JP2010536919A - 3-Azabicyclo (4.1.0) heptane derivatives useful as norepinephrine, serotonin or dopamine reuptake inhibitors - Google Patents

Abstract

The present invention relates to compounds represented by formula (I), methods for producing them, intermediates used in these methods, pharmaceutical compositions containing them, and serotonin (5-HT), dopamine (DA) and norepinephrine. (NE) relates to their use in therapy as reuptake inhibitors.

Description

  The present invention relates to novel compounds, methods for producing them, intermediates used in these methods, pharmaceutical compositions containing them, and inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) reuptake Relates to their use in therapy as agents.

  Brain tissue consists of nerve cells that can exchange information through specific cell structures called synapses. Signal exchange between neurons at the synapse occurs by neurochemical messengers called neurotransmitters that act on specific target protein molecules before and after synapses called receptors. Monoamines are a family of small neurotransmitter molecules that share common chemical characteristics, including serotonin (5-HT), dopamine (DA) and norepinephrine (NE).

  Monoamine neurotransmitters are released into the synaptic space between neurons and interact with receptors on the target cell membrane. The switching of neurochemical signals is mainly caused by the removal of neurotransmitter molecules via other protein molecules called monoamine transporters (SERT for 5-HT, DAT for DA, NET for NE). . Transporters can bind neurotransmitter molecules and move them to presynaptic terminals, and this cellular mechanism is called reuptake. Pharmacological inhibition of the reuptake process can cause an increase in monoamines at the synaptic level and, as a result, an increase in the physiological activity of the neurotransmitter.

  Serotonergic neurotransmission in the brain is mediated by a large family of receptors, including both G protein-coupled receptors, including 14 subtypes, and ligand-gated ion channels, and is involved in various physiological functions .

  Compounds with inhibitory properties at SERT are found in mammals, including humans, in various disorders associated with this nervous system, such as eating disorders, major depression and mood disorders, obsessive compulsive disorder, panic disorder, alcohol dependence Expected to have the ability to treat symptoms, pain, memory deficits and anxiety. These disorders include depression-related disorders such as pseudo-dementia or Ganza syndrome, migraine, bulimia, diabetes, premenstrual or late luteal syndrome, tobacco abuse, panic disorder, post-traumatic stress syndrome, memory Loss, senile dementia, acquired immune deficiency syndrome dementia complex, senile memory disorder, social phobia, attention deficit / hyperactivity disorder, chronic fatigue syndrome, premature ejaculation, difficulty erectile dysfunction, anorexia nervosa, sleep Disability, autism, speechlessness or hair loss.

  Major depression is a feeling of deep grief, self-negative feelings, feelings of despair, and indifference to all pleasures (indifference), rethinking about death, mental decline, energy loss, inability to make decisions (often anxiety and Emotional disorder or mood disorder characterized by several symptoms including (with excitement). These symptoms are persistent and can range from mild to severe.

  It is not well understood that the pathophysiology of major depression is a multifactor syndrome, and thus several types of neurotransmitter systems have been responsible. However, in general, the disorder is thought to be due to a decrease in synaptic concentrations of monoamine neurotransmitters (mainly NE and 5-HT) in critical brain areas, leading to a “monoamine theory” of depression. .

  Some preclinical and clinical evidence indicates that enhanced serotonin-mediated neurotransmission may be effective in the treatment of major depression, indeed selective serotonin reuptake inhibitors (SSRIs) Have come to dominate the treatment of depression in the last 20 years. The first SSRI introduced, fluoxetine, is the prototype for this group. Other members include paroxetine, sertraline, fluvoxamine, citalopram.

However, it is not exactly clear how these drugs work to alleviate depression. As with other classes of antidepressants, despite the rapid blockade of serotonin reuptake, there is a lag of several weeks before onset of the mood-lifting effect. It is believed that secondary adaptive changes at serotonergic synapses following chronic administration of SSRIs must occur: down-regulation of controlled release autoreceptors and increased neurotransmitter release. Delayed development of the antidepressant effect is considered a significant drawback of currently used SSRIs. Furthermore, although SSRIs are generally well tolerated, elevated 5-HT levels at central and peripheral synapses contribute to peristalsis and restlessness in addition to gastrointestinal and sexual side effects. Receptor subtypes such as 5-HT _2C and 5-HT ₃ are stimulated.

  The success of SSRI has rekindled interest in the development of selective norepinephrine reuptake inhibitors (SNRI) as promising antidepressants. Many such compounds have been synthesized, such as nisoxetine, maprotiline, tomoxetine and reboxetine. In addition, many compounds, including imipramine and amitriptyline (SERT titer> NET) and older tricyclic antidepressants such as desipramine, nortriptyline and protriptyline (NET titer> SERT) have a NET-SERT mixed inhibition profile. have.

  DAT pharmacological treatments may primarily have the ability to increase the level of DA in the mesolimbic system to improve anxiety, a core symptom of major depression. DAT-inhibiting components, in combination with SERT and NET blockade, may have the ability to ameliorate the motivation and attention deficits found in depressed patients and to enhance cognitive impairment. On the other hand, DAT blockage must be carefully managed to avoid potential strengthening effects and abuse trends. However, compounds with DAT inhibition in medicinal pharmacology such as dexmethylphenidate, methylphenidate and bupropion have successfully entered the market.

  Clinical studies show that combination therapy with drugs that enhance dopaminergic activity is effective for patients with poor response to SSRIs. As a result, compounds with potent SERT inhibitory activity combined with well-balanced NET blockade and moderate DAT inhibitory activity may provide an alternative to current combination therapies to treat unresponsive patients And can provide greater efficacy and therapeutic flexibility with faster onset of antidepressant effects.

  The compounds of the present invention, due to their useful DAT inhibition, are parkinsonism, depression, diabetes, narcolepsy, drug dependence or abuse, including abuse of cocaine, attention deficit / hyperactivity disorder, Jill de la Tourette syndrome and It is considered useful for the treatment of senile dementia. Dopamine reuptake inhibitors enhance acetylcholine release indirectly via dopamine neurons and are therefore useful in the treatment of memory deficits, for example in Alzheimer's disease, presenile dementia, senile memory impairment and chronic fatigue syndrome is there. Noradrenaline reuptake inhibitors are thought to be useful in attention, alertness, enhanced alertness and wakefulness, and treatment of depression.

  The object of the present invention is to provide novel pharmaceutical compositions comprising compounds that are serotonin (5-HT), dopamine (DA) and norepinephrine (NE) reuptake inhibitors. Furthermore, it is an object of the present invention to provide novel compounds that are serotonin (5-HT), dopamine (DA) and norepinephrine (NE) reuptake inhibitors.

［式中、
Ｒ₁は、水素またはＣ_1-4アルキルであり；
Ｒ₂は、基ＡまたはＷであり（ここで、
Ａは、

であり（ここで、ｐは、０、１、２、３、４または５であり、Ｒ₄は、ハロゲンである）；
Ｗは、水素、シアノおよびＣ_1-4アルキルからなる群から各々独立して選択される１〜７個の基Ｒ₆によって置換されていてもよいαまたはβナフチル基である）；
Ｒ₃は、基Ｐ：

である（ここで、Ｒ₅は、水素、Ｃ_1-4アルキル、ハロＣ_1-4アルキル、Ｃ_3-6シクロアルキルおよびＣ_3-6シクロアルキルＣ_1-3アルキルからなる群から選択され、ｎは、１または２である）］
で示される式（Ｉ）で示される化合物またはその医薬上許容される塩もしくは溶媒和物を提供する。 The present invention relates to a compound of formula (I):

[Where:
R ₁ is hydrogen or C _1-4 alkyl;
R ₂ is a group A or W (wherein
A is

Where p is 0, 1, 2, 3, ₄ or 5 and R ₄ is halogen;
W is an α or β naphthyl group optionally substituted by 1 to 7 groups R ₆ each independently selected from the group consisting of hydrogen, cyano and C _1-4 alkyl);
R ₃ is a group P:

Wherein R ₅ is selected from the group consisting of hydrogen, C _1-4 alkyl, halo C _1-4 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl C _1-3 alkyl; n is 1 or 2)]
Or a pharmaceutically acceptable salt or solvate thereof.

In the formula (I), “ ^* ” indicates a bonding site.

The term “C _1-4 alkyl” refers to any isomeric alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Say. The term “C _1-3 alkyl” refers to all isomeric alkyl groups having 1 to 3 carbon atoms, ie, methyl, ethyl, propyl and isopropyl.

The term “C _3-6 cycloalkyl” as used herein refers to a non-aromatic monocyclic hydrocarbon ring of 3 to 6 carbon atoms, which may be saturated or unsaturated. To do. Examples of saturated cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; while unsaturated cycloalkyl includes cyclopentenyl, cyclohexenyl and the like.

The term “C _3-6 cycloalkyl C _1-3 alkyl” as used herein refers to the replacement of one hydrogen atom with a C _3-6 cycloalkyl group as defined above, such as methylcyclopropane. Means alkyl having 1 to 3 carbon atoms.

The term “C _1-4 alkoxy” is a straight or branched chain having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. An alkoxy (or “alkyloxy”) group.

The term “haloC _1-4 alkyl” as used herein refers to a carbon in which at least one hydrogen atom is replaced with a halogen (preferably fluorine), such as a trifluoromethyl group and the like. An alkyl group having one or more atoms is meant.

  The term “halogen” and its abbreviation “halo” refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). When the term “halo” is used before another group, it indicates that the group is substituted by one or more halogen atoms.

In one embodiment, R ₁ is hydrogen.

In one embodiment, R ₁ is C _1-4 alkyl.

である（ここで、ｐは、０、１、２、３、４または５であり、Ｒ₄は、ハロゲンである）。 In one embodiment, R ₂ is

Where p is 0, 1, 2, 3, ₄ or 5 and R ₄ is halogen.

In one embodiment, R ₂ is phenyl substituted by 1, 2 or 3 halogens.

In one embodiment, R ₂ is phenyl substituted by two halogens.

In one embodiment, R ₂ is dichlorophenyl. In one embodiment, R ₂ is 3,4-dichlorophenyl.

In one embodiment, R ₂ is an α or β naphthyl group optionally substituted by 1 to 7 groups R ₁₅ each independently selected from the group consisting of hydrogen, cyano and C _1-4 alkyl. It is.

であり、ｎは１である。 In one embodiment, R ₃ is a group:

And n is 1.

  In one embodiment, n is 2.

In one embodiment, R ₅ is selected from the group consisting of C _1-4 alkyl, halo C _1-4 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl C _1-3 alkyl.

In one embodiment, R ₅ is C _1-4 alkyl.

In one embodiment, R ₅ is methyl or ethyl.

  It will be appreciated that compounds of formula (I) have at least three chiral centers, i.e. chiral centers at the 1-, 6- and 7-positions of the 3-azabicyclo [4.1.0] heptane part of the molecule. Have. The absolute configuration of the stereocenter at each corner of the fused cyclopropyl ring can be given using the Khan-Ingold-Prelog nomenclature based on group priority.

