CZ132897A3 - Antagonist of indolylneuropeptide y receptor - Google Patents

Abstract

This invention provides a series of substituted indoles which are useful in treating or preventing a condition associated with an excess of neuropeptide Y. This invention also provides the novel substituted indoles as well as pharmaceutical formulations which comprise as an active ingredient one or more of these substituted indoles.

Description

The invention relates to an antagonist of the indolylneuropeptide Y receptors.

This application claims the advantages of U.S. Provisional Application No. 60 / 003,150, filed September 1, 1995, U.S. Provisional Application No. 6Q0 / 0-2-1-638, filed July 12, 1996, and GB Patent Application 9523999.2, filed Nov. 23, 1995.

BACKGROUND OF THE INVENTION

Neuropeptide Y is a peptide that is present in the central and peripheral nervous systems. This peptide exists

.. together with noradrenaline in a number of neurons and as such act as a neuromediator or act synergistically, together ......

with norepinephrine. Fibers containing neuropeptide Y are numerous in number around arteries in the heart, but are also found around arteries in the respiratory tract, gastrointestinal tract, and in the genitourinary tract. Neuropeptide Y is also present in the large brain with effects on blood pressure, food intake and release of various hormones. Altered by the concentration of neuropeptide Y in the central nervous system, they interfere with the etiology of psychiatric disorders.

Neuropeptide Y was discovered, isolated and sequenced from the pig brain in 1982 as part of a general screening procedure to detect anidated carboxy-terminated peptides and was named neuropeptide Y due to its isolation from neural tissue and the presence of tyrosine as an amino acid terminated as amino and carboxy. Neuropeptide Y is a member of the pancreatic set and shares significant sequence homology with the pancreatic polypeptide and the YY peptide.

Neuropeptide Y and other members of this peptide set all have a tertiary structure feature consisting of an N-terminal polyproline helix and an amphiphilic α-helix associated with a β-bend, forming a loop similar to a hairpin structure, sometimes referred to as pancreatic. In this embodiment, the helix is maintained by hydrophobic interactions. The amidate C-terminal end designs are distant from the hairpin loop.

Additionally, after its discovery, neuropeptide Y has been identified as the most abundant peptide in the central nervous system with widespread occurrence, including in the cortex, brainstem, hippocampus, hypothalamus, tonsils and thalamus, as well as presence in the peripheral nervous system in sympathetic neurons and adrenal chromaffin cells. .

Neuropeptide Y appears to meet the major criteria for a neuromediator because it is embedded in synaptic granules, released upon electrical stimulation of the nerve and acting on specific receptors. Obviously, neuropeptide Y is an important messenger of its own right, probably in the brain, where neuropeptide Y potentially inhibits adenylate cyclase activity and induces an increase in intracellular calcium levels. Injection of neuropeptide Y into the central nervous system results in changes in blood pressure, increased food intake, increased fat storage, increased blood sugar and insulin levels, decreased locomotor activity, decreased body temperature and catalepsy.

Neuropeptide Y (as well as chemical compounds related to it) acts on membrane receptors that are dependent on guanyl nucleotide binding proteins known as protein G-coupled receptors. Proteins G belong to a set of membrane proteins that become activated only after binding of guanosine triphosphate . Activated G proteins in turn activate the enhancing enzyme on the inner membrane surface and the enzyme then converts the precursor molecules to

--second-rn-mesenger-y .___________________________________________......

Neuropeptide Y appears to interact with a system of closely related receptors. These receptors are generally classified into several subtypes based on the ability of different tissues and receptors to bind different fragments of neuropeptide

Y and other members of the PP peptide system. The Y1 receptor subtype appears to be the major vascular receptor of the neuropeptide Y. Y2 receptor subtypes may also occur upon fusion to vascular smooth muscle. The hitherto unisolated Y3 receptor subtype appears to be a Y-specific neuropeptide that does not bind to the YY peptide. This receptor is probably present in adrenal, spinal cord, heart, and brainstem tissue, among other areas. [Summary of Neuropeptide

Y and neuropeptide Y receptors are reported, for example, by C. Wahlestedt and D. Reis in the Annual Review of Pharmacology and Toxicology,

33, 309-352 (1993) and D. Gehlert and P. Hipkind in Current Pharmaceutical Design, 1, 295-304 (1995)].

In view of the wide variety of clinical diseases associated with an excess of neuropeptide Y, the development of neuropeptide Y receptor antagonists will serve to suppress these clinical conditions. First, such receptor antagonists were peptide derivatives as described in the PCT patent publication

WO 91/08223, published June 13, 1991, and PCT Patent Publication WO 94/00486, published January 6, 1994. These antagonists enabled limited pharmaceutical use to be achieved due to their metabolic instability.

The present invention provides a group of potent non-peptide neuropeptide Y receptor antagonists. Because of their non-peptide nature, the compounds of the invention do not suffer from metabolic instability deficiencies exhibited by known peptide-based neuropeptide Y receptor antagonists.

SUMMARY OF THE INVENTION

The invention includes methods of treating or preventing disorders associated with an excess of neuropeptide Y, the methods comprising administering to a mammal in need of such treatment / an effective amount of a compound of formula (1)

R ²

ÍCH ₂ ),

_from EH (CH ₂ ) _s - <fk γΐ X ¹ (CH ₂ ) _P —R (D in which

R ^ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms.

trifluoromethyl, hydroxy or halogen,

9 '7

R ¹ is hydrogen, alkyl having 1-5 carbon atoms or a group of formula - (CH ₂₎ -R ^a, where v is 1 to 12 and

R ^1a is phenyl, naphthyl, hexamethyleniminyl, piperazinyl, heptamethyleniminyl, imidazolinyl, piperidyl, tryptolinyl, pyrrolidin-1-ynyl, quinuclidinyl. or morpholinyl, wherein any of the phenyl, naphthyl, hexamethyleniminyl, piperazinyl, heptamethyleniminyl, imidazolinyl, piperidyl, tryptolinyl, pyrrolidinyl, quinuclidinyl or morpholinyl groups may be substituted by one or more moieties selected from the group consisting of up to 6 alkyl groups selected from the group consisting of up to 6 carbon atoms, halogen, trifluoromethyl, benzyl, phenyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylamino, C 2 -C 6 alkanoyl, C 2 -C 6 alkanoyloxy and C 1 -C 6 alkanoyloxy; C 3 -C 8 cycloalkyl, said phenyl, benzyl or C 3 -C 8 cycloalkyl optionally substituted with one, two or three moieties independently selected from C 1 -C 6 alkyl, halogen No or (C 1 -C 6) alkoxy, or R ^1a may be substituted with a group of formula

- (CH ₂ ) _W -R ^1b , wherein w represents 1 to 12 a

R ^1b means piperidyl, pyrimidyl, pyrrolidinyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 di [(dialkyl) amino (alkylenyl)] amino, both in the alkyl and alkylenyl moieties, di (alkyl) amino (alkylenyl) amino having 1 to 6 carbon atoms in both the alkyl and _______ alkylenyl moieties, phenyl, cycloalkyl of up to 8 atoms, carbon, pyrrolidinyl and acetamido, wherein said phenyl or cycloalkyl of 3 to 8 atoms The carbon atoms are optionally substituted by one, two or three moieties independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen or alkoxy of 1 to 6 carbon atoms. -

A represents a bond, a group of formula - (CH _{2) m} or -C (0) -,

A ¹ is a bond, -NR ^a -, -O-, ^- (CH ₂ ) _ni or -Ξ (O) _η -, q is 0-6, p is 0-6, n is 0, 1 , or 2, m is 0 to 6,

Ί s is a number from 0 to 6,

R ^a represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkanoyl group having 2 to 6 carbon atoms,

D represents a bond, a C 2 -C 4 alkenylenyl group or a group of formula -C (X) (Y) wherein one of X and Y represents a hydroxy group and the other represents an X-atom or both X and Y are exemplified by one another. they represent a hydrogen atom or X and Y together form a group of the formula = O or = NOR ^C , where R ^c represents a hydrogen atom, benzyl, acetyl, benzoyl or an alkyl group having 1 to 6 carbon atoms,

- one of X ¹ and Y ¹ represents a hydroxy group and the other represents a hydrogen atom or both X ¹ and Y ¹ represent a hydrogen atom or X ¹ and Y ¹ together form a group of the formula = O or = NOR ^d , where R ^d represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ² represents hydroxyl, alkyl skupinu.s l.až 6 carbon atoms, alkoxy of 1-6 carbon atoms, phenoxy or a group of formula

Β ⁴

Ν.

wherein R ⁴ and R ^{5 are} each independently hydrogen, C 1 -C 6 alkyl, phenyl or C 1 -C 6 phenylalkylenyl in the alkylenyl moiety; or

-R- represents a heterocyclic-cyclic ring selected from the group consisting of hexamethyleniminyl, piperazinyl, heptamethyleniminyl, imidazolinyl, piperidyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl or morpholinyl, wherein any of hexamethyleniminyl, imidazolinyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl , piperidyl, 2-tryptolinyl, pyrrolidine, ...........

the quinuclidinyl or morpholinyl group may be substituted by one or more moieties selected from the group consisting of C 1 -C 6 alkyl, halogen, trifluoromethyl, benzyl, phenyl, C 1 -C 6 dialkylamino, di (alkyl) C 1 -C 6 aminoalkylenyl groups as in the alkyl group; as well as alkylenyl moieties, C 1 -C 6 alkylaminoalkylenyl groups in both alkyl and alkylenyl moieties, C 2 -C 6 alkanoyl groups, carboxamido, 2-aminoacetyl, C 2 -C 6 alkanoyloxy groups, C 1 -C 6 alkoxycarbonyl groups C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, piperidyl, pyrrolidinyl, pyrimidyl, C 1 -C 6 phenylalkylenyl, C 1 -C 6 phenoxyalkylenyl C 1 -C 6 alkylenyl, C 1 -C 6 piperidylalkylenyl, C 1 -C 6 pyrrolidinylalkylenyl, C 1 -C 6 pyrimidylalkylenyl, C 1 -C 6 alkoxy, alkylthio C 1 -C 6, di [di (alkyl) amino (alkylenyl)] amino, C 1 -C 6 in both alkyl, alkylene, di (alkyl) amino (alkylenyl) amino groups of 1 to 6 carbon atoms in both alkyl and alkylenyl, and acetamido, wherein any one of benzyl, phenyl, piperidyl, cycloalkyl of 1 to 6 carbon atoms 6 carbon atoms, phenylalkylenyl groups having 1 to 6 carbon atoms in the alkylenyl moiety, phenoxyalkylenyl groups having 1 to 6 carbon atoms in the alkylenyl moiety, pyrrolidinyl, piperidylalkylenyl groups having 1 to 6 carbon atoms in the alkylenyl moiety, pyrrolidinylalkylenyl groups having 1 to 6 atoms the C 1 -C 6 -alkynyl, C 1 -C 6 -pyrimidyl-alkylenyl or pyrimidyl group may be substituted by one or more moieties selected from the group consisting of C 1 -C 6 alkyl, halogen, trifluoromethyl, acetamido, alkanoyl, and the like. C 2 -C 6 alkanoyloxy having 2 to 7 carbon atoms C 1 -C 6 -alkoxy or C 1 -C 6 -alkoxy or N-piperidyl, pyrrolidinyl, C 1 -C 6 -alkylenyl-C 1 -C 6 -alkylenyl, C 1 -C 6 -pyrrolidihylalkylenyl, C 1 -C 6 -pyrimidyl-alkylenyl The 6 carbon atoms in the alkylenyl moiety or the pyrimidyl group may be substituted with an amino protecting group, or may be a group of formula. .

R ^4a

I ^ R ^6a —------------—

R ^5a r

wherein R ^4a , R ^5a and R ^6a are each independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl or C 1 -C 6 alkoxy, or

R ^4a represents a hydrogen atom, a C 1 -C 6 alkyl group, a trifluoromethyl or a C 1 -C 6 alkoxy group ^, and R ^6a and R ^6a together form with the nitrogen atom to which they are attached pyrrolidinyl, piperidyl, hexamethyleniminyl or heptamethyleniminyl, or

R ^4a represents an oxygen atom and R ^5a and R ^6a together form with the nitrogen atom to which they are attached pyrrolidinyl, piperidyl, hexamethyleniminyl or heptamethyleniminyl means phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, cycloalkyl of 3 to 8 carbon atoms, pyrazinyl , allyl, thiazolyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethyleniminyl, heptamethyleniminyl, piperidyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any of which are any of the following: tetrahydronaphthyl, C 3 -C 8 cycloalkyl groups, pyrazinyl, thiazolyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethyleniminyl, molidamethyleniminyl, heptamethyleniminyl, heptamethyleniminyl, heptamethyleniminyl, heptamethyleniminyl, heptamethyleniminyl, heptamethyleniminyl, substituted once or a plurality of moieties selected from the group consisting of C 1 -C 12 alkyl, i

C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, halogen, trifluoromethyl, carboxamido, cyano, benzyl, phenyl / dialkylamino of 1 to 6 carbon atoms in each alkyl moiety, alkanoyl of up to 6 carbon atoms, C 2 -C 6 alkanoyloxy, C 1 -C 6 alkylamino, oxazolyl, dihydrooxazolyl> C 1 -C 12 piperidylalkoxy, C 1 -C 6 piperidylalkoxyalkylenyl and C 1 -C 12 alkylene carbon in the alkoxy moiety, piperidylalkylenyl having 1 to 12 carbon atoms in the alkylenyl moiety, phenylalkoxy having 1 to 12 carbon atoms in the alkoxy moiety, phenylalkylenyl having 2 to 12 carbon atoms in the alkylenyl moiety, cycloalkyl having up to 8 carbon atoms, piperidyl, pyrimidyl C 1 -C 6 alkoxy; C 1 -C 6 alkylthio

- 12-6 carbon atoms and a group of the formula R ^x R 4 NGL- (alkylenyl), wherein the alkylene group contains 0-6 carbon atoms, and acetamido, ₍ wherein R ^x and R 6 are independently hydrogen, alkyl having 1 to 6 carbon atoms); up to 6 carbon atoms, phenyl, benzyl, piperidyl, pyrrolidinyl, hexamethyleniminyl, heptamethyleniminyl, morpholinyl, piperazinyl or cycloalkyl of 1 to 6 carbon atoms, or

wherein R ^x R 7n is a ring selected from the group consisting of piperidyl, pyrrolidinyl, hexamethyleniminyl, hepta-methyleniminyl, azetidinyl, which may be attached to G at any convenient point on the ring, wherein G is C 1 -C 12 alkylenenyl, (C 2 -C 12) alkenylenyl or (C 2 -C 12) alkynylenyl and wherein L is a bond, -O-, -S-, -S (O) -,

-S (O) ₂ - or -NH-,

Provided that when A ¹ is -NR ^and -, -O- or -S (o) _n - 'and A is -CH ₂ -> R is not a hydrogen atom, or a pharmaceutically acceptable salt or solvate thereof.

The invention also encompasses novel compounds of Formula I as well as pharmaceutical compositions comprising a compound of Formula I in combination with at least one pharmaceutically acceptable carrier, diluent, or vehicle.

The following is a detailed description and preferred embodiments of the present invention.

The present invention is based on the discovery that a selected group of substituted indoles of Formula I are useful as neuropeptide Y receptor antagonists.

The term C 1 -C 6 alkoxy represents a straight or branched alkyl chain containing from 1 to 6 carbon atoms attached to an oxygen atom. Typical C 1 -C 6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and the like. The term C 1 -C 6 alkoxy includes the definitions of C 1 -C 4 alkoxy and C 1 -C 3 alkoxy.

As used herein, the term alkyl group of six carbon atoms refers to a straight or branched monovalent saturated aliphatic chain containing from 1 to 12 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- but not limited to butyl, pentyl, isopentyl and hexyl. The term C 1 -C 12 alkyl includes, by definition, C 1 -C 6 alkyl and C 1 -C 4 alkyl.

The term C 2 -C 7 alkanoyloxy represents a straight or branched alkyl chain containing from 1 to 6 carbon atoms attached to the carbonyl moiety through an oxygen atom. Typical C 2 -C 7 alkanoyloxy groups include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, tert-butanoyloxy, pentanoyloxy, hexanoyloxy, 3-methylpentanoyloxy.

C 3 -C 8 cycloalkyl represents a saturated hydrocarbon ring structure containing from 3 to 8 carbon atoms. Typical C 3 -C 8 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The term halogen or halogen represents chlorine, fluorine, bromine and iodine.

The term C 1 -C 10 alkylthio represents a straight or branched alkyl chain containing from 1 to 10 carbon atoms attached to a sulfur atom. Typical C 1 -C 10 alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, and the like, and the term C 1 -C 10 alkylthio includes the definition of C 1 -C 6 alkylthio and C 1 -C 3 alkylthio.

The term C 1 -C 12 alkylenyl represents a straight or branched, divalent, saturated aliphatic chain containing from 1 to 12 carbon atoms and includes methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, tert-butylenyl, pentylenyl, but is not limited to isopentylenyl, hexylenyl, octylenyl, 3-methyloctylenes and decylenyl. The term C 1 -C 6 alkylenyl is included in the C 1 -C 12 alkylenyl group. The term C 0 alkylenyl or any other term including that designation refers to a bond. For example, a (C 1 -C 6) alkylenyl group refers to a bond or (C 1 -C 6) alkylenyl group as defined above.

The term C 1 -C 10 alkylamino represents a group of the formula

- (NH-alkyl), wherein the chain comprises from 1 to 10 carbon atoms attached to the 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 refers to a straight or branched, monovalent, unsaturated aliphatic chain containing from 2 to 12 carbon atoms. Typical C 2 -C 12 alkenyl groups include ethenyl (also known as vinyl).

1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl,

2-methyl-2-propenyl, 2,4-hexadienyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl and the like.

The term C 2 -C 12 alkynyl, as used herein, represents a straight or branched, monovalent, unsaturated aliphatic chain containing from 2 to 12 carbon atoms. 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 alkenylenyl having 2 to 12 atoms

As used herein, represents a straight or branched, divalent, unsaturated aliphatic chain containing from 2 to 12 carbon atoms. Typical C 2 -C 12 alkenylenyl groups include -CH = CH-, -CH ₂ -CH = CH, -CH ₂ -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 containing from 2 to 12 carbon atoms and at least one triple

The bond of the C ₂ -C 12 alkynyl-alkynyl group includes the groups -C = C-, -CH ₂ -C = C-, -CH ₂ -C = C-CH ₂ CH ₂ and the like.

The term C 3 -C 8 cycloalkenyl represents a hydrocarbon ring structure having 3 to 8 carbon atoms and having at least one double bond in the ring.

The term C 1 -C 6 alkoxy represents a straight or branched alkyl chain containing from 1 to 6 carbon atoms attached to an oxygen atom. Typical C 1 -C 6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and the like. The term C 1 -C 6 alkoxy includes the definition of C 1 -C 3 alkoxy.

The term C 2 -C 6 alkanoyl represents a straight or branched alkyl chain containing from 1 to 5 carbon atoms attached to the carbonyl moiety. Common C 2 -C 6 alkanoyl groups include ethanoyl, propanoyl, isopropanoyl, butanoyl, tert-butanoyl, pentanoyl, hexanoyl, 3-methylpentanoyl and the like.

C 1 -C 6 alkoxycarbonyl represents a straight or branched alkoxy chain containing from 1 to 6 carbon atoms attached to the carbonyl moiety. Typical C 1 -C 6 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, and the like. ______ "__________"

The term amino protecting group as used herein refers to amino substituents commonly used to block or protect the function of an amino group while other functional groups on the compound react.

Examples of such amino protecting groups include formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbloxy, benzylcarbonyl, 4-methoxybenzyloxycarbonyl, , 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanbenzyloxycarbonyl, tert-butoxycarbonyl, 1,1-butoxycarbonyl, 1,1-butoxycarbonyl, 1,1-butoxycarbonyl, 1,1-butoxycarbonyl, 1,1-butoxycarbonyl diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,

2- (p-toluyl) prop-2-yloxycarbonyl, cyclopentyloxycarbonyl, 1-methylcyclopentyloxycarbonyl, cyclohexyloxycarbonyl, 1-methylcyclohexyloxycarbonyl, 2-methylcyclohexyloxycarbonyl, 2- (4-toluylsulfonyl) ethoxycarbonyl, 2- (methylsulfonyl), 2- (methylsulfonyl) ethoxycarbonyl, 2- (methylsulfonyl) ino) ethoxycarbonyl, fluorenylmethoxycarbonyl (FMOC), 2- (trimethylsilyl) ethoxy18 carbonyl, allyloxycarbonyl, 1- (trimethylsilylmethyl) prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-acetyloxybenzyloxycarbonyl, 2,2,2 2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4- (decyloxy) benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like, as well as benzoylmethylsulfonyl, 2-nitrophenylsulfenyl, diphenylphosphine oxide and similar amino protecting groups. The types of amino protecting groups used are usually not critical if the derivative amino group is stable under the conditions of the following reactions> ... in other positions of the intermediate molecule and can be selectively removed at the appropriate time without disturbing the rest of the molecule including any other protecting groups amino groups. preferred amino protecting groups are trityl, tert-butoxycarbonyl (t-BoC, Boc or t-Boc), allyloxycarbonyl and benzyloxycarbonyl. Further examples of groups related to the above expression are described by E. Haslam in Protective Groups in Organic Chemistry, edited by J. G. W. McOmie (1973), Chap. 2, and T. W. Greebe and P. G. M. Wuts in Protective Groups in Organic Synthesis (1991), Chap. 7.

The term carboxy protecting group as used herein refers to carboxy substituents commonly used to block or protect a carboxyl function while other functional groups on the compound react. Examples of such carboxy protecting groups include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl, 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, tert-butyl, tert-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4 ', 4-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, tert-butyl19 dimethylsilyl, 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 the like. Preferred carboxy protecting groups are allyl, benzyl and tert-butyl. Further examples of such groups relating to the above expression are described by E. Haslam, op. above, in Chap. 5 and T. W. Greebe et al., Loc. above, in Chap. 5.

The term hydroxy protecting group as used herein. in this specification, _u refers to hydroxy substituents commonly used to block or protect the hydroxyl function while other functional groups react on the compound. Examples of such hydroxy protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, methylthiomethyl, 2,2-dichloro-1,1-difluoroethyl, tetrahydropyranyl, phenacyl, cyclopropylmethyl, allyl, C 1 -C 6 alkyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl, tert-butyldimethylsilyl, levulinate, pivaloate, benzoate, dimethylsulfonate, dimethylphosphinyl, isobutyrate, adamantoate and tetrahydropyranyl residues. Further examples of such groups related to the above expression are described by TW Greebe and PGM Wuts in Protective Groups in Organic Synthesis (1991), Chapter 3.

The term leaving group, as used herein, refers to a group of atoms that are replaced by the action of a nucleophilic substance in a nucleophilic substitution reaction. The term leaving group as used herein includes, but is not limited to, activating groups.

The term activating groups as used herein refers to a leaving group which, when attached to the carbonyl group ( ^- C ⁼ 0) to which it is attached, is more likely to participate in the acylation reaction than would be if the such a group was not present, as in the free acid. Such activating groups are well known to the person skilled in the art and may be, for example, succinimidoxy, phthalimidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido or -O-CO-alkyl of 4 to 7 carbon atoms.

The compounds of this invention are indole derivatives that are labeled and numbered according to RING INDEX, The American Chemical Society, as follows:

The compounds of the invention may have one or more asymmetric centers. As a result of these chiral centers, the compounds of the invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such asymmetric forms, individual isomers and combinations thereof are within the scope of this invention.

the terms R and S are used herein as is commonly used in organic chemistry to denote a particular configuration of chiral centers. The term R (rectus) refers to the configuration of the chiral center with the relationship of the priority groups in the clockwise direction (highest to second lowest) when considering binding to the lowest priority group. The term S (sinester) refers to the configuration of the chiral center with the counter-clockwise relationship of the priority groups (highest to second lowest) when considering binding to the lowest priority group. The priority of groups is based on their atomic number (in order of decreasing atomic numbers). A partial inventory of priorities and analysis of stereochemistry is contained in Nomenclature of Organic Compounds: Principles and Practice (ed. JH Fletcher et al., 1974), p. 103 to 120.

In addition to the (R) - (S) system, an earlier D-L system may also be used herein to denote the absolute configuration, particularly in relation to amino acids. In this system, the Fischer projection of the formula is oriented so that the carbon number 1 of the main chain is at the top. The prefix D is used to indicate the absolute configuration of the isomers in which the functional (determining) group is to the right of the carbon atom in the chiral center and L denotes the isomer to the left.

In order to preferentially prepare one optical isomer over its enantiomers, one of ordinary skill in the art may follow one of two routes. One skilled in the art can first prepare a mixture of enantiomers and then separate the enantiomers into two enantiomers. A commonly used method for resolving a racemic mixture (or mixture of enantiomers) into individual enantiomers is to first convert the enantiomers into diastereomers by forming a salt with an optically active salt or base. These diastereomers may then be separated using differential solubility, fractional crystallization, chromatography or the like. methods. Further details on the resolution of enantiomeric mixtures can be found in J. Jacques et al., "EnantiomersRacemates, and Resolutions" (1991),

In addition to the schemes described above, one skilled in the art may also choose an enantiospecific process for preparing compounds of Formula I. Such process utilizes a conventional pattern of such synthetic reactions that maintain the chiral centers present in the starting material in the desired orientation. These reaction schemes usually result in the preparation of compounds in which more than 95% of the title compound is the desired enantiomer. ..... ~ ......... ’

As noted above, the present invention includes pharmaceutically acceptable salts of the compounds of Formula I. The compounds of this invention may contain sufficiently acidic groups, sufficiently basic groups, or both, and therefore react with any of a variety of organic or inorganic bases and inorganic bases. or

Oroawrcfc vch * kvs-e ^ nw ^ za * vz-n-i-feu-4-f-raseu-th-ck-v ^ nr ratella-ne * s o ,,

The term pharmaceutically acceptable salt as used herein refers to salts of compounds of the above formula which are substantially non-toxic to the living organism. Conventional pharmaceutically acceptable salts include those prepared by reaction of the compounds of this invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition salts and base addition salts.

The acids generally used to prepare the acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid 23, sulfuric acid, phosphoric acid and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, acids oxalic, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts are sulfates, pyrosulfates, hydrogensulfates, sulfites, hydrogensulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylateformates, hydrochlorides, dihydrochlorides. BBuXYRATED, CORATOES, HIPARIOATOOPIOlates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butin-1,4-dioates, hexin-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, hydroxybenzoates, hydroxybenzoates, hydroxybenzoates, xylene sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, τ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandates and the like The linking salts are the addition salts formed with mineral acids, such as acidic acid. other hydrochloric and hydrobromic acid; and addition salts formed with organic acids such as maleic acid and methanesulfonic acid.

Salts on amino groups may also include quaternary ammonium salts in which the nitrogen atom of the amino group carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl group.

Base addition salts include those derived from inorganic bases such as ammonia or alkali and alkaline earth hydroxides, carbonates and bicarbonates, and the like. Thus, such bases suitable for preparing the salts of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like. Sodium and potassium salt forms are particularly preferred.

It should be appreciated that the particular counterion forming part of any of the salts of the present invention is not normally critical if the salt as a whole is pharmacologically acceptable unless it contributes to the undesirable quality of the salt as a whole.

The present invention further includes pharmaceutically acceptable solvates of the compounds of Formula I. A number of compounds of Formula I may be combined with solvents such as water, methanol, ethanol, and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate, and acetone. trflát _................

The invention also encompasses pharmaceutically acceptable prodrugs of the compounds of Formula I. A prodrug is a drug that has been chemically modified and may be biologically inactive at its site of action, but which may be subject to degradation or modification by at least one enzymatic or other in vivo process to produce basic biologically active forms. Such a prodrug has a different pharmacokinetic profile than the parent compound, which allows easier absorption through the lining of the mucosa, better salt formation or solubility, or improved systemic stability (e.g., increased half life in plasma).

Typically, such chemical modifications include

(1) ester or amide derivatives which can be cleaved by esterase or lipase;

Peptides that can be detected by specific or non - specific proteases; or

3) derivatives that accumulate at the site of action of the membrane. by selecting the prodrug form or the modified prodrug form. drugs, or any combination of the cases listed under 1 to 3 above. conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, by H. Bundgaard in Design of Prodrugs (1985).

Preferred compounds of the invention are those compounds of formula (I) wherein. h .. ·

m.n ·. In p-UTtirh - '

y.

(a) R ^D represents a hydrogen, chlorine or fluorine atom, methyl, ethyl, hydroxy or acetyl;

(b) R is methyl or ethyl; or

R ^1a represents phenyl, piperidyl, pyrrolidinyl, hexamethyleniminyl, piperazinyl and v represents 1 to 6, π · ·

c) A ^x represents a bond or a group of formula -NH-, -N (CH ₃ ) -, "S- or -O-",

d) A is -CH ₂ - or -CH ₂ CH ₂ -,

e) q is 0, 1 or 2,

f) p is 0, 1 or 2;

(g) s is 0, 1, 2 or 3;

h) D represents a bond or a group of the formula -c (O) -, -CH (OH) or -CH ₂ -, i.

i) R ² represents a group of formula -NR ⁴ R ⁵ or -N ⁺ R ^4a R ^5a R ^6a,

j) R ⁴ and R ⁵ are each independently hydrogen, methyl, ethyl, benzyl or form together with the nitrogen atom to which they are attached a piperidyl, pyrrolidinyl or hexamethyleniminyl group,. Ρ? * - ,. ^R5a znamena.ii-.:nezá.visl-e--na»sobě*a-tom*·* ^{* 1} ^^ hydrogen, methyl or ethyl, or R ^5a and R ^6a together with the nitrogen atom to which they are attached, piperidyl, pyrrolidinyl or hexamethyleniminyl, and

1) R is phenyl, piperidyl, pyrrolidinyl, hexamethyleniminyl, heptamethyleniminyl, naphthyl, thiazolyl, furyl, quinolyl, isoquinolyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl or quinuclidinyl, or a pharmaceutically acceptable salt or solvate thereof;

Preferred methods of the invention are those which deal with compounds of Formula I wherein:

y.

a) R 0 represents a hydrogen, chlorine or fluorine atom, methyl, ethyl, hydroxy or acetyl;

b) R ¹ is methyl or ethyl, or

R ^1a is phenyl, piperidyl, pyrrolidinyl, hexamethyleniminyl, piperazinyl, and v is 1-to-6.

c) A ¹ represents a bond or a group of the formula -NH-, -N (CH ₃ ) -, -S- or -o-,

d) A is -CH ₂ - or -CH ₂ CH ₂ -,

e) q is 0, 1 or 2, ttOtT .--- "-"" ^IW " ^f ..... "

f) p 2 the known number 0, 1 or 2,

(g) s is 0, 1, 2 or 3;

h) D represents a bond or a group of formula -C (O) -, -CH (OH) or -CH ₂ -,

i) R ² represents a group of formula -NR ⁴ R ⁵ or -N ⁺ R ^4a R ^5a R ^6a,

j) R ⁴ and R ⁵ are each independently hydrogen, methyl, ethyl, benzyl or form together with the nitrogen atom to which they are attached a piperidyl, pyrrolidinyl or hexamethyleniminyl group,

k) R ^4a , R ^5a , R ^6a are each independently hydrogen, methyl or ethyl, or R ^5a and R ^6a together with the nitrogen atom to which they are attached form a piperidyl, pyrrolidinyl or hexamethyleniminyl group, and

l) R is phenyl, piperidyl, pyrrolidinyl, hexamethyleniminyl, heptamethyleniminyl, naphthyl, thiazolyl, furyl, quinolyl, isoquinolyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl or quinuclidines. ------- - ------ τ —--------- ~ or a pharmaceutically acceptable salt or solvate thereof.

*

Particularly preferred compounds of the invention are those compounds of formula (I) wherein:

and)

b) la

R is piperidyl, pyrrolidinyl or hexamethyleniminyl, and v is 1, 2 or 3,

Ί

c) A represents a bond or a group of the formula -NH-, -Ξ- or -O-,

d) A is -CH ₂ - or -CH ₂ CH ₂ -,

e) q is 0 or 1,

R ^d represents a hydrogen or fluorine atom or methyl

R is methyl or

F) P means 0 or 1, G) with means 0 or 1, (h) D represents a bond or a group of formula -C (Q) -, and) R ² represents a group of the formula -NR ^ R ^,

(R-5) R and R are each independently methyl or, together with the nitrogen atom to which they are attached, form a piperidinyl, piperazinyl or pyrimidinyl group,

k) R is optionally substituted phenyl, naphthyl or cyclohexyl, or pharmaceutically acceptable salts or solvates thereof.

Particularly preferred compounds of this invention are compounds of formula I wherein:

a) R 6 represents a hydrogen atom,

b) R is methyl, piperidylalkylenyl having 1 to 4 carbon atoms in the alkylenyl moiety, pyrrolidinylalkylenyl having 1 to 4 carbon atoms in the alkylenyl moiety,

c) A ¹ represents a bond or a group of the formula -O-,

d) A is -CH ₂ -,

e) q is zero,

f) p is 0 or 1,

g) s is 0 or 1,

h) D represents a bond or a group of formula -C (O) -,

i) R is piperidyl or pyrrolidinyl substituted by amino, dialkylamino having 1 to 6 carbon atoms in each alkyl moiety, alkylamino having 1 to 6 carbon atoms; - piperidyl or pyrrolidinyl, or R represents a piperazinyl group substituted with phenyl, cyclohexyl or benzyl, and

j) R is phenyl which is substituted with one to three groups selected from alkyl group of 1 to 6 carbon atoms, trifluoromethyl and halogen, or pharmaceutically acceptable salts or solvates thereof.

Particularly preferred methods and compositions of the present invention are those methods and compositions utilizing particularly preferred compounds.

The most preferred set of compounds of the present invention are those compounds of formula I that correspond to the formula

in which

D ^A is a group of the formula: -C (O) - · or - CH 3 -;

R ¹ is methyl, piperidin-3-yl-CH ₂ -CH ₂ -, piperid-3-yl-CH ₂ -CH ₂ -CH ₂ -, piperid-2-yl-CH ₂ -CH ₂ -, piperid-2 -yl-CH ₂ -CH ₂ -CH ₂ -, pyrrolidin-3-yl-CH ₂ -CH ₂ -, pyrrolidin-3-yl-CH ₂ -CH ₂ -CH ₂ -, piperid-4-yl-CH ₂ -CH ₂ or piperid-4-yl-CH ₂ -CH ₂ -CH ₂ -,

R is piperidinyl or pyrrolidinyl;

substituted amino, dialkylamino of 1-6 carbon atoms in each alkyl part, alkylamino l.až 6 carbon atoms, piperidyl or pyrrolidinyl, or R ² represents a piperazinyl group substituted fenyíem, cyclohexyl or benzyl, and

R is chlorine or bromine; and

R represents a hydrogen or chlorine atom, or a pharmaceutically acceptable salt or solvate thereof.

Methods and compositions that utilize any of these groups of the most preferred compounds are also most preferred.

The compounds of formula (I) may be prepared by a variety of methods known to those skilled in the art. One process for preparing such compounds of formula I in which R ¹ is methyl is shown in Scheme I as shown below.

Scheme I

reduction

COOH

alkylation or arylation

CH ₂ ) _P -R

One of skill in the art would appreciate that there are a number of ways to accomplish each of the steps illustrated above. Typical embodiments of such methods are described below, in the general discussion and in the examples.

Reduction

CH ₃ 'COOH

OH

Many compounds of Formula 1 are prepared by reducing 1-methyl-2-indolecarboxylic acid to the corresponding 2-hydroxymethyl-1-methylindole. This reduction can be carried out in several ways known in the art, including catalytic hydrogenation. The most preferred method of this reduction is to use a reducing agent such as sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium triethyl borohydride or borane-methylsulfide complex in tetrahydrofuran and triethoxysilane at reflux. Another means for reducing a carboxylic acid involves the use of sodium in ethanol, a method known as Bouveault-BÍancův .pos Tup _w ,. _The reducing agent used in the reduction process is preferably lithium aluminum hydride.

Alkylation or arylation

The condensation of the aryl group to the above alcohol can be carried out using conventional techniques. For those compounds of formula X wherein A is -Ο-, p is 0 and R is substituted phenyl, for example, the most preferred method involves phenol condensation using 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 is combined with diethyl azodicarboxylate (DEAD) and converted in situ alcohols into the corresponding alkoxyphosphonium salts, which are suitable alkylating agents.

Although this condensation can be achieved using different concentrations of reagents and with different reagents, it is best to use 1 to 2 equivalents of methanol, triphenylphosphine and diethyl azodicarboxylate for each equivalent of the substituted phenol used (formula ArOH).

This reaction is also preferably carried out in the presence of an inert solvent such as toluene, benzene or preferably tetrahydrofuran. The reaction is carried out at temperatures from _n . w>. Preferably, about 0 to about 40 ° C is preferably at room temperature until the desired compound is prepared. Usually, the reaction is run for about 18 hours at room temperature, but the progress of the reaction can be followed by conventional chromatographic techniques.

An alternative method of arylating a nucleophilic aromatic substitution with an prepared alkoxide. This reaction of the alcohol comprises the aryl fluoride beforehand carried out first by adding it to the alcohol and then introducing the aryl halide. A particularly preferred base is sodium hydride. Another preferred base is sodium hexamethyldisilazide. The reaction is conveniently carried out in a polar aprotic solvent such as acetonitrile, N, N-dimethylformamide, N, N-dimethylphenylacetamide, dimethylsulfoxide or hexamethylphosphoramide.

Alkylation

NR ⁴ R ⁵

The alkylation of 1,2-disubstituted indole can be carried out in various ways known to those skilled in the art. The preferred method of alkylation of this substituted indole is by the Mannich reaction. [Summary] about this_r-response * u-wadi * Tramontra *, ..........

11-11) ——- Γ * ι '**' «'· · - · -.- · ···

Synthesis, 703-775 (1973) and House, Modern Synthetic 'Reactions, (2nd ed., 1972) on pages 654 to 660.]

In this reaction, formaldehyde (or other aldehyde sometimes) is condensed with a compound HNR ⁴ of the formula R ⁵ which tetra allyl ammonium chloride as the salt, and a compound containing active hydrogen. Instead with ammonia, the reaction may be carried out with a salt of a primary amine (Formula RNH _2), secondary amine (of the formula R ₂ NH) or amides (formula RCONH _2), in which cases the compound is substituted on the nitrogen atom by R, R ₂ or RCO.

This reaction is usually carried out in lower alkyl alcohols, such as methanol or ethanol, or in an acid, such as acetic acid.

One method of preparing compounds of formula I in which A is an alkylenyl group is by first oxidizing the alcohol to give the corresponding aldehyde.

This reaction is generally carried out using an oxidizing agent such as pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC) in a solvent such as methylene chloride. The resulting aldehyde is then reacted with a substituted phosphate salt in the presence of a base.

This Wittig-type reaction results in the formation of an aralkenyl group. The preferred base used in this reaction is sodium hydride. This reaction generally results in a mixture of (E) and (Z) stereoisomers. The double bond is then reduced using either a reducing agent as described above or catalytic hydrogenation using conventional means. Among the preferred solvents for this reaction are

- 37 ..-.

II ch ₃ ch ₃

The resulting 1,2-disubstituted indole can then be substituted at the 3-position as described essentially above for the Mannich reaction.

Compounds in which -R- represents a substituted (*******) alkylenyl group of the formula [(CH ₂ ) _V -R ^1a ] can be prepared as illustrated in the scheme II.

where

Tr represents a trityl group.

