mmol). The resulting mixture 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 sodium hydroxide and extracted twice 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 (CDC1 3 was consistent with the proposed title structure.
Exact Mass for C 26
H
3 oC1N 3 0 2 Theory: 452.2105.
Found: 452.2099.
Method L Preparation of 2-[(4-chlorophenoxy)methyl]-l-methyl-3-[2- (methoxycarbonyl)ethyl]-1H-indole WO 97/09308 PCT/US96/14163 -82- O dCH 3 O ,CH 3 4\ reduction CH3 O'Cl CH
C
A round bottom flask was charged with 10% palladium on activated carbon (0.150 20 ml of N,N-dimethylformamide and chlorophenoxy)methyl]-1-methyl-3-[2-(methoxycarbonyl)ethenyl]-1Hindole (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 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.
Preparation of 3-{2-[(4-chlorophenoxy)methyl]- -methyl-1H-indol-3yl)propanoic acid O ,CH 0 O O OH hydrolysis CH3 C CH3 Cl Under a nitrogen atmosphere in a round bottom flask chlorophenoxy)methyl]-l-methyl-3-[2-(methoxycarbonyl)ethyl]-1H-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.
WO 97/09308 PCTIUS96/1416-3 -83- 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 combined, washed with brine, and dried over sodium sulfate. The solvents were removed in vacuo to yield the desired title product. Yield 0.2984 grams Preparation of 2-[(4-chlorophenoxy)methyl]-l-methyl-3-[2-[[4- (dimethylamino)piperidin-1-yl]carbonyl]ethyl]-1H-indole (Example 43).
0 OH N N \CH3 H- CH3 CHs O Cl CH3 "OCl Under a nitrogen atmosphere chlorophenoxy)methyl]-1-methyl-1H-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 mixture was then heated to 65°C and maintained at this temperature for about 35 minutes. To this reaction mixture dimethylaminopiperidine (0.112 g, 0.874 mmol), dissolved in about 3.6 ml of tetrahydrofuran. This mixture was stirred at room temperature overnight.
The reaction mixture was then heated to 60 0 C and maintained 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 WO 97/09308 PCT/US96/14163 -84solvents were removed in vacuo. The desired title product was further purified by chromatography.
NMR (CDC13) was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 453 Analysis for C 2 6
H
32 C1N 3 0 2 Theory: C, 68.78; H, 7.10; N, 9.26.
Found: C, 68.74; H, 7.04; N, 9.38.
Method M Preparation of 2-[(4-chlorophenoxy)methyl]-l-methyl-3-[3-[4-(N,Ndimethylamino)piperidin-1-yl]propyl]-lH-indole (Example 41).
0^ CH3 ON N Na
N
C
3 -OCl
CH
3 Cl Under a nitrogen atmosphere around bottom flask is charged with 2-[(4-chlorophenoxy)methyl]-l-methyl-3-[2-[[4- (dimethylamino)piperidin-l-yl]carbonyl]ethyl]-lH-indole (0.194 g, 0.428 mmol). The flask was then placed in an ice bath and boranetetrahydrofuran 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 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 WO 97/09308 PCT/US96/14163 washed with brine and dried over sodium sulfate. The solvents were removed in vacuo.
NMR (CDC13) was consistent with the proposed title structure.
FABMS 440 (M+1) IR was consistent with the desired title structure.
Analysis for C 26
H
34 C1N 3 0: Theory: C, 70.97; H, 7.79; N, 9.55.
Found: C, 70.73; H, 7.65; N, 9.44.
Method N Preparation of 2 -[(4-chlorophenoxy)methyl]-l-methyl-3-[3-(piperidin-3yl)propyl]-lH-indole (Example 42) and 1,2-dimethyl-3-[3-(piperidin-3yl)propyl]-lH-indole (Example 237) N
CH
3 CHs Under a nitrogen atmosphere 2 4 -chlorophenoxy)methyl]- 1-methyl-3-[3-(piperidin-3-yl)propanoyl]-lH-indole (0.0737 g, 0.1793 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 was monitored by thin layer chromatography. A 1:1 tetrahydrofuran:water mixture (0.3 ml) was then added as well as 1.5 ml of 5.0 N sodium WO 97/09308 PCT/US96/14163 -86hydroxide. The reaction mixture was heated to 85 0 C and maintained at this temperature overnight, and then briefly raised to 225 0
C.
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 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 Examples 42 and 237, infra).
Preparation of 2,4-dichloro- -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 admixed 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 bis(triphenylphosphine)palladium(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 1M potassium carbonate and ethyl acetate. The aqueous WO 97/09308 PCT/US96/14163 -87fraction 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-l-(2-bromoethen-l-yl)benzene Br C1 Cl In a 100 ml round bottom flask borane tetrahydrofuran complex (1M 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, 9.65 mmol) was added dropwise and the mixture was slowly warmed to ambient temperature and stirred at ambient temperature for one hour. The reaction mixture was diluted with hexamethylphosphoramide (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 g1, 4.82 mol). The resulting mixture was stirred at ambient temperature for six hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was diluted with brine and extracted thrice with diethyl ether.
The organic fractions were combined 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 the proposed title structure.
Preparation of 4-hydroxy-N-isopropylbutylamine WO 97/09308 PCT/US96/14163 88-
H
HoN y C H 3
CH
3 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 and sodium acetoxyborohydride (11.9 g, 56.09 mmol). The cloudy mixture was stirred at ambient temperature for about 18 hours. The reaction was quenched with saturated sodium bicarbonate. Sodium hydroxide (1 M) was added to adjust the pH to about 10. The aqueous layer was extracted with a mixture of isopropyl alcohol and methylene chloride 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-isopropylbutylamine BoC HO N
O
C H 3
CH
3 A solution of 4 -hydroxy-N-isopropylbutylamine (3.0 g, 22.8 mmol) in dioxane:water:1N 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 of a colorless oil.
Preparation of WO 97/09308 PCT/US96/14163 -89- F
O
H
Cl Lithium diisopropylamide was prepared by admixing diisopropylamine (5.79 ml, 41.3 mmol) in 5 ml of tetrahydrofuran. The resulting mixture was cooled to -78°C and treated with n-butyllithium in such a manner that the temperature did not raise above 64 0 C. After stirring the suspension for 45 minutes, the remainder of the tetrahydrofuran was added (70 ml), followed by the dropwise addition of 4-chlorophenyl fluoride (4.0 ml, 37.6 mmol). After 45 minutes N,Ndimethylformamide was added, also in a dropwise fashion. The resulting reaction mixture was stirred an additional ten minutes prior to quenching with acetic acid 6ml), followed by water (100 ml). The cold mixture was transferred to a separatory funnel and extracted twice with methylene chloride. The organic fractions were combined, dried over 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 0
C.
Preparation of 2-fluoro-5-methylbenzyl alcohol
F
-OH
CH
3 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 with sodium borohydride (0.93 g, 24.6 mmol). The reaction was slowly WO 97/09308 PCT/US96/14163 warmed to ambient 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 was further purified by high performance liquid chromatography to yield 1.3 grams of a clear oil.
Preparation of 2-fluoro-5-chlorobenzyl alcohol
'OH
The title intermediate was prepared essentially as was 2alcohol, supra, except that an equimolar amount of 2 -fluoro-5-chlorobenzaldehyde was employed instead of the methylbenzaldehyde employed therein.
Yield: 2.16 grams as a clear oil.
Preparation of 2-fluoro-5-chlorobenzyl bromide 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).
The resultant suspension was stirred for 3.5 hours, then filtered, WO 97/09308 PCT/US96/14163 -91washing 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
I
O CH3
CH
3 A solution of N-(t-butoxycarbonyl)-4-hydroxy-Nisopropylbutylamine (539 mg, 2.33 mmol) in tetrahydrofuran (11 ml) at was treated with potassium t-butoxide (1 M in tetrahydrofuran, 2.54 ml, 2.54 mmol). After 40 minutes, the suspension was cooled to -78 0 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 sulfate, filtered, and concentrated. The crude oil was purified by liquid chromatography to yield 555 mg of the title intermediate as a clear oil.
Preparation of 4 2 (isopropyl)butylamine BoC
I
CH
3 WO 97/09308 PCT/US96/14163 -92- The title intermediate was prep ared essentially as described supra for 4-( 2 -fluorobenzyloxy)-N-(t-butoxycarbonyl)-N.
(isopropyl)butylamine, except that an equimolar amount of chlorobenzyl bromide was employed instead of the 2-fluorobenzyl bromide employed therein.
Yield 237 mg Preparation of 4 2 -fluorobenzyloxy)-N-(isopropyl)butylamine F
H
yCH 3
CH
3 The desired intermediate was prepared from the deprotection of 4 2 -fluorobenzyloxy)-N-(t-butoxycarbonyl)-N (isopropyl~butylaine using standard techniques. The 4-(2flooezlx)N(-uoyabnl--iorplbtlmn was admixed 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-cbloro- 2 -fluorobenzyloxy)-N-(isopropyl)butylamine F
H
yCH 3
OH
3 The desired intermediate was prepared essentially as described for the 4 2 -fluorobenzyloxy)-N-(isopropyl)butylamine above, except that an equimolar amount of 4 -chloro-2-fluorobenzyloxy)-N-(t.
butoxycarbonyl)-N-(isopropyl)butylamine was employed in place of the 4- WO 97/09308 PCT/US96/14163 -93- 2 -fluorobenzyloxy)-N-(t-butoxycarbonyl)-N-(isopropyl)butylamine employed therein.
Yield: 138 mg Preparation of 3-(5-bromo-2-fluorobenzyloxy)-l-[l-(tbutoxycarbonyl)piperidin-2-yl]propane F BoC 0 N Br 3 -[l-(t-Butoxycarbonyl)piperidin-2-yl]propanol (800 mg, 3.29 mmol) was taken up in tetrahydrofuran (17 ml), cooled to -400C, and treated with potassium t-butoxide (1 M in tetrahydrofuran, 3.62 ml, 3.62 mmol). The resulting mixture was stirred at -40 0 C for about 35 minutes, then cooled to -78 0 C. To this mixture was then added 5-bromo-2fluorobenzyl bromide (881 mg, 3.29 mmol) as a solution in tetrahydrofuran (5 ml). The resultant yellow reaction mixture 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 sodium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by high performance liquid chromatography, yielding 707 mg of the title intermediate as a clear oil.
Analysis for C 2 0
H
2 9 BrFNO 3 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)-l-(piperidin-2-yl)propane WO 97/09308 PCT/US96/14163 -94- F
H
Br 3 -(5-Bromo-2-fluorobenzyloxy)-l-[l-(tbutoxycarbonyl)piperidin-2-yl]propane (590 mg, 1.37 mmol) was dissolved in methylene chloride (11 ml), cooled to o0C, and treated with 3 ml of trifluoroacetic acid. The reaction mixture was stirred at o0C for 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.
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 The resulting intermediate was used without further purification.
Preparation of 2-fluoro-5-bromobenzyl bromide
F
SBr Br 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 desired title product was further purified by bulb to bulb distillation [150°C, 5 mm Hg (house vacuum)]. Yield: 24.36 grams of a white, low melting solid.
WO 97/09308 PCT/US96/14163 Preparation of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol)
F
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-dihydroxy-2-butyne (20.0 g, 232 mmol) and sodium hydride (15.6 g of a 60% solution, 58.1 mmol). The resulting mixture 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 Preparation of 4 2
F
Br A solution of 1,4-dihydroxybutane (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 reaction mixture was then stirred for four hours at ambient temperature. The reaction was quenched with water. The aqueous WO 97/09308 PCT/US96/14163 -96fraction was 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: 1.8 grams as a clear oil. %max 271 nm.
Analysis for Cn 1
H
1 4 BrFO 2 Theory: C, 47.67; H, 5.09; Br, 28.83.
Found: C, 47.37; H, 5.15; Br, 28.55.
Preparation of N-(t-butoxycarbonyl)- 4 2 -fluoro-5-bromobenzyloxy)-3,3dimethylbutylamine
F
H
O N BoC H3C
CH
3 Br A stirred solution of 4 -(t-butoxycarbonylamino)-2,2dimethylbutan-1-ol (1.5 g, 6.90 mmol) in tetrahydrofuran (49 ml) at was treated with potassium t-butoxide (1 M in tetrahydrofuran, 7.59 ml, 7.59 mmol). The anion was stirred for 30 minutes at -45°C, then cooled to -78 0 C and treated with a tetrahydrofuran solution of 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 removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.45 grams of the title intermediate as a colorless oil.
Preparation of N-(t-butoxycarbonyl)-4-( 2 -fluoro-5-bromobenzyloxy)-2,2dimethylbutylamine WO 97/09308 PCT/US96/14163 -97- F HC H 3 S, H F O BoC Br A stirred solution of 4-(t-butoxycarbonylamino)-3,3dimethylbutan-1-ol (1.0 g, 4.60 mmol) in tetrahydrofuran (33 ml) at -450C was treated with potassium t-butoxide (1 M in tetrahydrofuran, 5.06 ml, 5.06 mmol). The anion was stirred for 30 minutes at -450C, then cooled to -78°C and treated with a tetrahydrofuran solution of 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 cloudy 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 of the title intermediate as a colorless oil.
Preparation of 2 -[(t-butoxycarbonyl)amino]-5-(2-fluoro-5bromobenzyloxy)-2-methylpentane
F
H
O N--BoC
H
3 C
CH
3 Br A stirred solution of 4-(t-butoxycarbonylamino)-4,4dimethylbutan-1-ol (1.11 g, 5.11 mmol) in tetrahydrofuran (49 ml) at was treated with potassium t-butoxide (1 M in tetrahydrofuran, 5.62 ml, 5.62 mmol). The anion was stirred for 30 minutes at -450C, then WO 97/09308 PCT/US96/14163 -98cooled to -78 0 C and treated with a tetrahydrofuran solution of 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 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 of the title intermediate as a colorless oil.
Preparation of trans- 4 -(t-butoxycarbonylamino)cyclohexanol
H
HOI"'" C BoC To a solution of trans-4-aminocyclohexanol (5.00 g, 33.0 mmol) in dioxane (132 ml), water (41 ml) and 1 N sodium hydroxide (41 ml) was added t-butoxycarbonyl 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 mixture was thrice extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, and concentrated in vacuo. The desired title intermediate was recrystallized from hexanes/ethyl acetate to yield 6.5 grams MS 216.24 Analysis for C 1 1
H
2 1N0 3 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)-l-[2-fluoro-5bromobenzyloxy]}cyclohexane WO 97/09308 PCT/US96/14163 -99- F
H
NN
-BoC Br A solution of trans-{ 4 -(butoxycarbonylamino))cyclohexanol (550 mg, 2.32 mmol) in dry tetrahydrofuran (16.6 ml) was cooled to -40 0
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 -78C, and treated with 2 bromide (622 mg, 2.32 mmol). The resulting yellow mixture was gradually warmed to 0°C and stirred for about two hours. 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 residue was purified further by high performance liquid chromatography to yield 558 mg of the desired title intermediate as a white solid.
Analysis for C 18
H
2 5 BrFNO 3 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- -(t-butoxycarbonyl)pyrrolidin-2-one
O
1C. N-BoC The desired intermediate was prepared essentially as described in F. Scheinmann and A.V. Stachulski, Journal of Chemical Research, 1993:414 (1993). A solution of 3-methyl-l-(tbutoxycarbonyl)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(CH 3 2 2 (56.3 ml, 56.3 mmol) and stirred for about 50 minutes WO 97/09308 PCT/US96/14163 -100prior to quenching 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), 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 of the title intermediate as a semi-solid. NMR was consistent with the title structure.
Preparation of 4 -(t-butoxycarbonylamino)-2,2-dimethylbutanol
H
HO N BoC
H
3 C CH 3 A solution of 3,3-dimethyl- l-(t-butoxycarbonyl)pyrrolidin-2one (3.35 g, 15.7 mmol) in absolute ethanol under a nitrogen atmosphere was treated with sodium 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 of the title intermediate as a clear oil. mp 75.5-76.5 0
C.
Preparation of 4-( 2 -fluoro-5-bromobenzyloxy)-l-methoxybut-2-yne WO 97/09308 PCT/US96/14163 -101-
F
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 0
C
and then treated with potassium 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 0 C and treated with methyl iodide (0.49 ml, 7.84 mmol). The reaction was warmed to 0°C and stirred for 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 as a clear oil.
Preparation of 4 2 -fluoro-5-bromobenzyloxy)-but-2-ynyl bromide
F
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 as a clear oil.
WO 97/09308 PCT/US96/14163 -102- 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
H
CH3
K-
Br A solution of aminomethane (89 ml of a 2 M solution in tetrahydrofuran, 178 mmol) was added to a solution of 4-(2-fluoro-5bromobenzyloxy)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 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 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 of the title intermediate as a yellow oil. NMR was consistent with the title structure.
Preparation of N-benzyl-4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl amine WO 97/09308 PCT/US96/14163 -103 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 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 were removed in vacuo. The resulting oil was further purified by flash chromatography, affording 200 mg of the title intermediate.
Preparation of N-isopropyl-4-(2-fluoro-5-bromobenzyloxy)but-2-yny amine
F
H
OY N
CH
3
CH
3 Br A solution of isopropylamine (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 of the title intermediate.
NMR was consistent with the title structure.
WO 97/09308 PCT/US96/14163 -104- Preparation of N-cyclopropyl-4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl amine
F
H
l N Br A solution of cyclopropylamine (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 tetrahydrofuran (8 ml). The cloudy reaction mixture was stirred for about thrity minutes. The reaction mixture was 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 of the title intermediate as a clear oil.
Preparation of 4 ,5-dihydro- 2 F 0 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 WO 97/09308 PCT/US96/14163 -105thin layer chromatography. After one hour of stirring, no starting material was visible. The reaction mixture 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, and concentrated to a white solid. The solid was dissolved in 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 chromatography, yielding 260 mg as a yellow oil.
Preparation of F O CH3
CH
3 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,N-dimethylformamide.
The resulting clear solution was stirred for about three hours. The 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 mixture was diluted with methylene chloride, and washed with saturated sodium bicarbonate and brine. The organic fraciton was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title product was further purified by liquid chromatography. Yield: 632 mg as a clear oil.
Preparation of 1-methoxy-4-( 2 WO 97/09308 PCT/US96/14163 -106-
F
O OCH 3 Br A solution of 4 2 -fluoro-5-bromobenzyloxy)butanol (897 mg, 3.24 mmol) in tetrahydrofuran (22 ml) was cooled to -40 0 C and then 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 0 C and treated with methyl iodide (0.40 ml, 6.48 mmol). The reaction was warmed to o0C and stirred for 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 687 mg as a clear oil.
FDMS 291.99 Preparation of 4 -(2-fluoro-5-bromobenzyloxy)butyl bromide
F
o Br 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 as a clear oil.
WO 97/09308 PCT/US96/14163 -107- Elemental analysis and NMR were consistent with the proposed title structure.
Preparation of N,N-dimethyl-4-(2-fluoro-5-bromobenzyloxy)butylamine 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 tetrahydrofuran (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 as a pale yellow oil.
Preparation of N-ethyl-4-( 2 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 (242 mg, 1.6 mmol). The resulting mixture was stirred at ambient temperature. After 1.5 hours, the sodium bromide was removed by WO 97/09308 PCT/US96/14163 -108 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 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 as a yellow oil. NMR was consistent with the proposed title structure.
Preparation of N-isopropyl-4-(2-fluoro-5-bromobenzyloxy)butylamine F
H
O N CH 3
CH
3 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 mixture was stirred at ambient temperature. After 1.5 hours, the sodium bromide was 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 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 mg as a yellow oil.
Analysis for C14H 2 1 BrFNO: WO 97/09308 PCT/US96/14163 -109- 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)butylamine F
H
O N
CH
3
H
3 C
CH
3 Br A solution of 4 2 -fluoro-5-bromobenzyloxy)butyl bromide (400 mg, 1.18 mmol) in tetrahydrofuran (6 ml) was treated with sodium iodide (242 mg, 1.6 mmol). The resulting mixture was stirred at ambient temperature. After 1.5 hours, the sodium bromide was removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of tert-butylamine (1.24 ml, 11.8 mmol). The progress of the reaction was monitored by thin layer 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 purified by radial chromatography. Yield: 261 mg as a yellow oil.
NMR was consistent with the proposed title structure.
Preparation of 1-(piperidin-l-yl)- 4 2 Br WO 97/09308 PCT/US96/14163 -110 A solution of 4 2 -fluoro-5-bromobenzyloxy)butyl bromide (520 mg, 1.53 mmol) in tetrahydrofuran (8 ml) was treated with piperidine (1.5 ml, 15.3 mmol). The resulting reaction mixture was 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 Preparation of 1-(morpholin- 4 -yl)-4-(2-fluoro-5-bromobenzyloxy)butane 0
F
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.
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 as a clear oil.
Preparation of 1-[2-fluoro-5-bromobenzyloxy]-3-[l-(tbutoxycarbonyl)piperidin-3-yl]propane WO 97/09308 PCT/US96/14163 111 F NBoC Br An amount of 3-[l-(t-butoxycarbonyl)piperidin-3-yl]propyl bromide (180 mg, 0.588 mmol) was dissolved in N,N-dimethylformamide (1.5 ml) in a 10 ml flask under a nitrogen 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-5-bromobenzyl alcohol (121 mg, 0.588 mmol), delivered as a solution in 0.5 ml of N,N-dimethylformamide. To this mixture was then added sodium hydride 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 430.
Analysis for C 20
H
2 9 BrFNO 3 Theory: C, 55.82; H, 6.79; N, 3.26.
Found: C, 55.70; H, 6.59; N, 3.04.
Preparation of l-[ 2 -fluoro-5-bromobenzyloxy]-3-(piperidin-3-yl)propane WO 97/09308 PCT/US96/14163 -112- In a 100 ml round bottom flask, 1-[2-fluoro-5bromobenzyloxy]-3-[l-(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 dropwise. The resulting mixture was stirred at o0C 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 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: 210 mg as a clear yellow oil.
Analysis for C 16
H
2 1 BrFNO: 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 (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 filtered and washed with cold diethyl ether. The filtrate was evaporated, yielding a light yellow oil. The oil was further purified by WO 97/09308 PCT/US96/14163 -113chromatography 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 standing.
Analysis for C 7
H
6 Br 2
F:
Theory: C, 31.39; H, 1.88.
Found: C, 31.18; H, 1.91.
Preparation of N,N-dimethyl- 3
F
CH3 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 62 mg, 1.55 mmol) was then added to the propanol solution. After thirty minutes of stirring, the benzyl bromide, sodium iodide solution was added to the propanol mixture. Some frothing occurred, but quickly dissipated. The resulting mixture 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 of the title intermediate. NMR, IR, and MS were consistent with the proposed title structure.
WO 97/09308 PCT/US96/14163 -114- Analysis for C 12
H
17 BrFNO: Theory: C, 49.67; H, 5.91; N, 4.83.
Found: C, 49.46; H, 5.92; N, 4.99.