  Of course, as with most biologically active molecules, the level of biological activity can vary between the individual stereoisomers of a given molecule. The scope of the present invention includes all individual stereoisomers (diastereoisomers and enantiomers) and mixtures thereof that exhibit appropriate biological activity with reference to the methods described herein (including racemic mixtures). But is not limited to this).

  Due to the presence of the fused cyclopropane ring, the compounds of formula (I) are considered to be in the “cis” configuration of substituents (both two hydrogens attached to the bicyclic ring system are both bicyclic rings). On the same side of the system).

［式中、Ｒ₁、Ｒ₂およびＲ₃は、式（Ｉ）で示される化合物について上記で定義したとおりである］
で示される化合物が提供される。 In one embodiment of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, solvate thereof having a “cis” configuration represented by a thick line of two bonds near the cyclopropyl moiety Or the formula (I ′) corresponding to a prodrug:

[Wherein R ₁ , R ₂ and R ₃ are as defined above for the compound of formula (I)]
Is provided.

  In the following, the symbol “′” (prime code) is used to indicate compounds having a “cis” configuration represented by a thick line of two bonds near the cyclopropyl moiety, these compounds being a mixture of stereoisomers. (Including but not limited to racemic mixtures).

As will be appreciated by those skilled in the art, the compounds of formula (I ′) may have exo or endo relative stereochemistry resulting from the relative arrangement in space of the two hydrogen atoms in the R ₂ and cis configurations. it can.

The structure below shows the exo / endo relative stereochemistry for compounds of formula endo- (I ′) and exo- (I ′):

The boldface bond in the compound of formula exo- (I ′) indicates that the group R ₂ and the two hydrogen atoms in the cis configuration are coplanar with the cyclopropane ring.

The boldface of the bond in the compound of formula endo- (I ′) indicates that the group R ₃ and the two hydrogen atoms in the cis configuration are coplanar with the cyclopropane ring.

The compound of formula (I ′) is present in the diastereoisomers of formula (IA) and (IB), ie enantiomers at the 1- and 6-positions of the bicyclic ring, as shown below Those skilled in the art will understand that this can be done:

As will be understood by those skilled in the art, the compound represented by the formula (I ′) has at least four compounds represented by the formulas (IC), (ID), (IE) and (IF) as shown below. Can exist in stereoisomers:

  It will be appreciated by those skilled in the art that the stereoisomers of formula (IC) and (ID) represent a single enantiomer of the compound of formula exo- (I ′).

  It will be understood by those skilled in the art that the stereoisomers of formula (IE) and (IF) represent the enantiomers of the compound of formula endo- (I ′).

  All the features and embodiments of the compounds of formula (I) are modified where necessary to change to formulas (I ′), (IA), (IB), (IC), (ID), (IE ) And (IF).

  The term “salt” as used herein refers to any salt, quaternary ammonium salt, and internally formed salt of a compound of the invention prepared from an inorganic or organic acid or base, and is pharmaceutically acceptable. Salt. Pharmaceutically acceptable salts are particularly suitable for pharmaceutical use because they are more water soluble than the parent compound. Such salts must clearly have a physiologically acceptable anion or cation.

  Some of the compounds of the present invention may form acid addition salts or base addition salts with up to 1 equivalent or more acids or bases. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

  Pharmaceutically acceptable salts can also be prepared from other salts, including other pharmaceutically acceptable salts, of the compounds of formula (I) using conventional methods.

  Preferably, pharmaceutically acceptable salts of the compounds of the present invention include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and tartaric acid, acetic acid, Trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, naphthoic acid, formic acid, propionic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, camphorsulfonic acid, isothionic acid, mucinic acid, gentisic acid , Isonicotinic acid, sugar acid, glucuronic acid, furoic acid, glutamic acid, ascorbic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid (pamonic acid), methanesulfonic acid, ethanesulfonic acid, pantothenic acid, stearic acid Sulfinic acid, arginic acid, galacturonic acid and aryl sulfonic acids such as benzenesulfuric acid Acid addition salts formed with acids and organic acids such as p-toluenesulfonic acid; alkali and alkaline earth metals and N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine Base addition salts formed with organic bases such as (N-methylglucamine), lysine and procaine; and internally formed salts. Salts having a pharmaceutically unacceptable anion or cation may be used as useful intermediates for the preparation of pharmaceutically acceptable salts and / or for use in non-therapeutic situations (eg, in vitro). Within the scope of the invention.

  It will be appreciated by those skilled in the art of organic chemistry that many organic compounds can form complexes with solvents that react with them or precipitate or crystallize them. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates of the compounds of the invention are within the scope of the invention. Compounds of formula (I) can be readily isolated with solvent molecules by crystallization or evaporation of a suitable solvent to give the corresponding solvate.

  Prodrugs are also included within the scope of the present invention. The term “prodrug” as used herein refers to a compound that is converted within the body, eg, by hydrolysis in blood, into an active form having a pharmaceutical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19 (2) 115-130. ing.

  Prodrugs are generally prepared by modifying functional groups in such a way that the modifier is cleaved by routine manipulation or in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention in which a hydroxy group, an amine group, or a sulfhydryl group is coupled to a group that is cleaved to form a hydroxy group, an amine group, or a sulfhydryl group when administered to a patient. Thus, representative examples of prodrugs include (but are not limited to) alcohol, sulfhydryl and amine functional acetate, formate and benzoate derivatives of compounds of structure (I). . In the case of carboxylic acid (—COOH), esters such as methyl ester and ethyl ester can be used. Esters can themselves be active and / or can be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those that readily decompose in the human body leaving the parent acid or salt thereof.

  Hereinafter, the compounds represented by the formula (I) as defined in the embodiments of the present invention and pharmaceutically acceptable salts, solvates and prodrugs thereof (excluding intermediate compounds in chemical processes) are referred to as “the present invention. Referred to as "compound".

  Furthermore, some of the crystalline forms of the compounds of the present invention may exist as polymorphs and are encompassed by the present invention.

  As will be appreciated by those skilled in the art, it may be necessary and / or desirable to protect one or more sensitive groups in a molecule to prevent undesired side reactions in the preparation of the compounds of the invention. . Suitable protecting groups for use in the present invention are well known to those skilled in the art and can be used in a conventional manner. See, for example, “Protective groups in organic synthesis” by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or “Protecting Groups” by P.J. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl-type protecting groups (eg formyl, trifluoroacetyl, acetyl), aromatic urethane-type protecting groups (eg benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane-type Protecting groups (eg 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl protecting groups (eg benzyl, trityl, chlorotrityl). It is done. Examples of suitable oxygen protecting groups include, for example, alkylsilyl groups such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.

The present invention is directed to formula (I) and subsequents, except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Also included are isotopically labeled compounds identical to those described in the formula. Examples of isotopes that may be incorporated into the compounds of the invention and their pharmaceutically acceptable salts include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine isotopes, for example ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I.

Compounds of the present invention and pharmaceutically unacceptable salts thereof containing the above isotopes and / or other isotopes of other atoms are within the scope of the present invention. Isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H, ¹⁴ C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritium isotopes (ie, ³ H) and carbon-14 isotopes (ie, ¹⁴ C) are particularly preferred for their ease of manufacture and detectability. ^{The 11} C and ¹⁸ F isotopes are particularly useful for PET (positron emission tomography), and the ¹²⁵ I isotope is particularly useful for SPECT (single photon emission computed tomography). Useful for diagnosis. Furthermore, substitution with heavier isotopes such as deuterium (ie ² H) may result in certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Can be preferred in some circumstances. The isotope-labeled compounds of the present invention and pharmaceutically unacceptable salts thereof are generally incorporated into the following schemes and / or examples by using readily available isotope-labeled reagents in place of unisotopically labeled reagents. It can be produced by performing the described method.

In one embodiment, the compounds of the invention are:
(1S, 6R, 7R) -7- (3,4-dichlorophenyl) -7-[(methyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(methyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1S, 6R, 7R) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1S, 6R, 7S) -7- (3,4-dichlorophenyl) -7- [2- (methyloxy) ethyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7R) -7- (3,4-dichlorophenyl) -7- [2- (methyloxy) ethyl] -3-azabicyclo [4.1.0] heptane,
(1S, 6R, 7S) -7- (3,4-dichlorophenyl) -7- [2- (ethyloxy) ethyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7R) -7- (3,4-Dichlorophenyl) -7- [2- (ethyloxy) ethyl] -3-azabicyclo [4.1.0] heptane and pharmaceutically acceptable salts thereof , Solvates and prodrugs.

In one embodiment, the compounds of the invention are:
(1S, 6R, 7R) -7- (3,4-dichlorophenyl) -7-[(methyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(methyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1S, 6R, 7R) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1S, 6R, 7S) -7- (3,4-dichlorophenyl) -7- [2- (methyloxy) ethyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7R) -7- (3,4-dichlorophenyl) -7- [2- (methyloxy) ethyl] -3-azabicyclo [4.1.0] heptane,
(1S, 6R, 7S) -7- (3,4-dichlorophenyl) -7- [2- (ethyloxy) ethyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7R) -7- (3,4-Dichlorophenyl) -7- [2- (ethyloxy) ethyl] -3-azabicyclo [4.1.0] heptane, and solvates and prodrugs thereof Selected from the group consisting of

  The present invention also provides a process for producing the compounds of the present invention. The compound of this invention can be manufactured according to the following synthetic schemes.

A compound of formula (Ia), ie a compound of formula (I) in which R ₁ is an alkyl group, is prepared according to Scheme 1 in a suitable aldehyde or ketone at room temperature in a protic solvent (eg methanol). And a compound of formula (Ib) by standard reductive amination using a reducing agent such as sodium triacetoxyborohydride, ie R ₁ is hydrogen and R ₃ is a group X Yes, it can be obtained by reacting a compound of formula (I) wherein n is 1.

  A compound of formula (Ib) as defined above is a compound of formula (Ib) according to Scheme 2, ie a compound of formula (Ib) wherein Pg is a suitable N protecting group (typically BOC) Can be obtained by deprotection of the N—Pg group (for example, in the case of BOC, using TFA in DCM at 0 ° C. to room temperature).

A compound of formula (Ic) is prepared from a compound of formula (Id) according to Scheme 3 by standard alkylation methods, eg in an aprotic solvent (eg DMF) at 0 ° C. to room temperature. R ₅ X alkylating agent (where X is a leaving group such as a halogen atom and R ₅ is as defined for formula (I) in the presence of a strong base (eg NaH). ) Can be used.

The compound of formula (Id) can be obtained from the compound of formula (II) according to scheme 4 by reduction with a reducing agent such as NaBH ₄ in MeOH at 0 ° C. to room temperature.

  The compound of formula (II) can be obtained from the compound of formula (III) according to scheme 5 by reduction of the nitrile group with a reducing agent such as DIBAL in toluene at 0 ° C. to 45 ° C.

  The compound of formula (III) is prepared from the compound of formula (IV) according to scheme 6 in formula (V) in an aprotic solvent such as DME in the presence of a strong base such as NaH. It can be obtained by reaction with the compounds shown.