Scheme II - continued

!

ϊ

For compounds of formula I wherein L is -S-, the thioderivatives and intermediates of this invention can be converted to the corresponding sulfoxide compounds (containing the group -SO-) after treatment with a mild oxidizing agent such as hydrogen peroxide in the methanol, m-chloroperbenzoic acid (MCPBA) in methylene chloride at 0 ° C or alkali metal periodate in aqueous alcohol. The corresponding sulfones (containing the group -SO ₂ -) are prepared from thio compounds or sulfoxide compounds by treatment with a strong oxidizing agent such as hydrogen peroxide in acetic acid or m-chloroperbenzoic acid in methylene chloride at a temperature of from 20 to 30 ° C. Noc: 2 ° C.

Compounds of formula I in which the benzole ring of the indole is substituted can be prepared by a number of methods known to those skilled in the art. For example, those compounds of formula I in which the 4-position of the indole is substituted with a methyl group ^, as described in Scheme III, included below.

In the following step a), a Knoevenagel condensation reaction is carried out, resulting in (after the dehydration step of the reaction) an olefin. This reaction is usually carried out with an excess of azide, although an equivalent amount of both reagents can be used.

The olefin product of step a) is then cyclized to form an indole ring. The usual means for this. cyclization is the heating of olefins. The course of the cyclization can be. follow thin-layer chromatography.

Scheme III

/

Scheme III - continued

1) base

Scheme IV

R ^b

H

R ^b

CH ₃

Tr

Scheme IV - continued

An alternative method of preparing compounds of formula I in which R * ^{5 is} not hydrogen may be used for the preparation as described in Scheme IV above.

Intermediates and other reagents necessary for _v . u: ------ 'ass ·' -. · * ---..... f ..-----— RnnÍímni ^ m ¹ · ** 4 * M * Mfcw **** * the preparation of the compounds of this invention are commercially available compounds, compounds known from the literature, or compounds that can be prepared by known methods. In addition, one skilled in the art will recognize that changes to these methods for preparing the claimed compounds as described above may be made without deviating from the synthesis of these compounds. For example, other esters may be used which contain protecting groups, precursors, direct introduction of the carboxylic acid group into the indole benzo ring (Kolbe-Schmitt reaction), or the like. In addition, certain R groups can be introduced directly into the benzo ring. For example, a chlorine atom can be introduced by treatment with iodobenzene, chlorine and pyridine [Murakami et al., Chem. Pharm. Bull., 19, 1696 (1971)] or with N-chlorosuccinimide

45 in dimethylformamide (U.S. Pat. No. 4,623,657, the entire contents of which are incorporated herein by reference). In addition to those described above, other transformations, cross-conversions, and derivatizations are either described in the examples below or are well known to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the compounds of this invention and methods for their preparation. The examples are not intended to limit the scope of the invention in any respect and are not to be construed in any way. All experiments are carried out under positive pressure of dry nitrogen or argon. All solvents and reagents are purchased from commercial sources and used as obtained unless otherwise noted. Dry tetrahydrofuran (THF) is obtained by distillation using sodium or sodium benzophenone ketyl prior to use.

Proton Magnetic Resonance Spectrum (¼ HMR) is obtained at 50 ° C at 50 ° C at 50 ° C from a Bruker AM-500 spectrometer at 500 MHz or a Bruker AC-200P spectrometer at 200 MHz or a similar model. (Unless otherwise indicated, the term NMR as used herein refers to proton nuclear magnetic resonance.)

The free atom bombardment mass spectrum (FAB) was performed on a VG ZAB-2SE. The desorption field mass spectrum (FD MS) was performed using either VG 70SE or Variant MAT 731.

Optical rotation is measured on a Perkin-Elmer 241 polarimeter. Chromatographic separation on a Waters Prep 500 LC is generally performed using the linear solvent gradient indicated herein unless otherwise specified.

Reactions are typically monitored for quantitative progress using thin layer chromatography (TLC). Thin layer chromatography was performed using Merck Kiesegel 60 F 254 silica gel plates 5 x 10 cm in size and 0.25 mm thick. A combination of ultraviolet radiation and chemical detection is used to spot the stains (plates are immersed in a solution of cerium ammonium molybdate (75 g ammonium molybdate and 4 g cerium sulfate in 500 ml 10% aqueous sulfuric acid) and then heated on a hot plate]. Preparative thin layer centrifugation chromatography was performed on a Harrison Model 7924A Chromatotron using Analtech silica gel GF rotors.

Cation exchange chromatography is carried out using an ion exchange resin Dowex @ 50X8-100 ^R. Anion exchange chromatography is performed with Bio-Rad AG ^ 1-X8 anion exchange resin (acetate form converted to hydroxide form). Flash chromatography was performed as described in et al., Et al., Which was proportional to chemistry (TT) 2923 (1978).

Optical rotations are reported at the D-line of sodium (354 nm).

. Elemental analyzes of carbon, hydrogen and nitrogen are determined on a Control Equipment Corporation 440 Elemental Analyzer or performed at the Universidad Complutense Analytical Center (Facultad de Farmacia, Madrid, Spain).

Melting points are determined in open glass capillaries on a Thomas Hoover melting point apparatus or Buchi temperature apparatus and are uncorrected.

The following methods provide an illustration of the operating instructions for the preparation of compounds of formula I as illustrated in the schemes above. In the procedures and examples below, the terms NMR, IR and UV show that proton nuclear magnetic resonance, infrared, and ultraviolet spectra are consistent with the data for the desired title compound.

Preparation 1

Preparation of (3'R) ethyl [2- (piperid-3-yl) acetate]

CH ₃

Ethyl 3-pyridylacetate (100 g, 0.606 mol) was dissolved in ethanol (1.8 L), treated with 5% rhodium on alumina (alumina, 100 g) and hydrogenated at 60 ° C at 40 psi hydrogen pressure night. Catalyst with. was filtered and the solvent was evaporated to give a brown liquid (101.4 g, 98%). This brown liquid was dissolved in ethyl acetate (600 mL) and treated with L - (+) - mandelic acid in hot ethyl acetate (600 mL). After cooling in the refrigerator for 4 hours, the solid was filtered off and the crystallization liquid was returned to further processing to the second enantiomer. The solid was recrystallized from ethyl acetate (1.55-1.6 liters, at room temperature overnight) to give the title compound as white needles. Yield 81.6 g (41%).

Optical rotation (ethanol): (a) 589 nm = +44.9 °, (α) 365 nm = +173.73 °, melting point: 118-119 ° C.

Preparation 2

Method for the preparation of (3'S) -ethyl- [2- (piperid-3-yl) acetate]

The crystallization liquid of Preparation 1 above is se. Evaporate to a dark oil (100.3 g). This oil was dissolved in a cold solution of potassium carbonate (52 g, 0.377 mol) in water (250 mL) and extracted five times with ethyl acetate (150 mL each). The extracts were combined and dried over magnesium sulfate. The solvents were evaporated under reduced pressure to give a dark liquid (40.25 g). This dark liquid was treated with a hot solution of D - (-) - mandelic acid (36 g) in ethyl acetate (650 mL) and stirred at room temperature overnight. The crystals were recrystallized twice from ethyl acetate (1.2 and 1.1 liters) to give the title compound as white needles. Yield 48.7 g (24.9%).

Chiral analytical method

A cold aqueous potassium carbonate solution (0.15 g in 10 mL water) was treated with the mandelic acid salt (0.3 g) and the mixture was extracted three times with ethyl acetate (5 mL each).

ί

The combined extracts were dried over magnesium sulfate and the solvents were evaporated under reduced pressure. The residue was dissolved in diethyl ether (10 ml) and treated with S - (-) - α-methylbenzyl isocyanate (0.12 ml). After 2.5 h, the reaction mixture was treated with 1 N hydrochloric acid (2 mL). The ether was evaporated and the residue was washed successively with brine, saturated aqueous sodium bicarbonate, and brine. The organic fraction was dried over magnesium sulfate and the solvents were evaporated. The residue is analyzed on a CHIRACEL OJ high performance liquid chromatography column (4.6 x 250 mm), eluting with 5% ethanol in hexanes as eluent, at a flow rate of 2.5 ml / min. L - (+) - mandelic acid salt is used as the slower component and D - (-) - mandelic acid salt as the faster component. Analysis by high-performance liquid chromatography of the final crystalline compounds of both enantiomers showed less than 3% of the opposite enantiomer.

Preparation 3

.................................................. ..........................

(3'R) -ethyl- [2- / N- (tert-butoxycarbonyl) piperid-3-yl] acetate

Boc (3'R) -Ethyl- [2- (piperidin-3-yl) acetate] (10.9 g, 34 mmol), prepared in Preparation 1, was dissolved in 50 mL

12% aqueous potassium carbonate solution and the resulting solution was extracted with chloroform. The extracts were dried and the solvents were evaporated. The residue was suspended in diethyl ether, filtered and evaporated to give the free base (5.36 g). The liquid was dissolved in ether (50 mL) and di-tert-butyl dicarbonate (7.9 g) in 10 mL of ether was added dropwise. After stirring overnight, the solution was cooled in an ice-water bath and treated dropwise with aqueous citric acid (25 mL). The aqueous fraction was extracted with diethyl ether. The organic fractions were combined, washed with water, saturated aqueous sodium bicarbonate solution and then brine, and then dried over magnesium sulfate. The solvents were evaporated under reduced pressure to give the title compound as a clear solution. NMR was consistent with the proposed structure of the title compound.

Preparation 4

(3'() -ethyl- [2- / N- (tert-butoxycarbonyl) piperid-3-yl] acetate

AND

Boc (3'S) -Ethyl- [2- (piperidin-3-yl) acetate] (48.6 g, 150 mmol) prepared in Preparation 2 was treated with a solution of potassium carbonate (30 g, 0.217 mol) in water (220 g). ml) and the resulting solution was extracted three times with chloroform (100 ml each). The extracts were dried over sodium sulfate and the solvents were evaporated under reduced pressure. The residue was mixed with diethyl ether (200 mL) and filtered to remove some suspended solids. Evaporation of ether gave a brownish liquid (25 g, 25.7 g). The residue was dissolved in diethyl ether (200 mL), cooled in an ice bath, and a solution of di-tert-butyl dicarbonate (31.8 g, 0.146 mol) in ether (25 mL) was added dropwise with stirring. The reaction was quenched and stirred overnight. The solution was then re-cooled in an ice water bath and a saturated aqueous citric acid solution (100 mL) was added dropwise. The organics were washed with brine, saturated aqueous sodium bicarbonate, then brine, and then dried over sodium sulfate. The solvents were evaporated under reduced pressure to give the title compound as a clear liquid (38.6 g, &gt; 99%). NMR was consistent with the proposed structure of the title compound.

Preparation 5

Process for the preparation of ethyl [3- (pyrid-3-yl) prop-2-enoate]

A solution of ethyl phosphinoacetate (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 2 hours and then cooled to 0 ° C. 3-Pyridinecarboxaldehyde (38.9 g, 0.36 mol) was added to the mixture, and the resulting reaction mixture was stirred for 1 to 2 hours while warming to room temperature. The progress of the reaction was monitored by thin layer chromatography.

To the reaction mixture was added water (1000 mL), organic

52 fractions were extracted three times with ethyl acetate (1000 ml each). The organic fractions were combined, washed twice with water (1000 ml each), once with brine (1000 ml) and dried over sodium sulfate. The solvents were evaporated under reduced pressure to give the title compound (62.5 g). Yield 97%.

Preparation 6

Preparation of (RS) -ethyl [3- (piperid-3-yl) propionate]

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 (alumina, 17.2 g). The mixture was placed under a '* hydrogen and TMOS era * f ^ -3'7 9 "Hg ^-)' ~ ~ z'á ťe'p'lotý '* * 60 ° C * ^ ria time ¹ 5 ***** hours. The reaction is stopped by removal of hydrogen and the reaction mixture is filtered through a pad of CELITE (diatomaceous earth). The residue was washed with hot ethanol. The filtrate was evaporated and purified by flash chromatography. Thus, 39.6 g of the title compound are obtained. Yield: 63%.

IR, NMR and UV were consistent with the proposed structure of the title compound.

Preparation 7

Process for the preparation of (3'S) -ethyl- [3- (piperid-3-yl) propionate] salt of mandelic acid

N. mandelic acid

A solution of (RS) ethyl [3- (piperid-3-yl) propionate] (52.0 g, 281 mmol) in hot ethyl acetate (300 mL) was added to a hot solution of R - (-) - mandelic acid (42 mL). , 7 g, 281 mmol). The resulting mixture was then filtered and the clear solution was allowed to stand at room temperature overnight. The newly formed white salt crystals were filtered from solution. These crystals were recrystallized twice after being dissolved in hot ethyl acetate (300 ml each) and each time thereafter. cooling to room temperature. The fine pure crystals were dried to give 33.1 g of the title compound. Yield 70%.

....... Úit l>! * L i - 'WH »γ ·· ^ * ι. · Ι ·) | ΊΒ lil '

NMR and ICs were consistent with the title compound. The conformation of the chiral center is confirmed by X-ray crystallography.

Preparation 8

Process for preparing the salt of (3'R) -ethyl- [3- (piperid-3-yl) -propionate] with mandelic acid

ch ₃ . mandelic acid

The title compound is prepared essentially as described in Preparation 7 above, except that S - (+) - mandelic acid is used in place of R - (-) - mandelic acid used in said preparation.

NMR and IR were consistent with the desired title compound.

Preparation 9

Method for preparing (3 &apos; S) -ethyl- [3- (piperid-3-yl) propionate]

O

A suspension of (3 ') -ethyl- [3- (piperid-3-yl)] - propionate-4-mandelic acid salt (-3-3.1-198 g) in ethyl acetate (500 ml) was added. The mixture was transferred to a separatory funnel and the organic fraction was extracted three times with ethyl acetate (300 ml each) .The combined organic fractions were washed twice with water (300 ml each), then once with brine (300 mL) and dried over sodium sulfate, and the solvents were evaporated under reduced pressure to give the resulting oily product in almost 100% yield.

NMR and IR were consistent with the title compound of the title. .

Preparation 10

Process for the preparation of (3'R) -ethyl- [3- (piperid-3-yl) -propionate]

ch ₃

The title compound is prepared essentially as described in Preparation 9 above, except that the (3'R) -ethyl- [3- (piperid-3-yl) -propionate] salt of mandelic acid is used for in place of the mandelic acid salt of (3'S) -ethyl- [3- (piperid-3-yl) -propionate] used in said preparation.

NMR and IR were consistent with the title compound.

Preparation 11

Method for preparing (3 &apos; S) -ethyl- [3- / 1- (tert-butoxycarbonyl) piperid-3-yl] propionate]

and

BoC

A solution of (3 ' S) -ethyl- [3- (piperid-3-yl) -propionate (12.5 g, 67.5 mmol) in tetrahydrofuran / water (2: 1.355, 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 5 hours. The mixture was then poured onto water (200 mL). The organic fraction was extracted three times with ethyl acetate (200 ml each). The organic fractions were combined, washed twice with water (200 ml each) and once with brine (200 ml) and then dried over sodium sulfate. The solvents were evaporated under reduced pressure and the title compound was further purified by flash chromatography. Yield 19.1 g (99.2%).

NMR and IR were consistent with the desired title compound.

Preparation 12

Method for preparing (3 &apos; R) -ethyl- [3- / 1- (tert-butoxycarbonyl) piperid-3-yl / propionate]

and

BoC

The title compound is prepared essentially as it is. as described in Preparation 11 above except that an equivalent amount of (3'R) -ethyl- [3- (piperid-3-yl) -propionate] was used in place of (3'S) -ethyl- [3 (piperidine- 3-yl) propionate] which was used in said preparation.

Preparation 13

Process for preparing (3'S) -3- [1- (tert-butoxycarbonyl) piperid-3-yl] propanol

OH

AND

BoC

A solution of (3's) -ethyl- [3- / 1- (tert-butoxycarbonyl) piperid-3-yl / propionate] (17.1 g, 60 mmol) in dry diethyl acetate (600 mL) was cooled to 0 ° C. . Powdered lithium aluminum hydride (2.5 g, 65 mmol) was gradually added to the reaction mixture. The resulting mixture was stirred at 0 ° C and then slowly warmed to room temperature over 2 hours. The reaction was quenched by the slow addition of water (200 mL) and 15% aqueous sodium hydroxide solution (50 mL). The organic fraction was extracted three times with diethyl ether (300 ml each). The combined layers were washed twice with water (200 ml each) and then once with brine (200 ml) and then dried over sodium sulfate. The solvents were evaporated under reduced pressure, T "d ^ štlLne ™ ^ e ^ in ^ ^^ meadow pdjměnóVáná vhádpÍšÚT * Yield * '** ****** ^{W 1} corresponds to 13.2 g (90%).

NMR and IR were consistent with the desired title compound.

Preparation 14

Process for preparing (3'S) -3- [1- (tert-butoxycarbonyl) piperid-3-yl] propanol

- “58 -

OH ¥

BoC

The title compound was prepared essentially as described in Preparation 13 above, except that an equimolar amount of (3'S) -ethyl- [3- / 1- (tert-butoxycarbonyl) -piperidine] was used. 3-yl / propionate] in place of (3'R) -ethyl- [3- / 1- (tert-butoxycarbonyl) piperidin-3-yl] propionate] which was used in said preparation.

Preparation 15

(3'S) -3- [1- (tert-butoxycarbonyl) piperidine-3-. -yl] propyl bromide

To a solution of triphenylphosphine (19.95 g, 76 mmol) in anhydrous methylene chloride (110 mL) cooled to 0 ° C was added dropwise bromine until the solution turned pale yellow, adding several triphenylphosphine crystals to the reaction mixture. and the color of the mixture goes back to white. To this mixture was added a suspension of (3's) -3- [1- (tert-butoxycarbonyl) piperid-3-yl] propanol (13.2 g, 54.4 mmol) and pyridine (8.0 g, 76 mmol) in dry methylene chloride (110 mL). The resulting mixture was stirred for 5 hours while warming to room temperature.

The reaction was quenched by the addition of water (200 mL). The organic fraction was extracted three times with methylene chloride (200 ml each). The combined organic layers were washed twice with water (200 ml each), once with brine and then dried over sodium sulfate. The solvents were evaporated under reduced pressure to give a light brownish crude material which was further purified by flash chromatography. 11.6 g of the title compound are obtained. Yield 70%.

NMR and IR were consistent with the desired title compound.

Preparation 16

Process for the preparation of (3'R) -3- [1- (tert-butoxycarbonyl) piperid-3-yl] propyl bromide

T

BoC *

The title compound was prepared essentially as described in Preparation 15, as indicated above, except that an equimolar amount of (3 ^R R) - 3- [1- (tert-butoxycarbonyl) piperidin-3- yl] propanol, instead of (3'S) -3- [1- (tert-butoxycarbonyl) piperid-3-yl] propanol, which was used in said preparation.

Method A

A process for the preparation of 1-methyl-2-hydroxymethyl-1H-indole

OH

OH

To 950 mL of dry tetrahydrofuran was added lithium aluminum hydride (18.40 g, 0.49 mol) under argon. The resulting mixture was placed on an ice bath. An aliquot of 1-methoxyindole-2-carboxylic acid (84.92 g, 0.49 mol) was dissolved in another 475 mL of dry tetrahydrofuran and then slowly (over about 45 to 50 minutes) added to the lithium aluminum hydride mixture.

Ice is removed near the round bottom flask and hot water is added to the bath to raise the reaction temperature. The reaction mixture was then stirred at room temperature for 60 '' R * -ΜΙ · '·' TBI Hnlu Hun · h. · »U Miimlj'iWlÍWÍhWř * ¹ b '·· IWWPHHiÍÍm» »WMWO» to 90 minutes. The progress of the reaction was monitored by thin layer chromatography.

Once the reaction is sufficiently advanced, the reaction vessel is placed in an ice bath and water (20 mL) is slowly added to the reaction mixture, followed by 5 N sodium hydroxide solution (20 mL) followed by water (60 mL). The organic fraction was treated with CELITE ™ (diatomaceous earth) and then dried over sodium sulfate. The organic solvents were then evaporated under reduced pressure to give a white solid.

The white solid obtained is then dissolved in toluene and the resulting solution is heated to reflux. The mixture was then cooled to room temperature and then left in the refrigerator overnight. The off-white crystals are then filtered off, washed with cold toluene and then dried in a vacuum oven. Yield: 63.65 g (81.4%).

FD MS 161.

Elemental analysis for ^C 10 ^H 11 ^NO Calcd: C, 74.51, H, 6.88, N, 8.69. Found: C, 74.73, H, 6.90, N, 8.76.

A process for preparing 1-methyl-2- (4-chlorophenoxymethyl) -1H-indole

Sodium hydride (9.28 g, 60% solution of sodium hydride in mineral oil, 0.232 mol) and N, N-dimethylformamide (211 ml) were added to a 1-liter round bottom flask under nitrogen. To the resulting mixture was slowly added 1-methyl-2-hydroxymethyl-1H-indole (34.0 g, 0.211 mol) which was dissolved in 100 mL of Ν, Ν-dimethylformamide. This addition results in a slightly exothermic reaction. The resulting reaction mixture was stirred at room temperature for about 3 hours.

To the above reaction mixture was added 1-chloro-4-fluorobenzene (30.29 g, 0.232 mmol), then the resulting mixture was heated to 80 ° C and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then allowed to cool, poured into about 1 liter of water and stirred for about 1 hour. The solids were filtered and washed with water.

The title compound is then recrystallized from benzene and the solvents are evaporated under reduced pressure.

IR, NMR, and UV were consistent with the desired title compound.

FD MS: 271 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₁₆ H ₁₄ ClNO (%):

Calculated C _of 70.72, H, 5.19, N, 5.15 Found: C, 70.98, H, 5.18, N, 5.37.

Process for preparing 1-methyl-2- (4-chlorophenoxymethyl) -3- (4-methylpiperid-1-yl) methyl-1H-indole (Example 14)

Under a nitrogen atmosphere, 4-methylpiperidine (0.109 mL, 0.09 g, 0.92 mmol), which is dissolved in ethyl acetate (2.0 mL), is charged to a round bottom flask, which is then placed in an ice bath. Concentrated hydrochloric acid (0.084 mL) was then added to the reaction mixture and the reaction mixture was removed from the ice bath. To the reaction mixture was then added formaldehyde (0.304 g, 1.01 mmol), sodium acetate (0.113 g, 1.38 mmol) and 1-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 evaporated under reduced pressure. The solids are then taken up in methylene chloride. The solvents were then re-evaporated under reduced pressure. The title compound is then recrystallized from ethyl acetate. The title compound is further purified by chromatography.

FD: MS 382.

Elemental analysis for ^C 23 ^H 27 ^ClN 2 ° Calculated: C, 72.14, H, 7.11, N, 7.31 Found: C, 72.33, H, 7.22, N, 7.47.

i. · J. ι. i »r '·' ——

Method B

1-Methyl-2- (4-chlorophenoxymethyl) -3- [2- [4- (piperid-1-yl) piperid-1-yl] -1,2-ethanedionyl] -1H-indole (Example 106)

1-Methyl-2- (4-chlorophenoxymethyl) -1H-indole (0.30 g,

1.10. mmol), which was dissolved in 2.0 mL of tetrahydrofuran, was placed in a round bottom flask under an argon atmosphere.

To this 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 evaporated under reduced pressure to give. θ ^d 99- · Hlt * imwmjww — wnw, 111.1 ^1. «Μ —emm?

The brown oil was taken up in 2.0 mL of dry tetrahydrofuran and then 4- (piperid-1-yl) piperidine (1.07 g, 6.38 mmol) dissolved in tetrahydrofuran (approximately 10 mL) 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 filtered off and the solvents were evaporated from the filtrate. The filtrate residue is taken up in methylene chloride, washed with saturated aqueous sodium bicarbonate solution and then extracted three times with 1.0 N hydrochloric acid.

The aqueous fractions from the above extractions were combined, basified with 1 N sodium hydroxide solution and extracted three times with methylene chloride. The organic fraction was dried over sodium sulfate and the solvents were evaporated under reduced pressure. The title compound is further purified by radial chromatography.

FD MS (M ^& lt ^{; +} & gt ^; ) 493.

Elemental analysis for ^C 28 ^H 32 ^ClN 3 ° 3 Calculated: C, 68.07, H, 6.53, N, 8.51. Found: C, 67.97, H, 6.66, N, 8.27. .

Process for the preparation of 1-methyl-2- (4-chlorophenoxymethyl) -3- [4 (phenyl) piperazin-1-yl] methyl-1H-indole (Example 20)

Phenylpiperazine (0.149 g, 0.920 mmol) was dissolved in dichloroethane (2.0 mL) under a nitrogen atmosphere under a round bottom flask. Place the reaction vessel on an ice bath.

Concentrated hydrochloric acid (0.804 mL, 1.01 mmol) was added to the reaction mixture and the reaction vessel was removed with 2 ice baths. To the reaction mixture was then added paraformaldehyde (0.304 g, 1.01 mmol) and sodium acetate (0.113 g, 0.920 mmol) followed by 1-methyl-2- (4-chlorophenoxymethyl) -1H-indole (0.250 g, 0.920 mmol). . The reaction mixture is then heated to reflux and maintained at this temperature for about 6 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then stirred at room temperature for about 3 days.

The solvents were removed in vacuo and the residue partitioned between ethyl acetate and 10% potassium carbonate solution. The organic fraction was washed with water and then with 1.0 N hydrochloric acid. The acidified aqueous fraction was basified with 10% potassium carbonate solution. The organic component is dried by dripping over sodium sulfate. The solvents were evaporated under reduced pressure.

The title compound is recrystallized from ethyl acetate.

NMR was consistent with the title compound.

PD. ; -MS '** ¹ wm ·! ¹ · W * ^rl1 ιτΜιπίπΑ ^ ΜΓ.ΠιιΐΜΐΙίΜι ·

Elemental analysis for ^C 27 ^H 28 ^C1N 3 ° Calculated: C, 72.71, H, 6.33, N, 9.42 Found: C, 73.00, H, 6.41, N, 9.51.

Method C1

1-Methyl-2- (4-chlorophenoxymethyl) -3- (2-chloro-1,2-ethanedionyl) -1H-indole

1-Methyl-2- (4-chlorophenoxymethyl) -1H-indole (1.00 g,

3.68 mmol), which is dissolved in 7.0 ml of diethyl ether, is placed in a round-bottomed 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.

Solvents were removed by decantation and the crystals were washed five times with cold diethyl ether. Solvents and washings were collected and placed in the freezer for 3 days. The crystals were collected and dried in a vacuum oven. Thus, 1.15 g of the title compound are obtained. Yield 86.3%.

1-Methyl-2- (4-chlorophenoxymethyl) -3- [2- (4-methylpiperid-1-yl) -1,2-ethanedionyl] -1H-indole (Example 102)

- 68

Under a nitrogen atmosphere, 4-methylpiperidine (0.490 mL, 0.411 g, 4.14 mmol), which is dissolved in dry tetrahydrofuran (3.0 mL), is charged to a round-bottom flask in an ice bath. To this reaction mixture was added 1-methyl-2- (4-chlorophenoxymethyl) -3- (2-chloro-1,2-ethanedionyl) -1H-indole (0.500 g, 1.39 mmol), and the resulting mixture was stirred under room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.

^* ^ * ^^ Ró'žpoušt'ě'dlá '* to ^"r evaporated under reduced pressure 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 and then brine. The organic fraction was then dried over sodium sulfate and the solvents were evaporated under reduced pressure. The title compound is recrystallized from ethyl acetate.

NMR and IR were consistent with the desired title compound.

FD-MS 425 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 24 ^H 25 ^C1N 2 ° 3 <*> = Calculated: C, 67.84, H, 5.93, N, 6.59 Found: C, 68.04; H, 5.85; N, , 6.74.

Method C2

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-1 - [[4- (piperid-1-yl) piperidin-1-yl] carbonylmethyl] -1H-indole (Example 77)

In a round-bottomed flask under nitrogen atmosphere, rhadávem is ** 1-methyl-2- (4-chlorophenoxymethyl) -3- [2- / 4 ^ ******** · * "

- (piperid-1-yl) piperid-1-yl] -1,2-ethanedionyl] -1H-indole (0.1414 g, 0.282 mmol) and denatured ethanol (2.8 mL).

*

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 evaporated 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 evaporated under reduced pressure. The title compound is further purified by chromatography.

NMR was consistent with the title compound.

FD-MS 495 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 28 ^H 34 ^ClN 3 ° ^3: Calc: C, 67.80, H, 6.91, N, 8.47 Found: C, 67.86, H, 6.90, N, 8, 45.

The Ď method

Method for the preparation of methylfindole-2-carboxylate]

Indole-2-carboxylic acid (47.0 g, 292 mmol) was dissolved in methanol (200 mL). This ^1! · About ztoku 'is ^ * s * da * 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 then washed with methanol (200 mL).

The crystals were dried in a vacuum oven to give 39.5 g of the desired title compound. white needles. Yield 77%.

The analytical values obtained are consistent with the proposed structure of the title compound.

Method for the preparation of methyl [1- [2- (1-tritylpiperid-4-yl) ethyl] indole-2-carboxylate].

OCH ₃

Under an argon atmosphere, methyl [indole-2-carboxylate] (1.50 g, 8.56 mmol) was dissolved in 8.6 mL of Ν, Ν-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 in an ice bath and then allowed to warm to room temperature. The reaction mixture was then stirred at room temperature for about 90 minutes and after that time was placed on an ice bath again.

2- (1-Tritylpiperid-4-yl) ethyl iodide (4.53 g, 9.42 mmol), prepared essentially as described in Preparation 15, was dissolved in 15 mL of N, N-dimethylformamide and the resulting mixture was stirred on an ice bath for approximately 3 days. The reaction mixture was then poured onto water and the solids were filtered off. These solids were treated with methylene chloride and dried over magnesium sulfate. The solvents were evaporated under reduced pressure to give 4.98 g of the title compound as a white foam with a shade of yellow. The yield corresponds to more than 99%.

designed

The analytical values obtained are consistent with the structure of the title compound.

.- -72

Method for the preparation of methyl [1- / 3- (1-tritylpiperidin-3-yl) propyl] indole-2-carboxylate]

Under argon atmosphere, methyl [indole-2-carboxylate] (1.00 g, 5.71 mmol) was dissolved in Ν, Ν-dimethylforithiamide (5.7 mL). The solution was placed in an ice bath and a solution of sodium hydride (0.251 g, 60% solution, 6.28 mmol) was added. The resulting mixture was stirred for 20 minutes in an ice bath and then allowed to warm to room temperature. The reaction mixture was' stirred žá'téploťý ^ ^r * * room after ^TRT, d6bir ^r přibiižně 60 minutes and after this time is placed again in an ice bath.

3- (1-Tritylpiperid-3-yl) ethyl iodide (3.11 g, 6.28 mmol) was dissolved in N, N-dimethylformamide (8 mL) and the resulting mixture was stirred in an ice bath overnight. The reaction mixture is then poured onto water and the solids are filtered off. The solids are taken up in methylene chloride, washed with water, brine and then dried over sodium sulfate. The solvents were evaporated under reduced pressure to give 3.38 g of the title compound. The yield corresponds to more than 99%.

The analytical values obtained are consistent with the proposed structure of the title compound.

A process for preparing 2-hydroxymethyl-1- [2- (1-tritylpiperid-4-yl) ethyl] -1H-indole.

Under argon, lithium aluminum hydride (0.325 g, 8.56 mmol) was dissolved in dry tetrahydrofuran (8.6 mL). Place the resulting solution in an ice bath and add methyl [1- [2- (1-tritylpiperid-4-yl) ethyl] indole-2-carboxylate] (4.68 g, 8.52 mmol), which is dissolved in dry tetrahydrofuran and '(approx-cut through-LO' ⁴ 'is mljxVýslednásměs * * * was stirred at room temperature overnight.

Water (0.35 mL) was carefully added to the reaction mixture, followed by 5.0 N sodium hydroxide solution (0.35 mL) followed by water (1.0 mL). The solids were filtered off and the solvents in the filtrate were evaporated under reduced pressure. The filtrate residue was redissolved in methylene chloride. The title compound is then dried over magnesium sulfate and the solvents are evaporated under reduced pressure. Yield: 3.96 g (92.4%) of the title compound as a foam.

The analytical values obtained are consistent with the proposed structure of the title compound.

74 Preparation of 2-hydroxymethyl-1- [3- (1-tritylpiperid-3-yl) propyl] -1H-indole

-tritylpiperid-3-yl) propyl / indole-2-carboxylate] (3.38 g,

6.23 mmol) in dry tetrahydrofuran (3.1 mL). Place the reaction vessel in an ice bath and add lithium aluminum hydride (0.236 g, 6.23 mmol) to the reaction mixture. The resulting mixture is stirred for leSbvě * n ^ '* * * after bath for approximately * * * 10 minutes *' ^and '* ^ir then be "** room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.

Water (0.24 mL) was added to the reaction mixture, followed by a 5.0 N sodium hydroxide solution (0.24 mL) followed by water (0.72 mL).

The residue was redissolved in methylene chloride. The title compound is then dried over sodium sulfate and the solvents are evaporated under reduced pressure. 2.89 g of the title compound are obtained as a foam. Yield 90.1%.

The analytical values obtained are in accordance with the proposed structure of the title compound.

Preparation of 2 - [(4-chlorophenoxy) methyl] -1- [2- (1-tritylpiperid-4-yl) ethyl] -1H-indole

Dissolve 2-hydroxymethyl-1- [2- (1-tritylpiperid-4-yl) ethyl] -1H-indole (3.91 g, 7.81 mmol) in Ν, Ν-dimethylformamide (approximately 10 mL) under argon. ). The resulting solution was placed on an ice bath, sodium hydride (0.468 g, 11.71 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for about 30 minutes. 1-Chloro-4-fluorobenzene (0.915 mL, 1.12 g, 8.59 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for about 4 days while preventing light access.

The reaction mixture was poured into ice water and the solids were filtered off. After washing with water, the solids are dried in a vacuum oven. The title compound was recrystallized from ethyl acetate and washed with cold ethyl acetate to give 2.62 g of the title compound. Yield 54.9%.

The analytical values obtained are consistent with the proposed structure of the title compound.

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1- [3- (1-tritylCl piperid-3-yl) propyl] -1'-indole

° ^H —► alkylation

Dissolve 2-hydroxymethyl-1- [3- (1-tritylpiperid-3-yl) propyl] -1H-indole (2.89 g, 5.61 mmol) in Ν, Ν-dimethylformamide (ca. 11, 2 ml). The resulting solution is placed in an ice bath, then sodium hydride (0.247 g of a 60% suspension in mineral oil) is added to the reaction mixture,

6.18 mmol) and the resulting mixture was stirred at room temperature for about 60 minutes. The reaction mixture was treated with 1-chloro-4-fluorobenzene (0.658 mL). (0.807 g, 6.18 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture is then heated to 80 and held at this temperature for approximately 8 hours. The reaction mixture was then cooled to room temperature and stirred at room temperature overnight. To the reaction mixture was added half an additional equivalent of sodium hydride and the reaction mixture was stirred again at room temperature overnight. Another half equivalent of 1-chloro-4-fluorobenzene was then added and the reaction mixture was heated to 80 ° 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 title compound is further purified by chromatography to give 1.0 g of the title compound. Yield 29%.

The analytical values obtained are consistent with the proposed structure of the title compound.

Preparation of 2 - [(4-chlorophenoxy) methyl] -1- [2- (piperid-4-yl) ethyl] -1H-indole (Example 137)

Dissolve 2 - [(4-chlorophenoxy) methyl] -1- [2- (1-tritylpiperid-4-yl) ethyl] -1H-indole in methylene chloride (7.0 mL) under argon. The reaction solution was then placed in an ice bath and treated with formic acid (0.3383 g). The resulting mixture was stirred in an ice bath for about 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 solution. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure to give a foam. The title compound is further purified by chromatography. This afforded 0.1864 g of the title compound (68.7%).

NMR was consistent with the proposed structure of the title compound.

FD MS 368 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 22 ^H 25 ^C1N 2 ° Calculated: C, 71.63, H, 6.83, N, 7.59 Found: C, 71.66, H, 6.86, N, 7.87.

Process for the preparation of 2 - [(4-chlorophenoxy) methyl] -1- [3- (piperid-3-yl) propyl] -1H-indole (Example 139)

-1- [2- (piperid-4-yl) ethyl] -1H-indole, except that an equimolar amount of 2 - [(4-chlorophenoxy) methyl] -1- [3- (1-tritylpiperide- 3-yl) propyl] -1H-indole instead of 2 - [(4-chlorophenoxy) methyl] -1- [2- (1-tritylpiperid-4-yl) ethyl] -1H-indole, which was used in said preparation.

NMR was consistent with the proposed structure of the title compound. A single compound of high purity is obtained as shown by chromatographic methods.

Method E

3-Bromo-2 - [(4-chlorophenoxy) methyl] -1- [3- (1-tritylpiperid-3-yl) propyl] -1H-indole

Dissolve 2 - [(4-chlorophenoxy) methyl] -1- [3- (1-tritylpiperid-3-yl) propyl] -1H-indole (0.992 g, 1.59 mmol) in a round bottom flask under argon atmosphere. in dry tetrahydrofuran (4.0 mL). The reaction vessel was then placed in an ice bath and N-bromosuccinimide (0.282 g, 1.587 mmol, recently recrystallized batch), which was dissolved in tetrahydrofuran (4.0 mL), was slowly added. The reaction mixture was stirred on an ice bath for about 3 hours.

The reaction mixture was poured onto water, in which sodium sulfate (2.5 g) was dissolved, and the aqueous phase was extracted three times with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure to give 0.26 g of the title compound. Yield 23%. The solvents were evaporated under reduced pressure from the mother liquors and the resulting residue was recrystallized from ethyl acetate and hexanes to give an additional 0.65. g of the title compound. Yield 58%.

The analytical values obtained are consistent with the proposed structure of the title compound.

(RS) -2 - [(4-Chlorophenoxy) methyl] -1- [3- (1-tritylpiperid-3-yl) propyl] -3 - [[4- (piperid-1-yl) piperid-1-yl]] (acetyl) -1H-indole

h ₃ c _xo

H ₃ CO ₃ ^N

3-Bromo-2 - [(4-chlorophenoxy) methyl] -1- [3- (1-tritylpiperid-3-yl) propyl] -1H-indole (0.225 g, 0.319) was dissolved in a round bottom flask under argon atmosphere. mmol) in dry tetrahydrofuran. Place the reaction vessel on a bath

- 81 of carbon dioxide (dry ice) and acetone. To this solution was added dropwise a solution of tert-butyllithium (0.64 mmol). The resulting mixture was stirred in a bath of carbon dioxide (dry ice) and acetone for 35 minutes.

To this reaction mixture was added Weinreb amide, N-methyl-N-methoxy- (4- (piperid-1-yl) piperidin-1-yl) acetamide (0.0903 g, 0.335 mmol) which was dissolved in tetrahydrofuran ( 2.0 ml) and cooled in a bath of carbon dioxide (dry ice) and acetone. The resulting mixture was stirred for about 2 hours and then poured into saturated ammonium chloride solution. The aqueous fraction was extracted three times with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title compound is further purified by chromatography.

The analytical values obtained are consistent with the proposed structure of the title compound.