Preparation of 2
F
SO'CH3 Br In a 10 ml flask, under a nitrogen atmosphere, 2methoxyethanol (0.125 ml, 1.60 mmol) was dissolved in N,Ndimethylformamide (2 ml). Sodium hydride 72 mg, 1.81 mmol) was added and the mixture was stirred at ambient temperature for about thirty minutes. To this reaction mixture was added bromobenzyl bromide (285 mg, 1.06 mmol) as a solution in N,Ndimethylformamide (2 ml). The resulting mixture was stirred at ambient 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 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 WO 97/09308 PCT/US96/14163 -115- In a 50 ml flask, under a nitrogen atmosphere, 2-(N,Ndimethylamino)ethanol (1.319 g, 4.92 mmol) was dissolved in N,Ndimethylformamide (16 ml). Sodium hydride 335 mg, 8.37 mmol) was added and the mixture was stirred at ambient temperature for about twenty minutes. To this reaction mixture was added bromobenzyl bromide (1.319 g, 4.92 mmol) as a solution in N,Ndimethylformamide (3 ml). The resulting mixture was stirred at ambient 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 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: 1.023 g Preparation of
F
CH3
CH
3 Br In a 50 ml flask, under a nitrogen atmosphere, bromobenzyl bromide (1.264 g, 4.72 mmol) was dissolved in methanol ml). Dimethylamine (8 M in H 2 0, 1.77 ml, 14.2 mmol) was added as a solution in methanol (5 ml), and the resulting mixture was stirred at 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, washed with brine (7 X) and dried over sodium sulfate. The solvents WO 97/09308 PCT/US96/14163 -116were removed in vacuo. The title intermediate was used without further purification. Yield: 0.987 g Preparation of 2 2
F
H
o |N CHs Br In a 50 ml flask, under a nitrogen atmosphere, 2-(2-fluoro- (317 mg, 1.15 mmol) was 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 the reaction mixture and the resulting mixture was stirred at ambient temperature for about three days. The mixture 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 was used without further purification. Yield: 210 mg Preparation of N-methyl-2-fluoro-5-bromobenzyl amine
F
NHCH3
H
WO 97/09308 PCT/US96/14163 -117- In a 25 ml flask, under a nitrogen atmosphere, bromobenzylbromide (755 mg, 2.82 mmol) was dissolved in methanol 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 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 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
F
O N,1CH3 I
H
Br In a 15 ml flask, under a nitrogen atmosphere, N,Ndimethyl-3-[2-fluoro-5-bromobenzyloxy]propylamine (351 mg, 1.21 mmol) 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 temperature for 18 hours. The reaction mixture was cooled to ambient temperature, and the solvents were removed in vacuo. The residue was taken up in methanol and refluxed 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 chromatography. NMR was consistent with the proposed title structure.
WO 97/09308 PCT/US96/14163 -118- Preparation Preparation of N,N-dimethyl-4-[2-fluoro-5-bromobenzyloxy]butylamine F CH3 N -CH3 Br In a 50 ml flask, under a nitrogen atmosphere, bromobenzyl bromide (967 mg, 3.61 mmol) was dissolved in N,Ndimethylformamide (3.5 ml). To this solution sodium hydride 245 mg, 6.14 mmol) was added and the resulting mixture was stirred for ten minutes. To the reaction mixture 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 NMR was consistent with the proposed title structure.
Preparation Preparation of N-methyl-4-[2-fluoro-5-bromobenzyloxy]butylamine
F
H
0 N CH WO 97/09308 PCT/US96/14163 -119- In a 10 ml flask, under a nitrogen atmosphere, N,Ndimethyl- 4 -[2-fluoro-5-bromobenzyloxy]butylamine (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 mixture 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 methanol. 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 sodium 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
F
O X Cl Br In a 50 ml flask, under a nitrogen atmosphere, bromobenzyl alcohol (2.139 g, 10.4 mmol) was dissolved in N,Ndimethylformamide (25 ml). To this solution sodium hydride 625 mg, 15.6 mmol) was added and the resulting mixture was stirred for twenty minutes. To the reaction mixture 5-chloropentyl bromide was added and the resulting mixture was stirred for two hours at ambient temperature. The progress of the reaction was monitored by thin layer WO 97/09308 PCT/US96/14163 120 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 intermediate was further purified by silica gel. Yield 1.82 g NMR was consistent with the proposed title structure.
Preparation Preparation of N,N-dimethyl-5-[2-fluoro-5-bromobenzyloxy]pentylamine
F
O 1
CHS
CH 3 Br In a sealable tube, under a nitrogen atmosphere, 5-[2fluoro-5-bromobenzyloxy]pentyl chloride (0.380 g, 1.23 mmol) was dissolved in N,N-dimethylformamide (5 ml). To this solution sodium iodide (55 mg, 0.368 mmol) was added and the resulting mixture was cooled to -78 0 C. To the reaction mixture dimethylamine (precondensed in anhydrous conditions) was added and the tube was sealed. The 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 dimethylamine. 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, dried over sodium sulfate, and the solvents were removed in vacuo. The title intermediate was further purified by silica gel.
Preparation WO 97/09308 PCT/US96/14163 -121- Preparation of N-methyl-5-[2-fluoro-5-bromobenzyloxy]pentylamine
F
O SVN CH3 I -H Br In a 25 ml flask, under a nitrogen atmosphere, N,N- 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 combined 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 C 13
H
19 BrFNO: Theory: C, 51.33; H, 6.30; N, 4.60.
Found: C, 51.06; H, 6.12; N, 4.49.
Preparation Preparation of 1-[ 2 WO 97/09308 PCT/US96/14163 -122-
F
O CH 3 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).
To this solution sodium hydride 521 mg, 13.0 mmol) was added and the resulting mixture 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 chromatography. The reaction mixture was partitioned between 1 M potassium carbonate/brine 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 g. NMR was consistent with the proposed title structure.
Preparation Preparation of 1-(t-butoxycarbonyl)-3-[2-(2-fluoro-5- 2 0 bromobenzyloxy)ethyl]piperidine
F
N
I BoC Br In a 25 ml round bottom flask, 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 97/09308 PCT/US96/14163 -123mmol) 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 208 mg, 5.19 mmol) were then added and the resulting mixture began to froth and exotherm. After thirty 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 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
F
N
Br In a 1- ml round bottom flask 1-(t-butoxycarbonyl)-3-[2-(2- (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 dropwise. The resulting mixture was stirred for thirty minutes 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 resulting residue was used as is. Yield: 240 mg. NMR was consistent with the proposed title structure.
WO 97/09308 PCT/US96/14163 -124- Preparation Preparation of 1-hydroxymethyl-2-[2-(2-fluoro-5bromobenyloxy)methyl]cyclopropane
F
I
N.^OH
Br In a 100 ml round bottom flask, 1,2di(hydroxymethyl)cyclopropane (398 mg, 3.90 mmol) was dissolved in N,N-dimethylformamide (15 ml). Sodium hydride 171 mg, 4.29 mmol) was added and the resulting mixture was stirred at o0C for fifteen minutes and then at ambient temperature for fifteen minutes.
The reaction solution was cooled to 0°C and 2 bromide (348 mg, 1.30 mmol) was then added as a solution in N,Ndimethylformamide. The resulting reaction was stirred at o0C for hours and at ambient temperature for thirty minutes. 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 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 NMR was consistent with proposed title structure.
Preparation Preparation of 1-bromomethyl-2-[2-(2-fluoro-5bromobenzyloxy)methyl]cyclopropane WO 97/09308 PCT/US96/14163 -125-
F
O Br Br In a 50 ml flask 1-hydroxymethyl-2-[2-(2-fluoro-5bromobenzyloxy)methyl]cyclopropane (420 mg, 1.45 mmol) was dissolved 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 ambient temperature for 17 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was treated wtih another 0.19 grams of triphenylphosphine and 0.241 grams of carbon tetrabromide.
After four additional hours of stirring at ambient temperature, the solvents were removed in vacuo. The title intermediate was further purified from the residue by liquid chromatography. Yield: 0.389 grams as a clear oil.
Preparation Preparation of 1-[(N-methylamino)methyl]-2-[2-(2-fluoro-5bromobenzyloxy)methyl]cyclopropane
F
o i 1 H CHs Br In a 100 ml flask 1-bromomethyl-2-[2-(2-fluoro-5bromobenzyloxy)methyl]cyclopropane (344 mg, 0.977 mmol) was dissolved in dry tetrahydrofuran (5 ml) under a nitrogen atmosphere.
The reaction mixture was treated with methylamine (2M in WO 97/09308 PCT/US96/14163 -126 tetrahydrofuran, 1.9 ml, 3.91 mmol). The resulting mixture was stirred at ambient temperature for one hour and then additional methylamine (2 ml) was added. The resulting mixture was heated to reflux and maintained at this temperature for four hours. The progress of the 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 intermediate was further purified by liquid chromatography. Yield: 0.131 grams 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-l-ol
OH
F
Br In a 500 ml flask, 1,4-dihydroxybut-2-ene (6.13 ml, 74.5 mmol) was dissolved in N,N-dimethylformamide (150 ml) under a nitrogen atmosphere. Sodium hydride 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 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 PCT/US96/14163 -127 combined and dried over sodium sulfate. The desired title intermediate was further purified by liquid chromatography. Yield: 2.145 grams 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 Br
F
Br In a 100 ml round bottom flask 4-(2-fluoro-5bromobenzyloxy)but-2-en-l-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 mixture 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 NMR and MS were consistent with the proposed title structure.
Preparation Preparation of cis N-methyl-4-(2-fluoro-5-bromobenzyloxy)but-2enylamine WO 97/09308 PCT/US96/14163 -128-
CH
3
NH
F
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 ml). To this solution methylamine (29.5 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 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 NMR and MS were consistent with the proposed title structure.
Preparation Preparation of N-(t-butoxycarbonyl)-4-(2-fluoro-5bromobenzyloxy)butylamine
F
^O N- BoC Br In a 25 ml flask 4 -(t-butoxycarbonylamino)butanol was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. The WO 97/09308 PCT/US96/14163 -129solution was cooled to -40 0 C and potassium tert-butoxide (1M in tetrahydrofuran, 2.14 ml, 2.14 mmol) was added slowly. The resulting mixture was stirred at -40 0 C for thirty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (521 mg, 1.94 mmol), added dropwise as a solution in tetrahydrofuran (3.5 ml). The resulting mixture was slowly warmed to o0C and stirred at this 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 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. Yield: 335 mg as a yellow oil.
Analysis for C 16
H
2 3 BrFNO 3 Theory: C, 51.07; H, 6.16; N, 3.72.
Found: C, 51.18; H, 6.18; N, 3.80.
Preparation Preparation of 4 2
F
Br In a 250 ml flask, N-(t-butoxycarbonyl)-4-(2-fluoro-5bromobenzyloxy)butylamine (3.5 grams) was dissolved in methylene chloride (60 ml) under a nitrogen atmosphere. Trifluoroacetic acid 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 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 WO 97/09308 PCT/US96/14163 -130 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-1H-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 cannulated into the organolithium solution. Carbon dioxide was bubbled through the reaction mixture, and the resulting mixture was stirred for thirty minutes over the dry ice/acetone bath. The reaction mixture was then stirred at room temperature for ten minutes with continued carbon dioxide bubbling. The carbon dioxide was shut off and the reaction mixture was stirred at room temperature for ninety minutes.
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 0 C under an argon atmosphere.
The residue was then dissolved in 12 ml warm 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 through 26 ml of tetrahydrofuran cooled over a dry ice/acetone bath. The carbon dioxide/tetrahydrofuran solution was added to the organolithium WO 97/09308 PCT/US96/14163 -131solution via cannula. The carbon dioxide was bubbled directly into the reaction mixture 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 milliliter of water was added to the reaction mixture and the reaction mixture was allowed to stir at room temperature for several hours.
The reaction mixture 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 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.
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-2carboxylic 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 mixture 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 WO 97/09308 PCT/US96/14163 132 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 0 C. The progress 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 proposed title structure.
Preparation Preparation of 2 -[4-chlorophenoxymethyl]-3-[2-[4-(piperidin-1yl)piperidin-1-yl]acetyl]-1H-indole To a slurry of 2 4 -chlorophenoxymethyl]-3-(2-bromoacetyl)- 1H-indole (3 mmol) and lithium carbonate (0.47 g, 6 mmol) in tetrahydrofuran (10 ml) 4-(piperidin-1-yl)piperidine (1.01 g, 6 mmol) was 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 twice with ethyl acetate, and then twice with methylene chloride. The organic fractions were combined and the solvents were removed in vacuo. After triturating with diethyl ether 0.46 grams of the desired product as crystalline material were obtained.
NMR, IR, and UV were consistent with the proposed title structure.
Exact Mass FAB for C 2 8
H
35 C1N 3 0 2 Theory: 480.2418 Found: 480.2411 FDMS 479 mp 144-145°C WO 97/09308 PCT/US96/14163 -133 The following Examples were prepared essentially as described in the Schemes and Methods, supra. In the following Examples, unless otherwise noted, NMR was consistent with the proposed title struture.
Example 1 Preparation of 2-[(4-chlorophenoxy)methyl]-l-methyl-3-(amino)methyl- 1H-indole NH2
N
H
3 Cl NMR (CDC13) was consistent with the proposed title structure.
FDMS 300 Analysis for C 17
H
1 7 C1N 2 0: Theory: C, 67.88; H, 5.70; N, 9.31.
Found: C, 67.64; H, 5.86; N, 9.24.
Example 2 Preparation of 2-[(4-chlorophenoxy)methyl]-l-methyl-3-[(N,Ndimethylamino)methyl]-1H-indole
N(CH
3 2
N
CH
3 c NMR (CDC13) was consistent with the proposed title structure.
FDMS 328 Analysis for C 19
H
2 1 C1N 2 0: Theory: C, 69.40; H, 6.44; N, 8.52.
Found: C, 69.18; H, 6.73; N, 8.54.
WO 97/09308 WO 9709308PCT/US96/14163 134 Example 3 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-j(N,Ndiethylamnino )methyl]- 1H-indole hydrochloride N (CH 2
CH
3 2 HC1 CH-4 NMR (DMSO) was consistent with the proposed title structure.
FDMS 356 Analysis for C 2 1
H
2 5
CIN
2 0 2 HCl: Theory: C, 64.12; H, 6.66; N, 7.12.
Found: C, 64.30; H, 6.69; N, 7.18.
Example 4 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[(N,N,Ntrimethylammonium)methyl]- 1H-indole iodide
CH
3
H
3 C, <CH 3
I
N
CH
3 NMR (DMSO) was consistent with the proposed title structure.
FDMS 343 Analysis for C 20
H
24 C1N 2 0 I: Theory: C, 51.03; H, 5.14; N, 5.95.
Found: C, 50.80; H, 4.93; N, 6.00.
WO 97/09308 WO 9709308PCTIUS96/14163 135 Example Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3- [(benzylamino)methyl]- 1H-indole hydrochloride -HC1
CH
3 NMR (DMSO) was consistent with the proposed title structure.
FDMS 390 Analysis for C 24
H
23 C1N 2 0 HCl: Theory: C, 67.45; H, 5.66; N, 6.56.
Found: C, 67.63; H, 5.70; N, 6.60.
Example 6 Preparation of 2 4 -chlorophenoxy)methyl-l-methyl-3-[(2.
phenylethylaniino)methyll 1H-indole hydrochloride iN -HC1 WO 97/09308 WO 9709308PCTIUS96/1 4163 136 NMR (DMSO) was consistent with the proposed title structure.
FDMS 404 Analysis for 0 25
H
25 C1N 2 0 HC1: Theory: C, 68.03; H, 5.94; N, 6.35.
Found: C, 68.27; H, 5.99; N, 6.60.
Example 7 Preparation of 2-I(4-chlorophenoxy)methyll- -methyl-3-[(N-methyl-Nbutylamino)methyl]- 1H-indole
CH
3
,N
Q 7- CH3 IN 01Q
CH
3
C
NMR (CDC1 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FDMS 370 Analysis for C 22
H
27 C1N 2 0: Theory: C, 71.24; H, 7.34; N, 7.55.
Found: C, 71.19; H, 7.48; N, 7.39.
Example 8 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[(N-methyl-Nbenzylamino)methyl]- 1H-indole hydrochloride WO 97/09308 WO 9709308PCT/US96/14163 137
N
CH
3 NMR, JR and UV were consistent with the desired title structure.
FDMS 404 Analysis for C 2 5
H
2 5 C1N 2 0 0 HC1: Theory: C, 68.03; H, 5.94; N, 6.35.
Found: C, 68.30; H, 5.92; N, 6.45.
Example 9 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[N-methyl-N-(3- N',N'-dimethylaminopropyl)aminolmethyl]- 1H-indole N (CH 3 2
N
OH
3 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 400 Analysis for C 2 3
H
3 0 C1N 3 0: Theory: C, 69.07; H, 7.56; N, 10.51.
Found: C, 69.33; H, 7.34; N, 10.41.
Example Preparation of 2-I(4-chlorophenoxy)methyl]- 1-methyl-3-[[N-methyl-N-[3.
(N',N'-dimethylamino 2-dimethyipropyl] aminolmethyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 138 N NCH 3 CH3
N
CHH3 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 414 (M+1) Analysis for C 2 4
H
3 2 C1N 3 0: Theory: C, 69.93; H, 7.79; N, 10.15.
Found: C, 69.67; H, 7.78; N, 10. 17.
Examle 11 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[(pyrrolidin- 1yl)methyl]- 1H-indole hydrochloride HC 1
N
CH
3 c NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 354 Analysis for C2 1
H
2 3 C1N 2 0 9 HCl: Theory: C, 64.45; H, 6.18; N, 7.16.
Found: C, 64.66; H, 6.33; N, 7.03.
Examnie 12 Preparation of 2-[(4-chlorophenoxy)methyl.. -methyl-3-[(piperidin-l-1 yl)methyl]- 1H-indole hydrochloride WO 97/09308 WO 9709308PCTJUS96/I 4163 139 No
CH
3 NMR, JR and UV were consistent with the desired title structure.
FDMS 368 Analysis for C 22
H
2 5 C1N 2 0 HCl: Theory: C, 65.19; H, 6.46; N, 6.91.
Found: C, 65.46; H, 6.52; N, 7.16.
Example 13 Preparation of 2 -[(4-chlorophenoxy)methyl-l-methyl-3[(3methylpiperidin- 1-yl)methyl]- 1H-indole H 3
N
CH
3
C
NMR (DMSO) was consistent with the proposed title structure.
FDMS 382 Analysis for C 2 3
H
2 7
CIN
2 0: Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 72.38; H, 7.22; N, 7.36.
Example 14 Preparation of 2 -[(4-chlorophenoxy)methyl-l-methy..3[(4methylpiperidin- 1-yl)methyl]- 1H-indole WO 97/09308 WO 9709308PCT/US96/14163 140 4D N Q CH3
CH
3 NMR (DMSO) was consistent with the proposed title structure.
FDMS 382 Analysis for C2 3
H
2 7 C1N 2 0: Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 72.33; H, 7.22; N, 7.47.
Example Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[14-(N,Ndimethyl amino )piperidin- 1-yllmethyl]- 1H-indole Na N (CH 3 2
N
CH
3 C NMR (DMSO) was consistent with the proposed title structure.
FDMS 411 Analysis for C2 4
H
3 oCIN 3
O:
Theory: C, 69.97; H, 7.34; N, 10.20.
Found: C, 69.74; H, 7.38; N, 10.13.
Example 16 Preparation of 2-I(4-chlorophenoxy)methyl]- l-methyl-3-[[4-(piperidin- 1yl)piperidin- 1-yllmethyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/141 63 141 Na No FDMS 451 Analysis for C27H 34 C1N 3 0: Theory: C, 71.74; H, 7.58; N, 9.30.
Found: C, 71.55; H, 7.44; N, 9.14.
Example 17 Preparation of 2-[(4-chlorophenoxy)methyl]- l-methyl-3-[(4-acetamido-4phenylpiperidin- 1-yl)methyl]- 1H-indole 0
ICH
3
NH
FDMS 501 Analysis for C 30
H
32 C1N 3 0 2 Theory: C, 71.77; H, 6.43; N, 8.37.
Found: C, 71.79; H, 6.61; N, 8.52.
Example 18 Preparation of 2 -[(4-cblorophenoxy)methyl-1-methyl.3-(4.
methylpiperazin- 1-yl)methyl]-1H-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 142 N N- CH 3 N0
CH
3 >C NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 383 Analysis for C22H 26 C1N 3 0: Theory: C, 68.83; H, 6.83; N, 10.95.
Found: C, 68.80; H, 6.71; N, 10.95.
Example 19 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[(4isopropylpiperazin- 1-yl)methyl]- 1H-indole
CH
3
CH,
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 411 Analysis for C 24
H
30 C1N 3 0: Theory: C, 69.97; H, 7.34; N, 10.20.
Found: C, 69.97; H, 7.36; N, 10.02.
Example Preparation of 2 -[(4-chlorophenoxy)methyl]-1-methyl-3-(4.
phenylpiperazin- 1-yl)methyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/14163 -143-
N
NMR was consistent with the desired title structure.
FDMS 445 Analysis for C 27
H
28 C1N 3 0: Theory: C, 72.71; H, 6.33; N, 9.42.
Found: C, 73.00; H, 6.41; N, 9.51.
Examnie 21 Preparation of 2-[(4-chlorophenoxy)methylI-1-methyl-3-[(4benzylpiperazin- 1-yl)methyl]- 1H-indole hydrochloride N N Q7- Olac,-I
C
N
CH
3 NMR (DMSO) was consistent with the proposed title structure.
FDMS 459 Exact Mass (FAB+) for C 28
H
31 C1N 3 0: Theory: 460.2155.
Found: 460.2145.
Example 22 Preparation of 2-[(4-chlorophenoxy)methyl]-l1-methyl-3-[(4cyclohexylpiperazin- 1-yl )methyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 144 NMR (DMSO) was consistent with the proposed title structure.
FDMS 451 Analysis for C2 7
H
34 C1N 3 0: Theory: C, 71.74; H, 7.58; N, 9.30.
Found: C, 71.48; H, 7.53; N, 9.26.
0 Exam~le 23 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[4-(pyrrimid-2yl)piperazin- 1-yl)methyl]- 1H-indole N N 1N
CH
3
C
NMR (CDCl 3 was consistent with the proposed title FDMS 447 Analysis for C 25
H
26 C1N 5 0: Theory: C, 67.03; H, 5.85; N, 15.63.
Found: C, 67.05; H, 5.93; N, 15.64.
structure.
Examile 24 Preparation of 2-[(4-chlorophenoxy)methyl]- l-methyl-3-(morpholin-4yl )methylllH-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 145 N 0 NMR was consistent with the desired title structure.
FDMS 370 Analysis for C2 1
H
23 C1N 2 0 2 Theory: C, 68.01; H, 6.25; N, 7.55.
Found: C, 67.84; H, 6.65; N, 7.25.
Exampie Preparation of 2-[(4-cblorophenoxy)methyl]- l-methyl-3-(tr-yptolin-2yl)methyl]- 1H-indole NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 455 Analysis for C 28
H
26 C1N 3
O:
Theory: C, 73.75; H, 5.75; N, 9.21.
Found: C, 73.99; H, 6.00; N, 9.03.
ExaMple 26 Preparation of ,4-dichlorophenoxy)methyl]- 1-methyl-3-[N-( 1methylpiperidin-4-yl )-N-methylaniinolmethyl]- 1H-indole dihydrochioride monohydrate WO 97/09308 WO 9709308PCT[US96/14163 146 -2 HC1
-H
2 0 NMR was consistent with the desired title structure.
mp 196-197'C.
FDMS 446 Analysis for C 24
H
29 C1 2
N
3 0 2HCl H 2 0: Theory: C, 53.64; H, 6.19; N, 7.82.
Found: C, 53.66; H, 5.92; N, 8.10.
0 Exam~le 27 Preparation of 2-[(2,4-dichlorophenoxy)methyl]- 1-methyl-3-[[4-(N,Ndimethylamino)piperidin-1-yllmethyl]- 1H-indole Na N (CH 3 2
IN
CH
3 C NMR, IR, and UV were consistent with the desired title structure.
mp 105-106'C.
2 0 FDMS 445 Analysis for C 24
H
29 C1 2
N
3 0: Theory: C, 64.57; H, 6.55; N, 9.41.