  A compound of formula (IV) is prepared according to scheme 7 from a compound of formula (VI) with a thionyl chloride in the presence of a base (eg triethylamine) in DCM and then the intermediate thus obtained. It can be obtained by oxidation of the body with sodium periodate and ruthenium (III) chloride hydrate.

  The compound represented by the formula (VI) is converted from the compound represented by the formula (VII) according to Scheme 8 into an osmium tetroxide-catalyzed dihydroxylation reaction in a THF / tert-butanol / water mixed solution in the presence of NMO. Can be obtained.

A compound of formula (Ie), which is a compound of formula (I) in which R ₁ is hydrogen, R ₃ is a group X and n is 2, is represented by formula (If) according to scheme 9. From the compound of formula (Ie) where Pg is a suitable N-protecting group (typically BOC) by deprotection of the N-Pg group (eg in the case of BOC, 0 ° C. ~ With TFA in DCM at room temperature).

A compound of formula (If) as defined above is obtained from a compound of formula (Ig) according to scheme 10 by standard alkylation methods, for example at 0 ° C. to room temperature, for example an aprotic solvent (eg R ₅ X alkylating agent (wherein X is a leaving group such as a halogen atom and R ₅ is defined for formula (I) in the presence of a strong base (eg NaH) in As described above).

  The compound of formula (Ig) is obtained from the compound of formula (VIII) according to scheme 11 from 0 ° C. to room temperature with a borane-THF complex in THF at 0 ° C. to room temperature followed by peroxidation at 0 ° C. It can be obtained by oxidation with hydrogen and 3.0 M NaOH.

  The compound of formula (VIII) is obtained from the compound of formula (IX) according to scheme 12 by Wittig reaction using methylenetriphenylphosphorane (triphenylphosphine methylidene) in THF at room temperature. Can do.

  Certain enantiomers or diastereoisomers of the compounds of the invention can be obtained from the corresponding enantiomeric or diastereoisomeric mixture using, for example, chiral chromatographic methods such as chiral HPLC. Alternatively, a particular enantiomer or diastereoisomer of the compound can be obtained from the corresponding enantiomeric or diastereoisomer mixture using chiral crystallization techniques such as precipitation with a chiral acid. Also, specific enantiomers or diastereoisomers of the compounds of the present invention can be synthesized from the appropriate optically active intermediate using any of the general methods described herein. Alternatively, a particular enantiomer or diastereoisomer of a compound of the invention can be obtained using any of the general methods described herein, in combination with any of the conventional resolution methods described above, It can be synthesized from a suitable stereochemically rich intermediate.

  Optically active intermediates or stereochemically enriched intermediates can be obtained by resolution of the corresponding enantiomeric or diastereoisomeric mixture using conventional methods, or in combination with the implementation of stereoselective reactions or different resolution techniques. Can be obtained. Moreover, the specific enantiomer or diastereoisomer of the compound can be obtained by using the above-mentioned conventional methods in combination.

  The compounds of the present invention are useful in the treatment of disorders or diseases that respond to the monoamine neurotransmitter reuptake inhibitory activity of the compounds. Because of this activity, the compounds of the present invention have parkinsonism, depression, eating disorders, sleep disorders, substance-related disorders, attention deficit / hyperactivity disorder, anxiety disorders, cognitive disorders, sexual dysfunction, obsession spectrum It is useful for the treatment of disorders, Gilles de la Tourette syndrome and senile dementia, and other disorders sensitive to the monoamine neurotransmitter reuptake inhibitory activity of the compounds.

  Within the context of the present invention, the terms describing the indications used herein are Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and / or International. It is classified in Classification of Diseases, 10th Edition (ICD-10). The various subtypes of disorders described herein are intended to be part of the present invention. The numbers in parentheses after the diseases listed below are the classification numbers in DSM-IV.

The term “depression” includes the following:
Depression and mood disorders (including major depression episodes, manic episodes, mixed episodes and hypomania episodes); Depressive disorders (major depression disorder, mood modulation disorder (300.4), unspecified depression) Other mood disorders (including subtypes with depressive features, subtypes with major depression-like episodes, subtypes with manic features and mixed features) Mood disorders due to general physical disease including subtypes (including 293.83); substance-induced mood disorders (subtypes with depressive features, subtypes with manic features and mixed features As well as unspecified mood disorders (296.90):
Bipolar disorder (bipolar I disorder, bipolar II disorder (ie, recurrent major depression episode with hypomania) (296.89), mood circulatory disorder (301.13) and unspecified bipolar disorder (296.80).

The term “anxiety disorder” includes the following:
Anxiety disorders (including panic attacks); panic disorders (including panic disorder without square fear (300.01) and panic disorder with square fear (300.21)); agoraphobia; no history of panic disorder Agoraphobia (300.22), specific phobias (300.29, formerly single fear) (including animal types, natural environment types, blood / injection / trauma types, situational types and other types of subtypes) Social phobia (social anxiety disorder, 300.23), obsessive compulsive disorder (300.3), post-traumatic stress disorder (309.81), acute stress disorder (308.3), generalized anxiety disorder (300. 02), anxiety disorder due to general physical disease (293.84), substance-induced anxiety disorder, separation anxiety disorder (309.21), adaptation disorder with anxiety (309.24) and unspecified anxiety disorder (300 .00).

The term “substance-related disorder” includes the following:
Substance-related disorders (including substance use disorders such as substance dependence, substance craving and substance abuse); substance-induced disorders (eg substance poisoning, substance withdrawal, substance-induced delirium, substance-induced persistent dementia, substance induction) Persistent amnesia disorder, substance-induced psychotic disorder, substance-induced mood disorder, substance-induced anxiety disorder, substance-induced dysfunction, substance-induced sleep disorder, and hallucinogen persistent perception disorder (flashback) Alcohol-related disorders (eg alcohol dependence (303.90), alcohol abuse (305.00), alcoholism (303.00), alcohol withdrawal (291.81), alcoholism delirium, alcohol withdrawal delirium, alcohol-induced Persistent dementia, alcohol-induced persistent amnestic disorder, alcohol-induced psychotic disorder, alcohol-induced mood disorder, alcohol -Induced anxiety disorders, alcohol-induced dysfunction, alcohol-induced sleep disorders and unspecified alcohol-related disorders (291.9)); amphetamine (or amphetamine-like) -related disorders (eg, amphetamine dependence (304.40) , Amphetamine abuse (305.70), amphetamine addiction (292.89), amphetamine withdrawal (292.0), amphetamine addiction delirium, amphetamine-induced psychotic disorder, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced Sexual dysfunction, amphetamine-induced sleep disorder and unspecified amphetamine-related disorder (292.9)); caffeine-related disorders (eg caffeine addiction (305.90), caffeine-induced anxiety disorder, caffeine-induced Sexual sleep disorder and special Uncertain Caffeine Related Disorders (292.9)); Cannabis Related Disorders (eg Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Addiction (292.89), Cannabis Addiction Delirium, Cannabis Induction Psychotic disorders, cannabis-induced anxiety disorders and unspecified cannabis-related disorders (292.9)); cocaine-related disorders (eg, cocaine dependence (304.20), cocaine abuse (305.60), cocaine addiction (292) .89), cocaine withdrawal (292.0), cocaine addiction delirium, cocaine-induced psychotic disorder, cocaine-induced mood disorder, cocaine-induced anxiety disorder, cocaine-induced dysfunction, cocaine-induced sleep disorder and unspecified Cocaine-related disorders (292.9)); hallucinogen-related disorders (eg, hallucinogen dependence (304.50), hallucinogen abuse (305.30), hallucinogen addiction (29 .89), hallucinogen persistent sensory impairment (flashback) (292.89), hallucinogen poisoning delirium, hallucinogen-induced psychotic disorder, hallucinogen-induced mood disorder, hallucinogen-induced anxiety disorder and unspecified Hallucinogen-related disorders (292.9)); inhalant-related disorders (eg, inhalant dependence (304.60), inhalant abuse (305.90), inhalant poisoning (292.89), Inhalant-induced persistent dementia, inhalant-induced psychotic disorder, inhalant-induced mood disorder, inhalant-induced anxiety disorder and unspecified inhalant-related disorder (292.9)); disorders related to nicotine (Eg, nicotine dependence (305.1), nicotine withdrawal (292.0) and unspecified nicotine related disorders (292.9)); opioid related disorders (eg, opioid dependence (304.00), opioid abuse) (305.50), opioid addiction (292.89), opioid withdrawal (292.0), opioid addiction delirium, opioid-induced psychotic disorder, opioid-induced mood disorder, opioid-induced dysfunction, opioid-induced sleep Disorders and unspecified opioid-related disorders (292.9)); phencyclidine (or phencyclidine-like) -related disorders (eg, phencyclidine-dependent (304.60), phencyclidine abuse (305.90), Phencyclidine addiction (292.89), phencyclidine addiction delirium, phencyclidine-induced psychotic disorder, phencyclidine-induced mood disorder, phencyclidine-induced anxiety disorder and unspecified phencyclidine-related disorder ( 292.9)); sedatives, hypnotics or anxiolytic-related disorders (eg sedatives, Hypnotic or anxiolytic dependence (304.10), sedative, hypnotic or anxiolytic abuse (305.40), sedative, hypnotic or anxiolytic addiction (292.89), sedative, hypnotic Or anxiolytic withdrawal (292.0), sedative, hypnotic or anxiolytic addiction delirium, sedative, hypnotic or anxiolytic withdrawal delirium, sedative, hypnotic or anxiolytic persistent dementia, sedation , Sedative, hypnotic or anti-anxiety drug persistent amnestic disorder, sedative, hypnotic or anxiolytic-induced psychotic disorder, sedative, hypnotic or anxiolytic-induced mood disorder, sedative, hypnotic or anti Anxiety-induced anxiety disorder, sedative, hypnotic or anxiolytic-induced dysfunction, sedative, hypnotic or anxiolytic-induced sleep disorder and unspecified sedative, hypnotic or anxiolytic-related disorder (292.9)); multi-substance related disorders (eg Multi substance dependence (304.80)); and the other (or unknown) substance-related disorders (e.g., anabolic steroids, nitrate inhalants and nitrous oxide).

The term “sleep disorder” includes the following:
Primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory-related sleep disorder (780.59), circadian rhythm sleep disorder (307.45) and unspecified Sleep disorders including primary sleep disorders such as sleep disorders such as sleep disorders (307.47); nightmare disorders (307.47), sleep startle disorders (307.46), sleepwalking (307.46) And primary sleep disorders such as unaccompanied sleep disorders (307.47); other sleep disorders associated with other mental disorders (307.42) and other mental disorders Sleep disorders associated with other mental disorders such as hypersomnia (307.44); sleep disorders due to general health; and substance-induced sleep disorders (subtypes of insomnia, hypersomnia, Including sleep-related and mixed types).

The term “eating disorder” includes the following:
Eating disorders such as anorexia nervosa (307.1) (including subtypes of restriction and gluttony / excretion); bulimia nervosa (307.51) (exclusion of subtypes) Obesity; obsessive compulsive eating disorder; whip eating disorder; and unspecified eating disorder (307.50).