Method příprávy- * (RSJ '^ 2 ^ ^[_ (4-'chl75řfěhoxyjmetfiýri-l ^ [3-' ^{l 'r'} '' ^{,, 1TOin 'three;}

- (piperid-3-yl) propyl] -3 - [[4- (piperid-1-yl) piperid-1-yl] acetyl-1H-indole (Example 70)

Dissolve (RS) -2 - [(4-chlorophenoxy) methyl] -1- [3- (1-tritylpiperid-3-yl) propyl] -3 - [[4- (piperid-1-yl) piperidine] under an argon atmosphere. 1-yl / acetyl] -1H-indole (0.0162 g, 0.0194 mmol) in methylene chloride (0.2 mL). The reaction mixture was then placed in an ice bath and formic acid (0.073 mL, 0.194 mmol) was added. The resulting mixture was stirred in an ice bath for about 1 hour. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then stirred at room temperature for a further 2 hours and then 5.0 equivalents of formic acid were added and stirred at room temperature.

The reaction mixture was partitioned between 1.0 N sodium hydroxide solution and methylene chloride. The aqueous phase is extracted twice with methylene chloride. The organic phases were combined and dried over sodium sulfate. The solvents were removed by evaporation.

NMR was consistent with the proposed structure of the title compound.

Exact Mass (M ^{+ 1} ) for C ₃₅ H ₄₈ ClN ₄ O ₂ : calculated: 591.3476, found: 591.3476,

Method F

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-2- (piperid-1-yl) ethyl] -1H-indole (Example 47)

ww * i * «-. M» w * w »Under argon © * u - TMOS a-Fe-rou * ^out * to * Ban-ky '* s' * kuTatým * '* ^w * day' charged 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [1- (piperidin-1-yl) -1,2-ethanedionyl] -1H-indole (Example 100) (0.203 g,

0.493 mmol), which is dissolved in dry tetrahydrofuran (2.0 mL). Lithium aluminum hydride (3.0 mL of a 1.0 M solution in tetrahydrofuran) was then added to the solution. The resulting mixture was then heated to reflux and maintained at this temperature for about 4 hours. The progress of the reaction was monitored by thin layer chromatography.

The reaction mixture was then cooled to room temperature and a mixture of tetrahydrofuran and methanol in a ratio was added

1: 1 (10 mL). 5 ml of a saturated solution of Rochelle's salt was then added. The solvents were evaporated under reduced pressure

84 pressure.

The residue was then partitioned between methylene chloride and a saturated Rochelle salt solution. The organic fraction was washed with water and brine. The organic fraction was then dried over sodium sulfate and the solvents were evaporated under reduced pressure.

The title compound is further purified by chromatography to give 0.1112 g of the title compound. Yield 56.9%.

NMR was consistent with the proposed structure of the title compound.

FD MS 398 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^H 27 ^C1N 2 ° 2 requires C, 69.25, H, 6.82, N, 7.02 'nalezehdi

Cl, 6'9751, H, £ 786

N, ^ - Μ ^ -. ·· '·· ΐ | ΐ _Α ! · ΜΙ

6.81.

iMMNMW

Method G

Process for the preparation of 2 - [(4-chlorophenoxylmethyl) -1-methyl-3- [1-hydroxy-2- (4-methylpiperid-1-yl) ethyl] -4-indole (Example 48) and 2 - [(4- chlorophenoxy) methyl] -1-methyl-3- [2- (4-methylpiperid-1-yl) ethyl] -1H-indole (Example 33)

'* ^ ** ^ ^{M ~} Poddusíkovou "Atmospheric era se'do'baňky * s ^ kuíatýitr day · ¹ ™ ** metered 2 - [(4-chlorophenoxy) methyl] -l-methyl-3- [l- ( piperidin-1-yl) -1,2-ethanedionyl] -1H-indole (Example 100) (0.305 g,

0.824 mmol) followed by the slow addition of borane-tetrahydrofuran complex (4.12 mL of 1.0 M borane solution in tetrahydrofuran, 4.12 mmol) and the resulting mixture was stirred for approximately 30 minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was stirred for a total of 1 hour and then quenched with methanol.

Ethanol, sodium carbonate and cesium fluoride were added to the reaction mixtures, and the resulting mixture was heated to reflux and maintained at this temperature overnight. The reaction mixture was then partitioned between 10% sodium carbonate solution 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 evaporated under reduced pressure. The title compound is further purified by radial chromatography

2 - [(4-Chlorophenoxy) methyl] -1-methyl-3- [2- (4-methylpiperid-1-yl) ethyl] -1H-indole (Example 33):

NMR was consistent with the proposed structure of the title compound.

FD MS 396 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 24 ^H 29 ^ClN 2 °.

H, 7.36; N, 7.06. Found: C, 72.40; H, 7.35; N, 7.25.

2qJ, (4-Chlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-2- (4-chlorophenoxy) methyl] -2- (4-chloro-phenoxy) methyl; _{ΤΤ | | <Ί || Ι1} · _{| ίί | KJ q} .

-methylpiperid-1-yl) ethyl] -1H-indole (Example 48):

NMR was consistent with the proposed structure of the title compound.

FD-MS 412 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 24 ^Feb 29 ^ClN 2 ° 2 requires C, 69.80, H, 7.08, N, 6.78 Found: C, 70.02, H, 7.13, N, 7.00 .

Preparation of 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-2- / N-methyl-N- (1-methylpiperid-4-yl) amino / ethyl] -ΙΗ indole (Example 54) and 2 - [(2,4-dichlorophenoxy) methyl] -1-87 -methyl-3- [2- / N-methyl-N- (1-methylpiperid-4-yl) amino] [ethyl] -1H-indole (Example 38)

H ₃ C.

Under a nitrogen atmosphere, 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3- [2- (N-methyl-N- (1-methylpiperid-4-yl) amino]] was added to a round-bottom flask. -1,2-ethanedionyl] -1H-indole (0.3349 g, 0.686 mmol) and then the flask was placed in an ice bath. Borane-tetrahydrofuran complex (4.11 mL of a 1.0 M borane solution in tetrahydrofuran, 4.11 mmol) was then slowly added to the flask and the ice bath was removed. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was stirred for approximately 1 hour and then 0.33 ml of a 1: 1 mixture of tetrahydrofuran and methanol was added. To the resulting mixture was added sodium hydride (1.74 mL of a 5.0 N solution) and the resulting mixture was heated to reflux and maintained at this temperature overnight.

The aqueous fraction was then extracted twice more with tetrahydrofuran. The organic fractions were combined, washed twice with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title compounds are further purified by radial chromatography. phi.

2 - [(2,4-Dichlorophenoxy) methyl] -1-methyl-3- [2- / N-methyl-N- (1-methylpiperid-4-yl) amino] ethyl] -ΙΗ-indole (Example 38) :

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS: 459 (M ^& lt ^{; +} & gt ^; ).

.Elementary analysis for C _{9 S} H ₉₁ Cl ₉ N _? 0 (%):

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- (1-methylpiperid-4-yl) amino] ethyl] -1H-indole (Example 54):

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS: 475 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 25 ^H 3i ^c - ^L 2 3 ^N ° 2 requires C, 63.02, H, 6.55, N, 8.82 Found: C, 63.43; H, 6.88; , 8.92.

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- [(3-dimethylaminopropyl) amino] ethyl] -1H-indole (Example 30) and 2 - [(4-chlorophenoxy) methyl] - 1-Methyl-3 - [[[3- (dimethylamino)] -

Under a nitrogen atmosphere, borane-tetrahydrofuran complex (7.42 mL of a 1.0 M solution in tetrahydrofuran, 7.42 mmol) was charged to a round bottom flask. containing 2 - [(4-chlorophenoxy) methyl) -1-methyl-3- [2- / 3- (dimethylamino) propylamino] -1,2-ethanedionyl] -1H-indole (0.529 g, 1.24 mmol). After stirring at room temperature for about 1 hour, the progress of the reaction was monitored by thin layer chromatography and then quenched by the addition of a 1: 1 solution of tetrahydrofuran and methanol.

The solvents were evaporated and 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 brought to reflux and maintained at this temperature overnight.

The reaction mixture was partitioned between methylene chloride and 10¾ sodium bisulfate solution. The aqueous phase is extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The desired title compounds are further purified by chromatography.

2 - [(4-Chlorophenoxy) methyl] -1-methyl-3- [2- [(3-dimethylaminopropyl) amino] ethyl] -1H-indole (Example 30):

NMR (CDC1 ₃₎ is consistent with the proposed structure of the title compound.

FD: MS 399 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C 23 ^H 30 ^ClN 3 ^O : C, 69.07; H, 7.56; N, 10.51. Found: C, 69.23; H, 7.79; N, 10.52.

AND

2 - [(4-Chlorophenoxy) methyl] -1-methyl-3 - [[[3- (dimethylamino) propylamino / carbonyl] methyl] -1H-indole (Example 76):

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS: 413 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^H 28 ^ClN 3 ° 2 Calculated: C, 66.74, H, 6.82, N, 10.15. Found: C, 66.89, H, 6.96, N, 10.11. .

Method H

3-Bromo-2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indole

Dissolve 2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indole (5.0 g, 18.40 mmol) in tetrahydrofuran (46 mL) in a round-bottomed flask and add this solution. N-bromosuccinimide (3.28 g, 18.4 mmol) was freshly recrystallized in a batch of JT which was a solvent of tetrahydrofuran (46%). The resulting mixture was stirred on an ice bath for about 3, After 5 hours, the reaction mixture was poured onto water (about 500 mL) in which sodium sulfate (5.0 g) was dissolved.

The aqueous fraction was extracted three times with methylene chloride. The organic fractions were combined, washed with saturated sodium bicarbonate solution and then brine. The organic fraction was dried over sodium sulfate and the solvents were evaporated under reduced pressure.

The title compound is recrystallized from ethyl acetate. Yield 5.36 g (83.1)

).

The analytical values obtained are consistent with the proposed structure of the title compound.

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[2- (1-tritylpiperid-4-yl) ethyl] carbonyl] -1H-indole

3-Bromo-2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indole (0.500 g, 1.426 mmol) was dissolved in tetrahydrofuran (3.0 mL) in a round-bottom flask under argon. The reaction vessel was then placed in a bath of carbon dioxide (dry ice) and acetone. of the solution is added. solution.terc. -butyllithium (1.68 mL, 2.85 mmol) and Weinreb's amide, N-methyl-N-methoxy- [2- (1-tritylpiperid-4-yl) ethyl] acetamide, (0.631 g, 1.426 mol). The resulting mixture was stirred in a carbon dioxide (dry ice) and acetone bath for about 30 minutes and then in a methanol / carbon dioxide (dry ice) bath for 30 minutes. The progress of the reaction was monitored by thin layer chromatography.

The reaction mixture was poured into a saturated solution of saturated ammonium chloride solution. The aqueous phase is extracted three times with methylene chloride and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title compound is further purified by chromatography and then recrystallized from ethyl acetate.

The analytical values obtained are consistent with the proposed structure of the title compound.

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[2- (piperid-4-yl) ethyl] carbonyl] -1H-indole (Example 67)

2 - [(4-chloro) under an argon atmosphere with phenoxy) methyl] -1-methyl-3 - [[2- (1-tritylpiperid-4-yl) ethyl] carbonyl] -4-indole (0.2723 g, 0.417 mmol) in methylene chloride (2.1 mL). To this solution was added formic acid (0.079 ηΙ-τ ^ ΟγΟ 96 57 57 * 2, 8484 * -mmo-1 -) - * 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.

'1

The reaction mixture was partitioned between methylene chloride and 1.0 N sodium hydroxide solution. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. Evaporate the solvents under reduced pressure to afford the title compound.

NMR (CDCl ₃ ) was consistent with the proposed structure of the title compound.

FD MS: 411 (M ^{+ 1} ). .

Elemental analysis for C ₂ 4 ^H 27 ^C1N 2 ° 2 Calculated: C, 70.15, H, 6.62, N, 6.82 Found: C, 69.87, H, 6.54, N, 6, 79.

Method I

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3-carboxy-1H-indole

Dissolve 2 - [(4-chlorophenoxy) methyl] -1-methyl-3-carboxy-1H-indole (0.500 g, 1.426 mmol) in dry tetrahydrofuran (114.3 mL) under argon. The reaction vessel is "1 ·, -. -.", -, -, -, -, -, -, -, -, -, -. ,. · .., _Ρ, Λ * * • "- • w ^r» ·, ». ..- ™ "|» ^{ι ΙΐΜΒΙΚίί} · IW ** ^ι '- |' ΐ ^{ι ι} '^ · then placed in a bath of carbon dioxide (dry ice) and acetone. To this solution was added t-butyllithium (1.72 mL of a 1.7-M solution in pentane, 2.92 mmol) dropwise. The resulting mixture was stirred in a bath of carbon dioxide (dry ice) and acetone for approximately 15 minutes. Carbon dioxide is then bubbled through the reaction mixture for about 10 minutes and then stirred.

another 10 minutes. The reaction vessel was then placed in a bath consisting of methanol, carbon dioxide (dry ice) and acetone, and carbon dioxide was bubbled through the reaction mixture for an additional minute.

The reaction mixture was allowed to warm to room temperature and then poured into 100 mL of 1.0 N hydrochloric acid to which approximately 50 g of carbon dioxide (dry ice) was added. The resulting mixture was stirred for approximately 30 minutes. The solids were filtered off and the title compound was triturated with methylene chloride. Yield 0.37 g (82%)

%).

Elemental analysis for O ^ H ^ ClNO ^ (%):

H, 4.47; N, 4.44. Found: C, 64.84; H, 4.60; N, 4.54.

Preparation of 2 - [(4-chlorophenoxy) methyl) -1-methyl-3 - [[N, N-bis (3-dimethylaminopropyl) amino] carbonyl] -1H-indole (Example

Dissolve 2 - [(4-chlorophenoxy) methyl] -1-methyl-3-carboxy-1H-indole (0.100 g, 0.317 mmol) in Ν, Ν-dimethylformamide (3.2 mL) under argon. To this solution was added N, N-bis (3-dimethylaminopropyl) amine (0.074 mL, 0.0623 g, 0.332 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.091 * g, 0.475 mmol). and hydroxybenzotriazole (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 three times with methylene chloride.

The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title compound is further purified by radial chromatography.

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS 483 ( ^-1 ),

FAB MS 485 (M ^{+ 1} ).

Elemental analysis for ^C 27 ^H 37 ^C 1 ^N 4 ° 2 (%):

H, 7.69; N, 11.55. Found: C, 66.91; H, 7.54; N, 11.69.

Method J

Preparation of 2 - [(4-chlorophenoxy) methyl] -l-methyl-3 - [[2- [l ~ / ³ ~ <tritylpiperid-1-one 3-yl) propyl-1 / piperidin-4-yl]] ethyl carbonyl] -1H-indole (Example 69B)

2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[(piperid-4-yl) ethyl] carbonyl] -1H-indole (0.091) was added to a 10 mL round bottom flask under nitrogen. G,

0.222 mmol). 3- (1-tritylpiperid-3-yl) propyl iodide (0.110 g,

Potassium carbonate (0.0450 g, 0.3255 mmol) and anhydrous Ν, Ν-dimethylformamide (1.5 mL). The resulting mixture was stirred overnight and then poured onto ice water. The solids are filtered off and rinsed with cold water. The solids were dissolved in methylene chloride and then dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title compound is further purified by chromatography. Yield: 0.1166 g (67.3%).

FD-MS 779 (M + ² ).

Elemental analysis for C ₅₁ H ₅₆ ClN ₃ 0 ₂ (%):

H, 7.25; N, 5.40. Found: C, 78.92; H, 7.41; N, 5.27.

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [• [2- [1- [3- (piperid-3-yl) propyl] piperid-4-yl]] ethyl] carbonyl] - -ΙΗ-indole (Example 69C)

aw

Under a nitrogen atmosphere, 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[2- [1- / 3- (1-tritylpiperid-3-yl) propyl] piperidine- 4-yl]] ethyl] carbonyl] -1H-indole (0.1006 g, 0.1292 mmol) dissolved in methylene chloride (0.6 mL), To this solution was added formic acid (0.0244 mL, 0.0297) g, 0.646 mmol). The resulting mixture was stirred at room temperature for several hours, avoiding light access. 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 solution. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title compound is further purified by radial chromatography.

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS 536 (M ^{+ 1} ).

Elemental analysis for ^C 32 ^H 42 ^C1N 3 ° 2 requires 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] -1-methyl-3-formyl-1H-indole (Example 236)

Anhydrous Ν, Ν-dimethylformamide (0.63 mL) was charged to a round bottom flask under nitrogen. The reaction vessel was placed in a -20 ° C bath and phosphorous oxychloride (0.187 mL, 0.310 g, 2.02 mmol) was carefully added. The resulting mixture was stirred on an ice bath for about 20 minutes and then 2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indole (0.50 g, 1.84 mmol) in N, was added. N-dimethylformamide (3.4 mL). The resulting mixture was stirred at room temperature for about 90 minutes. The reaction mixture was then placed in an oil bath, heated to 55 ° C and held at this temperature for about 1 hour. The reaction mixture is then allowed to cool to room temperature and then poured onto water.

To the reaction mixture was added 5.0 N sodium hydroxide solution (10 mL), and the mixture was heated to reflux. The resulting mixture was cooled and the solids collected by filtration.

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS 299. (M ^& lt ^{; +} & gt ^; ).

.. ... ... -. Ati .- * -.

Elemental analysis for C ₁₇ H ₁₄ ClNO ₂ (%):

H, 4.71; N, 4.67. Found: C, 67.90; H, 4.66; N, 4.76.

Method for the preparation of 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-2- (methoxycarbonyl) ethyl] -1H-indole (Example 55)

0.

'Cl

O.

Dry nitrogen tetrahydrofuran (6.7 mL) was added to a round bottom flask under a nitrogen atmosphere. Diisopropylamine (0.196 mL, 0.1417 g, 1.401 mmol) was added to the flask and the reaction vessel was placed in an ice bath. To this mixture was slowly added n-butyllithium (0.88 mL of a 1.6-M solution in hexanes,

1.401 mmol) and the resulting mixture was stirred in an ice bath for about 15 minutes. The reaction mixture was placed in a bath of carbon dioxide (dry ice) and acetone, methyl acetate was added, and the reaction mixture was stirred for 15 minutes in a bath of carbon dioxide (dry ice) and acetone. The starting aldehyde was added in a total amount of 7.0 mL of tetrahydrofuran and stirred in a bath of carbon dioxide (dry ice) and acetone for 1 hour and then transferred to an ice bath for about 30 minutes. The reaction mixture was poured into a solution of ammonium chloride (32 g in 100 mL water). The aqueous fraction was extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title compound is further purified by radial chromatography.

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound. IR is also consistent with the proposed structure of this compound.

FD MS 373 (M &lt; + &gt;).

Elemental analysis for ^C 20 ^H 20 ^ClNO 4 Calculated: C, 64.26; H, 5.39; N, 3.75. Found: C, 64.55; H, 5.23; N, 3.79.

Process for preparing 3- [2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] prop-2-enoic acid

Λ!

101

2 - [(2,4-Dichlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-2- (methoxycarbonyl) ethyl] -1H-indole (Example 55) was charged into a round-bottom flask under nitrogen. 0.149 g, 0.398 mmol) and dry tetrahydrofuran (6.11 mL).

To this was added a 2.0 N aqueous lithium hydroxide solution (1.22 mL), and the resulting mixture was stirred at room temperature for about 2 hours. The solvents were removed in vacuo and the residue 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 evaporated under reduced pressure. The title compound .............. "the title compound is triturated with diethyl ether.

The analytical values are consistent with the proposed structure of the title compound.

Preparation of 2 - [(4-chlorophenoxy) methyl) -1-methyl-3- [2 - [[4 (dimethylamino) piperid-1-yl] carbonyl] ethenyl] -1H-indole (Example 44).

O

Under a nitrogen atmosphere, dimethylaminopiperidine was dissolved in methylene chloride (3.0 mL). To this solution was added 3- [2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] prop-2-enoic acid (0.050 g, 0.1462 mmol) and 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.0356 g, 0.278 mmol). The resulting mixture was stirred at room temperature overnight.

The reaction mixture was partitioned between saturated sodium bicarbonate solution and methylene chloride. The aqueous fraction was. The organic fractions were combined, washed with 1.0 N hydrochloric acid, then brine and then dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title compound is further purified by radial chromatography.

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound. .

Exact weight for ^C 26 ^H 30 ^C1N 3 ° 2 ^; calculated: 452.2105, found: 452.2099.

103

Method L

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (methoxycarbonyl) ethyl] -1H-indole

To a round bottom flask was charged 10% palladium on activated carbon (0.150 g),,, Ν-dimethylformamide (20 mL) and 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (methoxycarbonyl) 1-Ethenyl] -1H-indole (1.44 g, 4.22 mmol). The reaction vessel was then placed under a hydrogen atmosphere for 2 hours. The reaction mixture was then passed přes.vrstvu CELITE ™ (diatomaceous earth) --jin-jjjr-- ίΐ | ΐ- ιυυί · · · -τΜΡΐιν. | Μ · W · x ^{_T, '-'ήΓ} Α τ ~ Γ- ---------- and ~ to-it * splits * me “vo'du ~ á ^? métKýIencHlori'ď. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined, washed with water, then brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure.

The title compound is further purified by chromatography.

Process for preparing 3- [2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] propanoic acid

- 104

Dissolve 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (methoxycarbonyl) ethyl] -1H-indole (0.275 g, 0.771 mmol) in dry tetrahydrofuran (8 mL). To this was added 2.0 N lithium hydroxide solution (4.0 mL). The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.

The solvents were evaporated under reduced pressure and the residue was partitioned between methylene chloride and 5% citric acid. The aqueous fraction was extracted twice with methylene chloride. Organic ............

The fractions were combined, washed with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure to give the title compound. Yield 0.2984 g (&gt; 99%).

Preparation of 2 - [(4-chlorophenoxy) methyl) -1-methyl-3- [2 - [[4 (dimethylamino) piperid-1-yl] carbonyl] ethyl] -1H-indole (Example 43)

--105

, CHí

CH ₃

Dissolve 3- [2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] propanoic acid (0.286 g, 0.832 mmol) in dry tetrahydrofuran (6 mL) under nitrogen.

To this solution was added 1,1'-carbonyldiimidazole (0.141 g, 0.874 mmol) and the resulting mixture was stirred at room temperature for about 2 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture is then warmed to temperature. 65 ° C and held at this temperature for about 35 minutes.

To this reaction mixture was added dimethylaminopiperidine (0.112 g, 0.874 mmol) dissolved in tetrahydrofuran (approximately 3.6 mL). The mixture was stirred at room temperature overnight.

The reaction mixture is then heated to 60 ° C and held at this temperature for about 30 minutes. The solvents were removed in vacuo and the residue partitioned between methylene chloride and water. The aqueous fraction was extracted again with methylene chloride. The organic fractions were combined, washed twice with water, then brine and then dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title compound is further purified by chromatography.

NMR (CDCl ₃ ) was consistent with the proposed structure of the title compound. IR is also consistent with the proposed structure of this compound.

106

MS F 453 (M +)

Elemental analysis for ^C 26 ^H 32 ^ClN 3 ° 2 (%):

H, 7.10; N, 9.26. Found: C, 68.74; H, 7.04; N, 9.38.

Method M

Process for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [3- [4- (N, N-dimethylamino) piperid-1-yl] propyl] -1H-indole (Example 41)

2 - [(4-chlorophenoxy) methyl) -1-methyl-3- [2 - [[4- (dimethylamino) piperid-1-yl] carbonyl] ethyl] ethyl] was added to a round bottom flask under nitrogen. 1H-Indole (0.194 g, 0.428 mmol). The flask was then placed in an ice bath and borane-tetrahydrofuran complex (1.71 mL of a 1.0 M solution in tetrahydrofuran, 1.71 mmol) was charged. 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 mixture of tetrahydrofuran and methanol (a total of 0.20 mL) was added to the reaction mixture, followed by the addition of 5.0 N sodium hydroxide solution (2.0 mL).

107

The resulting mixture was refluxed overnight. The solvents were evaporated and the residue partitioned between water and methylene chloride. The organic fraction was washed with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure.

NMR (CDCl3) was consistent with the proposed structure of the title compound.

FAB MS 440 (M ^{+ 1} ).

IR was consistent with the proposed structure of the title compound.

Elemental analysis for C ₂₆ H ₃₄ ClN ₃ O (%): Calculated: 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] -1-methyl-3- [3- (piperid-3-yl) propyl] -1H-indole (Example 42) and 1,2-dimethyl-3- [3] - (piperid-3-yl) propyl] -1H-indole (Example 237)

108

*

Dissolve 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [3- (piperid-3-yl) propanoyl] -1H-indole (0.0737 g, 0.1793 mmol) under nitrogen atmosphere in borane / dimethylsulfide complex ( _10.10 ml, 0.1%, 1.07 mmol) was added to the solution. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.

A 1: 1 mixture of tetrahydrofuran and water (0.3 mL) was added to the reaction mixture, as was a 5.0 N sodium hydroxide solution (1.5 mL). The reaction mixture was heated to 85 ° C and maintained at that temperature overnight, and then the temperature was raised briefly to 225 ° C.

The solvents were removed in vacuo and the residue partitioned between methylene chloride and 1.0 N sodium hydroxide solution. The organic fraction was washed with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The desired title compounds are further purified by chromatography.

109

The analytical values obtained are consistent with the proposed structure of the title compounds (see Examples 42 and 237 above).

A process for the preparation of 2,4-dichloro-1-ethynylbenzene, CH

Cl

Cl

In a 500 mL round bottom flask, mix 2,4-dichloroiodobenzene (3 mL, 22.1 mmol), triethylamine (6.16 mL, 44.2 mmol), and (trimethylsilyl) acetylene (3.12 mL, 22 mL). , 1 mmol) in acetonitrile (6.16 mL, 44.2 mmol) under a nitrogen atmosphere. Nitrogen gas was bubbled through the mixture for 10 minutes. To this mixture was added bis (triphenylphosphine) palladium (II) chloride (775 mg, 1.10 mmol) and copper (I) iodide (105 mg, 0.552 mmol), and the resulting mixture was refluxed for 4 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was cooled to room temperature and evaporated to leave an oil.

The residue was dissolved in methanol (50 mL) and tetrahydrofuran (150 mL), and then potassium carbonate (30.54 g, 0.221 mol) was added. The resulting mixture was stirred at room temperature for 19 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1M potassium carbonate solution and ethyl acetate. The aqueous fraction is recovered

110 was extracted three times with ethyl acetate. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure to give 2.6 g of the title compound.

NMR was consistent with the proposed structure, the title compound.

A process for the preparation of 2,4-dichloro-1- (2-bromoethen-1-yl) benzene

Br

Cl

In a 100 mL round bottom flask, borane-tetrahydrofuran complex (4.82 mL, 1-M in tetrahydrofuran, 4.82 mmol) was cooled to 0 ° C under a nitrogen atmosphere.

To this complex was added dropwise 2-methylprop-2-ene (1.02 mL, 9.65 mmol) and the mixture was allowed to warm slowly to room temperature and stirred at room temperature for 1 hour. The reaction mixture was diluted with a mixture of hexamethylphosphoramide (5 mL), tetrahydrofuran (5 mL), copper bromide (2.15 g, 9.65 mmol), and copper acetate (3.85 g, 19.3 mmol) and then water ( 86 μί, 4.82 mol). The resulting mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was diluted with brine and extracted three times with diethyl ether. The organic fractions were combined and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue is further purified by liquid chromatography. Yield 426 mg.

NMR was consistent with the proposed structure of the title compound.

A process for the preparation of 4-hydroxy-N-isopropylbutylamine

HIM

CH ₃

To a solution of 4-aminobutanol (2.0 mg, 22.4 mmol) in 110 mL of dichloroethane was added acetone (3.3 mL, 44.8 mmol), acetic acid (5 equivalents) and sodium acetoxyborohydride (11.9 g, 56 mL). , 09 mmol). The cloudy mixture was stirred at room temperature for approximately 18 hours. The reaction is then quenched by the addition of saturated sodium bicarbonate solution.

A 1 M sodium hydroxide solution was added to the reaction mixture to adjust the pH to about 10. The aqueous layer was extracted with a 1: 3 mixture of isopropyl alcohol and methylene chloride. The organic fractions were combined, dried over sodium sulfate, filtered and evaporated. The desired intermediate was further purified by flask-to-flask distillation to give 1.4 g of a clear oil. If desired, further increase in yield can be achieved by extracting the aqueous fraction with a 3: 1 mixture of toluene and butanol.

A process for the preparation of N- (tert-butoxycarbonyl) -4-hydroxy-N-isopropylbutylamine

112

BoC, Ν.

HIM

CH ₃

CH ₃

A solution of 4-hydroxy-N-isopropylbutylamine (3.0 g, 22.8 mmol) in a mixture of dioxane, water and 1 N sodium hydroxide solution in a volume of 91 mL: 28 mL: 28 mL was treated with di (tert-butoxycarbonyl). ) with ether (4.98 g, 22.8 mmol). The cloudy reaction mixture was stirred for 5 hours. The reaction mixture was extracted with methylene chloride. The organic phase was dried, filtered and evaporated. The title compound is further purified by high performance liquid chromatography. This afforded 2.6 g of a colorless oil compound. Yield 49%.

Process for the preparation of 2-fluoro-5-chlorobenzaldehyde

Cl

Lithium diisopropylamide was prepared by mixing diisopropylamine (5.79 mL, 41.3 mmol) in tetrahydrofuran (5 mL). The resulting mixture was cooled to -78 ° C and treated with n-butyllithium in such a way that the temperature did not rise above 64 ° C. The suspension was stirred for 45 minutes, then tetrahydrofuran (70 ml) was added to the residue, and 4-chlorophenyl fluoride (4.0 mL, 37.6 mmol) was added dropwise. After 45 minutes she is

113, rovněž, Ν-dimethylformamide, also added dropwise. The resulting reaction mixture was stirred for an additional 10 minutes and then quenched by the addition of acetic acid (6 mL) followed by the addition of 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 evaporated under reduced pressure. The residue is further purified by flash chromatography. Thus, 4.00 g of compound are obtained as a white solid, m.p. 41-43 ° C.

A process for the preparation of 2-fluoro-5-methylbenzyl alcohol

OH

CH ₃

A solution of 2-fluoro-5-methylbenzaldehyde (1.80 g, 12.3 mmol) in 1: 1 tetrahydrofuran / methanol (82 mL total) was treated with sodium borohydride (0.93 g, 24 mL) at 0 ° C. , 6.mmol). The reaction mixture was slowly warmed to room temperature and stirred for about 3 hours. The reaction was quenched by the addition of water, transferred to a separatory funnel, and extracted with methylene chloride. The organic fraction was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is further purified by high performance liquid chromatography. In this way, 1.3 g of compound are removed as a clear oil. Yield 76%.

A process for the preparation of 2-fluoro-5-chlorobenzyl alcohol

- 114 -

OH

The title intermediate is prepared essentially as 2-fluoro-5-methylbenzyl alcohol as described above, except that an equimolar amount of 2-fluoro-5-chlorobenzaldehyde is used in place of 2-fluoro-5-methylbenzaldehyde, which is used in that preparation. Yield 2.16 g (86%). The compound was a clear oil.

A process for the preparation of 2-fluoro-5-chlorobenzyl bromide

Br

Cl

A solution of 2-fluoro-5-chlorobenzyl alcohol (1.28 g, 7.97 mmol) in diethyl ether (26 mL) was treated with triphenylphosphine (2.72 g, 10.36 mmol) followed by carbon tetrabromide (3.44 g). , 10.36 mmol). The resulting suspension was stirred for 3.5 hours, then filtered and washed with diethyl ether. The filtrate was evaporated and then passed through a pad of silica to remove triphenyl phosphate. The residue is then purified by liquid chromatography. This gave 2.0 g of the title compound as a clear oil

115

Process for preparing 4- (2-fluorobenzyloxy) -N- (tert-butoxycarbonyl) -N- (isopropyl) butylamine

A solution of N- (tert-butoxycarbonyl) -4-hydroxy-N-isopropylbutylamine (539 mg, 2.33 mmol) in tetrahydrofuran (11 mL) was treated with potassium tert-butoxide (2.54) at -40 ° C. mL, 1-M in tetrahydrofuran, 2.54 mmol). After 40 minutes, the suspension was cooled to -78 ° C and treated with a solution of 2-fluorobenzyl bromide (400 mg, 2.12 mmol) in tetrahydrofuran (4 mL). The reaction mixture was slowly warmed to room temperature and stirred for about 5 hours. The reaction mixture was diluted with methylene chloride and washed with 1M potassium carbonate solution and brine. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude oil was purified by liquid chromatography. This gives 555 mg of the title intermediate as a clear oil. Yield 77%.

Process for preparing 4- (2-fluoro-5-chlorobenzyloxy) -N- (tert-butoxycarbonyl) -N- (isopropyl) butylamine

116

BoC

Nch ₃ ch ₃

Cl

The title intermediate is prepared essentially as described above for 4- (2-fluorobenzyloxy) -N- (tert-butoxycarbonyl) -N- (isopropyl) butylamine, except that an equimolar amount of 2-fluoro- 5-chlorobenzyl bromide in place of the 2-fluorobenzyl bromide used in said preparation. Yield 237 mg (35%).

A process for preparing 4- (2-fluorobenzyloxy) -N- (isopropyl) butylamine

The desired intermediate is prepared from 4- (2-fluorobenzyloxy) -N- (tert-butoxycarbonyl) -N- (isopropyl) butylamine by deprotection using a standardized technique. 4- (2-Fluorobenzyloxy) -N- (tert-butoxycarbonyl) -N- (isopropyl) butylamine is mixed with a 4: 1 mixture of methylene chloride and trifluoroacetic acid. The progress of the reaction was monitored by thin layer chromatography.

A process for preparing 4- (5-chloro-2-fluorobenzyloxy) -N- (isopropyl) butylamine

- 117 -

Cl

The desired intermediate is prepared essentially as described for 4- (2-fluorobenzyloxy) -N- (isopropyl) butylamine above except that an equimolar amount of 4- (5-chloro-2-fluorobenzyloxy) -N- (tert- butoxycarbonyl) -N- (isopropyl) butylamine, instead of 4- (2-fluorobenzyloxy) -N- (tert-butoxycarbonyl) -N- (isopropyl) butylamine, used in the above preparation, yield 138 mg (98%).

Process for the preparation of 3- (5-bromo-2-fluorobenzyloxy) -1- [1- (tert-butoxycarbonyl) piperid-2-yl] propane

3- [1- (tert-Butoxycarbonyl) piperid-2-yl] propanol (800 mg, 3.29 mmol) was treated with tetrahydrofuran (17 mL), cooled to -40 ° C, and treated with tert. potassium butoxide (3.62 mL, 1-M in tetrahydrofuran, 3.62 mmol). The resulting mixture was stirred at -40 ° C for about 35 minutes and then cooled to -78 ° C.

To this mixture was then added 5-bromo-2-fluorobenzyl bromide (881 mg, 3.29 mmol) as a solution in tetrahydrofuran (5 mL). . The resulting yellow reaction mixture was slowly warmed to 0 ° C and stirred for about 4 hours. The reaction mixture was diluted with methylene chloride and washed with 1M potassium carbonate solution and brine. The organic fraction was dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude oil was purified by high performance liquid chromatography. This afforded 707 mg of the title intermediate as a clear oil. Yield 50%. . .

Γ

Elemental analysis for ^c 20 ^H 29 ^BrFNO 3 (%):

H, 6.79; N, 3.25. Found: C, 55.54; H, 6.88; N, 3.34.

3- (5-Bromo-2-fluorobenzyloxy) -1- (piperid-2-yl) propane

3- (5-Bromo-2-fluorobenzyloxy) -1- [1- (tert-butoxycarbonyl) piperid-2-yl] propane (590 mg, 1.37 mmol) was dissolved in methylene chloride (11 mL), cooled to 0 ° C, and treated with trifluoroacetic acid (3 mL). The reaction mixture was stirred at 0 ° C for 20 minutes, then warmed to room temperature and stirred for an additional 10 minutes. The reaction mixture was diluted with methylene chloride and then quenched by the addition of saturated sodium bicarbonate solution. The pH is adjusted to 10 with 1 N sodium hydroxide solution. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, filtered and evaporated.

This gave 420 mg of compound. Yield 93%,

The resulting intermediate was used without further purification.

A process for the preparation of 2-fluoro-5-bromobenzyl bromide

Br

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 bromide (42.1 g, 127 mmol). ). The mixture was stirred at room temperature for about 4 hours. The precipitate was collected and washed with diethyl ether. The title compound is further purified by flask-to-flask distillation (150 ° C, 665 kPa, water pump vacuum). 24.36 g of the title compound are obtained as a white solid of low melting point. Yield = 93%. ,

A process for preparing 4- (2-fluoro-5-bromobenzyloxy) but-2-ynyl alcohol

A solution of 2-fluoro-5-bromobenzyl bromide (15.6 g, 58.1 mmol) in Ν, Ν-dimethylformamide (290 mL) was added over 35 minutes to a mixture of 1,4-dihydroxy-2-butine (20.0 g). (232 mmol) and sodium hydride (15.6 g of 60% solution, 58.1 mmol). The resulting mixture was stirred at room temperature for 4.5 hours. The reaction was. .

by addition of 100 ml of a solution containing sodium chloride solution, water and a 1-M solution of potassium carbonate

1 - 1. The aqueous fraction was extracted three times with methylene chloride (300 ml each). The desired compound named in the title * is “»>

further purified by chromatography. There was thus obtained 8.90 g of the desired compound. Yield 56%. . ' 4 '- ·. ^x '»' -. '' ·. · '···'''''.

Process for preparing 4- (2-fluoro-5-bromobenzyloxy) butanol

A solution of 1,4-dihydroxybutane (4.0 mL, 45.13 mmol) in Ν, Ν-dimethylformamide (62 mL) was treated with sodium hydride (1.98 g of 60% solution, 49.63 mmol) and stirred at room temperature. 50 minutes. The resulting mixture was cooled to 0 ° C and treated with 2-fluoro-5-bromo-benzyl bromide (3.0 g, 11.28 mmol). The reaction mixture was then stirred at room temperature for 4 hours. The reaction was quenched with water. The aqueous fraction was extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The desired title product is further purified by high performance liquid chromatography. 1.8 g of the title compound are obtained as a clear oil. Yield 58%.

..- L

121

Λλnax - 271 nm.

Elemental analysis for C ₁₁ H ₁₄ BrFO ₂ (%):

H, 5.09; Br, 28.83. Found: C, 47.37; H, 5.15; Br, 28.55.

%

Method for the preparation of N- (tert-butoxycarbonyl) -4- (2-fluoro-5-bromobenzyloxy) -3,3-dimethylbutylamine, F

A stirred solution of 4- (tert-butoxycarbonylamino) -2,2-dimethylbutan-1-ol (1.5 g, 6.90 mmol) in tetrahydrofuran (49 mL) was treated with tert-butoxide at -45 ° C. potassium (7.59 mL, 1-M in tetrahydrofuran, 7.59 mmol). The anion was stirred at -45 ° C for 30 minutes and then cooled to -78 ° C and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.85 g, 6.90 mmol). The resulting yellow mixture was slowly warmed to room temperature and stirred for approximately 18 hours. The cloudy reaction mixture was diluted with methylene chloride and washed with 1M potassium carbonate solution. The organic fraction was dried over sodium sulfate, filtered, and the solvents were evaporated under reduced pressure. The residue is further purified by preparative high performance liquid chromatography. 1.45 g of the title intermediate is obtained as a colorless oil. Yield 52%.