Found: C, 64.27; H, 6.48; N, 9.49.
25 E xample 28 WO 97/09308 WO 9709308PCTIUS96/1 4163 147 Preparation of ,4-dichlorophenoxy)methyl]- 1-methyl-3-[[4-(piperidin- 1-yl)piperidin- 1-yllmethyl]- 1H-indole
N
CH
3 1 NMR, IR, and UV were consistent with the desired title structure.
FDMS 485(M+).
mp 106-107'C Analysis for C 27
H
33 C1 2
N
3 0: Theory: C, 66.66; H, 6.84; N, 8.64.
Found: C, 66.92; H, 7.04; N, 8.74.
Example 29 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-(2-aminoethyl)- 1H-indole Nil 2
CH
3 NMR (CDC1 3 was consistent with the proposed title structure.
FDMS 314 Exact Mass (FAB) for C1gH 2 0ClN 2
O:
Theory: 315.1264.
Found: 315.1246.
Example WO 97/09308 WO 9709308PCT/US96/141 63 148 Preparation of 2-[(4-cblorophenoxy)methyl]- 1-methyl-3-[2-[(3dimethylaminopropyl)aminolethyl]- 1H-indole N (CH 3 2
H_/
N
N
CH
3 l: 1 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 399 Analysis for C 23
H
30 C1N 3 0: Theory: C, 69.07; H, 7.56; N, 10.51.
Found: C, 69.23; H, 7.79; N, 10.52.
Examnie 31 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-12-IIN-methyl-N- (3-dimethylaminopropyl)aminolethyl]- 1H-indole dihydrochioride N (CH 2 )3
H
3 C\ .2 Nd1
CH
3 NVR (DMSO) was consistent with the proposed title structure.
2 0 FDMS 413 Exact Mass (FAB) for C24H33C1N30: Theory: 414.2312.
Found: 414.2312.
WO 97/09308PCIS/146 PCTIUS96/14163 149 Examtile 32 Preparation of 2-I(4-chlorophenoxy)methyl]- l-methyl-3-112-(piperidin- 1yl ethyl]-M1-mndole no NMR (CDCl 3 was consistent with the proposed title Structure.
FDMS 382 Analysis for C 23
H
27 C1N 2 0: Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 72.40; H, 7.26; N, 7.37.
Example 33 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(4methylpipericlin- 1-yl)ethyl]-1H-indole
ICH
3
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 396 Analysis for C 24
H
29
CIN
2 0: Theory: C, 72.62; H, 7.36; N, 7.06.
WO 97/09308 WO 9709308PCT/US96/14163 150 Found: C, 72.40; H, 7.35; N, 7.25.
Examnie 34 Preparation of 2-[(4-chlorophenoxy)methyll- -methyl-3-[2-(4benzylpiperidin- 1-yl)ethyl]- 1H-indole NMR (ODC1 3 was consistent with the proposed title structure.
FDMS 472 Analysis for C3 0
H
33 C1N 2 0: Theory: C, 76.17; H, 7.03; N, 5.92.
Found: C, 76.37; H, 7.15; N, 5.85.
Example Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-14-(N,Ndimethylainino)piperidin- 1-yllethyl]- 1H-indole N (CH 3 2
N
WO 97/09308 WO 9709308PCTIUS96/1 4163 -151- NMR (CDC1 3 was consistent with the proposed title structure.
Exact Mass (FAB) for C 25
H
33 C1N 3 0: Theory: 426.2312.
Found: 426.2297.
Example 36 Preparation of 2-I(4-chlorophenoxy)methyl]- l-methyl-3-[2-[4-(piperidin- 1yl)pipericlin- 1-yllethyl]- 1H-indole
N
CH
3
C
FDMS 465 Analysis for C 28
H
36 C1N 3 0: Theory: C, 72.16; H, 7.79; N, 9.02.
Found: C, 72.09; H, 7.69; N, 9.09.
Example 37 Preparation of 2-I(4-chlorophenoxy)methyl]- 1-methyl-3-12-(4cyclohexylpiperazin- l-yl )ethyl]- 1H-indole WO 97/09308 WO 9709308PCT/US96/1 4163 152
Q
N
OH
3 O sQ NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 465 Analysis for C 2 8
H
36 C1N 3 0: Theory: C, 72.16; H, 7.79; N, 9.02.
Found: C, 72.00; H, 7.88; N, 9.05.
Example 38 Preparation of ,4-dichlorophenoxy)methyl]- 1-methyl-3-[2-[N-methyl- 1-methylpiperidin-4-yl )]ethyl]- 1H-indole
H
3
C,
N-OCH
3 01
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 459 Analysis for C 25
H
31 Cl 2
N
3 0: Theory: C, 65.21; H, 6.79; N, 9.13.
Found: C, 65 .07; H, 6.85; N, 9.06.
WO 97/09308 WO 9709308PCT/US96/1 4163 153 Examnie 39 Preparation of 2-[(2,4-dichlorophenoxy)methyl]- 1-methyl-3-[2-[4-(N,Ndimethylamino)piperidin- 1-yllethyl]- 1H-indole NMR (CDC1 3 was consistent with the proposed title structure.
Exact Mass for C 25
H
32 C1 2
N
3 0: Theory: 460.1922.
Found: 460.1890.
Examnie Preparation of ,4-dichlorophenoxy)methyl]- 1-methyl-3-[2-14- (piperidin- 1-yl)piperidin- 1-yl] ethyl]- 1H-indole 2 3 NMR (CDCl 3 was consistent with the proposed title structure.
WO 97/09308 WO 9709308PCT/US96/14163 154 Exact Mass for Theory: Found:
C
28
H
36 C1 2
N
3 0: 500.2235.
500.2215.
Example 41 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-13-[4-(N,N.
dimethylarnino )piperidin- 1-yllpropyl]- 1H-indole NQ-N
(CH
3 2
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FABMS 440 (M+1) Analysis for C2 6
H
34 C1N 3 0: Theory: C, 70.97; H, 7.79; N, 9.55.
Found: C, 70.73; H, 7.65; N, 9.44.
Example 42 Preparation of (RS) 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[3- (piperidin-3-yl)propyl]- 1H-indole CH-i WO 97/09308 WO 9709308PCT/US96/1 4163 155 NIMR (CDC1 3 was consistent with the proposed title structure.
Exact Mass for C 24
H
30 C1N 2 0: Theory: 397.2047.
Found: 397.2055.
Example 43 Preparation of 2-[(4-chlorophenoxy)methyl.. -methyl-3-[2-[[4- (dimethylamino )piperidin- l-yl] carbonyllethyl]- 1H-indole o NQ-N
(CH
3 2 NMR (CDCl 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FDMS 453 Analysis for C 26
H
32 C1N 3 0 2 Theory: C, 68.78; H, 7.10; N, 9.26.
Found: C, 68.74; H, 7.04; N, 9.38.
Example 44 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[[4- (dimethylamino )piperidin- 1-yllcarbonyl] ethenyl]- 1H-indole 0
CH
3 WO 97/09308 WO 9709308PCTIUS96/14163 156 NMR (CDCl 3 was consistent with the proposed title structure.
Exact Mass (FAB) for C 2 6
H
3 1 C1N 3 0 2 Theory: 452.2105.
Found: 452.2099.
Example 46 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-34 1-hydroxy-2-[(3acetamido)pyrrolidin- 1-yllethyl]- 1H-indole
H
N 'frCH 3 HO
N
CH'
3 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 442 Exact Mass FAB for C2411 2 9 C1N 3 0 3 Theory: 442.1897.
Found: 442.1878.
Example 47 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[ 1-hydroxy-2- (piperidin- 1-yl)ethyll- H-indole HO
N
WO 97/09308 WO 9709308PCTIUS96/1 4163 157 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 398 Analysis for C2 3
H
2 7 C1N 2 0 2 Theory: C, 69.25; H, 6.82; N, 7.02.
Found: C, 69.51; H, 6.86; N, 6.81.
Example 48 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-i1-hydroxy-2-(4methylpiperidin- 1-yl)ethyl]- 1H-indole
OH
3
HO
CH
3 NMR (CDC1 3 was consistent with the proposed title structure.
FDMS 412, Analysis for C 24
H
2 9 C1N 2 0 2 Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 70.02; H, 7.13; N, 7.00.
Example 49 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[ 1-hydroxy-2-(4benzylpiperidin- 1-yl )ethyli. 1H-indole WO 97/09308 PCT/US96/14163 -158- HO N
CH
3 NMR (CDC1 3 was consistent with the proposed title structure.
FDMS 488 Analysis for C 30
H
33 C1N 2 0 2 Theory: C, 73.67; H, 6.80; N, 5.73.
Found: C, 73.52; H, 6.87; N, 5.58.
Example Preparation of 2-[(4-chlorophenoxy)methyl]-l-metl-3-[hydroxy-2-(4dimethylaminopiperidin- 1-yl)ethyl]- 1H-indole
N(CH
3 2
HO
CH
3 Cl NMR (CDCI 3 was consistent with the proposed title structure.
IR was consistent with the desired title structure.
FDMS 442 Analysis for C 2 5
H
3 2 C1N 3 0 2 Theory: C, 67.94; H, 7.30; N, 9.51.
Found: C, 67.73; H, 7.52; N, 9.75.
WO 97/09308 WO 9709308PCT/US96/1 41 63 159 ExamDle 51 Preparation of 2-I(4-chlorophenoxy)methyl]- 1-methyl-3-[ 1-hydroxy-2-[4- (piperidin- 1-yl)piperidin- 1-yllethyl]- 1H-indole dihydrochloride 0 HO NO .2 HC1
CH
3 NMR (DMSO) was consistent with the proposed title structure.
FDMS 481 Analysis for C 28
H
35 C1N 3 0 2 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.
Example 52 Preparation of 2 -[(4-chlorophenoxy)methyl]- l-methyl-341-hydroxy-2-(4.
cyclohexylpiperazin- l-yl )ethyl]- 1H-indole 0
(N
CH
3 WO 97/09308 WO 9709308PCTIUS96/1 416-3 160 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 482 1).
Analysis for C 28
H
36 C1N 3 0 2 Theory: C, 69.76; H, 7.53; N, 8.72.
Found: C, 70.06; H, 7.61; N, 8.46.
Examule 53 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[ 1-hydroxy-3- (piperidin-4-yl)propyl]- 1H-indole NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 412 Single compound of high purity as evidenced by chromatographic methods.
Analysis for C 24
H
29 C1N 2 0 2 Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 68.18; H, 7.87; N, 6.58.
Example 54 Preparation of 2
-I(
2 4 -diclorophenoxy)methyl.. -methyl-3-[ 1-hydroxy-2- [N-methyl-N-( 1-methylpiperidin-4-yl )aminollethyl]- 1H-indole WO 97/09308 PCT/US96/1 4163 161 HO N-\,NH 3 NC 1
CH
3 C NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 475 Analysis for C2 5
H
3 IC1 2
N
3 0 2 Theory: C, 63.02; H, 6.55; N, 8.82.
Found: C, 63.43; H, 6.88; N, 8.92.
Examle Preparation of 2 4 -chlorophenoxy)methyl.. -methyl-3-[ 1-hydroxy-2- (methoxycarbonyl)ethyl.. H-indole 0 ~CH 3 HO0
N
CH
3 1 N-MR (CDC1 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FDMS 373 Analysis for C2OH 2 OClNO 4 Theory: C, 64.26; H, 5.39; N, 3.75.
Found: C, 64.55; H, 5.23; N, 3.79.
Example 56 WO 97/09308 WO 9709308PCT/US96/14163 162 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-carboxy- 1Hindole 0
OH
N
CH
3 NMR (DMSO) was consistent with the desired title structure.
FDMS 315 Analysis for C 7
H
14 C1N0 3 Theory: C, 64.67; H, 4.47; N, 4.44.
Found: C, 64.84; H, 4.60; N, 4.54.
Examp~le 57 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[3dimethylamino-2 ,3-dimethylpropylaminolcarbonyl]- 1H-indole
H
3
N
0 CH 3 N CH 3
H
N
CH c 1 NMR (CDCl 3 was consistent with the proposed title structure.
2 0 FAB 426 1).
Analysis for C 24
H
30 C1N 3 0 2 Theory: C, 67.36; H, 7.07; N, 9.82.
Found: C, 67.58; H, 6.79; N, 9.64.
Example 58 WO 97/09308 WO 9709308PCT/US96/1 4163 163 Preparation of 2 4 -chlorophenoxy)methyl]-1-methyl3[[N,N.bjs(3.
dimethylaminopropyl )aminolcarbonyl]- 1H-indole N (CH 3 2 0
N
\KN(CH
3 2 N ON1Q
CH
3
C
NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 483 FABMS 485 (M+1) Analysis for C 27
H
37 C1N 4 0 2 Theory: C, 66.86; H, 7.69; N, 11.55.
Found: C, 66.91; H, 7.54; N, 11.69.
Example 59 Preparation of 2 -[(4-chlorophenoxy)methyl]- l-methyl-3-[[N-methyl..N-(l methylpiperidn4yl)aminocarbonyl.. 1H-indole
CH-
Q7 CH3
N
CH-AC
NMR (CDC1 3 was consistent with the proposed title structure.
FDMS 427 (M+2) Analysis for C 24
H
28 C1N 3 0 2 Theory: C, 67.67; H, 6.63; N, 9.86.
Found: C, 67.38; H, 6.90; N, 9.94.
WO 97/09308 WO 9709308PCTIUS96/14163 164 Example Preparation of 2-[(4-chlorophenoxy)methyl]- l-methyl-3-[[4-(piperidin- 1yl)piperidin-1-yllcarbonyl]- iB-indole 0 NN
N
CH
3 1 NMR (CDCl 3 was consistent with the proposed title FDMS 465 Analysis for C 27
H
32 C1N 3 0 2 Theory: C, 69.59; H, 6.92; N, 9.02.
Found: C, 69.47; H, 7.00; N, 9.22.
structure.
Examle 61 Preparation of (RS) 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[(piperidin- 3-yl)acetyl]- 1H-indole NM (Dl 3 wscositntwihth poosd ilestutue Analysis for) C 2
H
2
CN
2 1 Theory: C, 69.60; H, 6.35; N, 7.06.
Found: C, 69.71; H, 6.28; N, 7.20.
WO 97/09308 WO 9709308PCTIUS96/1 4163 165 ExamDle 62 Preparation of 2-[(4-cblorophenoxy)methyl]- 1-methyl-3-[( 1tritylpipericlin-4-yl)acetyl]- iR-indole
CH
3 01::1 C 1 NMR (CDC1 3 was consistent with the proposed title structure.
FDMS 638 Analysis for C 42
H
39 C1N 2 0 2 Theory: C, 78.92; H, 6.15; N, 4.38.
Found: C, 78.73; H, 6.15; N, 4.25.
Example 63 Preparation of 2 -[(4-cblorophenoxy)methyl]- l-methyl-3-II(piperidin-4yl)acetyl]- 1H-indole NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 397 (M+1) Analysis for C 23
H
2 5 C1N 2 0 2 Theory: C, 69.60; H, 6.35; N, 7.06.
Found: C, 69.34; H, 6.43; N, 6.86.
WO 97/09308 WO 9709308PCTIUS96/14163 166 Example 64 Preparation of 2 -[(4-chlorophenoxy)methyl]- l-methyl-3-[[4-(piperidinyl)piperidin- l-yllacetyl]- 1H-indole dihydrochioride 0N *2HC1 N 1
CH
3 NMR (DMSO) was consistent with the proposed title structure.
FDMS 479 Analysis for C2 8
H
34
CIN
3 0 2 0 2HCL: Theory: C, 60.82; H, 6.56; N, 7.60.
Found: C, 60.67; H, 6.70; N, 7.38.
Example Preparation of 2 -[(4-chlorophenoxy)methyl]- l-methyl-3-[12-(piperidin-3.
yl)ethyllcarbonyl]- 1H-indole NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 411 Analysis for C 24
H
27 C1N 2 0 2 WO 97/09308 WO 9709308PCT/US96/141 63 167 Theory: Found: C, 70.15; H, 6.67; N, 6.82.
C, 70.38; H, 6.39; N, 7.02.
Example 66 Preparation of 2 -I(4-chlorophenoxy)methyl]- 1-methyl-3-[[2-( 1tritylpiperidin-4-yl)ethyllcarbonyll 1H-indole NMR (CDCl 3 was consistent with the proposed title structure.
C
43
H
4 1 C1N 2 0 2 FDMS 652 Single compound of high purity as evidenced by chromatographic means.
Example 67 Preparation of 2-[(4-chlorophenoxy)methyl]- l-methyl-3-[2-(pipericlin-4yl)ethyllcarbonyl]- 1H-indole NMR (CDC1 3 was consistent with the proposed title structure.
FDMS 411 (M+1) Analysis for C 24
H
27
CIN
2 0 2 Theory: C, 70.15; H, 6.62; N, 6.82.
WO 97/09308 WO 9709308PCTIUS96/14163 168 Found: C, 69.87; H, 6.54; N, 6.79.
Examnie 68 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[[2-[ 1tritylpiperidin-4-yl)propyllpiperidin.4yl]]ethyllcarbonyl] 1H-indole FDMS 779 (M+2) Analysis for C 5 1
H
56 C1N 3 0: Theory: C, 78.69; H, 7.25; N, 5.40.
Found: C, 78.90; H, 7.34; N, 5.60.
Example 69A Preparation of 2-[(4-chlorophenoxy)methyl.. -methyl-3-[[2-[ 1-[3- (piperidin-4-yl)propy]piperidin4-y]]ethy]carbony].. i-indole
CH
3 NMR (CDC1 3 was consistent with the proposed title structure.
FAB 536(M+).
Exact mass FAB for C 32
H
43 C1N 3 0 2 Theory: 536.3044.
Found: 536.3044.
WO 97/09308 WO 9709308PCTIUS96/141 63 169 Example 69B Preparation of 2-[(4-chlorophenoxy)methyl}. 1-methyl-3-[[2-[l143-( 1tritylpipericlin-3-yl)propyllpiperidin-4yl]]ethyllcarbonyl 1H-indole
CH-
FDMS 779 Analysis for C 5 1
H
56 C1N 3 0 2 Theory: C, 78.69; H, 7.25; N, 5.40.' Found: C, 78.92; H, 7.41; N, 5.27.
Example 69C Preparation of 2-II(4-chlorophenoxy)methyll.. -methyl-3-[[2-[ 1-13- (piperidin-3-yl)propyllpiperidin-4.yl]]ethyl]carbonyl.. H-indole
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 536 Analysis for C 32
H
42 C1N 3 0 2 Theory: C, 71.69; H, 7.90; N, 7.84.
Found: C, 71.45; H, 7.85; N, 7.61.
WO 97/09308 WO 9709308PCT/US96/1 416-3 170 Example Preparation of (RS) 2-[(4-cblorophenoxy)methyl.l-13-(piperidin-3yl )propylll-3-[[4-(piperidin- 1-yl)piperidin- 1-yllacetyl]- 1H-indole 0 NaZ ND
N
N
H
NMR (CDCl 3 was consistent with the proposed title structure.
Exact Mass FAB for C 35
H
48 C1N 4 0 2 Theory: 591.3466.
Found: 591.3476.
Exampile Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-13-(piperidin-3- 0 ND ND WO 97/09308 WO 9709308PCTIUS96/1416-3 -171- NMR (CDCl 3 was consistent with the proposed title structure.
FABMS 591.3476 Analysis for C 35
H
47 C1N 4 0 2 Theory: C, 71.10; H, 8.01; N, 9.48.
Found: C, 70.82; H, 8.14; N, 9.23.
Example Preparation of 2 -[(4-chlorophenoxy)methyl].l-[3-(piperidin-3- 0 N
H
NIVR (CDC1 3 was consistent with the proposed title structure.
Exact Mass for C35H48C1N402: Theory: 591.3466.
Found: 591.3458.
Example 71 Preparation of 2 4 -chlorophenoxy)methyl.. l4 3 -(piperidin-4-yl)propyl]-3- [[4-(piperidin- 1-yl)piperidin- 1-yllacetyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 172
NQ-NQ
NMR (CDCl 3 was consistent with the proposed title structure.
Exact Mass for C35H 48 C1N 4 0 2 Theory: 591.3466.
Found: 591.3464.
Examnie 72 Preparation of (RS) 2-I(4-chlorophenoxy)methyl]. l-13-(piperidin-3yl)propyl]-3-113-(piperidin-3-yl)propanoyl.. H-indole
H
NN
H
NMR (CDCl 3 was consistent with the proposed title structure.
Exact Mass for C 31
H
4 1 C1N 3 0 2 Theory: 522.2887.
Found: 522.2905.
WO 97/09308 WO 9709308PCT/US96/I 4163 173 Example 73 Preparation of 2-I(4-chlorophenoxy)methyl]- l4 3 -(piperidin-4-yl)propyl] -3- 3 -(piperidin-3-yl)propanoyl]- 1H-indole
H
N
H
NMR (CDCl 3 was consistent with the proposed title structure.
Exact Mass for C 31
H
4 1 C1N 3 0 2 Theory: 522.2887.
Found: 522.2910.
Example 74 Preparation of 2 -[(4-chlorophenoxy)methyl]- l43-(piperidin-3-yl )propyl]-3- 3 -(piperidin-4-yl)propanoyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 174 JR and NMR (CDCl 3 were consistent with the desired title structure.
FABMS 522 (M+1) Analysis for C3lH 40 C1N 3 0 2 Theory: C, 71.31; H, 7.72; N, 8.05.
Found: C, 71.04; H, 7.89; N, 7.78.
Example .0 Preparation of 2 -[(4-chlorophenoxy)methyl]- l-[ 3 -(piperidin-4-yl)propyl]-3- 3 -(piperidin-4-yl)propanoyl]- 1H-indole NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 522 (M+1) Analysis for C 31
H
40 C1N 3 0 2 Theory: C, 71.31; H, 7.72; N, 8.05.
WO 97/09308 WO 9709308PCT/US96/14163 175 Found: C, 7 1. 10; H, 7.66; N, 7.97.
Example 76 Preparation of 2 -I(4-chlorophenox y)methyl]- 1-methyl-3-[[[3- (dimethylamino)propylaminolcarbonyllmethyl.llH-indole 0H N 1 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 413 Analysis for C 23
H
28 C1N 3
O
2 Theory: C, 66.74; H, 6.82; N, 10.15.
Found: C, 66.89; H, 6.96; N, 10.11.
ExaMle 77 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[ 1-hydroxy- 1-114- (pipericlin- l-yl)piperidin- l-yllcarbonyllmethyl]- 1H-indole NQ Q
OH
N 0
CH
3 C1 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 495 Analysis for C 28
H
34 C1N 3 0 3 Theory: C, 67.80; H, 6.91; N, 8.47.
Found: C, 67.86; H, 6.90; N, 8.45.
WO 97/09308 WO 9709308PCTIUS96/1 4163 176 Example 78 Preparation of l-methyl-2-[(4-chlorophenoxy)methylindol.3 yllglyoxylic acid 0OH N 0 N 03 Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 343 Analysis for C 18
H
14 C1NO 4 Theory: C, 62.89; H, 4.11; N, 4.07.
Found: C, 63.15; H, 4.37; N, 3.92.
Example 79 Preparation of methyl l-methyl- 2 -[(4-chlorophenoxy)methylind 0 o..3 yllglyoxylate
OCH
3 0 Cl NMR (CDC1 3 and IR were consistent with the desired title structure.
Exact Mass FAB for C 19
H
17 C1N0 4 Theory: 358.0846.
Found: 358.0818.
