HK1033455B - Novel tricyclic compounds, preparation method and pharmaceutical compositions containing same - Google Patents
Novel tricyclic compounds, preparation method and pharmaceutical compositions containing same Download PDFInfo
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Description
The present invention relates to novel tricyclic compounds, processes for their preparation and pharmaceutical compositions containing them.
It is known in the art that 2, 3-dihydrobenzonaphthalene (phenalene) compounds (journal of chemist C1971, 9, pp1607-1609) are synthetic intermediates, and 1, 3, 4, 5-tetrahydrobenzo [ cd ] indole compounds (EP353557) are useful in the preparation of platelet aggregation inhibitors.
Furthermore, patent application EP737670 describes tricyclic amide compounds which are ligands of melatoninergic receptors.
Numerous studies carried out over the last decade have demonstrated that melatonin (N-acetyl-5-methoxytryptamine) plays a critical role in a variety of physiopathological phenomena and in the regulation of the circadian rhythm. However, since it is rapidly metabolized, the half-life is very short. Therefore, great attention is paid to the possibility of providing clinicians with melatonin analogs which are more metabolically stable, have agonist or antagonist properties, and are expected to have superior therapeutic effects than the hormone itself.
Besides having beneficial effects on circadian rhythm disturbances (neurosurgery 1985, 63, pp321-341) and sleep disorders (psychopharmacology 1990, 100, pp222-226), ligands of the melatoninergic system have important pharmacological properties on the central nervous system, in particular anxiolytic and antipsychotic properties (neuropharmacology secreted by the pineal 1990, 8(3-4), pp264-272) and analgesic properties (pharmacology psychiatry 1987, 20, pp222-223) and also for the treatment of Parkinson's disease (neuroscience 1985, 63, pp321-341) and Alzheimer's disease (brain research 1990, 528, pp 170-174). These compounds have also been shown to be active against certain cancers (melatonin-advance of clinical concern (Oxford university Press, 1988, pp164-165), ovulation (science, 1987, 227, pp714-720), diabetes (clinical Endocrinology, 1986, 24, pp359-364) and also in the treatment of obesity (journal of International dietary disorders, 1996, 20(4), pp 443-446).
These various effects are mediated by specific melatonin receptors. Molecular biological studies have demonstrated the existence of a large number of receptor subtypes capable of binding to this hormone (trends in pharmacology, 1995, 16, p.50; WO 97.04094). Some of these receptors can be located and characterized for a variety of organisms, including mammals. In order to be able to better understand the physiological functions of these receptors, it is very advantageous to have specific ligands available. Moreover, such compounds, by selectively interacting with these different receptors, may be excellent drugs for clinicians in the treatment of pathologies related to the melatoninergic system, some of which have been mentioned above.
The compounds of the present invention are novel, have a very strong affinity for melatonin receptors and/or have a very strong selectivity for different melatoninergic receptor subtypes.
The invention relates in particular to compounds of formula (I):
wherein:
a forms groups selected from A with the group to which it is bound1、A2、A3And A4The tricyclic ring system of (1):
◆R1represents a hydrogen atom, a halogen atom, a straight chain or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) An alkoxy, hydroxy or oxo group,
◆R2and R3May be the same or different and represents a halogen atom or Ra、ORa、CORa、OCORaOr COORaGroup (wherein RaRepresents a hydrogen atom, an optionally substituted linear or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) Trihaloalkyl, optionally substituted straight or branched chain (C)2-C6) Alkenyl, optionally substituted straight or branched chain (C)2-C6) Alkynyl, optionally substituted (C)3-C8) Cycloalkyl, optionally substituted (C)3-C8) Cycloalkyl-straight or branched chain (C)1-C6) Alkyl or optionally substituted aryl),
symbol (R)2)mAnd (R)3)m’Denotes that the ring in which it is located may be substituted by 1 to 3 substituents R2And R3Defined groups (which may be the same or different) are substituted,
when A represents the tricyclic system A1、A2、A3Or A4When X represents a sulfur atom, (CH)2)qA radical (where q is 1 or 2), -CH ═ CH-radical or NR4Group (wherein R4Represents a hydrogen atom or an optionally substituted linear or branched (C)1-C6) An alkyl group),
or when A represents a tricyclic ring system A1When, X represents an oxygen atom,
n is an integer satisfying 0. ltoreq. n.ltoreq.3,
when n is 1, 2 or 3,the chain being in position b, A represents a group A in which X represents a-CH ═ CH-group2、A3Or A4Or A represents a group A1When p is an integer satisfying 1. ltoreq. p.ltoreq.3,
in all other cases 0. ltoreq. p.ltoreq.3,
the chain may be unsubstituted or substituted by one or more groups, which may be the same or different, selected from Ra、ORa、CORa、COORaOr a halogen atom,
b stands for:
group, wherein RaAs defined above, Z represents an oxygen atom or a sulfur atom, R5Represents RaGroup or NR6R7Group, wherein R6And R7Which may be the same or different, represent RaThe radical(s) is (are),
orGroup of which Z, R6And R7The definition is the same as that of the above,
symbol ofMeaning that the bond may be a single or double bond, depending on the valency of the atom,
it is to be understood that the symbolsIs used for expressingOr(in this case p is not 0),
the precondition is that:
-if formula A1The tricyclic radical of (a) is 6-methoxytetrahydrobenzo [ cd ]]Indole, then B cannot represent a NHCOMe group,
the compound of formula (I) is not N- (4-methyl-2, 3-dihydro-1H-1-benzonaphthyl (phenalenyl)) -1-cyclopropanecarboxamide, N- (4-methyl-2, 3-dihydro-1H-1-benzonaphthyl) -2-chloroacetamide, 2-methyl-1, 3, 4, 5-tetrahydrobenzo [ cd ] indole-3-carboxamide, N- (5-hydroxy-1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthenyl) acetamide, N- (5-hydroxy-1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthenyl) benzamide or N- (1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthenyl) acetamide,
it should be understood that:
- "aryl" is intended to denote phenyl or naphthyl, each of which is optionally substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) Alkoxy, straight or branched chain (C)1-C6) Alkyl, cyano, nitro, amino, trihaloalkyl or halogen atoms,
the expression "optionally substituted" as used for the terms "alkyl", "alkenyl" and "alkynyl" means that these radicals may be substituted by one or more groups which may be the same or different, the substituents being chosen from hydroxyl, straight-chain or branched (C)1-C6) An alkoxy group, an aryl group or a halogen atom,
the expression "optionally substituted" as used for the terms "cycloalkyl" and "cycloalkylalkyl" denotes that the cyclic moiety may be substituted by one or more groups chosen from hydroxyl, linear or branched (C)1-C6) An alkoxy group, an oxo group or a halogen atom,
enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids, non-limiting examples thereof that may be mentioned are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, oxalic acid and the like.
Among the pharmaceutically acceptable bases, non-limiting examples that may be mentioned are sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
An advantageous embodiment of the invention relates to a composition of the formula (I)A) A compound represented by formula (I):
wherein:
a forms with the group to which it is bonded a'1、A’2、A’3And A'4The tricyclic ring system of (1):
◆R1represents a hydrogen atom, a halogen atom, a straight chain or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) An alkoxy, hydroxy or oxo group,
◆R2and R3May be the same or different and represents a halogen atom or Ra、ORa、CORa、OCORaOr COORaGroup (wherein RaRepresents a hydrogen atom, an optionally substituted linear or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) Trihaloalkyl, optionally substituted straight chainOr branched (C)2-C6) Alkenyl, optionally substituted straight or branched chain (C)2-C6) Alkynyl, optionally substituted (C)3-C8) Cycloalkyl, optionally substituted (C)3-C8) Cycloalkyl-straight or branched chain (C)1-C6) Alkyl or optionally substituted aryl),
symbol (R)2)mAnd (R)3)m’Denotes that the ring in which it is located may be substituted by 1 to 3 substituents R2And R3Defined groups (which may be the same or different) are substituted,
when A represents a tricyclic system A'1、A’2、A’3Or A'4When X represents a sulfur atom, (CH)2)qA radical (where q is 1 or 2), -CH ═ CH-radical or NR4Group (wherein R4Represents a hydrogen atom or an optionally substituted linear or branched (C)1-C6) An alkyl group),
or when A represents a tricyclic system A'1When, X represents an oxygen atom,
n is an integer satisfying 0. ltoreq. n.ltoreq.3,
when n is 1, 2 or 3, - (CH)2)p-the chain B is in position B, A represents a group A 'in which X represents a-CH ═ CH-group'2、A’3Or A'4Or A represents a group A'1When p is an integer satisfying 1. ltoreq. p.ltoreq.3,
in all other cases 0. ltoreq. p.ltoreq.3,
◆(CH2)pthe chain may be unsubstituted or substituted by one or more groups, which may be the same or different, selected from Ra、ORa、CORa、COORaOr a halogen atom,
b stands for:
group, wherein RaAs defined above, Z represents an oxygen atom or a sulfur atom, R5Represents RaGroup or NR6R7Group, wherein R6And R7Which may be the same or different, represent RaThe radical(s) is (are),
orGroup of which Z, R6And R7The definition is the same as that of the above,
symbol ofMeaning that the bond may be a single or double bond, depending on the valency of the atom, with the proviso that:
-if of formula A'1The tricyclic radical of (a) is 6-methoxytetrahydrobenzo [ cd ]]Indole, then B cannot represent a NHCOMe group,
the compound of formula (I) is not N- (4-methyl-2, 3-dihydro-1H-1-benzonaphthyl) -1-cyclopropanecarboxamide, N- (4-methyl-2, 3-dihydro-1H-1-benzonaphthyl) -2-chloroacetamide, 2-methyl-1, 3, 4, 5-tetrahydrobenzo [ cd ] indole-3-carboxamide, N- (5-hydroxy-1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthenyl) acetamide, N- (5-hydroxy-1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthenyl) benzamide or N- (1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthenyl) acetamide, with the understanding that:
- "aryl" is intended to denote phenyl or naphthyl, each of which is optionally substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) Alkoxy, straight or branched chain (C)1-C6) -an alkyl group, a cyano group, a nitro group, an amino group, a trihaloalkyl group or a halogen atom,
the expression "optionally substituted" for the terms "alkyl", "alkenyl" and "alkynyl" means that these radicals may be substituted by one or more groups which may be the same or different, substituentsSelected from hydroxyl, straight chain or branched chain (C)1-C6) An alkoxy group, an aryl group or a halogen atom,
the expression "optionally substituted" as used for the terms "cycloalkyl" and "cycloalkylalkyl" denotes that the cyclic moiety may be substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) -alkoxy, oxo or halogen atoms, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
A further advantageous embodiment of the present invention relates to a composition of the formula (I)R) A compound represented by formula (I):
wherein:
a forms with the group to which it is bound a member selected from the group consisting of A "1、A”2、A”3And A "4The tricyclic ring system of (1):
◆R1represents a hydrogen atom, a halogen atom, a straight chain or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) An alkoxy, hydroxy or oxo group,
◆R2and R3May be the same or different and represents a halogen atom or Ra、ORa、CORa、OCORaOr COORaGroup (wherein RaRepresents a hydrogen atom, an optionally substituted linear or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) Trihaloalkyl, optionally substituted straight or branched chain (C)2-C6) Alkenyl, optionally substituted straight or branched chain (C)2-C6) Alkynyl, optionally substituted (C)3-C8) Cycloalkyl, optionally substituted (C)3-C8) Cycloalkyl-straight or branched chain (C)1-C6) Alkyl or optionally substituted aryl),
symbol (R)2)mAnd (R)3)mDenotes that the ring in which it is located can be substituted by 1 to 3 radicals R2And R3Defined groups (which may be the same or different) are substituted,
when A represents the tricyclic system A "1、A”2、A”3Or A'4When X represents a sulfur atom, (CH)2)qA radical (where q is 1 or 2), -CH ═ CH-radical or NR4Group (wherein R4Represents a hydrogen atom or an optionally substituted linear or branched (C)1-C6) An alkyl group),
or when A represents a tricyclic ring system A "1When, X represents an oxygen atom,
n is an integer satisfying 0. ltoreq. n.ltoreq.3,
p is an integer satisfying 1. ltoreq. p.ltoreq.3,
◆ the chain may be unsubstituted or substituted by one or more groups, which may be the same or different, selected from Ra、ORa、CORa、COORaOr a halogen atom,
b stands for:
group, wherein RaAs defined above, Z represents an oxygen atom or a sulfur atom, R5Represents RaGroup or NR6R7Group, wherein R6And R7Which may be the same or different, represent RaThe radical(s) is (are),
orGroup of which Z, R6And R7The definition is the same as that of the above,
symbol ofIndicating that the bond may be a single or double bond, depending on the valency of the atom, it is understood that:
- "aryl" is intended to denote phenyl or naphthyl, each of which is optionally substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) Alkoxy, straight or branched chain (C)1-C6) -an alkyl group, a cyano group, a nitro group, an amino group, a trihaloalkyl group or a halogen atom,
the expression "optionally substituted" for the terms "alkyl", "alkenyl" and "alkynyl" means that these radicals may be substituted by one or more radicals which may be identical or different, chosen from hydroxyl, linear or branched (C)1-C6) An alkoxy group, an aryl group or a halogen atom,
the expression "optionally substituted" as used for the terms "cycloalkyl" and "cycloalkylalkyl" denotes that the cyclic moiety may be substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) -alkoxy, oxo or halogen atoms, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
Preferred compounds of the invention are those wherein A forms, together with the group to which it is bound, a formula A1Those of the tricyclic ring system of (1).
Preferred values of n are 0, 1 and 2.
The invention relates in particular to such compounds, whichWherein A forms with the group to which it is bound a formula A1Of the tricyclic ring system of the formula A1Wherein X represents (CH)2)qA radical (wherein q is as defined above) or a-CH ═ CH-radical, for example 2, 3-dihydrobenzonaphtalene, 1, 2-dihydroacenaphthylene (acenaphthylene) or 7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Tricyclic ring systems of naphthalene.
Preferred p values are 0, 1 and 2.
Preferred substituents R according to the invention2And R3Are hydrogen atoms, alkoxy groups and alkyl groups.
Preferred R of the invention1The radicals are hydrogen atoms.
The invention advantageously relates to the use of a or c-substituted amino acid in the form of aChain-substituted compounds, in particular those in which p represents 0 (in this case)A bond is a single bond), 1 or 2.
A preferred B group for the present invention is NHCOR5Group, wherein R5As defined above (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl), and CONHR6Group, wherein R6As defined above (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl).
The invention relates more advantageously to 2, 3-dihydrobenzonaphthalene, 1, 2-dihydroacenaphthylene or 7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Tricyclic ring systems of naphthalene, each unsubstituted or substituted on the naphthalene moiety by one or more alkoxy or alkyl groups and substituted in the a or c positionIs substituted, wherein B represents NHCOR5Or CONHR6Group (wherein R5And R6As defined above).
The invention relates in particular to 1, 2-dihydroacenaphthylene or 7, 8, 9, 10-tetrahydroareneHepto [ de ]]Tricyclic ring systems of naphthalene, each unsubstituted or substituted on the naphthalene moiety by one or two alkoxy groups, e.g. methoxy, and in the a or c position by ═ CH-B, ═ CH-CH2-B、-B、-CH2-B or- (CH)2)2-a B group, wherein B represents NHCOR5Or CONHR6Group, wherein R5And R6Represents alkyl, alkenyl, alkynyl, trihaloalkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, for example methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, vinyl, propargyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl or benzyl.
The present invention very advantageously relates to 2, 3-dihydrobenzonaphthalene compounds which are unsubstituted or substituted on the naphthalene moiety by one or two alkoxy groups, for example methoxy, and are substituted in the a or c position by ═ CH-B, ═ CH-CH2-B、-CH2-B or- (CH)2)2-a B group, wherein B represents NHCOR5Or CONHR6Group, wherein R5And R6Represents alkyl, alkenyl, alkynyl, trihaloalkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, for example methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, vinyl, propargyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl or benzyl.
The present invention still more advantageously relates to N- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] acetamide, N- [ (4-methoxy-2, 3-dihydro-1H-benzonaphthyl) methyl ] propionamide, N- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] cyclopropanecarboxamide, N- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] butyramide, N- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] acetamide, N- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] propionamide, N- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] -1-cyclopropanecarboxamide, N- (8-methoxy-1, 2-dihydro-1-acenaphthenyl) acetamide, N- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] butyramide, N- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] acetamide, N- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] butyramide, N- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] butyra, N- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] butanamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] propionamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] butanamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] -1-cyclopropanecarboxamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] acetamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzo, N- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] acetamide, N- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] butyramide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] acetamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] propionamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] butyramide, N- [2- (9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] -1-cyclopropanecarboxamide, (E) -N-methyl-2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthylene) acetamide, (Z) -N-methyl-2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthylene) acetamide, N- (1, 2-dihydro-1-acenaphthenylylmethyl) propionamide, N- (1, 2-dihydro-1-acenaphthenylylmethyl) butyramide, N- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphtalenyl) methyl ] -1-cyclopropanecarboxamide, N- (E) -N-methyl-2-methyl-, N- (1, 2-dihydro-1-acenaphthenylmethyl) -1-cyclopropanecarboxamide, N- (8-methoxy-1, 2-dihydro-1-acenaphthenyl (acenaphthenyl) methyl) acetamide, N- (8-methoxy-1, 2-dihydro-1-acenaphthylmethyl) propionamide, N- (8-methoxy-1, 2-dihydro-1-acenaphthylmethyl) -1-cyclopropanecarboxamide, N- (8-methoxy-1, 2-dihydro-1-acenaphthylmethyl) butyramide, N- [2- (1, 2-dihydro-1-acenaphthenyl) ethyl ] acetamide, N- [2- (1, 2-dihydro-1-acenaphthenyl) ethyl ] propionamide, N- (8-methoxy-1, 2-acenaphthenyl) methyl) propionamide, N- [2- (1, 2-dihydro-1-acenaphthyl) ethyl ] butyramide, N- [2- (1, 2-dihydro-1-acenaphthyl) ethyl ] cyclopropanecarboxamide, N- [2- (8-methoxy-1, 2-dihydro-1-acenaphthyl) ethyl ] acetamide, N- [2- (8-methoxy-1, 2-dihydro-1-acenaphthyl) ethyl ] propionamide, N- [2- (8-methoxy-1, 2-dihydro-1-acenaphthyl) ethyl ] butyramide, N- [2- (8-methoxy-1, 2-dihydro-1-acenaphthyl) ethyl ] -1-cyclopropanecarboxamide, N- [2- (8-methoxy-1, 2-dihydro-acenaphthyl) ethyl ] -1, N- [2- (1-methoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ] naphthalenen-7-yl) ethyl ] propanamide.