The term “attention deficit / hyperactivity disorder” encompasses the following:
Attention Deficit / Hyperactivity Disorder (Subtype Attention Deficit / Hyperactivity Disorder Mixed Type (314.01), Attention Deficit / Hyperactivity Disorder Inattention Predominant Type (314.00), Attention Deficit / Multiple Hyperactivity-including impulsive type (314.01) and unspecified attention deficit / hyperactivity disorder (314.9)); hyperactivity disorder; schizophrenic behavior disorder, eg behavior disorder (Including subtypes childhood-onset (321.81), adolescent-onset (312.82) and nonspecific onset (312.89)), rebellious disorder (313.81) and unspecified As well as tic disorders such as Tourette's disorder (307.23).

The term “cognitive impairment” includes the following:
Cognitive impairment in schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, eg other diseases such as Alzheimer's disease.

The term “sexual dysfunction” includes the following:
Sexual dysfunction (including sexual desire disorders such as hyposexual desire disorder (302.71) and sexual aversion disorder (302.79)); sexual arousal disorders (eg, female sexual arousal disorders) (302.72) and male erectile dysfunction (302.72)); orgasm disorders (eg, female orgasm disorder (302.73), male orgasm disorder (302.74) and premature ejaculation (302.75)); Disorders (eg, sexual pain (302.76) and vaginal spasms (306.51)); unspecified sexual dysfunction (302.70); sexual preference disorders (eg, exposure (302.4), fetishism ( 302.81), stealth (302.89), pedophilia (302.2), sexual masochism (302.83), sexual sadism (302.84), transsexual fetishism (302.3), Voyeurism (30 .82) and unspecified sexual preference disorders (302.9)); gender identity disorders (eg, childhood gender identity disorder (302.6) and adolescent or adult gender identity disorder (302.85)) ); As well as unspecified sexual disorders (302.9).

The term “compulsive spectrum disorder” includes the following:
Obsessive-compulsive disorder (300.3), somatic expression disorder (including body deformity disorder (300.7) and psychosis (300.7)), bulimia (307.51), anorexia nervosa ( 307.1), Eating Disorders not otherwise classified (307.50) (eg Distraction Eating), Impulse Control Disorders not classified elsewhere (Intermittent Explosive Disorder (312.34), Impulse Buying, Repetitive Self-Injury Nail bites, psychogenic epidermal exfoliation, stealing (312.32), pathological gambling (312.31), hair removal pupae (312.39) and Internet addiction), sexual perversion (302.70) and Obsessive compulsion spectrum including nonsexual perversion sex addiction, Sydenham chorea, torticollis, autistic disorder (299.0), compulsive stockpile, and movement disorders (including Tourette syndrome (307.23)) Failure.

  The various forms and sub-forms of the disorders described herein are all intended to be part of the present invention.

  In embodiments, the compounds of the invention may be useful as analgesics. For example, the compounds of the present invention provide chronic inflammatory pain (eg, pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, ventilatory arthritis and juvenile arthritis); musculoskeletal pain; lumbar neck pain; Neuropathic pain; sympathetic-dependent pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections (eg, cold); rheumatism Pain associated with fever; bowel dysfunction (eg, non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome); pain associated with myocardial ischemia; postoperative pain; headache; toothache; and dysmenorrhea Can be useful.

  The compounds of the present invention may be particularly useful for the treatment of neuropathic pain. Neuropathic pain syndrome can occur after nerve injury, and the resulting pain can persist for months or years, even after healing of the underlying injury. Nerve damage can occur in peripheral nerves, dorsal roots, spinal cord, or certain areas of the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that induced them. Neuropathic pain syndromes include diabetic neuropathy; sciatica; nonspecific low back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; postherpetic neuralgia; trigeminal neuralgia; and physical trauma, amputation Pain caused by cancer, toxins or chronic inflammatory conditions. Although these conditions are difficult to treat and some drugs are known to have limited efficacy, complete pain management is hardly achieved. The symptoms of neuropathic pain are very heterogeneous and are often referred to as sudden and severe pain, or ongoing burning pain. In addition, pain associated with normally painless sensations (sensory and abnormal sensations) such as “pins and needles”, increased sensitivity to touch (hypersensitivity), after non-noxious stimuli Sensation of pain (dynamic allodynia, static allodynia or thermal allodynia), increased sensitivity to noxious stimuli (thermal hyperalgesia, cold hyperalgesia, mechanical hyperalgesia), stimulus removal There is a subsequent sensation of pain (hyperalgesia), or lack or disappearance of a selective sensory pathway (hyperalgesia).

  The compounds of the present invention also provide remission of inflammatory disorders, such as skin conditions (eg, sunburn, burns, eczema, dermatitis, psoriasis); eye diseases such as glaucoma, retinitis, retinopathy, uveitis and ocular tissue. Acute injury (eg conjunctivitis); lung disorders (eg asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon enthusiast disease, farmer lung, chronic obstructive pulmonary disease (COPD)); gastrointestinal tract Disorders (eg, aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, celiac disease, localized ileitis, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal reflux disease) May be useful in the treatment of other conditions with inflammatory components such as migraine, multiple sclerosis, myocardial ischemia.

  In one embodiment, the compounds of the invention are useful for the treatment of depression and anxiety disorders.

  In another embodiment, the compounds of the invention are useful for the treatment of depression.

  “Treatment” includes prophylaxis where prophylaxis is appropriate for the relevant condition.

  In one aspect, the present invention provides a compound of the invention for use in therapy.

  The present invention also provides a compound of the invention for use in the treatment of a disorder or disease that is responsive to the monoamine neurotransmitter reuptake inhibitory activity of the compound.

  The invention also provides a compound of the invention for use in the treatment of conditions where inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) is effective.

  The present invention also provides a compound of the present invention for use in the treatment of depression or mood disorders.

  The present invention is also a method of treating a disorder or disease responsive to monoamine neurotransmitter reuptake inhibitory activity, wherein an effective amount of a compound of the present invention is administered to a mammal (eg, human) in need of such treatment. A method comprising:

  The present invention is also a method of treating a condition in which inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) is effective and is provided to a mammal (eg, human) in need of such treatment. There is provided a method comprising administering an effective amount of a compound of the invention.

  The present invention also provides a method of treating depression or mood disorders comprising administering to a mammal (eg, human) in need of such treatment an effective amount of a compound of the present invention.

  The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a disorder or disease that is responsive to the monoamine neurotransmitter reuptake inhibitory activity of the compound.

  The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a condition in a mammal in which inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) is effective.

  The present invention also provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of depression or mood disorders.

  The compounds of the present invention can also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of the invention together with a further therapeutic agent.

  The compounds of the present invention can be used in combination with the following agents to treat or prevent psychotic disorders: i) schizophrenia therapeutic agents; ii) drugs for extrapyramidal side effects, such as anticholine Agonists (eg benztropine, piperidene, procyclidine and trihexyphenidyl), antihistamines (eg diphenhydramine) and dopamine agonists (eg amantadine); iii) antidepressants; iv) anxiolytics; and v ) Nootropics such as cholinesterase inhibitors (eg tacrine, donepecil, rivastigmine and galantamine).

  The compounds of the present invention can be used in combination with antidepressants to treat or prevent depression and mood disorders.

  The compounds of the invention can be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilizers; ii) schizophrenia therapeutics; and iii) antidepressants.

  The compounds of the invention can be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.

  The compounds of the invention can be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy, eg, nicotine-β-cyclodextrin sublingual and nicotine patch; And ii) bupropion.

  The compounds of the present invention can be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists such as acamprosate; ii) GABA receptor agonists E.g., tetrabamate; and iii) opioid receptor antagonists such as naltrexone.

  The compounds of the present invention can be used in combination with the following agents to improve opiate withdrawal and reduce opiate cravings: i) opioid mu receptor agonist / opioid k receptor antagonists such as buprenorphine; ii ) Opioid receptor antagonists such as naltrexone; and iii) vasodilatory antihypertensive agents such as lofexidine.

  The compounds of the present invention can be used in combination with the following agents to treat or prevent sleep disorders: i) benzodiazepine drugs such as temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine sleep drugs such as Zolvidem, zopiclone, zaleplon and indiplon; iii) barbituric acid drugs such as aprobarbital, butabarbital, pentobarbital, secobarbital and phenobarbital; iv) antidepressants; v) other sedative-hypnotics, For example, chloral hydrate and chlormethiazole.

  The compounds of the present invention can be used in combination with the following agents to treat anorexia: i) appetite stimulants such as cyproheptidine; ii) antidepressants; iii) schizophrenia treatment; iv) zinc; and v) premenstrual drugs such as pyridoxine and progesterone.

  The compounds of the invention can be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics such as ondansetron; iv) testosterone receptor antagonists such as flutamide; v) mood stabilizers; vi) zinc; and vii) premenstrual drugs.

  The compounds of the present invention can be used in combination with the following drugs to treat or prevent autism: i) schizophrenia drugs; ii) antidepressants; iii) anxiolytics Drugs; and iv) stimulants such as methylphenidate, amphetamine and pemoline.

  The compounds of the invention can be used in combination with the following agents to treat or prevent ADHD: i) stimulants such as methylphenidate, amphetamine and pemoline; and ii) non-stimulants such as Norepinephrine reuptake inhibitors (eg, tomoxetine), α2 adrenergic receptor agonists (eg, clonidine), antidepressants, modafinil, and cholinesterase inhibitors (eg, galantamine and donepezil).

  The compounds of the present invention can be used in combination with the following agents to treat personality disorders: i) schizophrenia therapeutic agents; ii) antidepressants; iii) mood stabilizers; and iv) anxiolytics.

  The compounds of the invention can be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors such as vardenafil and sildenafil; ii) dopamine agonist / dopamine transport inhibition Agents such as apomorphine and buproprion; iii) alpha adrenergic receptor antagonists such as phentolamine; iv) prostaglandin agonists such as alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibition Agents such as serotonin reuptake inhibitors; v) noradrenaline transport inhibitors such as reboxetine; and vii) 5-HT1A agonists such as flibanserin.

  The compounds of the present invention can be used in combination with drugs and estrogen agonists (eg, estradiol) specifically listed for male sexual dysfunction to treat or prevent female sexual dysfunction.

  Schizophrenia treatments include typical schizophrenia treatments (eg, chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoroperazine, thiothixene, haloperidol, molindone and loxapine); and atypical Schizophrenia therapeutics (eg, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone and amisulpride).

  Antidepressants include serotonin reuptake inhibitors (eg, citalopram, ecitalopram, fluoxetine, paroxetine, and sertraline); serotonin / noradrenaline double reuptake inhibitors (eg, venlafaxine, duloxetine, and milnacipran); Reuptake inhibitors (eg reboxetine); tricyclic antidepressants (eg amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (eg isocarboxazide, moclobemide, phenelzine and trani) Lucipromin); and other antidepressants (eg, bupropion, mianserin, mirtazapine, nefazodone and trazodone).

  Mood stabilizers include lithium, sodium valproate / valproic acid / divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.

  Anti-anxiety agents include benzodiazepines such as alprazolam and lorazepam.

  For use in medicine, the compounds of the present invention are usually administered as a pharmaceutical composition. The invention thus provides, in a further aspect, a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be used for the treatment of any of the symptoms described herein.