WO 97/09308 WO 9709308PCTIUS96/14163 177 Examu~le Preparation of phenyl l-methyl-2-[(4-chlorophenoxy)methyllindol-3 yllglyoxylate 0
CH
3 Cl NMR (CDCl 3 was consistent With the proposed title structure.
FDMS 419 Analysis for C2 4
H
18 C1N0 4 Theory: C, 68.66; H, 4.32; N, 3.34.
Found: C, 68.90; H, 4.49; N, 3.33.
Example 81 Preparation of 2 -[(4-chlorophenoxy)methyl.. -methyl-3-[2-ainino- 1,2ethanedionyl]- 1H-indole
NH
2 h 0 N 0
CH
3 NMR (DMSO) was consistent with the proposed title structure.
FDMS 342 Analysis for C 18
H
15 C1N 2 0 3 Theory: C, 63.07; H, 4.41; N, 8.17.
Found: C, 63.36; H, 4.50; N, 8.18.
WO 97/09308 WO 9709308PCTIUS96/14163 178 Example 82 Preparation of 2 -[(4-cblorophenoxy)methyl]- l-methyl-3-[2-methylanino- 1 ,2-ethanedionyl]- iB-indole
NHCH
3 0 C1 NMR (CDCJ 3 was consistent with the proposed title structure.
FDMS 357 (M+1) Analysis for C 19
H
17 C1N 2 0 3 Theory: C, 63.96; H, 4.80; N, 7.85.
Found: C, 63.97; H, 4.83; N, 7.82.
Example 83 Preparation of 3-dimethylaminopropyl 1-methyl-2-[4chlorophenoxy)methyllindol.3.yllglyoxylate 0 N 0 Cl.
NMIR (CDCl 3 was consistent with the proposed title structure.
C
23
H
25 C1N 2 0 4 FAB 429 Single compound of high purity as evidenced by chromatographic methods.
Example 84 WO 97/09308 WO 9709308PCT/US96/1 4163 179 Preparation of 2 -I(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[2- (dimethylamino)ethylamino]- 1,2-ethanedionyl]- iR-indole hydrochloride N CH 3 N -0 CH 3 C1 *HCl NMR (CDCl 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FDMS 413 Analysis for C 2 2
H
2 4 C1N 3 0 3 0 HCl: Theory: C, 58.67; H, 5.59; N, 9.33.
Found: C, 58.38; H, 5.82; N, 9.48.
ExamDle Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[3- (dimethylamino)propylamino]- 1,2-ethanedionyl]- 1H-indole NN-N~N
(CH
3 2 200 NMR (CDCl 3 was consistent with the proposed title structure.
Exact Mass FAB for C 23
H
27 C1N 3 0 3 Theory: 428.1741.
Found: 428.1738.
Example 86 WO 97/09308 WO 9709308PCTIUS96/14163 180 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[3aminopropylamino]- 1,2-ethanedionyl]- 1H-indole IR, NMR, and UV were consistent with the desired title structure.
FDMS 399 Analysis for C 21
H
22
CIN
3
O
3 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.
Example 87 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[3-(tbutoxycarbonylamino)propylamnolJ.1 ,2-ethanedionyl]- 1H-indole HHo N 0 CH Cl1 IR, NIVR, and UV were consistent with the desired title structure.
FDMS 499 mp 175-176'C.
Analysis for C 26
H
30 C1N 3 0 5 Theory: C, 62.46; H, 6.05; N, 8.40.
WO 97/09308 WO 9709308PCT[US96/1 4163 -181- Found: C, 62.19; H, 6.08; N, 8.27.
Example 88 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[2 ,2-dimethyl- 3-(dimethylamino )propylamino]- 1,2-ethanedionyl]- iR-indole H
CH
3 N k N (CH 3 2 0 CH3 QN 0 C 1 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 455 Analysis for C 25
H
30 C1N 3 0 3 Theory: C, 65.85; H, 6.63; N, 9.22.
Found: C, 65.62; H, 6.76; N, 9.12.
Example 89 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[6- (dimethylamino )hexylamino]- 1,2-ethanedionyl]- 1H-indole
H
0 N (CH 3 2 N 0
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
Exact Mass FAB for C 2 7
H
33 C1N 3 0 3 Theory: 470.2210.
WO 97/09308 WO 9709308PCTLJS96/1 4163 182 Found: 470.2196.
Example Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[N-methyl.2- (dimethylamino)ethylamino]- 1,2-ethanedionyl]- 1H-indole
CH
3 N 0 CH3l NMR, UV, and JR were consistent with the desired title structure.
FDMS 427 mp 142-143TC.
Analysis for C 23
H
26 C1N 3 0 3 Theory: C, 64.56; H, 6.12; N, 9.82.
Found: C, 64.82; H, 6.32; N, 9.89.
Examnie 91 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-[N-methylk3 (dimethylamino)propylamino]- 1,2-ethanedionyl]- 1H-indole 0
CHN
2 N 0C3 C1 NMR (CDCl 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
Exact Mass FAB for C 24
H
29 C1N 3 0 3 Theory: 42.1897.
WO 97/09308 WO 9709308PCT/US96/141 63 183 Found: 442.1904.
Example 92 Preparation of 2-[(4-chlorophenoxy)methyl]- l-methyl-3-[2-[N-methyl3- (dimethylamino)propylamino]- 1,2-ethanedionyl]- 1H-indole hydrochloride 0
H
N~ (CH 3 2 N 0
CH
3 '1Z~
C'
NMR (CDCl 3 was consistent with the proposed title structure.
JR was consistent with the desired title product.
FDMS 441 Exact Mass FAB for C 24
H
29 C1N 3 0 3 442.1897.
Found: 442.1895.
Exam~le 93 Preparation of 2 -[(4-chlorophenoxy)methyl]-l-methyl.3-[2-[bis[3- (dimethylamino )propyllamino]- 1,2-ethanedionyl]- iR-indole (H3C) 2
N;
0 QN 0
CH?
''QCl WO 97/09308 WO 9709308PCTIUS96/14163 184 NMR (CDC1 3 was consistent with the proposed title structure.
FDMS 512 Analysis for C 28
H
37
CIN
4 0 3 Theory: C, 65.55; H, 7.27; N, 10.92.
Found: C, 65.85; H, 7.46; N, 11.04.
Example 94 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methy1-3-[2-jIN-benzyl-3- (dimethylamino)propylamino]- 1,2-ethanedionyl]- 1H-indole
(CH
3 2 0
CH
3 C1 IR, NMR, and UVY were consistent with the desired title structure.
FDMS 517 Analysis for C 30
)H
32 C1N 3 0 3 Theory: C, 69.55; H, 6.23; N, 8.11.
Found: C, 69.82; H, 6.31; N, 8.13.
Example Preparation of 2 -I(4-chlorophenoxy)methyl}. 1-methyl-3-[2-[N-methyl-3-[ 1- (t-butoxycarbonyl )pipericlin-3-yllpropylaino]- 1,2-ethanedionyl]-l1W indole WO 97/09308 WO 9709308PCTIUS96/14163 185 N C BoC C 3l NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 581 Analysis for C 3 2
H
4 0 C1N 3 0 5 Theory: C, 66.02; H, 6.93; N, 7.22.
Found: C, 65.91; H, 7.14; N, 7.08.
Example 96 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-12-( 1methylpiperidin-3-yl)amino]1,2ethaedionyl.. H-indole N
CH
3 h 0
N
N
C
CH
3 Cl- NMR (CDCl 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FDMS 439 Analysis for C 24
H
2 6
CIN
3 0 3 Theory: C, 65.52; H, 5.96; N, 9.55.
Found: C, 65.80; H, 5.96; N, 9.56.
ExaMle 97 Preparation of 2 4 -chlorophenoxy)methyl]1.-methyl.3[2[Nmethyl.(l1 methylpyrrolidin-3-yl)amino 1,2-ethanedionyl]- li-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 186 IR, NMR, and UV were consistent with the desired title structure.
FDMS 439 Analysis for C 24
H
26 C1N 3 0 3 Theory: C, 65.52; H, 5.96; N, 9.55.
Found: C, 65.54; H, 6.03; N, 9.69.
Example 98 Preparation of (RS) 2 -[(4-cblorophenoxy)methyl]- 1-methyl-3-[2-[Nmethyl-( l-methylpiperidin-3-yl)amino]- 1,2-ethanedionyl]- 1H-indole
CH
3 N 0
~CH
3
C
JR was consistent with the desired title structure. FDMS 453 Analysis for C 25
H
28 C1N 3 0 3 Theory: C, 66.14; H, 6.22; N, 9.26.
Found: C, 65.86; H, 6.17; N, 9.29.
Example 99 Preparation of 2 -[(4-chlorophenoxy)methyl..l-methyl-3-[2-[(quinuclidin.
3-yl )axmno]- 1,2-ethanedionyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/14163 187 0 H N 0
C'
NMR, UJV, and IR were consistent with the desired title structure.
FDMS 451 mp 204-2051C.
Analysis for C25H2 6 C1N 3 0 3 Theory: C, 66.44; H, 5.80; N, 9.30.
Found: C, 66.37; H, 5.88; N, 9.37.
Example 100 Preparation of 2 -[(4-chlorophenoxy)methyl..l-methyl-3-[2-(piperidin. 1yl)- 1,2-ethanedionyl]- 1H-indole 0
NQ
N 0 C1 NIVR (CDC1 3 was consistent with the proposed title structure.
FDMS 410 Analysis for C 2 3
H
2 3 C1N 2 0 3 Theory: C, 67.22; H, 5.64; N, 6.82.
Found: C, 67.50; H, 5.81; N, 6.63.
Example 10 1 WO 97/09308 WO 9709308PCT/US96/14163 188 Preparation of 2 -[(4-cblorophenoxy)methyl]-1-methyl..3[2-[2- (dimethylaminomethyl )cyclohexylamino- 1 ,2-ethanedionyl]- 1H-indole hydrochloride
N(CH
3 2
H
N
0 0
CH
3 Cl NMR (DMSO) was consistent with the proposed title structure.
FDMS 481 Analysis for C 2 7H 32 C1N 3 0 3 HCl: Theory: C, 62.55; H, 6.42; N, 8.10.
Found: C, 62.56; H, 6.44; N, 8.06.
Example 102 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-12-(4methylpiperidin- 1-yl)- 1, 2-ethanedionyl]- 1H-indole
CH-
3 NMR (CDCl 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FDMS 424 Analysis for C 24
H
25 C1N 2 0 3 Theory: C, 67.84; H, 5.93; N, 6.59.
WO 97/09308 WO 9709308PCT/US96/1 41 63 189 Found: C, 68.04; H, 5.85; N, 6.74.
Example 103 Preparation of 2-I(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(4benzylpiperidin- l-yl)- 1,2-ethanedionyl]-1H-indole h o 0
CH
3 Cl NMR (CDCl 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FDMS 500 Anallysis for C 30
H
29 C1N 2 0 3 Theory: C, 71.92; H, 5.83; N, 5.59.
Found: C, 71.69; H, 5.74; N, 5.38.
Example 104 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(4aminocarbonylpipericlin- l-yl 1,2-ethanedionyl]- 1H-indole
NH
2
CH-,
NMR, UV, and JR were consistent with the desired title structure.
WO 97/09308 WO 9709308PCTIUS96/1 4163 -190- FDMS 453 mp 220-221'C.
Analysis for C 24
H
24
CIN
3 0 4 Theory: C, 63.50; H, 5.33; N, 9.26.
Found: C, 63.45; H, 5.50; N, 9.18.
Example 105 Preparation of 2-[(4-chlorophenoxy)methyl-1.methy..3-2(4.
dimethylaminopiperidin- 1-yl)- 1,2-ethanedionyl] H-indole
CH
3
N
0o~ CH 3 N 0
CH
3 loci NiVR (CDCl 3 was consistent with the proposed title structure.
Exact Mass FAB for C 25
H
29 C1N 3 0 3 Theory: 454.1897.
Found: 454.1882.
ExaMrile 106 Preparation of 2 -[(4-chlorophenoxy)methyl]- l-methyl-3-[2-[4-(piperidinyl)piperidin- l-yl]- 1,2-ethanedionyl]- 1H-indole WO 97/09308 WO 9709308PCT/US96/1 4163 191
NN
CH a
CH
3 1 NMR (CDCl 3 and JR were consistent with the proposed title structure.
FDMS 493 Analysis for C 28
H
32 C1N 3 0 3 Theory: C, 68.07; H, 6.53; N, 8.51.
Found: C, 67.97; H, 6.66; N, 8.27.
Example 107 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(3aminocarbonylpiperidin- l-yl)-1 ,2-ethanedionyl]- 1H-indole
HN
00 0 QN 0 CH3l IR, NMR, and UV were consistent with the desired title structure.
FDMS 453.
mp 229-230'C Analysis for C 24
H
24 C1N 3 0 4 Theory: C, 63.50; H, 5.33; N, 9.26.
Found: C, 63.53; H, 5.44; N, 9.04.
WO 97/09308 WO 9709308PCTIUS96/141 63 192 Exam~le 108 Preparation of 2 -[(4-chlorophenoxy)methyl]- l-methyl-3-1j2-(piperazin-. 1 yl)- 1,2-ethanedionyl]- 1H-indole 0$NH h 0 N '0 C1 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 411 mp 168-169*C.
Analysis for C 2 2
H
2 2 C1N 3 0 3 Theory: C, 64.15; H, 5.38; N, 10.20.
Found: C, 63.95; H, 5.36; N, 10.08.
Example 109 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(4isopropylpiperazin- 1-yl)- 1,2-ethanedionyl]- 1H-indole
CH
3 M ZL H 3
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
WO 97/09308 WO 9709308PCTIUS96/1 4163 193 FDMS 453 Analysis for C 25
H
28
CIN
3 0 3 Theory: C, 66.15; H, 6.22; N, 9.26.
Found: C, 65.94; H, 6.48; N, 8.97.
Examplie 110 Preparation of 2 -I(4-chlorophenoxy)methyl.. -methyl-3-[2-[4-(tbutoxycarbony1)piperazin- 1-yl]- 1,2-ethanedionyl]- 1H-indole IR, NMR, and UV were consistent with the desired title structure.
FDMS 511 mp 200-201-C Analysis for C 27
H
30 C1N 3 0 5 Theory: C, 63.34; H, 5.91; N, 8.21.
Found: C, 63. 10; H, 5.80; N, 7.98.
Example Ill Preparation of 2-[(4-chlorophenoxy)methyl.. -methyl-3-[2-(4cyclohexylpiperazin-1-yl)- 1,2-ethanedionyl]- 1H-indole WO 97/09308 WO 9709308PCT/US96/1 4163 194 0 rN
NJ
N 0
CH
3
C'
NMR (CDCl 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FDMS 493 Analysis for C 28
H
32 C1N 3
O
3 Theory: C, 68.07; H, 6.53; N, 8.50.
Found: C, 67.81; H, 6.60; N, 8.24.
Example 112 Preparation of 2 -[(4-chlorophenoxy)methyl]. 1-methyl-3-[2-[4-(2dimethylanunoethyl)piperazin. 1,2-ethanedionyl]- iR-indole dihydrochioride 0 N C 3 N 0 C 3 C1 *2 HCl NAM (CDC1 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FDMS 482 Analysis for C 2 6
H
3 1
CIN
4 0 3 02 HCl: Theory: C, 56.17; H, 5.98; N, 10.07.
WO 97/09308 WO 9709308PCT/US96/j 4163 195 Found: C, 56.47; H, 6.07; N, 10.05.
Example 113 Preparation of 4 -chlorophenoxy)methyl]..lmethylp3[2-[3 aminoacetylpyrrolidin. 1,2-ethanedionyl]- 1H-indole 00
CH
3 C1 NMR (ODC1 3 was consistent with the proposed title structure.
JR was consistent with the desired title structure.
FDMS 453 Analysis for C24H 24
CIN
3 0 4 Theory: C, 63.50; H, 5.33; N, 9.26.
Found: C, 63.75; H, 5.37; N, 9.21.
Example 114 Preparation of 2-[(2,4-dichlorophenoxy)methyl.. -methyl-3-[2-IN.methyl.
3-(dimethylamino )propylamino]- 1,2-ethanedionyl]-lHidl
CH
3 3 01 h C H 3 N 0
CH
3 C 1 NMR (CDCl 3 was consistent with the proposed title structure.
WO 97/09308 WO 9709308PCTIUS96/14163 196 UV was consistent with the desired title structure.
FDMS 475 Analysis for C 24
H
27 C1 2
N
3 0 3 Theory: C, 60.51; H, 5.71; N, 8.82.
Found: C, 60.69; H, 5.80; N, 8.77.
Example 115 Preparation of 2-[(2,4-dichlorophenoxy)methyl.. 1-methyl-3-[2-[N-methylb (1-methylpiperidin-4-yl)amino]- 1,2-ethanedionyl]- 1H-indole
CH
3
N-CN-CH
3
N
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
C2 5
H
27 C1N 3 0 3 FDMS 487 Single compound of high purity as evidenced by chromatographic methods.
Examp-le 116 Preparation of ,4-dichlorophenoxy)methyl.. -methyl-3-[2-[4-(N,Ndimethylamino )piperidin- 1-ylI- 1 ,2-ethanedionyl]- iB-indole CH3 o CHI
N,
CH,
WO 97/09308 WO 9709308PCT/US96/I 416-3 197 NMR (CDC1 3 was consistent with the proposed title structure.
LTV was consistent with the desired title structure.
FDMS 487,489 Analysis for C 25
H
27 C1 2
N
3 0 3 Theory: C, 61.48; H, 5.57; N, 8.60.
Found: C, 61.75; H, 5.63; N, 8.59.
ExaMple 117 Preparation of 2-11(2 ,4-dichlorophenoxy)methyl]- 1-methyl-3-[2-[(4- (piperidin- l-yl)piperidin- l-yl]- 1,2-ethanedionyl]- 1H-indole
NO
h 0 N O
OH
3 C1 IR, NMR, and UV were consistent with the desired title structure.
FDMS 527,529 Analysis for C 28
H
31 C1 2
N
3 0 3 Theory: C, 63.64; H, 5.91; N, 7.95.
Found: C, 63.82; H, 6.08; N, 7.85.
Example 118 Preparation of 2
-I(
2 -cyano-4-bromophenoxy)methyl.. -methyl-3-[2-[Nmethyl-( 3 -dimethylaminopropyl )amino]- 1,2-ethanedionyl] H-indole WO 97/09308 WO 9709308PCTIUS96/14163 198 o CH 3 CH3 Lo,
CN
&H
3 Br IR, NMR, and UV were consistent with the desired title structure.
FDMS 511, 513 Analysis for C25H 27 BrN 4
O
3 0 0.5 H 2 0: Theory: C, 57.70; H, 5.42; N, 10.75.
Found: C, 57.56; H, 5.36; N, 10.60.
Exact Mass for C2 5
H
2 8 BrN 4
O
3 Theory: 511.1332.
Found: 511.1345.
Example 119 Preparation of 2 2 -cyano-4-bromophenoxy)methyl.. -methyl-3-[2-[Nmethyl-( l-rnethylpiperidin-4-yl)amino..1 ,2-ethanedionyl]- 1H-indole oCH 3 Q N -QN-CH3 N) O00CN
CH
3 Br IR, NMR, and UV were consistent with the desired title structure.
2 0 FDMS 522, 524 Analysis for C 2 6
H
2 7 BrN 4
O
3 Theory: C, 59.66; H, 5.20; N, 10.70.
Found: C, 59.38; H, 5.24; N, 10.49.
Example 120 WO 97/09308 WO 9709308PCTIUS96/1 4163 199 Preparation of 2
-I(
2 -cyano-4-bromophenoxy)methyl.. -methyl-3-12-(4dimethylaminopiperidin- 1,2-ethanedionyl)- iR-indole N fN C32
CH,
JR, NMR, and UV were consistent with the desired title structure.
FDMS 522,524 Analysis for C 26
H
27 BrN 4
O
3 0 0.5 H 2 0: Theory: C, 58.65; H, 5.30; N, 10.52.
Found: C, 58.61; H, 5.21; N, 10.42.
Exact Mass for C 26
H
28 BrN 4
O
3 Theory: 523.1345.
Found: 523.1365.
Example 121 Preparation of 2 2 -cyano-4-bromophenoxy)methyl.. -methyl-3-[2-14- (piperidin- 1-yl)piperidin- l-yl]]-1 ,2-ethanedionyl]- 1H-indole
N
IR, NiVR, and UV were consistent with the desired title structure.
FDMS 563,565 WO 97/09308 WO 9709308PCT/US96/1 4163 200 Analysis for C2 9
H
3 lBrN 4
O
3 Theory: C, 61.81; H, 5.54; N, 9.94.
Found: C, 61.56; H, 5.62; N, 9.91.
Example 122 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-ethyl-3-12-(4dimethylaminopipericlin- 1,2-ethanedionyl]- 1H-indole 0 NC TN (Gil 3 2 h 0
H
3
C
C1 IR, NMR, and LTV were consistent with the desired title structure.
FDMS 467.
Analysis for C 26
H
30 C1N 3 0 3 Theory: C, 66.73; H, 6.46; N, 8.98.
Found: C, 66.88; H, 6.57; N, 8.90.
Example 123 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-ethyl-3-[2-[N-methyl-( 1methylpiperidin-4-yl)aminol 1,2-ethanedionyl]- 1H-indole
H
3 C3 Il WO 97/09308 WO 9709308PCTIUS96/1 4163 -201- IR, NMR, and UV were consistent with the desired title structure.
FDMS 467.
Analysis for C 26
H
30 C1N 3 0 3 Theory: C, 66.73; H, 6.46; N, 8.98.
Found: C, 66.90; H, 6.70; N, 9.03.
Example 124 Preparation of 2 -I(4-chlorophenoxy)methyl]- 1-benzyl-3-12-(4dimethylaininopiperidin- 1,2-ethanedionyl]- 1H-indole 0 rI§1T N (CH 3 2 6 Cl IR, NMR, and UV were consistent with the desired title structure.
FDMS 529.
Analysis for C3 1
H
32 C1N 3 0 3 Theory: C, 70.24; H, 6.08; N, 7.93.
Found: C, 70.26; H, 6.18; N, 7.73.
Example 125 Preparation of 2-I(4-chlorophenoxy)methyl.. -(2-piperidin- 1-ylethyl [4-(piperidin- 1-yl)piperidin- 1-yl]- 1,2-ethanedionyl]- 1H-indole WO 97/09308 WO 9709308PCT/US96/14163 202 0 00 NMR (CDCl 3 was consistent with the proposed title structure.
Exact Mass FAB for C 34 H44ClN 4
O
5 Theory: 591.3102.
Found: 591.3100.
Example 126 Preparation of 2 -[(4-chlorophenoxy)methyl]- l-[ 3 -(piperidin-3-yl)propyl [piperidin- 1-ylmethyl]-1H-indole
QN
N 0
N
H
NMR (CDCl 3 was consistent with the proposed title structure.
Single compound of high purity as evidenced by chromatographic methods.
WO 97/09308 WO 9709308PCT/US96/14163 203 Example 127 Preparation, of 2-[(4-cblorophenoxy)methyl]- 1-113-( 1-methylpiperidin-3yl)propyl )-3-Ilpiperidin- 1-ylmethyl]- iR-indole 0W
CH
3 NMR (CDC1 3 was consistent with the proposed title structure.
Single compound of high purity as evidenced by chromatographic methods.
Example 128 Preparation of 2-I(4-chlorophenoxy)methyl]- 1-ethyl-3-[(4dimethylaminopiperidin- 1-yl)methyl]- 1H-indole N (CH 3 2
H
3
C
WO 97/09308 WO 9709308PCT/US96/1 4163 204 NMR and UV were consistent with the desired title structure. FDMS 425 mp 115-116 0
C.
