JP2008543828A - 3-Phenylazetidine derivatives as dopamine agonists - Google Patents

Abstract

The present invention provides a compound of formula (I) as described herein. These compounds are a class of dopamine agonists, more particularly a class of agonists selective for D3 over D2. These compounds are used for sexual dysfunction, such as female sexual dysfunction (FSD), especially female sexual arousal disorder (FSAD), hyposexual desire disorder (HSDD, lack of interest in sex), female orgasmic disorder (FOD, orgasm). ), And male sexual dysfunction, particularly male erectile dysfunction (MED). As used herein, male sexual dysfunction is a disorder of ejaculation such as premature ejaculation, anorgasmia (cannot obtain orgasm), or a sexual desire disorder (HSDD, lack of interest in sex). Including meaning. These compounds are also useful in the treatment of neuropsychiatric and neurodegenerative disorders.
[Chemical 1]

Description

  The present invention relates to a class of dopamine agonists, and more particularly to a class of agonists that are selective for D3 over D2.

These compounds are sexual dysfunctions such as female sexual dysfunction (FSD), especially female sexual arousal disorder (FSAD), hyposexual desire disorder (HSDD, lack of interest in sex), female orgasmic disorder (FOD, Orgasm), and male sexual dysfunction, particularly male erectile dysfunction (MED), is useful for the treatment and / or prevention. As used herein, male sexual dysfunction is a disorder of ejaculation such as premature ejaculation, anorgasmia (cannot obtain orgasm), or a sexual desire disorder (HSDD, lack of interest in sex). Including meaning. These compounds are also useful in the treatment of neuropsychiatric and neurodegenerative disorders.

  The present invention relates to a compound of formula (I)

［式中、
Ｒ^１は、Ｈおよび（Ｃ_１〜Ｃ_６）アルキルから選択され、
Ｒ^２は、Ｈ、ハロ、およびＣ（Ｏ）ＮＨ_２から選択され、
Ｒ^３は、Ｈ、Ｃ（Ｏ）ＯＨ、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）Ｏ（Ｃ_１〜Ｃ_６）アルキル、ＯＨ、およびハロから選択され、
Ｒ^４は、ＮＨ_２、Ｏ（Ｃ_１〜Ｃ_６）アルキル、ＯＣＨ_２Ｐｈ、Ｃ（Ｏ）ＯＨ、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）（Ｃ_１〜Ｃ_６）アルキル、Ｃ（Ｏ）Ｏ（Ｃ_１〜Ｃ_６）アルキル、ＯＨ、ハロ、および（Ｃ_１〜Ｃ_６）アルキルから選択され、前記アルキルは、ＯＨで置換されていてもよく、
Ｒ^５は、Ｈ、ＣＮ、およびＣ（Ｏ）ＮＨ_２から選択される。］
ならびに薬学的に許容できるその塩、溶媒和物、多形体、およびプロドラッグを提供するが、
但し、Ｒ^４がＮＨ_２であり、Ｒ^１、Ｒ^２、およびＲ^５がすべてＨであるとき、Ｒ^３はＯＨまたはＣｌにはなり得ず、Ｒ^４がＣｌであり、Ｒ^１がＨまたはＣＨ_３であり、Ｒ^２およびＲ^５がＨであるとき、Ｒ^３はＣｌにはなり得ない。

[Where:
R ¹ is selected from H and (C ₁ -C ₆ ) alkyl;
R ² is selected from H, halo, and C (O) NH ₂ ;
R ³ is selected from H, C (O) OH, C (O) NH ₂ , C (O) O (C ₁ -C ₆ ) alkyl, OH, and halo;
R ⁴ is NH ₂ , O (C ₁ -C ₆ ) alkyl, OCH ₂ Ph, C (O) OH, C (O) NH ₂ , C (O) (C ₁ -C ₆ ) alkyl, C (O ) O (C ₁ -C ₆ ) alkyl, OH, halo, and (C ₁ -C ₆ ) alkyl, wherein the alkyl may be substituted with OH;
R ⁵ is selected from H, CN, and C (O) NH ₂ . ]
And pharmaceutically acceptable salts, solvates, polymorphs, and prodrugs thereof,
However, when R ⁴ is NH ₂ and R ¹ , R ² , and R ⁵ are all H, R ³ cannot be OH or Cl, R ⁴ is Cl, and R ¹ is H or When CH ₃ and R ² and R ⁵ are H, R ³ cannot be Cl.