The enantiomers and diastereomers of the preferred compounds of the invention and their addition salts with pharmaceutically acceptable acids or bases form an integral part of the invention.
The invention also relates to a process for the preparation of compounds of formula (I) wherein A forms, together with the group to which it is bound, a compound of formula (A)1) Characterized in that the following compounds are used as starting materials:
compounds of formula (II):
wherein R is2、R3、R5X, m' and symbolsThe definition is the same as that of the above,
Y2is represented by (CH)2)qA group (wherein q is 1, 2 or 3, or when the symbolQ is 0 when it is a single bond),
Y1is represented by (CH)2)q’A group (wherein q' is 0, 1, 2 or 3), by R as defined above1The substitution of the group(s),
Y3is represented by (CH)2)q"group (wherein q" is 0, 1, 2 or 3), by R as defined above1Substituted by radicals, wherein q '+ q' is ≦ 3, and in both radicals Y1And Y3In at least one of (1), R1Must represent a hydrogen atom or atoms, and,
cyclisation of a compound of formula (II) in basic medium to give a compound of formula (III):
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
the compound of formula (III) is then reacted with a Lewis acid to give the compound of formula (I/a), a particular example of which is:
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
the compound of formula (I/a) is then reduced to give the compound of formula (I/b), which is a particular case of the compound of formula (I):
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
or a compound of formula (IV):
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
the compound is in turn-cyclized
Reaction with Lewis acids
Obtaining a compound of formula (I/c), which is a particular case of compounds of formula (I):
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
reduction of a compound of formula (I/c) to give a compound of formula (I/d), which is a particular case of compounds of formula (I):
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
the totality of compounds (I/a), (I/b), (I/c) and (I/d) constitutes a compound of formula (I/e), which is a particular case of compounds of formula (I):
wherein R is1、R2、R3、R5、n、p、X、mM' and symbolThe definition is the same as that of the above,
a compound of formula (I/e):
● is affected by a compound of formula (V): r'a-W (V), wherein R'aMay have R as defined aboveaAny meaning of the group other than hydrogen, W represents a leaving group, such as a halogen atom or tosyl group, to give a compound of formula (I/f), which is a particular example of a compound of formula (I):
wherein R is1、R2、R3、R5R 'a, n, p, X, m' and the symbolsThe definition is the same as that of the above,
the compounds of formulae (I/e) and (I/f) are all comprised of compounds of formula (I/g):
wherein R is1、R2、R3、R5、RaN, p, X, m' and symbolsThe definition is the same as that of the above,
the compound of formula (I/g) may be subjected to a thionation reagent, such as Lawesson's reagent, to give a compound of formula (I/h), a particular example of which is:
wherein R is1、R2、R3、R5、RaN, p, X, m' and symbolsThe definition is the same as that of the above,
● or in a basic medium to give a compound of formula (VI):
wherein R is1、R2、R3N, p, X, m' and symbolsThe definition is the same as that of the above,
a compound of formula (VI):
-by the action of a pyrylium salt to give a compound of formula (VII):
wherein Hal represents a halogen atom, R1、R2、R3N, p, X, m' and symbolsThe definition is the same as that of the above,
condensing a compound of formula (VII) with a cyanide salt to provide a compound of formula (VIII):
wherein R is1、R2、R3N, p, X, m' and symbolsThe definition is the same as that of the above,
(VIII) hydrolysis of the compound of formula (VIII) in an acidic or basic medium to give the compound of formula (IX):
wherein R is1、R2、R3N, p, X, m' and symbolsThe definition is the same as that of the above,
the compound of formula (IX) is subjected to an amine HNR after activation to the acid chloride or in the presence of a coupling agent6R7To obtain a compound of formula (I/I), which is a particular case of compounds of formula (I):
wherein R is1、R2、R3、R6、R7N, p, X, m' and symbolsThe definition is the same as that of the above,
the compound of formula (I/I) may be subjected to the action of a sulfurizing agent, such as Lawesson's reagent, to give a compound of formula (I/j), which is a particular case of the compounds of formula (I):
wherein R is1、R2、R3、R6、R7N, p, X, m' and symbolsThe definition is the same as that of the above,
-or by the action of a compound of formula (X):
Z＝C＝NR6R7 (X)
z, R therein6And R7The definition is the same as that of the above,
to obtain a compound of formula (I/k), which is a particular case of compounds of formula (I):
wherein R is1、R2、R3、R6、R7N, p, Z, m' and symbolsThe definition is the same as that of the above,
compounds of formula (I/k) may be condensed with compounds of formula (V) to give compounds of formula (I/l), a particular example of which is compounds of formula (I):
wherein R is1、R2、R3、R6、R7、R’aN, p, X, Z, m' and the symbolsThe definition is the same as that of the above,
the compounds (I/a) to (I/l) can be purified according to a conventional separation process, converted into an addition salt with a pharmaceutically acceptable acid or base if necessary, and separated into their isomers according to a conventional separation process, if appropriate.
The invention also relates to a process for the preparation of compounds of formula (I) wherein A forms, together with the group to which it is bound, a compound of formula (A)2)、(A3) Or (A)4) Characterized in that the following compounds are used as starting materials:
compounds of formula (XI):
wherein R is2、R5、Y2M and symbolThe definition is the same as that of the above,
Y’1is represented by R1Radical substituted (CH)2)q’Group, wherein q' and R1The definition is the same as that of the above,
Y’3is represented by R1Radical substituted (CH)2)q”Group, wherein q' and R1As defined above, wherein 0 ≦ (q '+ q ") ≦ 4, and in two radicals Y'1And Y'3In at least one of (1), R1Must represent a hydrogen atom or atoms, and,
d forms three structures with benzene ring (A)2a)、(A3a) And (A)4a) One of them is:
x, R therein2、R3M, m' and symbolsThe definition is the same as that of the above,
the compound is in turn-cyclized
Reaction with Lewis acids
Obtaining a compound of formula (I/m), which is a particular case of compounds of formula (I):
wherein R is2、R5、D、Y’1、Y2、Y’3M and symbolThe definition is the same as that of the above,
the compounds of formula (I/m) may be reduced to give compounds of formula (I/n), a particular example of which is:
wherein R is2、R5、D、Y’1、Y2、Y’3M and symbolThe definition is the same as that of the above,
or a compound of formula (XII):
wherein R is2、R5、D、Y’1、Y2、Y’3M and symbolThe definition is the same as that of the above,
the compound is in turn-cyclized
Reaction with Lewis acids
Obtaining a compound of formula (I/o), which is a particular case of compounds of formula (I):
wherein R is2、R5、D、Y’1、Y2、Y’3M and symbolThe definition is the same as that of the above,
the compound of formula (I/o) may be reduced to give a compound of formula (I/p), which is a particular example of a compound of formula (I):
wherein R is2、R5、D、Y’1、Y2、Y’3M and symbolThe definition is the same as that of the above,
the totality of compounds (I/m), (I/n), (I/o) and (I/p) constituting the compound of formula (I/q) is a particular case of the compound of formula (I):
wherein R is1、R2、R5D, n, p, m and symbolsThe definition is the same as that of the above,
a compound of formula (I/q):
● to give a compound of formula (I/r), which is a particular case of compounds of formula (I):
wherein R is1、R2、R5、R’aD, n, p, m and symbolsThe definition is the same as that of the above,
the compounds of formulae (I/q) and (I/r) as a whole constitute a compound of formula (I/s), which is a particular case of compounds of formula (I):
wherein R is1、R2、R5、RaD, n, p, m and symbolsThe definition is the same as that of the above,
the compound of formula (I/s) may be subjected to the action of a sulfurizing agent, such as Lawesson's reagent, to give a compound of formula (I/t), which is a particular case of the compounds of formula (I):
wherein R is1、R2、R5、RaD, n, p, m and symbolsThe definition is the same as that of the above,
● or in a basic medium to give a compound of formula (XIII):
wherein R is1、R2D, n, p, m and symbolsThe definition is the same as that of the above,
the compound is:
successively (same as in the synthesis of the compound of formula (I/I) from the compound of formula (VI))
By the action of pyrylium salts
By the action of cyanide salts
Performing acid hydrolysis or alkali hydrolysis
With amines HNR after activation or in the presence of coupling agents6R7Condensation to give a compound of formula (I/u), which is a particular case of compounds of formula (I):
wherein R is1、R2、R6、R7D, n, p, m and symbolsThe definition is the same as that of the above,
the compound of formula (I/u) may be subjected to the action of a sulfurizing agent, such as Lawesson's reagent, to give a compound of formula (I/v), which is a particular case of the compounds of formula (I):
wherein R is1、R2、R6、R7D, n, p, m and symbolsThe definition is the same as that of the above,
● or by the action of a compound of formula (X) to give a compound of formula (I/w), which is a particular case of compounds of formula (I):
wherein R is1、R2、R6、R7D, Z, n, p, m and symbolsThe definition is the same as that of the above,
the compounds of formula (I/w) may be condensed with compounds of formula (V) to give compounds of formula (I/X), a particular example of which is compounds of formula (I):
wherein R is1、R2、R6、R7、R’aD, Z, n, p, m and symbolsThe definition is the same as that of the above,
the compounds (I/m) to (I/X) can be purified according to a conventional separation process, converted into an addition salt with a pharmaceutically acceptable acid or base if necessary, and separated into their isomers according to a conventional separation process, if appropriate.
Furthermore, the compounds of the formulae (I/a) to (I/l) are substituted in the a or c positionParticular examples of chain-substituted compounds of the formula (I) which are obtainable by a process for the preparation of a compound of the formula (XIV):
wherein R is2、R3X, m and m 'are as defined above, T and T' are different and represent a hydrogen atom or a-CHO group,
subjecting the compound of formula (XIV) to a Wittig reaction followed by catalytic reduction to yield a compound of formula (XV):
wherein R is2、R3X, m and m 'are as defined above, T'1And T1Represents a hydrogen atom or a group of formula (XVI):
wherein G represents R optionally defined as above1Radical substituted (CH)2)n’Group, wherein n 'is 1, 2 or 3, with the proviso that two groups T'1And T1One of them represents a hydrogen atom,
the compound of formula (XV) is in turn hydrolyzed in basic medium and then decarboxylated by heating to give the compound of formula (XVII):
wherein R is2、R3X, m and m 'are as defined above, T'2And T2Represents a hydrogen atom or a group of formula (XVIII):
wherein G is as defined above, with the proviso that two radicals T'2And T2One of them represents a hydrogen atom,
after activation to oxalyl chloride, cyclization of the compound of formula (XVII) in the presence of a lewis acid affords the compound of formula (XIX):
wherein R is2、R3X, G, m and m 'are as defined above, T'3And T3Is different and represents a hydrogen atom or an oxo group,
a compound of formula (XIX):
-carrying out a wittig reaction (optionally followed by reduction) followed by hydrolysis to yield a compound of formula (XX):
wherein R is2、R3X, G, m' and symbolsEach T is as defined above4And T'4Representing a hydrogen atom or forming with a carbon atom carrying itGroup, wherein p1Is 1, 2 or 3 with the proviso that two radicals T4And T'4One of them represents a hydrogen atom,
-or successively reducing to the corresponding alcohol
E.g. in SOCl2In the presence of (2) halogenated
Condensation with cyanide salts
Performing acid hydrolysis or alkali hydrolysis
To give a compound of formula (XXI):
wherein R is2、R3X, G, m' and symbolsDefinition of same as above, T'5And T5Are different and represent a hydrogen atom or a COOH group,
the totality of compounds (XX) and (XXI) constitutes the compound of formula (XXII):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'6And T6Representing a hydrogen atom or forming with a carbon atom carrying itWherein p is as defined above, with the proviso that two radicals T'6And T6One of them represents a hydrogen atom,
the compound (XXII) can also be obtained from a compound of the formula (XIX) by condensation (optionally followed by reduction of the double bond) with a nitrile group-containing compound and hydrolysis of the nitrile according to the Wittig reaction, which compound (XXII):
by an amine HNR, either after activation to an acid chloride or in the presence of a coupling agent6R7To give a compound of formula (I/y), which is a particular case of compounds of formula (I):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'7And T7Representing a hydrogen atom or forming with a carbon atom carrying itGroup, wherein p, R6And R7With the proviso that two radicals T 'are mentioned'7And T7One of them represents a hydrogen atom,
the compound of formula (I/y) may be subjected to the action of a sulfurizing agent, such as Lawesson's reagent, to give a compound of formula (I/z), a particular example of which is the compound of formula (I):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'8And T8Representing a hydrogen atom or forming with a carbon atom carrying itGroup, wherein p, R6And R7As defined above, with the proviso that two radicals T8And T'8One of them represents a hydrogen atom,
or activation to the acid chloride, followed by treatment with azide, heating to form the corresponding isocyanate, and hydrolysis to give the compound of formula (XXIII):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'9And T9Representing a hydrogen atom or forming with a carbon atom carrying itA radical in which p is as defined above, with the proviso that two radicals TqAnd T'9One of them represents a hydrogen atom,
the compound of formula (XXIII) may also be obtained from a compound of formula (XIX) by condensation with a nitrile group-containing compound according to the Wittig reaction followed by reduction of the nitrile,
the compound of formula (XXIII) is condensed with:
-acyl chloride CICOR5Or the corresponding anhydrides (mixed or symmetrical) in which R5The same as defined above, to give a compound of formula (I/aa), which is a particular case of compounds of formula (I):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'10And T10Representing a hydrogen atom or forming with a carbon atom carrying itGroup, wherein p and R5With the proviso that two radicals T 'are mentioned'10And T10One of them represents a hydrogen atom,
the compound of formula (I/aa) may be subjected to the action of a sulfurizing agent, such as Lawesson's reagent, and/or substituted after the action of the compound of formula (V) to give a compound of formula (I/ab), which is a particular case of the compounds of formula (I):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'11And T11Representing a hydrogen atom or forming with a carbon atom carrying itGroup, wherein p, Ra、R5And Z is as defined above, with the proviso that two radicals T'11And T11One representsA hydrogen atom, and a nitrogen atom,
the compounds (I/y) to (I/ab) can be purified according to a conventional separation process, converted into an addition salt with a pharmaceutically acceptable acid or base if necessary, and separated into their isomers according to a conventional separation process, if appropriate.
Compounds (I/m) to (I/v) can also be obtained in a similar manner, which is characterized by using as starting material a compound of formula (XXIV):
wherein R is2D and m are as defined above.
The raw materials are as follows:
-the use of a commercially available source of,
readily available to the skilled person using conventional chemical reactions, or
As described in the literature, for example in patent application EP 737670.
The compounds of the present invention and pharmaceutical compositions containing them have proven useful in the treatment of disorders of the melatoninergic system. Pharmacological studies with the compounds of the invention have in fact shown that they are non-toxic, have a very high selective affinity for the melatonin receptors, have a remarkable activity on the central nervous system, and in particular have been found to have therapeutic properties on sleep disorders, and have been found to be anxiolytic, psychoinhibitory, analgesic and microcirculatory, thus making it possible to establish that the compounds of the invention are useful for the treatment of stress, sleep disorders, anxiety, seasonal affective psychosis, cardiovascular pathologies, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychosis, epilepsy, diabetes, parkinson's disease, senile dementia, various conditions associated with normal or pathological ageing, migraine, memory loss and alzheimer's disease and cerebral circulatory disorders. In another activity aspect, the compounds of the invention have been shown to have ovulation-inhibiting properties and immunomodulating properties in therapy, and they appear to be useful in the treatment of cancer.
The compounds are preferably used for the treatment of seasonal affective disorder, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jet lag, appetite disorders and obesity. For example, the compounds will be used in the treatment of seasonal affective disorder and sleep disorders.
The invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention, mention may in particular be made of those suitable for oral, parenteral, nasal feeding, transdermal or transdermal, rectal, lingual, ocular or respiratory administration, especially tablets or dragees, sublingual tablets, cachets, paques, gelatin capsules, glissettes, lozenges, suppositories, creams, ointments, dermal gels, drinkable or injectable ampoules.
The dosage will vary with the sex, age and weight of the patient, the route of administration, the nature of the indication being treated, or any relevant treatment, and will range from 0.01mg to 1g per 24 hours, given in 1 or more doses.
The following examples illustrate the invention without, in any way, limiting it. The following preparations give synthetic intermediates useful in the preparation of the compounds of the invention.