Analysis for C 2 5
H
3 2 C1N 3 0: Theory: C, 70.49; H, 7.57; N, 9.86.
Found: C, 70.70; H, 7.67; N, 9.80.
Example 129 Preparation of 2-[(4-chlorophenoxy)methyl]-1..benzyl-3[(4.
dimethylaxninopiperidin-1-y1)methyl..1Hindole NMR and UTV were consistent with the desired title structure. FDMS 488 mp 127-128 0
C.
Analysis for C 30
H
34
CIN
3 0: Theory: C, 73.83; H, 7.02; N, 8.61.
Found: C, 73.77; H, 7.21; N, 8.66.
ExamDle 130 Preparation of 2 -[(4-chlorophenoxy)methyl]. -[2-(piperidin- 1-yl)ethyl]-3- 4 -dimethylaminopiperidin- 1-yl)methyl]- iB-indole WO 97/09308 WO 9709308PCTIUS96/1 41&3 205 N (CH 3 2 0
C
NMR (CDC1 3 was consistent with the proposed title structure.
Exact Mass FAB for C30H 42 C1N 4 0: Theory: 509.3047.
Found 509.3018.
Example 131 Preparation of 2-[(4-cblorophenoxy)methyl]- l-[3-(piperidin- l-yl )propyl]-3- [(4-dimethylaminopiperidin- l-yl )methyl]- 1H-indole trihydrochloride N (CH 3 2 0 3 HC1
CC
NMR and UV were consistent with the desired title structure.
WO 97/09308 WO 9709308PCT[US96/1416-3 206 FDMS 523 mp 240-242'C.
Analysis for C 31
H
43 C1N 4 0 3 HCL: Theory: C, 58.86; H, 7.33; N, 8.86.
Found: C, 58.66; H, 7.09; N, 8.77.
Example 132 Preparation of 2 -[(4-cblorophenoxy)methyl]- l-[ 3 -(piperidin-3-yl)propyl..3 4 -dimethylaminopipericlin- 1-yl)methyl]- 1H-indole N (CH 3 2
N
N
NMR (CDCI 3 was consistent with the proposed title structure.
C
3 lH 43 C1N 4 0: FDMS 522 Single compound of high purity as evidenced by chromatographic methods.
Examnle 133 of 2 -[(4-chlorophenoxy)methyl].. -ethyl-3-[[4-(piperidin-l-1 yl)piperi din- 1-yllmethyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/14163 -207
NN
H
3
C
C1 NMR and UV were consistent with the desired title structure. FDMS 465 mp 130-1311C.
Analysis for C 2 8
H
36 C1N 3 0: Theory: C, 72.16; H, 7.79; N, 9.02.
Found: C, 72.12; H, 7.78; N, 8.86.
Example 134 Preparation of 2 -[(4-chlorophenoxy)methyl]- 1-benzyl-3-II[4-(piperidin- 1yl)piperidin- 1-yllmethyl]-1H-indole N 0 Cl NMR and IN were consistent with the desired title structure.
FDMS 527 mp 153-154'C.
Analysis for C 33
H
38 C1N 3 0: Theory: C, 75.05; H, 7.25; N, 7.96.
Found: C, 75.25; H, 7.40; N, 8.08.
Example 135 WO 97/09308 PCT/US96/14163 -208- Preparation of 2 -[(4-chlorophenoxy)methyl].l-[2-(piperidin-1-yl)ethyl]-3- [[4-(piperidin-l-yl)piperidin- 1-yl]methyl]- 1H-indole N 0 >C1 0 IR, NMR, and UV were consistent with the desired title structure.
FDMS 548 mp 102-103 0
C.
Analysis for C33H 4 5 C1N 4 0: Theory: C, 72.17; H, 8.26; N, 10.20.
Found: C, 72.12; H, 8.31; N, 10.17.
Example 136 Preparation of 2 -[(4-chlorophenoxy)methyl.l-[2-(piperidin-l-yl)ethyl]-1Hindole 0 0
CD
IR, NMR, and UV were consistent with the desired title structure.
FDMS 368 FAB 369 Analysis for C 2 2
H
2 5 C1N 2 0: Theory: C, 71.63; H, 6.83; N, 7.59.
WO 97/09308 WO 9709308PCTIUS96/141 63 -209- Found: C, 71.93; H, 7.28; N, 7.22.
Single compound of high purity as evidenced by chromatographic methods.
Examnie 137 Preparation of 2 -[(4-chlorophenoxy)methyl]- l-[ 2 -(piperidin-4-yl)ethyl]I-1Hindole N 0
"Q
NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 368 Analysis for C 22
H
25 C1N 2 0: Theory: C, 71.63; H, 6.83; N, 7.59.
Found: C, 71.66; H, 6.86; N, 7.87.
Exampl1e 138 Preparation of 2-I(phenylthio)methyl]- l-1 3 -(piperidin-3-yl)propyl]- 1Hindole WO 97/09308 WO 9709308PCTIUS96/14163 -210- N S N
H
NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 364 Analysis for C 2 3
H
2 8
N
2
S:
Theory: C, 75.78; H, 7.75; N, 7.69.
Found: C, 75.70; H, 7.73; N, 7.86.
Example 139 Preparation of 2 -[(4-chlorophenoxy)methyl]- l-[ 3 -(piperidin-3-yl)propyl]- 1H-indole N 0 ~C1
N
H
NMR (CDCl 3 was consistent with the proposed title structure.
Single compound of high purity as evidenced by chromatographic methods.
Example 140 WO 97/09308 WO 9709308PCT/US96/14163 -211- Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methylpiperidin-3yl)propyl]- 1H-indole ~0
N
CH
3 NMR and UV were consistent with the desired mp 97-98'C.
Analysis for C 24
H
29 C1N 2 0: Theory: C, 72.62; H, 7.36; N, 7.06.
Found: C, 72.59; H, 7.48; N, 7.14.
title structure.
Example 141 Preparation of hlorophenoxy)methyl]- l-[3-(piperidin-4-yl )propyl]- 1H-indole N 0 01
N
H
NMR (CDCl 3 was consistent with the proposed title structure.
2 0 C 23
H
27 C1N 2 0: FDMS 382 WO 97/09308 WO 9709308PCT/US96/14163 -212- Single compound of high purity as evidenced by chromatographic methods.
Example 142 Preparation of 2-[2-(4-chlorophenyl)ethyl]- l-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole hydrochloride 101 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 366 Anallysis for C 23
H
27 C1N 2 HCl: Theory: C, 68.48; H, 7.00; N, 6.94.
Found: C, 68.26; H, 6.87; N, 6.75.
Examnie 143 Preparation of 2-[(4-chlorophenylamino)methyl]- 1-methyl-3-[(piperidin- 1-yl)methyl]-1H-indole H3H QN N C1 NMR, UV, and JR were consistent with the desired title structure.
2 5 FDMS 367 mp 169'C.
WO 97/09308 WO 9709308PCTIUS96/1 4163 -213- Analysis for C 22
H
26 C1N 3 Theory: C, 71.82; H, 7.12; N, 11.42.
Found: C, 71.60; H, 7.05; N, 11.46.
Example 146 Preparation of 2 2 ,4-dichlorophenylamino)methyl]-l -methyl-3 [(piperidin- 1-yl)methyl]- 1H-indole NNo H C1
H
3
C
C1 NMR, UV, and JR were consistent with the desired title structure.
FDMS 401,403 mp 147-148'C.
Analysis for C 22
H
25 C1 2
N
3 Theory: C, 65.67; H, 6.26; N, 10.44.
Found: C, 65.48; H, 6.30; N, 10.59.
Examp-le 147 Preparation of 2 4 -chlorophenylamino)methyl].3-[(piperidin-l-1 yl)methyl]- 1H-indole
H
N N
H
WO 97/09308 WO 9709308PCT/US96/141 63 214 NMR, UV, and JR were consistent with the desired title structure.
FDMS 353, 354 mp 135'C.
Anailysis for C 21
H
24 C1N 3 Theory: C, 71.27; H, 6.84; N, 11.87.
Found: C, 71.90; H, 7.17; N, 12.02.
Exampl-e 148 Preparation of 2
-I(
2 ,4-dichlorophenylainino)methyl]-. -methyl-3- [(piperidin- 1-yl)methyl]- 1H-indole QN Nd
CH
3 C 1 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 401 mp 147-148'C.
Analysis for C 2 2H 25 C1 2
N
3 Theory: C, 65.47; H, 6.26; N, 10.44.
Found: C, 65.48; H, 6.30; N, 10.59.
Example 149 Preparation of 2-[(cyclohexylamino )methyl]- l-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole
~ND
QN N 63)D WO 97/09308 WO 9709308PCT/US96/1 4163 215 NMR, UV, and JR were consistent with the desired title structure.
FDMS 339 mp 162-164'C.
Analysis for C 2 2
H
3 3
N
3 Theory: C, 77.83; H, 9.80; N, 12.38.
Found: C, 75.98; H, 9. 11; N, 12.67.
Exact Mass FAB for C 22
H
3 4
N
3 Theory: 340.2753.
Found: 340.2770.
Example 150 Preparation of 2 -[(cyclohexylmethylanuno )methyl]- 1-methyl-3- [(piperidin- 1-yl )methyl]- 1H-indole dihydrochloride NO* 2HC1
CH
3 NMR, UV, and JR were consistent with the desired title structure.
FDMS 354, 390 mp 159-161'C.
Analysis for C2 3
H
3 5
N
3 0 2HCl: Theory: C, 64.78; H, 8.75; N, 9.85.
Found: C, 64.62; H, 8.82; N, 9.65.
Example 151 Preparation of 2-[(naphth-2-ylamino )methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole WO 97/09308 WO 9709308PCT/US96/14163 -216- 3
H
N
N
NMR (CDCl 3 IR, and UV were consistent with the proposed title structure.
FDMS 383 mp 144 0
C.
Analysis for C 26
H
29
N
3 Theory: C, 81.42; H, 7.62; N, 10.96.
Found: C, 81.26; H, 7.49; N, 10.89.
Example-152 Preparation of 2 -[[N-acetyl-N-(cyclohexylmethyl)aminolmethyl.. methyl-3-[(piperidin- 1-yl)methyl]- 1H-indole hydrochloride
N
N
N
CH
3 0 HC1
H
3
C
NMR, UV, and JR were consistent with the desired title structure.
FDMS 395 Analysis for C 2 5
H
3 7
N
3 0 0 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 C 25
H
38
N
3 0: Theory: 396.3015 Found: 396.3020 WO 97/09308 WO 9709308PCT/US96/14163 -217- ExaMle 153 Preparation of 2-[[IN-acetyl-N-(benzyl)amilnolmethyl]. 1-methyl-3- [(piperidin- 1-yl)methyl]-1H-indole hydrochloride
NNO
CH
3 0
H
3 C eC NMR, UV, and JR were consistent with the desired title structure.
FDMS 389 mp, 148-150*C.
Analysis for C 2 5
H
3 jN 3 0 HCl: Theory: C, 70.49; H, 7.57; N, 9.86.
Found: C, 70.21; H, 7.40; N, 9.73.
Example 154 Preparation of 2 -[[(3-chlorophenyl)aminolcarbonyl]- 1-methyl-3- [(piperi din- 1-yl)methyl]- 1H-indole
H
NMR, UV, and JR were consistent with the desired title structure.
FDMS 381, 383 mp 137-138 0
C.
Analysis for C 22
H
24 C1N 3 0: Theory: C, 69.19; H, 6.33; N, 11.00.
Found: C, 69.39; H, 6.39; N, 11.20.
WO 97/09308 WO 9709308PCT/US96/1 4163 218 Example 155 Preparation of 2 2 4 -dichlorophenyl)aininolcarbonyl.. -methyl-3- [(piperidin- 1-yl)methyl]- 1H-indole
NQ
H
N
0 NMR, UV, and JR were consistent with the desired title structure.
FDMS 417 mp 180-182'C.
Analysis for C 22
H
23 C1 2
N
3 0: Theory: C, 63.47; H, 5.57; N, 10.09.
Found: C, 63.27; H, 5.65; N, 10.18.
Example 156 Preparation of 2 -[[(cyclohexyl)arninolcarbonyl..l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole
~NQ
NN
CH
3 NMR, UV, and JR were consistent with the desired title structure.
FDMS 353 mp 180'C.
Exact Mass FAB for C2 2
H
32
N
3 0: Theory: 354.2545.
Found: 354.2543.
Example 157 WO 97/09308 WO 9709308PCTIUS96/14163 219 Preparation of 2 -[[~(cyclohexylmethyl)aminolcarbonyl]. 1-methyl-3- [(piperidin- 1-yl)methyl]- 1H-indole NMR (CDCl 3 IR, and UV were consistent with the proposed title structure.
mp 126TC.
Analysis for C 23
H
33
N
3 0: Theory: C, 75.16; H, 9.05; N, 11.43.
Found: C, 75.09; H, 9.03; N, 11.25.
Example 158 Preparation of 2 -[[(naphth-2-yl)aminolcarbonyl..l-methyl-3-[(piperidin- 1yl)methyl]- iB-indole NMR, UV, and JR were consistent with the desired title structure.
FDMS 397 mp 187TC.
Analysis for C 26
H
27
N
3 0: Theory: C, 78.56; H,,6.85; N, 10.57.
Found: C, 78.84; H, 7.02; N, 10.78.
Example 159 WO 97/09308 WO 9709308PCTIUS96/1 4163 220 Preparation of 2-[phenoxymethyl]- l-methyl-3-[(piperidin-1-yl)methyl].
iR-indole hydrochloride
N
OH
3 NMVR, UJV, and JR were consistent with the desired title structure.
FDMS 334 mp 2251C.
Analysis for C 2 2
H
2 6
N
2 0 HCl: Theory: C, 71.32; H, 7.34; N, 7.55.
Found: C, 71.45; H, 7.44; N, 7.79.
Example 160 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[(piperidin- 1yl)methyl]-1H-indole hydrochloride salt HCl
NN
OH
3 NMR, JR and UV were consistent with the desired title structure.
2 0 FDMS 368 mp, 214'C.
Analysis for C 22
H
25 C1N 2 0 HCL: Theory: C, 65.32; H, 6.46; N, 6.91.
Found: C, 65.46; H, 6.52; N, 7.16.
Examp~le 161 Preparation of 2-[(4-chlorophenoxy)methyl]- l-methyl-3-I(piperidin. yl )methyll- H-indole WO 97/09308 WO 9709308PCTIUS96/14163 221
NQ)
CH,
NMR was consistent with the desired title structure.
FDMS 368 Analysis for C 22
H
25 C1N 2 0: Theory: C, 71.63; H, 6.83; N, 7.59.
Found: C, 68.39; H, 6.55; N, 6.16.
Example 162 Preparation of 2-11(3 -chlorophenoxy)methyl]- 1-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole hydrochloride No HC 1
.C'
NMR, UV, and JR were consistent with the desired title structure.
FDMS 368 mp 222 0
C.
Analysis for C 22
H
25
CIN
2 0 HCl: Theory: C, 65.19; H, 6.46; N, 6,.91.
Found: C, 65.15; H, 6.55; N, 6.95.
Example 163 Preparation of -chlorophenoxy)methyl]- l-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole hydrochloride WO 97/09308 WO 9709308PCT/US96/I 4163 222 HC 1 NMR, UV, and IR were consistent with the desired title structure.
FDMS 369 Analysis for C 22
H
25 C1N 2 0 HCl: Theory: C, 65.19; H, 6.46; N, 6.91.
Found: C, 65.48; H, 6.65; N, 6.98.
Example 164 0 Preparation of 2 -[(4-fluorophenoxy)methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole hydrochloride No HC 1 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 352 Analysis for C2 2
H
25
FN
2 0 HCJ: Theory: C, 67.94; H, 6.74; N, 7.20.
Found: C, 67.74; H, 6.77; N, 7.16.
Example 165 Preparation of 2 3 -fluorophenoxy)methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole hydrochloride WO 97/09308 WO 9709308PCTIUS96/141 63 223 No
CH
3 1 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 352 Analysis for 02 2
H
2 5
FN
2 0 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.
Examile 166 Preparation of 2-[(2-fluorophenoxy)methyl]- 1-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole hydrochloride Qi- No.HC1
ICH
3 F: NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 352 Analysis for C 22
H
25
FN
2 0 HCL: Theory: C, 67.94; H, 6.74; N, 7.20.
Found: C, 67.67; H, 6.63; N, 7.40.
Example 167 Preparation of 2-[(4-trifluoromethylphenoxy)methyl.. -methyl-3- [(piperidin- 1-yl )methylllH-indole hydrochloride WO 97/09308 PCT/US96/14163 -224- O* •HC1
N
CH
3 O
CF
3 NMR, UV, and IR were consistent with the desired title structure.
FDMS 402 Analysis for C23H 2 5
F
3
N
2 0 HC1: 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.
Example 168 Preparation of 2 3 -trifluoromethylphenoxy)methyl]-l-methyl-3- [(piperidin-1-yl)methyl]- 1H-indole hydrochloride N T HC1 O 0 CF 3
N
CH
3 NMR, UV, and IR were consistent with the desired title structure.
FDMS 402 Analysis for C 2 3
H
2 5
F
3
N
2 0 HC1: 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.
Example 169 WO 97/09308 WO 9709308PCTIUS96/14163 225 Preparation of 2 -[(2-trifluoromethylphenoxy)methyl]-. -methyl-3- [(piperidin- l-yl )methyl]- 1H-indole hydrochloride No SHO 1 NMR, U-V, and JR were consistent with the desired title structure.
FDMS 402 Analysis for C 23
H
25
F
3
N
2 0 HCl: Theory: C, 62.94; H, 5.97; N, 6.38.
Found: C, 62.89; H, 6.02; N, 6.37.
Example 170 Preparation of 2 -[(4-acetylphenoxy)methyl]- 1-methyl-3-[(piperidin-1yl )methyl]- 1H-indole hydrochloride
N
OH
3
OH
3 NMR, UV, and JR were consistent with the desired title structure.
2 0 FDMS 376 Analysis for C 24 }1 28
N
2 0 0 HCL: Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 69.69; H, 7.27; N, 6.72.
Example 171 WO 97/09308 WO 9709308PCT/US96/14163 226 Preparation of 2 -[(3-acetylphenoxy)methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole hydrochloride NMR, UV, and JR were consistent with the desired title structure.
FDMS 376 Analysis for C 24
H
28
N
2 0 2 HCl: Theory: C, 69.80; H, 7.08; N, 6.78.
Found: C, 69.91; H, 7.18; N, 6.81.
Example 172 Preparation of 2 2 4 -dichlorophenoxy)methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- iR-indole hydrochloride -HC1 NMR and UV were consistent with the desired title structure.
2 0 FDMS 402 Analysis for C22H 24 C1 2
N
2 0: 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 methods.
Example 173 WO 97/09308 WO 9709308PCT/US96/1 4163 227 Preparation of 2-I(2,4-dichlorophenoxy)methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole hydrochloride Q HC 1
N
C
NMR, UV, and JR were consistent with the desired title structure.
FDMS 402 Analysis for C 22
H
24 C1 2
N
2 0 9 HCl: Theory: C, 60.08; H, 5.73; N, 6.37.
Found: C, 60.31; H, 6.00; N, 6.62.
Example 174 Preparation of 2 -[(3,5-dichlorophenoxy)methyl.. -methyl-3-[(piperidin- 1yl)methyl]- 1H-indole hydrochloride No7HC
CH
3 NMR, UV, and JR were consistent with the desired title structure.
FDMS 402 Analysis for C 22
H
24 C1 2
N
2 0 0 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.
WO 97/09308 WO 9709308PCT/U596/1 4163 228 Example 175 Preparation of 2-[(2,5-dichlorophenoxy)methyl]. l-methyl-3-[(piperidin-. 1 yl)methyl]- 1H-indole
NO
NMR, LUV, and JR were consistent with the desired title structure.
FDMS 402 Analysis for C 22
H
24 C1 2
N
2 0: Theory: C, 65.51; H, 6.00; N, 6.95.
Found: C, 65.71; H, 6.00; N, 6.93.
Example 176 Preparation of 2 -12,6-dichlorophenoxy)methyl.. lmethyl-3-[(piperidin- 1yl)methyl]- 1H-indole hydrochloride HC 1 NMR, UV, and JR were consistent with the desired title structure.
FDMS 402 Analysis for C2 2
H
24 C1 2
N
2 0 0 HCI: Theory: C, 60.08; H, 5.73; N, 6.37.
Found: C, 59.79; H, 5.43; N, 6.11.
Example 177 WO 97/09308 WO 9709308PCT/US96/1 4163 229 Preparation of ,4-dichlorophenoxy)methyl]- l-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole hydrochloride QO -HC1
N
CH
3
C
NMR, LTV, and JR were consistent with the desired title structure.
FDMS 402 Analysis for C 2 2
H
2 4 C1 2
N
2 0 HCl: Theory: C, 60.08; H, 5.73; N, 6.37.
Found: C, 59.82; H, 5.72; N, 6.21.
Example 178 Preparation of 2 -[(2,3-dichlorophenoxy)methyl l-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole
ICH
3 NMR, UV, and JR were consistent with the desired title structure.
FDMS 402 Analysis for C 24
H
24 C1 2
N
2 0: Theory: C, 65.51; H, 6.00; N, 6.95.
Found: C, 65.23; H, 5.96; N, 6.82.
Example 179 WO 97/09308 PCT/US96/14163 230 Preparation of 2-[(4-phenylphenoxy)methyl]l--methyl-3-[(piperidin-1yl)methyl]- H-indole
CH
3 NMR, UV, and IR were consistent with the desired title structure.
FDMS 410 Analysis for C 2 8
H
3 0
N
2 0: 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.
Example 180 Preparation of 2-[(3-phenylphenoxy)methyl]-l-methyl-3-[(piperidin-1yl)methyl]- 1H-indole hydrochloride NMR, UV, and IR were consistent with the desired title structure.
FDMS 410 Analysis for C 2 8
H
3 0
N
2 0 HC1: Theory: C, 75.23; H, 6.99; N, 6.27.
Found: C, 74.74; H, 7.10; N, 6.23.
WO 97/09308 WO 9709308PCT/US96/1 4163 -231- Single compound of high purity as evidenced by chromatographic methods.
Example 181 Preparation of 2 -I(2-phenylphenoxy)methyl]- 1-methyl-3-[(piperidin- 1yl)methyl]- iB-indole hydrochloride No HC 1 NMR, U-V, and JR were consistent with the desired title structure.
FDMS 410 Analysis for C 28
H
3 oN 2 0 9 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.
Example 182 Preparation of 2-[(4-methylphenoxy)methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole hydrochloride No *HC1 CH-i
ICH
3 NMR, LTV, and JR were consistent with the desired title structure.
WO 97/09308 WO 9709308PCTIUS96/1 4163 232 FDMS 348 Analysis for 0 2 3
H
2 8
N
2 0 0 HCl: Theory: C, 71.76; H, 7.59; N, 7.28.
Found: C, 70.88; H, 7.70; N, 7.32.
Single compound of high purity as evidenced by chromatographic methods.
Example 183 Preparation of 2 3 -methylphenoxy)methyl]- l-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole hydrochloride IND -HC 1 NMR, UV, and JR were consistent with the desired title structure.
FDMS 348 Analysis for C 23
H
28
N
2 0 HCL: Theory: C, 71.76; H, 7.59; N, 7.28.
Found: C, 72.41; H, 7.78; N, 7.29.
Single compound of high purity as evidenced by chromatographic methods.