  In one embodiment, a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier is provided.

  The compounds of the present invention may be administered by any conventional method, for example, oral, parenteral (eg, intravenous), buccal, sublingual, nasal, rectal or transdermal administration. Therefore, the pharmaceutical composition is suitable.

  The compounds of the invention which are active when administered orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

  Liquid formulations generally consist of a suspension or solution of the compound or salt in a suitable liquid carrier (eg, an aqueous solvent such as water, ethanol or glycerin, or a non-aqueous solvent such as polyethylene glycol or oil). The formulation may also contain a suspending agent, preservative, flavoring or coloring agent.

  A tablet dosage composition may be prepared using any suitable pharmaceutical carrier routinely used to prepare solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

  Capsule dosage form compositions can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsules; alternatively, suitable pharmaceutical carriers (eg, aqueous gums, celluloses, silicates or oils) ) Can be used to prepare a dispersion or suspension, which can then be filled into soft gelatin capsules.

  A typical parenteral composition consists of a solution or suspension of the compound or salt in a sterile aqueous carrier or parenterally acceptable oil (eg, polyethylene glycol, polyvinyl pyrrolidone, lecithin, peanut oil or sesame oil). . Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.

  Nasal compositions can be conveniently formulated as aerosols, drops, gels and powders. Aerosols typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent and can usually take the form of a cartridge or refill for use with a spray device. Provided in single or multiple doses in sterile form in a sealed container. Alternatively, the sealed container can be a single dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve that is scheduled to be discarded once the contents of the container are used up. . Where the dosage form comprises an aerosol dispenser, it contains a propellant which can be a compressed gas such as compressed air or an organic propellant (eg, fluorochlorohydrocarbon). The aerosol dosage form can also take the form of a pump nebulizer.

  Compositions suitable for buccal or sublingual administration include tablets, lozenges and lozenges where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth or gelatin and glycerin. It becomes.

  The composition for rectal administration is conveniently in the form of a suppository containing a conventional suppository base such as cocoa butter.

  Compositions suitable for transdermal administration include ointments, gels and patches.

  In one embodiment, the composition is in a single dosage form such as a tablet, capsule or ampoule.

  Each dosage unit for oral administration contains 0.5 to 250 mg of the compound of the present invention calculated as the free base (for parenteral administration, for example, 0.05 to 25 mg).

  Suitably the compound is administered for a period of continuous therapy, for example for a week or more.

  When the compound of the present invention or a pharmaceutically acceptable derivative thereof is used in combination with another therapeutic agent active against the same pathology, the dose of each compound is the dose when the compound is used alone. May be different. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of the compound of the invention required for use in therapy will depend on the nature of the condition being treated and the age and health of the patient and will ultimately be at the discretion of the attending physician or veterinarian.

  The above combinations can be conveniently provided for use in pharmaceutical dosage forms, thus a pharmaceutical formulation comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient is It constitutes a further aspect of the invention. The individual components of such a combination can be administered sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.

  The present invention also includes co-administration suitable for use in the treatment of disorders as defined above comprising a first dosage form comprising a compound of the invention and a second dosage form comprising another therapeutic agent, Intended for new kit-of-parts for individual or sequential administration.

  Where administration is continuous, either the compound of the invention or another therapeutic agent may be administered first. If administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

  When combined in the same formulation, it should be understood that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately, they can be provided in a convenient formulation, conveniently in a manner as is known for such compounds in the art.

Biological Assays Cell Biology Production of BacMam Virus for Expression of hSERT, hNET and hDAT in Mammalian Cells By HEK-293F cell infection with BacMam virus produced for each single human SERT, NET and DAT transporter Generate membranes for SPA binding assays. hSERT and hDAT are cloned into the pFBMRfA vector, while hNET is cloned into the pFASTBacMam1 vector. The production and use of BacMam virus is described in Condreay JP et al, Proc. Natl. Acad. Sci. USA, 1999, 96: 127-132 and Hassan NJ et al, Protein Expression and Purification, 47 (2): 591-598, It is described in 2006.

式中、Ｌは放射性リガンドであり、Ｋ_Ｄは輸送体に対する放射性リガンドの親和性である（Cheng and Prusoff, Biochem. Pharmacol. 22: 3099, 1973）。本発明では、Ｋ_iの代わりにｐＫ_i値（Ｋ_iの真数に対応する）を使用するＫ_i；ｐＫ_i結果は、正確には、たった約０.３〜０.５と見積もられる。 Affinities for the human transporters SERT, NET and DAT The affinity of the compounds of the invention for the human serotonin transporter (SERT), human norepinephrine transporter (NET) and human dopamine transporter (DAT) is determined by the assay described below. It can be determined by one of them. Such affinity is typically calculated from the IC ₅₀ obtained in competition experiments as the concentration of compound required to replace 50% of the radioligand from the transporter, and is calculated according to the following equation: “K Reported as ' _i ' value:

Wherein, L is the radioligand, K _D is the affinity of radioligand for transporter (Cheng and Prusoff, Biochem Pharmacol 22 :.. 3099, 1973). In the present invention, K _i using pK _i values instead a K _i of the (corresponding to the antilogarithm K _i of); pK _i results, precisely, is estimated to be only about 0.3 to 0.5.

Scintillation proximity assay (SPA) for human DAT, NET and SERT binding
Transduction of hSERT / hDAT / hNET BacMam virus into HEK-293F cells The HEK-293F suspension cell line (Invitrogen) is routinely grown in 293_Freestyle Expression medium (Invitrogen) in shake flask suspension culture. The culture was transduced with the appropriate transporter BacMam at an MOI (infection efficiency) of 100 viral particles per cell and incubated for 48 hours at 37 ° C. in a humidified shaker incubator with 5% CO ₂ in air. Shake at 90 rpm. The culture is then recovered by centrifugation at 1000 g for 10 minutes at 4 ° C. and the cell pellet is stored at −80 ° C. until needed.

Preparation of BacMam hSERT / hDAT / hNET-HEL293F cell membrane Transduced cell pellets were prepared using buffer-A (50 mM HEPES, 1 mM EDTA, 1 mM leupeptin, 25 ug / mL bacitracin, 1 mM phenylmethylsulfonyl fluoride, PMSF, 2 μM pepstatin A, pH 7 7) and re-suspend to 10 volumes and homogenize in a 2 × 15 second burst in a glass Waring blender. The homogenate is then centrifuged at 500 g for 20 minutes. Following this, the supernatants are pooled and centrifuged at 13,000 g for 30 minutes. The pellet is then resuspended to 4 times the initial pellet volume with buffer-B (50 mM TRIS pH 7.4, 130 mM NaCl) and forced through a 0.8 mm needle to ensure a uniform suspension. obtain. Store membrane aliquots at −80 ° C. until needed. Quantify protein concentration by Bradford assay.

SPA-binding assay protocol for hSERT, hNET and hDAT The affinity of the compounds of the invention for hSERT, hNET or hDAT is determined by SPA technology on BacMam-recombinant human SERT, NET and DAT membranes generated as described above. As well as [ ³ H] citalopram, [ ³ H] nisoxetine or [ ³ H] WIN-35,428 binding assays. For SPA technology (GE Healthcare, Amersham), only transporter-bound radioactivity can cause bead excitation and separation of bound / unbound radioligand is not necessary.
The protocol for hSERT-bound SPA is based on Trilux beta-counter (Wallac, Perkin-Elmer). That is, 0.5 μL of test compound in pure DMSO (or 1 μM fluoxetine as a positive control) was added to 2 mg / mL SPA beads (Amersham RPNQ0001) in assay buffer (20 mM HEPES, 145 mM NaCl, 5 mM KCl, pH 7.3). ) Add to 50 μL of SPA mixture containing 4 μg / mL hSERT Baccam membrane, 0.01% Pluronic F-127, 2.5 nM [ ³ H] citalopram. Incubation is carried out at room temperature for at least 2 hours. The count was stable and could be read until the third day.
Alternatively, hDAT, hNET and hSERT SPA-binding assays were performed in a 384-well plate format (Greiner 781075) with a final assay volume of 30 μL together with Imaging PS-WGA beads (Amersham RPNQ0260) with Viewlux beta-counter (Wallac, Perkin). -Elmer). That is, 0.3 μL of test compound in pure DMSO and 0% and 100% effect controls (DMSO for total binding and 10 or 1 μM indatorin as a positive control) in wells using Hummingbird (Genomic Solutions). 1 mg / mL SPA beads (hSERT) or 2 mg / ml SPA beads (hDAT and hNET), 40 μg / ml in assay buffer (20 mM HEPES, 145 mM NaCl, 5 mM KCl, pH 7.3-7.4) or 20 [mu] g / ml or 6 [mu] g / ml of hDAT or hNET or hSERT BacMam membranes, 0.02% pluronic F-127, hDAT or 10mM respect hNET or hSERT binding SPA ^[3 H] ^WIN-3 , Adding SPA mixture 30μL containing 428 or 10 nM ^[3 H] nisoxetine or 3 nM ^[3 H] citalopram. Incubation is performed at room temperature for at least 2 hours, best overnight in the dark. Bound radioactivity is recorded using a 600s 6 × binning and 613 nm emission filter with a Viewlux instrument.

  The invention is further illustrated by the following non-limiting examples.

  In the following procedures, each starting material is typically followed by a number by reference to a preparation or example. This is provided solely to assist chemists. The starting material did not necessarily have to be produced from the batch mentioned.

  When quoting the use of “similar” or “similar” procedures, as will be appreciated by those skilled in the art, such procedures can be modified with minor modifications such as reaction temperature, amount of reagents / solvents, reaction time, Work-up conditions or chromatographic purification conditions can be included.

  Compounds are named using ACD / Name PRO 6.02 compound naming software (Advanced Chemistry Development Inc., Toronto, Canada M5H2L3 Ontario).

  The absolute configuration was not determined for any of the following compounds at the time of filing. Compounds considered to be racemates may be referred to in their names by not referring to stereochemistry or, for example, Example 1: (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3 , 4-dichlorophenyl) -7-[(methyloxy) methyl] -3-azabicyclo [4.1.0] heptane by reference to both enantiomers in their names, separated by “/”, Indicated. Compounds that are considered to be enantiomerically enriched or pure are named in their name, for example, Example 2 “(1S, 6R, 7R) or (1R, 6S, 7S) -7- (3,4-dichlorophenyl). ) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane ".

  All temperatures are expressed in ° C.

  Proton magnetic resonance (NMR) spectra are typically recorded on a Varian instrument at 300, 400 or 500 MHz, or on a Bruker instrument at 300 and 400 MHz. Chemical shifts are reported in ppm (d) using the residual solvent system as an internal standard. The splitting pattern is shown as follows: s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; b, wide. NMR spectra were recorded at temperatures ranging from 25 to 90 ° C. When two or more conformers are detected, the most chemical shifts have been reported.