Preparation 1: (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methylamine
Step A: 2- [ (2-methoxy-1-naphthyl) methylene]Malonic acid diethyl ester
In a dean-Stark apparatus, in diethyl malonate (25ml, 1.65.10)-1mol, 1.23eq.) and piperidine (2ml, 2.02.10)-2mol, 0.15eq.) in the presence of 2-methoxy-1-Naphthaleneformaldehyde (25g, 1.34.10)-1mol) of benzene (200ml) was heated to reflux for 20 hours. After addition of a few drops of piperidine, the mixture was refluxed for a further 20 hours. The reaction mixture was diluted with toluene (200ml) and washed with water (125 ml). After phase separation, the organic phase is treated with 1N hydrochloric acid solution (190ml) and then with saturated NaHCO3The solution (125ml) and a saturated NaCl solution (125ml) were treated. Over MgSO4After drying and evaporation under reduced pressure, the resulting oil was recrystallized from cyclohexane.
Melting point: 86 deg.C
Elemental microanalysis:
C H
% calculated value 69.506.14
% found 69.536.23
Step B: 2- [ (2-methoxy-1-naphthyl) methyl group]Malonic acid diethyl ester
After solubilization in ethanol (510ml), the unsaturated compound obtained in step A (10g, 3.05.10) was added in the presence of Raney nickel-2mol) are hydrogenated at ambient temperature with vigorous stirring. After 4 hours of hydrogenation the reaction was monitored by TLC and GPC. After the disappearance of the raw material was confirmed, the catalyst was filtered off through celite, and the ethanol was evaporated under reduced pressure. The title compound was obtained as a colorless oil.
Elemental microanalysis:
C H
% calculated value 69.076.71
% found 69.146.76
Step C: 2- [ (2-methylhydroyl-1-naphthyl) methyl group]Malonic acid
In a 1 liter single-necked flask, in sodium hydroxide (20g, 5.00.10)-1mol) and water (340ml) the compound obtained in step B (20g, 6.05.10)-2mol) was heated to reflux for 4 hours and 30 minutes. After cooling, the mixture is diluted with 150ml of water, filtered through filter paper and acidified with concentrated hydrochloric acid in the hot state (80-90 ℃); after complete cooling, the white microspheres formed in the hot state were filtered off via a frit. The diacid is washed with cold water. After drying overnight in an oven (110 ℃ C.), at P2O5The title compound was dried in a desiccator in the presence of (a).
Melting point: 174- & ltSUB & gt 175- & lt/SUB & gt
Elemental microanalysis:
C H
% calculated value 65.695.15
% found 65.645.18
Step D: 3- (2-methoxy-1-naphthyl) propionic acid
The diacid obtained in step C (8.1g, 2.95.10) was carried out in a 100ml single-necked flask purged with argon-2mol) was heated with a metal bath at 165-178 ℃ until the evolution of gas ceased. By passing an acid from CH2Cl2Recrystallizing in petroleum ether mixture.
Melting point: 131 deg.C
Step (ii) ofE: 4-methoxy-2, 3-dihydro-1H-benzonaphthalenone (phenalenone)
The acid obtained in step D (5g, 2.17.10) was added to the solution in a 250ml three-necked flask at 0 ℃ under argon-2mol) to a solution of anhydrous dichloromethane (225ml) oxalyl chloride (1.95ml, 2.19.10) was added dropwise-2mol, 1 eq.). Then a few drops of anhydrous dimethylformamide were added. After 1 hour at 0 ℃ a slight evolution of gas was still observed, and the three-necked flask was placedLeft at ambient temperature for 40 minutes. After returning to 0 deg.C, aluminum chloride (7.5g, 5.62.10 g) was added to the spatula-2mol, 2.6 eq.). The initially yellow solution turns red, orange and then to its green color (khaki-green). After stirring at 0 ℃ for 15 minutes, the mixture was poured into an ice/1N HCl mixture. After phase separation and washing of the acidic aqueous phase with dichloromethane, the combined organic phases are washed with water and then with saturated NaHCO3The solution was treated and finally washed with saturated NaCl solution. Over MgSO4After drying and evaporation under reduced pressure, the resulting yellow oil crystallized in a refrigerator.
Melting point: 65 deg.C
Step F: 2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthylene) acetic acid ethyl ester
60% sodium hydride (650mg, 1.63.10) in oil, previously washed with pentane, was added under argon-2mol, 1.15eq.) to a suspension in anhydrous THF (24ml) triethyl phosphonoacetate (3.22ml, 1.63.10) was added dropwise-2mol, 1.15 eq.). After stirring for 50 minutes at ambient temperature, the compound obtained in step E (3g, 1.41.10) dissolved in anhydrous THF (20ml) was added over 10 minutes-2mol, 1 eq.). The reaction mixture was stirred overnight at ambient temperature. The mixture was diluted with water, filtered through celite and extracted several times with ether. Over MgSO4After drying and evaporation under reduced pressure, the oily residue is taken up in CH2Cl2Petroleum ether 60/40 was used for chromatographic separation. The resulting orange-yellow oil crystallized at ambient temperature and corresponded to a mixture of two E/Z isomers, the average ratio of which was determined by GPC analysis to be 45/55.
Elemental microanalysis: (E/Z mixture)
C H
% calculated value 76.576.43
% found 76.436.58
Step G: 2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) acetic acid ethyl ester 55mg of PdCl2Is treated with 25mg of sodium borohydride in 5ml of methanol. After stirring for 15 minutes, the compound (1g, 3.54.10) obtained in step F diluted with methanol (15ml) was added-3mol). The mixture was purged with argon and placed under hydrogen. The reaction was monitored by GPC analysis. After hydrogenation for 1 hour 30 minutes, the reaction mixture was filtered through celite, washed and evaporated under reduced pressure.
Step H: 2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) acetic acid
In potassium hydroxide (4g, 7.13.10)-2mol, 10eq.), water (16ml) and methanol (16ml) the ester obtained in step G (2G, 7.03.10)-3mol) was heated to reflux overnight. After removal of the solvent by evaporation, the residue was dissolved in water and extracted twice with diethyl ether. The aqueous alkaline phase was acidified with concentrated HCl in the cold state. The acid was extracted with ethyl acetate over MgSO4And (5) drying. After removal of the solvent by evaporation under reduced pressure, a brown oil was obtained which crystallized at ambient temperature.
Melting point: 120.5 deg.C
Elemental microanalysis:
C H
% calculated value 74.986.29
% found 74.806.34
Step I: hydrochloric acid (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methylamine
To a solution of the acid obtained in step H (1.03g, 4.02mmol) in a mixture of acetone (17ml) and water (1ml) cooled to 0 ℃ was added triethylamine (645 μ l, 4.63mmol, 1.15eq.) dropwise in a 100ml three-necked flask. Ethyl chloroformate (500 μ l, 5.23mmol, 1.30eq.) was then added slowly at 0 ℃; can see thatAnd (4) gas is discharged. The mixture was stirred at 0 ℃ for 30 minutes; in TLC (CH)2Cl2) After the disappearance of the starting material was confirmed, a solution of sodium azide (350mg, 5.23mmol, 1.30eq.) in water (1.7ml) was added at 0 ℃. The mixture was held at this temperature for one hour. TLC (CH)2Cl2) Azide formation is indicated. The mixture was poured into an ice/water mixture and then extracted with diethyl ether. The ether phase is washed with water and then with Na2SO4Dried and evaporated in vacuo without heating. After the azide was dissolved in 10ml of anhydrous toluene, it was heated at 80 ℃ until no more nitrogen gas was evolved. After removal of the toluene by evaporation, the oil corresponding to the isocyanate was heated with 20% hydrochloric acid solution (8ml) at 100 ℃ for 3 hours; the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water, filtered through filter paper and extracted with ether. The aqueous phase was made basic with solid sodium carbonate at pH 1 and then extracted with ether. The combined ether phases are washed with water and then K2CO3And (5) drying. After removal of the solvent by evaporation under reduced pressure, the amine is converted to the hydrochloride by solubilization in ether and treatment with 4N ethereal hydrogen chloride.
Melting point: 237 deg.C
Elemental microanalysis:
C H N
% calculated value 68.306.885.31
% found 68.236.905.25
Preparations 2 to 18 were obtained by working as described for preparation 1, starting from the appropriately substituted aldehyde.
Preparation 2: 2, 3-dihydro-1H-1-benzonaphthylmethylamine
Preparation 3: (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methylamine
Preparation 4: (4-ethyl-2, 3-dihydro-1H-1-benzonaphthyl) methylamine
Preparation 5: (4-chloro-2, 3-dihydro-1H-1-benzonaphthyl) methylamine
Preparation 6: (6-methoxy-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-5-yl) methylamine
Preparation 7: (6-methoxy-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-3-yl) methylamine
Preparation 8: (6-Ethyl-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-5-yl) methylamine
Preparation 9: (6-Ethyl-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-3-yl) methylamine
Preparation 10: (6-methoxy-4, 5-dihydro-3H-naphtho [1, 8-bc)]Thien-5-yl) methylamines
Preparation 11: (6-methoxy-4, 5-dihydro-3H-naphtho [1, 8-bc)]Thien-3-yl) methylamines
Preparation 12: (6-methoxy-1, 3, 4, 5-tetrahydrobenzo [ cd)]Indol-3-yl) methylamines
Preparation 13: (6-methoxy-1, 3, 4, 5-tetrahydro-3-acenaphthenyl) methylamine
Preparation 14: (7-methoxy-2, 3-dihydro-1H-cyclopenta [ b)]Naphthalen-1-yl) methylamines
Preparation 15: (6, 7-dihydro-5H-indeno [5, 6-b)]Thien-5-yl) methylamines
Preparation 16: (7, 8-dihydro-6H-indeno [4, 5-b)]Thien-6-yl) methylamines
Preparation 17: (7, 8-dihydro-6H-indeno [4, 5-b)]Thien-8-yl) methylamines
Preparation 18: (7, 8-dihydro-6H-indeno [5, 4-b)]Thien-8-yl) methylamines
Preparation 19: 2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethylamine
Step A: 2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthylene) acetonitrile
60% sodium hydride (433mg, 1.08.10) in oil previously washed with pentane under argon-2mol, 1.15eq.) to a suspension in anhydrous THF (15ml) diethyl cyanomethylphosphonate (1.75ml, 1.08.10)-2mol, 1.15 eq.). After stirring for 50 minutes at ambient temperature, the compound obtained in preparation 1, step E (2g, 9.42.10) dissolved in anhydrous THF (15ml) was added over 10 minutes-2mol, 1 eq.). The reaction mixture was stirred overnight at ambient temperature. The mixture was diluted with water, filtered through celite and extracted several times with ether. Over MgSO4After drying and evaporation under reduced pressure, the oily residue is taken up in CH2Cl2Petroleum ether 60/40 was used for chromatographic separation. The resulting orange-yellow oil crystallized at ambient temperature, corresponding to a mixture of two E/Z isomers, in ratios varying from 60/40 to 40/60.
Elemental microanalysis:
C H N
% calculated value 81.685.575.95
% found 81.625.655.86
Step B: 2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) acetonitrile
55mg of PdCl2The catalyst was prepared by treatment with 25mg sodium borohydride in 5ml methanol. After stirring for 15 minutes, the compound obtained in step A (1g, 4.25.10) diluted with methanol (15ml) was added-3mol). The mixture was purged with argon and placed under hydrogen. The reaction was monitored by GPC analysis. After hydrogenation for 2 hours and 30 minutes, the reaction mixture is passed over kieselguhrFiltered, washed and then evaporated under reduced pressure. The title product was isolated as a colorless oil.
Elemental microanalysis:
C H N
% calculated value 80.986.375.90
% found 80.966.475.91
Step C: hydrochloric acid 2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethylamine
The compound (1.26g, 5.31.10) obtained in step B diluted with methanol (15ml) was added in the presence of ammonium hydroxide (1ml) and Raney nickel-3mol) are hydrogenated at ambient temperature with vigorous stirring. The disappearance of the starting material took 48 hours. After filtration through celite, washing, evaporation under reduced pressure to remove the solvent, the amine is dissolved in diethyl ether and treated with a few drops of 4N ethereal hydrogen chloride. The hydrochloride salt was recrystallized from an ethanol/diethyl ether mixture.
Melting point: 223 deg.C
Elemental microanalysis:
C H N
% calculated value 80.986.375.90
% found 80.966.475.91
Preparations 20 to 26 were obtained by working as described for preparation 19, starting from the corresponding ketone intermediate.
Preparation 20: 2- (6-methoxy-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-5-yl) ethylamine
Preparation 21: 2- (6-chloro-4, 5-dihydro-3H)-benzo [ cd)]Isobenzofuran-5-yl) ethylamine
Preparation 22: 2- (6-methoxy-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-3-yl) ethylamine
Preparation 23: 2- (6-ethyl-4, 5-dihydro-3H-naphtho [1, 8-bc)]Thien-3-yl) ethylamine
Preparation 24: 2- (6-methoxy-1, 3, 4, 5-tetrahydro-3-acenaphthenyl) ethylamine
Preparation 25: 2- (6-methoxy-1, 3, 4, 5-tetrahydrobenzo [ cd)]Indol-3-yl) ethylamine
Preparation 26: 2- (1, 3, 4, 5-tetrahydrobenzo [ cd)]Indol-3-yl) ethylamine
Preparation 27: 2- (4-methoxy-2, 3-dihydro-1H-benzonaphthyl) acetic acid
A mixture of the compound obtained in preparation 19, step B and 10% sodium hydroxide solution was heated to reflux. The reaction was monitored by TLC. When the starting material has disappeared, the reaction mixture is cooled and extracted at alkaline pH; the mixture was then acidified with 2N, then 3N hydrochloric acid and extracted again. After evaporation of the solvent under reduced pressure, the title acid is obtained in pure form.
Preparations 28 to 31 were obtained by working as described for preparation 27, starting from the corresponding nitrile.
Preparation 28: 2- (4-chloro-2, 3-dihydro-1H-1-benzonaphthyl) acetic acid
Preparation 29: 2- (6-chloro-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-5-yl) acetic acid
Preparation 30: 2- (6-methoxy-1, 3, 4, 5-tetrahydrobenzo [ cd)]Indol-3-yl) acetic acid
Preparation 31: 2- (6-methoxy-1, 3, 4, 5-tetrahydro-3-acenaphthenyl) acetic acid
Preparation 32: 3- (4-methyl)Oxy-2, 3-dihydro-1H-1-benzonaphthyl) propanamine
Step A: 3- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthylene) propionic acid ethyl ester
The procedure was as in preparation 1, step F, substituting triethyl phosphonoacetate with triethyl phosphonopropionate.
Steps B, C and D are the same as Steps G, H and I of preparation 1.
Preparation 33 was obtained by proceeding as described for preparation 32, starting from the ketone obtained in preparation 3.
Preparation 33: 3- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) propylamine
Preparation 34: 4- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) butanoic acid
Step A: 4- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) nitrobutane
The conditions of preparation 19, steps a and B were applied to the ketone obtained in preparation 1, step E, replacing cyanomethylphosphonic acid diethyl ester with cyanopropylphosphonic acid diethyl ester.
Step B: 4- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) butanoic acid
The hydrolysis of the nitrile obtained in step A was carried out under the conditions of preparation 27.
Preparation 35: 2- (2, 2a, 3, 4-tetrahydroindeno [7, 1-bc)]Furan-4-yl) ethylamine
The procedure is as for preparation 19, starting from 2, 3-dihydrobenzo [ b ] furan-3-one.
Preparation 36: 2- (2, 2a, 3, 4-tetrahydroindeno [7, 1-bc)]Thien-4-yl) ethylamine
Following the procedure of preparation 35, starting from 2, 3-dihydrobenzo [ b ] thiophen-3-one, the title compound was obtained.
Preparation 37: 2- (1, 6-dimethoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-7-yl) ethylamines
Step A: 4- (2, 7-dimethoxy-1-naphthyl) -3-butenoic acid ethyl ester
The procedure is as in preparation 1, step F, and triethylphosphonopropionic acid ethyl ester is condensed with 2, 7-dimethoxy-1-naphthalene formaldehyde.
Step B: 4- (2, 7-dimethoxy-1-naphthyl) butanoic acid ethyl ester
The reduction of the compound obtained in step a is carried out under the conditions of preparation 1, step G.
Step C: 4- (2, 7-dimethoxy-1-naphthyl) butanoic acid
The hydrolysis of the ester obtained in step B is carried out under the conditions of preparation 1, step H.
Step D: 2- (1, 6-dimethoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-7-yl) ethylamines
The operation was the same as in step E of preparation 1 and steps A, B and C of preparation 19.
Preparation 38: 2- (1-methoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-7-yl) methylamines
Step A: 4- (2-methoxy-1-naphthyl) butanoic acid
The procedure was as in steps A, B and C of preparation 37, starting from 2-methoxy-1-naphthaldehyde.
Step B: 2- (1-methoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-7-yl) methylamines
The procedure was the same as steps E, F, G, H and I of preparation 1.
Preparation 39: 6, 7, 8, 9-tetrahydro-2-thiabenzo [ cd]Azulen-9-ylmethylamines
The procedure is as for preparation 38, starting from benzo [ b ] thiophene-4-carbaldehyde.
Preparation 40: (5-methoxy-6, 7, 8, 9-tetrahydro-2-oxobenzo [ cd)]Azulen-9-yl) methylamines
The procedure is as for preparation 38, starting from 5-methoxybenzo [ b ] furan-4-carbaldehyde.
Preparations 41 to 49 were obtained by working as described for preparation 38, starting from the appropriately substituted aldehyde.