Example 184 Preparation of 2-[(2-methylphenoxy)methyl..l-methyl-3-[(piperidin- 1yl )methyl]- iR-indole hydrochloride
N
HC 1 WO 97/09308 WO 9709308PCTIUS96/14163 233 NMR, UV, and JR were consistent with the desired title structure.
FDMS 348 Analysis for C 2 3
H
2 8
N
2 0 *HCl: Theory: C, 71.76; H, 7.59; N, 7.28.
Found: C, 71.71; H, 7.54; N, 7.21.
Example 185 Preparation of 2-[(4-methoxyphenoxy)methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole hydrochloride No
IOH
3 00H 3 NMR, UV, and IR were consistent with the desired title structure.
FDMS 364 Analysis for C2 3
H
2 8
N
2 0 2 e HCl: Theory: C, 68.90; H, 7.29; N, 6.99.
Found: C, 68.68; H, 7.30; N, 7.12.
Example 186 Preparation of 2-[(3-methoxyphenoxy)methyl..l-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole hydrochloride I~T NoV oHC
OCH
3 WO 97/09308 PCT/US96/14163 -234- NMR, UV, and IR were consistent with the desired title structure.
FDMS 364 Analysis for C 2 3
H
2 8
N
2 0 2 HC1: Theory: C, 68.90; H, 7.29; N, 6.99.
Found: C, 69.13; H, 7.38; N, 6.83.
Example 187 Preparation of 2-[(2-methoxyphenoxy)methyl]- l-methyl-3-[(piperidin-1yl)methyl]- 1H-indole hydrochloride HC1
N
CH
3
H
3
CO
NMR, UV, and IR were consistent with the desired title structure.
FDMS 364 Analysis for C 23
H
28
N
2 0 2 HC1: 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.
Example 188 Preparation of 2-[2-hydroxyethyl]-l-methyl-3-[(piperidin-l-yl)methyl]-lHindole No 0-1-
CH
3 WO 97/09308 WO 9709308PCTIUS96/141 63 235 Analysis for C1 6
H
22
N
2
O:
Theory: C, 74.38; H, 8.58; N, 10.84.
Found: C, 74.35; H, 8.78; N, 10.96.
Example 189 Preparation of 2-(2-methoxyethyl l-methyl-3-[(piperi din- 1-yl)methyl]iB-indole OCH3
N
CH3 NAM was consistent with the desired title structure.
FDMS 272, 273 Analysis for C 17
H
24
N
2 0: Theory: C, 74.96; H, 8.88; N, 10.28.
Found: C, 73.31; H, 8.86; N, 9.97.
Example 190 Preparation of 2 -(2-allyloxyethyl)- l-methyl-3-I(piperidin-.1-yl)methyl]- 1Hindole hydrochloride salt N C H 2 6H 3 HCl NMR, ITV, and JR were consistent with the desired title structure.
FDMS 298 Analysis for CjqH 2 6
N
2 0 9 HCl: Theory: C, 68.14; H, 8.13; N, 8.37.
WO 97/09308 WO 9709308PCT/US96/141 63 236 Found: C, 68.30; H, 8.14; N, 8.39.
Example 191 Preparation of 2-(benzyloxymethyl)- 1-methyl-3-II(piperidin- 1-yl)methyl]- 1H-indole hydrochloride
ND
CH
3 l0 IR, UV, and NMR (CDCl 3 were consistent with the proposed title structure.
FDMS 384 (M+i) Analysis for C2 3
H
2 8
N
2 0 0 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.
Example 192 Preparation of 2 -[(3-chlorobenzyloxy)methyl]- l-methyl-3-[(pipericlin- 1yl)methyl]- 1H-indole hydrochloride NMR was consistent with the desired title structure.
FDMS 382 Analysis for C 23
H
27
CIN
2 0 0 HCL: WO 97/09308 WO 9709308PCT/US96/I 4163 237 Theory: Found: C, 72.14; H, 7.11; N, 7.32.
C, 71.92; H, 7.22; N, 7.43.
Example 193 Preparation of 2 -[(2-chlorobenzyloxy)methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole
CH
3 C1 NMR was consistent with the desired title structure.
FDMS 382 mp 82-83 0
C.
Analysis for C2 3
H
27
CIN
2 0: Theory: C, 72.14; H, 7.11; N, 7.32.
Found: C, 71.87; H, 7.07; N, 7.36.
Example 194 Preparation of 2-[(4-chlorobenzyloxy)methyl]- l-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole hydrochloride *HCl NMR (CDC1 3 IR, and UJV were consistent with the proposed title structure.
FDMS 382 Analysis for C 23
H
27 C1N 2 0 9 HCl: Theory: C, 65.87; H, 6.73; N, 6.68.
WO 97/09308 WO 9709308PCT/US96/14163 238 Found: C, 65.54; H, 6.59; N, 6.39.
Example 195 Preparation of 2-[(naphth- 1-yloxy)methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole hydrochloride No HC 1 NMR, UV, and IR were consistent with the desired title structure.
FDMS 384 Analysis for C 2 6
H
28
N
2 0 HCl: Theory: C, 74.18; H, 6.94; N, 6.65.
Found: C, 74.47; H, 7.05; N, 6.64.
Example 196 Preparation of 2-[(naphth-2-yloxy)methyl]- l-methyl-3-[(piperidin-l-1 yl )methyl]- 1H-indole hydrochloride No NMR, UV, and JR were consistent with the desired title structure.
FDMS 384 Analysis for C 2 6
H
28
N
2 0 0 HCl: WO 97/09308 WO 9709308PCT/US96/141 63 239 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.
Example 197 Preparation of 2-[(thiazol-2-yl)methyl]- 1-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole No
CH
3 NMR was consistent with the desired title structure.
mp, 175-176'C.
FDMS 341 Analysis for CjqH 23
N
3 0S: Theory: C, 66.83; H, 6.79; N, 12.31.
Found: C, 66.64; H, 6.82; N, 12.03.
Example 198 Preparation of 2-[(pyrazin-2-yl)methyl]- 1-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole
~NQ
0,N
N
N
NMR, U-V, and JR were consistent with the desired title structure.
WO 97/09308 WO 9709308PCTIUS96/1 4163 240 FDMS 336 mp 101 0
C.
Analysis for C 2 oH 24
N
4 0: Theory: C, 71.40; H, 7.19; N, 16.65.
Found: C, 71.44; H, 7.33; N, 16.43.
Example 199 Preparation of 2 -[(6-chloropyrazin-2-yl)methyl]- l-methyl-3-i(pipeiridin-. 1 yl)methyl]- 1H-indole 3
NN
NMR, UV, and JR were consistent with the desired title structure.
FDMS 370 mp 94-961C.
Analysis for C 20
H
23 C1N 4 0: Theory: C, 64.77; H, 6.25; N, 15.11.
Found: C, 65.04; H, 6.45; N, 15.21.
Example 200 Preparation of 2-[(pyrimidin-2-yl )methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole
N
N
ICH
3 NMR, UV, and JR were consistent with the desired title structure.
FDMS 337 WO 97/09308 WO 9709308PCT/US96/1 4163 241 mp 123-125 0
C.
Analysis for C 2 oH 24
N
4 0: Theory: C, 71.40; H, 7.19; N, 16.65.
Found: C, 71.60; H, 7.43; N, 16.59.
Example 20 1 Preparation of 2-[(quinolin-2-yl)methyl]- l-methyl-3-[(piperidin- 1ylbmethyl]- 1H-indole 0N
NC
CH
3 4: NMR, UV, and IR were consistent with the desired title structure.
FDMS 385 mp 113'C.
Analysis for C 25
H
27
N
3 0: Theory: C, 77.89; H, 7.06; N, 10.90.
Found: C, 77.64; H, 7.00; N, 11.05.
Example 202 Preparation of 2-[(6-cbloropyridazin-2-yl)methyl]-l -methyl-3-[(piperidin- 1-yl)methyl]- 1H-indole 0, N..
N -'N
OH
3 z
C
NMR, UV, and JR were consistent with the desired title structure.
WO 97/09308 WO 9709308PCTIUS96/1 4163 242 FDMS 371 mp 138-139 0
C.
Analysis for C 20
H
23 01N 4 0: Theory: C, 64.77; H, 6.25; N, 15.11.
Found: C, 64.84; H, 6.28; N, 15.00.
Example 203 Preparation of 2-[(5,6,7,8-tetrahydronaphth-.1-yl)methyl]- 1-methyl-3-[(4dimethylaminopiperidin- 1-yl)methyl]- 1H-indole NaD N (CH 3 2
N
CH
3 N-MR was consistent with the desired title structure.
FDMS 431 Analysis for C 28
H
37
N
3 0: Theory: C, 77.92; H, 8.64; N, 9.74.
Found: C, 75.79; H, 8.74; N, 8.74.
Example 204 Preparation of 6 7 ,8-tetrahydronaphth-2-yl)methyl]. -methyl-3- dimethylaminopiperidin- 1-yl )methyl]- 1H-indole dihydrochioride hydrate NQa~N (H)2 N K 2 HC 1 WO 97/09308 WO 9709308PCTIUS96/14163 243 NMR and LUV were consistent with the desired title structure.
FDMS 431,432 mp 202'C.
Analysis for C 2 8
H
3 7
N
3 0 0 2 HCl 0 H 2 0: Theory: C, 64.36; H, 7.91; N, 8.04.
Found: C, 64.73; H, 7.50; N, 7.99.
Example- 205 Preparation of 2-liphenyithiomethyl]- l-methyl-3-[(piperidjn- 1-yl)methyl]- 1H-indole hydrochloride S-0 HC 1
N
ICH
3 NMR, LUV, and JR were consistent with the desired title structure.
FDMS 350 1).
Analysis for C 2 2
H
2 6
N
2 S e HCl: Theory: C, 68.28; H, 7.03; N, 7.24.
Found: C, 68.03; H, 7.00; N, 7.10.
Example 206 Preparation of 2-[(4-chlorophenylthio)methyl..l-methyl-3-I(piperidin- 1yl )methyl]- 1H-indole hydrochloride
N
CH
3 NNA1 NMR, UV, and JR were consistent with the desired title structure.
FDMS 384 WO 97/09308 PCT/US96/14163 -244- Analysis for C 22
H
2 5 C1N 2 S HC1: 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 methods.
Example 207 Preparation of 2-[(3-chlorophenylthio)methyl]-l-methyl-3-[(piperidin-1yl)methyl]- 1H-indole hydrochloride S HC1
CH
3 NMR, UV, and IR were consistent with the desired title structure.
FDMS 384 Analysis for C 2 2
H
25 C1N 2 S HC1: Theory: C, 62.70; H, 6.22; N, 6.65.
Found: C, 62.94; H, 6.23; N, 6.93.
Example 208 Preparation of 2-[(2-chlorophenylthio)methyl]-l-methyl-3-[(piperidin-1yl)methyl]-1H-indole hydrochloride *HC1 NMR, UV, and IR were consistent with the desired title structure.
FDMS 384 WO 97/09308 WO 9709308PCT/US96/14163 245 Analysis for C 2 2
H
2 5 C1N 2 S HCl: Theory: C, 62.70; H, 6.22; N, 6.65.
Found: C, 62.76; H, 6.20; N, 6.67.
Example 209 Preparation of ,4-dichlorophenylthio)methyl]- l-methyl-3-[(piperidinl-yl )methyl]- 1H-indole hydrochloride -HC1 NMR, UV, and JR were consistent with the desired title structure.
FDMS 418 Analysis for C 22
H
24 C1 2
N
2 S 0 HCl: Theory: C, 57.96; H, 5.53; N, 6.15.
Found: C, 56.61; H, 5.70; N, 6.05.
Single compound of high purity as evidenced by chromatographic methods.
ExaMple 210 Preparation of ,5-dichlorophenylthio)methyl..l-methyl-3-[(piperidin- 1-yl)methyl]-lH-indole hydrochloride HC 1
CH
3 1 NMR, LTV, and JR were consistent with the desired title structure.
WO 97/09308 WO 9709308PCT/US96/14163 246 FDMS 418,420 Analysis for C 22
H
24 C1 2
N
2 S 0 HCL: Theory: C, 57.96; H, 5.53; N, 6.15.
Found: C, 57.87; H, 5.50; N, 5.99.
Example 211 Preparation of ,6-dichlorophenylthio)methyl..l-methyl-3-I(piperilinl-yl )methyl]- 1H-indole hydrochloride No* HC 1 C1 N St
C,
NMR, UV, and IR were consistent with the desired title structure.
FDMS 417 Analysis for C22H 24 C1 2
N
2 S HCL: Theory: C, 57.96; H, 5.53; N, 6.15.
Found: C, 58.16; H, 5.68; N, 6.33.
Example 212 Preparation of ,4-dicblorophenylthio )methyl]-l1-methyl-3-[(piperidin- 1-yl)methyl]- 1H-indole hydrochloride No*HC1 S N Cl NMR, UV, and JR were consistent with the desired title structure.
FDMS 418,420 1).
WO 97/09308 WO 9709308PCTIUS96/141 63 247 Analysis for C 22
H
24 C1 2
N
2 S e HCL: Theory: C, 57.96; H, 5.53; N, 6.15.
Found: C, 57.98; H, 5.54; N, 6.16.
Example 213 Preparation of 2-[(cyclohexyltbio)methyl]- 1-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole hydrochloride No HC 1
N
CH
3 NMR (CDCl 3 UV, and JR were consistent with the proposed title structure.
FDMS 356 Analysis for C 2 2
H
32
N
2 S 0 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.
Exam~le 214 Preparation of 2-[(n-propylthio)methyl]- l-methyl-3-[(piperidin- 1yl )methylllH-indole hydrochloride WO 97/09308 WO 9709308PCTIUS96/1 416-3 248 NMR (CDCl 3 UV, and JR were consistent with the proposed title structure.
FDMS 316 Analysis for CjqH 2 8
N
2 S 0 HCL: Theory: C, 64.65; H, 8.28; N, 7.94.
Found: C, 64.72; H, 8.03; N, 8.12.
Example 215 Preparation of 2-I(benzylthio)methyl]- l-methyl-3-[(piperidin- 1-yl)methyl]- 1H-indole hydrochloride NO -HC1
ICH
3 NMR, UV, and JR were consistent with the desired title structure.
FDMS 365 Analysis for C 2 3
H
2 8
N
2 S HCL: Theory: C, 68.89; H, 7.29; N, 6.99.
Found: C, 68.63; H, 7.52; N, 7.11.
Example 216 Preparation of 2-[(2-phenylethylthio)methyl]- l-methyl-3-[(piperidin- 1yl )methyl]- 1H-indole
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
WO 97/09308 WO 9709308PCTIUS96/14163 249
C
24 1 3 oN- 2 S: FDMS 379 Single compound of high purity as evidenced by chromatographic methods.
Example 217 Preparation of 2-[(naphth-2-ylthio)methyl]- l-methyl-3-[(piperidin- 1yl)methyl]- 1H-indole N
T
sic~ NMR (CDCl 3 UV, and JR were consistent with the proposed title structure.
FDMS 400 Analysis for C 26
H
28
N
2 S 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.
Example 220 Preparation of 2-phenyl-3-(piperidin- 1-yl)methyl-1H-indole
ON
1A NMR, UV, and JR were consistent with the desired title structure.
WO 97/09308 WO 9709308PCT/US96/14163 250 FDMS 290 Analysis for C 20
H
22
N
2 Theory: C, 82.72; H, 7.64; N, 9.65.
Found: C, 82.97; H, 7.74; N, 9.81.
Example 221 Preparation of l-methyl-2-phenyl-3-(piperidin-l-yl)methyl-1H-indole No NMR, UV, and JR were consistent with the desired title structure.
FDMS 304, 305 Analysis for C 21
H
24
N
2 Theory: C, 82.85; H, 7.95; N, 9.20.
Found: C, 82.68; H, 7.92; N, 9.40.
Example 222 Preparation of 2-phenyl- l-methyl-3-[2-(piperidin- 1-yl)- 1,2-ethaneclionyl]- 1H-indole
NQ
0
N
NMR (CDCl 3 IR, and LTV were consistent with the proposed title structure.
FDMS 346 WO 97/09308 WO 9709308PCT/US96/1 4163 -251- Analysis for C 22
H
22
N
2 0 2 Theory: C, 76.28; H, 6.40; N, 8.09.
FOund: C, 76.09; H, 6.35; N, 8.09.
Example 223 Preparation of 2-phenyl- 1-methyl-3-[2-[N-benzyl-N-3- (dimethylaniinopropyl)amino]- 1,2-ethanedionyl]-1H-indole
CH
3 IR, NMR, and UV were consistent with the desired title structure.
FDMS 453 Analysis for C 29
H
31
N
3 0 2 Theory: C, 76.79; H, 6.89; N, 9.26.
Found: C, 77.06; H, 7.02; N, 9.45.
Example 224 Preparation of 2-phenyl- l-methyl-3-[2-(4-dimethylaminopipeidin-.1-yl 1 ,2-ethanedionyl]- 1H-indole 0 ZCH-
N&Z+N\
0 WO 97/09308 WO 9709308PCTIUS96/1 4163 252 IR, NMR, and UV were consistent with the desired title structure.
FDMS 389 Analysis for C 24
H
27
N
3 0 2 Theory: C, 74.01; H, 6.99; N, 10.79.
Found: C, 73.82; H, 6.98; N, 10.75.
Example 225 Preparation of 1-methyl-3-[2-[N-benzyl-N-3- (dimethylaminopropyl )amino]- 1,2-ethanedionyl]- 1H-indole o
OH
3
NCH
3 0
N
CH
3 JR, NMR, and UV were consistent with the desired title structure.
FDMS 377 FAB 378 (Mi-i).
Analysis for C 23
H
27
N
3 0 2 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.
Example 226 Preparation of l-methyl-3-[ 2 -(4-dimethylan-nnopiperidin-.1-yl)- 1,2ethanedionyl]-lH-indole WO 97/09308 WO 9709308PCTIUS96/14163 253 o CH 3 N N
N
CH
3 IR, NMR, and LTV were consistent with the desired title structure.
FDMS 313 Analysis for C 18
H
23
N
3 0 2 Theory: C, 68.98; H, 7.40; N, 13.41.
Found: C, 68.97; H, 7.59; N, 13.43.
Example 227 Preparation of 5-chloro- 2 -[(2,4-dichlorophenoxy)methyfl. 1-methyl-3- [(piperidin-1-yl)methyl]- 1H-indole hydrochloride HC 1 C1 NMR (CDCl 3 was consistent with the proposed title structure.
mp 177-179 0
C.
Analysis for C 22
H
23
CI
3
N
2 0 eHCl: Theory: C, 55.72; H, 5.10; N, 5.91.
Found: C, 55.70; H, 5.21; N, 6.16.
Example 228 Preparation of 5-methoxy-2-[(2,4-dichlorophenoxy)methyl]-l -methyl-3- [(piperidin- 1-yl)methyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 254
H
3 C
N
0
N
CH
3
C
NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 432 mp 119-121 0
C.
Analysis for C2 3
H
26 C1 2
N
2 0 2 Theory: C, 63.74; H, 6.05; N, 6.46.
Found: C, 63.70; H, 6.12; N, 6.46.
Example 229 Preparation of 5-chloro-2-[(2,4-dichlorophenoxy)methyl.. -methyl-3-[(4dimethylaminopiperidin- 1-yl)methyl]- 1H-indole dihydrochloride C1 N N (CH 3 2
N
CH
3 Ci1 ic 1C NMR (CDCl 3 was consistent with the proposed title structure.
Analysis for C 24
H
28 C1 3
N
3 0 0 2 HCL: Theory: C, 52.05; H, 5.46; N, 7.59.
Found: C, 52.05; H, 5.41; N, 7.56.
Example 230 Preparation of 5-chloro-2-[( 2 ,4-dicblorophenoxy)methyll-l. -methyl-3-[[14- (piperidin- 1-yl )piperidin- 1-yllmethyl]- 1H-indole dihydrochloride WO 97/09308 WO 9709308PCTIUS96/141 63 255 No NAM (CDCl 3 was consistent with the proposed title structure.
Analysis for C 27
H
32 C1 3
N
3 0 9 2 HCL: Theory: C, 54.61; H, 5.77; N, 7.08.
Found: C, 51.53; H, 6.53; N, 7.57.
Example 231 Preparation of 5-bromo-2-[(2,4-dichlorophenoxy)methyl]- 1-methyl-3-[2- (piperidin- 1-yl)ethyl]- 1H-indole NMR and IR were consistent with the desired title structure.
mp 158-160'C.
Analysis for C2 3
H
2 5BrCl 2
N
2
O:
Theory: C, 55.67; H, 5.08; N, 5.64.
Found: C, 55.96; H, 5.28; N, 5.69.
Example 232 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl- 1H-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 256
N
ICH
3 0Kk., Cl IR, NMR, and LTV were consistent with the desired title structure.
FDMS 271 Analysis for Ci6H1 4 ClNO: Theory: C, 70.72; H, 5.19; N, 5.15.
Found: C, 70.52; H, 5.26; N, 5.28.
Example 233 Preparation of ,4-dichlorophenoxy)methyl.. -methyl- 1H-indole
ICH
3 IR, NMR, and LTV were consistent with the desired title structure.
FDMS 305.
Analysis for C 16
H
13 C1 2 N0: Theory: C, 62.76; H, 4.28; N, 4.57.
Found: C, 63.37; H, 4.72; N, 4.37.
ExamplIe 234 Preparation of 6 7 8 -tetrahydronaphth-1-yloxy)methyl.. -methyl- 1Hindole WO 97/09308 WO 9709308PCT/US96/14163 257
N
CH
3 1 NMR was consistent with the desired title structure.
FDMS 292 Analysis for C 20
H
21 N0: Theory: C, 82.44; H, 7.26; N, 4.81.
Found: C, 82.51; H, 7.28; N, 4.80.
Example 235 Preparation of 6 7 ,8-tetrahydronaphth-2-yloxy)methyl.. -methyl- 1Hindole
N
NMIR (CDCl 3 was consistent with the proposed title structure.
FDMS 291 Analysis for C 2 0
H
2 1 N0: Theory: C, 82.44; H, 7.26; N, 4.81.
Found: C, 82.25; H, 6.98; N, 4.95.
Example 236 Preparation of 2 4 -chlorophenoxy)methyl-3.formyl-. -methyl- 1H-indole WO 97/09308 WO 9709308PCT[US96/1 4163 258 0
N
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 299 Analysis for C 17
H
14 C1N0 2 Theory: C, 68.12; H, 4.71; N, 4.67.
Found: C, 67.90; H, 4.93; N, 4.73.
Example 237 Preparation of (RS) l, 2 -dimethyl-3-[3-(piperidin-3-yl)propyl.. H-indole
N
N CH 3
H
ICH
3 NMR (CDCl 3 was consistent with the proposed title structure.
Exact Mass for C 18
H
27
N
2 Theory: 271.2174.
Found: 271.2176.
Example 238 Preparation of 1-methyl-2-[[2-[(piperidin-. -yl)methyllphenoxylmethyl..
1H-indole WO 97/09308 WO 9709308PCT/US96/14163 259
NC)
ICH
3 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 335 Analysis for C 22
H
26
N
2 0: Theory: C, 79.01; H, 7.84; N, 8.38.
Found: C, 78.78; H, 7.58; N, 8.56.
Example 239 0 Preparation of l-methyl- 3 2 -[(4-chlorophenoxy)methyllpiperidin. ylmethyl]- 1H-indole NMR (CDCl 3 was consistent with the FDMS 368 Analysis for C 22
H
25 C1N 2 0 HCL: Theory: C, 65.19; H, 6.46; N, Found: C, 64.93; H, 6.44; N, proposed title structure.
6.91.