  Mass spectra (MS) are typically measured on a 4 II triple quadrupole Mass Spectrometer (Micromass UK) or on an Agilent MSD 1100 Mass Spectrometer operating in ES (+) and ES (−) ionization modes. Or an Agilent LC / MSD 1100 Mass Spectrometer operating in ES (+) and ES (−) ionization mode connected to an HPLC instrument Agilent 1100 Series. In the mass spectrum, only one peak in the molecular ion cluster is reported.

If the HPLC walk-up retention time is recorded, the analysis is performed on an HPLC Agilent 1100 Series Instrument in the following manner: Column: Luna C18 100A 50 × 2 mm, 3 microns; Mobile phase: (MeCN + 0.05% TFA) / (H ₂ O + 0.05% TFA) 0/100 to 95/5 gradient within 8 minutes; flow rate 1 ml / min.

  Flash silica gel chromatography was performed on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or on a Varian Mega Be-Si prepacked cartridge or prepacked Biotage silica cartridge.

  In many preparations, purification was performed using a Biotage manual flash chromatography (Flash +) or automated flash chromatography (Horizon or SP1) system. All these devices work with Biotage Silica cartridges.

  The following abbreviations are used herein: Drying refers to a solution dried over anhydrous sodium sulfate or a phase separator cartridge; rt (RT) refers to room temperature. Rt = retention time, BOC: tert-butyloxycarbonyl, NaH = sodium hydride, DIBAL = diisobutylaluminum hydride, DME = 1,2-dimethoxyethane, NaOH = sodium hydroxide, NMO = N-methylmorpholine-N -Oxide, DCM = dichloromethane; DMF = N, N'-dimethylformamide; MeOH = methanol; THF = tetrahydrofuran; TFA = trifluoroacetic acid; SCX cartridge = strong cation exchange cartridge; MCX: mixed cation exchange cartridge; = Hours, min = minutes, HPLC: high performance liquid chromatography Doo chromatography.

３,６−ジヒドロ−１(２Ｈ)−ピリジンカルボン酸１,１−ジメチルエチル（５ｇ）およびＮＭＯ（４.７９ｇ）のテトラヒドロフラン（２４ｍＬ）、tert−ブタノール（１６ｍＬ）および水（６ｍＬ）中溶液に四酸化オスミウム（５.００ｍＬ）を添加した。該混合物を還流温度に加熱した。
３時間後、該混合物を真空濃縮した。酢酸エチルを添加し、有機相をブライン（２×）で洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、真空濃縮した。
粗生成物（６.２ｇ）をシリカゲルによるフラッシュクロマトグラフィーにより精製し、９３／７〜０／１００のシクロヘキサン／酢酸エチルで溶離して、標記化合物５.２９ｇを得た。

Production Example 1: 1,1-Dimethylethyl 3,4-dihydroxy-1-piperidinecarboxylic acid (P1)

To a solution of 1,1-dimethylethyl 3,5-dihydro-1 (2H) -pyridinecarboxylate (5 g) and NMO (4.79 g) in tetrahydrofuran (24 mL), tert-butanol (16 mL) and water (6 mL) Osmium tetroxide (5.00 mL) was added. The mixture was heated to reflux temperature.
After 3 hours, the mixture was concentrated in vacuo. Ethyl acetate was added and the organic phase was washed with brine (2 ×), dried over Na ₂ SO ₄ and concentrated in vacuo.
The crude product (6.2 g) was purified by flash chromatography on silica gel eluting with 93/7 to 0/100 cyclohexane / ethyl acetate to give 5.29 g of the title compound.

０℃にて３,４−ジヒドロキシ−１−ピペリジンカルボン酸１,１−ジメチルエチル（Ｐ１、５.２９ｇ）の乾燥ジクロロメタン（１２６ｍＬ）中溶液にトリエチルアミン（１３.５７ｍＬ）および塩化チオニル（２.６７ｍＬ）を添加した。該混合物をこの温度で１５分間撹拌した。水（５ｍＬ）の添加により反応物をクエンチした後、該反応物をジエチルエーテルおよび水で希釈した。有機抽出物を水、重炭酸ナトリウム飽和溶液およびブラインで洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、真空濃縮した。残留物を四塩化炭素（６９ｍＬ）、アセトニトリル（６９ｍＬ）および水（１０５ｍＬ）に溶解し、０℃で塩化ルテニウム(ＩＩＩ)・水和物（０.１０１ｇ）および過ヨウ素酸ナトリウム（１０.４２ｇ）を添加した。該混合物をこの温度で３時間３０分の間撹拌した。シクロヘキサンおよびエチルエーテルによる希釈の後、該混合物をエチルエーテルで抽出した。有機抽出物をブラインで洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、真空濃縮した。粗生成物（７.２ｇ）をシリカゲルによるフラッシュクロマトグラフィーにより精製し、８８／１２〜０／１００のシクロヘキサン／酢酸エチルで溶離して、標記化合物６.１８ｇを得た。

Production Example 2: Tetrahydro [1,3,2] dioxathiolo [4,5-c] pyridine-5 (4H) -carboxylic acid 1,1-dimethylethyl, 2,2-dioxide (P2)

To a solution of 1,1-dimethylethyl 3,4-dihydroxy-1-piperidinecarboxylate (P1, 5.29 g) in dry dichloromethane (126 mL) at 0 ° C. in triethylamine (13.57 mL) and thionyl chloride (2.67 mL). ) Was added. The mixture was stirred at this temperature for 15 minutes. After quenching the reaction by adding water (5 mL), the reaction was diluted with diethyl ether and water. The organic extract was washed with water, saturated sodium bicarbonate solution and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in carbon tetrachloride (69 mL), acetonitrile (69 mL) and water (105 mL), and ruthenium (III) chloride hydrate (0.101 g) and sodium periodate (10.42 g) at 0 ° C. Was added. The mixture was stirred at this temperature for 3 hours 30 minutes. After dilution with cyclohexane and ethyl ether, the mixture was extracted with ethyl ether. The organic extract was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product (7.2 g) was purified by flash chromatography on silica gel eluting with 88/12 to 0/100 cyclohexane / ethyl acetate to give 6.18 g of the title compound.

０℃にて、水素化ナトリウム（鉱油中６０％分散体、０.３８９ｇ）のＤＭＥ（１０ｍＬ）中懸濁液に、乾燥ＤＭＥ（８ｍＬ）に溶解した(３,４−ジクロロフェニル)アセトニトリル（０.９９６ｇ）を添加した。このようにして得られた橙色の懸濁液にテトラヒドロ[１,３,２]ジオキサチオロ[４,５−ｃ]ピリジン−５(４Ｈ)−カルボン酸１,１−ジメチルエチル，２,２−ジオキシド（Ｐ２、１.３６ｇ）のＤＭＥ（８ｍＬ）中溶液を添加した。５分後、反応混合物を室温に加温した。５時間後、該混合物をブライン（４００ｍＬ）で希釈し、酢酸エチル（４００ｍＬ）で抽出した。有機相をブラインで洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、真空濃縮した。
粗生成物（１.９ｇ）をシリカゲルによるフラッシュクロマトグラフィーにより精製し、９３／７〜４０／６０のシクロヘキサン／酢酸エチルで溶離して、標記化合物９６４ｍｇを得た。

Production Example 3: (1S, 6R, 7R) / (1R, 6S, 7S) -7-cyano-7- (3,4-dichlorophenyl) -3-azabicyclo [41.0] heptane-3-carboxylic acid 1,1-dimethylethyl (P3)

At 0 ° C., a suspension of sodium hydride (60% dispersion in mineral oil, 0.389 g) in DME (10 mL) dissolved in dry DME (8 mL) (3,4-dichlorophenyl) acetonitrile (0. 996 g) was added. To the orange suspension thus obtained, tetrahydro [1,3,2] dioxathiolo [4,5-c] pyridine-5 (4H) -carboxylic acid 1,1-dimethylethyl, 2,2-dioxide was added. A solution of (P2, 1.36 g) in DME (8 mL) was added. After 5 minutes, the reaction mixture was warmed to room temperature. After 5 hours, the mixture was diluted with brine (400 mL) and extracted with ethyl acetate (400 mL). The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo.
The crude product (1.9 g) was purified by flash chromatography on silica gel eluting with 93/7 to 40/60 cyclohexane / ethyl acetate to give 964 mg of the title compound.

０℃にて(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−シアノ−７−(３,４−ジクロロフェニル)−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（Ｐ３、８８５ｍｇ）の乾燥トルエン（２０ｍＬ）中溶液に水素化ジイソブチルアルミニウム（３.２１ｍＬ）を添加した。該混合物をこの温度で１時間撹拌し、次いで、室温に加温した。２時間後、水素化ジイソブチルアルミニウム（１.６ｍＬ）を添加した。次いで、該混合物を４５℃に加熱し、６時間後、水素化ジイソブチルアルミニウム（１.６ｍＬ）を再度添加した。８時間３０分の後、酢酸エチル（８ｍＬ）を添加し、該混合物を室温で一夜撹拌した。次いで、１Ｎ Ｈ₂ＳＯ₄水溶液を添加し、該混合物を室温で撹拌した。１時間後、該混合物を真空濃縮し、ＭＣＸカートリッジ（６ｇ）上に負荷し、水、ＭｅＯＨおよびＮＨ₃（ＭｅＯＨ中２Ｍ）で溶離した。塩基性フラクションを真空濃縮した。残留物（６０２ｍｇ）を乾燥ＴＨＦ（１０ｍＬ）に溶解した。トリエチルアミン（０.６２１ｍＬ）を添加し、次いで、ジ炭酸ジtert−ブチル（０.５６９ｍＬ）の乾燥ＴＨＦ（１０ｍＬ）中溶液を添加した。該溶液を室温で３時間３０分の間撹拌した。次いで、水を添加し、該混合物を酢酸エチルで抽出した。有機相をブラインで洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、真空濃縮した。粗物（７８０ｍｇ）をシリカゲルによるフラッシュクロマトグラフィーにより精製し、９３／７〜４０／６０のシクロヘキサン／酢酸エチルで溶離して、標記化合物１９６ｍｇを得た。

Production Example 4: (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-formyl-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethylethyl (P4)

(1S, 6R, 7R) / (1R, 6S, 7S) -7-cyano-7- (3,4-dichlorophenyl) -3-azabicyclo [4.1.0] heptane-3-carboxylic acid at 0 ° C. To a solution of 1,1-dimethylethyl (P3, 885 mg) in dry toluene (20 mL) was added diisobutylaluminum hydride (3.21 mL). The mixture was stirred at this temperature for 1 hour and then warmed to room temperature. After 2 hours, diisobutylaluminum hydride (1.6 mL) was added. The mixture was then heated to 45 ° C. and after 6 hours diisobutylaluminum hydride (1.6 mL) was added again. After 8 hours 30 minutes, ethyl acetate (8 mL) was added and the mixture was stirred at room temperature overnight. Then 1N H ₂ SO ₄ aqueous solution was added and the mixture was stirred at room temperature. After 1 hour, the mixture was concentrated in vacuo, loaded onto an MCX cartridge (6 g) and eluted with water, MeOH and NH ₃ (2M in MeOH). The basic fraction was concentrated in vacuo. The residue (602 mg) was dissolved in dry THF (10 mL). Triethylamine (0.621 mL) was added followed by a solution of di-tert-butyl dicarbonate (0.569 mL) in dry THF (10 mL). The solution was stirred at room temperature for 3 hours 30 minutes. Water was then added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude (780 mg) was purified by flash chromatography on silica gel eluting with 93/7 to 40/60 cyclohexane / ethyl acetate to give 196 mg of the title compound.