Preparation 41: (7-methoxy-1, 2, 3, 4-tetrahydro-1-anthracenyl) methylamine
Preparation 42: (6-methoxy-1, 2, 3, 4-tetrahydro-1-anthracenyl) methylamine
Preparation 43: (5, 6, 7, 8-tetrahydronaphtho [2, 3-b ]]Thien-5-yl) methylamines
Preparation 44: (3-Ethyl-5, 6, 7, 8-tetrahydronaphtho [2, 3-b ]]Thien-5-yl) methylamines
Preparation 45: (6, 7, 8, 9-Tetrahydronaphtho [1, 2-b ]]Thien-6-yl) methylamines
Preparation 46: (6, 7, 8, 9-Tetrahydronaphtho [1, 2-b ]]Thien-9-yl) methylamines
Preparation 47: (6, 7, 8, 9-tetrahydronaphtho [2, 1-b ]]Thien-9-yl) methylamines
Preparation 48: (1-methoxy-6, 7, 8, 9-tetrahydronaphtho [2, 1-b ]]Thien-9-yl) methylamines
Preparation 49: (1-methoxy-6, 7, 8, 9-tetrahydronaphtho [2, 1-b ]]Thien-9-yl) methylamines
Preparation 50: (3-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methylamine
In the same manner as in preparation 2, methanol was added to the double bond of diethyl 2- (1-naphthylmethylene) malonate obtained in step A.
Preparations 51 to 61 were obtained according to the method described in patent application EP 737670.
Preparation 51: 3- (3, 8-dimethoxy-1, 2-dihydro-1-acenaphthenyl) propylamine
Preparation 52: 4- (3, 8-dimethoxy-1, 2-dihydro-1-acenaphthenyl) butanoic acid
Preparation 53: (4-methoxy-2, 3-dihydro-1H-2-benzonaphthyl) methylamine
Preparation 54: (4-ethyl-2, 3-dihydro-1H-2-benzonaphthyl) methylamine
Preparation 55: 2- (4, 9-dimethoxy-2, 3-dihydro-1H-2-benzonaphthyl) acetic acid
Preparation 56: 4-methoxy-2, 3-dihydro-1H-2-benzonaphthalenecarboxylic acids
Preparation 57: 2- (4-methoxy-2, 3-dihydro-1H-2-benzonaphthyl) ethylamine
Preparation 58: 3- (4-methoxy-2, 3-dihydro-1H-2-benzonaphthyl) propylamine
Preparation 59: (6-chloro-2, 3-dihydro-1H-2-benzonaphthyl) methylamine
Preparation 60: (1, 6-dimethoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-8-yl) methylamines
Preparation 61: 2- (1, 6-dimethoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-8-yl) acetic acids
Preparation 62: 8-methoxy-1, 2-dihydro-1-acenaphthenylamine
Preparation 63: 2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) acetonitrile
The procedure was as in preparation 19, Steps A and B.
Melting point: 116 deg.C
Elemental microanalysis:
C H N
% calculated value 80.986.375.90
% found 80.776.475.74
Preparation 64: 2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethylamine
The procedure was as in preparation 19.
Preparation 65: (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methylamine
Step A: 2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) acetic acid
The nitrile obtained in preparation 63 (500mg, 2.11.10) was reacted in the presence of 30% sodium hydroxide solution (8ml), methanol (8ml) and ethanol (8ml) in a 250ml single-necked flask-3mol) was heated to reflux for 48 hours. After cooling, the mixture was poured into an ice/water mixture. The mixture was acidified with hydrochloric acid, extracted three times with ethyl acetate and once with dichloromethane. The organic phase is washed with water and saturated NaCl solution, respectively, over MgSO4Dried and then evaporated under reduced pressure. The title acid was obtained as a light yellow solid.
Melting point: 147 deg.C
Elemental microanalysis:
C H
% calculated +1/3H2O 73.26 6.40
% found 73.386.37
Step B: (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methylAmines as pesticides
Acid from step A (515mg, 2.01.10)-3mol) solution in a mixture of acetone (20ml) and water (600. mu.l), triethylamine (322. mu.l, 2.31.10)-3mol, 1.15eq.) and ethyl chloroformate (250. mu.l, 2.61.10)-3mol, 1.30eq.) to obtain the title product. By sodium azide (175mg, 2.61.10)-3mol, 1.30eq.) in water (1ml) to form the acyl azide. After heating in dry toluene (5ml), the isocyanate was hydrolyzed with 20% hydrochloric acid solution (6 ml). The mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water, filtered through filter paper and extracted with ether. The aqueous phase was made basic with solid sodium carbonate at pH 1 and then extracted with ether. The combined ether phases are washed with water and then K2CO3And (5) drying. After removal of the solvent by evaporation under reduced pressure, the amine is converted to the hydrochloride by solubilization in ether and treatment with 4N ethereal hydrogen chloride. After drying, the title product is obtained in the form of a white solid.
Preparation 66: [ (E) -2- (4-methoxy-2, 3-dihydro-1H-benzonaphthyl)]Acetic acid
In potassium hydroxide (377mg, 6.73.10)-3mol, 2.5eq.), water (10ml) and methanol (10ml) the trans ester obtained in preparation 1 step F (760mg, 2.69.10)-3mol) was heated to reflux overnight. After removal of the solvent by evaporation, the residue was dissolved in water and extracted twice with diethyl ether. The aqueous alkaline phase was acidified with concentrated HCl in the cold state. The acid was extracted with ethyl acetate, washed with water, over MgSO4And (5) drying. After removal of the solvent by evaporation under reduced pressure, the title product is obtained as a yellow solid.
Melting point: 208 deg.C
Elemental microanalysis:
C H
% calculated +2/3H2O 72.17 5.80
% found 72.375.56
Preparation 67: [ (Z) -2- (4-methoxy-2, 3-dihydro-1H-benzonaphthyl)]Acetic acid
The procedure is as for preparation 66, starting from the cis isomer.
Melting point: 187 deg.C
Elemental microanalysis:
C H
% calculated +1/3H2O 73.83 5.68
% found 73.555.63
Preparation 68:1, 2-dihydro-1-acenaphthenylmethylamine
Step A:1, 2-dihydro-1-acenaphthenone
To (naphthalen-1-yl) acetic acid (6g, 3.22.10) in a 1 liter three-necked flask at 0 ℃ under argon-2mol) in anhydrous dichloromethane (270ml) oxalyl chloride (2.87ml, 3.22.10) was added dropwise-2mol, 1 eq.). Then a few drops of anhydrous dimethylformamide were added. After 1 hour at 0 ℃, a slight evolution of gas was still observed and the three-necked flask was left at ambient temperature for 40 minutes. After returning to 0 deg.C, aluminum chloride (11.2g, 8.38.10 g) was gradually added to the solution with a spatula-2mol, 2.6 eq.). The solution was stirred for 20 minutes and the color changed to green-black. The mixture was poured into an ice/1N HCl mixture. After phase separation and washing of the acidic aqueous phase with dichloromethane, the combined organic phases are washed with water and then with saturated NaHCO3The solution was treated and finally washed with saturated NaCl solution. Over MgSO4After drying and evaporation under reduced pressure, the title product is obtained as a yellow solid.
Melting point: 123 deg.C
Elemental microanalysis:
C H
% calculated value 85.694.79
% found 85.594.80
And B: 2- (1, 2-dihydro-1-acenaphthenylidene) acetic acid ethyl ester
60% sodium hydride (1.43g, 3.58.10) in oil previously washed with pentane under argon-2mol, 1.15eq.) to a suspension in anhydrous THF (50ml) triethyl phosphonoacetate (7.11ml, 3.58.10) was added dropwise-2mol, 1.15 eq.). After stirring at ambient temperature for 40 minutes, the compound obtained in step A (5.24g, 3.12.10) dissolved in anhydrous THF (55ml) was added over 10 minutes-2mol, 1 eq.). The reaction mixture was stirred overnight at ambient temperature, then diluted with water, filtered through celite and extracted several times with ether. Over MgSO4After drying and evaporation under reduced pressure, the oily residue is applied to a silica gel column over CH2Cl2Petroleum ether 50/50 was used for chromatographic separation. The mixture of the two E/Z isomers is separated.
Elemental microanalysis:
C H
% calculated value 80.655.92
% found 80.685.97
Step C: 2- (1, 2-dihydro-1-acenaphthenyl) acetic acid ethyl ester
55mg of PdCl2Is treated with 25mg of sodium borohydride in 5ml of methanol. After stirring for 15 minutes, the compound (1g, 4.20.10) obtained in step B diluted with methanol (25ml) was added-3mol). The mixture was purged with argon and placed under a hydrogen atmosphere. After hydrogenation for 2 hours 30 minutes, the reaction mixture was filtered through celite, washed, and thenThen, the mixture is evaporated under reduced pressure.
Step D: 2- (1, 2-dioxo-1-acenaphthenyl) acetic acid
In the presence of potassium hydroxide (2.34g, 4.17.10)-2mol, 5.3eq.), water (16ml) and methanol (16ml) the ester obtained in step C (1.9g, 7.91.10)-3mol) was heated to reflux overnight. After removal of the solvent by evaporation, the residue was dissolved in water and extracted twice with diethyl ether. The aqueous alkaline phase was acidified with concentrated HCl in the cold state. The acid was extracted with ethyl acetate over MgSO4And (5) drying. After removal of the solvent by evaporation under reduced pressure, the title compound was obtained as a yellow solid.
Melting point: 123 deg.C
Elemental microanalysis:
C H
% calculated value 79.235.70
% found 79.125.77
Step E:1, 2-dihydro-1-acenaphthenylmethylamine
The acid obtained in step D (4.62g, 2.18.10) was cooled to 0 ℃ in a 250ml three-necked flask-2mol) Triethylamine (3.49ml, 2.50.10) was added dropwise to a solution of acetone (95ml) in a mixture of water (5.4ml)-2mol, 1.15 eq.). Ethyl chloroformate (2.71ml, 2.83.10) was then added slowly at 0 deg.C-2mol, 1.30 eq.); gas evolution can be seen. The mixture was stirred at 0 ℃ for 30 minutes; in TLC (CH)2Cl2) After the disappearance of the starting material was confirmed, sodium azide (1.89g, 2.83.10) was added at 0 deg.C-2mol, 1.30eq.) in water (9.2 ml). The mixture was held at this temperature for one hour. The mixture was poured into an ice/water mixture and then extracted with diethyl ether. The ether phase is washed with water and then with Na2SO4Dried and evaporated in vacuo without heating. Acyl azide was dissolved in 50ml anhydrous formazanBenzene, then heated at 80 ℃ until no more nitrogen gas is evolved. After removal of the toluene by evaporation, the oil corresponding to the isocyanate was heated at 100 ℃ for 3 hours together with a 20% hydrochloric acid solution (52 ml); the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water, filtered through filter paper and extracted with ether. The aqueous phase was made basic with solid sodium carbonate at pH 1 and then extracted three times with dichloromethane. The combined organic phases are washed with water and K2CO3And (5) drying. After removal of the solvent by evaporation under reduced pressure, the amine (820mg) was obtained as an oil. The solid after filtration and dissolution in dichloromethane was treated in the same manner as the filtrate. Solubilization in diethyl ether and treatment with 4N ethereal hydrogen chloride converted the resulting amine to the hydrochloride salt. After drying, the title product is obtained in the form of a white solid.
Melting point: higher than 250 DEG C
Elemental microanalysis:
C H N
% calculated value 71.076.426.37
% found 70.846.496.40
Preparation 69: (8-methoxy-1, 2-dihydro-1-acenaphthenyl) methylamine
The procedure was as for preparation 68, starting from (7-methoxynaphthalen-1-yl) acetic acid.
Preparation 70:1, 2-dihydro-1-acenaphthenylethylamine
Step A: (1, 2-dihydro-1-acenaphthylene) acetonitrile
The procedure is as in step B of preparation 68, substituting diethyl cyanomethylphosphonate for triethyl phosphonoacetate.
Elemental microanalysis:
C H N
% calculated value 87.934.747.32
% found 87.854.797.25
Step B: (1, 2-dihydro-1-acenaphthenyl) acetonitrile
55mg of PdCl2The catalyst was prepared by treatment with 25mg sodium borohydride in 5ml methanol. After stirring for 15 minutes, the compound obtained in step A (1g, 5.23.10) diluted with methanol (15ml) was added-3mol). The mixture was purged with argon and placed under hydrogen. After 3 days of hydrogenation, the reaction mixture was filtered through celite, washed and evaporated under reduced pressure. The title product was isolated as a light brown oil.
Elemental microanalysis:
C H N
% calculated +1/8H2O 86.01 5.80 7.16
% found 85.735.877.13
Step C:1, 2-dihydro-1-acenaphthenylethylamine
The compound (900mg, 4.66.10) obtained in step B diluted with methanol (30ml) was added in the presence of ammonium hydroxide (2ml) and Raney nickel-3mol) are hydrogenated at ambient temperature with vigorous stirring. After 23 hours, the starting material disappeared. After filtration through celite, washing and removal of the solvent by evaporation under reduced pressure, the title amine was obtained as an oil and used without purification.
Preparation 71: (8-methoxy-1, 2-dihydro-1-acenaphthenyl) ethylamine
The procedure was as for preparation 70.
Step A: (8-methoxy-1, 2-dihydro-1-acenaphthenyl) acetonitrile
Step B: (8-methoxy-1, 2-dihydro-1-acenaphthenyl) ethylamine
Elemental microanalysis:
C H N
% calculated value 71.076.426.37
% found 70.846.496.40
Preparation 72: 2- (1-methoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-7-yl) acetonitrile
Step A: 3- (2-methoxynaphthalen-1-yl) butenoic acid
60% sodium hydride (1.16g, 2.90.10) in an oil previously washed with pentane at 0 ℃ under argon-2mol, 2.2eq.) to a suspension in anhydrous THF (10ml) 2-methoxy-1-naphthaldehyde (2.45g, 1.32.10) solubilized in an anhydrous mixture of THF and DMSO (17ml/17ml) was added dropwise-2mol, 1eq.) with (3-triphenylphosphonium) propionyl bromide (6g, 1.44.10)-2mol, 1.1eq.) of the mixture. The reaction mixture was stirred overnight at ambient temperature, then diluted with water, filtered through celite, added with a few drops of sodium hydroxide solution and extracted twice with ether. The aqueous alkaline phase is acidified with HCl in the cold state. The desired acid was extracted with diethyl ether. After washing the ether phase with saturated NaCl solution, it is then passed over MgSO4Drying, evaporation under reduced pressure and chromatography of the solid residue on a column of silica gel (1. CH)2Cl2；2.CH2Cl2MeOH: 97/3). A white solid corresponding to a mixture of the two E/Z isomers of the title compound was obtained.
Melting point: 112 deg.C
Elemental microanalysis:
C H
% calculated value 74.365.82
% found 74.475.90
Step B: 4- (2-Methoxynaphthalen-1-yl) butanoic acid
The compound obtained in step A (3.4g, 1.40.10) was reacted in the presence of 5% palladium-carbon-2mol) was solubilized in ethyl acetate (90 ml). The mixture was purged with argon and placed under a hydrogen atmosphere. After hydrogenation for 15 hours, the reaction mixture was filtered through celite, washed and evaporated under reduced pressure. The title product was isolated as white crystals.
Melting point: 88 deg.C
Elemental microanalysis:
C H
% calculated value 73.756.60
% found 73.596.71
Step C: 1-methoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-7-ones
The procedure was as in preparation 1, step E.
Melting point: 67 deg.C
Elemental microanalysis:
C H
% calculated value 79.626.24
% found 79.736.31
Step D: 2- (1-methoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-7-yl) acetonitrile
The procedure was as in preparation 19, step A.
Melting point: 96 deg.C
Elemental microanalysis:
C H N
% calculated value 81.906.065.62
% found 81.886.185.64
Example 1: n- [ (4-methoxy-2.3-dihydro-1H-1-benzonaphthyl) methyl]Acetamide
In a 100ml three-necked flask, in sodium carbonate (854mg, 7.96.10)-3mol, 7eq.) of the hydrochloride obtained in preparation 1 (300mg, 1.14.10)-3mol, 1eq.) on two phases CH2Cl2Solubilisation in aqueous medium (17ml/17 ml). Acetic anhydride (110. mu.l, 1.17.10) was added at 0 deg.C-3mol, 1 eq.). The reaction mixture was stirred at ambient temperature for 20 minutes. After phase separation, saturated NaHCO was used3The organic phase was washed with solution, water and saturated NaCl solution over MgSO4Drying, and evaporating off the solvent under reduced pressure, and subjecting the residue to flash chromatography (1. CH)2Cl2；2.CH2Cl2MeOH: 99/1). Recrystallization from hexane/AcOEt isolated the title compound in pure form.
Melting point: 126 deg.C
Elemental microanalysis:
C H N
% calculated value 75.817.115.20
% found 75.647.195.15
Example 2：
N- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] propanamide
The procedure is as in example 1, propionic anhydride being used instead of acetic anhydride.
Melting point: 120 deg.C
Elemental microanalysis:
C H N
% calculated value 76.307.474.94
% found 76.217.594.89
Example 3：
N- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] cyclopropanecarboxamide
The hydrochloride salt obtained in preparation 1 (382mg, 1.45.10)-3mol) in dichloromethane, treated with ammonium hydroxide until the solid dissolves and the pH of the resulting aqueous phase is basic. After phase separation, the amine is passed over K2CO3And (5) drying. Triethylamine (295. mu.l, 2.12.10) on potassium hydroxide at 0 deg.C-3mol, 1.5eq.) of an amine (320mg, 1.41.10)-3mol) was dissolved in anhydrous dichloromethane (10 ml). Propionyl chloride (130. mu.l, 1.43.10) was added dropwise at 0 deg.C-3mol, 1 eq.). The reaction mixture was stirred at ambient temperature for 15 minutes. After washing with water, over MgSO4Drying, then evaporating off the solvent under reduced pressure, and chromatographing the residue (400mg) by flash chromatography (1. CH)2Cl2；2.CH2Cl2MeOH: 99/1). Recrystallization from hexane/AcOEt gave the title product in pure form.