,6.78.
Example 240 WO 97/09308 WO 9709308PCT/US96/14163 260 Preparation of l-methyl- 3 -[3-[(4-chlorophenoxy)methyllpiperidin-. 1 ylmethyl]- 1H-indole
CH
3 NMR (CDCl 3 was consistent with the proposed title structure.
FDMS 368 Analysis for C22H 25 C1N 2 0: Theory: C, 71.63; H, 6.83; N, 7.59.
Found: C, 63.74; H, 6.54; N, 6.86.
Example 241 Preparation of l-methyl- 3 -[2-[2-(4-chlorophenoxy)ethyllpiperidinylmethyl]- 1H-indole Q-
N
N
OH
3 0 NMR (CDCl 3 was consistent with the proposed title structure.
2 0 FDMS 382 Analysis for C 23
H
27
CIN
2 0: WO 97/09308 PCT/US96/14163 Theory: Found: -261- C, 65.87; H, 6.73; N, 6.68.
C, 62.05; H, 6.36; N, 6.18.
Example 243 Preparation of ethyl 3-[2-[(4-chlorophenoxy)methyl]-l-methyl-lH-indol-3yl]propanoate NMR (CDC1 3 was consistent with the proposed title structure.
FDMS 371 Single compound of high purity as evidenced by chromatographic methods.
Example 244 Preparation of (RS) ethyl 2 -amino-3-[2-[(4-chlorophenoxy)methyl]-lmethyl-1H-indol-3-yl]propanoate NMR was consistent with the desired title structure.
FDMS 386.
Analysis for C2 1
H
2 3 C1N 2 03: Theory: C, 65.20; H, 5.99; N, 7.24.
WO 97/09308 WO 9709308PCT/US96/1 4163 262 Found: C, 64.95; H, 5.95; N, 7.27.
Example 245 Preparation of ethyl 2-hydroxyimino-3-[2-[(4-chloropheno-xy)methyl.. 1 methyl- 1H-indol-3-yllpropanoate 0 fCH 3 0 C~eNOH CH C1l-02
H
2 0 IR, NMR, and UV were consistent with the desired title structure.
FDMS 400 mp 165-166'C.
Analysis for C 21
H
21
CIN
2 0 4 a 0.2 H 2 0: Theory: C, 62.36; H, 5.33; N, 6.93.
Found: C, 62.38; H, 5.38; N, 6.87.
ExampUle 246 Preparation of (RS) methyl 2-methoxyimino-3-[2-[(4chlorophenoxy)methyl]- 1-methyl- 1H-indol-3-yllpropanoate 1R, NMR, and UV were consistent with the desired title structure.
FDMS 414 mp 106-107'C.
WO 97/09308 WO 9709308PCTIUS96/1 4163 263 Analysis for C 22
H
23 C1N 2 0 4 Theory: C, 63.69; H, 5.59; N, 6.75.
Found: C, 63.95; H, 5.57; N, 7.01.
Example 247 Preparation of ethyl 2 -benzoxyirmno-3-[2-[(4-chlorophenoxy)methyl]. 1methyl- 1H-indol-3-yllpropanoate IR, NMR, and LUV were consistent with the desired title structure.
FDMS mp 96*C.
Analysis for C 28
H
27
CIN
2 0 4 Theory: C, 68.50; H, 5.54; N, 5.71.
Found: C, 68.78; H, 5.67; N, 5.64.
Example 248 Preparation of ethyl 2 -ethanoyloxyimino-3-[2-[(4-chlorophenoxy)methyl..
1-methyl- 1H-indol-3-yllpropanoate 0
CH-
3 WO 97/09308 WO 9709308PCT/US96/1 4163 264 IR, NMR, and LTV were consistent with the desired title structure.
FDMS 442 mp 128-1291C.
Analysis for C 23
H
23 C1N 2 0 5 Theory: C, 62.37; H, 5.23; N, 6.32.
Found: C, 62.44; H, 5.40; N, 6.33.
Example 249 Preparation of ethyl 2 -benzoyloxyimino-3-[2-[(4-chiorophenoxy)methyl]. methyl- 1H-indol-3-ylllpropanoate 0
-NO
0 N 0
CH
3 0
C
IR, NMR, and UV were consistent with the desired title structure.
FDMS 504 mp 146-147'C Analysis for C 28
H
25 C1N 2 0 5 Theory: C, 66.60; H, 4.99; N, 5.55.
Found: C, 66.88; H, 5.22; N, 5.80.
Examp~le 250 Preparation of 2 4 -chlorophenoxy)methyl]-3..(4.hydroxy. methylpiperidin-4-yl)- 1-methyl- 1H-indole WO 97/09308 PCT/US96/14163 265 o N/CH,
N
H CH 3 Cl NMR, IR and UV were consistent with the desired title structure.
FDMS 384 Analysis for C 2 2
H
25 C1N 2 0 2 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.
Example 251 Preparation of ethyl 2-hydroxyimino-3-[1-methyl-2-phenyl-lH-indol-3yl]propanoate 0 -CH3 0
NOH
CH
3 NMR (CDCI 3 was consistent with the proposed title structure.
UV and IR were consistent with the proposed title structure.
FDMS 322 mp 141-142 0
C.
Analysis for C19H18N203: Theory: C, 70.79; H, 5.62; N, 8.69.
Found: C, 70.64; H, 5.89; N, 8.58.
WO 97/09308 WO 9709308PCTIUS96/1 4163 266 Example 252 Preparation of ethyl 2 -hydroxyilnino-341lH-indol-3-yllpropanoate 0 /CH 3 0
NOH
N
H
IR, NMR, and UV were consistent with the desired title structure.
FDMS 246 mp 156'C.
Analysis for C 13
H
14
N
2 0 3 0.3 H 2 0: Theory: C, 62.04; H, 5.85; N, 11.13.
Found: C, 61.77; H, 5.55; N, 11.07.
Example 253 Preparation of 6-chloro-2-I(2,4-dichlorophenoxy)methyl.. -methyl-3-12- (piperidin- 1-yl)ethyl]- iR-indole
N
u- Q Cl IR and NMR were consistent with the desired title structure. FDMS 450 mp 116.5-118.5'C.
Analysis for C 23
H
25 C1 3
N
2 0: Theory: C, 61.14; H, 5.58; N, 6.20.
Found: C, 61.43; H, 5.67; N, 6.26.
WO 9709308PCTIUS96/1 4163 WO 97/09308 267 Example 255 Preparation of 7-chloro-2-[(2 ,4-dichlorophenoxy)methyl]- 1-methyl-3-12- (piperidin- 1-yl)ethyl]- 1H-indole JR and NMR were consistent with the desired title structure. mp, 134- 136 0
C.
Analysis for C 23
H
25 Cl 3
N
2
O:
Theory: C, 61.14; H, 5.58; N, 6.20.
Found: C, 61.39; H, 5.71; N, 6.47.
Example 256 Preparation of 4-methyl-2-[(2,4-dichlorophenoxy)methyl. -13-(piperidin- 3-yl)propyl]- 1H-indole NMR (CDC1 3 was consistent with the proposed title structure.
WO 97/09308 WO 9709308PCT/US96/1 4163 268 Exact Mass FAB for C2 4
II
30 C1N 2
O:
Theory: 397.2047.
Found: 397.2041.
Example 257 Preparation of 5-chloro-2-[(2,4-dichlorophenoxy)methyl]-. -methyl-3-I(4cimethylaminopiperidin-.1-yl)methyl]- 1H-indole dihydrochioride C1 Na N (CH 3 2
N
CH 1lc Analysis for C 24
H
2 8 C1 3
N
3 0: Theory: C, 52.05; H, 5.46; N, 7.59.
Found: C, 52.05; H, 5.41; N, 7.56.
Exampnle 258 Preparation of 7 -methyl- 2 -[(2,4-dichlorophenoxy)methyl.. -methyl-3-[3- (piperidin- 1-yl)propyl]- 1H-indole dihydrochioride
NQ
H
3 C
N
CH
3 C 1C 1 NMR (CDCl 3 was consistent with the proposed title structure.
mp 129-131'C.
Analysis for C 25
H
30 C1 2
N
2 0: Theory: C, 67.41; H, 6.79; N, 6.29.
Found: C, 67.34; H, 6.80; N, 6.05.
WO 97/09308 WO 9709308PCTIUS96/1 4163 269 Example 259 Preparation of 1 ,2-dimethyl-3-[[4-(piperidin- 1-yl )piperidin- 1-yllacetyl]- 1H-indole 0NQ-NQ I CH 3
H
3
C
NMR, JR and UV were consistent with the desired title structure.
FDMS 353 Analysis for C 22
H
3 1
N
3 0: Theory: C, 74.75; H, 8.84; N, 11.89.
Found: C, 74.76; H, 8.96; N, 11.76.
Example 260 Preparation of 1 ,2-dimethyl-3-[[4-(N ,N-dimethyaniino)piperidin- 1yllacetyl]- 1H-indole 0
CH
3 NaJ-N I
CH
3 I CH 3
H
3
C
NMR was consistent with the desired title structure.
C
19
H
27
N
3 0: FDMS 313 Example 261 Preparation of 2 4 -chlorophenoxy)methyl]-3-[[(4-cyclohexyl)piperazin. 1.
yllacetyl]- 1-methyl- iR-indole WO 97/09308 WO 9709308PCT/US96/1 4163 270
H
3
C
NMR was consistent with the desired title structure.
C
28
H
34 C1N 3 0 2 FDMS 480 Example 262 Preparation of 2 4 -chlorophenoxy)methyl]-3-[ii(4-phenyl)piperazinyllacetyl]- 1-methyl-1H-indole H3C NMR was consistent for the desiredtitle structure.
C28H 28
CIN
3 0 2 FDMS 474 Example 268 Preparation of 2-[(4-chlorophenoxy)methyll-3-[[4-(N,Ndimethylamino )piperidin- 1-yllacetyl]- 1-methyl H-indole WO 97/09308 WO 9709308PCT/US96/1 4163 -271-
CH
3
N
CH
3 NMR, JR and UV were consistent with the desired title structure.
MSFD 439 Analysis for C 25
H
30 C1N 3 0 2 Theory: C, 68.25; H, 6.87; N, 9.55.
Found: C, 67.98; H, 6.81; N, 9.40.
.0 Example 264 Preparation of 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[[N-methyl-N-(3- N'-dimethylaminopropyl)aminolacetyl] H-indole 0 CH 3 CH 3 r i 1 CN
H
3
C
NMR and JR were FDMS 428 (M+1) FAB exact mass consistent with the desired title structure.
Calculated for C 24
H
31
CIN
3 0 2 428.~ Found: 428.~ 2105 2113 WO 97/09308 WO 9709308PCT/UJS96/14163 272 Example 265 Preparation of 2[(4-chlorophenoxy)methyl]- l-methyl-3-[2-[(4-piperidin- 1yl)pipericlin- 1-yllacetyl]- 1H-indole Nr~N
H
3
C
ClI NMR, JR and UV were consistent with the desired title structure.
MSFD 479 FAB exact mass Calculated for C 2 8
H
3 5 C1N 3 0 2 480.2418 Found 480.2411 Example 266 Preparation of 2 4 -chlorophenoxy)methyl]-3-[2-[(4-piperilin-. 1 yl)piperidin- 1-yllacetyl]- 1-[2-(N,N-dimethylpiperidin-4-ylium)ethyl]. 1Hindole iodide WO 97/09308 WO 9709308PCTIUS96/14163 273
N~ND
O\/Cl N+ I-
H
3 C CR 3 NMR was consistent with the desired title structure.
Analysis for C 36
H
50 C11N 4 0 2
H
2 0: Theory: C, 57.56; H, 6.90; N, 7.46.
Found: C, 57.85; H, 6.86; N, 7.04 Example 267 2-[(4-chlorophenoxy)methyl]-1-[(2-piperidin.4yl )ethyl]-3-[2-[4-(piperidinl-yl)piperidin-1-yllacet- 1-yl]-lH-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 274 ,O\/Cl NMR was consistent with FABMS 577 (M+1) Analysis for C 34
H
45 C1N 4 0 2 Theory: C, 70.75; H, Found: C, 70.55; H, the desired title structure.
7.86; N, 9.71 7.87; N, 9.52 Example 268 2-[(4-chlorophenoxy)methyl]-3-[2- (methylaminopropyldimethylamine )acet- 1-yl]- l-[(2-piperidin-3-yl)ethyl]indole WO 97/09308 WO 9709308PCT/US96/1 4163 275
H
3
CQ
CH
3 N-CH 3 0ONL
NN
NMR was consistent with the desired title structure.
FABMS 525(M+1) Exact Mass for C 3 oH 4 2
N
4 0 2 C1: Theory: 525.2996 Found: 525.3003 Example 269 2-I(4-chlorophenoxy)methyl]- 1-[(2-piperidin-3-yl )ethyl]-3-[2-(4-(piperidinl-yl )piperidin- 1-yl)acet- l-yl]- l-indole WO 97/09308 WO 9709308PCT/US96/14163 276 NMR was consistent with the desired title structure.
FDMS (M+1) Analysis for: C 34
H
45
N
4 0 2 C1: Theory: C, 70.75; H, 7.86; N, 9.71 Found: C, 70.72; H, 7.83; N, 9.63 Example 270 2-I(4-chlorophenoxy)methyl]-3-[2- (methylaminopropyldimethylamine)acet- l-yl]- 1-[(2-piperidin-4-yl)ethyl]- 1H-indole
H
3
C,
CH
3 N-CH3 0ON O\/Cl
N
H
NMR was consistent with the desired title structure.
Exact Mass for C 30
H
42
N
4 0 4 Cl Theory: 525.2996 Found: 525.3013 Examule 271
S-
2 -I(4-chlorophenoxy)methyl]-3-[2-(4-(piperidin-.1-yl )piperidin- 1-yl )acet- 1-yl]- 1-I(3-piperidin-3-yl)propyl]- 1H-indole WO 97/09308 WO 9709308PCT/US96/1 4163 277 0D 0 0\&/Cl
N
NH
NMR was consistent with the desired title structure.
FABMS (M+ 1 Analysis for: C 35
H
47 C1N 4 0 2 Theory: C, 71.10; H, 8.01; N, 9.48 Found: C, 70.82; H, 8.14; N, 9.23 Example 272
R-
2 -[(4-chlorophenoxy)methyl]-3-[2-(4-(piperidin-.1-ybpiperidin- l-yl )acetl-yl] -1-I(3-piperidin-3-yl)propyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 278
N
NMR was consistent with the desired title structure.
Exact Mass for C3 5
H
48 C1N 4 0 2 Theory: 591.3466 Found: 591.3458 Example 273 cis/trans-2-[(4-chlorophenoxy)methyl]- l-methyl-3-[2-(4-(piperidin- 1yl)cyclohex- 1-yl)acet- 1-yl]-lH-indole
CH
3 Mixture of cis/trans isomers 1 2 WO 97/09308 WO 9709308PCTIUS96/1 4163 279 NMR was consistent with the desired title structure.
FDMS 478 Analysis for: C 29
H
35 C1N 2 0 2 Theory: C, 72.71; H, 7.36; N, 5.85 Found: C, 72.65; H, 7.61; N, 5.95 Example 274 2 -[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(4-(piperidin- 1-yl)cyclohex- 1yl)acet- l-yl]- 1H-indole
QD
Isomer 1 NMR was consistent with the desired title structure.
FDMS 478 Analysis for: C 29
H
35
CIN
2 0 2 Theory: C, 72.7 1; H, 7.36; N, 5.85 Found: C, 72.55; H, 7.52; N, 5.67 Example 275 2 -[(4-chlorophenoxy)methyl] -3-[2-(4-(piperidin- 1-yl)cyclohex- 1-yl )acet- 1-yl l-[(2-piperidin-4-yl)ethyl]- 1H-indole WO 97/09308 WO 9709308PCTIUS96/1 4163 280 0N 0 a N 0\/Cl Isomer 1
N
H
NMR was consistent with the desired title structure.
FDMS 575 Analysis for: C 35
H
46 C1N 3 0 2 Theory: C, 72.95; H, 8.05; N, 7.29 Found: C, 72.88; H, 8.23; N, 7.53 Example 276, 2-[(4-chlorophenoxy)methyl]- 1-methyl-3-[2-(4-(piperidin- 1-yl)cyclohex- 1yl)acet- 1-yl]-indole WO 9709308PCT/US96/1 4163 WO 97/09308 -281- 2o
CH
3 Isomer 2 NMR was consistent with the desired title structure.
FDMS 478 Analysis for: C 29
H
35 C1N 2 0 2 Theory: C, 72.7 1; H, 7.36; N, 5.85 Found: C, 72.43; H, 7.42; N, 5.86 Example 277 2-[(4-chlorophenoxy)methyl]-5-fluoro- 1-methyl-3-[2-(4-(piperidin- 1yl)piperidin- lyl )acet- 1-yl]-1H-indole 0O
CH
3 NMR was consistent with the desired title structure.
FABMS 498 (M+1) WO 97/09308 PCT/US96/14163 282 Analysis for C28H 33 C1FN 3 0 2 Theory: C, 67.53; H, 6.68; N, 8.44 Found: C, 67.34; H, 6.59; N, 8.58 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.
[For a review of neuropeptide Y receptors, see, D. Gehlert, Life Sciences, 55:551-562 (1994); P.A. Hipskind and D.R. Gehlert, Annual Reports in Medicinal Chemistry, 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 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 affinity of the 13-36 fragment of neuropeptide Y using a preparation of the sympathetic nervous system. While these are the best established receptors for neuropeptide Y, a substantial body of evidence exists that there are additional receptor subtypes. The best established is a Y-3 receptor that is responsive to neuropeptide Y, but not to peptide YY. Another recently delineated 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 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 summarize 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 periphery. Originally, this receptor was described as having poor WO 97/09308 PCT/US96/14163 283 affinity for C-terminal fragments of neuropeptide Y, such as the 13-36 fragment, but interacts with the full length neuropeptide Y and peptide YY with equal affinity. C. Wahlestedt, et al., Regulatory Peptides, 13:307-318 (1986); C. Wahlestedt, etal., NEURONAL MESSENGERS IN VASCULAR FUNCTION, 231-241 (Nobin, et al., eds. 1987). Substitution of the amino acid at position 34 with a proline (Pro 3 4 results in a protein which is specific for the Y-1 receptor. E.K. Potter, et al., European Journal of Pharmacology, 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, depending on the type of cell in which the receptor is expressed. H.
Herzog, et al., Proceedings 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 WO 96/16542, published June 6, 1996, at page 135, and the references cited therein.
Y-2 Receptor WO 97/09308 PCT/US96/14163 -284- 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 fragments of neuropeptide Y. The receptor is most often differentiated by the use of neuropeptide Y(13-36), though the 3-36 fragment 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 receptor, this receptor is coupled to the inhibition of adenylate cyclase, though in some preparations it may not be sensitive to 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 channels. 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 modulating hypertension, epileptic seizure, and 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, thalamus, hypothalamus, and brainstem. In the periphery, Y-2 is found in the peripheral nervous system, such as sympathetic, 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 Biological Chemistry, 270:22661 (1995); C. Gerald, et al. Journal of Biological Chemistry, 270:26758 (1995); D.R. Gehlert, etal., Molecular Pharmacology, 49:224 (1996).
Y-3 Receptor This receptor has high affinity for neuropeptide Y while 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 similar pharmacology to the Y-3 receptor has been identified in the CA3 region of the hippocampus using electrophysiological techniques. This receptor may potentiate the excitatory response of these neurons to N-methyl-D-aspartate
(NMDA).
WO 97/09308 PCT/US96/14163 285 F.P. Monnet, etal., European Journal of Pharmacology, 182:207-208 (1990). This receptor is believed to modulate hypertension. PCT Patent Publication WO 96/16542, published 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, etal., Life Sciences, 50:PL7-PL14 (1992).
Peptide YY Preferring Receptor 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., Endocrinology, 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 manner 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 localized to the crypt cells where intestinal chloride secretion is believed to take place. The peptide YY preferring receptor in adipocytes mediates a reduction in lipolysis by way of a cyclic adenosine monophosphate (cAMP)-dependent mechanism.
"Feeding Receptor" One of the earliest discovered central effects of neuropeptide Y was a profound increase in food intake that was observed following the hypothalmic administration of the peptide to rats. The response was greatest when the peptide was infused into the perifornical region of the hypothalamus. B.G. Stanley, et al., Brain Research, 604:304-317 (1993).
While the pharmacology of this response resembled the Y-1 receptor, the WO 97/09308 PCT/US96/14163 286 2-36 fragment 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 AO, 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 binding 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.g., United States Patents 5,284,839, issued February 8, 1994, which is herein incorporated by reference. See also, M.W. Walker, et al., Journal of Neurosciences, 8:2438-2446 (1988).
Neuropeptide Y Binding 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 Minimal Essential Media (DMEM) supplemented with 5% fetal calf serum. The cells were manually removed from the flasks by scraping, pelleted, and stored at 0
C.
The pellets were resuspended using a glass homogenizer in mM HEPES (pH 7.4) buffer containing 2.5 mM calcium chloride, 1 mM magnesium chloride, and 2 g/L bacitracin. Incubations were performed in a final volume of 200 l. containing 0.1 nM 12 5 I-peptide YY (2200 Ci/mmol) and 0.2-0.4 mg protein for about two hours at room temperature.
WO 97/09308 PCT/US96/14163 287 Nonspecific binding was defined as the amount of radioactivity remaining bound to the tissue after incubating in the presence of 1 iiM 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% polyethyleneimine 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 0 C. The filters were then treated with melt-on scintillation sheets and the radioactivity retained on the filters were counted. The results were analyzed using various software packages. Protein concentrations were measured using standard coumassie protein assay reagents using bovine serum albumin as standards.
Many of the compounds prepared supra showed significant activity as neuropeptide Y receptor antagonists (Ki 10 pM 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 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 administering to a mammal in need of said treatment 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 inappropriate stimulation of neuropeptide Y receptors, regardless of the actual amount of neuropeptide Y present in the locale.
These physiological disorders include: disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, congestive heart failure, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure; WO 97/09308 PCT/US96/14163 -288conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, 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, bulimia, and metabolic disorders; diseases related to sexual dysfunction and reproductive disorders; conditions or disorders associated with inflammation; respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin.
The compounds of Formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
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 making the compositions of the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a WO 97/09308 PCT/US96/14163 -289diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
WO 97/09308 PCT/US96/14163 290 The active compound is effective over a wide dosage range.
For examples, dosages per day normally fall within the range of about to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
For preparing solid compositions such as tablets the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous 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 preformulation is then subdivided into unit dosage forms of the type described above containing 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 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 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 WO 97/09308 PCT/US96/14163 -291of 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 administration orally or by 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 similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compsoitions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The following examples illustrate the pharmaceutical compositions of the present invention.
WO 97/09308 PCT/US96/14163 292 Formulation Preparation 1 Hard gelatin capsules containing the following ingredients are prepared: Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0 Magnesium stearate The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
Formulation Preparation 2 A tablet formula is prepared using the ingredients below: Quantity Ingredient (me/tablet) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid The components are blended and compressed to form tablets, each weighing 240 mg.
WO 97/09308 PCT/US96/14163 293 Formulation Preparation 3 A dry powder inhaler formulation is prepared containing the following components: Ingredient Weight Active Ingredient Lactose The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
Formulation Preparation 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows: Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in water) Sodium carboxymethyl starch Magnesium stearate Talc Total 4.0 mg 4.5 mg 0.5 mg 1.0 mg 120 mg WO 97/09308 PCT/US96/14163 -294- The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-600C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
Formulation Preparation Capsules, each containing 40 mg of medicament are made as follows: Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg 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 150 mg quantities.