Unless otherwise indicated, (C ₁ -C ₆ ) alkyl may be linear or branched.

  Unless otherwise indicated, the term halo means fluoro, chloro, bromo, or iodo.

  Unless otherwise indicated, the term substituted means substituted by one or more defined groups. If the group is selected from several group options, the selected groups may be the same or different.

  Pharmaceutically acceptable salts of the compound of formula (1) include acid addition salts and base salts of the compound of formula (1).

  The pharmaceutically acceptable salt of the compound of formula (I) can be easily prepared by appropriately mixing a solution of the compound of formula (I) with a desired acid or base solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

  Suitable acid addition salts are those formed from acids that form non-toxic salts, examples being acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate. , Bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edicylate, esylate, formate, fumarate, glucoceptate, gluconate, glucuronate , Hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malon Acid salt, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate Salt / dihydrogen phosphate, pyroglutamic acid Saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and Kishinoho salts, (xinofoate).

  Suitable base salts are those formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, allamine, potassium, sodium, tromethamine, and zinc salts.

  Acid and base half salts may be produced, for example, half sulfate and half calcium salts.

  For a review on suitable salts, see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by one or more of the following three methods.
(I) a process by reacting a compound of formula (I) with the desired acid or base;
(Ii) removing an acid or base labile protecting group from a suitable precursor of the compound of formula (I), or a suitable cyclic precursor, such as a lactone or lactam, using the desired acid or base. A method by ring opening or (iii) by converting a salt of a compound of formula (I) into another salt by reacting with a suitable acid or base or by a suitable ion exchange column.

  All three reactions are usually carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized.

  The compounds of the invention can exist in a series of solid states ranging from completely amorphous to fully crystalline. The term “amorphous” refers to a state in which a material lacks a long range of order at the molecular level and can exhibit solid or liquid physical properties depending on temperature. Typically, such materials are described as liquids more formally, while exhibiting the properties of solids but not giving a unique X-ray diffraction pattern. On heating, a change from a solid property to a liquid property occurs, usually characterized by a secondary state change ("glass transition"). The term “crystalline” refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinct X-ray diffraction pattern with distinct peaks. Such materials also exhibit liquid properties when fully heated, but the change from solid to liquid is usually characterized by a first order phase transition ("melting point").

  The compounds of the invention may exist in unsolvated and solvated forms. The term “solvate” is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term “hydrate” is used when the solvent is water.

  Currently accepted organic hydrate classification systems are those that define isolated site hydrates, channels, or metal ion coordination hydrates. K. R. See Morris' "Polymorphism in Pharmaceutical Solids" (edited by HG Brittain, Marcel Dekker, 1995). Isolation site hydrates are those in which water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, water molecules are located in lattice channels where they are next to other water molecules. In metal ion coordination hydrate, water molecules are bound to metal ions.

  When the solvent or water is tightly bound, the complex has a well-defined stoichiometry regardless of humidity. However, when the solvent or water is weakly bound, such as channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry is the standard.

  The scope of the present invention also includes multi-component complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes clathrates (drug-host inclusion complexes) and co-crystals. The latter is usually defined as a crystalline complex of neutral molecular components joined together by non-covalent interactions, but could be a complex of neutral molecule and salt. Co-crystals can be prepared by melt crystallization, by recrystallization from a solvent, or by physically rubbing the components. O. Almarsson and M.M. J. et al. See Zawortko's Chem Commun, Vol. 17, 1889-1896 (2004). For a general review of multi-component complexes, see Halebrian, J Pharm Sci, Vol. 64 (8) 1269-1288 (August 1975).

The compounds of the invention may exist in an intermediate state (mesophase or liquid crystal) when placed under appropriate conditions. The intermediate state is intermediate between the true crystalline state and the true liquid state (either melt or solution). The intermediate state resulting from the temperature change is described as “temperature transfer type”, and the result of adding a second component such as water or another solvent is described as “concentration transfer type”. The Compounds with the potential to form a concentration-transition mesophase are described as “amphiphilic” (such as —COO ⁻ Na ⁺ , —COO ⁻ K ⁺ , or —SO ₃ ⁻ Na ⁺ ). comprise molecules having ^{- (N} + _{^(CH 3),} such as ₃ -N) nonionic polar head group ionic or. For more information, see N.C. H. Harthorne and A.H. See Stuart's “Crystals and the Polarizing Microscope”, 4th edition (Edward Arnold, 1970).

  In the following, all references to compounds of formula (I) are references to salts, solvates, multicomponent complexes and liquid crystals thereof, and solvates of the salts, multicomponent complexes and liquid crystals. Includes a reference to.

  The compounds of the present invention include all polymorphs and crystal habits thereof, prodrugs thereof defined below and isomers (including optical isomers, geometric isomers, and tautomers), and isotopically labeled Included are compounds of formula (I) as defined above, including compounds of formula (I).

  As indicated, so-called “prodrugs” of the compounds of formula (I) are also within the scope of the present invention. Accordingly, certain derivatives of the compounds of formula (I) that may have little or no pharmacological activity per se, when administered in or on the body have the desired activity, for example by cleavage by hydrolysis. Can be converted to compounds of formula (I) having: Such derivatives are referred to as “prodrugs”. Further information on the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems”, Volume 14, ACS Symposium Series (T. Higuchi and W. Stella), and “Bioreversible Carriers inDr. 1987 (E.B. Roche, edited by the American Pharmacists Association).

  Prodrugs according to the invention are described, for example, in H.P. As described in Bundgaard's “Design of Prodrugs” (Elsevier, 1985), for example, suitable functional groups present in compounds of formula (I) are known to those skilled in the art as “pro-moieties”. Can be generated by substituting with specific parts.

Some examples of prodrugs according to the invention include:
(I) When the compound of formula (I) contains a carboxylic acid functional group (—COOH), the ester, for example, the hydrogen of the carboxylic acid functional group of the compound of formula (I) is (C ₁ -C ₈ ) Compounds substituted by alkyl,
(Ii) when the compound of formula (I) contains an alcohol functional group (—OH), the ether, for example, the hydrogen of the alcohol functional group of the compound of formula (I) is (C ₁ -C ₆ ) alkanoyloxy A compound substituted by methyl,
(Iii) when the compound of formula (I) contains a primary or secondary amino function (—NH ₂ or —NHR (R ≠ H)), its amide, eg optionally Compounds in which one or both hydrogens of the amino function of the compound of I) are replaced by (C ₁ -C ₁₀ ) alkanoyl.

  Other examples of substituents according to the above examples and examples of other prodrug types can be found in the above references.

  Also, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo after administration of the drug. Some examples of metabolites according to the present invention include:
(I) when the compound of formula (I) contains a methyl group, its hydroxymethyl derivative (—CH ₃ —> — CH ₂ OH),
(Ii) when the compound of formula (I) contains an alkoxy group, its hydroxy derivative (-OR->-OH),
(Iii) when the compound of formula (I) contains a tertiary amino group, its secondary amino derivative (—NR ¹ R ² —> — NHR ¹ or —NHR ² ),
(Iv) if the compound of formula (I) contains a secondary amino group, its primary derivative (—NHR ¹ —> — NH ₂ ),
(V) when the compound of formula (I) contains a phenyl moiety, its phenol derivative (-Ph->-PhOH), and (vi) when the compound of formula (I) contains an amide group, carboxylic acid derivatives _(-CONH 2 -> COOH)
Is included.