Melting point: 119 deg.C
Elemental microanalysis:
C H N
% calculated value 77.267.174.74
% found 77.197.244.70
Example 4: n- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Butyramide was performed as in example 1, replacing acetic anhydride with butyric anhydride.
Melting point: 100 deg.C
Elemental microanalysis:
C H N
% calculated value 76.747.804.71
% found 76.657.894.67
Example 5: n- [ (4-methoxy-2.3-dihydro-1H-1-benzonaphthyl) methyl]-N-methyl-1-cyclopropanecarboxamide
The compound obtained in example 3 was reacted in the presence of NaR (1.5eq) and dimethyl sulfate (1.2 eq). The reaction was monitored by TLC. When all the starting materials have disappeared, the reaction mixture is hydrolyzed and then extracted. After removal of the solvent by evaporation, the title product is isolated by flash chromatography.
Example 6: n- [ (4-hydroxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]-N-methylcyclopropanecarboxamides
In BBr3The compound obtained in example 3 is subjected to demethylation in the presence of one of the conventional reagents.
Example 7: n- [ (4-benzyloxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Cyclopropane carboxamides
The compound obtained in example 6 was reacted in a basic system in the presence of benzyl chloride.
Example 8: n- [ (4-allyloxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Cyclopropane carboxamides
The procedure is as in example 7, allyl chloride being used instead of benzyl chloride.
Example 9: N-cyclobutyl-N' - [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Urea
Suspending the compound of preparation 1 in pyridine; the cyclobutyl isocyanate is then added dropwise and the reaction mixture is heated. When the reaction was complete, the reaction mixture was poured into ice-cold water and acidified with 1N hydrochloric acid solution. After conventional workup, the title compound is isolated in pure form.
Example 10: n- (2, 3-dihydro-1H-1-benzonaphthylmethyl) -2-iodoacetamide
In the same manner as in example 1, 1-iodoacetic anhydride was condensed with the compound obtained in preparation 2.
Example 11: n- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Benzamide derivatives
The procedure is as in example 1, benzoic anhydride being used instead of acetic anhydride.
Example 12: n- [ (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Caproamide
The procedure of example 1 was followed to condense hexanoic anhydride with the compound obtained in preparation 3.
Example 13: n- [ (4-ethyl-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Cyclohexane carboxamides
In the same manner as in example 1, a cyclohexane carboxylic acid anhydride was condensed with the compound obtained in preparation 4.
Example 14：N-[(4-chloro-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Heptamide
In the same manner as in example 1, heptanoic anhydride was condensed with the compound obtained in preparation 5.
Example 15: n- [ (4-chloro-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 5.
Example 16: n- [ (6-methoxy-4, 5-dihydro-3H-1-benzo [ cd)]Isobenzofuran-5-yl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 6.
Example 17: n- [ (6-methoxy-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-5-yl) methyl]Cyclohexane carboxamides
The procedure is as in example 16, using cyclohexanecarboxylic anhydride instead of acetic anhydride.
Example 18: n- [ (6-methoxy-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-3-yl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 7.
Example 19: n- [ (6-ethyl-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-5-yl) methyl]Pentamides
The procedure of example 1 was followed to condense valeric anhydride with the compound obtained in preparation 8.
Example 20: n- [ (6-ethyl-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-3-yl) methyl]Butylamide
In the same manner as in example 1, butyric anhydride was condensed with the compound obtained in preparation 9.
Example 21: n- [ (6-methoxy-4, 5-dihydro-3H-naphtho [1, 8-bc)]Thien-5-yl) methylBase of]Propionamide
The procedure is as in example 2, starting from the compound obtained in preparation 10.
Example 22: n- [ (6-methoxy-4, 5-dihydro-3H-naphtho [1, 8-bc)]Thien-3-yl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 11.
Example 23: n- [ (6-methoxy-4, 5-dihydro-3H-naphtho [1, 8-bc)]Thien-3-yl) methyl]-N-methylacetamide
The procedure is as in example 5, starting from the compound obtained in example 22.
Example 24: n- [ (6-methoxy-4, 5-dihydro-3H-naphtho [1, 8-bc)]Thien-3-yl) methyl]-N-methylethane thioamides
The compound obtained in example 23 was treated with Lawesson's reagent according to a conventional method.
Example 25: N-cyclobutyl-N' - [ (6-methoxy-4, 5-dihydro-3H-naphtho [1, 8-bc)]Thien-3-yl) methyl]Urea
The procedure is as in example 9, starting from the compound obtained in preparation 11.
Example 26: n- [ (6-methoxy-1, 3, 4, 5-tetrahydrobenzo [ cd ]]Indol-3-yl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 12.
Example 27: n- [ (6-methoxy-1-methyl-1, 3, 4, 5-tetrahydrobenzo [ cd)]Indol-3-yl) methyl]-N-methylacetamide
To a suspension of NaH (2.2eq.) in THF at 0 ℃, a solution of the compound obtained in example 26 in tetrahydrofuran was added dropwise. Dimethyl sulfate (2.3eq.) was added very slowly at 0 ℃ and the reaction mixture was then stirred at ambient temperature. When the reaction is complete, it is worked up conventionally and chromatographically isolated to give the title product.
Example 28: n- [ (6-hydroxy-1-methyl-1, 3, 4, 5-tetrahydrobenzo [ cd)]Indol-3-yl) methyl]-N-methylacetamide
To a suspension of aluminum chloride and benzylmercaptan a solution of the compound obtained in example 27 in dichloromethane is added dropwise at 0 ℃. The reaction was monitored by TLC. When the reaction was complete, the reaction mixture was poured onto ice and then acidified with 1N HCl. Conventional extraction was carried out and the title compound was isolated by chromatography.
Example 29: N-methyl-N- [ (1-methyl-6- (2-propynyloxy) -1, 3, 4, 5-tetrahydrobenzo [ cd)]Indol-3-yl) methyl]Acetamide
The procedure is as in example 7, starting from the compound obtained in example 28 and replacing benzyl chloride by 3-chloro-1-propyne.
Example 30: n- [ (6-methoxy-1, 3, 4, 5-tetrahydro-3-acenaphthenyl) methyl]-1-cyclopropane carboxylic acid amide
The procedure is as in example 3, starting from the compound obtained in preparation 13.
Example 31: n- [ (6-hydroxy-1, 3, 4, 5-tetrahydro-3-acenaphthenyl) methyl]-1-cyclopropane carboxylic acid amide
The procedure is as in example 6, starting from the compound obtained in example 30.
Example 32: n- [ (6-benzyloxy-1, 3, 4, 5-tetrahydro-3-acenaphthenyl) methyl]-1-cyclopropane carboxylic acid amide
The procedure is as in example 7, starting from the compound obtained in example 31.
Example 33: n- [ (7-methoxy-2, 3-dihydro-1H-cyclopenta [ b ]]Naphthalen-1-yl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 14.
Example 34: n- (6, 7-dihydro-5H-indeno [5, 6-b)]Thien-5-ylmethyl) butanamide
In the same manner as in example 1, butyric anhydride was condensed with the compound obtained in production 15.
Example 35: n- (7, 8-dihydro-6H-indeno [4, 5-b)]Thien-6-ylmethyl) acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 16.
Example 36: n- (7, 8-dihydro-6H-indeno [4, 5-b)]Thien-8-ylmethyl) acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 17.
Example 37: n- (7, 8-dihydro-6H-indeno [5, 4-b)]Thien-8-ylmethyl) -2-chloroacetamide
In the same manner as in example 1, chloroacetic anhydride was condensed with the compound obtained in preparation 18.
Example 38: n- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Acetamide
In acetic anhydride (430. mu.l, 4.56.10)-3mol, 2.5eq.) and Raney nickel in the presence of tetrahydrofuran (12ml) the nitrile obtained in preparation 19 step A (440mg, 1.85.10)-3mol) are hydrogenated at ambient temperature. After hydrogenation for 8 hours, the reaction mixture was filtered through celite, washed and evaporated under reduced pressure. The residue was then dissolved in dichloromethane, washed with water and then with saturated NaHCO3The solution was then washed with water. Over MgSO4After drying and removal of the solvent by evaporation, the residue is purified by flash Chromatography (CH)2Cl2Methanol: 99/1).
Elemental microanalysis:
C H N
% calculated +1/4H2O 75.10 7.53 4.87
% found 74.957.504.80
Example 39: n- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Propionamide
In propionic anhydride (500. mu.l, 3.90.10)-3mol, 1.85eq.) and Raney nickel in the presence of the nitrile obtained in preparation of 19 step A (500mg, 2.11.10)-3mol) of tetrahydrofuran (25ml) was hydrogenated at ambient temperature. After hydrogenation for 30 hours, the reaction mixture was filtered through celite, washed and evaporated under reduced pressure. The residue was then dissolved in dichloromethane, washed with water and then with saturated NaHCO3The solution was then washed with water. Over MgSO4After drying and removal of the solvent by evaporation, the residue weighing 650mg is purified by flash Chromatography (CH)2Cl2Methanol: 99/1).
Elemental microanalysis:
C H N
% calculated +1/4H2O 75.59 7.85 4.64
% found 75.547.884.61
Example 40: n- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]-1-cyclopropane carboxylic acid amide
The hydrochloride salt obtained in preparation 19 (350mg, 1.26.10 mg) was added in the presence of sodium carbonate (940mg)-3mol) in a dichloromethane/water mixture (16ml/16 ml). Propionyl chloride (115. mu.l, 1.27.10) was added dropwise at 0 deg.C-3mol, 1 eq.). The reaction mixture is stirred at ambient temperature 1For 5 minutes. Several drops of ammonium hydroxide were added for neutralization. After washing with water, over MgSO4Drying, then evaporating off the solvent under reduced pressure, and purifying the residue by flash chromatography (1. CH)2Cl2；2.CH2Cl2/MeOH：99/1)。
Melting point: 118 deg.C
Elemental microanalysis:
C H N
% calculated +1/4H2O 76.52 7.55 4.64
% found 76.557.514.42
EXAMPLE 41: n- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]-4-methoxybenzamide
The procedure is as in example 40, 4-methoxybenzoyl chloride being used instead of cyclopropylyl chloride.
Example 42: n- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]-3-chlorobenzamide
The procedure is as in example 41, 3-chlorobenzoyl chloride being used instead of propionyl chloride.
Example 43: n- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Propane thioamides
Lawesson's reagent was allowed to act on the compound of example 39 to afford the title compound.
Example 44: n- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]-3-butenamide
The procedure is as in example 40, but using butenoyl chloride instead of propionyl chloride.
Example 45: n- [2- (4-hydroxy)Radical-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Acetamide
The procedure is as in example 6, starting from the compound obtained in example 38.
Example 46: n- [2- (4-Cyclopropoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Acetamide
The procedure is as in example 7, cyclopropyl chloride being used instead of benzyl chloride.
Example 47: n- [2- (6-methoxy-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-5-yl) ethyl]Butylamide
In the same manner as in example 38, butyryl chloride was condensed with the compound obtained in preparation 20.
Example 48: N-butyl-N- [2- (6-methoxy-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-5-yl) ethyl]Acetamide
The procedure is as in example 5, starting from the compound of example 38 and replacing methyl sulfate by butyl iodide.
Example 49: n- [2- (6-chloro-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-5-yl) ethyl]Acetamide
The procedure is as in example 38, starting from the compound obtained in preparation 21.
Example 50: n- [2- (6-methoxy-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-3-yl) ethyl]Butylamide
The procedure is as in example 47, starting from the compound obtained in preparation 22.
Example 51: N-hexyl-N- [2- (6-methoxy-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-3-yl) ethyl]Butylamide
The procedure is as in example 48, starting from the compound of example 50 and substituting hexyl iodide for butyl iodide.
Example 52：N-[2- (6-ethyl-4, 5-dihydro-3H-naphtho [1, 8-bc)]Thien-3-yl) ethyl]Heptamide
In the same manner as in example 38, heptanoyl chloride was condensed with the compound obtained in preparation 23.
Example 53: n- [2- (6-methoxy-1, 3, 4, 5-tetrahydro-3-acenaphthenyl) ethyl]-1-cyclobutanecarboxamide
In the same manner as in example 38, cyclobutyl chloride was condensed with the compound obtained in preparation 24.
Example 54: n- [2- (6-methoxy-1, 3, 4, 5-tetrahydrobenzo [ cd ]]Indol-3-yl) ethyl]Butylamide
The procedure is as in example 47, starting from the compound obtained in preparation 25.
Example 55: n- [2- (6-hydroxy-1, 3, 4, 5-tetrahydrobenzo [ cd ]]Indol-3-yl) ethyl]Butylamide
The procedure is as in example 28, starting from the compound obtained in example 54.
Example 56: n- [2- (1, 3, 4, 5-tetrahydrobenzo [ cd)]Indol-3-yl) ethyl]The acetamide procedure is as in example 38, starting from the compound obtained in preparation 26.
Example 57: n-cyclobutyl-2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Acetamide
After conversion of the acid obtained in preparation 27 to the acid chloride, N-cyclobutylamine was condensed therewith to give the title product.
Example 58: n-propyl-2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) acetamide
The procedure is as in example 57, N-propylamine being used instead of N-cyclobutylamine.
Example 59: n-hexyl-2- (4-chloro-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Acetamide
In the same manner as in example 57, N-hexylamine was condensed with an acid chloride of the compound obtained in preparation 28.
Example 60: n-phenyl-2- (6-chloro-4, 5-dihydro-3H-benzo [ cd)]Isobenzofuran-5-yl) ethyl]Acetamide
In the same manner as in example 57, N-aniline was condensed with acid chloride of the compound obtained in production 29.
Example 61: n- (2, 3, 4-trimethoxyphenyl-2- (6-methoxy-1, 3, 4, 5-tetrahydrobenzo [ cd)]Indol-3-yl) acetamides
In the same manner as in example 57, N- (2, 3, 4-trimethoxyphenyl) amine was condensed with an acid chloride of the compound obtained in preparation 30.
Example 62: n-hexyl-2- (6-methoxy-1, 3, 4, 5-tetrahydro-3-acenaphthenyl) acetamide
The procedure is as in example 59, starting from the compound obtained in preparation 31.
Example 63: n- [3- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) propyl]Pentamides
The procedure is as in example 19, starting from the compound obtained in preparation 32.
Example 64: N-methyl-N- [3- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) propyl]Pentamides
The procedure is as in example 23, starting from the compound obtained in example 63.
Example 65: n- [3- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) propyl]Acetamide
The procedure is as in example 38, starting from the compound obtained in preparation 33.
Example 66: n-cyclopentyl-4- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) butanamide
In the same manner as in example 57, N-cyclopentylamine was condensed with an acid chloride of the compound obtained in preparation 34.
Example 67: N-cyclopentyl-N-methyl-4- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) butanamide
The procedure is as in example 64, starting from the compound obtained in example 66.
Example 68: n- [2- (2, 2a, 3, 4-tetrahydroindeno [7, 1-bc)]Furan-4-yl) ethyl]-1-cyclopropane carboxylic acid amide
The procedure is as in example 40, starting from the compound obtained in preparation 35.
Example 69: n- [2- (2, 2a, 3, 4-tetrahydroindeno [7, 1-bc)]Thien-4-yl) ethyl]Acetamide
The procedure is as in example 38, starting from the compound obtained in preparation 36.
Example 70: n- [2- (1, 6-dimethoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-7-yl) ethyl]Acetamide
The procedure is as in example 38, starting from the compound obtained in preparation 37.
Example 71: n- [ (1-methoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-7-yl) methyl]Acetamide
The procedure is as in example 38, starting from the compound obtained in preparation 38.
Example 72: n- (6, 7, 8, 9-tetrahydro-2-thiabenzo [ cd)]Azulen-9-yl) methyl]Acetamide
The procedure is as in example 19, starting from the compound obtained in preparation 39.
Example 73: n- [ (5-methoxy-6, 7, 8, 9-tetrahydro-2-oxabenzo [ cd)]Azulen-9-yl) methyl]Propionamide
The procedure is as in example 2, starting from the compound obtained in preparation 40.
Example 74: n- (7-methoxy-1, 2, 3, 4-tetrahydro-1-anthryl) acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 41.
Example 75: n- (6-methoxy-1, 2, 3, 4-tetrahydro-1-anthryl) acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 42.
Example 76: n- (5, 6, 7, 8-tetrahydronaphtho [2, 3-b ]]Thien-5-yl) -1-cyclopropylcarboxamides
The procedure is as in example 3, starting from the compound obtained in preparation 43.
Example 77: n- (3-ethyl-5, 6, 7, 8-tetrahydronaphtho [2, 3-b ]]Thien-5-yl) heptanamide
The procedure is as in example 14, starting from the compound obtained in preparation 44.
Example 78: n- (6, 7, 8, 9-tetrahydronaphtho [1, 2-b ]]Thien-6-yl) acetamides
The procedure is as in example 1, starting from the compound obtained in preparation 45.
Example 79: n- (6, 7, 8, 9-tetrahydronaphtho [1, 2-b ]]Thien-9-yl) acetamides
The procedure is as in example 1, starting from the compound obtained in preparation 46.
Example 80: n- (6, 7, 8, 9-tetrahydronaphtho [2, 1-b ]]Thien-9-yl) -1-cyclohexanecarboxamide
The procedure is as in example 13, starting from the compound obtained in preparation 47.
Example 81: n- (6, 7, 8, 9-tetrahydronaphtho [2, 1-b ]]Thien-9-yl) -2, 2, 2-trifluoroacetamide
The procedure is as in example 1, starting from the compound obtained in preparation 47, trifluoroacetic anhydride being used instead of acetic anhydride.