WO 97/09308 PCT/US96/14163 295 Formulation Preparation 6 Suppositories, each containing 25 mg of active ingredient are made as follows: Ingredient Amount Active Ingredient 25 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 nominal 2.0 g capacity and allowed to cool.
Formulation Preparation 7 Suspensions, each containing 50 mg of medicament per ml dose are made as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v.
Purified water to 5.0 ml Purified water to 5.0 ml WO 97/09308 PCT/US96/14163 296 The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring.
Sufficient water is then added to produce the required volume.
Formulation Preparation 8 Capsules, each containing 15 mg of medicament, are made as follows: Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg 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 into hard gelatin capsules in 425 mg quantities.
WO 97/09308 PCT/US96/14163 297 Formulation Preparation 9 An intravenous formulation may be prepared as follows: Ingredient Active Ingredient Isotonic saline Quantity 250.0 mg 1000 ml Formulation Preparation A topical formulation may be prepared as follows: Ingredient Active Ingredient Emulsifying Wax Liquid Paraffin White Soft Paraffin Quantity 1-10 g 30 g 20 g to 100 g The white soft paraffin is heated until molten. The liquid praffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
WO 97/09308 PCT/US96/14163 298 Formulation Preparation 11 Sublingual or buccal tablets, each containing 10 mg of active ingredient, may be prepared as follows: Quantity Ingredient 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 Polyvinylpyrrolidone 15.5 mg Total 410.0 mg The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C. When the polymers have gone into solution, the solution is cooled to about 50-55 0 C and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by WO 97/09308 PCT/US96/14163 299 reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly.
Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S.
Patent 5,011,472, issued April 30, 1991, which is herein incorporated by refernce.
Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
Claims (17)
1. A compound of the formula R2 D-(CH 2 )s -C (CH;)q Y 'X Rb A N A' (CH 2 )p-R I R wherein: R is a single substituent selected from the group consisting of hydrogen, C,-C 6 alkyl, CI-C 6 alkoxy, C 2 -C 6 alkanoyl, trifluoromethyl, hydroxy, and halo; R' is hydrogen, C 1 -C6 alkyl, or -(CH 2 )v-Rla where v is I to 12, and Rla is phenyl naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, o 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 CI-C 6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(CI-Cs .alkyl)amino, CI-C 6 alkylamino, C 2 -C 6 alkanoyl, C 2 -C 6 alkanoyloxy, and C 3 -C 8 cycloalkyl, is said said phenyl, benzyl, or C 3 -Cs cycloalkyl, being optionally substituted S* with one, two, or three moieties independently selected from the group consisting of CI-C 6 alkyl, halo, or C 1 -C 6 alkoxy, or R Ia may be substituted with -(CH 2 )w-R1b, where w is 1 to 12 and Rib is Spiperidinyl, pyrimidyl, pyrrolidinyl, C,-Cs alkoxy, C 1 -C 6 alkylthio, di[di(C,-C 6 alkyl)amino(C-C 6 alkylenyl)]amino, di(Ci-C 6 alkyl)amino(Ci-C 6 alkylenyl)amino, phenyl, SC 3 -Cs cycloalkyl, pyrrolidinyl, and acetamido, said phenyl, or C 3 -C 8 cycloalkyl, being optionally substituted with one, *two, or three moieties independently selected from the group consisting of CI-Cs alkyl, halo, or CI-C 6 alkoxy; A is a bond, -(CH 2 or A' is or q is 0 to 6; p is0 to 6; n isO, 1, or 2; m is 0 to 6; s is0 to 6; [R:\LIBVV]02121 .doc:NJC 301 W' is hydrogen, C 1 -C 6 alkyl, or C 2 -C 6 alkanoyl; D is a bond, C 2 -C 4 alkenylenyl, or (R:\LII3VV]0212 I .doc:NIC WO 97/09308 PCT/US96/14163 -302- 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 or =NORc; RC is hydrogen, benzyl, acetyl, benzoyl, or C 1 -C 6 alkyl; one of X1 and Y1 is hydroxy and the other is hydrogen, or both X 1 and Y 1 are hydrogen, or X1 and Y 1 combine to form or =NORd. Rd is hydrogen or C1-C 6 alkyl; R 2 is hydroxy, Ci-Cs alkyl, C1-C 6 alkoxy, phenoxy, or a group of the formula R4 -N \R wherein R 4 and R 5 are independently hydrogen, C1-C 6 alkyl, phenyl, or phenyl(C1-C 6 alkylenyl)-, or R 2 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 Ci-C 6 alkyl, halo, trifluoromethyl, benzyl, phenyl, di(Ci-C 6 alkyl)amino, di(Ci-C 6 alkyl)amino(Ci-C 6 alkylenyl)-, C 1 -C 6 alkylamino(Cl-C alkylenyl)-, C 2 -C 6 WO 97/09308 WO 9709308PCTIUS96/14163 303 alkanoyl, carboxarnido, 2-aminoacetyl, C 2 -C 6 alkanoyloxy, Cl-C 6 alkoxycarbonyl-, Cl-C 6 alkylamino, C 3 -C 8 cycloalkyl, piperidinyl, pyrrolidinyl, pyrimidyl, phenyl(C i-C 6 alkylenyl)-, phenoxy(C i-C 6 alkylenyl)-, piperidinyl(C i-C 6 alkylenyl)-, pyrrolidinyl(C i-C 6 alkylenyl)-, pyrimidyl(Cl-C 6 alkylenyl)-, Cl-C 6 ailkoxy, Cl-C 6 alkylthio, di[di(C i-C 6 alkylbaiino(C i-C 6 alkylenyl)]axmno, di(Cl-C 6 alkyl)amino(Cl-C 6 alkylenyl)amino, and acetainido, any one of which benzyl, phenyl, piperidinyl, C 3 -C 8 cycloalkyl, phenyl(C i-C 6 alkylenyl)-, phenoxy(C i-C 6 alkylenyl)-, pyrrolidinyl, piperidinyl(C i-C 6 alkylenyl)-, pyrrolidinyl(C 1- C 6 alkylenyl)-, pyrimidyl(Cl-C 6 alkylenyl)-, or pyrimidyl group may be substituted with one or more moieties selected from the group consisting Of C 1 -C 6 alkyl, halo, trifluoromethyl, acetamido, C 2 -C 6 alkanoyl, (D 2 -C 7 alkanoyloxy, and C i- 0 6 alkoxy, or the nitrogen on said piperidinyl, pyrrolidinyl, piperidinyl(C i-C 6 alkylenyl)-, pyrrolidinyl(C i-C 6 alkylenyl)-, pyrimidyl(C i-C 6 alkylenyl)-, or pyrimidyl may be substituted with an amino-protecting group, or R 2 is a group of the formula IR 6a R where R 4 a, R5a, and R 6 a are independently hydrogen, C i-C6 alkyl, trifluoromethyl, or Ci-C 6 alkoxy, WO 97/09308 WO 9709308PCT/US96/1 4163 304 or R4a is hydrogen, C 1 -C 6 alkyl, trifluoromethyl, or C 1 -C 6 ailkoxy and R5a and R 6 a combine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or heptamethyleneiminyl, or R4a is oxygen, and R 5 a and R 6 a combine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or heptamethyleneiminyl; R is phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C3-C 8 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, C 3 -C 8 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 Cl-C 12 alkyl, C 2 -C 1 o alkenyl, C 2 -C 1 o alkynyl, halo, trifluoromethyl, carboxamido, cyano, benzyl, phenyl, di(Cl-C 6 alkyl)amino, C 2 -C 6 alkanoyl, C 2 -C 6 alkanoyloxy, C i-C 6 alkylaino, oxazolyl, dihydrooxazolyl, piperidinyl(C i-C 12 alkoxy)-, piperidinyl(C i-C 12 alkoxy)(C i-C 6 alkylenyl)-, piperidinyl( C -C1 2 alkylenyl)- ,phenyl(Cl 12 alkoxy pheny(C2-12 alkylenyl C 3 -C8 cycloalkyl, piperidinyl, pyrimidyl, Cl-C 6 alkoxy, Cl-C 6 alkylthio, 305 a group of the formula RxRYN-G-L-(Co-C 6 alkylenyl)-, and acetamido, where Rx and RY are independently hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, morpholinyl, piperazinyl, or C 3 -C 8 cycloalkyl, j 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 CI-C 12 alkylenyl, C 2 -C1 2 alkenylenyl, or C 2 -CI 2 alkynylenyl, and L is a bond, or -NH-; Io with the proviso that when, A' is -NRa-, or and A is -CH 2 R' 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 Rla is piperidinyl, pyrrolidinyl, piperazinyl, or quinuclidinyl, or a pharmaceutically acceptable salt i or solvate thereof.
3. A compound as claimed in claim 2 wherein R"a is piperidin-3-yl, piperidin-2-yl, pyrrolidin-3-yl, or pyrrolidin-2-yl, piperidin-l-yl, piperidin-4-yl, pyrroldin-1-yl, or pyrrolidin-4-yl, phenyl, or a pharmaceutically acceptable salt or solvate thereof
4. A compound as claimed in claim 3 wherein A' is or a pharmaceutically acceptable salt or solvate thereof. 0 [R:\LIBVV]02121 .doc:NJC 306 A compound as claimed in claim 4 wherein -(CH 2 is a bond, methylene, ethylene, or or a pharmaceutically acceptable salt or solvate thereof.
6. A compound as claimed in claim 5 wherein both X' and Y' are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.
7. A compound as claimed in claim 6 wherein R 2 is a piperdinyl group substituted with C,-C 6 alkylamino, or piperidinyl, or R 2 is a pyrrolidinyl group substituted with alkylamino, or pyrrolidinyl, or R 2 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 is o or 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. 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. An indolyl neuropeptide Y receptor antagonist, substantially as hereinbefore described with reference to any one of the Examples.
12. A pharmaceutical formulation, comprising, as an active ingredient, a compound as claimed in any one of claims 1 to 11, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients, therefor.
13. A compound as claimed in any one of claims 1 to 11, for use in treating a condition associated with an excess of neuropeptide Y, or a related peptide.
14. A method of treating a condition associated with an excess of *2 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 11 or of a formulation as claimed in claim 12.
15. The use of a compound as claimed in any one of claims 1 to 11, for the manufacture of a medicament for the treatment of a condition associated with an excess of o neuropeptide Y.
16. 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 11.
17. A compound as claimed in any one of claims 1 to 11 when used to treat a condition associated with an excess of neuropeptide Y in a mammal in need thereof. [R:\LIBVV]00973.doc: LMK
18.
19. which process Examples. 307 A medicament whenever manufactured by the use of claim A process of preparing an indolyl neuropeptide Y receptor antagonist, is substantially as herein described with reference to any one of the An indolyl neuropeptide Y receptor antagonist whenever prepared by the process of claim 19. Dated 12 October, 1999 Eli Lilly and Company Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON oo o [R:\LIBVV]00973.doc:LMK
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US315095P | 1995-09-01 | 1995-09-01 | |
| US60/003150 | 1995-09-01 | ||
| GBGB9523999.2A GB9523999D0 (en) | 1995-11-23 | 1995-11-23 | Indolyl neuropeptide y receptor antagonists |
| GB9523999 | 1995-11-23 | ||
| US2163896P | 1996-07-12 | 1996-07-12 | |
| US60/021638 | 1996-07-12 | ||
| PCT/US1996/014163 WO1997009308A1 (en) | 1995-09-01 | 1996-08-30 | Indolyl neuropeptide y receptor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6965096A AU6965096A (en) | 1997-03-27 |
| AU717422B2 true AU717422B2 (en) | 2000-03-23 |
Family
ID=27267993
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU69650/96A Ceased AU717422B2 (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) |
Families Citing this family (58)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU729590B2 (en) * | 1996-10-23 | 2001-02-08 | Sanofi-Aventis | Cosmetic composition containing a neuropeptide Y receptor antagonist |
| EP0975584B1 (en) * | 1997-04-16 | 2002-09-25 | Arqule, Inc. | Synthesis and use of alpha-ketoamide derivatives and arrays |
| US6143931A (en) | 1997-04-16 | 2000-11-07 | Arqule, Inc. | Synthesis and use of α-ketoamide derivatives and arrays |
| US6337332B1 (en) | 1998-09-17 | 2002-01-08 | Pfizer Inc. | Neuropeptide Y receptor antagonists |
| US6200990B1 (en) * | 1998-12-21 | 2001-03-13 | Alcon Laboratories, Inc. | Neuroprotective agents having antioxidant and NMDA antagonist activity |
| AU3840000A (en) * | 1999-04-20 | 2000-11-02 | Meiji Seika Kaisha Ltd. | Tricyclic compounds |
| US6469006B1 (en) * | 1999-06-15 | 2002-10-22 | Bristol-Myers Squibb Company | Antiviral indoleoxoacetyl piperazine derivatives |
| MXPA00006605A (en) | 1999-07-02 | 2004-12-09 | Pfizer | Bicycliccarbonyl indole compounds as anti-inflammatory/analgesic agents. |
| JP2004502642A (en) | 2000-02-11 | 2004-01-29 | ブリストル−マイヤーズ スクイブ カンパニー | Cannabinoid receptor modulators, methods for their production, and use of cannabinoid receptor modulators for the treatment of respiratory and non-respiratory diseases |
| WO2001066110A2 (en) * | 2000-03-09 | 2001-09-13 | Eli Lilly And Company | METHOD FOR THE TREATMENT OF RENAL DYSFUNCTION WITH sPLA2 INHIBITORS |
| US6900226B2 (en) | 2000-09-06 | 2005-05-31 | Hoffman-La Roche Inc. | Neuropeptide Y antagonists |
| TWI224101B (en) | 2001-06-20 | 2004-11-21 | Wyeth Corp | Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1) |
| DK1397130T3 (en) | 2001-06-20 | 2007-11-12 | Wyeth Corp | Substituted Indole Acid Derivatives as Inhibitors of Plasminogen Activator Inhibitor-1 (PAI-1) |
| ATE479655T1 (en) | 2001-09-14 | 2010-09-15 | High Point Pharmaceuticals Llc | NEW AMINOAZETIDINE, AMINOPYRROLIDINE AND AMINOPIPERIDINE DERIVATIVES |
| US6673829B2 (en) | 2001-09-14 | 2004-01-06 | Novo Nordisk A/S | Aminoazetidine,-pyrrolidine and -piperidine derivatives |
| AU2003218962B2 (en) | 2002-02-01 | 2008-09-25 | F. Hoffmann-La Roche Ag | Substituted indoles as alpha-1 agonists |
| EP1569899B1 (en) | 2002-12-10 | 2006-06-28 | Wyeth | Substituted 3-alkyl- and 3-arylalkyl-1h-indol-1-yl-acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) |
| CN1726191A (en) | 2002-12-10 | 2006-01-25 | 惠氏公司 | Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
| CN1723198A (en) | 2002-12-10 | 2006-01-18 | 惠氏公司 | Aryl, aryloxy, and alkyloxy substituted 1h-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
| DK1569900T3 (en) | 2002-12-10 | 2006-10-23 | Wyeth Corp | Substituted 3-carbonyl-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
| UA80453C2 (en) | 2002-12-10 | 2007-09-25 | Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1) | |
| AU2003297048A1 (en) | 2002-12-13 | 2004-07-09 | Smithkline Beecham Corporation | Cyclohexyl compounds as ccr5 antagonists |
| WO2004098591A2 (en) | 2003-05-05 | 2004-11-18 | Probiodrug Ag | Inhibitors of glutaminyl cyclase and their use in the treatment of neurological diseases |
| US7317025B2 (en) | 2003-09-24 | 2008-01-08 | Johnson & Johnson Pharmaceutical Research & Development, Llc | Non-peptidic NPY Y2 receptor inhibitors |
| US7332521B2 (en) | 2003-09-25 | 2008-02-19 | Wyeth | Substituted indoles |
| US7446201B2 (en) | 2003-09-25 | 2008-11-04 | Wyeth | Substituted heteroaryl benzofuran acids |
| US7411083B2 (en) | 2003-09-25 | 2008-08-12 | Wyeth | Substituted acetic acid derivatives |
| US7268159B2 (en) | 2003-09-25 | 2007-09-11 | Wyeth | Substituted indoles |
| US7420083B2 (en) | 2003-09-25 | 2008-09-02 | Wyeth | Substituted aryloximes |
| US7265148B2 (en) | 2003-09-25 | 2007-09-04 | Wyeth | Substituted pyrrole-indoles |
| US7442805B2 (en) | 2003-09-25 | 2008-10-28 | Wyeth | Substituted sulfonamide-indoles |
| US7163954B2 (en) | 2003-09-25 | 2007-01-16 | Wyeth | Substituted naphthyl benzothiophene acids |
| US7582773B2 (en) | 2003-09-25 | 2009-09-01 | Wyeth | Substituted phenyl indoles |
| US7141592B2 (en) | 2003-09-25 | 2006-11-28 | Wyeth | Substituted oxadiazolidinediones |
| US7342039B2 (en) | 2003-09-25 | 2008-03-11 | Wyeth | Substituted indole oximes |
| US7351726B2 (en) | 2003-09-25 | 2008-04-01 | Wyeth | Substituted oxadiazolidinediones |
| EP1680120A2 (en) | 2003-11-03 | 2006-07-19 | Probiodrug AG | Combinations useful for the treatment of neuronal disorders |
| CN1918131B (en) | 2004-02-05 | 2011-05-04 | 前体生物药物股份公司 | Novel inhibitors of glutaminyl cyclase |
| MX2007002178A (en) | 2004-08-23 | 2007-04-02 | Wyeth Corp | Oxazolo-naphthyl acids as plaminogen activator inhibtor type-1 (pai-1) modulators useful in the treatment of thrombosis and cardiovascular diseases. |
| BRPI0606871A2 (en) | 2005-01-27 | 2009-07-21 | Wyeth Corp | "Processes and compounds for the preparation of substituted naphthylindole derivatives |
| AU2006279496A1 (en) | 2005-08-17 | 2007-02-22 | Wyeth | Substituted indoles and use thereof |
| WO2007046112A1 (en) * | 2005-10-19 | 2007-04-26 | Suven Life Sciences Inc. | Arylthioether tryptamine derivatives as functional 5-ht6 ligands |
| WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | 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 |
| SI2091948T1 (en) | 2006-11-30 | 2012-07-31 | Probiodrug Ag | Novel inhibitors of glutaminyl cyclase |
| EP2481408A3 (en) | 2007-03-01 | 2013-01-09 | Probiodrug AG | New use of glutaminyl cyclase inhibitors |
| DK2142514T3 (en) | 2007-04-18 | 2015-03-23 | Probiodrug Ag | Thiourea derivatives as glutaminyl cyclase inhibitors |
| CN102123990B (en) | 2008-06-19 | 2014-07-09 | 武田药品工业株式会社 | Heterocyclic compound and use thereof |
| AU2010294214B2 (en) | 2009-09-11 | 2015-05-07 | Vivoryon Therapeutics N.V. | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
| JP6026284B2 (en) | 2010-03-03 | 2016-11-16 | プロビオドルグ エージー | Inhibitors of glutaminyl cyclase |
| AU2011226074B2 (en) | 2010-03-10 | 2015-01-22 | Vivoryon Therapeutics N.V. | Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5) |
| EP2560953B1 (en) | 2010-04-21 | 2016-01-06 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
| JP6050264B2 (en) | 2011-03-16 | 2016-12-21 | プロビオドルグ エージー | Benzimidazole derivatives as inhibitors of glutaminyl cyclase |
| CN103635230B (en) | 2011-05-12 | 2017-10-31 | 普罗蒂斯特斯治疗公司 | Albumen homeostasis conditioning agent |
| 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 |
| PL3461819T3 (en) | 2017-09-29 | 2020-11-30 | 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 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 | |
| EP0716854A3 (en) * | 1994-10-20 | 1996-08-28 | Lilly Co Eli | Compositions for inhibiting neuropeptide y receptors |
-
1996
- 1996-08-30 IL IL12072496A patent/IL120724A0/en unknown
- 1996-08-30 CA CA002203912A patent/CA2203912A1/en not_active Abandoned
- 1996-08-30 TR TR97/00334T patent/TR199700334T1/en unknown
- 1996-08-30 HU HU9701714A patent/HUP9701714A3/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 CZ CZ971328A patent/CZ132897A3/en unknown
- 1996-08-30 MX MX9703186A patent/MX9703186A/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 NZ NZ318228A patent/NZ318228A/en unknown
- 1996-08-30 PL PL96320010A patent/PL320010A1/en unknown
- 1996-08-30 AU AU69650/96A patent/AU717422B2/en not_active Ceased
-
1997
- 1997-04-30 NO NO972016A patent/NO308296B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| MX9703186A (en) | 1997-07-31 |
| NO972016D0 (en) | 1997-04-30 |
| NO972016L (en) | 1997-06-17 |
| EP0789688A1 (en) | 1997-08-20 |
| AU6965096A (en) | 1997-03-27 |
| BR9606619A (en) | 1997-12-23 |
| HUP9701714A3 (en) | 2000-03-28 |
| PL320010A1 (en) | 1997-09-01 |
| CA2203912A1 (en) | 1997-03-13 |
| EP0789688A4 (en) | 1997-11-19 |
| CZ132897A3 (en) | 1997-11-12 |
| HUP9701714A2 (en) | 1999-06-28 |
| NO308296B1 (en) | 2000-08-28 |
| NZ318228A (en) | 1999-07-29 |
| WO1997009308A1 (en) | 1997-03-13 |
| CN1173867A (en) | 1998-02-18 |
| IL120724A0 (en) | 1997-08-14 |
| TR199700334T1 (en) | 1997-08-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU717422B2 (en) | Indolyl neuropeptide Y receptor antagonists | |
| US6403577B1 (en) | Hexamethyleneiminyl tachykinin receptor antagonists | |
| US6329389B1 (en) | Amine compounds, their production and use | |
| WO1997025041A1 (en) | Benzimidzolyl neuropeptide y receptor antagonists | |
| US6025372A (en) | Somatostatin agonists | |
| US20050245571A1 (en) | Amine derivative | |
| CA2162786A1 (en) | Heterocyclic tachykinin receptor antagonists | |
| SK126695A3 (en) | Amino(thio)ether derivative, preparing method and pharmaceutical composition containing its | |
| US6245761B1 (en) | Indolyl neuropeptide Y receptor antagonists | |
| US6358994B1 (en) | 2-acylaminopropanamines as tachykinin receptor antagonists | |
| US6255494B1 (en) | Benzimidzolyl neuropeptide Y receptor antagonists | |
| US5776931A (en) | Naphthimidazolyl neuropeptide Y receptor antagonists | |
| US6175013B1 (en) | Imidazolinyl tachykinin receptor antagonists | |
| JPH10508321A (en) | Indolyl neuropeptide Y receptor antagonist | |
| US5563133A (en) | Hexamethyleneiminyl tachykinin receptor antagonists | |
| US6869957B1 (en) | Non-peptide tachykinin receptor antagonists | |
| US6339094B1 (en) | 2-acylaminopropanamines as tachykinin receptor antagonists | |
| US5607947A (en) | Pyrrolidinyl tachykinin receptor antagonists | |
| AU721935B2 (en) | Non-peptide tachykinin receptor antagonists | |
| JP2000226373A (en) | Amine derivative, its production and agent therefor | |
| US20040152688A1 (en) | Aminopyridine derivatives as estrogen receptor modulators | |
| JP3657982B6 (en) | Non-peptide tachykinin receptor antagonist | |
| MXPA00001167A (en) | 2-acylaminopropanamines as tachykinin receptor antagonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |