HK1030937B - New substituted dimeric compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

Novel substituted dimeric compounds, process for their preparation and pharmaceutical compositions containing them

Technical Field

The present invention relates to novel substituted dimeric compounds, to a process for their preparation and to pharmaceutical compositions containing them.

Background

Dimeric structures are known in the prior art in the naphthalene series and their coordination in metal complexes is investigatedProperties ("chem.Soc., Dalton Tran., (J.chem.Soc., Dalton Tran.), (1979), (10), pages 1497-502), or" curare-like "activities in indole lines (Khim. -farm. Zh., 1984,18(1) pages 29-31). Furthermore, patent applications WO 9600720 and WO9414771 disclose mixed dimeric structures as 5-HT, respectively₁Ligands and synthetic intermediates.

Based on their novel structure, the compounds of the present invention are novel, and their pharmaceutical properties in terms of melatoninergic receptors are of great value.

Many studies over the last decade have demonstrated a key role for melatonin (N-acetyl-5-methoxytryptamine) in many pathophysiological phenomena and control of the twenty-four hour rhythm. However, its half-life is short due to rapid metabolism. Therefore, there is a great interest in the possibility of providing clinicians with melatonin analogs which are more metabolically stable, have agonist or antagonist properties and which are expected to have therapeutic effects superior to those of the hormones themselves.

Except in the case of twenty-four hour rhythm disorders (J.neurosurgery (1985), 63, page 321-341) and sleep disorders (Psychopharmacology, 1990,100222-226), ligands of the melatoninergic system have valuable pharmacological properties also on the central nervous system, in particular in anxiolytic and antipsychotic properties (Neuropharmacology of pinal secretions), 1990,8(3-4), pages 264-272) and analgesic properties (pharmacosychiat, 1987,20222-223), and in the treatment of parkinson's disease (journal of neurosurgery (j. neurosurg.) (1985),63p. 321-341) and alzheimer's disease (Brain Research, 1990,528page 170-174) has valuable pharmacological properties. Those compounds have been demonstratedCertain specific cancers (Meldonin-clinical perspectives, Oxford university Press, 1988, page 164-,227714, page 720), diabetes mellitus (clinical endocrinology, 1986,24359-364), and in the treatment of obesity ((International Journal of Eathing disorders), 1996.20(4) Page 443-446) also has therapeutic activity.

Those different effects act via mediation of specific melatonin receptors. Molecular biological studies have demonstrated that there are many receptor subtypes capable of binding this hormone (Trends pharmacol. sci., 1995,16page 50; WO 97.04094). For various species, including mammals, some of those receptors can be located and characterized. In order to be able to better understand the physiological functions of those receptors, it is very advantageous to obtain specific ligands. Furthermore, by selectively interacting with those receptors, these compounds are very useful as drugs for the clinical treatment of diseases related to the melatoninergic system, some of which have been mentioned above.

Disclosure of Invention

In addition to being novel, the compounds of the present invention exhibit very strong affinity for melatonin receptors and/or selectivity for various melatoninergic (malatoninergic) receptor subtypes.

The invention more particularly relates to compounds of formula (I):

A-G₁-Cy-G₂-Cy’-G₃-B (I)

wherein: a is represented byOrThe group of (a) or (b),

wherein:

-Q represents a sulfur or oxygen atom,

-R¹、R²and R³Which may be the same or different, represent a hydrogen atom or a group Ra (wherein Ra represents a substituted or unsubstituted, linear or branched (C)₁-C₆) Alkyl, substituted or unsubstituted, linear or branched (C)₂-C₆) Alkenyl, substituted or unsubstituted, straight or branched (C)₂-C₆) Alkynyl, substituted or unsubstituted (C)₃-C₈) Cycloalkyl of (1), substituted or unsubstituted cycloalkyl- (C)₃-C₈) Alkyl-the alkyl part of which is straight-chain or branched, polyhalo- (C)₁-C₆) Alkyl-the alkyl part of which is straight-chain or branched, aryl- (C)₁-C₆) Alkyl-the alkyl part of which is straight-chain or branched, aryl- (C)₂-C₆) Alkenyl-the alkenyl radical of which is linear or branched, heteroaryl- (C)₁-C₆) Alkyl-the alkyl part of which is straight-chain or branched or heteroaryl- (C)₂-C₆) Alkenyl-which alkenyl moiety is straight or branched),

or a radical R²And R³Capable of forming together with the N atom to which it is attached a group selected from piperazinyl, piperidinyl and pyrrolidinyl. B is represented by

or-NR²R³Group of (1), whichMiddle Q, R¹、R²And R³The meaning is the same as above.

◆G₁And G₃Which may be identical or different, represent a linear or branched alkylene chain containing from 1 to 4 carbon atoms, which may optionally be substituted by one or more identical or different groups selected from hydroxyl, carboxyformyl, Ra, ORa, COORa and CORa (wherein Ra has the same meaning as above).

Cy and Cy' are different, indicating

-a ring structure of formula (II):

wherein:

x and Y, which may be the same or different, represent a sulfur atom, an oxygen atom or a carbon atom, or CH₂A group.

*R⁴Represents a hydrogen atom or a halogen atom, or CF₃Hydroxy, carboxy, formyl, amino, NHRa, NRaR¹a. NHCORa, CONHRa, Ra, ORa, CORa or COORa group, (wherein Ra is as defined above and R is¹a may have any meaning of Ra),. symbolRepresents a single bond or a double bond, and satisfies the valence of the atom. Wherein, in Cy, G₂Substituted phenyl ring, and G₁By substitution of rings containing X and Y, and G in Cy₂Substituted phenyl ring, and G₃Substitution of a ring containing X and Y, -or a ring structure of formula (III):wherein: z represents a sulfur atom or an oxygen atom, or CH₂、NH、NSO₂Ph or NRa (wherein Ra is as defined above), D represents a benzene or pyridine ring, R⁴The meaning is the same as that of the above,

symbolRepresents a single bond or a double bond and satisfies the atomThe valence of (3).

Wherein, in Cy, G₂Substituted D ring, and G₁In place of the ring containing Z, a substituent,

and in Cy' G₂Substituted D ring, and G₃In place of the ring containing Z, a substituent,

in the compound of formula (I), both of the two different rings Cy and Cy' can be represented by the structure of formula (II) or formula (III), or one of the two rings is represented by the structure of formula (II) and the other is represented by the structure of formula (III).

◆G₂A chain of formula (IV):

wherein:

-W₁、W₂and W₃Which may be the same or different, represent a chemical bond, an oxygen atom or a sulfur atom, or CH₂A CHRa, NH or NRa group (wherein Ra has the same meaning as above),

n represents an integer, where 0. ltoreq. n.ltoreq.6,

-m represents an integer, where 0. ltoreq. m.ltoreq.6,

with the proviso that it may not contain two consecutive heteroatoms and that the chain of formula (IV) as defined thus may have one or more unsaturated bonds.

It should be understood that:

"aryl" is to be understood as meaning naphthyl, phenyl and biphenyl radicals,

"heteroaryl" is to be understood as meaning any saturated or unsaturated monocyclic or bicyclic radical containing 5 to 10 ring atoms and containing 1 to 3 heteroatoms selected from nitrogen, sulfur or oxygen,

- "aryl" and "heteroaryl" may be substituted by one or more identical or different radicals chosen from hydroxyl, carboxyl, linear or branched (C)₁-C₆) Alkoxy, straight or branched (C)₁-C₆) Alkyl, polyhalo- (C)₁-C₆) Alkyl-the alkyl part of which is straight-chain or branched, formyl, cyano, nitro, amino, straight-chain or branched (C)₁-C₆) Alkylamino, di- (C)₁-C₆) Alkylamino-wherein each alkyl moiety is straight or branched, and a halogen atom,

the term "substituted" as used for the terms "alkyl", "alkenyl" and "alkynyl" means that those groups are substituted by one or more identical or different groups selected from hydroxyl, linear or branched (C)₁-C₆) Alkoxy, polyhalo- (C)₁-C₆) Alkyl-the alkyl part of which is straight-chain or branched, amino, straight-chain or branched (C)₁-C₆) Alkylamino, di- (C)₁-C₆) Alkylamino-wherein each alkyl moiety is straight or branched, and a halogen atom,

the term "substituted" as used for the terms "cycloalkyl" and "cycloalkylalkyl" means that the ring portion of those groups is substituted by one or more identical or different groups selected from hydroxyl, linear or branched (C)₁-C₆) Alkoxy, polyhalo- (C)₁-C₆) Alkyl-wherein the alkyl moiety is linear or branched, amino, linear or branched (C)₁-C₆) Alkylamino, di- (C)₁-C₆) Alkylamino-wherein each alkyl moiety is straight or branched chain, and halogen atoms, their enantiomers and diastereomers, and their addition salts with pharmaceutically acceptable acids or bases.

Among the pharmaceutically acceptable acids, mention may be made, by way of non-limiting example, of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetyl, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid and the like.

Among the pharmaceutically acceptable bases, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, and the like may be mentioned by way of non-limiting example.

Preferred compounds of the invention are compounds of formula (I) wherein:

-Cy and Cy' are different and represent a ring structure of formula (II), such as naphthalene, tetrahydronaphthalene, 1, 4-benzodioxine or chroman,

-Cy and Cy' are different and represent a ring structure of formula (III), such as indole, azaindole, benzothiophene or benzofuran,

-Cy represents the ring structure of formula (II) and Cy' represents the ring structure of formula (III).

Advantageously, the invention relates to compounds of formula (I) wherein G₂Represents a single bond, and is a hydrogen atom,

or a group-W₄-(CH₂)p-W’₄- (wherein W)₄And W'₄Which may be identical or different, represent an oxygen atom or a sulfur atom, or an NH or NRa group, and p represents an integer, 1. ltoreq. p.ltoreq.12), for example the group-O- (CH)₂) p-O- (wherein p is as defined above),

or a group-W₄-(CH₂)_p’-W’₄-(CH₂)_p”-W”₄- (wherein W)₄、W’₄And W'₄Which may be identical or different, represent an oxygen atom or a sulfur atom, or an NH or NRa group, and p 'and p "represent integers, 2. ltoreq. p' + p". ltoreq.12), for example the group-O- (CH)₂)_p’-O-(CH₂)_p”-O- (wherein p' and p "are as defined above).