Process for the preparation of N- (tert-butoxycarbonyl) -4- (2-fluoro-5-bromo122 benzyloxy) -2,2-dimethylbutylamine

A stirred solution of 4- (tert-butoxycarbonylamino) -3,3-dimethylbutan-1-ol (1/0 g, 4.60 mmol) in tetrahydrofuran (33 mL) was treated with tert-butoxide at -45 ° C. potassium (5.06 mL, 1-M in tetrahydrofuran, 5.06 mmol). Anion was stirred. after -the_ -45. ^o C-for 30 minutes and then cooled to -78 ° C and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow mixture was slowly warmed to 0 ° C and stirred for about 4 hours. The cloudy reaction mixture was diluted with methylene chloride (100 mL) and washed with 1M potassium carbonate solution. The organic fraction was dried over sodium sulfate, filtered, and the solvents were evaporated under reduced pressure. The residue is further purified by preparative high performance liquid chromatography. 1.38 g of the title intermediate is obtained as a colorless oil. Yield 74%.

Process for preparing 2 - [(tert-butoxycarbonyl) amino] -5- (2-fluoro-5-bromobenzyloxy) -2-methylpentane

123

A stirred solution of 4- (tert-butoxycarbonylamino) -4,4-dimethylbutan-4-ol (1.11 g, 5.11 mmol) in tetrahydrofuran (49 mL) at -45 ° C was treated with t-butoxide, potassium ¹ '(5th, 62 mL, 1 M in tetrahydrofuran, 5.62 mmol).' Anion *. · '* * Λ'',

Stir at -45 ° C for 30 minutes and then cool ¹ to -78 ° C and treat with tetrahydrofuran solution. 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow mixture was slowly warmed to 0 ° C and stirred for about 4 hours. The reaction mixture was diluted with methylene chloride / (100 mL) and washed with 1M potassium carbonate solution (20 mL). The organic fraction was dried over sodium sulfate, filtered, and the solvents were evaporated under reduced pressure. The residue is further purified by preparative high performance liquid chromatography.

• 4 hrs! ’/

1.53 g of the intermediate title compound are obtained. colorless ¹ oil. Yield 74%.

A process for the preparation of trans-4- (tert-butoxycarbonylamino) cyclohexanol

HIM'

To a solution of trans-4-aminocyclohexanol (5.00 g, 33.0

and

124 mmol) in dioxane (132 mL), water (41 mL) and an NN sodium hydroxide solution (41 mL) were added tert-butoxycarbonylanhydride (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 reaction mixture was extracted three times with methylene chloride. The organic fractions were combined, dried over sodium sulfate and evaporated under reduced pressure. Intermediate required *

The title compound was recrystallized from hexanes / ethyl acetate. This afforded 6.5 g of the title compound. Yield 92%.

MS 216.24.

Elemental Analysis for C ^ ₁ g In0 _{2 3} (%): _........., ..............

calculated: C, 61.37, H, 9.83, N, 6.50. Found: C, 61.16, H, 9.54, N, 6.39.

Process for the preparation of trans- [4- (butoxycarbonylamino) -1- (2-fluoro-5-bromobenzyloxy)] cyclohexane

Br

A solution of trans- [4- (butoxycarbonylamino) -cyclohexanol (550 mg, 2.32 mmol) in dry tetrahydrofuran (16.6 mL) was cooled to -40 ° C and treated with potassium tert-butoxide (2.55 mL). , 1-M in tetrahydrofuran, 2.55 mmol). The cloudy yellow reaction mixture was stirred for 30 minutes and then cooled to -78 ° C and treated with 2-fluoro-5-bromo.

125 with benzyl bromide (622 mg, 2.32 mmol). The resulting yellow mixture was gradually warmed to 0 ° C and stirred for about 2 hours. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate solution. The organic fraction was dried over sodium sulfate and the solvents were evaporated under reduced pressure. The residue is further purified by high performance liquid chromatography. This gives 558 mg of the desired intermediate title compound as a white oil. Yield 62;

*

Elemental analysis for C ₁₈ H ₂₅ BrFNO ₃ (%): *.

H, 6.26; N, 3.48. Found: C, 53.87; H, 6.16; N, 3.11.

Process for the preparation of 3,3-dimethyl-1- (tert-butoxycarbonyl) pyrrolidin-2-one

The desired intermediate is prepared essentially as described by F. Scheinmann and AV Stachulski in the Journal of Chemical Research, 1993, 414 (1993). A solution of 3-methyl-1- (tert-butoxycarbonyl) pyrrolidin-2-one (8.63 g, 43.3 mmol) in tetrahydrofuran (48 mL) was cooled to -78 ° C. The cooled solution was treated with NaN [Si (CH ₃ ) ₂ ] ₂ (56.3 mL, 56.3 mmol) and stirred for about 50 minutes before the reaction was quenched by addition of methyl iodide (8.1 mL, 130 mmol). The reaction mixture was slowly warmed to room temperature and stirring was continued for approximately 1 hour. The reaction mixture is diluted with ethyl acetate (100 mL) and washed with pH 7.0 phosphate buffer (40 mL),

126 water (40 mL) and brine (40 mL). The organic fraction was dried over sodium sulfate, filtered and evaporated under reduced pressure. The precipitate was collected and further purified by flash chromatography. There was thus obtained 8.49 g of the title intermediate as a semi-solid; .The yield corresponds to 92%.

NMR was consistent with the structure of the title compound.

A process for preparing 4- (tert-butoxycarbonylamino) -2,2-dimethylbutanol

A solution of 3,3-dimethyl-1- (tert-butoxycarbonyl) pyrrolidin-2-one (3.35 g, 15.7 mmol) in absolute ethanol was treated with sodium borohydride (1.79 g, 47.1) under a nitrogen atmosphere. mmol). The resulting mixture was stirred at room temperature for 24 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate solution. The aqueous fraction was back-extracted twice with ethyl acetate. The organic fraction was dried over sodium sulfate and evaporated under reduced pressure. The residue is further purified by chromatography. This afforded 3.17 g of the title product as a clear oil having a melting point of 75.5-76.5 ° C. Yield 93%.

Process for preparing 4- (2-fluoro-5-bromobenzyloxy) -1-methoxybut-2-yne

127

A solution of 4- (2-fluoro-4-bromobenzyloxy) but-2-ynyl alcohol (1.07 g, 3.92 mmol) in tetrahydrofuran (26 mL) was cooled to -40 ° C and then treated with potassium tert-butoxide. (4.31 mL of a 1-M solution in tetrahydrofuran, 4.31 mmol). The resulting dark orange solution was stirred for 30 minutes, cooled to -78 ° C and treated with methyl iodide (0.49 mL, 7.84 mmol). Warm the reaction mixture to 0 ° C and stir for 90 minutes. . The reaction mixture was then partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic fraction was dried over sodium sulfate and the solvents were evaporated under reduced pressure. The desired title product is further purified by high performance liquid chromatography. 790 mg of compound is obtained as a clear oil. Yield 70%.

A process for preparing 4- (2-fluoro-5-bromobenzyloxy) but-2-ynyl bromide.

4- (2-Fluoro-5-bromobenzyloxy) but-2-ynyl alcohol solution

128 (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 room temperature for approximately 14 hours. The precipitate was filtered off and the filtrate was evaporated. The title intermediate is purified from the filtrate by flash chromatography. 9.83 g of compound are obtained in the form of a clear oil. Yield 90%.

Elemental analysis and NMR were consistent with the proposed structure of the title compound.

A process for the preparation of N-methyl-4- (2-fluoro-5-bromobenzyloxy) but-2-ynylamine.

A solution of aminomethane (89 mL of a 2-M solution in tetrahydrofuran, 178 mmol) was added to a solution of 4- (2-fluoro-5-bromobenzyloxy) but-2-ynyl bromide (6.0 g, 17.8 mmol) in tetrahydrofuran (89 ml). The cloudy reaction mixture was stirred for about 15 minutes at which time no starting compound remained as determined by thin layer chromatography. The solvents were evaporated under reduced pressure. The residue was taken up in methylene chloride and washed with 1M potassium carbonate solution. The aqueous phase is back-extracted three times with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The resulting oil is further purified very quickly

Chromatography gave 4.24 g of the title intermediate as a yellow oil. Yield 83%.

NMR was consistent with the structure of the title compound.

Process for the preparation of N-benzyl-4- (2-fluoro-5-bromobenzyloxy) but-2-ynylamine

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 20 minutes at which time no starting compound remained as determined by thin layer chromatography. The solvents were evaporated under reduced pressure. The residue was taken up in methylene chloride and washed with 1M potassium carbonate solution. The aqueous phase was back-extracted twice with methylene chloride (15 ml each). The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The resulting oil was further purified by flash chromatography to give 200 mg of the title intermediate, yield 62%.

Process for the preparation of N-isopropyl-4- (2-fluoro-5-bromobenzyloxy) but-2-ynylamine

- 130 -

^An isopropylamine solution (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 20 hours, after which time no starting compound remained as determined by chromatography on

The solvent was removed under reduced pressure. The residue was taken up in methylene chloride and washed with 1M potassium carbonate solution. The aqueous phase is back-extracted twice with T methylene chloride (5 ml each). The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The resulting oil was further purified by flash chromatography to give 78 mg of the intermediate title

v.nadpisu. Yield 86%. The NMR conforms to the structure of the title compound. .

Process for the preparation of N-cyclopropyl-4- (2-fluoro-5-bromobenzyloxy) but-2-ynylamine

131

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 (530.4 mg, 1.58 mmol) in tetrahydrofuran (8 mL). . The cloudy reaction mixture was stirred for about 30 minutes. The reaction mixture was then cooled to 0 ° C and held at this temperature for about -6 hours until no starting compound remained as determined by chromatography. on a thin layer. The reaction mixture was diluted with methylene chloride (50 mL) and washed with 1M potassium carbonate solution (10 mL). The organic fractions were dried over sodium sulfate. The solvents were evaporated under reduced pressure. The resulting oil was further purified by preparative flash chromatography to give 362 mg of the title intermediate as a clear oil. Yield 73%. . /

A process for the preparation of 4,5-dihydro-2- (2-fluoro-5-bromophenyl) oxazole

Solution. N- (2-hydroxyethyl) -5-bromo-2-fluorobenzamide

132 (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 room temperature and the progress of the reaction was monitored by thin layer chromatography. After stirring for 1 hour, the starting compound is no longer visible. The reaction mixture was diluted with methylene chloride and quenched by addition of water and 1 N sodium hydroxide solution. The organic fraction was dried over sodium sulfate and evaporated to a white solid. Graphite. the material was dissolved in 80% aqueous acetonitrile (25 mL) and excess potassium carbonate was added. The resulting mixture was stirred at room temperature for about 72 hours, heated to reflux for 30 hours, and worked up as above. The title compound is then further purified by liquid chromatography. 260 mg of compound are obtained in the form of a yellow oil.

A process for the preparation of N, N-dimethyl-2-fluoro-5-bromobenzamide

2-Fluoro-5-bromobenzoic acid suspension (680 mg,

3.10 mmol) in methylene chloride (20 mL) was treated with oxalyl chloride (0.35 mL, 4.04 mmol) and then 4 drops of Ν, Ν-dimethylformamide were added. The resulting clear solution was then stirred for about 3 hours. The solvents were evaporated under reduced pressure and the residue was redissolved in methylene chloride and treated with dimethylamine (4.6 mL, 9 * 3 mL). Stirring of the reaction mixture was continued for 18 hours. The reaction mixture was diluted

- 133 methylene chloride and washed with saturated sodium bicarbonate solution and brine. The organic fraction was dried over sodium sulfate and the solvents were evaporated under reduced pressure. The title compound is further purified by liquid chromatography. 632 mg of compound is obtained as a clear oil. Yield = 83%. p. ¹ ·. c.

^L ' ^: ' * '* y.' - '

Process for preparing 1-methoxy-4- (2-fluoro-5-bromobenzyloxy) butane

Br

A solution of 4- (2-fluoro-5-bromobenzyloxy) butanol (897 mg,

3.24 mmol) in tetrahydrofuran (22 mL) was cooled to -40 ° C and then treated with potassium tert-butoxide (3.56 mL of a 1-M solution in tetrahydrofuran, 3.56 mmol). . The resulting dark orange solution was stirred for 3030 minutes, cooled to -78 ° C, and treated with methyl iodide (0.40 mL, 6.48 mmol ·) ’.

- The reaction mixture was warmed to 0 ^DEG-9 C, and stirred for 90 minutes. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate solution. The fraction was dried over sodium sulfate and the solvents were evaporated under reduced pressure. The desired title product is further purified by high performance liquid chromatography. 687 mg of compound are obtained which is in the form of a clear oil. Yield 73

FD MS 291.99,.

- 134

A process for preparing 4- (2-fluoro-5-bromobenzyloxy) butyl bromide

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). The turbid solution was stirred at room temperature for about 30 hours, then stirred for 30 minutes, filtered and filtered. The title intermediate was purified from the filtrate by distillation from flask to flask to give 8.68 g (86%) of the title compound as a clear oil.

Elemental analysis and NMR were consistent with the proposed structure of the title compound.

.4.

Process for the preparation of N, N-dimethyl-4- (2-fluoro-5-bromobenzyloxy) butylamine

CH ₃

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).

135 in tetrahydrofuran (18 mL). The resulting mixture was stirred at room temperature for about 18 hours. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate solution. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The desired title product is further purified by high performance liquid chromatography. 842 mg of compound is obtained as a pale yellow oil. Yield 79%.

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 room temperature. After 90 minutes, sodium bromide was filtered off and the filtrate was evaporated. The residue was treated with tetrahydrofuran solution of ethylamine (11 mL, 22.0 mmol). The resulting mixture was stirred at room temperature for about 17 hours. 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 evaporated under reduced pressure. The desired title product is further purified by radial chromatography. 337 mg of compound are obtained in the form of a yellow oil. Yield 75%.

136

NMR was consistent with the proposed structure of the title compound.

A process for the preparation of N-isopropyl-4- (2-fluoro-5-bromobenzyloxy) butylamine,

Br

A solution of 4- (2j ^fluoroborate or 5-brombenzylOxyJbutylbromidu (1.2 g, 3753 mmol) in tetrahydrofuran (18 ml) was treated with sodium iodide (484 mg, 3.2 mmol). The resulting mixture was stirred at room temperature After 90 minutes, sodium bromide was filtered off and the filtrate was evaporated, the residue was treated with a tetrahydrofuran solution of isopropylamine (3.01 mL, 35.3 mmol) and the reaction progress was monitored by thin layer chromatography, and the resulting mixture was stirred at room temperature for approximately The reaction mixture was diluted with methylene chloride and washed with 25 mM phosphate buffer and brine, and the organic fraction was dried over sodium sulfate and the solvents were evaporated under reduced pressure. The title intermediate was further purified by liquid chromatography to give 517 mg (46%) of the title compound as a yellow oil.

Elemental analysis for C ₁₄ H ₂₁ BrFNO (%):

H, 6.65; N, 4.40.

Found: C, 52.87, H, 6.77, N, 4.64.

A process for the preparation of N- (tert-butyl) -4- (2-fluoro-5-bromobenzyloxy) butylamine

A solution of 4- (2-fluoro-5-bromobenzyloxy) butyl bromide (400 mg, 1.18 mmol) in tetrahydrofuran (6 mL) was treated with sodium iodide (24 mg, 1.6 mL, 6 mmol). After 90 minutes, the sodium bromide was filtered off and the filtrate was evaporated, and the residue was treated with a tetrahydrofuran solution of tert-butylamine (1.24 mL, 11.8 mmol) and the reaction progress was monitored by TLC. The resulting mixture was stirred at room temperature for approximately 19 hours, at which time it was diluted with methylene chloride and washed with saturated sodium bicarbonate solution. The organic fraction was dried over sodium sulfate and the solvents were evaporated under reduced pressure. The title compound was further purified by radial chromatography to give 261 mg (66%) of the title compound as a yellow oil.

NMR was consistent with the proposed structure of the title compound.

A process for preparing 1- (piperid-1-yl) -4- (2-fluoro-5-bromobenzyloxy) butane

- 133-

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 mixture was stirred for approximately 24 hours. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate solution. The organic fraction was dried over sodium sulfate and the solvents were evaporated under reduced pressure. The desired title intermediate was further purified by radial chromatography., To give ¹ mg of compound 399. Yield 76%.

1- (Morpholin-4-yl) -4- (2-fluoro-5-bromobenzyloxy) butane

A solution of 4- (2-fluoro-5-bromobenzyloxy) butyl bromide (550 mg, 1.62 mmol) in tetrahydrofuran (8 mL) was treated with

139 with morpholine (1.4 mL, 16.2 mmol). The resulting mixture was stirred for approximately 72 hours. The reaction mixture was diluted with methylene chloride and washed with saturated bicarbonate solution. sodium. The organic fraction was dried over sodium sulfate and the solvents were evaporated under reduced pressure. The desired title product is further purified by radial chromatography. 446 mg of compound is obtained as a clear oil. Yield 79%.

1- (2-Fluoro-5-bromobenzyloxy) -3- [1- (tert-butoxycarbonyl) piperid-3-yl] propane

3- [1- (tert-Butoxycarbonyl) piperid-3-yl] propyl bromide (180 mg, 0.588 mmol) was dissolved in Ν, Ν-dimethylformamide (1.5 mL) in a 10 mL flask under a nitrogen atmosphere.

Sodium iodide (176 mg, 1.18 mmol) was added to the reaction mixture at room temperature and the resulting mixture was stirred for 10 minutes.

The reaction mixture was then treated with 2-fluoro-5-bromobenzyl * alcohol (121 mg, 0.588 mmol) supplied as a solution in N, N-dimethylformamide (0.5 mL). To this mixture was then added sodium hydride (35 mg, 60% solution, 0.882 mmol) and the resulting mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1M potassium carbonate solution and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The cleavage solvents are evaporated under reduced pressure. The title compound is further purified by liquid chromatography. Yield: 0.115 g.

MS (M ^& lt ^{; +} & gt ^; ) 430.

Elemental analysis for ^c 20 ^ 29 ^BrFNO 3 (%):

H, 6.79; N, 3.26. Found: C, 55.70; H, 6.59; N, 3.04.

H

1- (2-Fluoro-5-bromobenzyloxy) -3- (piperid-3-yl) propane

Dissolve 1- [2-fluoro-5-bromobenzyloxy) -3- [1- (tert-butoxycarbonyl) piperid-3-yl] propane (0.395 g) in methylene chloride (4) in a 100 mL round-bottom flask. , 2 ml). The solution was cooled to 0 ° C and trifluoroacetic acid (0.8 mL) was slowly added dropwise. ^Resulting: a mixture was stirred at 0 ° C for 30 minutes and then further stirred at room temperature for 30 minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1-potassium carbonate solution 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 evaporated under reduced pressure. The desired intermediate title in the title is below. purifies by liquid chromatography. 210 mg are obtained

141 compounds as a clear yellow oil.

Elemental analysis for C ₁₆ H ₂₁ BrFNO (%): calculated: C, 54.54, H, 6.41, N, 4.24, found: C, 54.32, H, 6.41, N, 4, 34.

A process for the preparation of 2-fluoro-5-bromobenzyl bromide

In a 250 mL round bottom flask, 2-fluoro-5-bromobenzyl alcohol (5.85 g, 28.5 mmol) was dissolved in diethyl ether (125 mL) under a nitrogen atmosphere. To this solution was added triphenylphosphine (9.73 g, 37.1 mmol) and carbon bromide (12.30 g, 37.1 mmol). The resulting mixture was stirred at room temperature for about 3 hours. The progress of the reaction was monitored by thin layer chromatography. The mixture was then stirred at room temperature for a further 19 hours. The reaction mixture was filtered and washed with cold diethyl ether. The filtrate was evaporated to give a pale yellow oil. The oil was further purified by chromatography on silica gel with hexanes as eluent. The desired fractions were purified by evaporation. In this way, 5.8 g of the title intermediate was obtained. The compound slowly crystallizes on standing.

Elemental analysis for C ₇ H ₆ Br ₂ F (%):

calculated: C, 31.39, H, 1.88, found: C, 31.18, H, 1.91.

- ‘142

A process for the preparation of N, N-dimethyl-3- (2-fluoro-5-bromobenzyloxy) propylamine

Dissolve 2-fluoro-5-bromobenzylbromide (245 mg, 250 ml) in a 10 ml round-bottom flask under nitrogen.

0.914 mmol in Ν, Ν-dimethylformamide (2.0 mL). To this solution was added sodium iodide (91-4-mmol), followed by stirring the resulting mixture for 30 minutes at room temperature.

In another 10 mL flask, 3- (N, N-dimethylamino) propanol (0.162 mL, 1.37 mmol) was dissolved in N, Ν-dimethylformamide (2.0 mL) under a nitrogen atmosphere. Sodium hydride (62 mg, 60% solution,

1.55 mmol) and the resulting mixture was stirred for 30 minutes. To the resulting propanol mixture was added benzyl bromide and sodium iodide solution. Some foaming occurs, which dissolves quickly.

'

The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by thin layer chromatography.

The reaction mixture was partitioned between 1M potassium carbonate solution 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 evaporated under reduced pressure. The desired intermediate is further purified by liquid chromatography. 182 mg of the title intermediate are obtained. Yield 69%.

143

NMR, IR and MS were consistent with the proposed structure of the title compound.

Elemental analysis for ^C 12 ^H 17 ^BrFNO (%): Calculated: C, 49.67; 5.91, N, 4.83, found :. C, 49.46; H, 5.92; N, 4.99.

Preparation of 2- (2-fluoro-5-bromobenzyloxy) -1-methoxyethan

In a 10 mL flask, 2-methoxyethanol (0.125 mL, 1.60 mmol) was dissolved in N, N-dimethylformamide (2 mL) under a nitrogen atmosphere. Sodium hydride (72 mg, 60% solution, 1.81 mmol) was added and the mixture was stirred at room temperature for approximately 30 minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl alcohol (285 mg, 1.06 mmol) as a solution in Ν, Ν-dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1M potassium carbonate solution and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic fractions were combined, washed seven times with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The desired intermediate title compound was used without further purification. The yield corresponds to 165.mg.

-ΐ

144 Preparation of 2- (2-fluoro-5-bromobenzyloxy) - (N, N-dimethyl) ethylamine

In a 50 mL flask, 2- (Ν, Ν-dimethylamino) ethanol (1.329 g, 4.92 mmol) was dissolved in N, N-dimethylformamide (16 mL) under a nitrogen atmosphere. To the reaction was added _n-i-ATR umhydr-id - (- 3-3 mg of _{the T-5} --- 60 -% - _y -8 - - 3-7-meso-and-lj vše- The reaction mixture was treated with 2-fluoro-5-bromobenzyl bromide (1.329 g, 4.92 mmol) as a solution in N, N-dimethylformamide (3 mL). The resulting mixture was stirred at room temperature for 2 hours, the progress of the reaction was monitored by thin layer chromatography, the reaction mixture was partitioned between 1M potassium carbonate solution and diethyl ether, and the aqueous fraction was back extracted with diethyl ether. The solvents were evaporated under reduced pressure and the title intermediate was used without further purification to yield 1.023 g (75%).

A process for the preparation of N, N-dimethyl-2-fluoro-5-bromobenzylamine

145 -

In a 50 mL flask, 2-fluoro-5-bromobenzyl bromide (1.264 g, 4.72 mmol) was dissolved in methanol (10 mL) under a nitrogen atmosphere. Dimethylamine (1.77 ml, 8-M in water,

14.2 mmol) was added as a solution in methanol (5 mL) and the resulting mixture was stirred at room temperature for about 2 hours. The progress of the reaction was monitored by thin layer chromatography. Methanol was evaporated and the residue was partitioned between 1M solution of carbonate, potassium and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic fractions were combined, washed seven times with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title intermediate was used without further purification. Yield 0.987 g.

A process for preparing 2- (2-fluoro-5-bromobenzyloxy) - (N-methyl) ethylamine

In a 1 ml flask under nitrogen

146 mg of 2- (2-fluoro-5-bromobenzyloxy) - (N-, N-dimethyl) ethylamine (317 mg, 1.15 mmol) in dichloromethane (3.5 mL). This solution was cooled to 0 ° C and ACE.C1 (0.50 mL, 4.59 mmol) was added to the solution. The resulting mixture was warmed to room temperature, then heated to reflux and maintained at this temperature for about 3 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 room temperature for about 3 days. The mixture was then heated to reflux for 30 minutes; The solvent was evaporated under reduced pressure. The evaporator is taken up in methanol, heated to reflux for approximately 30 minutes and the solvents are then evaporated off under reduced pressure. The title intermediate was used without further purification. Yield: 210 mg. _____.

A process for the preparation of N-methyl-2-fluoro-5-bromobenzylamine

In a 25 mL flask, 2-fluoro-5-bromobenzyl bromide (755 mg, 2.82 mmol) was dissolved in methanol (10 mL) under a nitrogen atmosphere. To the solution was added methylamine (0.99 mL, 14.1 mmol) and the mixture was stirred at room temperature for about 3 days. The progress of the reaction was monitored by thin layer chromatography. The solvents were evaporated and the residue was partitioned between 1M potassium carbonate solution and methylene chloride.

The aqueous fraction was extracted again with methylene chloride. Organic

147 fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The title intermediate was further purified by liquid chromatography. Yield 0.435 g.

NMR was consistent with the proposed structure of the title compound.

.. *

Process for the preparation of N-methyl-3- (2-fluoro-5-bromobenzyloxy) propylamine

In a 15 mL flask, Ν, N-dimethyl-3- (2-fluoro-5-bromobenzyloxy) propylamine (351 mg, 1.21 mmol) was dissolved in dichloroethane (3.5 mL) under a nitrogen atmosphere. To this solution was added ACE.Cl (0.78 mL, 7.26 mmol) and the resulting mixture was heated to reflux and maintained at this temperature for 18 hours. The reaction mixture was cooled to room temperature and the solvents were evaporated under reduced pressure.

The residue is taken up in methanol and refluxed for 90 minutes. The methanol solution was partitioned between 1M potassium carbonate solution 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 evaporated under reduced pressure. The title intermediate was further purified by liquid chromatography.

- 148 NMR was consistent with the proposed structure of the title compound.

Preparation.

A process for the preparation of N, N-dimethyl-4- (2-fluoro-5-bromobenzyloxy) butylamine

In a 50 mL flask, 2-fluoro-5-bromobenzyl bromide (967 mg, 3.61 mmol) was dissolved in N, Ν-dimethylformamide (3.5 mL) under a nitrogen atmosphere. To this solution was added sodium hydride (245 mg, 60%, 6.14 mmol) and the resulting mixture was stirred for 10 minutes. 4- (N, N-dimethylamino) butanol (633 mg, 5.41 mmol) was added to the reaction mixture, and the resulting mixture was stirred for 6 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1M potassium carbonate solution 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 evaporated under reduced pressure. The title intermediate was further purified by liquid chromatography. Yield: 260 mg (24%).

NMR was consistent with the proposed structure of the title compound.

Preparation

149 A process for preparing N-methyl-4- (2-fluoro-5-bromobenzyloxy) butylamine

In a 10 mL flask, N, N-dimethyl-4- (2-fluoro-5-bromobenzyloxy) butylamine (215 mg, 0.707 mmol) was dissolved in dichloroethane (2.0 mL) under a nitrogen atmosphere, to which ACE was added. Cl (0.305 mL, 2.83 mmol) was added and the resulting mixture was heated to reflux and the reaction mixture was further refluxed for 4 hours.The reaction progress was monitored by thin layer chromatography. The solvents were evaporated under reduced pressure and the residue was taken up in methanol, the methanol solution was refluxed for 90 minutes, and the solvents were evaporated.

I <

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 evaporated under reduced pressure. The title intermediate was further purified by liquid chromatography. Yield 108 mg.

NMR was consistent with the proposed structure of the title compound.

Preparation

Process for preparing 5- (2-fluoro-5-bromobenzyloxy) pentyl chloride

In a 50 mL flask, 2-fluoro-5-bromobenzyl alcohol (2.139 g, 10.4 mmol) was dissolved in Ν, Ν-dimethylformamide (25 mL) under a nitrogen atmosphere. To this solution was added sodium hydride (625 mg, 60%, 15.6 mmol) and the resulting mixture was stirred for 20 minutes. To the reaction mixture was added 5-chloropentyl bromide, and the resulting mixture was stirred at room temperature. room within 2 hours. The progress of the reaction was monitored by thin layer chromatography. Sodium iodide (3.127 g, 20.9 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with diethyl ether and washed seven times with brine. The solvents were evaporated under reduced pressure. The title intermediate was further purified on silica gel. Yield 1.82 g (56%).

NMR was consistent with the proposed structure of the title compound.

Preparation

A process for the preparation of N, N-dimethyl-5- (2-fluoro-5-bromobenzyloxy) pentylamine

- 151 F

· ','. _Λ% .1.V sealable tube under dusíkovou'atmosférou ^{1 'b} * Dissolve 5- (2-fluoro-5-bromobenzyloxy) pentylehlorid (0.380 g ,.

1.23 mmol) in N, N-dimethylformamide (5 ml). To this solution is added. Sodium iodide (55 mg, 0.368 mmol) was added and the resulting mixture was cooled to -78 ° C.

d-i-meth-y-lamin (- condensed under anhydrous conditions).

i '-' ·, · ► _t and seal the tube tightly. The mixture was heated to 85 ° C and stirred for 8 hours. The mixture was cooled to room temperature and stirred for an additional 12 hours. Nitrogen gas was bubbled through the mixture for 15 minutes and the excess dimethylamine was evaporated in ^1% . The reaction mixture was partitioned between 1M potassium carbonate * solution and methylene chloride. Aqueous fraction with return

1 ', extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate and the solvents were evaporated under reduced pressure. The title intermediate was further purified on silica gel. 'Preparation

A process for the preparation of N-methyl-5- (2-fluoro-5-bromobenzyloxy) pentylamine

- 152 -

In a 25 mL flask, N, N-dimethyl-5- (2-fluoro-5-bromobenzyloxy) pentylamine (696 mg, 1.87 mmol) was dissolved in dichloroethane (6.0 mL) under a nitrogen atmosphere. To this solution was added ACE.Cl (0.305 mL, 2.83 mmol) and the resulting mixture was heated to reflux. The reaction mixture was further refluxed for 20 hours. The reaction progress is ^"_ chromatograph monitored by thin layer chromatography. The mixture was refluxed for an additional 16 hours. The solvents were evaporated under reduced pressure and the residue was partitioned between 1M potassium carbonate solution 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 evaporated under reduced pressure. The title intermediate was further purified by liquid chromatography. Yield 248 mg.

NMR was consistent with the proposed structure of the title compound #.

Elemental analysis for C ₁₃ H ^ _g BrFNO (%): C, 51.33, H, 6.30, N, 4.60 Found: C, 51.06, H, 6.12, N, 4 , 49.

Preparation

Process for preparing 1- [2-fluoro-5-bromobenzyloxy] hexane i

153

In a 100 mL flask, n-hexanol (1.44 mL, 11.5 mmol) was dissolved in N, N-dimethylformamide (35 mL) under a nitrogen atmosphere. To this solution was added sodium hydride (521 mg, 60%, 13.0 mmol) and the resulting mixture was stirred for 10 minutes.

To the reaction mixture was added 2-fluoro-5-bromo-isyl bromide (2.054 g;

7.67 mmol) and the resulting mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1-M potassium carbonate solution and 1: 1 sodium chloride solution and diethyl ether. The organic fraction was washed six times with brine. The organic fraction was dried over sodium sulfate.

The solvents were evaporated under reduced pressure. The title intermediate was further purified by liquid chromatography. Yield 1.32 g.

AND

NMR was consistent with the proposed structure of the title compound.

Preparation

Process for preparing 1- (tert-butoxycarbonyl) -3- [2- (2-fluoro-5-bromobenzyloxy) ethyl] piperidine

154

Dissolve 2- [1- (tert-butoxycarbonyl) piperid-3-yl] ethyl bromide (1.011 g, 3.46 mmol) in Ν,)-dimethylformamide (9 mL) in a 25 mL round bottom flask.

Sodium iodide (1.037 g, 6.92 mmol) was added to the solution, and the resulting mixture was stirred for 10 minutes. To the reaction mixture was then added 2-fluoro-5-bromobenzyla-1-alcohol (- 0.852 µg, 4 - 15 µM) and sodium hydride (208 mg, 60%, 5.19 mmol) and the resulting mixture starts to foam and is exothermic. After 30 minutes, the solution was cooled and solidified. N, N-dimethylformamide (30 ml) was added to the reaction mixture, and the mass was suspended and stirred for an additional 3 hours. Method *

the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between sodium chloride solution and diethyl ether. The organic fraction was washed six times with brine and then dried over sodium sulfate. The desired title compounds are further purified by liquid chromatography. Yield 0.540 g.

NMR was consistent with the proposed structure of the title compound.

Preparation, 1

A process for preparing 3- [2- (2-fluoro-5-bromobenzyloxy) ethyl] piperidine

- 155 -

In a 1 ml round bottom flask, 1- (tert-butoxycarbonyl) -3- [2- (2-fluoro-5-bromobenzyloxy) ethyl] piperidine (0.495 g) was dissolved in methylene chloride (4 ml) under a nitrogen atmosphere. . The solution was cooled to 0 ° C and trifluoroacetic acid (1 mL) was slowly added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. Reaction progress: follow thin layer chromatography. The reaction mixture was partitioned between 1M potassium carbonate solution 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 evaporated under reduced pressure. The resulting residue was used as is. Yield 240 mg.

NMR was consistent with the proposed structure of the title compound.

Preparation

Process for the preparation of 1-hydroxymethyl-2- [2- (2-fluoro-5-bromobenzyloxy) methyl] cyclopropane

In a 100 mL round bottom flask, 1,2-di (hydroxymethyl) cyclopropane (398 mg, 3.90 mmol) was dissolved in N, N-dimethylformamide (15 mL). Sodium hydride (171 mg, 60%, 4.29 mmol) was added to the solution, and the resulting mixture was stirred at 0 ° C for 15 minutes and then at room temperature for 15 minutes. The reaction solution was cooled to 0 ° C and then 2-fluoro-5-bromobenzyl bromide (348 mg, 1.30 mmol) was added as a solution in N, N-dimethylformamide. The resulting reaction mixture was stirred at 0 ° C for 90 minutes and at room temperature for 30 minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between sodium chloride solution and diethyl ether. The organic fraction was washed seven times with brine and then dried over sodium sulfate. The title compound * can be purified by liquid chromatography. Yield 0.240 g (21%).

NMR was consistent with the proposed structure of the title compound.

Preparation

Process for preparing 1-bromomethyl-2- [2- (2-fluoro-5-bromobenzyloxy) methyl] cyclopropane.

- 157

In a flask, 50 ml of volume, dissolve 1-hydroxymethy 1-21 'i ¹ * ... fr A. · Ϊ́ »-, - [2- (2 ^x fluoro-5) -bromobenzyloxy) methyl ^, ] cyclopropane (420 mg,

1.45 mmol) 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) 'with stirring-at room temperature for 17 hours. The progress of the reaction was monitored by the addition of triphenylphosphine (0.19 mg) to the reaction mixture, which was followed by the addition of thromo-tartaric acid to the reaction mixture. carbon tetrabromide (0.241 mg). The reaction mixture was further stirred at room temperature for one hour and then the solvent was evaporated under reduced pressure. The title intermediate was further purified by flash chromatography. 0.389 g of compound is obtained in the form of a clear oil. Yield 76%.

Preparation

Process for the preparation of 1 - [(N-methylamino) methyl] -2- [2- (2-fluoro-5-bromobenzyloxy) methyl] cyclopropane

158 -

In a 100 mL flask, 1-bromomethyl-2- [2- (2-fluoro-5-bromobenzyloxy) 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 (1.9 mL, 2-M solution in tetrahydrofuran, 3.91 mmol). The resulting mixture was stirred at room temperature for 1 hour and then added to the additional C2-mL mixture. The resulting mixture was heated to reflux and maintained at reflux temperature. at this temperature for 4 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1M potassium carbonate solution 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 evaporated under reduced pressure. The title intermediate was further purified by liquid chromatography. 0.131 g of compound is obtained as a pale yellow oil. Yield 44%.

NMR was consistent with the proposed structure of the title compound.

Preparation

Process for preparing cis-4- (2-fluoro-5-bromobenzyloxy) but-2-en-1-ol

- 159 -

OH

In a 500 mL flask, 1,4-dihydroxybut-2-ene (6.13 mL, 74.5 mmol) was dissolved in Ν, Ν-dimethylformamide (150 mL) under a nitrogen atmosphere. Sodium hydride (2.98 g, 60%, 74.5 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then cooled to 0 ° C and 2-fluoro-5-bromobenzyl bromide (3.99 g, 14.9 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred at room temperature for 4 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1M potassium carbonate solution and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The desired title product is further purified by liquid chromatography. 2.145 g of compound is obtained as a clear oil. Yield 61%.

NMR and MS were consistent with the proposed structure of the title compound.

Preparation

A process for the preparation of cis-4- (2-fluoro-5-bromobenzyloxy) but-2-enyl bromide

160

In a 100 mL round bottom flask, 4- (2-fluoro-5-bromobenzyloxy) but-2-en-1-ol (2.145 g, 7.80 mmol) was dissolved in diethyl ether under a nitrogen atmosphere. To the resulting solution was added triphenylphosphine (2.66 g, 10.1 mmol) followed by carbon bromide (3.36 g, 10.1 mmol). The resulting mixture was stirred at ¹ room temperature for 6 hours. A white precipitate forms during stirring. The progress of the reaction was monitored by thin layer chromatography. The solution was filtered and the filtrate was evaporated to give a viscous oil. The desired title product is further purified by liquid chromatography. Yield 2.16 g (83%).

NMR and MS were consistent with the proposed structure of the title compound.

Preparation

Process for preparing cis-N-methyl-4- (2-fluoro-5-bromobenzyloxy) but-2-enylamine

161 -

In a 250 mL flask, 4- (2-fluoro-5-bromobenzyloxy) but-2-phenyl bromide (1.968 g, 5.89 mmol) was dissolved in dry tetrahydrofuran (40 mL). To this solution was added all at once, methylamine (29.5 mL, 58.9 mmol) and the resulting mixture was stirred at room temperature for 5 hours. The progress of the reaction was monitored by thin layer chromatography. The solvents were removed in vacuo and the residue taken up in 17M potassium carbonate solution and extracted three times with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were evaporated under reduced pressure. The desired title product is further purified by liquid chromatography. Yield 1.199 g (70%).

NMR and MS were consistent with the proposed structure of the title compound.

Preparation

Preparation of N- (tert-butoxycarbonyl) -4- (2-fluoro-5-bromobenzyloxy) butylamine>

AND-

162

In a 25 mL flask, 4- (tert-butoxycarbonylamino) butanol was dissolved in tetrahydrofuran (15 mL) under a nitrogen atmosphere. The solution was cooled to -40 ° C and then potassium tert-butoxide (2.14 mL, 1-M solution in tetrahydrofuran, 2.14 mmol) was added slowly. The resulting mixture was stirred at -40 ° C for 30 minutes. To this reaction mixture was added dropwise 2-fluoro-5-bromobenzyl bromide (521 mg, 1.94 mmol) as a solution in tetrahydrofuran (3.5 mL). The resulting mixture was slowly warmed to 0 ° C and stirred at this temperature for 2 i

hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1M potassium carbonate solution 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 evaporated under reduced pressure. The desired intermediate is further purified by liquid chromatography. 335 mg of a yellow oil compound are obtained. Yield 46%.

Elemental analysis for ^C 16 ^H 23 ^BrFNO 3 Calcd: C, 51.07, H, 6.16, N, 3.72. Found: C, 51.18, H, 6.18, N, 3.80.

Preparation

A process for preparing 4- (2-fluoro-5-bromobenzyloxy) butylamine

- 163 fr · ·

In a 250 mL flask, N- (tert-butoxycarbonyl) -4- (2-fluoro-5-bromobenzyloxy) butylamine (3.5 g) was dissolved in methylene chloride (60 mL) under a nitrogen atmosphere.

Trifluoroacetic acid (15 mL) was added to the solution at 0 ° C. The resulting mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 15 minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1M potassium carbonate solution 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 evaporated under reduced pressure. The desired intermediate is further purified by liquid chromatography. Yield 1.82 g.

NMR was consistent with the proposed structure of the title compound.

Preparation

Process for preparing 4-methyl-1H-indole-2-carboxylic acid

4-Methylindole (0.91 g, 6.96 mmol) was dissolved in tetrahydrofuran (12 mL) under an argon atmosphere. The resulting solution was cooled in a bath of carbon dioxide (dry ice) and acetone. To this solution was carefully added n-butyllithium

164 (4.48 mL, 1.6-M solution in hexanes, 7.17 mmol) and the resulting mixture was stirred for 50 minutes. Carbon dioxide was bubbled through 26 ml of tetrahydrofuran in a carbon dioxide (dry ice) and acetone bath for 20 minutes. A cold solution of carbon dioxide in tetrahydrofuran was added to the organolithium solution via the lance. Carbon dioxide was bubbled through the reaction mixture and the resulting mixture was stirred for 30 minutes in a carbon dioxide (dry ice) and acetone bath. The reaction mixture was then stirred at room temperature for 10 minutes with continuous carbon dioxide bubbling. The carbon dioxide feed was discontinued and the reaction mixture was stirred at room temperature for 90 minutes.

^The solvents were evaporated under reduced pressure and argon was introduced into the reaction vessel. The reaction vessel was then rinsed with tetrahydrofuran (5 mL). The solvents were evaporated under reduced pressure and the brown solid obtained was stored at 4 ° C overnight under argon atmosphere.

The residue was then dissolved in hot tetrahydrofuran (12 mL) and the resulting solution was cooled in a bath of carbon dioxide (dry ice) and acetone. Tert-Butyl lithium (4.22 mL, 1.7-M solution in pentane, 7.17 mmol) was carefully added to this solution over 15 minutes. The resulting mixture was allowed to stir for about 70 minutes in a bath of carbon dioxide (dry ice) and acetone. Carbon dioxide was bubbled into a separate vessel with 26 ml of tetrahydrofuran cooled in a bath of carbon dioxide (dry ice) and acetone. A solution of carbon dioxide in tetrahydrofuran was added via an introduction tube to the organolithium solution. Carbon dioxide was directly bubbled through the reaction mixture for an additional 5 minutes. The reaction mixture was then stirred in a bath of carbon dioxide (dry ice) and acetone for 1 hour, after which carbon dioxide was bubbled through the reaction mixture for 30 minutes. Reaction

Water (1 mL) was further added to the mixture and allowed to stir at room temperature for several hours.

The reaction mixture was poured into saturated ammonium chloride solution and extracted twice with diethyl ether. The organic fractions were combined and the solvents were evaporated under reduced pressure and recrystallized from water. This afforded the desired intermediate (0.17 g). The aqueous fraction was acidified by the addition of 5% sulfuric acid and stirred at room temperature for 1 hour. The solids were filtered off to give the next desired title intermediate (0.48 g).

NMR was consistent with the proposed structure of the title compound.

Preparation

Method for the preparation of methyl (4-methyl-1H-indole-2-carboxylate)

4-Methyl-1H-indole-2-carboxylic acid (0.64 g, 3.65 mmol) was dissolved in 20 mL of methanol under argon. Concentrated sulfuric acid (0.5 mL) was added to the reaction mixture 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 evaporated under reduced pressure and the resulting crystals were filtered off. The solids were taken up in diethyl ether and washed twice with saturated sodium bicarbonate solution and then once with brine. The organic fraction was dried over magnesium sulfate and the solvents were evaporated under reduced pressure. Yield 0.38 g (55.1%).

Preparation

166

Preparation of 2- (4-chlorophenoxymethyl) -3- (2-bromoacetyl) -1H-indole

Under a nitrogen atmosphere, bromoacetyl bromide (1.31 mL, 0.015 mole) was added to a suspension of 2- (4-chlorophenoxymethyl) -1Η-indole (0.81 g, 0.003 mole) and lithium carbonate (2.22 g, 0 M). , 03 mol) in diethyl ether (37.5 ml). The resulting mixture was heated to 55 ° C. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between diethyl ether and sodium bicarbonate solution. The organic fraction was washed with water and then brine, then dried over sodium sulfate. The solvents were evaporated under reduced pressure. Yield 1.34 g.

NMR was consistent with the proposed structure of the title compound.

• ¹

Preparing "

2- (4-Chlorophenoxymethyl) -3- [2- / 4- (piperid-1-yl) piperid-1-yl] acetyl] -1H-indole

To a suspension of 2- (4-chlorophenoxymethyl) -3- (2-bromoacetyl) -1H-indole (3 mmol) and lithium carbonate (0.47 g, 6 mmol) in tetrahydrofuran (10 mL) was added 4- (piperidine- 1-yl) piperidine (1.01 g, 6 mmol). 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 three times with 1 N hydrochloric acid. The combined acid extracts were extracted with ethyl acetate, then basified with sodium carbonate, then extracted twice with ethyl acetate, and then extracted twice with methylene chloride. Organic fractions

The combined solvents were evaporated and the solvents were evaporated under reduced pressure. After trituration with diethyl ether, the desired title compound (0.46 g) is obtained as a crystalline solid.

NMR, IR, and UV were consistent with the proposed structure of the title compound. , · '

... ..

. '...

γ _λ __ · * k 'λ ¹ i. »

Exact FAB Mass for ^C 28 ^H 35 ^C1N 3 ° 2 ^: ,. calculated: 480.2418, ⁴ \ '· \ ..

found: 480.2411.

· / '.. ** ·' 1! ' ’··’ '. <'μ.

I l r,,

FD MS: 479 (M ^& lt ^{; +} & gt ^; ). . ;

Mp 144-145 ° C. · /

---- Dai-uyedené - When ^{ki-series-to-carry-in} "," substantially "j'ák" is _V '· _»R' f H described in Scheme A, the methods described above. In the examples below, NMR spectra are consistent with the proposed structure of the compounds named in the title, unless otherwise indicated. . ··· '' t '-F ^1,

T ‘/ ··!. ·. > '? / - -. ‘’.

. Example 1: Process for the preparation of 2-E (4-chlorophenoxy) methyl] -1-methyl-3- (amino) methyl-1H-indole.

NMR (CDCl 3) was consistent with the proposed structure of the title compound.

. · ¹ '\' · In 't ·' ^J

AND

168 FD MS 300 (M ^& lt ^{; +} & gt ^; ).

*

Elemental analysis for C ₁₇ H ₁₇ ClN ₂ O (%):

calculated: C, 67.88; H, 5.70; N, 9.31. Found: C, 67.64;? / 5.86; N, 9.24.

Example 2 ₍ .

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(N, N ¹ .

(dimethylamino) methyl] -1H-indole; . .. '' ^r

NMR (CDC1 _3), a phenomenon consistent with the proposed structure of compound 'give the. Title compound.

FD MS 328 (M ⁴⁾ .. \

Elemental analysis for ^C 19 ^H 21 ^ClN 2 ° (%) ^: calculated: C, 69.40, H, 6.44, -N, 8.52, found: c, 69.18, H, 6.73, N, 8.54.

Example 3

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(N, N'-diethylamino) methyl] -1H-indole hydrochloride

NMR (DMSO) was consistent with the proposed structure of the compound

- 169 named in the title.

FD MS 356 (M ^& lt ^{; +} & gt ^; ). '

Elemental analysis for ^C 21 ^H 25 ^C1N 2 ° 2 * ^HC1: C, 64.12, H, 6.66, N, 7.12, found:. C, 64.30, H, 6.69, N, 7.18.

'i. T · * ·'

Example 4. . , ·.

NMR (DMSO) was consistent with the proposed structure of the compound

1. '. '. _ named in the title. · - -; ] • * ~ '1 .fd · MS 343 (M ⁺⁾ · .. * ^4'.

Elemental Analysis for 20 ¢ ^ ⁴⁰¹¹ ^ ^{1 i%):} C, 51,0.3, H, 5.14, N, 5.95 ,. Found: C, 50.80, H, 4.93, N, 6.00. _; ., ':. F

Example 5. . * · · '

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3-

- [(benzylamino) methyl] -4-indole hydrochloride

I Jr

170

HN

- ^for Cl

Cl

NMR (DMSO) was consistent with the proposed structure of the title compound.

FD MS 390 (M ^& lt ^{; +} & gt ^; ). \

Elemental analysis for C 24 H 23 ClN 2 O · HCl (%): Calculated: C, 67.45, H, 5.66, N, 6.56. Found: C, 67.63, H, 5.70, N, 6.60.

Example 6

Process for preparing 2 - [(4-chlorophenoxy) methyl) -1-methyl-3 - [(2-phenylethylamino) methyl] -1H-indole hydrochloride

Cl HCl

NMR (DMSO) was consistent with the proposed structure of the title compound.

171

FD MS: 404 (M @ ⁺ .

Elemental analysis for C 25 ^H 25 ^ClN 2 ^{O · Hcl} (%): Calculated: C, 68.03, H, 5.94, N, 6.35. Found: C, 68.27, H, 5.99, N , 6.60.

NMR (CDCl 3) was consistent with the proposed structure of the title compound.

¹ ..

It is consistent with the desired structure) of the compound named _f in the title. ^; . ·,

FD MS 370 (M ^& lt ^{; +} & gt ^; ). Elemental analysis for C ₂₂ H ₂₇ C ₂ O 6%: Calculated: C, 71.24, H, 7.34, N, 7.55. Found: C, 71.19, H, 7.48. N, 7.39.

Example 8

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(N-methyl-N-benzylamino) methyl] -1H-indole hydrochloride

NMR, IR, and UV were consistent with the desired structure of the title compound.

FD: MS 404 (M ^& lt ^{; +} & gt ^; ). '

Elemental Analysis for C2 ₅ H ₂₅ C1N ₂ O.HC1 (%):

Calculated: C, 68.03, H, 5.94, N, 6.35, Le from the eno <^ - 6 8-3 _0-H-T 5 9 2 'Νχ6ν4-5τ .-- Example 9

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[N -methyl-N- (3-N ', N'-dimethylaminopropyl) amino] methyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound ..

FD-MS 400 (M ^{+ 1} ).

Elemental analysis for ^c 23 ^H 30 ^clN 3 ^O:

Ϊ73 calculated: C, 69.07, H, 7.56, N, 10.51. Found: C, 69.33, H, 7.34, N, 10.41.

Example 10

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[N-methyl-N- [3- (N ', N'-dimethylamino) -2,2-dimethylpropyl / amino] methyl] 1H-indole

Ϊ

NMR (CDC1 ₃₎ was consistent with the proposed structure of compound 'title.

FD MS 414 (M ^{+ 1} ).

Elemental analysis for C ₂₄ H ₃₂ ClN ₃ O (%): Calculated: C, 69.93, H, 7.79, N, 10.15. Found: C, 69.67, H, 7.78, N, 10.17.

Example 11

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(pyrrolidin-1-yl) methyl] -1H-indole hydrochloride

- 174 -

NMR (CDC1 ₃₎ is consistent with, the proposed structure of the title compound. . . . ^; FD MS 354 (M ^& lt ^{; +} & gt ^; ). \ 7 <. '. / / ' _L :

>. ···. N, 7.16. Found: C, 64.66; H, 6.33; N, 7. Elemental analysis for: C, 64.4; H, 6.18; N, 7.16. , 03.

Example 12. . \

Process for preparing 2-7 (4-chlorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride f.

NMR, IR and UV were consistent with the desired structure of the title compound.

FD MS 368 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₂ H ₂₅ ClN ₂ O · HCl (%): Calculated: C, 65.19, H, 6.46, N, 6.91. Found: C, 65.46, H, 6.52. N, 7.16.

•IN

- 175 Example 13

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(3-methylpiperid-1-yl) methyl] -1H-indole

NMR (DMSO) was consistent with the proposed structure of the title compound.

FD MS 382 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis (for C C ^H HFNCTO Ú):

H, 7.11; N, 7.32. Found: C, 72.38; H, 7.22; N, 7.36.

Example 14

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- (4-methylpiperid-1-yl) methyl] -1H-indole

NMR (DMSO) was consistent with the proposed structure of the title compound.

FD MS 382 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₃ H ₂₇ ClN ₂ O (%):

H, 7.11; N, 7.32. Found: C, 72.33; H, 7.22; N, 7.47.

Example 15

2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[4- (Ν, N-dimethylamino) piperid-1-yl] methyl] -1H-indole

NMR (DMSO) was consistent with the proposed structure of the title compounds. ,

FD MS: 411 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 24 ^H 30 ^ClN 3 ° Calculated: C, 69.97; H, 7.34; N, 10.20. Found: C, 69.74; H, 7.38; N, 10.13.

_t Example 16

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[4- (piperid-1-yl) piperid-1-yl] methyl] -1H-indole

J '

Elemental analysis for C ₂₇ H ₃₄ ClN ₃ O (%): Calculated: 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, 4-acetamido ^L féhylpiperid-yl) methyl] -lH-indole

Elemental analysis for C ₃₀ ^H 32 ^ClN 3 ° 2 calculated: C, 71.77, H, 6.43, ν, 8.37, found: C, 71.79, H, 6.61, N, 8.52.

Λ *. . Example 18. ' ^:

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(4-, ethyl-piperazin-1-yl) methyl] -1H-indole

NMR (CDCl 3) was consistent with the proposed structure of compound • X

178 in the title.

FD MS 383 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₂ H ₂₆ ClN ₃ O (%):

calculated:. H, 6.83; N, 10.95. Found: C, 68.80; H, 6.71; N, 10.95.

Example 19 · .1 ’'

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(4-isopropylpiperazin-1-yl) methyl] -1H-indole

NMR (CDCl ₃ ) was consistent with the proposed structure of the title compound.

*

FD MS: 411 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₄ H ₃₀ clN ₃ O (% j:

H, 7.34; N, 10.20. Found: C, 69.97; H, 7.36; N, 10.02.

Example 20

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(4-phenylpiperazin-1-yl) methyl] -1H-indole

1 - 179 - t r '1 ¹ · ΌΌ vel '... 'I ·' CHy ⁱⁿ '« ’* NMR was consistent with the desired structure of the compound named in the title / ? '. ‘. FD MS 445. (M ^& lt ^{; +} & gt ^; ). * 11 '' · * In ', i ' * · ' Elemental analysis for ^C 27 ^H 28 ^ClN 3 ° ( ^% ) ^{: C} C, 72.71; H, 6.33, N, 9.42 found: C, 73.00, H, 6.41; N, 9.51. '’

Example 21. . .

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(4-benzylpiperazin-1-yl) methyl] -1H-indole-hydrochloride

NMR (DMSO) was consistent with the proposed structure of the title compound.

FD MS: 459 (M ^& lt ^{; +} & gt ^; ).

Exact weight (FAB ⁺ ) for C ₂ qH ₃₁ Č1N ₃ O:

calcd, 460.2155, found 460.2145. *. .1.

180

Example 22

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(4-cyclohexylpiperazin-1-yl) methyl] -1H-indole

NMR (DMSO) was consistent with the proposed structure of the title compound. ___ '_

FD MS: 451 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 27 ^H 34 ^C1N 3 ° Calculated: C, 71.74, H, 7.58, N, 9.30 Found: C, 71.48, H, 7.53, N, 9.26.

and

Example 23

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[4- (pyrimid-2-yl) piperazin-1-yl) methyl] -1H-indole

NMR (CDCl3) was consistent with the proposed structure of the title compound.

FD MS: 447 (M ^& lt ^{; +} & gt ^; ). ·

Analysis for ^C 25 ^H 26 ^ClN 5 ° (%): Calculated: C, 67.03; H, 5.85; N, 15.63. C, 67.05; H, 5.93; N, 15.64.

... ⁱ ·, .. ', Example 24. ; ί ' ^T. . - '. Ί ^: ·, · ''. '

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(morpholin-4-yl) methyl] -1H-indole. .. * ·; -. / '

NMR was consistent with the desired structure of the title compound. '.

FD MS -370 (M ^& lt ^{; +} & gt ^; ). '''. ix ·, '·' *. · «, ¹ '· ·' Elemental analysis for C ₂₁ H ₂₃ ClN ₂ O ₂ (%):

H, 6.25; N, 7.55; Found: C, 67.84, H, 6.65. N, 7.25.

• '' ¹ · «·» ···· '

Example 25

Method for the preparation of 2- [K-chlorophenoxy) methyl] -1H-methyl-3-, - [(tryptolin-2-yl) methyl] -1H-indole

- 182 -

NMR (CDCl 3) + is consistent with the proposed structure of the title compound. ’\

FD MS: 455 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₈ H ₃ O ₂ gClN (%) :, '. C, 73.75; H, 5.75; N, 9.21. Found: C, 73.99; H, 6.00; N, 9.03.

Example 26. '·. .

I P. · ^ ^ · - J

Method for preparing 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3 - [[N- (1-methylpiperid-4-yl) -N-methylamino] -] monohydrate. . '*,. and

-methyl] -1H-indole dihydrochloride

NMR was consistent with the desired structure of the title compound.

Mp 196-197 ° C.

FD MS: 446 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis, for C ₂₄ H ₂ gCl ₂ N ₃ O.2 HCl · H ₂ O, (%):

183 Calcd: C, 53.64; H, 6.19; N, 7.82. Found: C, 53.66; H, 5.92; N, 8.10.

Example 27

Method for the preparation of 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3 - ([4- (Ν, N-dimethylamino) piperid-1-yl) methyl] -1H-indole

NMR, IR and UV were consistent with the desired structure of the title compound.

Mp 105-106 ° C.

FD MS: 445 (M ^& lt ^{; +} & gt ^; ). Elementární'analýza for C ₂ 4H ₂ GCL ₂ N ₃ O (%):

Calcd: C, 64.57; H, 6.55; N, 9.41;

Found: C, 64.27, H, 6.48, N, 9.49.

Example 28

Method for the preparation of 2 - [(2,4-dichlorophenoxy) methyl) -1-methyl-3 - ([4- (piperid-1-yl) piperid-1-yl) methyl] -1H-indole

- 184 -

NMR, IR and UV were consistent with the desired structure of the title compound.

FD-MS 485 (M ^& lt ^{; +} & gt ^; ).

Mp 106-107 ° C.

Elemental analysis for ^C 27 ^H 33 ^Cl 2 ^N 3 ^O calculated: C, 66.66, H, 6.84, N, 8.64. Found: C, 66.92, H, 7.04, N, 8.74.

Example 29

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- (2-aminoethyl) -1H-indole

NMR (CDC1 ₃₎ was consistent with. The proposed structure of the title compound.

FD MS 314 (M ^& lt ^{; +} & gt ^; ).

Exact Mass (FAB) for ^C 18 ^H 2 O ^C - ^ln 2 ° Calculated: 315.1264, Found: 315.1246.

Example 185

Method for the preparation of 2 - [(4-chlorophenoxy) methyl) -1-methyl-3- [2- [(3-dimethylaminopropyl) amino] ethyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD: MS 399 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₃ H _{3 3} 0 oClN (%):

C, 69.07; H, 7.56; N, 10.51. C, 69.23; H, 7.79; N, 10.52.

Example 31

2-f (4-Chlorophenoxy) methyl] -1-methyl-3- [2- (N-methyl-N- (3-dimethylaminopropyl) amino) ethyl] -1H-indole dihydrochloride

NMR (DMSO) was consistent with the proposed structure of the compound

186 named in the title.

FD MS: 413 (M ^& lt ^{; +} & gt ^; ).

Exact Weight (FAB) for C ₂₄ ^h 33C1N ₃ o:

calcd: 414.2312, found: 414.2312.

Example 32, ¹ , *

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (piperid-1-yl) ethyl] -1H-indole

named in the title. MS F 382 (M ⁺ )

Elemental analysis, for ^C 23 ^H 27 ^N 2 ^C ^ ° Calculated: C, 72.14, H, 7.11, N, 7.32 Found: C, 72.40, H, 7.26, N, 7.37.

Example 33

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (4-methylpiperid-1-yl) ethyl] -1H-indole

187 _CH3

Cl

NMR (CDCl 3) was consistent with the proposed structure of the title compound.

FD MS 396 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 24 ^H 29 ^ClN 2 ° Calculated: C, 72.62, H, 7.36, N, 7.06. Found: C, 72.40, H, 7.35, N, 7.25.

Example 34

Preparation method. 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (4-benzylpiperid-1-yl) ethyl] -1H-indole

Cl

NMR (CDCl3) was consistent with the proposed structure of the title compound.

FD MS: 472 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 30 ^H 33 ^ClN 2 °

H, 7.03; N, 5.92. Found: C, 76.37; H, 7.15;

Example 35

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- / 4- (ethy, N-dimethylamino) piperid-1-yl] ethyl] -1H-indole

N _{(CH3) 2}

Cl

NMR (CDCl ₃ ) was consistent with the proposed structure of the title compound. ,

Exact Mass (FAB) for C ₂₅ H ₃₃ ClN ₃ O: Calculated: 426.2312.

found: 426.2297.

Example 36

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- / 4- (piperid-1-yl) piperid-1-yl] ethyl] -1H-indole

- - 190 -

FD MS 465 (M ^& lt ^{; +} & gt ^; ). '

Elemental analysis for ^C 28 ^H 36 ^ClN 3 ^O 4 ^: Calculated: C, 72.16; H, 7.79; N, 9.02 _; . . .

found:. C, 72.09; H, 7.69; N, 9.09.

»»

I · 1,

Example 37

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (4'-cyclohexylpiperazin-1-yl) ethyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS: 465 (M ^& lt ^{; +} & gt ^; ).

fb • Λ

-190 <<Γ ·,

Elemental analysis for ^C 28 ^H 36 ^{C N} ° ^3: Calc: C, 72.16, H, 7.79, / N, 9.02 Found :, C, 72.00; H, 7.88; N, , 9.05. .

h> Λ

Example 38 . . i *

Method for the preparation of 2 - [(2,4-dichlorophioxy) methyl] -1-methyl-3- [2- / N-methyl-N- (1-methylpiperid-4-yl) / ethyl] -1H-indole

* * ' .... Ϊ _T Ί w. ^f '' h ₃ c, - '. TO- ΐ and ’1 and, N - CH3 < ^Γ t • Mři • N | CL ^Ox A . r. ' 'ch ₃ ' r \. . °, II ^ Cl OF and* r 'Jť · • --------- NMR (CDC1 ₃₎ is in accordance with the proposed structure of the compound , T named in the title. - ' 4 FD MS: 459 (M ^& lt ^{; +} & gt ^; ). · Elementary Analysis for 'C ₂₅ H ₃₁ ' or ₂ n ₃ ° calculated: C, 65.21, H, 6.79 , .N, 9, 13/ : .,· ' found: C, 65.07, H, 6.85 , N, 9, 06 /

Example 39 ‘

Preparation of 2 - [(2,4-dichlorophenoxy) methyl) -1-methyl-3- [2- / 4- (N, N-dimethylamino) piperid-1-yl] ethyl] -1H-indole

NMR (CDCl ₃ ) was consistent with the proposed structure of the title compound. , *

Exact mass calcd for ^C 25 ^C 32 ⁱ ^ - ^ ^S 2 ^{O 3:} Calc '460.1922,. »Found: 460.1890.

Example 40

2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3- [2- / 4- (piperid-1-yl) piperid-1-yl] ethyl] -1H-indole

NMR (ČDC1 ₃₎ was consistent with the proposed structure of the title compound.

Exact weight for C ₂₈ H ₃ gCl ₂ N ₃ O: ,,

192calculated: 500.2235, found: 500.2215.

Example 41

2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [3- / 4- (Ν, N-dimethylamino) piperid-1-yl] propyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

IR was consistent with the desired structure of the title compound.

FAB MS 440 (M ^{+ 1} ).

Elemental analysis for ^C 26 ^H 34 ^C1N 3 ° Calculated: 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- (piperid-3-yl) propyl] -1H-indole

- 193 '- ·

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

t

Exact ¹ mass for ^C 24 ^H 30 ^ClN 2 ° ^: calculated: 397.2047, found: 397.2055.

Example 43

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2 - [[4- (dimethylamino) piperid-1-yl] carbonyl] ethyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

IR were consistent with the desired structure of the title compound.

FD MS: 453 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 26 ^H 32 ^ClN 3 ° 2 Calculated: C, 68.78, H, 7.10, N, 9.26. Found: C, 68.74, H, 7.04, N, 9.38. .

Example 44 Tf. .

Preparation of 2- [. (4-Chlorophenoxy) methyl] -1-methyl-3- [2 - [[4 '] (dimethylamino) piperid-1-yl] carbonyl-lethenyl] -1H-indole * _f .

*> ·. . ·>

. '·% ·

N MR (CDCl, consistent with the superimposed structure of the title compound.

Exact Mass (FAB) for ^C 26 ^H 31 ^ClN 3 ° 2 ^: calculated: 452.2105, found: 452.2099.

Example 46 _: >

Process for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-2 - [(3-acetanido) pyrrolidin-1-yl] ethyl] -1H-indole

(CDCl ₃ ) is consistent with the proposed structure for the title compound. , ·

195

FD MS: 442 (M ^& lt ^{; +} & gt ^; ).

-Exact weight FAB (M ⁺¹ ) for C ₂₄ H ₂₉ C1N ₃ O ₃ :

calculated:

Ť.

found:

442.1897,

442.1878.

4 '...

Example 47 ·.

'' - .. Λ -. . ',

Process for preparing 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [1- _? -hydroxy-2- (piperid-1-yl) ethyl] -1H-: indole ⁷ '-

v i

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound. , -, ·,,

FD MS 398 (M ^& lt ^{; +} & gt ^; ).

Elemental Analysis, Pro. 23i ^{C I} 27 ^C1N 2 ° 2 ^'Calculated: C, 69.25, H, 6, '82; N, 7.02' * · f. '.

Found: "C, 69.51, H 6. 86, N 6.81 _r. '7' • '' J · '

Example 48

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [1 ']

hydroxy-2- (4-methylpiperid-1-yl) ethyl] -1H-indole

- 196 -7

NMR (CDC1 _3). is consistent with the proposed structure of the title compound. 7 FD MS · 412 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 2 ₄ H ₂₉ C1N ₂ O 2. (%): \.

H, 7.08; N, 6.78. Found: C, 70.02; H, 7.13; N, 7.00.

Example 49 ϊ,. · Method of preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-2- (4-benzylpiperid-1-yl) ethyl} -1H-indole

NMR (CDCl3) was consistent with the proposed structure of the title compound.

197 F

FD MS.488 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C 90 H 94 N 4 (%):

calculated: C, 73.67, H, 6.80, N, 5.73. Found: C, 73.52, Ή, 6.87, N, 5.58.

Example 50 i;

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-ethyl-3T [1-hydroxy-2- (4-dimethylaminopiperidin-1-yl) ethyl] -1H-indole

NMR (CDCl3) was consistent with the proposed structure, the title compound.

IR was consistent with the desired structure of the title compound. ·· '..- *

FD MS: 442 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 25 ^H 32 ^ClN 3 ° 2 Calculated: C, 67.94, H, 7.30, N, 9.51. Found: C, 67.73, H, 7.52, N, 9.75. .

Example 51

Method for the preparation of 2 - [(4-chlorophenoxy) methyl) -1-methyl-3- [1-hydroxy-2- [4- (piperid-1-yl) piperid-1-yl] ethyl] -1H-indole dihydrochloride F

- 198-- ^-

<. Named in the title.

FD MS 481 (M ^{+ 1} ) ⁺ .

Elemental analysis for ^c ₂₈ H ₃₅ ClN ₃ O ₂ · 2 HCl (%): calculated: 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 · ····. ··, · ·

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-2- (4-cyclohexylpiperazin-1-yl) ethyl] -1H-indole

NMR: (CDCl ₃ ) was consistent with the proposed structure of the compound.

- 199 named in the title.

FD MS 482 (M ^{+ 1} ). . ,

Elemental analysis for C 8 ^H 36 ₂ 3 ° ^C1N 2 S *> ^Calculated: C, 69.76, H, 7.53, N, 8.72 Found: C, 70.06; H, 7.61; N, 8.46.

• I * i. ,.

Example 53

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [1,1-hydroxy-3- (piperid-4-yl) propyl] -1H-indole ^.

J-.

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

j. '. , · ». ·. ··, ·. '····' ···· · ·>

FD-MS 412 (M ^& lt ^{; +} & gt ^; ). . .

It is the only compound of high purity as is. according to chromatographic methods. · F

Elemental analysis for C 24 ^H 29 ^{C 1} N 2 ° 2 (%):

H, 7.08; N, 6.78. Found: C, 68.18; H, 7.87; N, 6.58.

Example 54

Method for the preparation of 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-2- / N-methyl-N- (1-methylpiperid-4-yl) amino] ethyl] - 1H-indole. . , V ~

- 200 -

named in the * headings. FD MS: 475 (M ^& lt ^{; +} & gt ^; ). '* ·' Í '·

Elemental analysis for ^ 25 ^ 31 ^ 2 ^ 302 (¾):

Calcd. 63.02, H, 6.55, N, 8.82. Found: G, 63.43, H, 6.88, N, 8.92.

J *

Example 55.

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [1]. <'V. . · '#

-hydroxy-2- (methoxycarbonyl) ethyl] -1H-indole.

C ₃ ', CH ₃ w.

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

IR was consistent with the desired structure of the title compound.

FD MS 373 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₀ H ₂₀ ClNO ₄ (%):

• Ί

Calcd: C, 64.26;,, 5.39, N, 3.75. Found: C, 64.55, H, 5.23, N, 3.79.

Example 56. t

Process for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3-carboxy-1H-indole

Cl

NMR (DMSO) was consistent with the desired structure for the title compound.

FD MS 315 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ^ HH- ^ClNO-(%):

Calcd: C, 64.67, H, 4.47; N, 4.44. Found: C, 64.84; H, 4.60; N, 4.54. ,

Example 57 ‘· '····, ...

Method for the preparation of 2 - [(4-chloro-phosphoxy) -methyl] -1-methyl-3 - [(3-dimethylamino-2,3-dimethyl-propylamino) -carbonyl] -1H-indole

NMR (CDCl 3) was consistent with the proposed structure of the compound

F>;

w pS '' ·

202 named in the title.

FAB 426 (M ^1).

Elemental analysis for ^C 24 ^H 30 ^ClN 3 ° 2 Calculated: C, 67.36, H, 7.07, N, 9.82. Found: C, 67.58, H, 6.79, N, 9, 64.

Example 58. ,

Preparation of 2 - [(4-chlorophenoxy) methyl) -1-methyl-3 - [[N, N-bis (3-dimethylaminopropyl) amino] carbonyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS 483 ( ^-1 ),

FAB MS 485 (M ^{+ 1} ).

Elemental analysis for ^C 27 ^H 37 ^C1N 4 ° 2 requires C, 66.86, H, 7.69, N, 11.55 Found: C, 66.91, H, 7.54, N, 11.69 .

Example 59

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[N -methyl-N- (1-methylpiperid-4-yl) amino] carbonyl] -1H-indole

203 -

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS: 427 (M + ² ). . .

Elemental analysis for ^C 24 ^H 28 ^ClN 3 ° 2 Calculated: C, 67.67, H, 6.63, N, 9.86. Found: C, 67.38, H, 6.90, N, 9.94. .

Example 60

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[4- (piperid-1-yl) piperid-1-yl] carbonyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS: 465 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 27 ^H 32 ^C 1 ^N 3 ° 2 (*):

H, 6.92; N, 9.02. Found: C, 69.47; H, 7.00; N, 9.22.

Example 61.

Method for preparing (RS) -2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(piperid-3-yl) acetyl] -1H-indole

NMR (CDCl3) was consistent with the proposed structure of the title compound.

FD MS 396 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^H 25 ^ClN 2 ^O 2 calculated: C, 69.60, H, 6.35, N, 7.06. Found: C, 69.71, H, 6.28, N, 7.20. .

'· $

Example 62

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(1-tritylpiperid-4-yl) acetyl] -1H-indole

NMR (CDCl ₃ ) was consistent with the proposed structure of the compound

- 205 -:

named in the title.

FD MS.638 (M ^& lt ^{; +} & gt ^; ). . '. ''.

^Elementary analysis for ^C 42 ^H 39 ^C1N 2 ° 2 requires C, 78.92, H ,, 6.15; N, 4.38 Found: C, 78.73, H, 6.15, N, 4 , 25. ¹ _; ·· '. ·'

Example 63. \ · F '·' Process for the preparation of 2- [(4: chlorophenoxy) methyl] -l-methyl-3- ^{[(piperidin-4:} yl) -acetyl] -lH-indole ¹ 7 ¹ · f * ^'J í ^{1 v} · *

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS - 397 (Μ ⁺¹ ). . . \, '; i * '····,'. · - ·

Elemental analysis for ^C 23 ^H 25 ^ClN 2 ° ^J 2 Calculated: C, 69.60, H, 6.35, N, 7.06 Found: C, 69.34, H, 6.43, N, 6, 86.

Example 64

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[4- (piperid-1-yl) piperid-1-yl] acetyl] -1H-indole dihydrochloride

- 206 -

NMR (DMSO) was consistent with the proposed structure of the title compound.

FD MS: 479 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₈ H ₃ 4C1N ₃ O ₂ .HCl .2 (%):

H, 6.56; N, 7.60. Found: C, 60.67; H, 6.70; N, 7.38.

in

Example 65 ’Λ ·

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[2- (piperid-3-yl) ethyl] carbonyl] -1H-indole

NMR (CDC1 _3), a phenomenon consistent with the proposed structure of the title compound.

FD MS: 411 (M ^{+ 1} ).

Elemental analysis for ^C 24 ^H 27 ^CLN 2 ° 2 requires C, 70.15, H, 6.67, N, 6.82;

1 ·. ·. ’

t - / 207

Found: C, 70.38, Η, 6.39, N, 7.021

Example 66

Method for the preparation of 2 - [(4-chlorophenoxy) methyl) -1-methyl-3- [2- (1-tritylpiperid-4-yl) ethyl] carbonyl] -1H-indole *

. · '' \ v; . ‘J '- / \. NTr \ ·. . '^;  Ý if * ·! 'j - '*  A-O . <* i 1 if ¹ - I 5. ' ^Ί to 'ch < 1 ^To C1 ', ·''. . H · · NMR (CDC1 ₃₎ 'is in accordance with designed structure of the compound named in the title.

^C 43 ^H 41 ClN ₂ ^O 2 ^FD MS ' ₆ S ₂ (M ⁺ ). '

It is the only compound of high purity, as seen by chromatographic methods. .

'' ^ř '''' ¹

Example 67 ¹ v. · F - 7

Preparation of 2 - [(4-chlorophenoxy) methyl] -1H-ethyl-3 - [[2- (piperid-4-yl) ethyl] carbonyl] -1H-indole.

NMR (CDCl3) was consistent with the proposed structure of the title compound. ..

FD MS: 411 (M ^{+ 1} ).

208 Elemental analysis for ^C 24 ^H 27 ^ClN 2 ° 2 ^: Calculated: C, 70.15; H, 6.62; N, 6.82. Found: C, 69.87; H, 6.54; , 6.79.

L · 4 ' '. .

í '' ^J * ''. ,> ^r ·. * · • -Λ. '·.''. · 'R.

Example 68. . Preparation of 2 - [(4-chlorophenoxy / methyl) -1-ethyl-3 - [[2R [1- [3 -] (1-tritylpiperid-4-yl) propyl] piperide -4-yl]] ethyl · 1 -, carbonyl] -1H-indole -.

NTr

FD MS .779 (M ⁺² )

* ' ¹

Elemental 'Analysis ^ 51 ^H 56 ^C1N 3 ^0' calc · C H, 7.25; N _, 5.40. Found: C, 78.90; H, 7.34; N, 5.60.

Example 69A.

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[2- [1, m, m]]. ·

[3- (piperid-4-yl) propyl / piperid-4-yl] ethyl] carbonyl-1H-indole. X

209 -

Exact Mass FAB (M + 1) calcd for C 24 H 25 ClN 4 O 2: 536.3044,.

found: 536.3044.

Example 69B

2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(2- [1- / 3- (1-tritylpiperid-3-yl) propyl] piperid-4-yl]] ethyl. 1 H-indole.

FD-MS 779 (M + ² ).

Elemental analysis for ^C 51 ^H 56 ^ClN 3 ° 2 requires C, 78.69, H, 7.25, N, 5.40 Found: C, 78.92, H, 7.41, N, 5.27 .

- 210

Example 69C

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[2- [1 ']]. E, 1 '

- [3- (piperid-3-yl) propyl / piperid-4-yl]] ethyl] carbonyl] -

FD MS 536- (M ^{+ 1} ). '.

Elemental analysis for C ₃₂ ^H 42 ClN ₃ O ₂ (%): Calculated: C, 71.69, H, 7.90, N, 7.84. Found: C, 71.45, H, 7.85. , 7.61.

Example 70. ; '/? <. ·,

Ί ^'1' method of preparation. "(RS) -2 - [(4-chlorophenoxy) methyl] -! - [3-by (piperidin-3-yl) propyl] -3- [/ 4- (piperidin-l -yl) piperid-1-yl / acetyl] -1H-indole

211 -

NMR (CDCl souladu.s ^ J is the proposed structure of the title compound. ^R: Exact Mass _FAB (M ⁺⁾ for ^C 35 ^H 48 ^C1N 4 ° = 2 Calculated: ^591.3466,! Found: 591.3476. ·

Example 70A '. '···

Process for the preparation of (S) -2 - [(4-chlorophenoxy) methyl] -l- [3 ^T - (piperidin-3-yl) pfopyl] -3 - [/ 4- (piperidin-l-yl) -piperidin-l · . -yl / acetyl] -1H-indole 212 -

NMR (CDCl 3) is consistent with the proposed structure of the title compound.

FAB MS 591.3476 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 35 ^H 47 ^ClN 4 ° 2 ( ^{% :} calculated: C, 71.10, H) 8.01, N, 9.48, found: C, 70.82, H, 8.14, N , 9.23.

Example 70B,

(R) -2 - [(4-Chloro-phenoxy) methyl] -1- [3- (piperid-3-yl) propyl] -3 - [[4- (piperid-1-yl) piperid-1-yl]] [acetyl] -1H-indole -

• -a *

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

Exact mass for ^c 35 ^H 48 ° ^C 4 ° 2 calculated 591.3466, found 591.3458.

AND

Example 71

Preparation of 2 - [(4-chlorophenoxy) methyl] -1- [3- (piperid-4-yl) propyl] -3- [[4- (piperid-1-yl) piperid-1-yl] acetyl] -1H -indolu

214

NMR (CDCl 3) was consistent with the proposed structure of the title compound. '»

Exact weight at ^C 35 ^H 48 ^C1N 4 ° 2 ^: ΐ

calculated: 591.3466, found: 591.3464.

Example 72 ''

Method of Preparation (RS) -2 - [(4-Chlorophenoxy) methyl] -1- [3-. (piperid-3-yl) propyl] -3- [3- (piperid-3-yl) propanolyl] -1H- ¹ '

-indole <, ’

215

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

Exact mass calcd for C ₃₁ H ₄₁ C1N ₃ O _2: Calculated: 522.2887, Found: 522.2905.

Example 73

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1- [3- (piperid-4-yl) propyl] -3- [3- (piperid-3-yl) propanoyl] -1H-indole

NMR (CDCl ₃ ) was consistent with the proposed structure for Compound 216 title.

Exaktní'hmotnost for ^C 31 ^H 41 ^C1N 3 ° 2 ^{(M + 1):} Calculated: 522.2887, '1 r Found: 522.2910. I · t ¹ ,. Ϊ · *. Example 74 '- ₄ ''.

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1- [3- (piperid-3-yl) propyl] -3- [3- (piperidin-4-yl) propanoyl] -1H-indole

IR and NMR (CDCl3) were consistent with the desired structure for the title compound.

FAB MS 522 (M ^{+ 1} ). . ..

Elemental analysis for C and ₃ ^h 4oC1N ₃ 0 ₂ (%): C, 71.31, H, 7.72, N, 8.05 Found: C, 71.04, H, 7.89, N , 7.78.

Example 75

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1- [3- (piperid-4-yl) propyl] -3- [3- (piperid-4-yl) propanoyl] -1H-indole

- 217 -

NMR (CpCl ₃ ) is consistent with the proposed structure of the title compound.

FD. MS 522 (M ^{+ 1} ) ⁺ .

Elemental analysis for C ₃₁ H ₄₀ O 1 ^N 3 ° 2 < ^% > ^: calculated: C, 71.31, Ή, 7.72, N, 8.05, found: C, 71.10, H, 7, 66, N, 7.97.

. + ... »I

'. . T ',''·. . ¹ ' ^Λ ·' ^,. »»

Example 76 /. '' ’'

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[[3- (= dimethylamino) propylamino / carbonyl] methyl] -1H-indole ·

N (CH _3}

3/2

NMR (ČDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS: 413 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^I I28 ^C1N 3 ° 2 (%):

> '-' · · ’'\, * i'.

.ν './.

C, 66.74; H, 6.82; N, 10.15. Found: C, 66.89; H, 6.96; N, 10.11.

'P' · '' Example 77. _r . ¹ : Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [1-hydroxy-1- [[4- (piperid-1-yl) piperid-1-yl] carbonyl] methyl] -1H -indolu

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound. FD MS: 495 (M ^& lt ^{; +} & gt ^; ). \ ~. '

Elemental analysis for ^C 28 ^H 34 ^Cl 2 ^N 3 ^O 3 requires C, 67.80; H, 6.91; N ,, 8.47 · Found: C, 67J86 ^F, H, 6.90, N, 8.45. ' ^v

Example 78

Method for the preparation of 2- [1-methyl-2 - [(4-chlorophenoxy) methyl] indol-3-yl] glyoxylic acid]

X

- 219 "

⁷ NMR (DMSO) was consistent with the proposed structure of the title compound. '. FD MS 343 (M ⁺ ).

Elementární'analýza for C ₁₄ H speedboat _{LG 4} (%): C, 62.89, H, 4.11, N, 4.07 Found: 'C, ¹ 63.15, H, 4.37, N, 3.92.

^Λ f.>

Example 79;

Method for the preparation of methyl [2- [1-methyl-2 - [(4-chlorophenoxy) and ¹ methyl] indol-3-yl] glyoxylate]. ..

NMR (CDCl3) and IR were consistent with the desired structure of the title compound.

Exact Mass FAB (M ^{+ 1} ) for C ₁₉ H ₁₇ ClNO ₄ : calculated: 358.0846, found: 358.0818.

Example 80

220

Process for the preparation of phenyl [2- [1-methyl-2 - [(4-chlorophenoxy) methyl] indol-3-yl] glyoxylate]

* NMR (CDCl3) was consistent with the proposed structure of the title compound.

FD MS: 419 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 24 ^H 18 ^C1NO 4 Calculated: C 68.66 / H 4.32, N, 3.34 Found: C, 68.90 ,. H, 4.49; N, 3.33.

Example 81

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- (2-amino-1 ', 2-ethanedionyl) -1H-indole

NMR (DMSO) was consistent with the proposed structure of the title compound.

FD MS 342 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 18 ^H 15 ^C1N 2 ° 3 calcd: C, 63.07, H, 4.41, N, 8.17,

221 found: C, 63.36, H, 4.50, N, 8.18.

Example 82

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- (2-methylamino-1,2-ethanedionyl) -1H-indole

Cl

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS 357 (M ^{+ 1} ).

Elemental analysis for C ₁₉ H ₁₇ ClN ₂ O ₃ (%):

H, 4.80; N, 7.85. Found: C, 63.97; H, 4.83; N, 7.82.

Example 83

3-Dimethylaminopropyl [2- [1-methyl-2 - [(4'-chlorophenoxy) methyl] indol-3-yl] glyoxylate]

N _{(CH3) 2}

NMR (CDC1 ₃₎ was consistent with the title compound.

the proposed compound structure

- 222- ^C 23 ^H 25 ^C1N 2 ° ^{4: FAB 429 (M +)} ·

It is the only compound of high purity, as seen by chromatographic methods.

*

Example 84

A process for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- [2- (dimethylamino) ethylamino] -1,2-ethanedionyl] -1H-indole hydrochloride.

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

IR were consistent with the desired structure of the title compound.

FD MS: 413 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₂ H ₂₄ ClN ₃ O ₃ .HCl (%):

calculated:. C, 58.67; H, 5.59; N, 9.33. Found: C, 58.38; H, 5.82; N, 9.48.

IP

Example 85

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- [3- (dimethylamino) propylamino] -1,2-ethanedionyl] -1H-indole

223

N (CH _S) η

NMR (CDCl3) was consistent with the proposed structure of the title compound.

Exact mass FAB (M ⁺¹ ) for ^c 23 ^H 27 ^clN 3 ° 3:

calculated: 428.1741, found: 428.1738. ·, ·.

Example 86

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (3-aminopropylamino) -1,2-ethanedionyl] -1H-indole

IR, NMR and UV were consistent with the desired structure of the title compound.

FD: MS 399 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 21 ^H 22 ^clN 3 ° 3 (%):

H, 5.55; N, 10.51. Found: C, 69.53; H, 6.18; N, 11.70.

It is the only compound of high purity, as seen by chromatographic methods.

Example 87 '. ‘'

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- / 3-

IR, NMR, and UV were consistent with the desired structure of the title compound.

FD MS 499 (M ⁺ J ')

Mp 175-176 ° C.

·:. · *. ,. . '. . ’. ’

Elemental analysis for ^C 26 ^H 30 ^C1N 3 ° 5: Calculated: C, 62.46 ', H 6.05 / N 8.40 Found: C, 62.19, H, 6.08, N, 8, 27 Mar: . .

«-Í. _{f 4} . E · \. '·''·F''- 1 -

Example 88, * '

Process for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- / 2 ', 2-dimethyl-3- (dimethylamino) propylamino] -1,2-ethanedionyl] -1H-indole;

225 -

NMR (CDCl3) was consistent with the proposed structure of the title compound.

FD MS: 455 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 25 ^{H C1N} 3 O 3 ° 3 calcd: C, 65.85, H, 6.63, N, 9.22 Found: C, 65.62, H, 6.76, N, 9.12 .

Example 89

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -4-methyl-3- [2- [6- (dimethylamino) hexylamino] -1,2-ethanedionyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

IR was consistent with the desired structure of the title compound. Exact weight FAB (M ⁺¹ ) for C ₂₇ H ₃₃ C1N ₃ O ₃ :

calcd, 470.2210, found 470.2196.

- 225 f

Example 90 ·

2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- [N-methyl-2- (dimethylamino) ethylamino] -1,2-ethanedionyl] -1H-indole

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 427 (M ^& lt ^{; +} & gt ^; ) ...

· 'E ·' · ..

Mp 142-143 ° C.

Elemental analysis, for ^C 23 ^H 26 ^C1N 3 ° 3 (Λ)

Calcd: C, 64.56; H, 6.12; N, 9.82. C, 64.82, H, 6.32, N, 9.89.

' _t ' x *!. ··· '', .S. (B)

Example 91 '* ’\. .>

'4 1' I

•. i * i; ’'. {"♦»

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (N-methyl-3- (dimethylamino) propylamino) -1,2-ethanedionyl] -1H-indole. - 227 -

·· ...... . · · · ..... - '. ’-,

NMR (CDCl3) is consistent with the proposed structure of Compound _λ named in the title. . ;

»’; - ’.i (,

IR were consistent with the desired structure of the compound ₊ named- in the title: ^J

Exact Mass FAB (M) for C ₂₄ ^H 29 ^C 1 N ₃ Q _3, ', calculated: 442.1897,' found 442.1904.

Example, 92

Preparation of 2, - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (6-methyl-3- (dimethylamino) propylamino) -1,2-ethanedionyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound. . >''

IR was consistent with the desired structure of the title compound.

FD-MS 441 (M ^& lt ^{; +} & gt ^; ).

228

Exact weight FAB (M ⁺¹ ) for C ₂ 4 ^H 29 ^C1N 3 ° 3 ^! calcd .: 442) 1897>

found:. 442.1895. '..',. Λ

Example 93 ..

Process for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- [bis-

NMR '(CDC1 ₃₎ are consistent with the proposed structure of the title compound. _Ř . ,

FD MS: 512 (M ^& lt ^{; +} & gt ^; ). ; _; / '

Elemental analysis for ^ 28 ^ 37 ^^^ 4 ^ 3.

H, 7.27; N, 10.92. Found: C, 65.85; H, 7.46; N, 11.04.

*

Example 94

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (N-benzyl-3- (dimethylamino) propylamino) -1,2-ethanedionyl] -1H-indole

IR, NMR and NMR were consistent with the desired structure. the title compounds. '

FD MS 517 (M ^& lt ^{; +} & gt ^; ). . / '' \ '

Elemental analysis for C ₃₀ H ₃₂ ClN ₃ 0 ₃ (%): Calculated: C, 69.55, H, 6.23, N, 8.11. Found: C, 69.82, H, 6.31, N , 8.13.

Example 95. , ‘·.

1. T. Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- [N-methyl-3- [1- (tert-butoxycarbonyl) piperid-3-yl] propylamino] -1, 2-ethanediol] -1H-indole

NMR (CDČ1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS - 581 (M ⁺ ). ,

230. Elemental analysis for ^C 32 ^H 40 ^ClN 3 ° 5 Calculated: C, 66.02, H, 6.93, N, 7.22. Found: C, 65.91, H, 7.14, N, 7.08, ^τ μ '' _ *

Example.96 ''

Preparation method

2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2 - [(1

-methylpiperid-3-yl) amino] -1,2-ethanedione] -1H-indole

the phi compounds named in the title.

IR was consistent with the desired structure of the title compound. FD MS 439 (M ^& lt ^{; +} & gt ^; ). ''. .v .... i ''. ·,. > Λ

Elemental analysis for ^C 24 ^H 26 ^C1N 3 ° 3 calcd: 'C, 65.52, H, 5.96, N, 9.55,' ·· ·. . ¹ '>Found> C, 65.80, H, 5.96, N, 9.56. '

Example 97

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- / N-methyl- (1-methylpyrrolidin-3-yl) amino] -1,2-ethanedionyl] -1H-indole

231

IR, NMR, and UV were consistent with the desired structure of the title compound. '-.

FD MS 439 (MH &lt; + &gt;). ,

Elemental analysis for ^C 24 ^H 26 ^ClN 3 ° 3 * calculated: C, 65.52, Ή, 5.96, N, 9.55. Found: C, 65.54, H, 6.03, N, 9, 69. ·,

Example 98

Preparation of (RS) -2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- [N-methyl- (1-methylpiperid-3-yl) amino] -1,2-ethanedionyl] -1H -indole;

IR was consistent with the desired structure of the title compound.

FD MS: 453 (M ^& lt ^{; +} & gt ^; ). '. .

Elemental analysis for ^C 25 ^H 28 ^ClN 3 ° 3 Calculated: C, 66.14, H, 6.22, N, 9.26. Found: C, 65.86, H, 6.17, N, 9. 29.

232

Example 99

Process for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2 - [(quinuclidin-3-yl) amino] -1,2-ethanedionyl] -1H-indole

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS: 451 (M ^& lt ^{; +} & gt ^; ).

Mp 204-205 ° C.

Elemental analysis for ^C 25 ^H 26 ^ClN 3 ° 3 Calculated: 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 ^'w (piperidin-I-yl) -l, 2-ethanedionyl] -lH-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound. .

τ · ·

233 FD MS 410 (MH +).

. Elemental analysis for ^C 23 ^H 23 ^ClN 2 ^O 3: Calculated: G, 67.22; H, 5.64; N, 6.82, ,, ^-1 , #; ^J Found: C, 67.50; H, 5.81; N, 6.63. '·,.

. <'· ...' * '''' ·. · ·. ' * 1 · ¹ '' put ir * *; ·· '··'''

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- / 2'H]. ₍ r _t , <. <. ', ··. ·: · · «· -., · ·.' ·.» · ..

_'It - (dimethylaminomethyl) cyclohexylamino / -l, 2-ethanedionyl.] - ^IH:. , 1 ,,. ·. . ,. . .. '

-indole-hydrochloride. ’: · -

row '. '’% R,

NMR (DMSO) were consistent with the proposed structure of the compound. . '' ^j . ^J '¥', _v . _{| T.}

named in the title, j '* ϊ,''.FD MS 481' (MI). . '' / ¹ . '. ...,. .

Elemental analysis for ^G 27 ^H 32 ^C1N 3 ° 3 ^{'HC1 ^):} calculated: C, 62.55, H> 6.42, N, 8.10 Found: C, 62.56, H, 6.44 , N, 8.06. ' ^Λ

Example 102

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (4-methylpiperid-1-yl) -1,2-ethanedionyl] -1H-indole

234 -

NMR (CDCl3) was consistent with the proposed structure of the title compound.

IR was consistent with the desired structure of the title compound.

FD-MS 424 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 24 ^H 25 ^ClN 2 ° 3 Calculated: C, 67.84, H, 5.93, N> 6.59. Found: C, 68.04, H, 5.85, N, 6.74. .

Example 103

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (4-benzylpiperid-1-yl) -1,2-ethanedionyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

IR was consistent with the desired structure of the compound

235 named in the title.

FD-MS 500 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 30 ^H 29 ^ClN 2 ^O 3 calculated: C, 71.92, H, 5.83, N, 5.59. Found: C, 71.69, H, 5.74, N, 5.85, 38.

Example 104

Preparation of 2 - [(4-chlorophenoxy} methyl] -1-methyl-3- [2- (4-aminocarboethylpiperid-1-yl) -1,2-ethanedionyl) -1H-indole

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS: 453 (M ^& lt ^{; +} & gt ^; ).

Mp 220-221 ° C.

Elemental analysis for ^C 24 ^H 24 ^C1N 3 ° 4 <*> = Calculated: C, 63.50, H, 5.33, N, 9.26 Found: C, 63.45, H, 5.50, N , 9.18.

Example 105

2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (4-dimethylaminopiperid-1-yl) -1,2-ethanedionyl] -1H-indole

- 23 6 · -

named in the title. 'j ..

' ¹ ''a-ι'

Exact mass FAB (M +) for ^C 25 ^H 29 ^Cl 2 ^N 3 ^O 3 ^: calculated: 454.1897, ·. ...... ..

found: 454.1882.

¹ /., '' · ','''.

ί ¹ _r J ', * -' ^f ·· ..-. <*, «·

Example 106 ‘> '.

Preparation of 2 - [(4-chlorophenoxy) methyl] -l-methyl-3- [2- / 4-yl - ^ ^ί ·! :. '· _P

- (piperid-1-yl) piperid-1-yl / -1,2-ethanedionyl) -1H-indole

NMR (CDC1 ₃₎ and IR were consistent with the proposed structure of the title compound.

FD-MS 493 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^ 2θΗ ₃ 2ύ1Ν ₃ 0 ₃ - (%):

j | · .p

}

Γ *.

- 237 calculated: C, 68.07, Η, 6.53, Ν, 8.51, / found: C, 67.97, Η, 6.66, Ν, 8.27.

. .

, '*

Example 107 ”: *

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (3-. Aminocarbonylpiperid-1-yl) -1,2-ethanedionyl] -1H-indole

IR, NMR, and UV were consistent with the desired structure of the title compound.

FD MS.453. ''

Mp 229-230 ° C.

Elemental analysis for ^C 24 ^H 24 ^ 3 ^{1 N} ° 4: Calculated: C, 63.50, H, 5.33, N, 9.26 Found: C, 63.53; H, 5.44; N, 9.04. / 'I •' i

Example 108

2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (piperazin-1-yl) -1,2-ethanedionyl] -1H-indole

238

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS: 411 (M ^& lt ^{; +} & gt ^; ).

Mp 168-169 ° C.

Elemental analysis for ^C 22 ^H 22 ^ClN 3 ° 3

H, 5.38; N, 10.10. Found: C, 63.95; H, 5.36; N, 10.08.

Example 109

-t

2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (4-isopropylpiperazin-1-yl) -1,2-ethanedionyl] -1H-indole

NMR (CDCl3) was consistent with the proposed structure of the title compound.

FD MS: 453 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^c 25 ^h 28 ^{c 3n} 3 ° 3

239 calculated:

found:

C, 66.15; H, 6.22; N, 9.26; C, 65.94; H, 6.48; N, 8.97.

Example 110.

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-4- [2- [4- (tert-butoxycarbonyl) piperazin-1-yl] -1,2-ethanedionyl] -1H-indole

* ·

IR, NMR, and UV were consistent with the desired structure. * * »# Compounds named in the title.,

FD MS 511 (M ^& lt ^{; +} & gt ^; ). * fy · ·· ',.

<y- · ». . h -λ 'J. .1.

Compound * has a melting point of 200-201 ° C.

Elemental analysis for ^C 27 ^H 3 O ^C 1N3 ° 5 (%): - _Λ Calculated: C 63.34, H 5.91> N, 8.21 'Found C, 63.10; H, 5 80, N / 7 / 98.7

Example 111

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (4-cyclohexylpiperazin-1-yl) -1,2-ethanedionyl] -1H-indole

240

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

IR was consistent with the desired structure of the title compound.

FD-MS 493 (M ^& lt ^{; +} & gt ^; ).

Elemental Analysis ^ 28 ^H 32 ^C1N 3 ° 3 calcd: C, 68.07, H, 6.53, N, 8.50 Found: C, 67.81, H, 6.60, N, 8.24 .

l ·

Example 112 *

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- / 4- (2-dimethylaminoethyl) piperazin-1-yl] -1,2-ethanedionyl] -1H-indole dihydrochloride

241 -

I, ₄ ß

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

IR was consistent with the desired structure of the title compound.

FD MS: 482 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₆ H ₃₁ ClN ₄ O ₃ · 2 HCl (%):

H, 5.98; N, 10.07. Found: C, 56.47; H, 6.07; N, 10.05.

Example 113 '

2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- (3-aminoacetylpyrrolidin-1-yl) -1,2-ethanedionyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

IR was consistent with the desired structure of the title compound.

242

FD MS: 453 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₄ H ₂₄ ClN ₃ O ₄ (%):

calculated: C, 63.50, H, 5.33, N, 9.26. Found: C, 63.75, H, 5.37, N, 9.21.

Example 114

Method for the preparation of 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3- [2- (N-methyl-3- (dimethylamino) propylamino) -1,2-ethanedionyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

UV is consistent with the desired structure of the title compound.

FD MS 475 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 24 ^H 27 ^C 1 ^L 2 ^N 3 ° 3 (%):

H, 5.71; N, 8.82. Found: C, 60.69; H, 5.80; N, 8.77.

Example 115

Method for the preparation of 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3- [2- [N-methyl- (1-methylpiperid-4-yl) amino] -1,2-ethanedionyl] -1H- indole

243 -

NMR (CDCl3) was consistent with the proposed structure of the title compound.

^C 25 ^H 27 ^C1N 3 ° 3 ^Ft> MS 487 (M ^+). '

It is the only compound of high purity, as seen by chromatographic methods.

Example 116

2 - [(2,4-Dichlorophenoxy) methyl] -1-methyl-3- [2- / 4- (N, N-dimethylamino) piperid-1-yl] -1,2-ethanedionyl] -1H- indole

NMR (CDCl3) was consistent with the proposed structure of the title compound.

UV is consistent with the desired structure of the title compound.

FD MS 487.489 (M ^& lt ^{; +} & gt ^; ).

Elementary analysis for C ₂₅ H ₂₇ Cl ₂ N ₃ O ₃ (%):

calculated: C, 61.48, Η, 5> 57, N, 8.60. C, 61.75; H, 5.63; N, 8.59.

Example 117

Method for the preparation of 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3- [2 - [(4- (piperid-1-yl) piperid-1-yl) -1,2-ethanedionyl] -1H -indolu

IR, NMR and UV were consistent with the desired structure

Λ.

the title compounds

FD MS 527.529 (M ⁺ ) Elemental analysis for ^C 28 ^H 31 ^Cl 2 ^N 3 ° 3 ( ^% ) ^: calculated: C, 63.64, H, 5.91, N, 7.95. H, 6.08; N, 7.85.

Example 118

Method for the preparation of 2 - [(2-cyano-4-bromophenoxy) methyl] -1-methyl-3- [2- [N-methyl- (3-dimethylaminopropyl) amino] -1,2-ethanedionyl] -1H-indole

245

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 511.513 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₅ H ₂₇ BrN ₄ O ₃ .0.5 H ₂ 0 (%):

H, 5.42; N, 10.75. Found: C, 57.56; H, 5.36; N, 10.60.

Exact weight for ^c 25 ^H 27 ^BrN 4 ° 3:

calculated: 511.1332, found: 511.1345.

. ‘Ft

Example 119

Preparation of 2 - [(2-cyano-4-bromophenoxy) methyl] -1-methyl-3- [2- [N-methyl- (1-methylpiperid-4-yl) amino] -1,2-ethane].

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 522.524 (M ^& lt ^{; +} & gt ^; ).

- 246 -.

Elemental analysis for C ₂₆ H ₂₇ BrN ₄ O ₃ (%):

calculated: C, 59.66, H, 5.20, N, 10.70. Found: C, 59.38, Η, 5.24, N, 10.49.

Example 120

Preparation of 2 - [(2-cyano-4-bromophenoxy) methyl] -1-methyl-3- [2- (4-dimethylaminopiperid-1-yl) -1,2-ethanedionyl] -1H-indole

IR, NMR and UV were consistent with the desired structure of the title compounds.

FD MS - 52 2.524 (M ⁺ ). '

Elemental analysis for ^C 26 ^H 27 ^BrN 4 ^O 3 · ^0.5 H ₂ O: Calculated: 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 ° 3 ^: calculated: 523.1345, found: 523.1365.

*

Example 121 ...

Preparation of 2 - [(2-cyano-4-bromophenoxy) methyl] -1-methyl-3- [2- / 4- (piperid-1-yl) piperid-1-yl] -1,2-ethanedionyl] - 1H-indole

247

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 563.565 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C29H32BTN4O3 (%) · calculated: C, 61.81, H, 5.54, N, 9.94. Found: C, 61.56, H, 5.62, N, 9.91.

Example 122

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-ethyl-3- [2 '(4-dimethylaminopiperid-1-yl) -1,2-ethanedionyl] -1H-indole

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 467.:

Elemental analysis for ^C 26 ^H 30 ^Cl - ^N 3 ^O 3

248 Calcd: C, 66.73; H, 6.46; N, 8.98. Found: C, 66.88; H, 6.57; N, 8.90.

Example 123

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-ethyl-3- [2- [N-methyl- (1-methylpiperid-4-yl) amino] -1,2-ethanedionyl] -1H-indole

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 467.>

Elemental analysis for ^C 26 ^H 30 ^ClN 3 ° 3 Calculated: C, 66.73, H, 6.46, N, 8.98. Found: C, 66.90, H, 6.70, N, 9.03 .

Example 124

2 - [(4-chlorophenoxy) methyl] -1-benzyl-3- [2- (4-dimethylaminopiperid-1-yl) -1,2-ethanedionyl] -1H-indole

249

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS, 529.

Elemental analysis for ^C 31 ^H 32 ^C1N 3 ° 3 calcd: C, 70.24, H, 6.08, N, 7.93 Found: C, 70.26, H, 6.18, N, 7.73 .

Example 125

Preparation of 2 - [(4-chlorophenoxy) methyl] -1- (2-piperid-1-ylethyl) -3- [2- / 4- (piperid-1-yl) piperid-1-yl] -1,2 ethanedionyl] -1H-indole

NMR (CDC1 _3), a phenomenon consistent with the proposed structure of compound

250 named in the title.

Exact FAB mass for ^C 34 ^H 44 ^Cl 2 ^N 4 ^O 5 ^: calculated 591.3102, found 591.3100.

Example 126

2 - [(4-chlorophenoxy) methyl) -1- [3- (piperid-3-yl) propyl] -3- (piperid-1-ylmethyl) -1H-indole.

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound. >

It is the only compound of high purity, as seen by chromatographic methods.

Example 127 '

Preparation of 2 - [(4-chlorophenoxy) methyl] -1- [3- (1-methylpiperid-3-yl) propyl] -3- (piperid-1-ylmethyl) -1H-indole

- 251 -

NMR (CDC1 ₃₎ was consistent with ·: ·-designed structure of the title compound. . . *

Ί

It is the only compound of high purity, as seen by chromatographic methods

Example 128 '' ¹ >'\

Preparation of 2 - [(4-chlorophenoxy) methyl} -1-ethyl-3 - [(4 '' WS ») ·

J t ¹ .1

-dimethylamiriopiperid-1-yl) methyl] -1H-indole -

252 named in the title.

FD-MS 425 (M ^& lt ^{; +} & gt ^; ).

The compound has. melting point Ϊ15 to 116 ° C.

Elemental analysis for ^C 25 ^H 32 ^c1n ° 3 calcd: C, 70.49, H, 7.57, N, 9.86 Found: C, 7.0,70 · ,. H, 7.67; N, 9.80.

Example 129 _;

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-benzyl-3 - [(4-dimethylaminopiperid-1-yl) methyl] -1H-indole

NMR and UV were consistent with the desired structure of the title compound.

FD MS 488 (M ^& lt ^{; +} & gt ^; ). .

Mp 127-128 ° C.

Elemental analysis for ^C 30 ^H 34 ^C1N 3 ° Calculated: C, 73.83, H, 7.02, N, 8.61 Found: C, 73.77, H, 7.21, N, 8.66.

Example 130

Preparation of 2 - [(4-chlorophenoxy) methyl] -1- [2- (piperid-1-yl) ethyl] -3 - [(4-dimethylaminopiperid-1-yl) methyl] -1H-253

-indolu

NMR (CDCl3) was consistent with the proposed structure of the title compound.

Exact weight for C ₃ 0 ^H 42 ^C1N 4 ^O! calcd, 509.3047, found 509.3018. Example 131

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1- [3- (piperid-1-yl) propyl] -3- [(4-dimethylaminopiperid-1-yl) methyl] -1H-indole trihydrochloride

254

O

NMR and UV were consistent with the desired structure of compound

named in the title.

FD MS 523 (M ^{+ 1} ).

Mp 240-242 ° C.

Elemental analysis for C ₃₁ H ₄₃ ClN ₄ O.3 HCl (%):

H, 7.33; N, 8.86. Found: C, 58.66; H, 7.09; N, 8.77.

I +

Example 132 *

2 - [(4-chlorophenoxy) methyl] -1- [3- (piperid-3-yl) propyl] -3 - [(4-dimethylaminopiperid-1-yl) methyl] -1H-indole. ,

255

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

^C 31 ^H 43 ^C1N 4 ^{O: FD MS 522 (M +)} ·

It is the only compound of high purity, as seen by chromatographic methods.

Example 133

Preparation of 2 - [(4-chlorophenoxy) methyl] -1-ethyl-3 - [[4- (piperid-1-yl) piperid-1-yl] methyl] -1H-indole

NMR and uv were consistent with the desired structure of the title compound.

256

FD MS: 465 (M ^& lt ^{; +} & gt ^; ). .

Mp 130-131 ° C.

Elemental analysis for ^C 28 ^H 36 ^C1N 3 ° Calculated: C 72 _F 16 H, 7.79; N, 9.02 Found: C, 72.12, H, 7.78, N, 8.86.

Example 134

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-benzyl-3 - [[4- (piperid-1-yl) piperid-1-yl] methyl] -1H-indole

NMR and UV were consistent with the desired structure of the title compound.

FD MS: 527 (M ^& lt ^{; +} & gt ^; ).

Mp 153-154 ° C.

Elemental analysis for C ₃₃ H ₃₈ ClN ₃ O (%):

H, 7.25; N, 7.96. Found: C, 75.25; H, 7.40; N, 8.08.

• v

Example 135

Preparation of 2 - [(4-chlorophenoxy) methyl] -1- [2- (piperid-1-yl) ethyl] -3 - [[4- (piperid-1-yl) piperid-1-yl] methyl] - 1H-indole

257

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 548 (M ^& lt ^{; +} & gt ^; ).

Mp 102-103 ° C.

Elemental analysis for ^C 33 ^H 45 ^C1N 4 ° ^'d: C, 72.17, H, 8.26, N, 10.20 Found: C, 72.12, H, 8.31, N, 10 , 17.

Example 136

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1- [2- (piperid-1-yl) ethyl] -1H-indole

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 368 (M ^& lt ^{; +} & gt ^; ),

-. 258

FAB MS 369 (M ^{+ 1} ).

Elemental analysis for C ₂₂ H ₂₅ ClN ₂ ° (%):

calculated: C, 71.63, H, 6.83, N, 7.59;

found: c, 71.93, H, 7.28, N, 7.22.

It is the only compound of high purity, as seen by chromatographic methods.

Example 137

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1- [2- (piperid-4-yl) ethyl] -1H-indole

Cl

NMR (CDCl ₃ ) was consistent with the proposed structure of the title compound.

FD MS 368 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 22 ^H 25 ^N 2 ^C ^ ° Calculated: C, 71.63. H, 6.83, N, 7.59 Found: C, 71.66, H, 6.86, N, 7 , 87.

Example 138

Process for preparing 2 - [(phenylthio) methyl] -1- [3- (piperid-3-yl) propyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS 364 (M ^& lt ^; + &^gt;).

Elemental analysis for C ₂₃ H ₂₈ N2S (%):

H, 7.75; N, 7.69. Found: C, 75.70; H, 7.73; N, 7.86.

Example 139

2 - [(4-chlorophenoxy) methyl] -1- [3- (piperid-3-yl) propyl] -1H-indole. . - '

NMR (CDC1 ₃₎ was consistent with the proposed structure of compound named in the headings

It is the only compound of high purity, as can be seen from t

260 according to chromatographic methods.

Example 140

Preparation of 2 - [(4-chlorophenoxy) methyl] -1- [3- (1-methylpiperid-3-yl) propyl] -1H-indole

NMR and UV were consistent with the desired structure of the title compound.

Mp 97-98 ° C.

Elemental analysis for C ₂₄ ^H 29 ^ClN 2 ° (%):

H, 7.36; N, 7.06. Found: C, 72.59; H, 7.48; N, 7.14.

Example 141

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1- [3- (piperid-4-yl) propyl] -1H-indole

NMR (CĎC1 ₃₎ in accordance 'with the proposed structure of the title compound. . . *. ^C 23 ^H 27 ^ClN 2 ° ^: FD MS 382 (M ⁺ ). '• <v. · * -

It is the only compound of high purity, as evidenced by chromatographic methods ·

Example 142

Preparation of 27 [2- (4-chlorophenyl) ethyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride _:

. NMR. (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

. FD MS 366 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^H 27 ^C1N 2 HCl:

, _t J; C, 68.48; H, 7.00; N, 6.94.

Found: C, 68.26, H, 6.87, N, 6.75.

• 4 '

262

Example 143

Method for the preparation of 2 - [(4-chlorophenylamino) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 367 (M ^& lt ^{; +} & gt ^; ). ,

Mp 169 ° C.

Elemental analysis for C ₂ ^H 26 ^C1N 2 3 Calculated: C, 71.82, H, 7.12, N, 11.42 Found: C, 71.60, H, 7.05, N, 11.46.

Example 146

Method for the preparation of 2 - [(2,4-dichlorophenylamino) methyl] -1-methyl-3 - ((piperid-1-yl) methyl] -1H-indole

the title compounds.

263

FD MS 401.403 (M ^& lt ^{; +} & gt ^; ).

Mp 147-148 ° C.

Elemental analysis for C 22 H 25 Cl 2 N 3 (%):

calculated :. C, 65.67; H, 6.26; N, 10.44. Found: C, 65.48; H, 6.30; N, 10.59.

Example 147

Method for the preparation of 2 - [(4-chlorophenylamino) methyl] -3 - [(piperid-1-yl) methyl] -1H-indole

the title compounds.

FD MS 353.354 (M ⁺ ) ... The compound has a melting point of 135 ° C.

Elemental analysis for ^C 21 ^H 24 ^ClN 3 ^: Calculated: C, 71.27; H, 6.84; N, 11.87. Found: C, 71.90; H, 7.17; N, 12.02.

Example 148

Method for the preparation of 2 - [(2,4-dichlorophenylamino) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

264 "-" '

NMR (CDCl ₃ ) was consistent with the proposed structure of the compound; named in the title.

FD-MS 401 (M ^& lt ^{; +} & gt ^; ). '. ''''.

T ^; . Mp 147-148 ° C. ^J

Elemental analysis for ^C 22 ^H 25 ^N 2 ^C ^ third Calcd: 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] -1-methyl-3- ¹ '

- [(piperid-1-yl) methyl] -1H-indole

1 H NMR, UV and IR were consistent with the desired structure of the title compound.

FD MS 339. (M ^& lt ^{; +} & gt ^; ).

The compound has a melting point of 162-164 ° C.

265

Elemental analysis for ^C 22 ^H 33 ^N 3 ^Calculated: C, 77.83, H, 9.80, N, 12.38 Found: C, 75.98, H, 9.11, N, 12.67.

Exact FAB mass for ^C 22 ^H 34 ^K 3 ^: calculated: 340.2753, found: 340.2770.

Example 150 '

Method for the preparation of 2 - [(cyclohexylmethylamino) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole dihydrochloride ₃ • 2HCl

NMR, UV and IR were consistent with the desired structure of the title compound. . ¹ FD MS 354.390 (M ^& lt ^{; +} & gt ^; ).

Mp 159-161 ° C.

Elemental analysis for C ₂₃ H ₃₅ N ₃ · 2 HCl (%):

calculated: C, 64.78, H, 8.75, N, 9.85. Found: C, 64.62, H, 8.82, N, 9.65.

Example 151

Process for the preparation of 2 - [(naphth-2-ylamino) methyl] -1-methyl-3 - ['(piperid-1-yl) methyl] -1H-indole

266

NMR (CDC1 ₃₎ IR, and W were consistent with the proposed structure of the title compound.

FD MS 383 (M ^& lt ^{; +} & gt ^; ).

Mp 144 ° C.

Elemental analysis for C ₂₆ H ₂₉ N ₃ (%):

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) amino / methyl) -l-methyl-3 - [(piperidin-l-yl) methyl] -lH-indole, hydrochloride H ₃ NO • HCl

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 395 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 25 ^H 37 ^N 3 ° * ^HCl (%):

H, 8.87; N, 9.73. Found: C, 68.87; H, 9.29; N, 9.30.

Exact weight FAB for C ₂₅ H ₃ gN ₃ O:

calc .: 396.3015, found: 396.3020.

Example 153

Method for the preparation of 2 - [[N-acetyl-N- (benzyl) amino] methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 389 (M ^& lt ^{; +} & gt ^; ).

Mp 148-150 ° C.

Elemental analysis for C ₂₅ H ₃₁ N ₃ O.HCl (%):

calculated: C, 70.49, H, 7.57, N, 9.86. Found: C, 70.21, H, 7.40, N, 9.73.

*

Example 154

Method for the preparation of 2 - [[(3-chlorophenyl) amino] carbonyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

- 268

ch ₃

NMR, UV and IR were consistent with the desired structure. the title compounds.

FD MS.381, 383 (M ⁺ ).

Mp 137-138 ° C;

Elemental analysis for C2 ₂ H ₂₄ C1N ₃ O (%):

H, 6.33; N, 11.00. Found: C, 69.39; H, 6.39; N, 11.20.

Example 155

Method for the preparation of 2 - [[(2,4-dichlorophenyl) amino] carbonyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

Cl

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS: 417 (M ^& lt ^{; +} & gt ^; ). "

Mp 180-182 ° C.

Elemental analysis for ^C 22 ^H 23 ^C 12 ^N 3 ° (%): Calculated: C, 63.47; H, 5.57; N, 10.09. Found: C, 63.27; N, 10.18.

269

Example 156

Method for the preparation of 2 - [[(cyclohexyl) amino] carbonyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 353 (M ^& lt ^{; +} & gt ^; ).

Mp 180 ° C.

Exact FAB Weight for C22H32N3O:

calculated: 354.2545, found: 354.2543.

Example 157

Process for the preparation of 2 - [[(cyclohexylmethyl) amino] carbonyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR (CDCl 3), IR and UV were consistent with the proposed structure of the title compound.

Mp 126 ° C.

Elemental analysis for C23H33N3O (%):

H, 9.05; N, 11.43. Found: C, 75.09; H, 9.03; N, 11.25. · I - ....

EXAMPLE 158 Preparation of 2 - [[(naphth-2-yl) amirto] carbonyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR / UV and IR were consistent with the desired structure of the title compound. ‘

FD MS 397 (M ^& lt ^{; +} & gt ^; ).

Mp 187 ° C.

'· ...

Elemental analysis for C 2 -C ₆ H 7 N ₃ O ₂ (%):

calculated: ^- C, 78.56, H, 6.85 / N, 10.57. Found: C, 78.84; H, 7.02; N, 10.78.

- ' ^e . · ' of . · -; Example 159

Preparation of 2- (phenoxymethyl) -1-methyl-3 - [(piperidine-1-.

-yl) methyl] -1H-indole hydrochloride _;

NMR, UV, and IR were consistent with the desired structure of the title compound.

271 FD MS 334 (M ^& lt ^{; +} & gt ^; ).

Mp 225 ° C; Elemental analysis for ^C 22 ^H 26 ^N 2 ^O · ^HCl ( ^{% :} calculated: C, 71.32, H, 7.34, N, 7.55. Found: C, 71, 45, H, 7.44, N, 7.79.

Example 160

Process for preparing a salt of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole with hydrochloric acid

NMR, IR and UV were consistent with the desired structure of the title compound.

FD MS 368 (M ^& lt ^{; +} & gt ^; ).

Mp 214 ° C.

Elemental analysis for ^C 22 ^H 25 ^ClN 2 ° - ^HCl calculated: C, 65.32, H, 6.46, N, 6.91. Found: C, 65.46, H, 6.52, N, 7. 16.

Example 161

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

- 272 -

NMR. is consistent with the desired structure, the title compound. ’.

FD MS 368 (M ^& lt ^{; +} & gt ^; ). '' * ·. . ,

Elemental analysis for ^C 22 ^H 25 ^C1N 2 ° Calculated: 'C, 71.63, H, 6.83, N, 7] 59. Found: C, 68.39, H, 6.55, N> 6.16.