０℃にて、(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−ホルミル−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（Ｐ４、１１６ｍｇ）のメタノール（４ｍＬ）中溶液に水素化ホウ素ナトリウム（１７.７８ｍｇ）を添加した。該混合物を室温に加温した。１１時間後、水（１ｍＬ）を添加した：該混合物を室温で１０分間撹拌し、次いで、真空濃縮した。残留物をジクロロメタンで抽出した。有機相をブラインで洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、真空濃縮した。粗物（１１４ｍｇ）をシリカゲルフラッシュクロマトグラフィーにより精製し、９５／５〜８０／２０のシクロヘキサン／酢酸エチルで溶離して、標記化合物９４ｍｇを得た。

Production Example 5: (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-Dichlorophenyl) -7- (hydroxymethyl) -3-azabicyclo [4.1.0] heptane-3 -1,1-dimethylethyl carboxylate (P5)

At 0 ° C., (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-formyl-3-azabicyclo [4.1.0] heptane-3-carvone To a solution of the acid 1,1-dimethylethyl (P4, 116 mg) in methanol (4 mL) was added sodium borohydride (17.78 mg). The mixture was warmed to room temperature. After 11 hours, water (1 mL) was added: the mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo. The residue was extracted with dichloromethane. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude (114 mg) was purified by silica gel flash chromatography eluting with 95 / 5-80 / 20 cyclohexane / ethyl acetate to give 94 mg of the title compound.

０℃にて、(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−(ヒドロキシメチル)−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（Ｐ５、４６ｍｇ）の乾燥ＤＭＦ（１.２ｍＬ）中溶液に水素化ナトリウム（５.９３ｍｇ、鉱油中６０％分散体）を添加した。該懸濁液を０℃にて１５分間撹拌し、次いで、室温に１０分間加温した。次いで、ヨウ化メチル（０.０１５ｍＬ）を室温にて添加した。さらに３時間後および５時間後にヨウ化メチル（各０.０１５ｍＬ）を添加した。６時間後、酢酸エチルを添加し、該混合物を水およびブラインで洗浄した。有機相をＮａ₂ＳＯ₄で乾燥させ、真空濃縮した。粗化合物（４５ｍｇ）をシリカゲルフラッシュクロマトグラフィーにより精製し、９５／５〜８０／２０のシクロヘキサン／酢酸エチルで溶離して、標記化合物３７ｍｇを得た。

Production Example 6: (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(methyloxy) methyl] -3-azabicyclo [4.1.0] 1,1-dimethylethyl heptane-3-carboxylic acid (P6)

At 0 ° C., (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7- (hydroxymethyl) -3-azabicyclo [4.1.0] heptane- To a solution of 1,1-dimethylethyl 3-carboxylate (P5, 46 mg) in dry DMF (1.2 mL) was added sodium hydride (5.93 mg, 60% dispersion in mineral oil). The suspension was stirred at 0 ° C. for 15 minutes and then warmed to room temperature for 10 minutes. Then methyl iodide (0.015 mL) was added at room temperature. After another 3 hours and 5 hours, methyl iodide (0.015 mL each) was added. After 6 hours, ethyl acetate was added and the mixture was washed with water and brine. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound (45 mg) was purified by flash chromatography on silica gel eluting with 95/5 to 80/20 cyclohexane / ethyl acetate to give 37 mg of the title compound.

(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−(ヒドロキシメチル)−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（方法Ｐ５に従って得られた、５３ｍｇ）を半分取ＨＰＬＣ（カラム：Ｃｈｉｒａｌｐａｃｋ ＡＤ−Ｈ ２５×２.０ｃｍ、粒径５ｕ、移動相：ｎ−ヘキサン／エタノール（７０／３０、ｖ／ｖ）、流速：１４ｍＬ／分、２１５ｎｍでのＵＶ検出）で処理して、エナンチオマー１（保持時間＝７.３４分）２３ｍｇおよびエナンチオマー２（保持時間＝９.６５分）２３ｍｇを得た。

Production Example 7: (1S, 6R, 7R) and (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7- (hydroxymethyl) -3-azabicyclo [4.1.0] heptane-3 -1,1-dimethylethyl carboxylate (P7)

(1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-Dichlorophenyl) -7- (hydroxymethyl) -3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1 , 1-Dimethylethyl (obtained according to method P5, 53 mg) was semi-prepared by HPLC (column: Chiralpack AD-H 25 × 2.0 cm, particle size 5 u, mobile phase: n-hexane / ethanol (70/30, v / V), flow rate: 14 mL / min, UV detection at 215 nm) to give 23 mg of enantiomer 1 (retention time = 7.34 min) and 23 mg of enantiomer 2 (retention time = 9.65 min).

０℃にて、メチルトリフェニルホスホニウムブロミド（１４９ｍｇ）の乾燥ＴＨＦ（１ｍＬ）中懸濁液にブチルリチウム（０.１６７ｍＬ、ヘキサン中２.５Ｍ）を添加した。このようにして得られた黄色の混合物を室温に加温し、３０分間撹拌した。次いで、室温にて、(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−ホルミル−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（Ｐ４、１１９ｍｇ）の乾燥ＴＨＦ（１ｍＬ）中溶液を添加した。２時間３０分の後、ＮＨ₄Ｃｌ飽和溶液を添加し、該混合物を真空濃縮した。残留物をジエチルエーテルで抽出した。有機相をＮａ₂ＳＯ₄で乾燥させ、真空濃縮した。粗生成物（１７３ｍｇ）をシリカゲルフラッシュクロマトグラフィーにより精製し、９３／７〜４０／６０のシクロヘキサン／酢酸エチルで溶離して、標記化合物５８ｍｇを得た。

Production Example 8: (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-ethenyl-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethylethyl (P8)

At 0 ° C., butyl lithium (0.167 mL, 2.5 M in hexanes) was added to a suspension of methyltriphenylphosphonium bromide (149 mg) in dry THF (1 mL). The yellow mixture thus obtained was warmed to room temperature and stirred for 30 minutes. Then, at room temperature, (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-formyl-3-azabicyclo [4.1.0] heptane-3- A solution of 1,1-dimethylethyl carboxylic acid (P4, 119 mg) in dry THF (1 mL) was added. After 2 hours 30 minutes, a saturated solution of NH ₄ Cl was added and the mixture was concentrated in vacuo. The residue was extracted with diethyl ether. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product (173 mg) was purified by flash chromatography on silica gel eluting with 93/7 to 40/60 cyclohexane / ethyl acetate to give 58 mg of the title compound.

０℃にて、(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−エテニル−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（Ｐ８、５８ｍｇ）の乾燥ＴＨＦ（１ｍＬ）中溶液にボラン−テトラヒドロフラン錯体（０.２０５ｍＬ）を添加した。該混合物を室温に２時間加温した。次いで、該混合物を０℃に冷却し、水（９０μｌ）、３Ｎ ＮａＯＨ（２３０μｌ）および過酸化水素（３０％、０.０１６ｍＬ）を添加し、該混合物を０℃で２時間３０分の間撹拌し、次いで、室温で２時間３０分の間撹拌した。次いで、水を添加し、該混合物を酢酸エチルで抽出した。有機相をブラインで洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、真空濃縮した。粗物（５９ｍｇ）をシリカゲルフラッシュクロマトグラフィーにより精製し、９５／５〜２０／８０のシクロヘキサン／酢酸エチルで溶離して、標記化合物４１ｍｇを得た。

Production Example 9: (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7- (2-hydroxyethyl) -3-azabicyclo [4.1.0] heptane -3-Carboxylic acid 1,1-dimethylethyl (P9)

At 0 ° C., (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-ethenyl-3-azabicyclo [4.1.0] heptane-3-carbon Borane-tetrahydrofuran complex (0.205 mL) was added to a solution of the acid 1,1-dimethylethyl (P8, 58 mg) in dry THF (1 mL). The mixture was warmed to room temperature for 2 hours. The mixture was then cooled to 0 ° C., water (90 μl), 3N NaOH (230 μl) and hydrogen peroxide (30%, 0.016 mL) were added and the mixture was stirred at 0 ° C. for 2 h 30 min. And then stirred at room temperature for 2 hours 30 minutes. Water was then added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude (59 mg) was purified by silica gel flash chromatography eluting with 95/5 to 20/80 cyclohexane / ethyl acetate to give 41 mg of the title compound.

(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−[(メチルオキシ)メチル]−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（Ｐ６、３５ｍｇ）の乾燥ジクロロメタン（１ｍＬ）中溶液にトリフルオロ酢酸（０.０７０ｍＬ）を添加した。該反応混合物を２５℃で撹拌した。１時間１５分の後、反応混合物を真空濃縮した。粗生成物をＳＣＸカートリッジ（１ｇ、最初にＭｅＯＨで溶離、次いで、ＮＨ₃（ＭｅＯＨ中０.５Ｍ）で溶離）によって精製して、標記化合物２５ｍｇを得た。

Example 1: (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(methyloxy) methyl] -3-azabicyclo [4.1.0] Heptane (E1)

(1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-Dichlorophenyl) -7-[(methyloxy) methyl] -3-azabicyclo [4.1.0] heptane-3- To a solution of 1,1-dimethylethyl carboxylate (P6, 35 mg) in dry dichloromethane (1 mL) was added trifluoroacetic acid (0.070 mL). The reaction mixture was stirred at 25 ° C. After 1 hour 15 minutes, the reaction mixture was concentrated in vacuo. The crude product was purified by SCX cartridge (1 g, first eluted with MeOH, then eluted with NH ₃ (0.5M in MeOH)) to give 25 mg of the title compound.

０℃にて、(１Ｓ,６Ｒ,７Ｒ)または(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−(ヒドロキシメチル)−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（Ｐ７、エナンチオマー１、２３ｍｇ）の乾燥ＤＭＦ（０.６ｍＬ）中溶液に水素化ナトリウム（３.２１ｍｇ）を添加した。該混合物をこの温度で１５分間撹拌し、次いで、室温に２５分間加温した。次いで、ヨウ化エチル（０.０１５ｍＬ）を添加し、該混合物を２５℃で１時間３０分の間撹拌し、次いで、４５℃に加温した。さらに４時間後および６時間後にヨウ化エチル（各０.０１５ｍＬ）を添加した。７時間後、ＮＨ₄Ｃｌ飽和水溶液を添加し、該混合物を酢酸エチルで抽出した。有機相をブラインで洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、真空濃縮した。粗物（２３ｍｇ）をシリカゲルフラッシュクロマトグラフィーにより精製し、９５／５〜６０／４０のシクロヘキサン／酢酸エチル勾配液で溶離して、実施例１で報告した手順に従って反応させた中間体(１Ｓ,６Ｒ,７Ｒ)または(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−[(エチルオキシ)メチル]−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル１７ｍｇを得て、標記化合物１２ｍｇを得た。

Example 2: (1S, 6R, 7R) or (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane , (E2)

At 0 ° C., (1S, 6R, 7R) or (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7- (hydroxymethyl) -3-azabicyclo [4.1.0] heptane- To a solution of 1,1-dimethylethyl 3-carboxylate (P7, enantiomer, 23 mg) in dry DMF (0.6 mL) was added sodium hydride (3.21 mg). The mixture was stirred at this temperature for 15 minutes and then warmed to room temperature for 25 minutes. Ethyl iodide (0.015 mL) was then added and the mixture was stirred at 25 ° C. for 1 hour 30 minutes and then warmed to 45 ° C. After an additional 4 and 6 hours, ethyl iodide (0.015 mL each) was added. After 7 hours, saturated aqueous NH ₄ Cl was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude (23 mg) was purified by flash chromatography on silica gel, eluting with a 95 / 5-60 / 40 cyclohexane / ethyl acetate gradient and reacted according to the procedure reported in Example 1 (1S, 6R). , 7R) or (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1 -17 mg of dimethylethyl was obtained, and 12 mg of the title compound was obtained.