Preferred substituents A and B according to the invention are the radicals NR¹C(Q)R²、NR¹C(Q)NR²R³And C (Q) NR²R³Especially the group NR¹COR²And CONR²R³。

The invention relates to compounds of formula (I), more particularly:

-N- (2- {7- [2- ({3- [2- (acetylamino) ethyl ] -1-benzofuran-5-yl } oxy) ethoxy ] -1-naphthyl } -ethyl) acetamide,

-N- (2- {5- [2- ({8- [2- (acetylamino) ethyl ] -2-naphthyl- } oxy) ethoxy ] -1-benzofuran-3-yl } ethyl) -2-furoamide,

-N- (2- {5- [2- ({8- [2- (acetylamino) ethyl ] -2-naphthyl- } oxy) ethoxy ] -1H-pyrrolo [2, 3-b ] pyridin-3-yl } ethyl) cyclopropanecarboxamide,

-N- (2- {7- [3- ({3- [2- (acetylamino) ethyl ] -1-benzothien-5-yl } oxy) propoxy ] -1-naphthyl } -ethyl) acetamide,

-N- [2- (5- { [6- ({8- [2- (acetylamino) ethyl ] -2-naphthyl } oxy) hexyl ] oxy } -1H-pyrrolo [2, 3-b ] pyridin-3-yl) ethyl ] acetamide,

-N- (2- {7- [4- ({3- [2- (acetylamino) ethyl ] -1-benzofuran-5-yl } oxy) butoxy ] -1-naphthyl } -ethyl) acetamide,

-N- {2- [5- [4- ({8- [2- (acetylamino) ethyl ] -2-naphthyl } oxy) butoxy ] -1- (benzenesulfonyl) -1H-indol-3-yl ] ethyl } acetamide,

-N- (2- {7- [4- ({8- [2- (acetylamino) ethyl ] -2-naphthyl } oxy) butoxy ] -1, 2, 3, 4-tetrahydro-1-naphthyl } -ethyl) acetamide,

-N- (2- {5- [4- ({3- [2- (acetylamino) ethyl ] -3a, 7a dihydro-1-benzofuran-5-yl } oxy) butoxy ] -1H-indol-3-yl ] ethyl ] acetamide,

-N- (2- {7- [4- ({3- [2- (acetylamino) ethyl ] -1-benzothien-5-yl } oxy) butoxy ] -1-naphthyl } -ethyl) acetamide,

-N- (2- {5- [4- ({3- [2- (acetylamino) ethyl ] -1-benzothien-5-yl } oxy) butoxy ] -1H-indol-3-yl } ethyl) acetamide,

-N- (2- {5- [4- ({3- [2- (acetylamino) ethyl ] -1-benzothien-5-yl } oxy) butoxy ] -1H-pyrrolo [2, 3-b ] pyridin-3-yl } ethyl) acetamide,

-N- (2- {5- [4- ({3- [2- (acetylamino) ethyl ] -1-benzofuran-5-yl } oxy) butoxy ] -1H-pyrrolo [2, 3-b ] pyridin-3-yl } ethyl) acetamide,

-N- (2- {5- [4- ({3- [2- (acetylamino) ethyl ] -1H-indol-5-yl } oxy) butoxy ] -1H-pyrrolo [2, 3-b ] pyridin-3-yl } ethyl) acetamide,

-N- [2- (7- {3- [2- (acetylamino) ethyl ] -1-benzofuran-5-yl } -1-naphthyl) ethyl ] acetamide,

-N- [3- (5- {8- [2- (acetylamino) ethyl ] -2-naphthyl } -1H-pyrrolo [2, 3-b ] pyridin-3-yl) propyl ] heptanamide,

-N- [2- (7- {3- [2- (acetylamino) ethyl ] -1-benzothien-5-yl } -1-naphthyl) ethyl ] acetamide,

-N- [2- (5- {8- [2- (acetylamino) ethyl ] -2-naphthyl } -1H-pyrrolo [2, 3-b ] pyridin-3-yl) ethyl ] acetamide,

-N- [2- (5- {3- [2- (acetylamino) ethyl ] -1-benzofuran-5-yl } -1-benzothien-3-yl) ethyl ] -acetamide,

-N- [2- (5- {3- [2- (acetylamino) ethyl ] -1-benzofuran-5-yl } -1H-indol-3-yl) ethyl ] -acetamide,

-N- [2- (5- {3- [2- (acetylamino) ethyl ] -1-benzofuran-5-yl } -1H-pyrrolo [2, 3-b ] pyridin-3-yl) ethyl ] acetamide,

-N- [2- (5- {3- [2- (acetylamino) ethyl ] -1H-indol-5-yl } -1H-pyrrolo [2, 3-b ] pyridin-3-yl) ethyl ] acetamide,

-N- [2- (5- {3- [2- (acetylamino) ethyl ] -1-benzothien-5-yl } -1H-pyrrolo [2, 3-b ] pyridin-3-yl) ethyl ] acetamide.

The enantiomers, diastereomers and addition salts thereof with pharmaceutically acceptable acids or bases of the preferred compounds of the invention form an integral part of the invention.

The invention also relates to a process for the preparation of the compounds of formula (I), characterized in that compounds of formula (V) are used as starting materials:

A-G₁-Gy-OMe (V)

wherein A, G₁And Cy has the same meaning as in formula (I),

using conventional reagents, e.g. HBr, AlCl₃、AlBr₃、BBr₃Or a Lewis acid/nucleophile binary system, e.g. AlCl₃/PhCh₂SH or BBr₃/Me₂S, demethylation thereof to yield a compound of formula (VI): A-G₁-Cy-OH (VI)

Wherein A, G₁And Cy have the same meanings as above.

In a conventional manner, the solid phase is removed,

-conversion thereof, for example, by the action of sodium N, N-dimethylthiocarbamate, into the mercaptan corresponding to formula (VII):

A-G₁-Cy-SH (VII)

wherein A, G₁And Cy has the same meaning as above,

-or to an amine compound corresponding to formula (VIII):

A-G₁-Cy-NHR’a (VIII)

wherein A, G₁And Cy have the same meanings as above, and R' a may have any of the meanings of Ra as defined in formula (I), and may also represent a hydrogen atom.

The compounds of formulae (VI), (VII) and (VIII) represent compounds of formula (IX):

A-G₁-Cy-W₄H (IX)

wherein W₄Represents an oxygen atom or a sulfur atom, or an NH or NRa group (wherein Ra is as defined)As above) in the above-mentioned manner,

a compound of formula (IX) is condensed with:

a compound of formula (X):

wherein Hal represents a bromine, chlorine or iodine atom, and n, W₂And m is defined by the same formula (I), (provided that it may not contain two consecutive heteroatoms, and that the chain thus defined may contain one or more unsaturated bonds),

or a compound of formula (XI):

wherein Hal, n, m and W₂Defined above, and Alk represents an alkyl group (provided that it may not contain two consecutive heteroatoms, and that the chain so defined may contain one or more unsaturated bonds), followed by reduction,

to give a compound of formula (XII):

A-G₁-Cy-W₄(CH₂)n-W₂(CH₂)m-OH (XII)

wherein, A, G₁、Cy、W₄N, m and W₂The same as above (provided that-W is₄-(CH₂)n-W₂-(CH₂) It being not possible for two successive heteroatoms to be present in the m-OH chain, and the chain thus defined may contain one or more unsaturated bonds),

wherein the hydroxy function may be converted to a leaving group, such as mesylate, tosylate or a halo compound, in a conventional manner to give a compound of formula (XII'):

A-G₁-Cy-W₄-(CH₂)n-W₂-(CH₂)m-E (XII’)

wherein, A, G₁、Cy、W₄、n、W₂And m has the same meaning as above, and E represents a methanesulfonyl group or a toluenesulfonyl group or a halogen atom,

it is reacted with a compound of formula (XIII):

B-G₃-Cy’-W’₄H (XIII)

b, G therein₃And Cy 'is as defined for formula (I), and W'₄Can be reacted with the above-mentioned W₄Have the same definition.

To obtain a compound of formula (I/a), which is a special case of the compound of formula (I): A-G₁-Cy-W₄-(CH₂)n-W₂-(CH₂)m-W’₄-Cy’-G₃-B (I/a)

A, G therein₁、Cy、Cy’、W₄、n、W₂、m、W’₄、G₃And B is as defined above for the first time,

this is converted into the triflate corresponding to formula (XIV) using, for example, phenyl bis (trifluoromethanesulfonimide) (phenylbis (trifluoromethylmethanesulphonamide)):

A-G₁-Cy-OSO₂CF₃ (XIV)

wherein, A, G₁And Cy is as defined above for the compound,

by means of a suitable palladium compound, under catalytic conditions, with a boronic acid compound (R)_bB(OH)₂) Or a tin compound (R)_bSnBu₃) (wherein R is_bA group of formula (XV):

B-G₃-Cy’W₃-(CH₂)m-W₂-(CH₂)n-CH₂- (XV)

b, G therein₃、Cy’、W₃、m、W₂And n is as defined above, with the proviso that₃-(CH₂)m-W₂The chain may not contain two consecutive heteroatoms and the chain thus defined may contain one or more unsaturated bonds),

obtaining a compound of formula (I/b), which is a special case of the compound of formula (I):

A-G₁-Cy-CH₂-(CH₂)n-W₂-(CH₂)m-W₃-Cy’-G₃-B (I/b)

a, G therein₁、Cy、Cy’、n、W₂、m、W₃、G₃And B is as defined above (provided that-W is₂-(CH₂)m-W₃The chain may not contain two consecutive heteroatoms and the chain thus defined may contain one or more unsaturated bonds),

among these, the compounds of formula (I/c), which are particular cases of the compounds of formula (I):

A-G₁-Cy-W₁-(CH₂)n-W₂-(CH₂)m-CH₂-Cy’-G₃-B (I/c)

a, G therein₁、Cy、Cy’、W₁、n、W₂、m、G₃And B is as defined above (provided that-W is₁-(CH₂)n-W₂The chain may not contain two consecutive heteroatoms and the chain thus defined may contain one or more unsaturated bonds),

obtained by a similar procedure starting from a compound of formula (XIV'):

B-G₃-Cy’-OSO₂CF₃ (XIV’)

b, G therein₃And Cy' is as defined above,

or by treatment with a compound of formula (XIV') under coupling conditions, using, for example, a nickel or palladium compound, to give a compound of formula (I/d), which is a special case of compounds of formula (I):

A-G₁-Cy-Cy’-G₃-B (I/d)

wherein, A, G₁、Cy、Cy’、G₃And B is as defined above for the first time,

the compounds (I/a) to (I/d) constituting the whole of the compound of the formula (I) are purified by a conventional separation technique, if necessary, separated into their isomers by a conventional purification technique, if appropriate, and converted into their addition salts with a pharmaceutically acceptable acid or base, if necessary.

The compounds of formula (V) are readily available to the skilled worker by methods described in the literature.

The compounds of the invention, as well as the pharmaceutical compositions containing them, have proven to be very effective in the treatment of disorders of the melatonin system (melatoninergic system).

Pharmacological studies with the compounds of the present invention demonstrate the fact that they are non-toxic, have a high affinity for melatonin receptors and have comparable activity in the central nervous system and the microcirculatory system, and therefore, the compounds of the present invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal affective disorders, cardiovascular disease, digestive system disease, jet lag induced insomnia and fatigue, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, pain, psychiatric disorders, epilepsy, diabetes, parkinson's disease, senile dementia, various disorders resulting from normal or pathological aging, migraine, memory loss, alzheimer's disease and cerebral circulation disorders. In another field of activity, the compounds of the invention are useful in the treatment of sexual dysfunction, they have ovulation-inhibiting and immunomodulating effects and can be used in the treatment of cancer.

The compounds of the invention are preferably used for the treatment of seasonal affective disorders, sleep disorders, cardiovascular disease, insomnia and fatigue caused by jet lag, appetite disorders and obesity.

For example, the compounds of the present invention are useful for the treatment of seasonal affective disorders and sleep disorders.

The invention also relates to pharmaceutical compositions containing at least one compound of formula (I), either by itself or in combination with one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those suitable for oral, parenteral, intranasal, transdermal or transdermal administration, rectal, lingual, ocular or respiratory administration, in particular tablets or dragees, sublingual tablets, sachets, cartridges (paques), capsules, glossettes, lozenges, suppositories, creams, ointments, skin gels, and drinkable or injectable ampoules.

The dosage will vary depending on the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any relevant treatment, and will be from 0.01mg to 1g per 24 hours, administered in one or more doses.

Detailed Description

The following examples illustrate the invention but do not limit it in any way. The following preparations give the compounds of the invention or synthetic intermediates used in the preparation of the invention.

Preparation 1: n- [2- (7-hydroxy-1-naphthyl) ethyl]-acetamide

Under an inert atmosphere, 27.5mmol of boron tribromide/dimethylsulfide complex was dissolved in 100ml of dichloromethane and stirred at room temperature for 15 minutes. A solution of 13.7mmol of N- [2- (7-methoxy-1-naphthyl) ethyl ] -acetamide in 50ml of dichloromethane was added and the reaction mixture was refluxed for 30 hours. After cooling, the reaction mixture was carefully hydrolyzed and the dichloromethane was evaporated off. The mixture was extracted with ethyl acetate and the combined organic phases were washed with 1M aqueous potassium bicarbonate. The organic phase was dried over magnesium sulfate and concentrated to give the title compound. As a white solid.

Melting Point：125-126℃

By starting from the appropriate substrate, using the same procedure as in preparation 1, compounds of preparations 2 to 35 are obtained:

preparation 2: n- [2- (5-hydroxy-1-benzofuran-3-yl) ethyl]Acetamide

Preparation 3: n- [2- (5-hydroxy-1-benzofuran-3-yl) ethyl]Cyclopropanecarboxamides

Preparation 4: n- [2- (5-hydroxy-1-benzofuran-3-yl) ethyl]-2-furoamides

Preparation 5: n- [2- (7-hydroxy-1-naphthyl-) ethyl]Benzamide derivatives

Preparation 6: n- [2- (7-hydroxy-1-naphthyl-) ethyl]-3-butenamide

Preparation 7: n- [2- (5-hydroxy-1-benzofuran-3-yl) ethyl]-2-methylpropionamide

Preparation 8: n- [2- (7-hydroxy-1-naphthyl-) ethyl-]-2-phenylacetamide

Preparation 9: n- [2- (5-hydroxy-1-benzothien-3-yl) ethyl]Acetamide

Preparation 10: n- [2- (5-hydroxy-1H-pyrrolo [2, 3-b ]]Pyridin-3-yl) ethyl]-cyclopropanecarboxamides

Preparation 11: n- [2- (5-hydroxy-1H-indol-3-yl) ethyl]Acetamide

Preparation 12: n- [2- (5-hydroxy-1H-pyrrolo [2, 3-b ]]Pyridin-3-yl) ethyl]Acetamide

Preparation 13: n- [2- (7-hydroxy-1-naphthyl-) ethyl]Cyclobutanecarboxamide

Preparation 14: 2, 2, 2-trifluoro-N- [2- (7-hydroxy-1-naphthyl-) ethyl]Acetamide

Preparation 15: n- [ (6-hydroxy-2H-benzopyran-3-yl) methyl group]Butylamide

Preparation 16: n- [ (6-hydroxy-2H-benzopyran-3-yl) methyl group]Acetamide

Preparation 17: n- [ (7-hydroxy-1, 4-benzodioxine-2-yl) methyl group]-N' -propylurea

Preparation 18: n- [ (7-hydroxy-1, 4-benzodioxin-2-yl) methyl group]Acetamide

Preparation 19: n- [2- (7-hydroxy-1-naphthyl-) ethyl]Furoamides

Preparation 20: n- [2- (2-benzyl-5-hydroxy-1H-pyrrolo [2, 3-b ]]Pyridin-3-yl) ethyl]Acetamide

Preparation 21: n- [2- (5-hydroxy-1-benzothien-3-yl) ethyl]Cyclohexanecarboxamide

Preparation 22: n-hexyl-2- (5-hydroxy-1-benzofuran-3-yl) acetamide

Preparation 23: 2, 2, 2-trifluoro-N- [2- (5-hydroxy-1-benzothien-3-yl) ethyl]Acetamide

Preparation 24: n- [2- (6-hydroxy-3, 4-dihydro-2H-benzopyran-4-yl) ethyl]Acetamide

Preparation 25: n- [2- (7-hydroxy-1, 2, 3, 4-tetrahydro-1-naphthyl) ethyl) acetamide

Preparation 26: n- [2- (7-hydroxy-1, 2, 3, 4-tetrahydro-1-naphthyl) ethyl]Cyclopropanecarboxamides

Preparation 27: n- [2- (7-hydroxy-1-naphthyl) ethyl]Heptamide

Preparation 28: n- [2- (5-hydroxy-1H-indol-3-yl) ethyl]Cyclobutanecarboxamide

Preparation 29: 4- (7-hydroxy-1-naphthyl) -N-isopropylbutanamide

Preparation 30: n- [2- (5-hydroxy-1-benzofuran-3-yl) ethyl]-N' -phenylurea

Preparation 31: n-benzyl-2- (5-hydroxy-1-benzothien-3-yl) acetamide

Preparation 32: n- [2- (5-hydroxy-1H-inden-3-yl) ethyl]Pentamides

Preparation 33: 3- (5-hydroxy-1-benzofuran-3-yl) -N-methylpropanamide

Preparation 34: n- [2- (5-hydroxy-1H-pyrrolo [2, 3-b ]]Pyridin-3-yl) ethyl]-N' -methylurea

Preparation 35: 4- (5-hydroxy-1H-indol-3-yl) N-methylbutyramide

Preparation 36: n- [2- (5-mercapto-1-benzofuran-3-yl) ethyl]Acetamide

The product obtained in step (A) (9mmol) was added to a solution of potassium hydroxide (10mmol) dissolved in 15ml of water and 16ml of tetrahydrofuran, with stirring. The solution was cooled using a ice salt bath and a solution of dimethylthiocarbamoyl chloride (9mmol) in 15ml of tetrahydrofuran was added dropwise with stirring. After stirring for half an hour while maintaining the cooler temperature, the reaction mixture was extracted with chloroform. The organic phases were combined, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was treated in diphenyl ether (10ml) and refluxed under a nitrogen atmosphere for 1 hour. The diphenyl ether was removed by evaporation under reduced pressure until about 2ml of solution was obtained. The 2ml distillate, still hot, was carefully poured into 50ml of hexane and, after cooling, isolated by filtration to give a solid. The solid thus collected was added to a solution of potassium hydroxide (380mg) in a water/methanol mixture (1ml/10 ml). The solution was refluxed for 12 hours, then cooled and concentrated under reduced pressure. The residue was treated in 20ml chloroform and extracted 3 times with water. The organic phase was dry-exploded over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title product.

Preparation 37: n- [2- (5-mercapto-1-benzothien-3-yl) ethyl]Butylamide

Step A: n- [2- (5-hydroxy-1-benzothien-3-yl) ethyl]Butylamide

The method is the same as the preparation method of 1 by taking N- [2- (5-methoxy-1-benzothiophene-3-yl) ethyl ] butyramide as a raw material.

Step B: n- [2- (5-mercapto-1-benzothien-3-yl) ethyl]Butylamide

And (4) taking the compound obtained in the step (A) as a raw material, and preparing 36 by the same method.

Preparation 38: n- (2- { 5-mercapto-2- [4- (trifluoromethyl) benzyl]-1-benzothien-3-yl } ethyl) acetamide

Step A: n- (2- { 5-hydroxy-2- [4- (trifluoromethyl) benzyl]-1-benzothien-3-yl } ethyl) acetamide

The method is the same as the preparation method of 1 by taking N- (2- { 5-methoxy-2- [4- (trifluoromethyl) benzyl ] -1-benzothiophene-3 yl } ethyl) acetamide as a raw material.

Step B: n- (2- { 5-mercapto-2- [4- (trifluoromethyl) benzyl]-1-benzothien-3-yl } ethyl) acetamide

And (4) taking the compound obtained in the step (A) as a raw material, and preparing 36 by the same method.

Preparation 39: n- [2- (7-mercapto-1, 2, 3, 4-tetrahydro-1-naphthyl) ethyl]-cyclopropanecarboxamides

The compound obtained in preparation 26 was used as a starting material in the same manner as in preparation 36.

Preparation 40: n- [2- (5-amino-1-benzofuran-3-yl) ethyl]Acetamide

Step A: n- [2- (5-bromo-1-benzofuran-3-yl) ethyl]Acetamide

Triphenylphosphine (10mmol) and acetonitrile (70ml) were poured into a 150ml three-necked flask equipped with a dropping funnel, a condenser (with a test tube filled with calcium chloride at the top) and a mechanical stirrer. While maintaining stirring, the solution was cooled with an ice bath and bromine (10mmol) was added. When the addition was complete, the ice bath was removed and the product from preparation 2 (8mmol) was added. The reaction mixture was stirred at 60-70 ℃ until the starting material disappeared. After the reaction was completed, the reaction mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with water and then with saturated potassium hydrogen carbonate solution, again with water, then dried over magnesium sulfate and concentrated under reduced pressure. The residue was filtered through silica gel to give the title product.

Step B: n- [2- (5-iodo-1-benzofuran-3-yl) ethyl]Acetamide

A mixture of the product obtained in step A (2mmol), potassium iodide (30mmol) and copper (I) iodide (10mmol) in hexamethylphosphoramide (6ml) was heated at 160 ℃ under nitrogen with stirring until a conversion of 90% was reached. Dilute hydrochloric acid was then added followed by diethyl ether, after which the mixture was filtered to remove insoluble copper (I) salt. The organic phase is separated off, washed first with sodium sulfite solution and then with water, dried over magnesium sulfate and evaporated, and the residue obtained is purified by chromatography on silica gel to give the title product.

Step C: n- [2- (5-vinyl-1-benzofuran-3-yl) ethyl]Acetamide

15mmol of the product from step B, 16mmol of vinyltributyltin and 0.43mmol of tetrakis (triphenylphosphine) palladium were heated in 30ml of N-methylpyrrolidone with stirring at 110 ℃ for 3 hours. After removal of the solvent by evaporation, the residue was treated with 20ml of dichloromethane and with 10% aqueous potassium fluoride. Extraction, concentration under reduced pressure and purification by silica gel chromatography gave the pure title product.

Step D: n- [2- (5-formyl-1-benzofuran-3-yl) ethyl]Acetamide

1.10g of osmium tetroxide, 8.70g of sodium periodate dissolved in 2-methyl-2-propanol are added in succession to a solution of 10mmol of the product from step C dissolved in a mixture of 50ml of dioxane and 25ml of water at room temperature. After stirring overnight at room temperature, the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was treated with dichloromethane. The organic phase is washed with water, dried and evaporated. The residue was purified by silica gel chromatography to give the title product.

Step E: 3- [2- (acetylamino) ethyl group]-1-benzofuran-5-carboxylic acid

2.7g of potassium permanganate dissolved in 50ml of acetone/water mixture (50/50) are added at room temperature to a solution of 6.88mmol of the product obtained in step D in 30ml of acetone. The solution was stirred at room temperature for 2 hours and then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to give the title product.

Step F: 3- [2- (acetylamino) ethyl group]-1-benzofuran-5-carboxylic acid chloride

5mmol of the product from step E are dissolved in 40ml of thionyl chloride. After stirring under an inert atmosphere for 1 hour, thionyl chloride was evaporated under reduced pressure to give the title product.

Step G: n- [2- (5-amino-1-benzofuran-3-yl) ethyl]Acetamide

A solution of the product (20mmol) obtained in step F dissolved in dichloromethane (30ml) containing tetrabutylammonium bromide (20mg) was cooled in an ice bath. After the addition of 5ml of an aqueous solution of sodium azide (25mmol), the solution was stirred vigorously at 0 ℃ for 2 hours. The organic phase was separated, washed with water (2X 5ml) and dried over magnesium sulphate. After filtration, trifluoroacetic acid (30mmol) was added and the solution was stirred at reflux for 60 h. After cooling, the organic phase was washed with saturated aqueous sodium bicarbonate (2X 5ml) and concentrated under reduced pressure. The residue was then treated with methanol (20ml) and water (80ml) and potassium carbonate (30mmol) was subsequently added. After stirring at room temperature for 20 hours, the reaction mixture was concentrated under reduced pressure to a volume of about 60ml, followed by extraction with diethyl ether 3 times (3X 50 ml). After drying over sodium sulfate, the organic phase is filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title product.

Preparation 41: n- [2- (5-amino-1-benzothien-3-yl) ethyl]Pentamides

Step A: n- [2- (5-hydroxy-1-benzothien-3-yl) ethyl]Pentamides

The method is the same as the preparation method of 1 by taking N- [2- (5-methoxy-1-benzothiophene-3-yl) ethyl ] pentanamide as a raw material.

Step B: n- [2- (5-amino-1-benzothien-3-yl) ethyl]Pentamides

And C, taking the compound obtained in the step A as a raw material, and preparing 40 by the same method.

Preparation 42: n- {2- (5-amino-2- (3-methoxybenzyl) -1-benzofuran-3-yl]Ethyl acetamide

Step A: n-2- (5-hydroxy-2- (3-methoxybenzyl) -1-benzofuran-3-yl]Ethyl acetamide

The method is the same as the preparation method of 1 by taking N- {2- [ 5-methoxy-2- (3-methoxybenzyl) -1-benzofuran-3-yl ] ethyl } acetamide as a raw material.

Step B: n- {2- [ 5-amino-2- (3-methoxybenzyl) -1-benzofuran-3-yl]Ethyl) acetamide

And C, taking the compound obtained in the step A as a raw material, and preparing 40 by the same method.

Preparation 43: n- [2- (5-amino-1-benzothien-3-yl) ethyl]-2-furoamides

The compound obtained in preparation 4 was used as a starting material in the same manner as in preparation 40.

Preparation 44: n- [2- (5-amino-1-benzofuran-3-yl) ethyl]-N' -cyclopropylurea

Step A: n- [2- (5-hydroxy-1-benzofuran-3-yl) ethyl]-N' -cyclopropylurea

The preparation method is the same as that of the 1 preparation method by taking N- [2- (5-methoxy-1-benzofuran-3-yl) ethyl ] -N' -cyclopropyl urea as a raw material.

Step B: n- [2- (5-amino-1-benzofuran-3-yl) ethyl]-N' -cyclopropylurea

And C, taking the compound obtained in the step A as a raw material, and preparing 40 by the same method.

Preparation 45: 3- [2- (acetylamino) ethyl group]-1-benzofuran-5-yl trifluoromethanesulfonate

60ml of triethylamine were added to a solution of 0.07mol of the compound obtained in preparation 2 in 1 l of dichloromethane. The reaction mixture was refluxed until dissolved, and then 0.1mol of phenyl bis (trifluoromethanesulfonimide) (phenylbis (trifluoromethylsulfonimide)) and 0.75mol of potassium carbonate were added. After refluxing for 4 hours, the mixture was washed successively with 1 l of 1M sodium bicarbonate, 1 l of 1M hydrochloric acid. The organic phase was dried, concentrated and purified by silica gel chromatography to give the title product.

By the process of preparation 45, compounds of preparations 46-70 are obtained.

Preparation 46: 8- [2- (acetylamino) ethyl]-2-naphthyl trifluoromethanesulfonate

Raw materials: preparation 1

Preparation 47: 3- {2- [ (cyclopropylcarbonyl) amino group]-ethyl } -1-benzothien-5-yl trifluoromethanesulfonate

Raw materials: with N- [2- (5-methoxy-1-benzothien-3-yl) ethyl group]The cyclopropane formamide is used as raw material to obtain N- [2- (5-hydroxy-1-Benzothien-3-yl) ethyl]-cyclopropanecarboxamide.

Preparation 48: 8- (2- [ (methylamino) carbonyl)]Amino } ethyl) -2-naphthyl triflate starting material: with N- [2- (7-methoxy-1-naphthyl) ethyl]N- [2- (7-hydroxy-1-naphthyl) ethyl prepared by using (E) -N' -methylurea as a raw material and carrying out the same steps as in the preparation 1]-N' -methylurea.

Preparation 49: 3- {2- [ (anilinocarbonyl) amino group]Ethyl } -1-benzofuran-esters

Raw materials: preparation 30

Preparation 50: 3- [2- (2-Glycoylamino) ethyl]-1-benzothien-5-yl trifluoromethanesulfonate

Raw materials: with N- [2- (5-methoxy-1-benzothien-3-yl) ethyl group]The N- [2- (5-hydroxy-1-benzothiophen-3-yl) ethyl is obtained by taking the (E) -2-furoamide as a raw material and carrying out the same steps as the preparation 1]-2-furoamide.

Preparation 51: 3- [2- (benzylamino) -2-oxoethyl group)]-1H-indol-5-yl trifluoromethanesulfonate starting material: the N-benzyl-2- (5-hydroxy-1H-indol-3-yl) acetamide is obtained by taking N-benzyl-2- (5-methoxy-1H-indol-3-yl) acetamide as a raw material and carrying out the same steps as the preparation 1.

Preparation 52: 3- [3- (benzoylamino) propyl]-1H-indol-5-yl trifluoromethanesulfonate

Raw materials: by N- [3- (5-methoxy-1H-indol-3-yl) propyl group]Benzamide is used as a raw material, and N- [3- (5-hydroxy-1H-indol-3-yl) propyl ] is obtained through the same steps as the preparation 1]A benzamide.

Preparation 53: 3- [2- (isobutyrylamino) ethyl]-1-benzothien-5-yl trifluoromethanesulfonate

Raw materials: with N- [2- (5-methoxy-1-benzothien-3-yl) ethyl group]The 2-methylpropionamide is used as a raw material and is obtained by the same steps as the preparation 1N- [2- (5-hydroxy-1-benzothien-3-yl) ethyl]-2-methylpropionamide.

Preparation 54: 3- [2- (Heptamido) ethyl]-1H-pyrrolo [2, 3-b]Pyridin-5-yl trifluoromethanesulfonate

Raw materials: with N- [2- (5-methoxy-1H-pyrrolo [2, 3-b ]]Pyridin-3-yl) ethyl]The enanthoamide is used as a raw material to obtain the N- [2- (5-hydroxy-1H-pyrrolo [2, 3-b ] through the same steps as the preparation 1]Pyridin-3-yl) ethyl) heptanamide.

Preparation 55: 3- [2- (acetylamino) ethyl group]-1H-pyrrolo [2, 3-b]Pyridin-5-yl trifluoromethanesulfonate

Raw materials: preparation 12

Preparation 56: 3- [4- (Cyclopentylamino) -4-oxobutyl]-1-benzofuran-5-yl trifluoromethanesulfonate

Raw materials: n-cyclopentyl-4- (5-hydroxy-1-benzofuran-3-yl) butyramide is obtained by using N-cyclopentyl-4- (5-methoxy-1-benzofuran-3-yl) butyramide as a raw material and carrying out the same steps as in preparation 1.

Preparation 57: 3- {2- [ (cyclopropylcarbonyl) amino group]Ethyl } -1H-pyrrolo [2, 3-b)]Pyridin-5-yl trifluoromethanesulfonate

Raw materials: preparation 10

Preparation 58: 3- (2- { [ (allylamino) carbonyl]Amino } ethyl) -1-benzothien-5-yl trifluoromethanesulfonate

Raw materials: with N-allyl-N' - [2- (5-methoxy-1-benzothien-3-yl) ethyl]Urea is used as raw material to obtain N-allyl-N' - [2- (5-hydroxy-1-benzothiophen-3-yl) ethyl]Urea.

Preparation 59: 3- [ (acetylamino) ethyl group]-1, 4-benzodioxine-6-yl trifluoromethanesulfonate

Raw materials: preparation 18

Preparation 60: 3- [2- (isobutyrylamino) ethyl]-1-benzofuran-5-yl trifluoromethanesulfonate

Raw materials: preparation 7

Preparation 61: 4- {2- [ (2, 2, 2-trifluoroacetyl) amino]Ethyl } -3, 4-dihydro-2H-chromen-6-yl trifluoromethanesulfonate

Raw materials: with 2, 2, 2-trifluoro-N- [2- (6-methoxy-3, 4-dihydro-2H-benzopyran-4-yl) ethyl]Acetamide as raw material, and the same steps as the preparation 1 are carried out to obtain 2, 2, 2-trifluoro-N- [2- (6-methoxy-3, 4-dihydro-2H-benzopyran-4-yl) ethyl]An acetamide.

Preparation 62: 3- (4-anilino-4-oxobutyl) -1-benzothien-5-yl triflate starting material: 4- (5-hydroxy-1-benzothiophen-3-yl) -N-phenylbutanamide is obtained by using 4- (5-methoxy-1-benzothiophen-3-yl) -N-phenylbutanamide as a raw material through the same steps as the preparation 1.

Preparation 63: 3- [ (acetylamino) methyl group]-3, 4-dihydro-2H-benzopyran-6-yl trifluoromethanesulfonate

Raw materials: with N- [ (6-methoxy-3, 4-dihydro-2H-benzopyran-3-yl) methyl group]Acetamide as raw material, and the same steps as the preparation 1 are carried out to obtain N- [ (6-hydroxy-3, 4-dihydro-2H-benzopyran-3-yl) methyl]An acetamide.

Preparation 64: 3- [2- (acetylamino) ethyl group]-2- [4- (trifluoromethyl) benzyl]-1-benzofuran-5-yl trifluoromethanesulfonate

Raw materials: with N- (2- { 5-methoxy-2- [4- (trifluoromethyl) benzyl group]The N- (2- { 5-hydroxy-2- [4- (trifluoromethyl) benzyl) acetamide which is obtained by the same steps as the preparation 1 and is used as the raw material]-1-benzofuran-3-yl } ethyl) acetamide.

Preparation 65: 3- (2- { [ (methylamino) carbonyl]Amino } ethyl) -1H-indol-5-yl trifluoromethanesulfonate starting material: with N- [2- (5-methoxy-1H-indol-3-yl) ethyl group]The N- [2- (5-hydroxy-1H-indol-3-yl) ethyl is obtained by using (E) -N' -methylurea as a raw material and carrying out the same steps as the preparation 1]-N' -methylurea.

Preparation 66: 4- {2- [ (2, 2-dimethylpropionyl) amino]Ethyl } -3, 4-dihydro-2H-chromen-6-yl trifluoromethanesulfonate

Raw materials: with N- [2- (6-methoxy-3, 4-dihydro-2H-benzopyran-4-yl) ethyl]N- [2- (6-hydroxy-3, 4-dihydro-2H-benzopyran-4-yl) ethyl prepared from (E) -2, 2-dimethylpropionamide by the same steps as in preparation 1]-2, 2-dimethylpropionamide.

Preparation 67: 3- [2- (acetylamino) ethyl group]-1H-indol-5-yl trifluoromethanesulfonate

Raw materials: n-acetyl-5-hydroxytryptamine

Preparation 68: 3- { [ (Cyclohexylcarbonyl) amino]Methyl } -1, 4-benzodioxine-6-yl trifluoromethanesulfonate

Raw materials: n- [ (7-hydroxy-1, 4-benzodioxine-2-yl) methyl is obtained by using N- [ (7-methoxy-1, 4-benzodioxine-2-yl) methyl) -cyclohexane formamide as a raw material through the same steps as the preparation 1]-cyclohexanecarboxamide.

Preparation 69: 3- [2- (acetylamino) ethyl } -2- (3-methoxybenzyl) -1-benzothien-5-yl trifluoromethanesulfonate

Raw materials: with N- {2- [ 5-methoxy-2- (3-methoxybenzyl) -1-benzothiophen-3-yl]Ethyl acetamide as material to obtain N- {2- [ 5-hydroxy-2- (3-methoxy benzyl) -1-benzothiophene-3-yl]Ethyl } acetamide.

Preparation 70: 3- [3- (acetyl)Amino) propyl group]-1-benzofuran-5-yl trifluoromethanesulfonate

Raw materials: with N- [3- (5-methoxy-1-benzofuran-3-yl) propyl group]Acetamide as raw material, and the same steps as the preparation 1 are carried out to obtain N- [3- (5-hydroxy-1-benzofuran-3-yl) propyl]An acetamide.

Preparation 71: n- {2- [ 5-hydroxy-1- (phenylsulfonyl) -1H-indol-3-yl]Ethyl-acetamide

Step A: n- {2- [ 5-methoxy-1- (phenylsulfonyl) -1H-indol-3-yl]Ethyl acetamide

5g of melatonin are dissolved in 150ml of dichloromethane, and then 3.41g of sodium hydroxide and 0.35g of tetrabutylammonium hydrogen sulfate are added. The reaction mixture was then cooled in an ice bath and 4.06ml of benzenesulfonyl chloride was added dropwise. After stirring overnight at room temperature, the excess sodium hydroxide and catalyst were filtered off, the solvent was removed by evaporation in vacuo and the resulting solid was recrystallized to give the title product in the form of white crystals.

Melting Point：140-141℃

Step B: n- {2- [ 5-hydroxy-1- (phenylsulfonyl) -1H-indol-3-yl]Ethyl acetamide

5g of the compound obtained in step A are dissolved in 100ml of dichloromethane. The reaction mixture was then cooled in an ice bath and 3.81ml of boron tribromide were added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was poured into 500ml of water and ice. The precipitate formed is filtered off, washed with water and dried in an oven at 50 ℃.

Melting Point：205-206℃

Preparation 72: 3- [2- (acetylamino) ethyl) -1-benzothien-5-yl trifluoromethanesulfonate

The compound obtained in preparation 9 is used as a raw material, and the method is the same as that of preparation 45.

Example 1: n- (2- {7- [2({3- [2- (acetylamino) ethyl)]-1-benzofuran-5-yl } oxy) Ethoxy radical]-1-naphthyl } ethyl) acetamide

Step A: n- {2- [7- (2-Bromoethoxy) naphthalen-1-yl]Ethyl acetamide the compound from preparation 1 (0.009mol) was dissolved in a mixture of 20ml dimethylsulfoxide (6ml) and butanone (14 ml). 0.027mol of potassium carbonate and 0.036mol of dibromoethane were added, and the mixture was heated under reflux for 48 hours. The reaction mixture was then cooled and poured into water. With Et₂The aqueous phase is extracted O, the organic phase is subsequently washed with water until the wash water becomes neutral, then dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: acetone/cyclohexane (2/8)) and recrystallized. A white solid was obtained.

Melting Point：110-111℃

Elemental microanalysis：

％C H N

Calculated values: 57.155.404.17

Measured value: 57.285.383.91

Step B: n- (2- {7- [2- ({3- [2- (acetylamino) ethyl)]-1-benzofuran-5-yl } oxy) ethoxy]-1-naphthyl } ethyl) acetamide

In a 100ml round-bottom flask, 0.003mol of the compound obtained in preparation 2 and 0.003mol of the compound obtained in step A were dissolved in a mixture of 3ml of dimethyl sulfoxide and 20ml of butanone. 0.009mol of potassium carbonate and one potassium iodide crystal were added, and then the mixture was heated under reflux for 12 hours. The reaction mixture is subsequently cooled and poured into 100ml of water. The precipitate formed is filtered off with suction and recrystallized.

Example 2: n- (2- {5- [2- ({8- [2- (acetylamino) ethyl)]-2-naphthyl } oxy) ethoxy]-1-benzofuran-3-yl } ethyl) cyclopropanecarboxamide

The procedure is as in example 1, except that in step B, the compound obtained in preparation 3 is used instead of the compound obtained in preparation 2.

Example 3: n- (2- {5- [2- ({8- [2- (acetylamino) ethyl)]-2-naphthyl } oxy) ethoxy]-1-benzofuran-3-yl } ethyl) -2-furoamide

The procedure is as in example 1, except that in step B, the compound obtained in preparation 4 is used instead of the compound obtained in preparation 2.

Example 4: n- (2- {7- [2- ({3- [2- (acetylamino) ethyl)]-1-benzofuran-5-yl } thio) ethoxy]-1-naphthyl } ethyl) benzamide

The procedure is as in example 1, except that

-in step A, replacing the compound obtained in preparation 1 with the compound obtained in preparation 5,

-in step B, the compound obtained in preparation 36 is used instead of the compound obtained in preparation 2.

Example 5: n- (2- {7- [2- ({3- [2- (acetylamino) ethyl)]-1-benzofuran-5-yl } amino) -ethoxy]-1-naphthyl } ethyl) acetamide

The procedure is as in example 1, except that in step B the compound obtained in preparation 40 is used instead of the compound obtained in preparation 2.

Example 6: n- (2- {7- [2- ({3- [2- (isobutyrylamino) ethyl)]-1-benzofuran-5-yl } oxy) -ethoxy]-1-naphthyl } ethyl) -3-butenamide

The procedure is as in example 1, except that

-in step A, the compound obtained in preparation 6 is used instead of the compound obtained in preparation 1,

-in step B, the compound obtained in preparation 7 is used instead of the compound obtained in preparation 2.

Example 7: n- (2- {7- [2- ({3- [2- (acetylamino) ethyl)]-1-benzothien-5-yl } oxy) -Ethoxy radical]-1-naphthyl } ethyl) -2-phenylacetamide

The procedure is as in example 1, except that

-in step A, replacing the compound obtained in preparation 1 with the compound obtained in preparation 5,

-in step B, the compound obtained in preparation 2 is replaced by the compound obtained in preparation 9.

Example 8: n- (2- {5- [2- ({8- [2- (acetylamino) ethyl)]-2-naphthyl } oxy) ethoxy]-1H-pyrrolo [2, 3-b]Pyridin-3-yl } ethyl) cyclopropanecarboxamide

The procedure is as in example 1, except that in step B the compound obtained in preparation 10 is used instead of the compound obtained in preparation 2.

Example 9: n- (2- {5- [2- ({3- [2- (acetylamino) ethyl)]-3a, 7 a-dihydro-1-benzofuran-5-yl } amino) -ethylamino]-1-benzothien-3-yl } ethyl) acetamide

The procedure is as in example 1, except that

-in step A, replacing the compound obtained in preparation 1 with the compound obtained in preparation 2,

-in step B, the compound obtained in preparation 2 is replaced by the compound obtained in preparation 9.

Example 10: n- (2- {5- [2- ({3- [2- (acetylamino) ethyl)]-1H-indol-5-yl } oxy) ethoxy]-3a, 7 a-dihydro-1-benzofuran-3-yl } ethyl) -2-furoamide

The procedure is as in example 1, except that

-in step A, the compound obtained in preparation 4 is used instead of the compound obtained in preparation 1,

-in step B, the compound obtained in preparation 11 is used instead of the compound obtained in preparation 2.

Example 11: n- (2- {5- [2- ({3- [2- (acetylamino) ethyl)]-1H-pyrroleAnd [2, 3-b ]]Pyridin-5-yl } oxy) ethoxy]-3a, 7 a-dihydro-1-benzofuran-3-yl } ethyl) -2-methylpropanamide

The procedure is as in example 1, except that

-in step A, the compound obtained in preparation 7 is used instead of the compound obtained in preparation 1,

-in step B, the compound obtained in preparation 2 is replaced by the compound obtained in preparation 12.

Example 12: n- (2- {7- [3- ({3- [2- (acetylamino) ethyl)]-1-benzothien-5-yl } oxy) -propoxy]-1-naphthyl } ethyl) acetamide

Step A: n- (2- [7- (3-hydroxypropyloxy) naphthalen-1-yl)]Ethyl acetamide

In a 100ml round-bottom flask, 0.022mol of the compound obtained in preparation 1 was dissolved in 30ml of dimethylformamide. 0.066mol of potassium carbonate and 0.033mol of 3-bromopropan-1-ol are added, and the mixture is subsequently heated at 80 ℃ for 4 hours. The reaction mixture was then cooled and poured into 100ml of 1M HCl solution. With Et₂The aqueous phase is extracted 3 times, and the organic phase is subsequently dried over magnesium sulfate and evaporated under reduced pressure. Recrystallization afforded the title product. As a white solid.

Melting Point：141-142℃

Step B: 3- ({8- [2- (acetylamino) ethyl]-2-naphthyl } oxy) propyl methanesulfonate

In a 250ml round bottom flask, the alcohol from step A was dissolved in 50ml dichloromethane and 0.012mol triethylamine was added. The mixture was cooled in an ice/salt bath at-10 ℃ and subsequently 0.012mol of methanesulfonyl chloride was added dropwise with stirring by a magnetic stirrer. The reaction mixture was stirred at room temperature for 4 hours. Then 100ml of water are added, followed by CH₂Cl₂And (4) extracting. The organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The resulting oil was purified by chromatography on silica gel (eluent: acetone/cyclohexane (2/8))

Step C: n- (2- {7- [3- ({3- [2- (acetylamino) ethyl)]-1-benzothien-3-yl } oxy) -propoxy]-1-naphthyl } ethyl) acetamide

To a 100ml round bottom flask containing 30ml of methanol, 0.06g of sodium was added in small portions. When the sodium was used up, 0.0033mol of the compound obtained in preparation 9 was added and the mixture was stirred for 20 minutes. Methanol was removed by evaporation under reduced pressure, the residue was taken up in 15ml of DMF and 0.0027mol of the compound obtained in step B was subsequently added. The reaction mixture was heated at reflux for 12 hours, then cooled and poured into 100ml of water and 10ml of 3M HCl. After extraction with ethyl acetate, the organic phase was washed successively with 10% sodium hydroxide solution and water. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure and the title compound was purified by silica gel chromatography.

Example 13: n- (2- {7- [3- ({3- [2- (butyrylamino) ethyl)]-1-benzothien-5-yl } thio) -propoxy]-1-naphthyl } ethyl) cyclobutanecarboxamide

The procedure is as in example 12, except that

-in step A, the compound obtained in preparation 13 is used instead of the compound obtained in preparation 1,

-in step C, the compound obtained in preparation 37 is used instead of the compound obtained in preparation 9.

Example 14: n- {2- [5- ({3- [ (8- {2- [ (2, 2, 2-trifluoroacetyl) amino group]Ethyl } -2-naphthyl) oxy]Propyl } amino) -1-benzothien-3-yl]-ethyl } pentanamide

The procedure is as in example 12, except that

In step A, the compound obtained in preparation 14 is used instead of the compound obtained in preparation 1,

-in step C, the compound obtained in preparation 9 is replaced by the compound obtained in preparation 41.

Example 15: n- ({6- [3- ({8- [2- (acetylamino) ethyl)]-2-naphthyl } oxy) propoxy]-2H-benzopyran-3-ylMethyl) butanamide

The procedure is as in example 12, except that in step C, the compound obtained in preparation 15 is used instead of the compound obtained in preparation 9.

Example 16: n- (2- {5- [3- ({3- [ (acetylamino) methyl)]-2H-benzopyran-6-yl } oxy) propoxy group]-1-benzofuran-3-yl } ethyl) cyclopropanecarboxamide

The procedure is as in example 12, except that

-in step A, the compound obtained in preparation 1 is replaced by the compound obtained in preparation 16,

-in step C, the compound obtained in preparation 3 is substituted for the compound obtained in preparation 9.

Example 17: n- {2- [5- (3- { [3- ({ [ (propylamino) carbonyl)]Amino } methyl) -1, 4-benzodioxine-6-yl]Oxy } propoxy) -1H-pyrrolo [2, 3-b]Pyridin-3-yl]Ethyl-acetamide

The procedure is as in example 12, except that

In step A, the compound obtained in preparation No. 1 is replaced by the compound obtained in preparation No. 17,

-in step C, the compound obtained in preparation 12 is used instead of the compound obtained in preparation 9.

Example 18: n- ({7- [4- ({8- [2- (acetylamino) ethyl)]-2-naphthyl } oxy) butoxy]-1, 4-benzodioxine-2-yl } methyl) acetamide

Step A: 4- ({8- [2- (acetylamino) ethyl]-2-naphthyl } oxy) butanoic acid ethyl ester

In a 100ml round-bottom flask, 0.022mol of the compound obtained in preparation 1 was dissolved in 50ml of acetonitrile. 0.066mol of potassium carbonate was added and the reaction mixture was stirred at 80 ℃ for 30 minutes. 0.033mol 1-bromobutyric acid ethyl ester was then added dropwise and the reaction mixture was stirred at 80 ℃ for 1 hour. Acetonitrile was removed by evaporation under reduced pressure and the residue was dissolved in 1n hcl solution. After extraction with ethyl acetate, the organic phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, and the title compound is purified by recrystallization. A beige solid was obtained.

Melting Point：64-66℃

Step B: n- {2- [7- (4-Hydroxybutoxy) naphthalen-1-yl]Ethyl acetamide

The ester from step A (0.009mol) was dissolved in 100ml of anhydrous ether in a 250ml round-bottom flask. 0.009mol of lithium aluminium hydride are added portionwise and the reaction mixture is stirred at room temperature for 6 hours. The reaction mixture was then hydrolyzed with a few drops of 1M sodium hydroxide and the resulting precipitate was filtered off. The filtrate was dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is taken up in Et₂The O/petroleum ether mixture (1/1) was precipitated, filtered off with suction and recrystallized. As a white solid.

Melting Point：82-84℃

Elemental microanalysis：

％C H N

Calculated values: 71.737.694.64

Measured value: 72.007.584.45

Step C: 4- ({8- [2- (acetylamino) ethyl]-2-naphthyl } oxy) butyl methanesulfonate

The procedure is as in example 12, step B, starting from the compound obtained in step B.

Step D: n- ({7- [4- ({8- [2- (acetylamino) ethyl)]-2-naphthyl } oxy) butoxy]-1, 4-benzodioxine-2-yl } methyl) acetamide

The procedure is as in step C of example 12, except that the compound obtained in preparation 18 is used instead of the compound obtained in preparation 9.

Example 19: n- {2- [7- (4- {3- [ (acetylamino) ethyl ] ethyl]-2- (3-methoxybenzyl) -1-benzofuran-5-yl]Amino } butoxy) -1-naphthyl]Ethyl } -2-furoamide

The procedure is as in example 18, except that in step A, the compound obtained in preparation 19 is used instead of the compound of preparation 1, and in step D, the compound of preparation 42 is used instead of the compound of preparation 9.

Example 20: n- ({6- [4- ({3- [ (acetylamino) ethyl)]-2-benzyl-1H-pyrrolo [2, 3-b]Pyridin-5 yl } oxy) butoxy]-4a, 8 a-dihydro-2H-benzopyran-3-yl } methyl) butanamide

The procedure is as in example 18, except that in step A, the compound obtained in preparation 15 is used instead of the compound of preparation 1, and in step D, the compound of preparation 20 is used instead of the compound of preparation 9.

Example 21: n- (2- {5- [4- ({3- [2- (acetylamino) ethyl)]-2- [4- (trifluoromethyl) benzyl]-1-benzothien-5-yl } thio) butoxy]-1H-pyrrolo [2, 3-b]Pyridin-3-yl } ethyl) -cyclopropanecarboxamide

The procedure is as in example 18, except that in step A, the compound obtained in preparation 10 is used instead of the compound of preparation 1, and in step D, the compound of preparation 38 is used instead of the compound of preparation 9.

Example 22: n- {2- [5- (4- { [3- [ (acetylamino) methyl ] methyl]-4a, 8 a-dihydro-2H-benzopyran-6-yl } oxy) butoxy]-1-benzothien-3-yl } ethyl) cyclohexanecarboxamide

The procedure is as in example 18, except that in step A, the compound obtained in preparation 16 is used instead of the compound of preparation 1, and in step D, the compound of preparation 21 is used instead of the compound of preparation 9.

Example 23: 2, 2, 2-trifluoro-N- (2- {5- [4- ({3- [2- (hexylamino) -2-oxoethyl)]-3a, 7 a-dihydro-1-benzofuran-5-yl } oxy) butoxy]-1-benzothien-3-yl } ethyl) -acetamide

The procedure is as in example 18, except that in step A, the compound obtained in preparation 22 is used instead of the compound of preparation 1, and in step D, the compound of preparation 23 is used instead of the compound of preparation 9.

Example 24: n- (2- {7- [4- ({4- [2- (acetylamino) ethyl)]-3, 4-dihydro-2H-chromen-6-yl } -oxy) butoxy]-1, 2, 3, 4-tetrahydro-1-naphthyl } ethyl) acetamide

The procedure is as in example 18, except that in step A, the compound obtained in preparation 24 is used instead of the compound of preparation 1, and in step D, the compound of preparation 25 is used instead of the compound of preparation 9.

Example 25: n- {2- [5- ({4- [ (8- {2- [ (cyclopropylcarbonyl) amino group)]Ethyl } -5, 6, 7, 8-tetrahydro-2-naphthyl) oxy]Butyl } amino) -1-benzofuran-3-yl]Ethyl } -2-furoamide

The procedure is as in example 18, except that in step A, the compound obtained in preparation 26 is used instead of the compound of preparation 1, and in step D, the compound of preparation 43 is used instead of the compound of preparation 9.

Example 26: n- (2- {5- [4- ({8- [2- (heptanoylamino) ethyl)]-2-naphthyl } oxy) butoxy]-1H-indol-3-yl } ethyl) cyclobutanecarboxamide

The procedure is as in example 18, except that in step A, the compound obtained in preparation 27 is used instead of the compound of preparation 1, and in step D, the compound of preparation 28 is used instead of the compound of preparation 9.

Example 27: n- [2- (5- { [6- ({8- [2- (acetylamino) ethyl]-2-naphthyl } oxy) hexyl radical]Oxy } -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) ethyl acetamide

Step A: n- (2- {7- [ (6-hydroxyhexyl) oxy]-1-naphthyl } ethyl) acetamide

The procedure is as in step A of example 12, except that 6-bromohexan-1-ol is used instead of 3-bromopropan-1-ol. A white solid.

Melting Point：58-61℃

Elemental microanalysis：

％C H N

Calculated values: 72.918.414.25

Measured value: 73.228.174.02

Step B: 6- ({8- [2- (acetylamino) ethyl]-2-naphthyl } oxy) hexyl methanesulfonate

The procedure is as in step B of example 12. A white solid.

Melting Point：66-67℃

Step C: n- [2- (5- { [6- ({8- [2- (acetylamino) ethyl]-2-naphthyl } oxy) hexyl radical]Oxy } -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) ethyl]Acetamide

The procedure is as in step C of example 12, except that the compound obtained in preparation 12 is used instead of the compound obtained in preparation 9.

Example 28: 4- (7- { [6- ({3- [ (acetylamino) methyl)]-2H-benzopyran-6-yl } oxy) hexyl radical]Oxy } -1-naphthyl) -N-isopropylbutanamide

The procedure is as in example 27, except that in step A, the compound obtained in preparation 29 is used instead of the compound obtained in preparation 1, and in step C, the compound obtained in preparation 16 is used instead of the compound obtained in preparation 9.

Example 29: n- { [7- ({6- [ (3- {2- [ (anilinocarbonyl) amino group)]Ethyl } -1-benzofuran-5-yl) -oxy]Hexyl } oxy) -1, 4 benzodioxine-2-yl]Methyl acetamide

The procedure is as in example 27, except that in step A, the compound obtained in preparation 30 is used instead of the compound obtained in preparation 1, and in step C, the compound obtained in preparation 18 is used instead of the compound obtained in preparation 9.

Example 30: n- [2- (7- { [6- ({3- [2- (benzylamino) -2-oxoethyl)]-1-benzothien-5-yl } oxy) hexyl radical]Thio } -1, 2, 3, 4-tetrahydro-1-naphthyl) ethyl]-cyclopropanecarboxamides

The procedure is as in example 27, except that

-in step A, replacing the compound of preparation 1 with the compound of preparation 31

In step C, the compound of preparation 9 is replaced by the compound of preparation 26.

Example 31: n- [2- (5- { [6- ({3- [3- (methylamino) -3-oxopropyl) radical]-1-benzofuran-5-yl } oxy) hexyl]Oxy } -1H-inden-3-yl) ethyl]Pentamides

The procedure is as in example 17, except that in step A, the compound of preparation 32 is used instead of the compound of preparation 1, and in step C, the compound of preparation 33 is used instead of the compound of preparation 9.

Example 32: N-cyclopropyl-N' - (2- {5- [ (6- { [3- (2- { [ (methylamino) carbonyl) amino group]Amino } -ethyl) -1H-pyrrolo [2, 3-b]Pyridin-5-yl]Oxy } hexyl) amino]-1-benzofuran-3-yl } ethyl) urea

The procedure is as in example 27, except that in step A, the compound of preparation 34 is used instead of the compound of preparation 1, and in step C, the compound of preparation 44 is used instead of the compound of preparation 9.

Example 33: n- [2- (7- { [6- ({3- [4- (methylamino) -4-oxobutyl)]-1H-indol-5-yl } oxy) hexyl radical]Oxy } -1-naphthyl) ethyl]-3-butenamide

The procedure is as in example 27, except that

-in step A, replacing the compound of preparation 1 with the compound of preparation 6

-in step C, the compound of preparation 9 is replaced by the compound of preparation 35.

Example 34: n- [2- (7- {3- [2- (acetylamino) ethyl group]-1-benzofuran-5-yl } -1-naphthyl) -ethyl]Acetamide

Under a nitrogen atmosphere, 2.76mmol of the compound obtained in preparation 45, 2.76mmol of the compound obtained in preparation 46, 1.94mmol of dichlorobis (triphenylphosphine) nickel, 3.87 mmol of 1 triphenylphosphine and 8.30mmol of zinc were suspended in 20ml of anhydrous DMF. After heating at 120 ℃ for 48 hours under nitrogen, the reaction mixture was concentrated, and the residue was in CH₂Cl₂And M NaHCO₃And (4) distributing. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The title compound was isolated by silica gel chromatography.

In examples 35 to 48, the procedure is as in example 34, starting from the appropriate compounds of the preparations.

Example 35: n- (2- {5- [8- (2- { (methylamino) carbonyl)]Amino } ethyl) -2-naphthyl]-1-benzothien-3-yl } ethyl) cyclopropanecarboxamide

Raw materials: preparation 47 and 48

Example 36: n- {2- [5- (3- {2- [ (anilinocarbonyl) amino group]Ethyl } -1-benzofuran-5-yl) -1-benzothien-3-yl]Ethyl } -2-furoamide

Raw materials: preparation 49 and 50

Example 37: 2- (5- {3- [2- (acetylamino) ethyl]-1-benzofuran-5-yl } -1H-indol-3-yl) -N-benzylacetamide

Raw materials: preparation 45 and 51

Example 38: n- [3- (5- {3- [2- (isobutyrylamino) ethyl ] methyl ester]-1-benzothien-5-yl } -1H-indol-3-yl) propyl]Benzamide derivatives

Raw materials: preparation 52 and 53

Example 39: n- [3- (5- {8- [2- (acetylamino) ethyl group]-2-naphthyl } -1H-pyrrolo [2, 3-b)]-pyridin-3-yl) propyl]Heptamide

Raw materials: preparation 46 and 54

Example 40: 4- (5- {3- [3- (acetylamino) ethyl group]-1H-pyrrolo [2, 3-b]-pyridin-5-yl } -1-benzofuran-3-yl) -N-cyclopentylbutanamide

Raw materials: preparation 55 and 56

EXAMPLE 41: n- (2- {5- [3- (2- { [ (allylamino) carbonyl]Amino } ethyl) -1-benzothien-5-yl]-1H-pyrrolo [2, 3-b]Pyridin-3-yl } ethyl) cyclopropanecarboxamide

Raw materials: preparation 57 and 58

Example 42: n- [2- (5- {3- [ (acetylamino) methyl group)]-1, 4-benzodioxin-6-yl } -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) ethyl]Cyclopropanecarboxamides

Raw materials: preparation 57 and 59

Example 43: 2-methyl-N- {2- [5- (4- {2- [ (2, 2, 2-trifluoroacetyl) amino group]Ethyl } -3, 4-dihydro-2H-chromen-6-yl) -1-benzofuran-3-yl]Ethyl propionamide

Raw materials: preparation 60 and 61

Example 44: 4- (5- {3- [ (acetylamino) methyl group]-3, 4-dihydro-2H-chromen-6-yl } -1-benzothien-3-yl) -N-phenylbutanamide

Raw materials: preparation 62 and 63

Example 45: n- (2- {5- {8- [2- (acetylamino) ethyl]-2-naphthyl } -2- [4- (trifluoromethyl) -benzyl]-1-benzofuran-3-yl } ethyl) acetamide

Raw materials: preparation 64 and 46

Example 46: 2, 2-dimethyl-N- (2- {6- [3- (2- { [ (methylamino) carbonyl)]Amino } ethyl) -1H-indol-5-yl]-3, 4-dihydro-2H-benzopyran-4-yl } ethyl) propanamide

Raw materials: preparation 65 and 66

Example 47: n- [ (7- {3- [2- (acetylamino) ethyl)]-1H-indol-5-yl } -1, 4-benzodioxine-2-yl) -methyl]Cyclohexanecarboxamide

Raw materialsPreparation 67 and 68

Example 48: n- (3- {5- [3- [2- (acetylamino) ethyl)]-2- (3-methoxybenzyl) -1-benzothien-5-yl]-1-benzofuran-3-yl } propyl) acetamide

Raw materials: preparation 69 and 70

Example 49: n- (2- {7- [4- ({3- [2- (acetylamino) ethyl)]-1-benzofuran-5-yl } oxy) butoxy]-1 naphthyl } ethyl) acetamide

Step A: n- {2- [7- (4-Bromobutoxy) -1-naphthyl]Ethyl acetamide

In a 100ml round-bottom flask, 10mmol of the compound obtained in preparation 1 was dissolved in 50ml of acetonitrile. 30mmol of potassium carbonate were added and the mixture was stirred under reflux for 30 minutes with a magnetic stirrer, followed by the addition of 10mmol of 1, 4-dibromobutane. After 12 hours of reflux, the acetonitrile was evaporated in vacuo and the resulting residue was treated in 1M sodium hydroxide solution. The resulting precipitate was filtered off and recrystallized to yield the title product.

Step B: n- (2- {7- [4- ({3- [2- (acetylamino) ethyl)]-1-benzofuran-5-yl } oxy) butoxy]-1-naphthyl } ethyl) acetamide

To a 100ml round bottom flask containing 30ml of methanol was added sodium (0.07 g; 0.0030at.g) in small portions. When the sodium usage was complete, 3.6mmol of the compound from preparation 2 was added. After stirring for 20 minutes, the methanol was evaporated off under reduced pressure and the residue was worked up in 15ml of DMF. 3mmol of the compound obtained in step A was added and the mixture was refluxed for 12 hours. The reaction mixture was cooled and poured into a mixture of 100ml water and 10ml3M hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate and the organic phase was washed successively with 10% sodium hydroxide solution and water. The resulting solid was recrystallized from acetonitrile to give the title product.

Melting Point：160-162℃

Example 50: n- {2- [5- [8- ({8- [2- (acetylamino) ethyl)]-2-naphthyl } oxy) butoxy]-1- (phenylsulfonyl) -1H-indol-3-yl]Ethyl acetamide

In a 100ml round-bottom flask, 10mmol of the compound from preparation 71 were dissolved in 50ml of acetonitrile and subsequently 4.17g of potassium carbonate were added and the reaction mixture was refluxed for 30 minutes with the aid of a magnetic stirrer. Then 10mmol of the compound obtained in step A of example 49 was added and the mixture was heated under reflux for 12 hours. Acetonitrile was removed by evaporation in vacuo and the resulting residue was treated with 1M sodium hydroxide solution. The precipitate obtained is filtered off and recrystallized from ethanol at 95 ℃.

Melting Point：135-137℃

Example 51: n- (2- {7- [4- ({8- [2- (acetylamino) ethyl)]-2-naphthyl } oxy) butoxy]-1, 2, 3, 4-tetrahydro-1-naphthyl } ethyl) acetamide

The procedure is as in example 49 except that in step B, the product obtained in preparation 25 is used instead of the product obtained in preparation 2.

Melting Point：63-65℃

Example 52: n- (2- {5- [4- ({3- [2- (acetylamino) ethyl)]-1-benzofuran-5-yl } oxy) butoxy]-1H-indol-3-yl } ethyl) acetamide

Step A: 4- ({3- [2- (acetylamino) ethyl]-1H-indoleIndole-5-yl } oxy) butyric acid ethyl ester

5.9g of the compound obtained in preparation 11 was dissolved in 100ml of acetonitrile, followed by addition of 11.22.g of potassium carbonate and 5.81ml of ethyl 4-bromobutyrate. After refluxing overnight, the potassium carbonate is filtered off, the acetonitrile is removed by evaporation and the residue is worked up in 100ml of water. Three extractions were carried out, using 50ml of ethyl acetate each time, followed by washing of the organic phase with water until the pH value was neutral, drying over magnesium sulfate and evaporation in vacuo. The resulting oil precipitated from isopropyl ether.

Melting Point：107-108℃

Step B: n- {2- [5- (4-Hydroxybutoxy) -1H-indol-3-yl]Ethyl acetamide

To a suspension of 1.42g lithium aluminum hydride in 50ml dry IHF cooled with an ice bath was added dropwise a solution of 6.2g of the compound obtained in step A dissolved in 50ml dry THF. After stirring at room temperature for 30 minutes, 5% sodium hydroxide solution was added dropwise until the evolution of gas ceased. The precipitate formed is filtered off, the organic phase is evaporated and the residue is worked up in 70ml of ethyl acetate. The organic phase was washed with water until neutral, dried over magnesium sulfate and evaporated in vacuo to give the title product as an oil.

Step C: n- {2- [5- (4-Bromobutoxy) -1H-indol-3-yl]Ethyl acetamide

3.92g of the compound obtained in step B were dissolved in 50ml of acetonitrile, and then 5.31g of triphenylphosphine and 6.71g of carbon tetrabromide were added with stirring. After standing overnight at room temperature, the acetonitrile was removed by evaporation in vacuo and the resulting residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol 96/4).

An oil was obtained.

Step D: n- (2- {5- [4- ({3- [2- (acetylamino) ethyl)]-1-benzofuran-5-yl } oxy) butoxy]-1H-indol-3-yl } ethyl) acetamide

0.72g of the compound obtained in step C was dissolved in 20ml of acetonitrile, followed by addition of 0.57g of potassium carbonate and 0.30g of the compound obtained in preparation 2. After refluxing overnight, the reaction mixture was poured into 200ml of water and ice. The resulting precipitate was filtered off, washed with diethyl ether, dried and recrystallized to give the title product as a white powder.

Melting Point：164-166℃

Example 53: n- (2- {7- [4- ({3- [2- (acetylamino) ethyl)]-1-benzothien-5-yl } oxy) butoxy]-1-naphthyl } ethyl) acetamide

The procedure is as in example 49, except that in step B, the product obtained in preparation 9 is substituted for the product obtained in preparation 2.

Recrystallisation from acetonitrile/methanol (2/1).

Melting Point：169-170℃

Example 54: n- (2- {5- [4- ({3- [2- (acetylamino) ethyl)]-1-benzothien-5-yl } oxy) butoxy]-1H-indol-3-yl } ethyl) acetamide

The procedure is as in example 49, except that in step A, the product obtained in preparation 9 is substituted for the product obtained in preparation 1, and in step B, the product obtained in preparation 11 is substituted for the product obtained in preparation 2.

Example 55: n- (2- {5- [4- ({3- [2- (acetylamino) ethyl)]-1-benzothien-5-yl } oxy) butoxy]-1H-pyrrolo [2, 3-b]Pyridin-3-yl } ethyl) acetamide

The procedure is as in example 49, except that in step A, the product obtained in preparation 9 is substituted for the product obtained in preparation 1, and in step B, the product obtained in preparation 12 is substituted for the product obtained in preparation 2.

Example 56: n- (2- {5- [4- ({3- [2- (acetylamino) ethyl)]-1-benzofuran-5-yl } oxy) butoxy]-1H-pyrrolo [2, 3-b]Pyridin-3-yl } ethyl) acetamide

The procedure is as in example 49 except that in step A, the product obtained in preparation 2 is substituted for the product obtained in preparation 1, and in step B, the product obtained in preparation 12 is substituted for the product obtained in preparation 2.

Example 57: n- (2- {5- [4- ({3- [2- (acetylamino) ethyl)]-1H-indol-5-yl } oxy) butoxy]-1H-pyrrolo [2, 3-b]Pyridin-3-yl } ethyl) acetamide

The procedure is as in example 49, except that in step A, the product obtained in preparation 11 is substituted for the product obtained in preparation 1, and in step B, the product obtained in preparation 12 is substituted for the product obtained in preparation 2.

The compounds of examples 58 to 64 were obtained in the same manner as in example 34, starting from the compounds of the appropriate preparations.

Example 58: n- [2- (7- {3- [2- (acetylamino) ethyl group]-1-benzothien-5-yl } -1-naphthyl) ethyl]Acetamide

Raw materials: preparation 46 and 72

Example 59: n- [2- (5- {8- [2- (acetylamino) ethyl group]-2-naphthyl } -1H-pyrrolo [2, 3-b)]-pyridin-3-yl) ethyl]Acetamide

Raw materials: preparation 46 and 55

Example 60: n- [2- (5- {3- [2- (acetylamino) ethyl group]-1-benzofuran-5-yl } -1-benzothien-3-yl) ethyl]Acetamide

Raw materials: preparation 72 and 45

Example 61: n- [2- (5- {3- [2- (acetylamino) ethyl group]-1-benzofuran-5-yl } -1H-indol-3-yl) ethyl]Acetamide

Raw materials: preparation 67 and 45

Example 62: n- [2- (5- {3- [2- (acetylamino) ethyl group]-1-benzofuran-5-yl } -1H-pyrrolo [2, 3-b)]-pyridin-3-yl) ethyl]Acetamide

Raw materials: preparation 55 and 45

Example 63: n- [2- (5- {3- [2- (acetylamino) ethyl group]-1H-indol-5-yl } -1H-pyrrolo [2, 3-b]Pyridin-3-yl) ethyl]Acetamide

Raw materials: preparation 55 and 67

Example 64: n- [2- (5- {3- [2- (acetylamino) ethyl group]-1-benzothien-5-yl } -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) ethyl]Acetamide

Raw materials: preparation 55 and 72

Pharmacological study

Example A: acute toxicity study

Acute toxicity was assessed after oral administration of several groups of eight mice (26 ± 2 grams) per group. Animals were observed at regular intervals during the first day of the procedure, and daily during the next two weeks. Calculating LD₅₀The value of (the dose that causes lethality in 50% of animals) and demonstrates the low toxicity of the compounds of the present invention.

Example B: binding studies of melatonin receptors on sheep pituitary nodule (pars cubalis) cells

Binding studies of the compound melatonin receptors of the present invention were performed on sheep pituitary nodular cells using conventional techniques. The pituitary nodule of the adenohypophysis is believed to be the site of higher melatonin receptor density in mammals. ("Journal of Neuroendocrinology", 1, pages 1-4, 1989)

Scheme(s)

1. The prepared pituitary nodular membrane of sheep is used as a target tissue in a saturation experiment to determine the 2-, [ alpha ], [ alpha¹²⁵I]-binding and affinity of iodo-melatonin.

2. The ovine pituitary sarcoid membranes served as target tissues in competitive binding experiments comparing each test compound to melatonin.

Each experiment was repeated three times and each compound was tested over a range of concentrations. The binding affinity of the compound can be determined from the results after statistical treatment.

Results

The compounds of the present invention exhibit strong affinity for melatonin receptors.