Example 82: n- (1-methoxy-6, 7, 8, 9-tetrahydronaphtho [2, 1-b ]]Thien-9-yl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 48.
Example 83: n- (1-methoxy-6, 7, 8, 9-tetrahydronaphtho [2, 1-b ]]Thien-9-yl) methyl]Acetamide
The procedure is as in example 2, starting from the compound obtained in preparation 49.
Example 84: n- [ (3-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 50.
Example 85: n- [3- (3, 8-dimethoxy-1, 2-dihydro-1-acenaphthenyl) propyl]-2, 2, 2-trifluoroacetamide
In the same manner as in example 63, acetyl chloride was condensed with the compound obtained in preparation 51.
Example 86: n-pentyl-4- (3, 8-dimethoxy-1, 2-dihydro-1-acenaphthenyl) butanamide example 66 was performed by condensing N-pentylamine with the acid chloride of the compound obtained in preparation 52.
Example 87: n- [ (4-methoxy-2, 3-dihydro-1H-2-benzonaphthyl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 53.
Example 88: n- [ (4-methoxy-2, 3-dihydro-1H-2-benzonaphthyl) methyl]-1-CyclobutanesAlkanecarboxamides
The procedure is as in example 1, starting from the compound obtained in preparation 53, with cyclobutanecarboxylic anhydride instead of acetic anhydride.
Example 89: n- [ (4-hydroxy-2, 3-dihydro-1H-2-benzonaphthyl) methyl]-1-cyclobutanecarboxamide
The procedure is as in example 6, starting from the compound obtained in example 88.
Example 90: n- [ (4-benzyloxy-2, 3-dihydro-1H-2-benzonaphthyl) methyl]-1-cyclobutanecarboxamide
The procedure is as in example 7, starting from the compound obtained in example 89.
Example 91: n- [ (4-allyloxy-2, 3-dihydro-1H-2-benzonaphthyl) methyl]-11-cyclobutanecarboxamide
The procedure is as in example 8, starting from the compound obtained in example 89.
Example 92: n- [ (4-methoxy-2, 3-dihydro-1H-2-benzonaphthyl) methyl]Ethane thioamides
The procedure is as in example 24, starting from the compound obtained in example 87.
Example 93: n- [ (4-ethyl-2, 3-dihydro-1H-2-benzonaphthyl) methyl]Propionamide the procedure is as in example 2, starting from the compound obtained in preparation 54.
Example 94: n-cyclopropyl-2- (4, 9-dimethoxy-2, 3-dihydro-1H-2-benzonaphthyl) acetamide
In the same manner as in example 57, N-cyclopropylamine was condensed with the acid chloride obtained in preparation 55.
Example 95: n-methyl-4-methoxy-2, 3-dihydro-1H-2-benzonaphthamide
In the same manner as in example 57, N-methylamine was condensed with the acid chloride obtained in preparation 56.
Example 96: n- [2- (4-methoxy-2, 3-dihydro-1H-2-benzonaphthyl) ethyl]Heptamide
The procedure is as in example 52, starting from the compound obtained in preparation 57.
Example 97: N-methyl-N- [2- (4-methoxy-2, 3-dihydro-1H-2-benzonaphthyl) ethyl]Heptamide
The procedure is as in example 5, starting from the compound obtained in example 96.
Example 98: n- [3- (4-methoxy-2, 3-dihydro-1H-2-benzonaphthyl) propyl]Acetamide
The procedure is as in example 38, starting from the compound obtained in preparation 58.
Example 99: n- [ (6-chloro-2, 3-dihydro-1H-2-benzonaphthyl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 59.
Example 100: n- [ (1, 6-dimethoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-8-yl) methyl]Acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 60.
Example 101: n- [ (1, 6-dimethoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-8-yl) methyl]-1-cyclopropane carboxylic acid amide
The procedure is as in example 3, starting from the compound obtained in preparation 60.
Example 102: n-ethyl-1, 6-dimethoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalene-8-carboxamides
In the same manner as in example 57, N-ethylamine was condensed with the acid chloride obtained in preparation 61.
Example 103: n- (8-methoxy-1, 2-dihydro-1-acenaphthenyl) acetamide
The procedure is as in example 1, starting from the compound obtained in preparation 62.
Melting point: 217 ℃ 219 DEG C
The compounds of examples 104 and 105 were obtained by the action of HBr on the compound obtained in example 84.
Example 104: n- [ (3-hydroxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Acetamide
Example 105: n- [ (3-bromo-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Acetamide
Example 106: n- [ (3-oxo-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Acetamide
The title compound was obtained by conventional oxidation of the alcohol obtained in example 104.
Example 107: n- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Butylamide
In triethylamine (368. mu.l, 2.64.10)-3mol, 1.5eq.) the amine obtained in preparation 1 (400mg, 1.76.10)-3mol, 1eq.) was diluted with anhydrous dichloromethane (12 ml). Butyrylchloride (183. mu.l, 1.76.10) was added slowly at 0 deg.C-3mol, 1 eq.). The reaction mixture was stirred at ambient temperature for 40 minutes. After phase separation, saturated NaHCO was used3The organic phase is washed with solution, water and then saturated NaCl solution over MgSO4Drying, and evaporating off the solvent under reduced pressure, and purifying the residue by flash chromatography (1. CH)2Cl2；2.CH2Cl2MeOH: 99/1). Recrystallisation from a hexane/AcOEt mixture gave the title compound as a white solid.
Melting point: 100 deg.C
Elemental microanalysis:
C H N
% calculated value 76.747.804.71
% found 76.657.894.67
Example 108: n- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Acetamide
In acetic anhydride (174. mu.l, 1.85.10)-3mol, 2eq.) and Raney nickel in tetrahydrofuran (22ml) the nitrile obtained in preparation 63 (219mg, 9.23.10)-4mol) are hydrogenated at ambient temperature. After hydrogenation for 4 hours, the reaction mixture was filtered through celite, washed and evaporated under reduced pressure. The residue was then dissolved in dichloromethane, washed with water and then with saturated NaHCO3The solution was then washed with water. Over MgSO4After drying and removal of the solvent by evaporation, the residue is purified by flash chromatography (AcOEt/petroleum ether: 30/50) and recrystallized from a cyclohexane/AcOEt mixture. The title product was isolated as a white solid.
Melting point: 98 deg.C
Elemental microanalysis:
C H N
% calculated value 76.307.604.94
% found 76.137.474.79
Example 109: n- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Butylamide
The procedure is as in example 108, substituting butyric anhydride for acetic anhydride. The title product was isolated as an oil.
Example 110：N-[2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Butylamide
In a 100ml three-necked flask, in sodium carbonate (801mg, 7.56.10)-3mol, 7eq.) of the hydrochloride obtained in preparation 19 (300mg, 1.08.10)-3mol, 1eq.) on two phases CH2Cl2Solubilisation in aqueous medium (12ml/12 ml). Butyrylchloride (112. mu.l, 1.08.10) was added at 0 deg.C-3mol, 1 eq.). The reaction mixture was stirred at ambient temperature for 20 minutes. After phase separation, saturated NaHCO was used3Solution, H2O, then washing the organic phase with saturated NaCl solution and then MgSO4Drying, and evaporating off the solvent under reduced pressure, and purifying the residue by flash chromatography (1. CH)2Cl2；2.CH2Cl2MeOH: 99/1). The title product was obtained as oil.
Example 111: n- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Propionamide
The procedure is as in example 108, starting from the amine obtained in preparation 64, with propionic anhydride instead of acetic anhydride. The title product was obtained as a white solid.
Melting point: 111 deg.C
Elemental microanalysis:
C H N
% calculated value 73.377.704.28
% found 73.457.874.18
Example 112: n- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Butylamide
The procedure is as in example 111, substituting butyric anhydride for propionic anhydride. The title product was obtained as a white solid.
Melting point: 99 deg.C
Elemental microanalysis:
C H N
% calculated +1/8H2O 73.39 7.99 4.08
% found 73.128.163.97
Example 113: n- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]-1-cyclopropane carboxylic acid amide
At 0 deg.C, in sodium carbonate (547mg, 5.16.10)-3mol, 7eq.) to the amine obtained in preparation 64 (200mg, 7.37.10)-4mol, 1eq.) to a solution of dichloromethane/water mixture (10ml/10ml) was added propionyl chloride (67. mu.l, 7.37.10-3mol, 1 eq.). The reaction mixture was stirred at ambient temperature for 15 minutes. Several drops of ammonium hydroxide were added for neutralization. After washing with water, over MgSO4Drying and then evaporation of the solvent under reduced pressure, the residue was purified by flash chromatography (AcOEt/petroleum ether 40/60). Recrystallization from a cyclohexane/AcOEt mixture isolated as a white solid to give the title product.
Melting point: 120 deg.C
Elemental microanalysis:
C H N
% calculated value 74.317.424.13
% found 74.177.574.05
Example 114: n- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl]Acetamide
The procedure is as in example 111, acetic anhydride being used instead of propionic anhydride. The title product was obtained as a white solid.
Melting point: 125 deg.C
Elemental microanalysis:
C H N
% calculated value 72.827.404.47
% found 72.687.604.35
Example 115: n- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Acetamide
In a 50ml three-necked flask, in sodium carbonate (561mg, 5.30.10)-3mol, 7eq.) of the amine obtained in preparation 65 (172mg, 7.57.10)-3mol, 1eq.) on two phases CH2Cl2Solubilisation in aqueous medium (9ml/9 ml). Acetic anhydride (72. mu.l, 7.57.10) was added at 0 deg.C-3mol, 1 eq.). The reaction mixture was stirred at ambient temperature for 20 minutes. After phase separation, saturated NaHCO was used3Solution, H2O, then washing the organic phase with saturated NaCl solution and then MgSO4Drying and finally evaporation of the solvent under reduced pressure, the residue (180mg) was purified by flash chromatography (AcOEt/petroleum ether 40/60). Recrystallization from a cyclohexane/AcOEt mixture gave the title product as a white solid.
Melting point: 192 deg.C
Elemental microanalysis:
C H N
% calculated value 75.817.115.20
% found 75.437.355.12
Example 116: n- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Butylamide
The procedure is as in example 115, but using butyryl chloride instead of acetic anhydride. The title product was isolated as a white solid.
Melting point: 114 deg.C
Elemental microanalysis:
C H N
% calculated value 76.747.804.71
% found 76.528.024.55
Example 117: n- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Acetamide
The procedure is as in example 115, starting from the amine obtained in preparation 3. The title product was isolated as a white solid.
Melting point: 184 ℃ C
Elemental microanalysis:
C H N
% calculated value 72.227.074.68
% found 71.857.304.52
Example 118: n- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Propionamide
The procedure is as in example 117, propionyl chloride being used instead of acetic anhydride. The title product was isolated as a white solid.
Melting point: 158 deg.C
Elemental microanalysis:
C H N
% calculated value 72.827.404.47
% found 72.617.554.39
Example 119: n- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]Butylamide
The procedure is as in example 117, but butyryl chloride is used instead of acetic anhydride. The title product was isolated as a white solid.
Melting point: 140 deg.C
Elemental microanalysis:
C H N
% calculated value 73.377.704.23
% found 73.157.804.14
The separation of the two enantiomers was performed on a chiral column: [ alpha ] to]D(589nm, T ═ 23 ℃) enantiomer 1 ═ 22 ° ± (CHCl)3，5mg/ml)
Enantiomer 2 ═ 20 ° ± 2 (CHCl)3，5mg/ml)
Example 120: n- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl]-1-cyclopropane carboxylic acid amide
The procedure is as in example 117, using propionyl chloride instead of acetic anhydride. The title product was isolated as a white solid.
Melting point: 192 deg.C
Elemental microanalysis:
C H N
% calculated value 73.827.124.30
% found 73.627.274.18
Example 121: (E) -N-methyl-2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthylene) acetamide
The acid obtained in preparation 66 (250mg, 9.84.10)-4mol, 1eq.) was solubilized in anhydrous dichloromethane (20 ml). Triethylamine (164. mu.l, 1.18.10) on potassium hydroxide was added at 0 ℃ under argon-3mol, 1.2eq.), followed by isobutyl chloroformate (153. mu.l, 1.18.10)-3mol, 1.2 eq.). At 0 deg.C, it took 1 hour and 10 minutes for the acid to be completely converted to the anhydride. Methylamine hydrochloride (199mg, 2.95.10) was added separately-3mol, 3eq.) under argon with anhydrous dichloromethane (18ml) and triethylamine (411. mu.l, 2.95.10)-3mol, 3eq.) are stirred together. After stirring for 10 minutes, the resulting suspension was added to the reaction mixture and stirring was continued overnight at ambient temperature. After washing once with water and drying over magnesium sulfate, the filtrate was evaporated to dryness under reduced pressure. Purification on a silica gel column (dichloromethane/methanol 98/2) followed by recrystallization from an AcOEt/cyclohexane mixture gave the title product isolated as a beige solid.
Melting point: 174 deg.C
Elemental microanalysis:
C H N
% calculated value 76.386.415.24
% found 76.106.395.18
Example 122: (Z) -N-methyl-2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthylene) acetamide
The procedure is as in example 121, starting from the acid obtained in preparation 67.
Melting point: 175 deg.C
Elemental microanalysis:
C H N
% calculated +1/8H2O 75.74 6.45 5.20
% found 75.726.555.06
Example 123: n- (1, 2-dihydro-1-acenaphthenylmethyl) acetamide
In a 100ml three-necked flask, in sodium carbonate (1.86g, 1.75.10)-2mol, 7eq.) of the hydrochloride obtained in preparation 68 (550mg, 2.50.10)-3mol, 1eq.) on two phases CH2Cl2Solubilisation in aqueous medium (20ml/20 ml). Acetic anhydride (236. mu.l, 2.50.10) was added at 0 deg.C-3mol, 1 eq.). The reaction mixture was stirred at ambient temperature for 20 minutes. After phase separation, saturated NaHCO was used3Solution, H2O, then washing the organic phase with saturated NaCl solution and then MgSO4Drying, finally evaporating off the solvent under reduced pressure, and purifying the residue weighing 500mg by flash chromatography (1. CH)2Cl2；2.CH2Cl2MeOH: 99/1). Recrystallization from a cyclohexane/AcOEt mixture isolated as a white solid to give the title product.
Melting point: 145 deg.C
Elemental microanalysis:
C H N
% calculated value 79.976.716.22
% found 79.836.826.15
Example 124: n- (1, 2-dihydro-1-acenaphthenylmethyl) propanamide
The procedure is as in example 123, propionic anhydride being used instead of acetic anhydride. The title product was isolated as a white solid.
Melting point: 111 deg.C
Elemental microanalysis:
C H N
% calculated value 80.307.165.85
% found 80.157.285.70
Example 125: n- (1, 2-dihydro-1-acenaphthenylmethyl) butanamide
The procedure is as in example 123, but butyryl chloride is used instead of acetic anhydride. The title product was isolated as a white solid.
Melting point: 111 deg.C
Elemental microanalysis:
C H N
% calculated value 80.577.565.53
% found 80.027.705.40
Example 126: n- (1, 2-dihydro-1-acenaphthenylmethyl) -1-cyclopropanecarboxamide
The procedure is as in example 123, using propionyl chloride instead of acetic anhydride.
Melting point: 146 deg.C
Elemental microanalysis:
C H N
% calculated value 81.246.825.57
% found 81.136.885.52
Example 127: n- (8-methoxy-1, 2-dihydro-1-acenaphthenyl methyl) acetamide
In a 100ml three-necked flask, in sodium carbonate (1.34g, 1.26.10)-2mol, 7eq.) of the amine obtained in preparation 69 (385mg, 1.81.10)-3mol, 1eq.) on two phases CH2Cl2Solubilisation in aqueous medium (20ml/20 ml). Acetic anhydride (170. mu.l, 1.81.10) was added at 0 deg.C-3mol, 1 eq.). The reaction mixture was stirred at ambient temperature for 40 minutes. After phase separation, saturated NaHCO was used3Solution, H2O, then washing the organic phase with saturated NaCl solution and then MgSO4Drying, finally evaporating off the solvent under reduced pressure, and purifying the residue weighing 360mg by flash chromatography (1. CH)2Cl2；2.CH2Cl2MeOH: 99/1). Recrystallization from a cyclohexane/AcOEt mixture isolated as a white solid to give the title product.
Melting point: 148 deg.C
Elemental microanalysis:
C H N
% calculated +1/2H2O 72.70 6.86 5.30
% found 72.086.865.24
Example 128: n- (8-methoxy-1, 2-di)Hydro-1-acenaphthylmethyl) propanamide
The procedure is as in example 127, propionic anhydride being used instead of acetic anhydride.
Melting point: 160 deg.C
Elemental microanalysis:
C H N
% calculated +1/2H2O 73.35 7.24 5.03
% found 73.887.255.15
Example 129: n- (8-methoxy-1, 2-dihydro-1-acenaphthylmethyl) -1-cyclopropanecarboxamide
The procedure is as in example 127, using propionyl chloride instead of acetic anhydride.
Melting point: 185 deg.C
Elemental microanalysis:
C H N
% calculated +1/4H2O 75.63 6.88 4.90
% found 75.786.984.93
Example 130: n- (8-methoxy-1, 2-dihydro-1-acenaphthenylmethyl) butanamide
The procedure is as in example 127, but butyryl chloride is used instead of acetic anhydride. The title product was isolated as a white solid.
Melting point: 146 deg.C
Elemental microanalysis:
C H N
% calculated value 76.307.474.94
% found 76.127.514.93
The separation of the two enantiomers was performed on a chiral column:
[α]D(589nm, T ═ 23 ℃) enantiomer 1 ═ 20 ° ± (CHCl)3，5mg/ml)
Enantiomer 2 ═ 18 ° ± 2 (CHCl)3，5mg/ml)
Example 131: n- [2- (1, 2-dihydro-1-acenaphthenyl) ethyl]Acetamide
In acetic anhydride (200. mu.l, 2.12.10)-3mol, 1.8eq.) and Raney nickel in the presence of tetrahydrofuran (25ml) the nitrile obtained in preparation of 70, step B (230mg, 1.20.10)-3mol) are hydrogenated at ambient temperature. After 5 hours of hydrogenation, the reaction mixture was filtered through celite, washed and evaporated under reduced pressure. The residue was then dissolved in dichloromethane, washed with water and then with saturated NaHCO3The solution was then washed with water. Over MgSO4After drying and removal of the solvent by evaporation, the residue is purified by flash Chromatography (CH)2Cl2Methanol: 99/1).
Melting point: 116 deg.C
Elemental microanalysis:
C H N
% calculated value 80.307.105.85
% found 80.117.235.89
Example 132：N-[2-(1, 2-dihydro-1-acenaphthenyl) ethyl]Propionamide
The procedure is as in example 131, propionic anhydride being used instead of acetic anhydride.
Melting point: 100 deg.C
Elemental microanalysis:
C H N
% calculated value 80.577.565.53
% found 80.347.545.50
Example 133: n- [2- (1, 2-dihydro-1-acenaphthenyl) ethyl]Butylamide
The procedure is as in example 131, substituting butyric anhydride for acetic anhydride. The title product was isolated as a white solid.
Melting point: 98 deg.C
Elemental microanalysis:
C H N
% calculated value 80.867.925.24
% found 80.867.965.21
Example 134: n- [2- (1, 2-dihydro-1-acenaphthenyl) ethyl]Cyclopropane carboxamides
At 0 deg.C under argon in triethylamine (530. mu.l, 3.80.10)-3mol, 1.5eq.) of the amine obtained in preparation 70 (500mg, 2.53.10)-3mol, 1eq.) was solubilized in anhydrous dichloromethane (17 ml). Propionyl chloride (230. mu.l, 2.53.10) was added dropwise at 0 deg.C-3mol, 1 eq.). The reaction mixture was stirred at ambient temperature for 20 minutes. After washing with water and saturated NaCl solution, MgSO4Drying and then evaporating off the solvent under reduced pressure, the residue being recrystallized from a cyclohexane/AcOEt mixture.
Melting point: 159 ℃ C
Example 135: n- [2- (8-methoxy-1, 2-dihydro-1-acenaphthenyl) ethyl]Acetamide
The operation is as in example 131, starting from the preparation 71 of the nitrile obtained in step A. The title product was isolated as a white solid.
Melting point: 118 deg.C
Elemental microanalysis:
C H N
% calculated value 80.307.105.85
% found 80.117.235.89
Example 136: n- [2- (8-methoxy-1, 2-dihydro-1-acenaphthenyl) ethyl]Propionamide
The procedure is as in example 135, propionic anhydride being used instead of acetic anhydride.
Melting point: 100 deg.C
Elemental microanalysis:
C H N
% calculated value 80.577.565.53
% found 80.347.545.50
Example 137: n- [2- (8-methoxy-1, 2-dihydro-1-acenaphthenyl) ethyl]Butylamide
The procedure is as in example 135, substituting butyric anhydride for acetic anhydride.
Melting point: 98 deg.C
Elemental microanalysis:
C H N
% calculated value 80.867.925.24
% found 80.867.965.21
Example 138: n- [2- (8-methoxy-1, 2-dihydro-1-acenaphthenyl) ethyl]-1-cyclopropane carboxylic acid amide
The procedure is as in example 134, starting from the amine obtained in preparation 71.
Melting point: 159 ℃ C
Example 139: n- [2- (1-methoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ]]Naphthalen-7-yl) ethyl]Propionamide
In propionic anhydride (480. mu.l, 3.74.10)-3mol, 2eq.) and Raney nickel the nitrile obtained in preparation 72 (465mg, 1.87.10) diluted with tetrahydrofuran (25ml) was added-3mol) are hydrogenated at ambient temperature. After 24 hours of hydrogenation, the reaction mixture was filtered through celite, washed and evaporated under reduced pressure. The residue was then dissolved in dichloromethane, washed with water and then with saturated NaHCO3The solution was then washed with water. Over MgSO4After drying and removal of the solvent by evaporation, the residue is purified by flash chromatography (1. CH)2Cl2；2.CH2Cl2MeOH: 99/1). The title product was isolated as a white solid.
E isomer:
the E isomer was obtained in pure form by recrystallization from an AcOEt/cyclohexane mixture of the solid obtained above corresponding to the E/Z mixture.
Melting point: 131 deg.C
Elemental microanalysis:
C H N
% calculated value 77.647.494.53
% found 77.287.544.36
Pharmacological research
Example A: acute toxicity study
After oral administration of 8 mice (26 ± 2 g) per group, acute toxicity was evaluated. Animals were observed at regular intervals during the first day, and then once daily for two weeks after treatment. Evaluation of LD50(the dose that caused death in 50% of the animals) demonstrates the low toxicity of the compounds of the invention.
Example B: melatonin receptor binding studies using sheep nodular cells
Melatonin receptor binding studies of the compounds of the invention were performed on cells of the nodular portion of sheep according to conventional procedures, and the nodular portion of the pituitary gland of mammals is characterized by high-density melatonin receptors (journal of neuroendocrinology 1, pp 1-4, 1989).
Scheme(s)
1) A nodular membrane of sheep was prepared and used as a target tissue in a saturation experiment to measure the binding ability and the binding ability to 2-, [2 ]125I]Affinity of iodomelatonin.
2) The ovine sarcomeric membranes were used as target tissues in competitive binding experiments using different test compounds compared to melatonin.
Each experiment was performed in triplicate and each compound was tested at a different concentration range. The results obtained after statistical treatment enable the binding affinity of the test compound to be determined.
Results
The compounds of the present invention show strong affinity for melatonin receptors.
Example C: melatonin mt1And MT2Receptor binding studies
Use of 2-125I]-melatonin as reference radioligand, for mt1Or MT2Binding assays for receptors. By BeckmanThe retained radioactivity was measured in a LS6000 liquid scintillation counter.
The competitive binding experiment was then repeated three times using different test compounds. Each compound was tested at a different concentration range. As a result, the binding affinity (IC) of the test compound50) Can be measured.
IC of the tested Compound of the present invention50Value display, test Compound vs. mt1Or MT2The receptor subtypes have very strong binding capacity, IC50Values ranged from 0.1 to 10 nM.
Example D: four plate test
The products of the invention were administered to ten mice per group by the oesophageal route. One group was given a gum cement. Thirty minutes after administration of the study product, the animals were placed in cages, the bottom of which consisted of four metal plates. Each time the animal passed from one plate to another, a slight shock (0.35mA) was applied. The number of passes from one plate to another in one minute is recorded. After administration, the compounds of the present invention significantly increased the number of passes from one plate to the other, confirming the anxiolytic activity of the compounds of the present invention.
Example E: effect of Compounds of the invention on the circadian rhythm of locomotor Activity in rats
By alternating day/night, melatonin is involved in the circadian rhythms that affect most of the physiology, biochemistry and behavior, which makes it possible to establish pharmacological models for studying melatoninergic ligands.
The effect of the molecule on a number of parameters, in particular on the circadian rhythm of motor activity, was tested and represents a reliable indicator of endogenous circadian clock activity.
In this study, the effect of this class of molecules on a particular experimental model, namely rats in time isolation (permanent darkness), was evaluated.
Experimental protocol
One month old Long Evans male rats entered a light cycle of 12 hours light every 24 hours (LD 12:12) immediately upon arrival at the laboratory. After 2 to 3 weeks of acclimation, they were placed in cages equipped with a wheel connected to a recording system, in order to detect the phase of locomotor activity and thus monitor the nychhelmial rhythm (LD) or circadian rhythm (DD).
Once the rhythm was recorded to show a stable pattern in the light cycle LD 12:12, the rats were immediately placed in permanent darkness (DD).
After two to three weeks, the test molecules were administered daily to the rats when free-path (reflecting the rhythm of the endogenous biological clock) was clearly established.
Observations were made by visual depiction of the activity rhythm:
the effect of the light rhythm on the activity rhythm,
the effect on the rhythm disappears in permanent darkness,
-effect of daily dosing of molecules; temporary or long term effects.
The software package is capable of:
measuring the duration and intensity of the activity, the rhythmic period of the animal in the free path and during the treatment,
the presence of circadian and non-circadian (e.g. infradian) components is confirmed by spectral analysis, where possible.
Results
The compounds of the invention exert a powerful effect on the circadian rhythm, notably via the melatoninergic system.
Example F: antiarrhythmic activity
Scheme(s)
(see LAWSON J.W., et al, J. Pharmacology & Experimental therapeutics 1968, 160, pp22-31)
The test substance was administered intraperitoneally to 3 mice per group, and 30 minutes later, anesthetized with chloroform. The animals were then observed for 15 minutes. At least two animals did not record arrhythmias and heart rates in excess of 200 beats/min (control: 400-.
Example G: the pharmaceutical composition comprises: tablet formulation
1000 tablets, each tablet containing 5mg
[ (4-methoxy-2, 3-dihydro-1H-benzonaphthyl) methyl ] propanamide (example 2) 5g
Wheat starch 20g
Corn starch 20g
Lactose 30g
Magnesium stearate 2g
Silica 1g
Hydroxypropyl cellulose 2g
Claims (26)
1. A compound of formula (I), enantiomers and diastereoisomers thereof, and addition salts thereof with a pharmaceutically acceptable acid or base:
wherein:
◆R1represents a hydrogen atom, a halogen atom, a straight chain or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) An alkoxy, hydroxy or oxo group,
◆R2and R3May be the same or different and represents a halogen atom or Ra、ORa、CORa、OCORaOr COORaGroup, wherein RaRepresents a hydrogen atom, an optionally substituted linear or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) Trihaloalkyl, optionally substituted straight or branched chain (C)2-C6) Alkenyl, optionally substituted straight or branched chain (C)2-C6) Alkynyl, optionally substituted (C)3-C8) Cycloalkyl, optionally substituted (C)3-C8) Cycloalkyl-straight or branched chain (C)1-C6) An alkyl group or an optionally substituted aryl group,
symbol (R)2)mAnd (R)3)m’Denotes that the ring in which it is located may be substituted by 1 to 3 identical or different members of the genus R2And R3The substitution of the defined group(s),
x represents (CH)2)qA group wherein q is 1 or 2, or-CH ═ CH-group,
n is an integer satisfying 0. ltoreq. n.ltoreq.3,
when n is 1, 2 or 3, andwhen the chain is in the b position, p is an integer satisfying 1. ltoreq. p.ltoreq.3,
in all other cases 0. ltoreq. p.ltoreq.3,
the chain may be unsubstituted or substituted by one or more groups, which may be the same or different, selected from Ra、ORa、CORa、COORaOr a halogen atom,
b stands for:
group, wherein RaAs defined above, Z represents an oxygen atom or a sulfur atom, R5Represents RaGroup or NR6R7Group, wherein R6And R7Which may be the same or different, represent RaThe radical(s) is (are),
orGroup of which Z, R6And R7The definition is the same as that of the above,
symbol ofIndicating that the bond may be a single or double bond, depending on the valency of the atom, it being understood that the symbolsIs used for expressingOrIn this case p is not 0,
the precondition is that:
the compound of formula (I) is not N- (4-methyl-2, 3-dihydro-1H-1-benzonaphthyl) -1-cyclopropanecarboxamide, N- (4-methyl-2, 3-dihydro-1H-1-benzonaphthyl) -2-chloroacetamide, N- (5-hydroxy-1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthyl) acetamide, N- (5-hydroxy-1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthyl) benzamide or N- (1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthyl) acetamide,
it should be understood that:
- "aryl" is intended to denote phenyl or naphthyl, each of which is optionally substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) Alkoxy, straight or branched chain (C)1-C6) Alkyl, cyano, nitro, amino, trihaloalkyl or halogen atoms,
the expression "optionally substituted" for the terms "alkyl", "alkenyl" and "alkynyl" means that these radicals may be substituted by one or more radicals which may be identical or different, chosen from hydroxyl, linear or branched (C)1-C6) Alkoxy, arylOr a halogen atom,
the expression "optionally substituted" as used for the terms "cycloalkyl" and "cycloalkylalkyl" denotes that the cyclic moiety may be substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) Alkoxy, oxo or halogen.
2. A compound of formula (I) represented by formula (IA), the enantiomers and diastereomers thereof, and the addition salts thereof with a pharmaceutically acceptable acid or base, according to claim 1:
wherein:
◆R1represents a hydrogen atom, a halogen atom, a straight chain or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) An alkoxy, hydroxy or oxo group,
◆R2and R3May be the same or different and represents a halogen atom or Ra、ORa、CORa、OCORaOr COORaGroup, wherein RaRepresents a hydrogen atom, an optionally substituted linear or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) Trihaloalkyl, optionally substituted straight or branched chain (C)2-C6) Alkenyl, optionally substituted straight or branched chain (C)2-C6) Alkynyl, optionally substituted (C)3-C8) Cycloalkyl, optionally substituted (C)3-C8) Cycloalkyl-straight or branched chain (C)1-C6) An alkyl group or an optionally substituted aryl group,
symbol (R)2)mAnd (R)3)m’Denotes that the ring in which it is located may be substituted by 1 to 3 identical or different members of the genus R2And R3The substitution of the defined group(s),
x represents (CH)2)qA group wherein q is 1 or 2, or-CH ═ CH-group,
n is an integer satisfying 0. ltoreq. n.ltoreq.3,
when n is 1, 2 or 3, - (CH)2)pWhen the B chain is in the B position, p is an integer satisfying 1. ltoreq. p.ltoreq.3,
in all other cases 0. ltoreq. p.ltoreq.3,
◆(CH2)pthe chain may be unsubstituted or substituted by one or more groups, which may be the same or different, selected from Ra、ORa、CORa、COORaOr a halogen atom,
b stands for:
group, wherein RaAs defined above, Z represents an oxygen atom or a sulfur atom, R5Represents RaGroup or NR6R7Group, wherein R6And R7Which may be the same or different, represent RaThe radical(s) is (are),
orGroup of which Z, R6And R7The definition is the same as that of the above,
symbol ofMeaning that the bond may be a single or double bond, depending on the valency of the atom, with the proviso that:
the compound of formula (I) is not N- (4-methyl-2, 3-dihydro-1H-1-benzonaphthyl) -1-cyclopropanecarboxamide, N- (4-methyl-2, 3-dihydro-1H-1-benzonaphthyl) -2-chloroacetamide, N- (5-hydroxy-1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthyl) acetamide, N- (5-hydroxy-1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthyl) benzamide or N- (1, 2, 2a, 3, 4, 5-hexahydro-4-acenaphthyl) acetamide,
it should be understood that:
- "aryl" is intended to denote phenyl or naphthyl, each of which is optionally substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) -alkoxy radicalRadical, straight-chain or branched (C)1-C6) -an alkyl group, a cyano group, a nitro group, an amino group, a trihaloalkyl group or a halogen atom,
the expression "optionally substituted" for the terms "alkyl", "alkenyl" and "alkynyl" means that these radicals may be substituted by one or more radicals which may be identical or different, chosen from hydroxyl, linear or branched (C)1-C6) An alkoxy group, an aryl group or a halogen atom,
the expression "optionally substituted" as used for the terms "cycloalkyl" and "cycloalkylalkyl" denotes that the cyclic moiety may be substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) -an alkoxy group, an oxo group or a halogen atom.
3. A compound of formula (I) according to claim 1 represented by formula (IB), enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base:
wherein:
◆R1represents a hydrogen atom, a halogen atom, a straight chain or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) An alkoxy, hydroxy or oxo group,
◆R2and R3May be the same or different and represents a halogen atom or Ra、ORa、CORa、OCORaOr COORaGroup, wherein RaRepresents a hydrogen atom, an optionally substituted linear or branched chain (C)1-C6) Alkyl, straight or branched chain (C)1-C6) Trihaloalkyl, optionally substituted straight or branched chain (C)2-C6) Alkenyl, optionally substituted straight or branched chain (C)2-C6) Alkynyl, optionally substituted (C)3-C8) Cycloalkyl, optionally substituted (C)3-C8) Cycloalkyl-straight or branched chain(C1-C6) An alkyl group or an optionally substituted aryl group,
symbol (R)2)mAnd (R)3)m’Denotes that the ring in which it is located may be substituted by 1 to 3 identical or different members of the genus R2And R3The substitution of the defined group(s),
x represents (CH)2)qA group wherein q is 1 or 2, or-CH ═ CH-group,
n is an integer satisfying 0. ltoreq. n.ltoreq.3,
p is an integer satisfying 1. ltoreq. p.ltoreq.3,
◆ the chain may be unsubstituted or substituted by one or more groups, which may be the same or different, selected from Ra、ORa、CORa、COORaOr a halogen atom,
b stands for:group, wherein RaAs defined above, Z represents an oxygen atom or a sulfur atom, R5Represents RaGroup or NR6R7Group, wherein R6And R7Which may be the same or different, represent RaThe radical(s) is (are),
orGroup of which Z, R6And R7The definition is the same as that of the above,
symbol ofIndicating that the bond may be a single or double bond, depending on the valency of the atom, it is understood that:
- "aryl" is intended to denote phenyl or naphthyl, each of which is optionally substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) Alkoxy, straight or branched chain (C)1-C6) -an alkyl group, a cyano group, a nitro group, an amino group, a trihaloalkyl group or a halogen atom,
the expression "optionally substituted" for the terms "alkyl", "alkenyl" and "alkynyl" means that these radicals may be substituted by one or more radicals which may be identical or different, chosen from hydroxyl, linear or branched (C)1-C6) An alkoxy group, an aryl group or a halogen atom,
the expression "optionally substituted" as used for the terms "cycloalkyl" and "cycloalkylalkyl" denotes that the cyclic moiety may be substituted by one or more groups which may be the same or different, chosen from hydroxyl, linear or branched (C)1-C6) -an alkoxy group, an oxo group or a halogen atom.