(１Ｓ,６Ｒ,７Ｒ)または(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−[(エチルオキシ)メチル]−３−アザビシクロ[４.１.０]ヘプタン（Ｅ２、１２ｍｇ）のジクロロメタン（４ｍＬ）中溶液にＨＣｌ（ジエチルエーテル中１Ｍ、４０μＬ）を添加した。該混合物を蒸発させ、残留物をジエチルエーテルと一緒にトリチュレートして、白色の僅かに吸湿性の固体として標記化合物を得た（１２ｍｇ）。

Example 3: (1S, 6R, 7R) or (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane・ Hydrochloride, (E3)

(1S, 6R, 7R) or (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane (E2, 12 mg ) In dichloromethane (4 mL) was added HCl (1 M in diethyl ether, 40 μL). The mixture was evaporated and the residue was triturated with diethyl ether to give the title compound as a white slightly hygroscopic solid (12 mg).

実施例２に記載の方法に従って、(１Ｓ,６Ｒ,７Ｒ)または(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−(ヒドロキシメチル)−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（エナンチオマー２、Ｐ７、２３ｍｇ）から標記化合物１１ｍｇを製造した。

Example 4: (1S, 6R, 7R) or (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane (E4)

According to the method described in Example 2, (1S, 6R, 7R) or (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7- (hydroxymethyl) -3-azabicyclo [4.1. 0] Heptane-3-carboxylic acid 1,1-dimethylethyl (enantiomer 2, P7, 23 mg) produced 11 mg of the title compound.

実施例３に記載の方法に従って、(１Ｓ,６Ｒ,７Ｒ)または(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−[(エチルオキシ)メチル]−３−アザビシクロ[４.１.０]ヘプタン（Ｅ４）から標記化合物１１ｍｇを製造した。

Example 5: (1S, 6R, 7R) or (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane・ Hydrochloride, (E5)

According to the method described in Example 3, (1S, 6R, 7R) or (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4. 1.0 mg of the title compound was prepared from 1.0] heptane (E4).

０℃にて、(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−(２−ヒドロキシエチル)−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（Ｐ９、４１ｍｇ）の乾燥ＤＭＦ（１.０ｍＬ）中溶液に水素化ナトリウム（鉱油中６０％分散体、５.５２ｍｇ）を添加した。該混合物をこの温度で１５分間撹拌し、次いで、室温に２５分間加温した。次いで、ヨウ化メチル（０.０１３ｍＬ）を添加し、該混合物を２５℃で５時間撹拌した。さらなるヨウ化メチル（５０μｌ）を添加し、反応混合物を５０℃で撹拌した。７時間後、ＮＨ₄Ｃｌ飽和水溶液を添加し、該混合物を酢酸エチルで抽出した。有機相をブラインで洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、真空濃縮した。粗物（４１ｍｇ）をシリカゲルフラッシュクロマトグラフィーにより精製し、９３／７〜２０／８０のシクロヘキサン／酢酸エチルで溶離して、中間体(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−[２−(メチルオキシ)エチル]−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル１２ｍｇを得た。この化合物を実施例１に記載の手順に従って反応させて、標記化合物８ｍｇを得た。

Example 6: (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7- [2- (methyloxy) ethyl] -3-azabicyclo [4.1. 0] Heptane (E6)

At 0 ° C., (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7- (2-hydroxyethyl) -3-azabicyclo [4.1.0] To a solution of 1,1-dimethylethyl heptane-3-carboxylate (P9, 41 mg) in dry DMF (1.0 mL) was added sodium hydride (60% dispersion in mineral oil, 5.52 mg). The mixture was stirred at this temperature for 15 minutes and then warmed to room temperature for 25 minutes. Methyl iodide (0.013 mL) was then added and the mixture was stirred at 25 ° C. for 5 hours. Additional methyl iodide (50 μl) was added and the reaction mixture was stirred at 50 ° C. After 7 hours, saturated aqueous NH ₄ Cl was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude (41 mg) was purified by silica gel flash chromatography eluting with 93 / 7-20 / 80 cyclohexane / ethyl acetate to give intermediate (1S, 6R, 7R) / (1R, 6S, 7S) -7. There was obtained 12 mg of 1,1-dimethylethyl-(3,4-dichlorophenyl) -7- [2- (methyloxy) ethyl] -3-azabicyclo [4.1.0] heptane-3-carboxylic acid. This compound was reacted according to the procedure described in Example 1 to give 8 mg of the title compound.

０℃にて、(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−(２−ヒドロキシエチル)−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル（Ｐ９、２０ｍｇ）の乾燥ＤＭＦ（０.５ｍＬ）中溶液に水素化ナトリウム（２.９０ｍｇ）を添加した。該懸濁液をこの温度で１５分間撹拌し、次いで、室温に１５分間加温した。ヨードエタン（０.０１３ｍＬ）を添加し、反応混合物を室温で２時間撹拌し、次いで、４５℃で加熱した。３時間後、ヨードエタン（０.０１３ｍＬ）を添加し、混合物を室温で一夜撹拌した。１８時間後、ＮＨ₄Ｃｌ飽和水溶液を添加し、該混合物を酢酸エチルで抽出した。有機相をブラインで洗浄し、Ｎａ₂ＳＯ₄で乾燥させ、真空濃縮した。粗物（２１ｍｇ）をシリカゲルフラッシュクロマトグラフィーにより精製し、９３／７〜０／１００のシクロヘキサン／酢酸エチルで溶離して、中間体(１Ｓ,６Ｒ,７Ｒ)／(１Ｒ,６Ｓ,７Ｓ)−７−(３,４−ジクロロフェニル)−７−[２−(エチルオキシ)エチル]−３−アザビシクロ[４.１.０]ヘプタン−３−カルボン酸１,１−ジメチルエチル７ｍｇを得た。この化合物を実施例１に記載の手順に従って反応させて、標記化合物５ｍｇを得た。

Example 7: (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7- [2- (ethyloxy) ethyl] -3-azabicyclo [4.1.0 ] Heptane (E7)

At 0 ° C., (1S, 6R, 7R) / (1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7- (2-hydroxyethyl) -3-azabicyclo [4.1.0] To a solution of 1,1-dimethylethyl heptane-3-carboxylate (P9, 20 mg) in dry DMF (0.5 mL) was added sodium hydride (2.90 mg). The suspension was stirred at this temperature for 15 minutes and then warmed to room temperature for 15 minutes. Iodoethane (0.013 mL) was added and the reaction mixture was stirred at room temperature for 2 hours and then heated at 45 ° C. After 3 hours, iodoethane (0.013 mL) was added and the mixture was stirred at room temperature overnight. After 18 hours, saturated aqueous NH ₄ Cl was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude (21 mg) was purified by silica gel flash chromatography eluting with 93/7 to 0/100 cyclohexane / ethyl acetate to give intermediate (1S, 6R, 7R) / (1R, 6S, 7S) -7. There was obtained 7 mg of 1,1-dimethylethyl- (3,4-dichlorophenyl) -7- [2- (ethyloxy) ethyl] -3-azabicyclo [4.1.0] heptane-3-carboxylic acid. This compound was reacted according to the procedure described in Example 1 to give 5 mg of the title compound.

Claims (13)

Formula (I):

[Where:
R ₁ is hydrogen or C _1-4 alkyl;
R ₂ is a group A or W (wherein
A is

Where p is 0, 1, 2, 3, ₄ or 5 and R ₄ is halogen;
W is an α or β naphthyl group optionally substituted by 1 to 7 groups R ₆ each independently selected from the group consisting of hydrogen, cyano and C _1-4 alkyl);
R ₃ is a group P:

Wherein R ₅ is selected from the group consisting of hydrogen, C _1-4 alkyl, halo C _1-4 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl C _1-3 alkyl; n is 1 or 2)]
Or a pharmaceutically acceptable salt or solvate thereof. (1S, 6R, 7R) -7- (3,4-dichlorophenyl) -7-[(methyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(methyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7S) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1S, 6R, 7R) -7- (3,4-dichlorophenyl) -7-[(ethyloxy) methyl] -3-azabicyclo [4.1.0] heptane,
(1S, 6R, 7S) -7- (3,4-dichlorophenyl) -7- [2- (methyloxy) ethyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7R) -7- (3,4-dichlorophenyl) -7- [2- (methyloxy) ethyl] -3-azabicyclo [4.1.0] heptane,
(1S, 6R, 7S) -7- (3,4-dichlorophenyl) -7- [2- (ethyloxy) ethyl] -3-azabicyclo [4.1.0] heptane,
(1R, 6S, 7R) -7- (3,4-Dichlorophenyl) -7- [2- (ethyloxy) ethyl] -3-azabicyclo [4.1.0] heptane and pharmaceutically acceptable salts thereof 2. The compound of claim 1 selected from the group consisting of solvates and prodrugs.   3. A compound according to claim 1 or 2 for use in therapy.   3. A compound according to claim 1 or 2 for use in the treatment of a disorder or disease responsive to the monoamine neurotransmitter reuptake inhibitory activity of the compound.   3. A compound according to claim 1 or 2 for use in the treatment of conditions where inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) is effective.   3. A compound according to claim 1 or 2 for use in the treatment of depression or mood disorders.   A method of treating a disorder or disease responsive to monoamine neurotransmitter reuptake inhibitory activity, comprising administering an effective amount of the compound of claim 1 or 2 to a mammal (eg, human) in need of such treatment. Including methods.   A method of treating a condition in which inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) is effective, wherein the mammal (eg, human) in need of such treatment is claim 1 or 2. Administering an effective amount of a compound of:   9. A method according to claim 8, wherein the symptoms to be treated are depression and mood disorders.   Use of a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of a disorder or disease responsive to the monoamine neurotransmitter reuptake inhibitory activity of the compound.   Use of a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of symptoms in a mammal in which inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) is effective.   12. Use according to claim 11, wherein the symptom to be treated is depression or mood disorder.   A pharmaceutical composition comprising the compound according to claim 1 or 2 and a pharmaceutically acceptable carrier.