•,. . . · ’· I- · '

Example 162. ’

Method for the preparation of 2 - [(3-chlorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 368 (M ^& lt ^{; +} & gt ^; ).

Mp 222 ° C.

Elemental analysis for ^C 22 ^H 25 ^{N C-2®, H} ^ (%): C, 65.19, H, 6.46, N, 6.91, _t found. C, 65.15; H, 6.55; N, 6.95.

Example 163

273

Method for the preparation of 2 - [(2-chlorophenoxy) methyl] -1-methyl-3 - [(piperidin-1-yl) methyl] -1H-indole hydrochloride

HCl

Cl

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 369 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C 2 H _{2 25} ^O C1N2 .HC1 (%):

C, 65.19; H, 6.46; N, 6.91;

Found: C, 65.48, H, 6.65, N, 6.98.

Example 164 _Λ

Method for the preparation of 2 - [(4-fluorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

HCl

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS 352. (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 22 ^H 25 ^FN 2 ° - ^HC1 · W 'Calculated: C, 67.94, H, 6.74, N, 7.20 Found: C, 67.74; H, 6.77; N, , 7.16.

- 274 Example 165

Method for the preparation of 2 - [(3-fluorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR (CDCl3) was consistent with the proposed structure of the title compound.

FD MS 352 (M ^& lt ^{; +} & gt ^; ).

Elemental Analysis 922 ^H 25 ^FN 2 ° ^HC1 Calculated: C, 67.94, H, 6.74, N, 7.20 Found: C, 65.85, H, 6.51, N, 6.68.

It is the only compound of high purity, as seen by chromatographic methods.

Example 166

Method for the preparation of 2 - [(2-fluorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound. FD MS 352 (M ^& lt ^{; +} & gt ^; ).

275

Elemental analysis for C2 ₂ H ₂₅ FN ₂ O.HCl (%}:

H, 6.74; N, 7.20. Found: C, 67.67; H, 6.63; N, 7.40.

Example 167.

Method for the preparation of 2 - [(4-trifluoromethylphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

the title compound,

FD: MS 402 (M ^& lt ^{; +} & gt ^; ). .

Elemental analysis for ^C 23 ^H 25 N 3 ^O 2 ^{· HCl} (%):

calculated: C, 62.94, H, 5.97, N, 6.38, found: C, 63.51, H, 6.05, N, 6.41 *

It is the only compound of high purity, as seen by chromatographic methods.

• ř

Example 168

Method for the preparation of 2 - [(3-trifluoromethylphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

276

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD: MS 402 (M ^& lt ^{; +} & gt ^; ).

HER

Elemental analysis for ^C 23 ^H 25 ^F 3 ^N 2 ^{O, HCl} (%):

calculated: C, 62.94; H, 5.97; N, 6.38. Found: C, 64.11; H, 6.07; N, 6.42.

It is the only compound of high purity, as seen by chromatographic methods.

'' ^{1 1}

Example.169

Method for the preparation of 2 - [(2-trifluoromethylphenoxy) methyl] -1-methyl-3- [• (piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD: MS 402 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^H 25 ^F 3 ^N 2 ^O · ^HCl <%> = calculated: C, 62.94, H, 5.97, N, 6.38. C, 62.89; H, 6.02; N, 6.37.

- 277 Example 170

Method for the preparation of 2 - [(4-acetylphenoxy) methyl] -1-methyl-3 - ((piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV and IR were consistent with the desired structure of the title compound.

FD MS 376 (M ^& lt ^{; +} & gt ^; ). . .

N, 6.78. Found: C, 69.69; H, 7.27; C, 69.80; H, 7.08; N, 6.78. , N, 6.72.

Example 171 _f

Method for the preparation of 2 - [(3-acetylphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV and IR were consistent with the desired structure of the title compound,

FD MS 376 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 24 ^H 28 ^N 2 ^O 2 ^{· HCl} < ^% > ^! calculated: C, 69.80, H, 7.08; N, 6.78. F

278 Found: C, 69.91, H, 7.18, N, 6.81.

Example 172

Method for the preparation of 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

HCl.

Cl

NMR and UV were consistent with the desired structure of the title compound.

FD MS 402 (M ^& lt ^{; +} & gt ^; ),

Elemental Analysis for _C2 2H24 ^ ¹ 2 ^N ° 2 requires C, 60.26, H, 5.75, N, 6.39 Found: C, 61.61, H, 5.69, N, 6, 34.,

It is the only compound of high purity, as seen by chromatographic methods.

Example 173

Method for the preparation of 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl 3-ΙΗ-indole hydrochloride

- / 213

NMR, UV, / and IR are consistent ^. the desired structure of the title compound ¹ ; * '·.'

FD MS 402 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C 22 H 24 G 12 N 2 O · HCl (%):

calculated: C, 60.08, H, 5.73, N, 6.37. Found: C, 60.31, H, 6.00, N, 6.62.

Example 174 k. '

Method for the preparation of 2 - [(3,5-dichlorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD: MS 402 (M ^& lt ^{; +} & gt ^; ).

Elemental Analysis ^ 2 ^ 24 ^ 2 ¹ ^ ^0.11 ^: Calculated: C, 60.08, H, 5.73, N, 6.37 Found: C, 58.13; H, 5.25; N, , 5,99,

It is the only compound of high purity, as is evident

- -280 according to chromatographic methods.

Example 175

Method for the preparation of 2 - [(2,5-dichlorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD: MS 402 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 22 ^H 24 ^Cl 2 ^N 2 ° Calculated: C, 65.51, H, 6.00, N, 6.95 Found: C, 65.71, H, 6.00, Ν, '6 , 93.

L

Example 176 ·

Method for the preparation of 2 - [(2,6-dichlorophenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, W, and IR were consistent with the desired structure of the title compound.

FD: MS 402 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 22 ^H 24 ^Cl 2 ^N 2 ° * ^HCl:

H, 5.73; N, 6.37. Found: C, 59.79; H, 5.43; N, 6.11.

Example 177

Preparation of 2 - [(3,4-dichlorophenoxy) methyl] -1-methyl-3A

- [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 402 (M ^& lt ^{; +} & gt ^; ).

I ¹

Elemental analysis for ^C 22 ^H 24 ^C - ¹ : 2 ^N 2 ^O calculated: C, 60.08, H, 5.73, N, 6.37. Found: C, 59.82, H, 5.72, N , 6.21.

Example 178

Method for the preparation of 2 - [(2,3-dichlorophenoxy) methyl) -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR, UV and IR are consistent with the desired structure ’

282 of the title compound.

FD: MS 402 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 24 ^H 24 ^Cl 2 ^N 2 ° (%):

H, 6.00; N, 6.95. Found: C, 65.23; H, 5.96; N, 6.82.

Example 179

Method for the preparation of 2 - [(4-phenylphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD-MS 410 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C 18 H 17 N 4 O (%):

H, 7.36; N, 6.82. Found: C, 80.96; H, 7.34; N, 6.73.

It is the only compound of high purity, as seen by chromatographic methods.

Example 180

Method for the preparation of 2 - [(3-phenylphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

283

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 410 (M ^& lt ^{; +} & gt ^; ).

-AND

Elemental analysis for ^c 28 ^H 30 ^N 2 ^O · ^HCl (%): C, 75.23; H, 6.99; N, 6.27. Found: C, 74.74; H, 7; N, 6.23.

It is the only compound of high purity as evidenced by chromatographic methods.

Example 181 '

Method for the preparation of 2 - [(2-phenylphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD-MS 410 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 28 ^H 30 ^N ° R 2 ^HCl Calcd: C, 75.23, H, 6.99, N, 6.27;

284 found: C, 74.03, H, 7.10, N, 6.35.

It is the only compound of high purity, as seen by chromatographic methods.

Example 182

Method for the preparation of 2 - [(4-methylphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl) -1H-indole hydrochloride

HCl

CH

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 348 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂ ^H 3 ^N 2 ° 28 ^'HC1 Calculated: C, 71.76, H, 7.59, N, 7.28' Found C, 70.88, H, 7.70, N, 7.32.

It is the only compound of high purity, as seen by chromatographic methods.

Examples 183

Method for the preparation of 2 - [(3-methylphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

285

NMR, UV and IR were consistent with the desired structure of the title compound.

FD MS 348 (M ^& lt ^{; +} & gt ^; ). ,

Elemental analysis for ^C 23 ^H 28 ^N 2 ° - ^HC1 Calculated: C, 71.76, H, 7.59, N, 7.28 Found: C, 72.41, H, 7.78, N, 7, 29.

It is the only compound of high purity, as seen by chromatographic methods.

Example 184 '

Method for the preparation of 2 - [(2-methylphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride • HCl

NMR, UV and IR were consistent with the desired structure of the title compound,

FD MS 348 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^H 28 ^N 2 ° ^'HC1 Calculated: C, 71.76, H, 7.59, N, 7.28 Found: C, 71.71, H, 7.54, N, 7, 21.

- 286 Example 185 »

Method for the preparation of 2 - [(4-methoxyphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 364 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C 23 H 23 N 2 O 2 .HCl (%):

H, 7.29; N, 6.99. Found: C, 68.68; H, 7.30; N, 7.12.

Example 186

Method for the preparation of 2 - [(3-methoxyphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 364 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^H 28 ^N 2 ° ^{2, H} ^ ¹ Calcd: C, 68.90, H, 7.29, N, 6.99,

287 found: C, 69.13, H, 7.38, N, 6.83.

Example 187

Method for the preparation of 2 - [(2-methoxyphenoxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 364 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^H 28 ^N 2 ° 2'HCl (%):

H, 7.29; N, 6.99. Found: C, 73.45; H, 7.94; N, 6.92.

It is the only compound of high purity, as seen by chromatographic methods.

Example 188.

Method for the preparation of 2- (2-hydroxyethyl) -1-methyl-3 - [(piperidine-1-)

ch ₃

Elemental analysis for ^C 16 ^H 22 ^N 2 °

288, found: C, 74.35, H, 8.78, N, 10.96.

Example 189 '

2- (2-Methoxyethyl) -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR was consistent with the desired structure of the title compound.

FD MS 272.273 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₁₇ H ₂₄ N ₂ O (%):

H, 8.88; N, 10.28. Found: C, 73.31; H, 8.86; N, 9.97.

Example 190 ' .

A process for preparing a salt of 2- (2-allyloxyethyl) -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole with hydrochloric acid

NMR, UV and IR are consistent with the desired structure • 1 »

-289 title compound.

FD MS: 298 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₁₉ H ₂ gN ₂ O.HCl (%):

H, 8.13; N, 8.37. Found: C, 68.30; H, 8.14; N, 8.39.

Example 191

Method for the preparation of 2- (benzyloxymethyl) -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

IR, UV and NMR (cbcl ₃ ) were consistent with the proposed structure of the title compound.

FD: MS 384 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^H 28 ^N 2 ^{O, HCl} (*): calcd. H, 7.59; N, 7.28. Found: C, 68.44; H, 7.04; N, 6.36.

It is the only compound of high purity, as seen by chromatographic methods.

Example 192.

Method for the preparation of 2 - [(3-chlorobenzyloxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

- ‘290 -

NMR was consistent with the desired structure of the title compound. '

FD MS 382 (M ⁺⁾ i. '''

Elemental Analysis for C ₃ H ₂₇ C1N ₂ O ^H C1 'i%):

calculated: C, 72.14, H, 7.11, N, 7.32. Found: C, 71.92, H, 7.22, N, 7.43.

lf,. . ·

Example 193

Method for the preparation of 2 - [(2-chlorobenzyloxy) methyl] -1-methyl-3- (piperid-1-yl) methyl] -1H-indole

NMR was consistent with the desired structure of the title compound.

FD. MS: 382 (M ^& lt ^{; +} & gt ^; ).

Mp 82-83 ° C.

Elemental analysis for C ₂₃ H ₂₇ ClN ₂ O (%):

H, 7.11; N, 7.32. Found: C, 71.87; H, 7.07; N, 7.36.

. · »

T

Example 194 '’

- 29ΙΛProcedure for the preparation of 2 - [(4-chlorobenzyloxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR (CDCl 3), IR and UV were consistent with the proposed structure of the title compound.

FD MS 382 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C 23 H 27 ClN 2 O · HCl (%):

H, 6.73; N, 6.68. Found: C, 65.54; H, 6.59; N, 6.39.

Example 195

Method for the preparation of 2 - [(naphth-1-yloxy) methyl] -1-methyl-3 '- [(piperid-1-yl) methyl] -1H-indole hydrochloride

HCl

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 384 (M ^& lt ^{; +} & gt ^; ),

Elemental analysis for ^C 26 ^H 28 ^N 2 ° ^-HCl .

calculated: C, 74.18, H, 6.94, N, 6.65,

292 found: C, 7.4.47, H, 7.05, N, 6.64.

Example 196

A method for preparing 2 - [(naphth-2-yloxy) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride.

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD: MS 384 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 26 ^H 28 ^N 2 ^O - ^HCl < ^% > ^: Calculated: C, 74.18, H, 6.94, N, 6.65. Found: C, 71.44, H, 6.93. N, 6.67.

It is the only compound of high purity, as seen by chromatographic methods.

Example .197

Method for the preparation of 2 - [(thiazol-2-yl) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR was consistent with the desired structure of the title compound.

293

Mp 175-176 ° C.

FD MS 341 (M ^& lt ^{; +} & gt ^; ). . .

Elemental analysis for C ₁₉ H ₂₃ N ₃ OS (%): Calculated: C, 66.83, H, 6.79, N, 12.31. Found: C, 66.64, H, 6.82, N, 12.03.

Example 198. 3 ¹ _t t, 2 - [(pyrazin-2-yl) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR, UV, and IR were consistent with the desired structure of the title compound.

* ‘

FD MS 336 (M ^& lt ^{; +} & gt ^; ).

Mp 101 ° C.

Elemental analysis for [?] 24 D + 4 ° (¾) ^: Calculated: C, 71.40, H, 7.19, N, 16.65. Found: C, 71.44, H, 7.33, N, 16.43.

Example 199

Method for the preparation of 2 - [(6-chloropyrazin-2-yl) methyl] -1-methyl-3 (piperid-1-yl) methyl] -1H-indole

294

NMR, UV and IR were consistent with the desired structure ¹ of the title compound.

FD-MS 370 (M ^& lt ^{; +} & gt ^; ). '' ...

Mp 94-96 ° C.

Elemental analysis for C ₂ q ₂ 3C1N O ₄ (%):

C, 64.77; H, 6.25; N, 15.11. C, 65.04; H, 6.45; N, 15.21.

Example 200

Method for the preparation of 2 - [(pyrimidin-2-yl) methyl] -1-methyl-3 - [(piperid-1-yl) methyl} -1H-indole

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 337 (M ^{+ 1} ).

Mp 123-125 ° C.

Elemental analysis for C ₂ qH2 N ₄ O ₄ (%):

calculated: C, 71.40, H, 7.19, N, 16.65. Found: C, 71.60, H, 7.43, N, 16.59.

- 295 Example 201 "

A method for preparing 2 - [(quinol-2-yl) methyl) -1-methyl-3 - [(piperid-1-yl) methyl] -1H-iridol. -

NMR, UV, and IR were consistent with the desired structure of the title compound. FD MS 385 (M ^{+ 1} ). '

Mp 113 ° C.

Elemental analysis for ^C 25 ^H 27 ^N 3 ^O 3 ^: Calculated: C, 77.89, H, 7.06, N, 10.90. Found: C, 77.64, H, 7.00, N, 11.05.

Example 202. ¹ ·.

Method for the preparation of 2 - [(6-chloropyridazine-2-yl) methyl] -l-methyl-3- (piperidin-l-yl) methyl] -lH-indole * ... · »· ·· _t

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 371 (M ^{+ 1} ).

Mp 138-139 ° C.

296 Elemental analysis for C ₂₀ H ₂₃ ClN ₄ 0 (%):

H, 6.25; N, 15.11. Found: C, 64.84; H, 6.28; N, 15.00.

Example 203

Method for the preparation of 2 - [(5,6,7,8-tetrahydronaphth-1-yl) methyl] -1-methyl-3 - [(4-dimethylaminopiperid-1-yl) methyl] -1H-inidol

NMR was consistent with the desired structure of the title compound.

FD-MS 431 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 28 ^H 37 ^N 3 ° (%):

calculated: C, 77.92; H, 8.64; N, 9.74. Found: C, 75.79; H, 8.74; N, 8.74.

Example 204

Process for preparing 2 - [(5,6,7,8-tetrahydronaphth-2-yl) methyl] -1-methyl-3 - [(4-dimethylaminopiperid-1-yl) methyl] -1H-indole dihydrochloride hydrate

297

.2 HCl

NMR and UV were consistent with the desired structure of the title compound.

FD MS 431.432 (M ^& lt ^{; +} & gt ^; ).

Mp 202 ° C;

For C ₂ gH ₃₇ N ₃ 0.2 HC1.H ₂ O (%):

calculated: C, 64.36, H, 7.91, N, 8.04. Found: C, 64.73, H, 7.50, N, 7.99.

Example 205

Method for the preparation of 2- (phenylthiomethyl) -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

HCl

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 350 (M ^{+ 1} ).

Elemental analysis for ^C 22 ^Ii 26 ^N 2 ^S · ^HCl · ¹ Calculated: C, 68.28, H, 7.03, N, 7.24 Found: C, 68.03; H, 7.00; N, , 7.10.

Example 298.

Process for the preparation of 2 - [(4-chlorophenylthio) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV and IR were consistent with the desired structure of the title compound.

. FĎ MS. 384 (M ^& lt ^{; +} & gt ^; ). Elemental analysis for C C l ^ ^ Cl ^ ^ S.HCl · (%): Calculated: C, 62.70, H, 6.22, N, 6.65. Found: C, 62.12, H, 6.42, N, 6.22.

It is the only * high purity compound as seen by chromatographic methods.

Example 207 7 '*

Method for the preparation of 2 - [(3-chlorophenylthio) methyl] -1-methyl-3 - [(piperidin-1-yl) methyl] -1H-indole hydrochloride

HCl

Cl

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS, 384 (M ^& lt ^{; +} &^gt;).

299

Elemental analysis for C22H25ClN2S.HCl (%):

C, 62.70; H, 6.22; N, 6.65. Found: C, 62.94; H, 6.23; N, 6.93.

Example 208

Method for the preparation of 2 - [(2-chlorophenylthio) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD: MS 384 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 22 ^H 25 ^ClN 2 ^{S, HCl} (%):

H, 6.22; N, 6.65. Found: C, 62.76; H, 6.20; N, 6.67.

Example 209; . '

Method for the preparation of 2 - [(2,4-dichlorophenylthio) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV and IR were consistent with the desired structure

300 of the title compound.

FD MS: 418 (M ^& lt ^{; +} & gt ^; ). 't,

Elemental analysis for ^C 22 ^H 24 ^Cl 2 ^N 2 ^S · ^HCl calculated: C, 57.96 / H, 5.53, N, 6.15. C, 56.61, H, 5.7.0, N, 6.05.

It is the only high purity compounding as evident by chromatographic methods. ‘'·.

'* f / « ¹ » ./ \'', \ <', - '

Example 210. ·. -, '· - *

Process for the preparation of 2 - [(2,5-dichlorophenylthio) methyl] -1-methyl-3 '- [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV, and IR were consistent with the desired structure of the title compound.

. FD MS 418.420 (M ^{+ 1} ).

. '. \ e. Elemental analysis for ^C 22 ^H 24 ^C1 2 ^N 2 ^{S HC} 1 (%), ·,> »calculated: C, 57.96, H, 5.53, N, 6.15; Found: C, 57.87, H, 5.50, N, 5.99.

Example 211. .

Method for the preparation of 2 - [(2,6-dichlorophenylthio) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

- 301 '-

N

AND

Cl • HCl _CH3

c ±

NMR. UV and IR are consistent with the desired structure of the title compound.

FD MS 417 (MH +).

Elemental analysis for ^C 22 ^H 24 ^Cl 2 ^N 2 ^{S, HCl} Calculated: C, 57.96, H, 5.53, N, 6.15. Found: C, 58.16, H, 5.68, N, 6.33.

Example 212

Method for the preparation of 2 - [(3,4-dichlorophenylthio) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole-hydrochiorium

NMR, UV, and IR were consistent with the desired structure of the title compound.

FD MS 418.420 (M ^{+ 1} ).

Elemental analysis for C 22 H ₂ N ₂ 4C1 ₂ S.HCI (%):

calculated: C, 57.96, H, 5.53, Ν, 6.15. Found: C, 57.98, H, 5.54, N, 6.16.

Example 213

Preparation of 2 - [(cyclohexylthio) methyl] -1-methyl-3302

- [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR (CDCl ₃ , UV and IR was consistent with the proposed structure of the title compound).

FD MS 356 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₂ H ₃₂ N ₂ S.HCl Calculated: C, 67.23; H, 8.46; N, 7.13. Found: C, 66.28; H, 9.27; 71

It is the only compound of high purity, as seen by chromatographic methods.

Example 214

Process for the preparation of 2 - [(n-propylthio) methyl] -1-methyl-3 - [(piperidin-1-yl) methyl] -1H-indole hydrochloride

NMR (CDC1 ₃ J, W, and IR were consistent with the proposed structure of the title compound.

FD-MS 316 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 19 ^H 28 ^N 2 ^S · -HCl (%) ^: Calculated: C, 64.65, H, 8.28, N, 7.94. Found: C, 64.72, H, 8.03 N, 8.12.

i J

». 303-Example 215 &quot;. Method for the preparation of 2 - [(benzylthio) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

NMR, UV and ICUjsou consistent with the desired structure • * _¥ *. '·. \ * ^Λ '

I title compounds.

FD-MS 365 (M ^& lt ^{; +} & gt ^; ). . / -. , '

Elemental analysis for ^C 23 ^H 28 ^N 2 ^S · ^HCl requires: C, 68.89; H, 7.29; N, 6.99. found:. C, * 68.63, H, 7.52, N, 7.11.

Example 216: · «; 'V r, /''i. . ¹

- Process for the preparation of 2- _j [(2-phenylethylthio) methyl] '- l-Methyl-3' - [(piperidin-l-yl) methyl] -lH-indole, - ^z, 'F' ^Ί. - ^{1 r} ''. · ·

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

^C 24 ^H ₂ S ^3-one: FDMS 379 (M ^+1).

It is the only compound of high purity, as seen by chromatographic methods.

304

Example 217

Method for the preparation of 2 - [(naphth-2-ylthio) methyl] -1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole

NMR (CDC1 _3), UV and IR were consistent with the proposed structure of the title compound.

FD-MS 400 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂ ^H 28 ^N 6 ^S 2 - ^HC1 Calculated: C, 71.45, H, 6.69, N, 6.41, found, NO, 69.59, H, 6.67, N, 6.21.

It is the only compound of high purity, as seen by chromatographic methods.

Example 220

A process for the preparation of 2-phenyl-3- (piperid-1-yl) methyl-1H-indole

NMR, UV, and IR were consistent with the desired structure of the title compound.

305

FD-MS 290 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂ q ₂ 2N2 Calc: C, 82.72, H, 7.64, N, 9.65 Found: C, 82.97, H, 7.74, N, 9.81.

- Example 221

A process for preparing 1-methyl-2-phenyl-3- (piperid-1-yl) methyl-1H-indole

NMR, UV and IR were consistent with the desired structure of the title compound.

FD MS 304.305 (M ^{+ 1} ).

Elemental analysis for ^C 21 ^H 24 ^N 2 ^{O ):} Calculated: C, 82.85, H, 7.95, N, 9.20. Found: C, 82.68, H, 7.92, N, 9. , 40.

Example 222

2-phenyl-1-methyl-3- [2- (piperid-1-yl) -1,2-ethanedionyl] -1H-indole

NMR (CDC1 _3), IR, and W were consistent with the proposed structure

306 of the title compound.

FD MS 346 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 22 ^H 22 ^N 2 ° 2 (%) · calculated: C, 76.28, H, 6.40, N, 8.09, found: C, 76.09, H, 6.35, N, 8.09.

Example 223 ’

Process for the preparation of 2-phenyl-1-methyl-3- [2- (N-benzyl-N-3- (dimethylaminopropyl) amino) -1,2-ethanedionyl] -1H-indole

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS: 453 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^c 29 ^H 31 ^N 3 ° 2 (%):

calculated: C, 76.79; H, 6.89; N, 9.26. Found: C, 77.06; H, 7.02; N, 9.45.

Example 224

Process for the preparation of 2-phenyl-1-methyl-3- [2- (4-dimethylaminopiperid-1-yl) -1,2-ethanedionyl] -1H-indole

307

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 389 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C 24 ^H 27 ^N 3 ° 2 (%):

H, 6.99; N, 10.79. Found: C, 73.82; H, 6.98; N, 10.75.

Example 225

1-Methyl-3- [2- (N-benzyl-N-3- (dimethylaminopropyl) amino) -1,2-ethanedionyl] -1H-indole

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 377 (M ^& lt ^{; +} & gt ^; ),

FAB MS 378 (M ^{+ 1} ).

Elemental analysis for ^ 23 ^Η 27 ^Ν 3 ° 2 (%):

calculated: C, 73.18, H, 7.21, N, 11.13,

308 found: C, 70.74, H, 7.14, N, 10.75.

It is the only compound of high purity, as seen by chromatographic methods.

Example 226

Process for the preparation of 1-methyl-3- [2- (4-dimethylaminopiperid-1).

-yl) -1,2-ethanedionyl] -1H-indole

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 313 (M ^{+ 1} ).

Elemental analysis for C ₁₈ H ₂₃ N ₃ O ₂ (%):

H, 7.40; N, 13.41. Found: C, 68.97; H, 7.59; N, 13.43.

Example 227.

5-Chloro-2 - [(2,4-dichlorophenoxy) methyl-1-methyl-3 - [(piperid-1-yl) methyl] -1H-indole hydrochloride

Cl r ~ N Vo * HCl AND CH ₃ C/ Cl NMR (CDC1 ₃₎ is consistent with the the proposed compound structure

309 named in the title.

Mp 177-179 ° C.

Elemental analysis for ^C 22 ^H 23 ^C1 3 ^N 2 ^{O HC1:} C, 55.72, H, 5.10, N, 5.91 Found: C, 55.70, H, 5.21, N, 6.16.

Example 228

5-Methoxy-2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3 - [(piperidin-1-yl) methyl] -1H-indole

NMR (CDC1 _3), a phenomenon consistent with the proposed structure of the title compound.

FD MS 432 (M ^{+ 1} ).

Mp 119-121 ° C.

Elemental analysis for C 23 H 22 N ₂ O ₂ (%): Calculated: C, 63.74, H, 6.05, N, 6.46. Found: C, 63.70, H, 6.12, N, 6, 46;

Example 229

5-Chloro-2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3 - [(4-dimethylaminopiperid-1-yl) methyl] -1H-indole dihydrochloride

NMR (CDCl 3) was consistent with the proposed structure of the title compound.

Elemental analysis for C ₂₄ ^H 28 ^Cl 3 ^N 3 ° · ² Cl Cl (%):

H, 5.46; N, 7.59. Found: C, 52.05; H, 5.41; N, 7.56.

Example 230,

5-Chloro-2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3 - [[4- (piperid-1-yl) piperid-1-yl] methyl] -1H-indole dihydrochloride

NMR (CDCl3) was consistent with the proposed structure of the title compound.

Elemental analysis for C ₂₇ H ₃₂ C1 ₃ N ₃ O.2 HCl (%):

H, 5.77; N, 7.08. Found: C, 51.53; H, 6.53; N, 7.57.

Example 231

311

5-Bromo-2 - [(2,4-dichlorophenoxy) methyl) -1-methyl-3- [2- (piperid-1-yl) ethyl] -1H-indole

NMR and IR were consistent with the desired structure of the title compound.

Mp 158-160 ° C.

Elemental analysis for ^C 23 ^H 25 ^BrCl 2 ^N 2 ° (%):

calculated; C, 55.67, H, 5.08, N, 5.64. Found: C, 55.96, H, 5.28, N, 5.69.

Example 232

Process for preparing 2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indole

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS: 271 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₁₆ H ₄ ClNO (%):

H, 5.19; N, 5.15. Found: C, 70.52; H, 5.26; N, 5.28.

312

Example 233

A process for preparing 2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-1H-indole

Cl

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 305.

Elemental analysis for ^{C16 H13 C1?} -2 ^NO: Calculated: C, 62.76, H, 4.28, N, 4.57 Found: C, 63.37, H, 4.72, N, 4 , 37.

Example 234

Method for the preparation of 2 - [(5,6,7,8-tetrahydronaphth-1-yloxy) methyl] -1-methyl-1H-indole

NMR was consistent with the desired structure of the title compound.

FD MS 292 (M ^{+ 1} ).

Elemental analysis for C ₂₀ H ₂₁ NO (%):

calculated: C, 82.44, H, 7.26, N, 4.81,

313 found: C, 82.51, H, 7.28, N, 4.80.

Example 235

Method for the preparation of 2 - [(5,6,7,8-tetrahydronaphth-2-yloxy) methyl] -1-methyl-1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD-MS 291 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for Ο ₂ θΗ ₂₁ ΝΟ (%):

calculated: C, 82.44; H, 7.26; N, 4.81. Found: C, 82.25; H, 6.98; N, 4.95.

Example 236

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -3-formyl-1-methyl-1H-indole

O.

Cl

NMR (CDCl3 ₎ was consistent with the proposed structure of the title compound.

FD-MS 299 (M ^& lt ^{; +} & gt ^; ).

314 Elemental analysis for ^C 17 ^H 14 ^ClNO 2 calculated: 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] -lH-indole tT CH ₃ CH ₃

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

Exact Mass Calcd: 271.2174, found: 271.2176.

Example 238

Process for preparing 1-methyl-2 - [[2 - [(piperidin-1'-yl) methyl] phenoxy] methyl] -ΙΗ-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD-MS 335 (M ^& lt ^{; +} & gt ^; ).

315

Elemental analysis for C 22 ^H 26 ^N 2 ° (%):

H, 7.84; N, 8.38. Found: C, 78.78; H, 7.58; N, 8.56.

Example 239

1-Methyl-3- [2 - [(4-chlorophenoxy) methyl] piperid-1-ylmethyl] -1H-indole

NMR (CDCl3) was consistent with the proposed structure of the title compound.

FD MS 368 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₂ H ₂₅ C1N ₂ O.HC1 (%):

H, 6.46; N, 6.91. Found: C, 64.93; H, 6.44; N, 6.78.

Example 240

1-Methyl-3- [3 - [(4-chlorophenoxy) methyl] piperid-1-ylmethyl] -1H-indole

316

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS 368 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 22 ^H 25 ^C1N 2 ° Calculated: C, 71.63, H, 6.83, N, 7.59 Found: C, 63.74, H, 6.54, N, 6.86.

Example 241

1-Methyl-3- [2- [2- (4-chlorophenoxy) ethyl] piperid-1-ylmethyl] -1H-indole

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

317

FD MS 382 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 23 ^ 27 ^C 2 ^N 2 ° (%):

H, 6.73; N, 6.68. Found: C, 62.05; H, 6.36; N, 6.18.

Example 243

Process for preparing ethyl [3- [2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] propanoate]

O CH

Cl

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

FD MS: 371 (M ^& lt ^{; +} & gt ^; ).

It is the only compound of high purity, as seen by chromatographic methods.

Example 244

(RS) -ethyl [2-amino-3- [2- [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] propanoate]

318

NMR was consistent with the desired structure of the title compound.

FD: MS 386.

Elemental analysis for ^c 21 ^H 23 ^ClN 2 ° 3 calculated: C, 65.20, H, 5.99, N, 7.24. Found: C, 64.95, H, 5.95, N, 7.27. .

Example 245

Method for the preparation of ethyl [2-hydroxyimino-3- [2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] propanoate]

IR, NMR and UV were consistent with the desired structure of the title compound.

FD-MS 400 (M ^& lt ^{; +} & gt ^; ).

Mp 165-166 ° C.

Elemental analysis for C ₂₁ H ₂₁ ClN ₂ 0 ₄ .0.2 H ₂ 0 (%):

H, 5.33; N, 6.93. Found: C, 62.38; H, 5.38; N, 6.87.

Example 246

Method for the preparation of (RS) -methyl- [2-methoxyimino-3- [2- [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] propanoate]

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS: 414 (M ^& lt ^{; +} & gt ^; ).

Mp 106-107 ° C.

Elemental analysis for ^C 22 ^H 23 ^ClN 2 ° 4 (%):

H, 5.59; N, 6.75. Found: C, 63.95; H, 5.57; N, 7.01.

Example 247

Process for the preparation of ethyl [2-benzyloxyimino-3- [2 - [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] propanoate]

--320 -

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS 490 (M ^& lt ^{; +} & gt ^; ).

Mp 96 ° C;

Elemental analysis for ^C 28 ^H 27 ^N 2O4 ^C l (%):

H, 5.54; N, 5.71. Found: C, 68.78; H, 5.67; N, 5.64.

Example 248

Process for the preparation of ethyl [2-ethanoyloxyimino-3- [2- [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] propanoate]

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS: 442 (M ^& lt ^{; +} & gt ^; ).

Mp 128-129 ° C.

Elemental analysis' for C ₂ ^H 23 ^C1N 3 2 ° 5: Calculated: C, 62.37, H, 5.23, N, 6.32 Found: C, 62.44; H, 5.40; N, 6 , 33.

Example 249

Process for the preparation of ethyl [2-benzoyloxyimino-3- [2- [(4-chlorophenoxy) methyl] -1-methyl-1H-indol-3-yl] propanoate]

IR, NMR and UV were consistent with the desired structure of the title compound.

FD-MS 504 (M ^& lt ^{; +} & gt ^; ).

Mp 146-147 ° C.

Elemental analysis for ^C 28 ^H 25 ^ClN 2 ^O 5 Calculated: C, 66.60, H, 4.99, N, 5.55. Found: C, 66.88, H, 5.22, N, 5.80. .

Example 250

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -3- (4-hydroxy-1-methylpiperid-4-yl) -1-methyl-1H-indole

322

<1

NMR, IR and UV were consistent with the desired structure of the title compound.

FD: MS 384 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂ ^H 25 ^ClN 2 ° 2

H, 6.55; N, 7.28. Found: C, 69.46; H, 6.44; N, 7.28.

It is the only compound of high purity, as seen by chromatographic methods.

Example 251

A process for the preparation of ethyl [2-hydroxyimino-3- (1-methyl-2-phenyl-1H-indol-3-yl) propanoate]. '*

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

UV and IR are consistent with the proposed compound structure

323 named in the title.

FD MS 322 (M ^& lt ^{; +} & gt ^; ).

Mp 141-142 ° C.

Elemental analysis for C, H, _{Ig lg} N ₂ O ₃ (%):

H, 5.62; N, 8.69. Found: C, 70.64; H, 5.89; N, 8.58.

Example 252

Process for the preparation of ethyl [2-hydroxyimino-3- (1H-indol-3-yl) propanoate]

IR, NMR and UV were consistent with the desired structure of the title compound.

FD MS: 246 (M ^& lt ^{; +} & gt ^; ).

Mp 156 ° C.

Elemental analysis for C ₃₃ H ₃₄ N ₂ O ₃ .0.3 H ₂ O (%):

Calcd: C, 62.04; H, 5.85; N, 11.13 _; Found: C, 61.77, H, 5.55, N, 11.07.

Example 253

6-Chloro-2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3- [2- (piperid-1-yl) ethyl] -1H-indole

324

Cl

IR and NMR were consistent with the desired structure of the title compound.

FD-MS 450 (M ^& lt ^{; +} & gt ^; ).

Mp 116.5-118.5 ° C.

Elemental analysis for C ₂₃ H ₂₅ Cl ₃ N ₂ O (%):

H, 5.58; N, 6.20. Found: C, 61.43; H, 5.67; N, 6.26.

Example 255

7-Chloro-2 - [(2-, 4-dichlorophenoxy) methyl] -1-methyl-3- [2- (piperid-1-yl) ethyl] -1H-indole

Cl '

Cl

IR and NMR were consistent with the desired structure of the title compound.

Mp 134-136 ° C.

Elemental analysis for C ₂₃ H ₂ 5 ^c -'- ^N 2 ⁰ 3 (%) · Calculated: C, 61.14, H, 5.58, N, 6.20;

325 found: C, 61.39, H, 5.71, N, 6.47.

Example 256

4-Methyl-2 - [(2,4-dichlorophenoxy) methyl] -1- [3- (piperid-3-yl) propyl] -1H-indole ₃

Cl

NMR (CDC1 ₃₎ was consistent with the proposed structure of the title compound.

Exact mass FAB (M ^{+ 1} ) for ^C 24 ^H 30 O 1 ^N 2 ° ^: calculated: 397.2047, found: 397.2041.

Example 257

5-Chloro-2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3 - [(4-dimethylaminopiperid-1-yl) methyl] -1H-indole dihydrochloride

- 326 -

Elemental analysis for ^C 24 ^H 28 ^Cl 3 ^N 3 ° (%):

H, 5.46; N, 7.59. Found: C, 52.05; H, 5.41; N, 7.56.

Example 258

7-Methyl-2 - [(2,4-dichlorophenoxy) methyl] -1-methyl-3- [3- (piperid-1-yl) propyl] -1H-indole dihydrochloride

NMR (CDCl3) was consistent with the proposed structure of the title compound.

Mp 129-131 ° C.

Elemental analysis for ^C 25 ^H 30 ^Cl 2 ^N 2 ° (%).

H, 6.79; N, 6.29. Found: C, 67.34; H, 6.80;

Example 259

Process for the preparation of 1,2-dimethyl-3 - [[4- (piperid-1-yl) piperidine] -1,3-yl / acetyl]-]-indole

NMR, IR and UV were consistent with the desired structure of the title compound.

FD MS 353 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₂ H ₃₁ N ₃ O (%):

H, 8.84; N, 11.89. Found: C, 74.76; H, 8.96; N, 11.76.

Example 260

Process for the preparation of 1,2-dimethyl-3 - [[4- (N, N-dimethylamino) piperid-1-yl] acetyl] -1H-indole

NMR was consistent with the desired structure of the title compound.

^C 19 ^H 27 ^N 3 ^O: FD MS 313 (M ⁺ ).

Example 261

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -3 - [[(4-cyclohexyl) piperazin-1-yl] acetyl] -1-methyl-1H-indole

328

NMR was consistent with the desired structure of the title compound. ^c 28 ^H 34 ^ClN 3 ° 2 ^{: fd ms 480}

Example 262

Preparation of 2 - [(4-chlorophenoxy) methyl] -3 - [[(4-phenyl) piperazin-1-yl] acetyl] -1-methyl-1H-indole

NMR was consistent with the desired structure of the title compound.

^C 28 ^H 28 ^C1N 3 ° ^{2: FD MS 474 <M +)} ·

Example 263

Preparation of 2 - [(4-chlorophenoxy) methyl] -3 - [[4- (N, N-dimethylamino) piperid-1-yl] acetyl] -1-methyl-1H-indole

NMR, IR and UV were consistent with the desired structure of the title compound.

MS: FD 439 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for C ₂₅ H ₃₀ ClN ₃ 0 ₂ (%):

H, 6.87; N, 9.55. Found: C, 67.98; H, 6.81; N, 9.40.

Example 264

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3 - [[N-methyl-N- (3-N *, N'-dimethylaminopropyl) amino] acetyl] -1H-indole

330

NMR and IR were consistent with the desired structure of the title compound.

FD MS: 428 (M ^{+ 1} ).

Exact weight FAB for C ₂₄ H ₃ iC1N ₃ O ₂ :

calc .: 428.2105, found: 428.2113.