4. A compound of formula (I) according to claim 1, wherein n represents the integer 0, 1 or 2, the enantiomers and diastereomers thereof and the addition salts thereof with a pharmaceutically acceptable acid or base.
5. A compound of formula (I) according to claim 1, wherein a forms with the group to which it is bound a tricyclic ring system of 2, 3-dihydrobenzonaphthalene, 1, 2-dihydroacenaphthylene or 7, 8, 9, 10-tetrahydrocyclohepta [ de ] naphthalene, the enantiomers and diastereomers thereof, and the addition salts thereof with a pharmaceutically acceptable acid or base.
6. A compound of formula (I) according to claim 1, wherein p represents the integer 0, 1 or 2, the enantiomers and diastereomers thereof and the addition salts thereof with a pharmaceutically acceptable acid or base.
7. A compound of formula (I) according to claim 1, wherein R2And R3Which may be identical or different, represent an alkoxy group or an alkyl group or a hydrogen atom, the enantiomers and diastereomers thereof and the addition salts thereof with a pharmaceutically acceptable acid or base.
8. A compound of formula (I) according to claim 1, wherein R1Represents a hydrogen atom, an enantiomer thereof anddiastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.
9. A compound of formula (I) according to claim 1, whereinThe chain is in position a or c, enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.
10. A compound of formula (I) according to claim 1, whereinThe chain being in position a or c, p representing the integer 0 (in this caseBond is a single bond), 1 or 2, enantiomers and diastereomers thereof, and addition salts thereof with a pharmaceutically acceptable acid or base.
11. A compound of formula (I) according to claim 1, wherein B represents NHCOR5The group, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.
12. A compound of formula (I) according to claim 1 wherein B represents CONHR6The group, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.
13. A compound of formula (I) according to claim 1 wherein a forms, together with the group to which it is bound, 2, 3-dihydrobenzonaphthalene, 1, 2-dihydroacenaphthylene or 7, 8, 9, 10-tetrahydrocyclohepta [ de [ ]]Tricyclic ring systems of naphthalene, each unsubstituted or substituted on the naphthalene moiety by one or more alkoxy or alkyl groups and substituted in the a or c positionIs substituted by radicals in which B represents NHCOR5Or CONHR6The group, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.
14. A compound of formula (I) according to claim 1 wherein a forms with the group to which it is bound 1, 2-acenaphthylene or 7, 8, 9, 10-tetrahydrocyclohepta [ de [ ] -1]Tricyclic ring systems of naphthalene, each unsubstituted or substituted on the naphthalene moiety by one or two alkoxy groups and in the a or c position by ═ CH-B, ═ CH-CH2-B、-B、-CH2-B or- (CH)2)2-a B group, wherein B represents NHCOR5Or CONHR6The group, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.
15. Compounds of formula (I) according to claim 1, wherein a forms, together with the group to which it is bound, a tricyclic ring system of 2, 3-dihydrobenzonaphthalene, which is unsubstituted or substituted on the naphthalene moiety by one or two alkoxy groups and is substituted in the a or c position by ═ CH-B, ═ CH-CH2-B、-CH2-B or- (CH)2)2-a B group, wherein B represents NHCOR5Or CONHR6The group, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.
16. The compound of formula (I) according to claim 1, which is N- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] acetamide, N- [ (4-methoxy-2, 3-dihydro-1H-benzonaphthyl) methyl ] propionamide, N- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] cyclopropanecarboxamide, N- [ (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] butyramide, N- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] acetamide, N- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] butyramide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] acetamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] propionamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] butyramide and N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) methyl ] -1-cyclopropane carboxamide, its enantiomers and diastereoisomers and addition salts thereof with pharmaceutically acceptable acids or bases.
17. The compounds of formula (I) according to claim 1, which are N- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] acetamide, N- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] propionamide, N- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] -1-cyclopropanecarboxamide, N- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] acetamide, N- [2- (9-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] butanamide, N- [2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] butanamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] propionamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] butanamide, N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] -1-cyclopropanecarboxamide and N- [2- (4, 9-dimethoxy-2, 3-dihydro-1H-1-benzonaphthyl) ethyl ] acetamide, its enantiomers and diastereomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
18. A compound of formula (I) according to claim 1 which is N- (8-methoxy-1, 2-dihydro-1-acenaphthenyl) acetamide, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.
19. Compounds of formula (I) according to claim 1, which are (E) -N-methyl-2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthylene) acetamide and (Z) -N-methyl-2- (4-methoxy-2, 3-dihydro-1H-1-benzonaphthylene) acetamide, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
20. The compounds of formula (I) according to claim 1 which are N- (1, 2-dihydro-1-acenaphthylmethyl) acetamide, N- (1, 2-dihydro-1-acenaphthylmethyl) propionamide, N- (1, 2-dihydro-1-acenaphthylmethyl) butyramide, N- (1, 2-dihydro-1-acenaphthylmethyl) -1-cyclopropanecarboxamide, N- (8-methoxy-1, 2-dihydro-1-acenaphthylmethyl) acetamide, N- (8-methoxy-1, 2-dihydro-1-acenaphthylmethyl) propionamide, N- (8-methoxy-1, 2-dihydro-1-acenaphthylmethyl) -1-cyclopropanecarboxamide and N- (8-methoxy-1, 2-dihydro-1-acenaphthylmethyl) -1-cyclopropanecarboxamide 1, 2-dihydro-1-acenaphthylmethyl) butanamide, its enantiomers and diastereomers and its addition salts with a pharmaceutically acceptable acid or base.
21. The compound of formula (I) according to claim 1 which is N- [2- (1, 2-dihydro-1-acenaphthenyl) ethyl ] acetamide, N- [2- (1, 2-dihydro-1-acenaphthenyl) ethyl ] propionamide, N- [2- (1, 2-dihydro-1-acenaphthenyl) ethyl ] butyramide, N- [2- (1, 2-dihydro-1-acenaphthenyl) ethyl ] cyclopropanecarboxamide, N- [2- (8-methoxy-1, 2-dihydro-1-acenaphthenyl) ethyl ] acetamide, N- [2- (8-methoxy-1, 2-dihydro-1-acenaphthenyl) ethyl ] propionamide, 2-dihydro-1-acenaphthenyl) ethyl ] butyramide and N- [2- (8-methoxy-1, 2-dihydro-1-acenaphthenyl) ethyl ] -1-cyclopropanecarboxamide, their enantiomers and diastereomers and their addition salts with a pharmaceutically acceptable acid or base.
22. A compound of formula (I) according to claim 1 which is N- [2- (1-methoxy-7, 8, 9, 10-tetrahydrocyclohepta [ de ] naphthalenen-7-yl) ethyl ] propanamide, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.
23. A process for the preparation of a compound of formula (I) according to claim 1, wherein a forms, with the group to which it is bound, a formula (a)1) Characterized in that a compound of formula (II) is used as starting material:
wherein R is2、R3、R5X, m' and symbolsThe definition is the same as that of the above,
Y2is represented by (CH)2)qA group (wherein q is 1, 2 or 3, or when the symbolQ is 0 when it is a single bond),
Y1is represented by (CH)2)q’A group (wherein q' is 0, 1, 2 or 3), by R as defined above1The substitution of the group(s),
Y3is represented by (CH)2)q”A group (wherein q "is 0, 1, 2 or 3), with R as defined above1Substituted by radicals, wherein q '+ q' is ≦ 3, and in both radicals Y1And Y3In at least one of (1), R1Must represent a hydrogen atom or atoms, and,
cyclisation of a compound of formula (II) in basic medium to give a compound of formula (III):
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
the compound of formula (III) is then reacted with a Lewis acid to give the compound of formula (I/a), a particular example of which is:
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
the compound of formula (I/a) is then reduced to give the compound of formula (I/b), which is a particular case of the compound of formula (I):
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
or a compound of formula (IV):
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
the compound is in turn-cyclized
Reaction with Lewis acids
Obtaining a compound of formula (I/c), which is a particular case of compounds of formula (I):
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
reduction of a compound of formula (I/c) to give a compound of formula (I/d), which is a particular case of compounds of formula (I):
wherein R is2、R3、R5、X、Y1、Y2、Y3M, m' and symbolsThe definition is the same as that of the above,
the totality of compounds (I/a), (I/b), (I/c) and (I/d) constitutes a compound of formula (I/e), which is a particular case of compounds of formula (I):
wherein R is1、R2、R3、R5N, p, X, m' and symbolsThe definition is the same as that of the above,
a compound of formula (I/e):
by the action of a compound of formula (V): r'a-W (V), wherein R'aMay have R as defined aboveaAny meaning of the group other than hydrogen, W represents a leaving group, such as a halogen atom or tosyl group, to give a compound of formula (I/f), which is a particular example of a compound of formula (I):
wherein R is1、R2、R3、R5R 'a, n, p, X, m' and the symbolsThe definition is the same as that of the above,
the compounds of formulae (I/e) and (I/f) are all comprised of compounds of formula (I/g):
wherein R is1、R2、R3、R5、RaN, p, X, m' and symbols The definition is the same as that of the above,
the compound of formula (I/g) may be subjected to the action of a sulfurizing agent, such as Lawesson's reagent, to give a compound of formula (I/h), which is a particular case of the compounds of formula (I):
wherein R is1、R2、R3、R5、RaN, p, X, m' and symbolsThe definition is the same as that of the above,
or in a basic medium, to give a compound of formula (VI):
wherein R is1、R2、R3N, p, X, m' and symbolsThe definition is the same as that of the above,
a compound of formula (VI):
-by the action of a pyrylium salt to give a compound of formula (VII):
wherein Hal represents a halogen atom, R1、R2、R3N, p, X, m' and symbolsThe definition is the same as that of the above,
condensing a compound of formula (VII) with a cyanide salt to provide a compound of formula (VIII):
wherein R is1、R2、R3N, p, X, m' and symbolsThe definition is the same as that of the above,
(VIII) hydrolysis of the compound of formula (VIII) in an acidic or basic medium to give the compound of formula (IX):
wherein R is1、R2、R3N, p, X, m' and symbolsThe definition is the same as that of the above,
the compound of formula (IX) is subjected to an amine HNR after activation to the acid chloride or in the presence of a coupling agent6R7To obtain a compound of formula (I/I), which is a particular case of compounds of formula (I):
wherein R is1、R2、R3、R6、R7N, p, X, m' and symbolsThe definition is the same as that of the above,
(I/I) the compound may be subjected to the action of a sulfurizing agent, such as Lawesson's reagent, to give a compound of formula (I/j), which is a particular case of compounds of formula (I):
wherein R is1、R2、R3、R6、R7N, p, X, m' and symbolsThe definition is the same as that of the above,
-or by the action of a compound of formula (X):
Z＝C＝NR6R7 (X)
z, R therein6And R7The same as defined above, to obtain a compound of formula (I/k), which is a particular case of the compound of formula (I):
wherein R is1、R2、R3、R6、R7N, p, Z, m' and symbolsThe definition is the same as that of the above,
the compounds of formula (I/k) may be condensed with compounds of formula (V) to give compounds of formula (I/1), a particular example of which is compounds of formula (I):
wherein R is1、R2、R3、R6、R7、R’aN, p, X, Z, m' and the symbolsThe definition is the same as that of the above,
the compounds (I/a) to (I/1) can be purified according to a conventional separation process, converted into an addition salt with a pharmaceutically acceptable acid or base if necessary, and separated into their isomers according to a conventional separation process, if appropriate.
24. A process for the preparation of a compound of formula (I) according to claim 1, wherein a forms, with the group to which it is bound, a formula (a)1) Of the tricyclic ring system of (1), whereinThe chain being in position a or c, characterized in that a compound of formula (XIV) is used as starting material:
wherein R is2、R3X, m and m 'are as defined above, T and T' are different and represent a hydrogen atom or a-CHO group,
subjecting the compound of formula (XIV) to a Wittig reaction followed by catalytic reduction to yield a compound of formula (XV):
wherein R is2、R3X, m and m 'are as defined above, T'1And T1Represents a hydrogen atom or a group of formula (XVI):
wherein G represents R optionally defined as above1Radical substituted (CH)2)n’Group, wherein n 'is 1, 2 or 3, with the proviso that two groups T'1And T1One of them represents a hydrogen atom,
the compound of formula (XV) is in turn hydrolyzed in basic medium and then decarboxylated by heating to give the compound of formula (XVII):
wherein R is2、R3X, m and m 'are as defined above, T'2And T2Represents a hydrogen atom or a group of formula (XVIII):
wherein G is as defined above, with the proviso that two radicals T'2And T2One of them represents a hydrogen atom,
after activation to oxalyl chloride, cyclization of the compound of formula (XVII) in the presence of a lewis acid affords the compound of formula (XIX):
wherein R is2、R3X, G, m and m 'are as defined above, T'3And T3Is different and represents a hydrogen atom or an oxo group,
a compound of formula (XIX):
-carrying out a wittig reaction (optionally followed by reduction) followed by hydrolysis to yield a compound of formula (XX):
wherein R is2、R3X, G, m' and symbolsEach T is as defined above4And T'4Representing a hydrogen atom or forming with a carbon atom carrying itGroup, wherein p1Is 1, 2 or 3, with the proviso that two radicals T4And T'4One of them represents a hydrogen atom,
-or successively reducing to the corresponding alcohol
E.g. in SOCl2In the presence of (2) halogenated
Condensation with cyanide salts
Performing acid hydrolysis or alkali hydrolysis
To give a compound of formula (XXI):
wherein R is2、R3X, G, m' and symbolsDefinition of same as above, T'5And T5Are different and represent a hydrogen atom or a COOH group,
the totality of compounds (XX) and (XXI) constitutes the compound of formula (XXII):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'6And T6Representing a hydrogen atom or forming with a carbon atom carrying itWherein p is as defined above, with the proviso that two radicals T'6And T6One of them represents a hydrogen atom,
the compound (XXII) can also be obtained from a compound of the formula (XIX) by condensation (optionally followed by reduction of the double bond) with a nitrile group-containing compound and hydrolysis of the nitrile according to the Wittig reaction, which compound (XXII):
-being subjected to an amine HNR, either after activation to the acid chloride or in the presence of a coupling agent6R7To give a compound of formula (I/y), which is a particular case of compounds of formula (I):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'7And T7Representing a hydrogen atom or forming with a carbon atom carrying itGroup, wherein p, R6And R7With the proviso that two radicals T 'are mentioned'7And T7One of them represents a hydrogen atom,
the compound of formula (I/y) may be subjected to the action of a sulfurizing agent, such as Lawesson's reagent, to give a compound of formula (I/z), a particular example of which is the compound of formula (I):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'8And T8Representing a hydrogen atom or forming with a carbon atom carrying itGroup, wherein p, R6And R7As defined above, with the proviso that two radicals T8And T'8One of them represents a hydrogen atom,
or activation to the acid chloride, followed by treatment with azide, heating to form the corresponding isocyanate, and hydrolysis to give the compound of formula (XXIII):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'9And T9Representing a hydrogen atom or forming with a carbon atom carrying itA radical in which p is as defined above, with the proviso that two radicals T9And T'9One of them represents a hydrogen atom,
the compound of formula (XXIII) may also be obtained from a compound of formula (XIX) by condensation with a nitrile group-containing compound according to the Wittig reaction followed by reduction of the nitrile,
the compound of formula (XXIII) is condensed with:
-acyl chloride ClCOR5Or the corresponding anhydrides (mixed or symmetrical) in which R5As defined above, to give a compound of formula (I/aa) which is a particular feature of the compound of formula (I)Example (c):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'10And T10Representing a hydrogen atom or forming with a carbon atom carrying itGroup, wherein p and R5With the proviso that two radicals T 'are mentioned'10And T10One of them represents a hydrogen atom,
the compound of formula (I/aa) may be subjected to the action of a sulfurizing agent, such as Lawesson's reagent, and/or substituted after the action of the compound of formula (V) to give a compound of formula (I/ab), which is a particular case of the compounds of formula (I):
wherein R is2、R3X, G, m' and symbolsEach T 'is as defined above'11And T11Representing a hydrogen atom or forming with a carbon atom carrying itGroup, wherein p, Ra、R5And Z is as defined above, with the proviso that two radicals T'11And T11One of them represents a hydrogen atom,
the compounds (I/y) to (I/ab) can be purified according to a conventional separation process, converted into an addition salt with a pharmaceutically acceptable acid or base if necessary, and separated into their isomers according to a conventional separation process, if appropriate.
25. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 22 or an addition salt thereof with a pharmaceutically acceptable acid or base, and one or more pharmaceutically acceptable excipients.
26. A pharmaceutical composition according to claim 25 for the treatment of disorders related to the melatoninergic system.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9800424A FR2773798B1 (en) | 1998-01-16 | 1998-01-16 | NOVEL TRICYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR98/00424 | 1998-01-16 | ||
| PCT/FR1998/002694 WO1999036392A1 (en) | 1998-01-16 | 1998-12-11 | Novel tricyclic compounds, preparation method and pharmaceutical compositions containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1033455A1 HK1033455A1 (en) | 2001-08-31 |
| HK1033455B true HK1033455B (en) | 2006-09-22 |
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