Example C: melatonin mt₁And MT₂Receptor binding studies

mt₁And MT₂2-, [2 ] for receptor binding assay¹²⁵I]-iodo-melatonin as reference radioligand. Radioactivity was measured with a liquid scintillation counter.

The competitive binding assay was repeated three times with each test compound. Different concentration ranges for each compound were tested. The results allow determination of the binding affinity (IC) of the test compound₅₀)。

Thus, IC of the compounds of the invention₅₀Value representation and mt₁And MT₂The binding capacity of one or the other receptor subtype, these values being ≦ 10. mu.M.

Example D: action of the compound of the invention in the twenty-four hour rhythm of rat motor behavior

The effect of melatonin on the circadian, biochemical and behavioral twenty-four hour rhythm of day/night alternation makes it possible to establish physiological models in the study of melatoninergic ligands.

The testing of the effect of compounds is associated with a large number of parameters, in particular with the twenty-four hour rhythm of the motor behaviour, which is a reliable indicator of the activity of the endogenous biological clock.

In this study, the effect of such compounds on the temporal sequestration (permanent darkness) of the particular experimental model, i.e. rats, was evaluated.

Experimental protocol

Once a month old male rats reached the laboratory they were subjected to a 12 hour photopic circadian change every 24 hours (LD 12: 12).

After 2-3 weeks of acclimation, they were placed in cages equipped with wheels connected to a recording system, and the locomotor activity status was detected and thereby monitored for changes in circadian rhythm (LD) or circadian rhythm (DD).

Once the recorded rhythm is displayed in circadian alternation LD 12: 12, immediately place the mice in permanent darkness (DD).

After 2-3 weeks, mice enter the daily dosing phase of the test compound when free processes (the rhythm of the endogenous clock reflecting this phenomenon) have been established apparently.

Observed by visual observation of the active rhythm.

The effect of light alternation on the active rhythm.

Disappearance of the effect on the rhythm in permanent darkness.

-the effect of daily administration of the compound; short term or long term effects.

By means of the software package it is made possible to:

measuring the duration and intensity of the activity, the time period of the animal's rhythms in the free processes and experiments.

The presence of circadian and non-circadian (e.g. infradian) components can be demonstrated by spectroscopic analysis.

Results

It is clearly shown that the compounds of the invention have a powerful effect on the circadian rhythm via the melatoninergic system.

Example E: light/dark cage test

Anxiolytic activity of the compounds of the invention can be revealed by testing the compounds of the invention in a light/dark cage assay by means of a behavioral model.

The device comprises two polyethylene boxes covered with plexiglas. One box is in the dark. A lamp was placed on the other box to produce a light intensity of about 4000 lux at the center of the box. An opaque plastic channel separates the light box from the cassette. Animals were individually tested for a 5 minute period. The bottom of the box is cleaned at each time. At the beginning of each experiment, mice were placed in the tunnel, facing the dark box. The time the mouse stayed in the light box and the number of passages through the channel were recorded after the first entry into the cassette.

The compounds of the invention significantly increased the time the mice stayed in the light box and the number of passages after administration of the compound 30 minutes before the start of the test, demonstrating the anxiolytic activity of the compounds of the invention.

Example F: activity of the Compounds of the invention on rat Tail artery

The compounds of the invention were tested in vitro in the tail artery of rats. Melatoninergic receptors are present in these blood vessels, providing a corresponding pharmacological model for studying melatoninergic ligand activity. Stimulation of the receptor induces vasoconstriction or dilation of the segment of the artery under study.

Scheme(s)

January rats were habituated to a 12 hour/12 hour light/dark circadian variation over 2-3 weeks.

After sacrifice, the tail artery was isolated and stored in a medium with a high concentration of oxygen. Catheters are inserted at both ends of the artery, suspended vertically in a suitable medium in the organ compartment and perfused through the proximal end, and changes in perfusion flow pressure can assess the effect of vasoconstriction or dilation of the compound.

The activity of the compounds can be assessed on arterial segments previously contracted with phenylephrine (1 μ M). The concentration/response curve is determined non-cumulatively by adding a concentration of the test compound to the pre-contracted arterial segment. When the observed effect reaches equilibrium, the medium is changed and after 20 minutes the same concentration of phenylephrine and other concentrations of test compound are added.

Results

The compounds of the present invention significantly alter the diameter of the tail artery constricted by phenylephrine.

Example G: the pharmaceutical composition comprises: tablet formulation

A dose of 5mg of N- (2- {7- [4- ({3- [2- (acetylamino) ethyl ] -1-benzofuran-5-yl } oxy) butoxy ] -1-naphthyl } ethyl) acetamide in 1000 tablets (example 49)

5g of wheat starch: 20g of corn starch: 20g of lactose: 30g of magnesium stearate: 2g of silica: 1g of hydroxypropyl cellulose: 2g

Claims (10)

1. A compound of the formula (I),

A-G₁-Gy-G₂-Gy’-G₃-B (I)

wherein:

a is represented byThe group of (a) or (b),

wherein:

-Q represents a sulfur or oxygen atom,

-R¹represents hydrogenAtom and R²Represents a linear or branched (C)₁-C₆) Alkyl radical

B represents the formula described aboveOr groupWherein Q is as defined above, and R¹Represents a straight chain or branched chain (C)₁-C₆) An alkyl group or a hydrogen atom, or a salt thereof,

◆G₁and G₃Which may be identical or different, represent a linear or branched alkylene chain containing from 1 to 4 carbon atoms,

cy and Cy' are different, indicating

-a ring structure of formula (II):

wherein:

x and Y, which may be the same or different, represent a carbon atom, or CH₂The radical(s) is (are),

*R⁴represents a hydrogen atom, and is represented by,

symbolRepresents a single bond or a double bond, and satisfies the valence of the atom,

wherein, if Cy represents formula (II), then G₂To the benzene ring of formula (II), and G₁To the ring of formula (II) containing X and Y,

and if Cy' represents (II), then G₂To a benzene ring of formula (II) and G₃To the ring of formula (II) containing X and Y,

-or a ring structure of formula (III):wherein: z represents a sulfur atom or an oxygen atom, or CH₂NH or NSO₂Ph group, D represents a benzene ring, R represents a benzene ring⁴As defined above, symbolRepresents a single bond or a double bond, and satisfies the valence of the atom,wherein, if Cy represents formula (III), then G₂To the D ring of formula (III), and G₁To the Z-containing ring of formula (III),

and if Cy' represents (III), then G₂To the D ring of formula (III), and G₃To the Z-containing ring of formula (III),

in the compound of formula (I), both of the two different rings Cy and Cy' can be represented by the structure of formula (II) or formula (III), or one of the two rings is represented by the structure of formula (II) and the other is represented by the structure of formula (III),

◆G₂a chain of formula (IV): -W₁-(CH₂)_m-(CH₂)_m-W₃ (IV)

Wherein:

-W₁and W₃Represents an oxygen atom, and represents an oxygen atom,

n represents an integer, where 0. ltoreq. n.ltoreq.6,

-m represents an integer, where 0. ltoreq. m.ltoreq.6,

provided that there cannot be two heteroatoms in succession,

their enantiomers and diastereomers, and their addition salts with a pharmaceutically acceptable acid or base.

2. A compound of formula (I) according to claim 1, wherein Cy and Cy' are different and represent the ring structures of formula (II), their enantiomers and diastereomers, and their addition salts with pharmaceutically acceptable acids or bases.

3. A compound of formula (I) according to claim 1, wherein Cy and Cy' are different and represent the ring structure of formula (III), their enantiomers and diastereomers, and their addition salts with pharmaceutically acceptable acids or bases.

4. A compound of formula (I) according to claim 1, wherein Cy represents a ring structure of formula (II) and Cy' represents a ring structure of formula (III), their enantiomers and diastereomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

5. A compound of formula (I) as claimed in claim 1 wherein G₂Represents a group-O- (CH)₂) p-O, wherein p represents an integer and 1. ltoreq. p.ltoreq.12, their enantiomers and diastereomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

6. A compound of formula (I) as claimed in claim 1 wherein A and B, which may be the same or different, represent a group NR¹COR²Their enantiomers and diastereomers, and their addition salts with pharmaceutically acceptable acids or bases.

7. Compounds of formula (I) according to claim 1, which are:

-N- (2- {7- [4- ({3- [2- (acetylamino) ethyl ] -1-benzofuran-5-yl } oxy) butoxy ] -1-naphthyl } ethyl) acetamide, -N- {2- [5- [4- ({8- [2- (acetylamino) ethyl ] -2-naphthyl } oxy) butoxy ] -1- (benzenesulfonyl) -1H-indol-3-yl ] ethyl } acetamide,

-N- (2- {7- [4- ({8- [2- (acetylamino) ethyl ] -2-naphthyl } oxy) butoxy ] -1, 2, 3, 4-tetrahydro-1-naphthyl } ethyl) acetamide,

-N- (2- {5- [4- ({3- [2- (acetylamino) ethyl ] -1-benzofuran-5-yl } oxy) butoxy ] -1H-indol-3-yl } ethyl) acetamide,

-N- (2- {7- [4- ({3- [2- (acetylamino) ethyl ] -1-benzothien-5-yl } oxy) butoxy ] -1-naphthyl } ethyl) acetamide,

and their addition salts with pharmaceutically acceptable acids or bases.

8. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that a compound of formula (V):

A-G₁-Cy-OMe (V)

wherein A, G₁And Cy means of the same claimObtaining a compound of formula (I) 1,

use of HBr and AlCl₃、AlBr₃Or Lewis acid/nucleophile PhCH₂SH or Me₂An S binary system which is demethylated to yield a compound of formula (VI): A-G₁-Cy-OH (VI)

Wherein A, G₁And Cy has the same meaning as in claim 1,

which is condensed with:

a compound of formula (X): hal- (CH)₂)_n-(CH₂)_m-OH (X)

Wherein Hal represents a bromine, chlorine or iodine atom and n and m are as defined in claim 1, with the proviso that it may not contain two successive heteroatoms,

or a compound of formula (XI): hal- (CH)₂)_n(CH₂)_m-1-COOAlk (XI)

Wherein Hal is as defined above, n and m are as defined in claim 1, formula (I), and Alk represents an alkyl group, followed by reduction,

to give a compound of formula (XII): A-G₁-Cy-W₁-(CH₂)_n-(CH₂)_m-OH (XII)

Wherein, A, G₁Cy, n, m and W₁Have the meaning of formula (I) according to claim 1, with the proviso that₁-(CH₂)n-(CH₂) The m-OH chain may not contain two consecutive heteroatoms,

converting the hydroxy function to a leaving group mesylate, tosylate or halo compound in a conventional manner to give a compound of formula (XII'):

A-G₁-Cy-W₁-(CH₂)_n-(CH₂)_m-E (XII’)

wherein, A, G₁Cy, n, m and W₁Has the meaning of formula (I) according to claim 1, and E represents a methanesulfonyl group or a toluenesulfonyl group or a halogen atom,

it is reacted with a compound of formula (XIII):

B-G₃-Cy’-OH (XIII)

b, G therein₃And Cy' is as defined in claim 1, formula (I), to give a compound of formula (I/a), which is a compound of formula (I): A-G₁-Cy-W₁-(CH₂)_n-(CH₂)_m-W₃-Cy’-G₃-B (I/a)

A, G therein₁、Cy、Cy’、n、m、G₃、W₁、W₃And B is as defined in claim 1,

optionally, the compounds (I/a) constituting the totality of the compounds of formula (I) are purified, optionally isolated as their isomers, and optionally converted into their addition salts with pharmaceutically acceptable acids or bases.

9. A pharmaceutical composition comprising, as active principle, at least one compound of formula (I) according to claim 1 or an addition salt thereof with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients.

10. Use of a compound of formula (I) according to claim 1 for the preparation of a medicament for the treatment of disorders related to the melatoninergic system.