Example 265

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2 - [(4-piperid-1-yl) piperidin-1-yl] acetyl] -1H-indole

331

NMR, IR, and UV were consistent with the desired structure of the title compound.

MS FD 479 (M ^{+ 1} ).

Exact weight FAB for C2 ₈ H ₃₅ C1N ₃ O ₂ :

calculated: 480.2418, found: 480.2411,

Example 266

Preparation of 2 - [(4-chlorophenoxy) methyl] -3- [2 - [(4-piperid-1-yl) piperid-1-yl] acetyl] -1- [2- (N, N-dimethylpiperid-4)] (yl) ethyl] -1H-indole iodide

- 332

H ₃ C ^Z CHs

NMR was consistent with the desired structure of the title compound.

Elemental analysis for C ₃₆ H ₅₀ ClIN ₄ O ₂ .H ₂ O (%):

H, 6.90; N, 7.46. Found: C, 57.85; H, 6.86; N, 7.04.

Example 267

Preparation of 2 - [(4-chlorophenoxy) methyl] -1 - [(2-piperid-4-yl) ethyl] -3- [2- / 4- (piperid-1-yl) piperid-1-yl] acetic acid -1-yl] -1H-indole

333

NMR was consistent with the desired structure of the title compound.

FAB MS 577 (M ^{+ 1} ).

Elemental analysis for C ₃₄ H ₄₅ ClN ₄ O ₂ (%):

H, 7.86; N, 9.71 Found: C, 70.55; H, 7.87; N, 9.52.

Example 268

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -3- [2- (methylaminopropyldimethylamino) acet-1-yl] -1 - [(2-piperid-3-yl) ethyl] indole

NMR was consistent with the desired structure of compound ' _r '. named in the title.

FAB MS 525 (M ^{+ 1} ).

Exact weight for C ₃₀ H ₄₂ N ₄ O ₂ Cl (%):

calculated: 525.2996, found: 525,3003.- *

Example 269 'a. - ¹

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1 - [(2-; piperid-3-yl) ethyl] -3- [2- (4- (piperid-1-yl) piperid-1-yl)] acet-1-yl] -4-indole

335

NMR was consistent with the desired structure of the title compound.

FD MS (M ^{+ 1} ). '

Elemental analysis calculated: C, 70.75; H, 7.86; N, 9.71. Found: C, 70.72; H, 7.83; N, 9.63.

ΐ *,

Example 270

2 - [(4-chlorophenoxy) methyl] -3- [2- (methylaminopropyldimethylamine) acet-1-yl] -1 - [(2-piperidin-4-yl) ethyl] -1H-indole

336

NMR was consistent with the desired structure for the title compound.

Exact mass for ^C 30 ^H 42 ^N 4 ° 4 ^Cl calculated 525.2996, found 525.3013.

Example 271,

Method for preparing S-2 - [(4-chlorophenoxy) methyl] -3- [2- / 4- (piperid-1-yl) piperid-1-yl] acet-1-yl] -1 - [(3-piperid) 3-yl) propyl] -1H-indole

337

NMR was consistent with the desired structure of the title compound.

FAB MS (M ^{+ 1} ).

Elemental analysis for ^C 35 ^H 47 ^ClN 4 ^O 2 - Calculated: C, 71.10, H, 8.01, N, 9.48. Found: C, 70.82, H, 8.14, N, 9.23.

Example 272.

Preparation of R-2 - [(4-chlorophenoxy) methyl] -3- [2- / 4- (piperid-1-yl) piperid-1-yl] acet-1-yl] -1 - [(3-piperid) -3-yl) propyl] -1H-indole | f '

338

NMR was consistent with the desired structure of the title compound.

Exact weight for ^C 35 ^H 48 ^C1H 4 ° 2 ^! calculated: 591.3466, found: 591.3458.

Example 273

Preparation of cis / traris-2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- / 4- (piperid-1-yl) cyclohex-1-yl] acet-1-yl] -1H -indolu

339

ch ₃

Mixture of cis / trans isomers 1 and 2

NMR was consistent with the desired structure of the title compound.

FD MS: 478 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 29 ^H 35 ^C1N 2 ° 2 requires 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- (piperid-1-yl) cyclohex-1-yl] acet-1-yl] -1H-indole

CH ₃

Isomer 1

- 340 NMR was consistent with the desired structure of the title compound.

FD MS: 478 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 29 ^H 35 ^c1n 2 ° 2 requires C, 72.71, H, 7.36, N, 5.85 Found: C, 72.55, H, 7.52, N, 5.67 .

Example 275

Preparation of 2 - [(4-chlorophenoxy) methyl] -3- [2- / 4- (piperidin-1-ylcyclohex-1-yl) acet-1-yl] -1- (2-piperid-4-yl) ethyl] 1H-indole

NMR was consistent with the desired structure of the title compound.

FD MS: 575 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 35 ^H 46 ^C1N 3 ° 2 requires C, 72.95, H, 8.05, N, 7.29 Found: C, 72.88, H, 8.23, N, 7.53 .

341

Example 276

Method for the preparation of 2 - [(4-chlorophenoxy) methyl] -1-methyl-3- [2- / 4- (piperid-1-yl) cyclohex-1-yl] acet-1-yl] indole

CH ₃

Isomer 2

NMR was consistent with the desired structure of the title compound.

FD MS: 478 (M ^& lt ^{; +} & gt ^; ).

Elemental analysis for ^C 29 ^H 35 ^C1N 2 ° 2 ») calcd: C, 72.71, H, 7.36, N, 5.85 Found: C, 72.43, H, 7.42, N, 5.86.

Example 277

Preparation of 2 - [(4-chlorophenoxy) methyl] -5-fluoro-1-methyl-3- [2- / 4- (piperid-1-yl) piperid-1-yl] acet-1-yl] -1H -indolu

342

NMR was consistent with the desired structure of the title compound.

FAB MS 498 (M ^{+ 1} ).

Elemental analysis for ^C 28 ^H 33 ^ClFN 3 ° 2 Calculated: C, 67.53, H, 6.68, N, 8.44. Found: C, 67.34, H, 6.59, N, 8.58. .

Essentially, according to the methods described above, one of ordinary skill in the art can prepare other compounds of Formula I.

The compounds of this invention bind receptors specific for neuropeptide Y, as well as closely related neuropeptides. [A review of neuropeptide Y receptors is provided by D. Gehlert in Life Sciences, 55, 551-562 (1994) and P. A. Hipskind and D. R. Gehlert, Annual Reports in Medical Chemistry, 91.

(1996)]. The receptors for neuropeptide Y and peptide YY have considerable overlap, while the 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 the peptide YY.

-. 343

Both neuropeptide Y receptor subtypes were originally designed based on the affinity of the 13 to .36 neuropeptide fragments.

Y using a preparation from the sympathetic nervous system.

Although these are the best proven receptors for neuropeptide Y, there is substantial evidence that there are other receptor subtypes. The Y-3 receptor which is sensitive to the neuropeptide Y but not to the YY peptide has proven to be the best. Also described is another recently defined receptor that binds a high affinity YY peptide and a lower affinity neuropeptide Y. Although the pharmacology of nutritional response in neuropeptide Y appears to be Y-1 in nature, a separate feeding receptor has been proposed. Several receptors have been successfully cloned to date. The following paragraphs summarize available information on known neuropeptide receptor subtypes

Y and its potential role in physiological function.

Receptor Y-1

The Y-1 receptor is the best characterized neuropeptide Y receptor. This receptor is generally considered postsynaptic and mediates a number of known neuropeptide effects

Y in the peripheral region. Originally, this receptor has been described as having a low affinity for c-terminal fragments of neuropeptide Y, such as fragments 13-36, but interacting with a full-length neuropeptide Y and a peptide of YY with the same affinity [C. Wahlenstedt et al., Regulators of Peptides, 13, 307-318 (1986), C. Wahlenstedt et al., Neuronal Messengers in Vascular Function, 231-241, edited by Nobin et al. (1987)]. The amino acid substitution at position 34 with proline (Pro ³⁴ ) results in a protein that is specific for the Y1 receptor [Ε. K. Potter et al., European Journal of Pharmatology, 193. 15-19. (1991)]. This composition is used to determine the role of the Y1 receptor in various functions. It is believed that the receptor is condensed to adenylate cyclase in an inhibitory manner in the cerebral cortex, vascular smooth muscle cells, and SK-N-MC cells. [Review by BJ McDermott et al. in Cardiovascular Research, 27,

893-905 (1993)]. This effect is prevented by the administration of pertussis toxins, confirming the role of the condensed receptor

G-protein. Y-l receptor mediates the mobilization of intracellular »resentative of calcium into vascular smooth muscle cells * ¹ pig and human erythroleukemia cells.

The cloned human Y-1 receptor may be associated with either phosphotidylinositol hydrolysis or 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)]. It is reported that the Y-1 receptor condenses to any secondary mesenger system when studied using tissue preparations or cell lines naturally expressing the receptor [D. Gehlert, supra, p. 553]. Therefore, the Y-1 receptor cannot be distinguished solely on the basis of condensation to a single secondary mesenger.

Modulation of the Y1 receptor (either a typical or atypical Y1 receptor) appears to affect a number of physiological conditions including obesity or taste disorders, adult onset diabetes, bulimic nervousness, pheochromocytor-induced hypertension, subarachnoid haemorrhage, neurogenic vascular hypertrophy, hypertension, anoxeric nervousness [PCT patent application WO 96/16542, published Jun. 6, 1996, p. 135 and references cited therein].

Y-2 receptor

As with the Y-1 receptor, this receptor subtype is first delineated using vascular preparations. Pharmacologically, the Y-2 receptor differs from the Y1 receptor in that it exhibits affinity for the C-terminal fragments of neuropeptide Y. The receptor is more frequently distinguished by the use of neuropeptide Y (13-36), with fragment 3 to 36 of neuropeptide Y and peptide YY providing improved affinity and selectivity [Y. Dumont et al., Society for Neuroscience Abstracts, 19, 726 (1993)]. Like the Y-1 receptor, this receptor binds to the inhibition of adenylate cyclase, although in some preparations it may not be sensitive to pertussis toxin. The 'Y-2 receptor has been found to reduce intracellular calcium levels in the synapse by selective inhibition of N-type calcium channels. Like the Y-1 receptor, the Y-2 receptor may also manifest itself by different condensation to secondary meseners. The Y-2 receptor appears to be involved in modulating hypertension, epileptic seizure, and neurogenic vascular hypertrophy [PCT Patent Application WO 96/16542, published Jun. 6, 1996, p. 135 and references cited therein]. ·, ·

Y-2 receptors are found in various areas of the brain, including the hippocampus, substantia nigraateralis, thalamus, ¹ hypothalamus and brainstem. In all these tissues, Y-2 receptors mediate a decrease in neuromediator release. The Y-2 receptor is cloned using the techniky cloning expression technique. M. Rose et al., Journal of Biological Chemistry, 270, 22661. (1995), C. Gerald et al., Journal of Biological Chemistry, 270, 26758 (1995) and DR Gehlert et al., Molecular Pharmacology, 49, 224 (1996).

346

Y-3 receptor

This receptor has a high affinity for the neuropeptide Y, while having a lower affinity for the YY peptide. Although neuropeptide Y is fully active against this set of receptors, the YY peptide is poorly active. This pharmacological property is used to define this receptor. A receptor having similar pharmacological properties to the Y-3 receptor has been identified in the CA3 region of the hippocampus using an electrophysiological technique. This receptor can potentiate the excitatory response of these * neurons to N-methyl-D-aspartate (NMDA) [F. Monnet, P. et al., European Journal of Pharmacology, 182, 207-208 (1990)]. This receptor seems to

Λ modulate hypertension [PCT patent application WO 96/16542, published Jun. 6, 1996, p. 135 and references cited therein].

The presence of these receptors is best demonstrated in the brain stem of the rat, especially in the nucleus tractus solitarius. Application of neuropeptide Y in this area results in dose-related reductions in blood pressure and heart rate. This area of the brain can also. to obtain significant contributions from Y-1 and Y-2 receptors. Neuropeptide Y also

Ί I inhibits acetylcholine-induced catecholamine release from the adrenal medulla, possibly due to the Y-3 receptor [C. Wahlestedt et al., Life Sciences, 50 PL7-PL14 (1992)].

AND

Receptor preferring peptide YY ·.

A fourth receptor is shown that exhibits a slight preference for the YY peptide over the neuropeptide Y. This receptor was first described in the rat small intestine as having a 5 to 10-fold higher affinity for the peptides.

347

YY, compared to the neuropeptide Υ [Y. M. Laburthe et al., Endocrinology, 118, 1910-1917 (1986)]. Subsequently, this receptor is found in the adipocyte and in the proximal kidney canal cell line. This receptor is condensed in an inhibitory manner to adenylate cyclase and is sensitive to pertussis toxin.

In the intestine, this receptor causes a strong inhibition of fluid and electrolyte secretion. The receptor is placed in cell passages where internal chloride secretion is expected to occur. The receptor preferred for the YY peptide in adipocytes mediates the reduction of lipolysis via a mechanism dependent on cyclic adenosine monophosphate (cAMP).

Nutritional receptor

One of the earliest central effects of neuropeptide Y found was the profound increase in food intake observed after administration of peptides to the hypothalamus in rats. The response is greatest when the peptide is infused into the peripheral area of the hypothalamus [B. G. Stanley et al., Brain Research,

604, 304-317 (1993)]. Although the pharmacology of this response resembles the Y1 receptor, fragment 2-36 of neuropeptide Y is significantly stronger than that of neuropeptide Y. In addition, intracerebroventricular neuropeptide Y (2-36) fully stimulates nutrition but does not lower body temperature as caused by the neuropeptide. Full Length Y [Y. F. B. Jolicoeur et al., Brain Research Bulletin, 26, 309-311 (1991)]. Two earlier patent publications describe the cloning and expression of the Y5 receptor considered to be a nutritional receptor [PCT patent publication WO 96/16542, published June 6, 1996, and Australian patent publication AU 956 467 AO, published November 30, 1995. ],

-. 348 -.

The biological activity of the compounds of this invention is evaluated using an initial screening assay to quickly and accurately measure binding of the test compound to known neuropeptide Y receptor sites. Assays useful for evaluating neuropeptide Y receptor antagonists are well known in the art [see, e.g. No. 5,284,839, issued February 8, 1994, which is incorporated herein by reference, and also see MW Walker et al., Journal of ¹ Neurosciences, 8, 2438-2446 (1988)].

Neuropeptide Y Binding Assay

The ability of the compounds of this invention is determined by their ability to bind neuropeptide Y, using a procedure as essentially described by M. W. Walker et al. (cited above). The SK-N-MC cell line is used in this assay. This cell line was obtained from the Sloane-Kettering Memorial Hospital, New York (USA). Said cells are cultured in a T-150 flask using Dulbecco's minimal baseline (DMEM) supplemented with 5% fetal calf sera. Cells are removed manually from the flask by scraping and pelleted and stored at -70 ° C.

The pellets were resuspended using a glass homogenizer in 25 mM HEPES (pH 7.4), a buffer containing 2/5 mM calcium chloride, 1 mM magnesium chloride and 2 mg per liter bacitracin. Incubations are carried out in a final volume of 200 μΐ containing 0.1 nM ¹²⁵ I-YY peptide (activity 8140.10 ¹⁰ , with ¹ .mmol ^-1 ) and 0.2 to 0.4 mg protein, for approximately 2 hours at room temperature.

Non-specific binding is defined as a measure of radio349 activity that remains bound to tissue after incubation in the presence of 1 μΜ of neuropeptide Y. In some experiments, different concentrations of compounds are included in the incubation mixture.

Incubation is terminated by rapid filtration of glass fiber filters that have been pre-treated by wetting in 0.3% polyethyleneimines using a 96-well trap. The filters were washed with 5 ml of 50 mM Tris (pH 7.4) at 4 ° C and rapidly dried at 60 ° C. The filters are then treated with melted scintillation sheets and the radioactivity remaining on the filters is determined. The results are analyzed using various software complex blocks. Protein concentration is measured using a normalized kumasie-protein as a test reaction preparation, using bovine serum albumin as standards.

Many of the compounds prepared above exhibit significant activity as a neuropeptide Y receptor antagonist (= = 10 μΜ to 0.1 nM). Since the compounds of formula I are potent neuropeptide Y receptor antagonists, these compounds are valuable for the treatment of a wide variety of clinical conditions characterized by the presence of an excess of neuropeptide Y. Thus, the present invention provides methods for treating or preventing a physiological disorder associated with an excess of neuropeptide Y. in administering 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 includes those disorders that are associated with inappropriate stimulation of neuropeptide Y receptors, regardless of the actual amount of neuropeptide Y present at the site.

350

These physiological disorders include disorders or diseases of the heart, blood vessels or the renal system such as angiospasm, heart failure, shock, cardiac hypertrophy, elevated blood pressure, angina.

myocardial infarction, sudden cardiac death, congestive heart failure, arrhythmias, peripheral vascular disease and abnormal renal conditions such as insufficient fluid flow, abnormal mass transfer or kidney failure

Conditions associated with increased sympathetic nerve activity, for example during or after coronary artery surgery and gastrointestinal surgery and surgery,

cerebral diseases and disorders related to the central nervous system such as cerebral infarction, neurodegeneration, epilepsy, stroke and stroke-related conditions, cerebral angiospasm and haemorrhage, depression, anxiety states, schizophrenia, dementia, seizures and epilepsy, conditions associated with pain or nociception , diseases associated with abnormal gastrointestinal motility and secretion, such as various forms of ileum, urinary insufficiency and Crohn's disease, disorders associated with abnormal beverage intake. and foods such as obesity, anorexia, bulimia and metabolic disorders, diseases related to sexual dysfunction and reproductive disorders,

- 351 conditions and disorders associated with inflammation, uj (Al respiratory diseases such as asthma and conditions related \

- ·! * 'With asthma and bronchoconstriction and /

J diseases related to abnormal hormone release, such as LH, 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 routes. These compounds are effective in both injectable and oral compositions. Such compositions are prepared by methods well known in the art of pharmacy and include at least one active compound.

The present invention also encompasses methods using pharmaceutical compositions comprising as an active ingredient a compound of Formula I together with pharmaceutically acceptable carriers. In the preparation of the compositions of the invention, the following: the active ingredient is usually mixed with a vehicle, diluted with a vehicle, or enclosed in a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the vehicle serves as a diluent, it may be solid, semi-solid, or a liquid material that acts as a vehicle,. carrier or medium for the active ingredient. Such compositions may take the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, &lt; RTI ID = 0.0 &gt;

in syrups, aerosols (solid or liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories,

352 sterile injectable solutions and sterile packaged powders.

When preparing the compositions, it may be necessary to grind the active compound to give the appropriate particle size prior to contact with the other ingredients. If f

the active compound is substantially insoluble, normally ground to a particle size of less than 0.074 mm. If the active ingredient is substantially water-soluble, the particle size is normally adjusted by grinding to achieve a substantially uniform distribution in the formulation, for example to a particle size of about 0.370 mm.

Some examples of a suitable vehicle include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.

The compositions may additionally contain lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methylhydroxybenzoate and propylhydroxybenzoate, sweetening and flavoring agents. The compositions of the invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient using techniques known in the art.

'../AND

The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, suitably from about 10 to about 30 mg, of the active ingredient. Dosage unit form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each dosage being

353 contains a predetermined amount of active material, calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical vehicle.

The active compound is effective over a wide dosage range. For example, daily dosages commonly fall within the range of about 0.5 to about 30 mg / kg body weight. In the treatment of adult humans, a range of about 1 to about 15 mg / kg per day in a single dose or in a divided dose is particularly preferred. However, it will be appreciated that the amount of compound actually administered will be determined by the physician in light of significant circumstances, including the condition to be treated, the route of administration chosen, the compound actually administered, the individual patient's age, weight and response, is not intended to limit the scope of the invention in any way.

In some cases, dosage levels below the lower limit of the above range may be more than adequate, while in other cases even larger doses may be used without causing any harmful side effects, provided that such larger doses are first subdivided into several smaller doses. doses for daytime administration i

For preparing solid compositions such as tablets, the principal active ingredient is admixed with a pharmaceutically acceptable vehicle to form a solid preformulated composition comprising a homogeneous mixture of a compound of the invention. By referring to the preformulated formulation as homogeneous, it is meant that the active ingredient is dispersed quite uniformly throughout the formulation so that the formulation can be readily subdivided into equally effective dosage unit forms such as tablets, pills, and capsules. Such a solid preformulated composition is then subdivided into dosage unit forms of the type described above

354 above, which contain from 0.1 to about 500 mg of the active ingredient of the invention.

The tablets or pills of the present invention may be coated or otherwise formulated to provide a dosage form that affords the advantage of prolonged action. For example, tablets or pills may comprise an in-dose dose and a component outside the dose which is in the form of a coating and surrounds the in-dose dose. Both components can be separated by an enteric layer to prevent disintegration in the stomach *

and permits the internally placed component to pass intact into the duodenum or to be released deferred. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures thereof with such materials as shellac, cetyl alcohol and cellulose acetate.

Liquid forms into which the novel compositions of this invention for oral or injection administration can be incorporated include aqueous solutions, suitably flavored syrups, aqueous or oily 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 or suspensions in pharmaceutically acceptable, aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid compositions may contain pharmaceutically acceptable vehicles as described above. Preferably, the compositions are administered by the oral or nasal respiratory route to achieve a local or systemic effect. Compositions in preferred pharmaceutically acceptable solvents may be nebulized using inert gases. Spray solutions

355 may be inhaled directly from the spray device or the spray device may be attached to a face mask, a blanket or a breathing apparatus that periodically generates positive pressure. The compositions in solution, suspension or powder may be administered, preferably orally or nasally, from a device that releases the composition in an appropriate manner.

F

The following examples illustrate pharmaceutical compositions of the present invention.

Example of composition 1

Hard gelatin capsules are prepared containing the following ingredients. . - -.

Component Quantity (mg / capsule) active ingredient 1 ' 30.0 starch 305.0 magnesium stearate i 5,0 _:

The above ingredients are mixed and filled into hard gelatin capsules in an amount corresponding to 340 mg.

Example of device 2

Tablets are prepared using the following ingredients:

356

Component Quantity (mg / tablet) active ingredient 25.0 cellulose, microcrystalline 200.0 silica, colloidal 10.0 stearic acid 5.0

The ingredients are mixed and compressed into tablets, each weighing 240 mg.

Example of device 3

A dry powder inhalation composition is prepared containing the following ingredients.

Ingredient% by weight active ingredient 5 lactose ´ · 95

The active ingredient is mixed with lactose and the mixture is introduced into a dry powder inhaler.

Example of device 4

Tablets, each containing 30 mg of active ingredient, are prepared as follows:

357

Component Quantity (mg / tablet) active ingredient 30.0 starch 45.0 cellulose, microcrystalline 35.0 polyvinylpyrrolidone (as a 10% solution in water) 4.0 sodium carboxymethylated starch 4,5 « magnesium stearate 0.5 talc · '. 1 1.0. total 120 mg

The active ingredient, starch and cellulose are passed through a sieve through which US33 mesh particles are passed and mixed thoroughly. A solution of polyvinylpyrrolidone is mixed with the resulting powder and passed through a sieve through which 0 mesh (16 mesh) particles are passed. The granules so prepared are dried at 50-60 ° C and passed through a 0 mesh screen (US mesh 16). (US mesh 30), and then added to the granules which, after mixing, are compressed on a tabletting machine to form tablets, each having a weight of 120 mg.

Example of device 5

Capsules, each containing 40 mg of the drug, are prepared as follows:

358

Ingredient Quantity (mg / capsule)

active ingredient starch magnesium stearate 40.0 109.0 1.0 total 150.0 mg The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a sieve through which the particles pass '' '. , .X, * 0.833 mm (US mesh 20), and filled into hard gelatin capsules in an amount corresponding to 150 mg. Example of composition 6 *. t (· Suppositories, each containing 25 mg active, are prepared as follows: ingredients; Component Amount l. active ingredient .25 mg

saturated fatty acid glycerides up to 2000 mg.

The active ingredient is passed through a 0.246 mm (60 mesh) sieve and suspended in saturated fatty acid glycerides that have previously been melted using minimal heat. The mixture is then poured into a suppository mold having a nominal content of 2.0 g and allowed to cool.

Example of device 7

359

Suspensions, each containing 50 mg of drug per 5.0 ml dose, are prepared as follows:

Component

Amount of active ingredient 50.0 mg xanthan gum 4.0 mg sodium carboxymethylated cellulose (11% a

-cellulose, microcrystalline (89%) 50.0 mg • .r sucrose 1.75 g sodium benzoate 10.0 mg flavoring and coloring agent purified water up to 5.0 ml as needed

The drug, sucrose, and xanthan gum are mixed, passed through a sieve through which particles of 1.51 mm (US mesh 10) pass, and then mixed with a pre-prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. A certain amount of water is diluted with sodium benzoate, flavored and colorant and brought into contact with the mixture prepared above with stirring. Sufficient water is then added to achieve the desired volume.

Example of device 8

Capsules, each containing 15 mg of the drug, are prepared as follows:

360

Component Quantity (mg / capsule) active ingredient 15.0 starch 407.0 magnesium stearate 3.0 total 425 mg 0 mg

The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a sieve through which 0.833 µm particles pass through, and filled into hard gelatin capsules in an amount of 425 mg.

Example of device 9

An intravenous formulation can be prepared as follows:

Ingredient Amount Active Ingredient 250.0 mg Isotonic saline 1000 ml t

Example of device 10

A topical formulation can be prepared as follows:

Component Amount active ingredient 1 to 10 g emulsifying. wax liquid paraffin white solid paraffin 30 g 20 g up to 100 g

361

The white solid wax is heated until it melts. Liquid paraffin and emulsifying wax are introduced into the melt and mixed until dissolved. To the resulting mixture is added the active ingredient and stirring is continued until the compound is dispersed. The mixture was then cooled until it solidified.

Example of device 11

Sublingual or buccal tablets, each of _{which, contains} 10 mg of active ingredient, can be prepared as follows:

Ϊ

Quantity (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

Glycerol, water, sodium citrate, polyvinyl alcohol and polyvinylpyrrolidone are brought into contact with continuous stirring and maintained at a temperature of about 90 ° C. When the polymer goes into solution, the solution is cooled to a temperature of about 50-55 ° C and the drug is slowly admixed to the resulting solution. The homogeneous mixture is poured into molds made of an inert material to prepare a drug-containing diffusion matrix having a thickness of about 2 to 4 mm. The diffusion matrix is then cut into individual tablets of appropriate size.

- 362

Another preferred composition used in the methods of the invention uses ‘patches (transdermal release device). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of this invention in a controlled amount. The construction and use of transdermal patches for the release of pharmaceutical preparations is well known in the art [see, for example, U.S. Patent No. 5,023,252, issued June 11, 1991, which is incorporated herein by reference]. Such patches may be formulated as sustained release, pulsatile or as desired pharmaceutical formulations. , it is often desirable or necessary to introduce the pharmaceutical composition into the brain, either directly or indirectly. The direct technical method typically involves placing the drug delivery catheter into the patient's ventricular system to perform a bypass of the hernatoencephalitic barrier. One such implantable release system used to deliver biological factors 4 to specific anatomical areas of the body is described in U.S. Patent No. 5,011,472, issued April 30, 1991, which is incorporated herein by reference.

* u

An indirect technique, which is generally preferred, typically involves providing a composition that provides drug latency by converting hydrophilic drug substances to lipid soluble drugs or drug precursors. Latency is usually achieved by blocking the hydroxy, carbonyl, sulfate moiety, and primary amino groups present in the drug to achieve easier lipid solubility of the drug and to allow transport across the hernatoencephalitic barrier. According to another embodiment of the invention, the release of hydrophilic drug substances may be increased

363 by intra-arterial infusion of hypertonic solutions that may temporarily open the blood-brain barrier.

Claims (15)

PATENTOVÉ AND Claims 1, Compound of formula ; cn θ ' O . CJ O < 1 r ^- ** O ó -íc. t in which ' R ^b is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkanoyl, trifluoromethyl, hydroxy or halogen, R ¹ represents a hydrogen atom, an alkyl group having 1 to 6, carbon atoms or a group of the formula - (CH ₂ ) _V -R ^1a , wherein v is an integer from 1 to 12 and R ^1a represents a phenyl, naphthyl, hexamethyleniminyl, piperazinyl, heptamethyleniminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl or morpholinyl group, wherein any of the phenyl, naphthyl, hexamethyleniminyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, The 365 morpholinyl group may be substituted with one or more moieties selected from the group consisting of (C 1 -C 6) alkyl, C 1 -C 6 alkyl; halogen, trifluoromethyl, benzyl, phenyl, dialkyl of 1 to 6 carbon atoms in each alkyl moiety, alkylamino of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms C 3 -C 8 cycloalkyl, said phenyl, benzyl or C 3 -C 8 cycloalkyl optionally substituted with one, two or three moieties independently selected from the group consisting of C 1 -C 6 alkyl, halogen or alkoxy having 1 to 6 carbon atoms, or R ^1a may be substituted by a group of the formula - <CH ₂ ) _W -R ^1b,. ,, where w stands for. 1 to 12 and ^p R ^1b is piperidyl, pyrimidyl, pyrrolidinyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 di [(dialkyl) amino (alkylene 1)] amino in both the alkyl and alkylenyl moieties, di (alkyl) amino (alkylenyl) amino. C 1 -C 6 alkyl and alkylenyl, phenyl, C 3 -C 8 cycloalkyl, pyrrolidinyl and acetamido, wherein said phenyl or C 3 -C 8 cycloalkyl is optionally substituted once; 366 two or three moieties independently selected from the group consisting of (C1-C6) alkyl, halogen or (C1-C6) alkoxy, A represents a bond, a group of formula - _(CH2) m or -C (O) -, A ¹ is a bond, a group of the formula -NR ^a -, -O-, - (CH ₂ ) _m or -S (O) _n -, q is 0-6, p is 0-6, n is 0, 1 , or 2, m is 0 to 6, s is 0 to 6, ^And R is hydrogen, alkyl sl to 6 'carbon atoms or alkanoyl with 2-6 C atoms, D is a bond, a C 2 -C 4 alkenylenyl group or a group of formula -C (X) (Y) wherein one of X and Y is hydroxy and the other is hydrogen or both X and Y are hydrogen or X and Y together form a group of formula = O or = NOR ^C , wherein R ^c is hydrogen, benzyl, acetyl, benzoyl Λ ř 367 <. 'J. or an alkyl group having 1 to 6 carbon atoms; J is one of X ¹ and Y ¹ is hydroxy and the other is hydrogen or both and Y ^{1 are} hydrogen or X ¹ and Y ¹ together form a group of formula = O or = NOR ^d , "f"> wherein R ^d represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, r f í l · i i is hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy. 6 carbon atoms, phenoxy. or a group of formula · '. wherein R ⁴ and R ^{5 are each} independently hydrogen, C 1 -C 6 alkyl, phenyl, or C 1 -C 6 phenylalkylenyl, or is a heterocyclic ring selected from hexamethyleniminyl, piperazinyl, heptamethyleniminyl, imidazolinyl, piperidyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl or morpholinyl, wherein / any of hexamethyleniminyl, piperazinyl, heptamethyleniminyl, imidazolinyl, piperidyl, 2-tryptolinyl, pyrrolidinyl, The 368 quinuclidinyl or irtorfolinyl group may be substituted by one or more moieties selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen, trifluoromethyl, benzyl, phenyl, dialkylamino of 1 to 6 atoms. carbon in the alkyl moiety, di (C 1 -C 6 alkylamino) alkylenyl, both C 1 -C 6 alkylaminoalkylenyl, both C 2 -C 6 alkyl and alkylenyl, C 2 -C 6 alkanoyl, carboxamido, 2-aminoacetyl, C 2 -C 6 alkanoyloxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, piperidyl, pyrrolidinyl, pyrimidyl, phenylalkylenyl C 1 -C 6 alkylenyl, C 1 -C 6 phenoxyalkylenyl, C 1 -C 6 piperidylalkylenyl, C 1 -C 6 pyrrolidinylalkylenyl and C 1 -C 6 alkylenyl, C 1 -C 6 pyrimidinylalkylenyl carbon in the alkylenyl moiety, alkoxy groups having 1 to 6 carbon atoms C 1 -C 6 alkylthio, C 1 -C 6 di [di (alkyl) amino (alkylenyl)] amino in both the alkyl and alkylenyl moieties, C 1 -C 6 di (alkyl) amino (alkylenyl) amino groups carbon atoms in both the alkyl and alkylenyl moieties, and acetamido, wherein any one of benzyl, phenyl, piperidyl or cycloalkyl of 1 to 6 carbon atoms, phenylalkylenyl of 1 to 6 carbon atoms - 369 in the alkylenyl moiety, C 1 -C 6 phenoxyalkylenenyl, pyrrolidinyl, piperidylalkylenyl C 1 -C 6 alkylene, C 1 -C 6 pyrrolidinylalkylenyl, C 1 -C 6 pyrimidylalkylennyl the carbon atoms in the alkylenyl moiety or the pyrimidyl group may be substituted by one or more moieties selected from the group consisting of C 1 -C 6 alkyl, halogen, trifluoromethyl, acetamido; C 2 -C 6 alkanoyl, C 2 -C 7 alkanoyloxy and C 1 -C 6 alkoxy, or piperidyl, pyrrolidinyl, piperidyl, C 1 -C 6 alkylenyl, C 1 -C 6 alkylenyl, pyrrolidinylalkylenyl C 1 -C 6 alkylenyl, pyrimidylalkylenyl C 1 -C 6 alkylenyl or pyrimidyl may be substituted with an amino protecting group, or R ² represents a group of the formula wherein R ^{4a and} R ^6a and R are independently hydrogen, alkyl of 1-6 carbon atoms, trifluoromethyl or alkoxy having 1-6 carbon atoms, or _(t R ^4a represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group or an alkoxy group having 1 to 6 carbon atoms; 370 to 6 carbon atoms and R ^5a and R ^6a together form, with the nitrogen atom to which they are attached, pyrrolidinyl, piperidyl, hexamethyleniminyl or heptamethyleniminyl, or R ^4a represents an oxygen atom and R ^5a and R ^6a together with the nitrogen atom to which they are attached form pyrrolidinyl, piperidyl, hexamethyleniminyl or heptamethyleniminyl, R is phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C 3 -C 8 cycloalkyl, pyrazinyl, allyl, thiazolyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethylenimethyl, hexamethylene piperidyl, pyrrolidinyl, quinuclidinyl or morpholinyl, wherein any of the phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, cyclic alkyl groups of 3 to 8 carbon atoms, pyrazinyl, thiazolyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, pyridazylol, oxazinolyl, oxazinolyl, oxazinolyl, oxazinolyl, oxazinyl, oxazinolyl, oxazinolyl, oxazinyl, , tetrazolyl, hexamethyleniminyl, heptamethyleniminyl, piperidyl, pyrrolidinyl, quinuclidinyl or morpholinyl groups may be substituted by one or more moieties selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 10 alkenyl, alkynyl group 2 to 10 carbon atoms, halogen, trifluoromethyl, carboxamido, cyano, benzyl, phenyl, dialkylamino of 1 to 6 atoms ’Χ 371 carbon in each alkyl moiety; C 2 -C 6 alkanoyloxy, C 2 -C 6 alkanoyloxy, C 1 -C 6 alkylamino, oxazolyl, dihydrooxazolyl, C 1 -C 12 piperidylalkoxy, C 1 -C 6 piperidylalkoxyalkylene, C 1 -C 6 alkylene and C 1 -C 6 alkylene; 1 to 12 carbon atoms in the alkoxy moiety, piperidylalkylenyl having 1 to 12 carbon atoms in the alkylenyl moiety, phenylalkoxy having 1 to 12 carbon atoms in the alkoxy moiety, phenylalkylenyl having 2 to 12 carbon atoms in the alkylenyl moiety, cycloalkyl being C 3 -C 8, piperidyl, pyrimidyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and R ^x R ^y NGL- (alkylenyl) wherein the alkylenyl group contains 0 to 6 carbon atoms, and acetamido , 'Γ. ''. wherein R ^x and R 6 are independently hydrogen, C 1 -C 6 -alkyl, phenyl, benzyl, piperidyl, pyrrolidinyl, hexamethyleniminyl, heptamethyleniminyl, morpholinyl, piperazinyl or C 1 -C 6 cycloalkyl, or wherein R 1 ^X R ^ N represents a ring selected from piperidyl, pyrrolidinyl, hexamethyleniminyl, heptamethyleniminyl, azetidinyl, which may be attached to G at any convenient point on the ring, wherein G is C 1 -C 12 alkylenyl, C 2 -C 12 alkenylenyl Or a C 2 -C 12 alkynylenyl group I carbon and 372 wherein L is a bond, a group of the formula -O-, -S-, -S (O) -, -S (O) 2 - or -NH-, provided that when A · * · represents -NR ^a -, -O- or -s (O) _n and A represents -CH ₂ -, R ^{1 is} not hydrogen or a pharmaceutically acceptable salt or solvate thereof. ', .1,) - ... ·.? 2. A compound according to claim 1 wherein R ¹ is hydrogen or methyl, or R ^A represents piperidyl, pyrrolidinyl, piperazinyl or quinuclidinyl, or a pharmaceutically ^J acceptable salt or solvate. A compound according to claim 2, wherein R ^1a represents piperid-3-yl, piperid-2-yl, pyrrolidin-3-yl or pyrrolidin-2-yl, piperid-1-yl, piperid-4-yl, pyrrolidin-1 -yl or pyrrolidin-4-yl or phenyl, or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 3, wherein A ¹ is a bond or a group of the formula -O-, or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 4, wherein the group of formula - (CH ₂₎ Gd (CH _{2) s} - represents a bond, methylene, ethylene or < a group of formula -C (O) -, or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein both X and Y- ¹ are hydrogen, or a pharmaceutically acceptable salt or solvate thereof. : and; 373 A compound according to claim 6, wherein R ² is an amino substituted piperidyl group, a C 1-6 dialkylamino group, up to 6 carbon atoms in each alkyl moiety, a C 1-6 alkylamino group or piperidyl, or R ² is an amino substituted pyrrolidinyl group, a 1-6 dialkylamino group or R ² is a phenyl or cyclohexyl-substituted piperazinyl group, or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 7, wherein the group of the formula -AA 4 - (CH ₂ ) p - is -CH ₂ -O-, -CH ₂ -NH- or -CH ₂ -S-, or a pharmaceutically acceptable salt or solvate thereof . The compound of claim 8, wherein R is naphthyl, phenyl, piperidyl, pyrrolidinyl or cyclohexyl, or a pharmaceutically acceptable salt or solvate thereof. . . The compound of claim 9, wherein R is phenyl, which is optionally substituted at the 4-position and at the 2-position by a halogen atom, or a pharmaceutically acceptable salt or solvate thereof. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1 to 10 in combination with at least one of its carrier, diluent or vehicle. . A compound according to any one of claims 1 to 10, for use in treating a condition associated with an excess of neuropeptide Y or related peptides. 374 13. A method of treating a condition associated with an excess of neuropeptide Y, wherein the neuropeptide Y is an excess. administering to a mammal in need of such treatment an effective amount of a compound according to any one of claims 1 to 10. Use of a compound according to any one of claims 1 to 14 10, for the preparation of a medicament for treating a condition associated with an excess of neuropeptide Y. " ' ..OF . 15. A pharmaceutical composition adapted for the treatment of 't'. a condition associated with an excess of neuropeptide Y comprising a compound according to any one of claims 1 to 10.