  The present invention relates to all pharmaceuticals in which one or more atoms are replaced by atoms having the same atomic number but different in atomic mass or mass number from the atomic mass or mass number that is predominantly natural in nature. Include an isotope-labeled compound of formula (I).

Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen such as ² H and ³ H, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ Cl, fluorine such as ¹⁸ F, Iodine such as ¹²³ I and ¹²⁵ I, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus such as ³² P, and sulfur isotopes such as ³⁵ S are included.

Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ O, are particularly useful for this purpose because of their easy incorporation and ready means of detection.

Substitution with a heavier isotope such as deuterium, ie ² H, results in certain therapeutic benefits that result from higher metabolic stability, for example, increased in vivo half-life or reduced dosage requirements Therefore, it may be preferable in certain situations.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O, ¹³ N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

  Isotopically labeled compounds of formula (I) have generally been used previously by conventional techniques known to those skilled in the art or by methods analogous to those described in the appended examples and preparations. It can be prepared using a suitable isotope labeled reagent instead of the unlabeled reagent.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may isotopically substituted, e.g. D _{2 O,} d 6 _- acetone, include those wherein d _6-DMSO.

  The following alternative embodiments are also included in the present invention.

In a first alternative embodiment, R ¹ is selected from H and (C ₁ -C ₄ ) alkyl.
In a second alternative embodiment, R ¹ is H or propyl.
In a third alternative embodiment, R ¹ is n-propyl.

In a first alternative embodiment, R ² is selected from H and halo.
In a second alternative embodiment, R ² is selected from H and Br.
In a third alternative embodiment, R ² is H.

In a first alternative embodiment, R ³ is selected from H, C (O) OH, C (O) NH ₂ , C (O) OCH ₃ OH, and I.
In a second alternative embodiment, R ³ is selected from H, I, and OH.
In a third alternative embodiment, R ³ is selected from H and OH.
In a fourth alternative embodiment, R ³ is H.
In a fifth alternative embodiment, R ³ is OH.

In a first alternative embodiment, R ⁴ is NH ₂ , OCH ₃ , OCH ₂ Ph, C (O) OH, C (O) NH ₂ , C (O) CH ₃ , C (O) OCH ₃ , OH. , Halo, and CH ₂ OH.
In a second alternative embodiment, R ⁴ is NH ₂ , OCH ₃ , OCH ₂ Ph, C (O) OH, C (O) NH ₂ , C (O) CH ₃ , C (O) OCH ₃ , OH. , Br, and CH ₂ OH.
In a third alternative embodiment, R ⁴ is OH or Br.
In a fourth alternative embodiment, R ⁴ is OH.
In a fifth alternative embodiment, R ⁴ is Br.

In a first alternative embodiment, R ⁵ is H or CN.
In a second alternative embodiment, R ⁵ is H.

In an alternative embodiment of the invention, at least one of R ³ and R ⁴ is OH.

Representative compounds of the present invention include
3-azetidin-3-ylphenol hydrochloride,
3- (1-propylazetidin-3-yl) phenol trifluoroacetate,
2-iodo-5- (1-propylazetidin-3-yl) phenol,
2,6-dibromo-4- (1-propylazetidin-3-yl) phenol and 2-bromo-4- (1-propylazetidin-3-yl) phenol are included.

  The compounds of the invention can be prepared in a manner known in various ways. The following pathways exemplify methods for synthesizing compounds of formula (I).

A formula (I) wherein R ¹ is H, R ² is H, R ³ , R ⁴ , and R ⁵ are H or OH, and one of R ³ , R ⁴ , and R ⁵ is OH ) Can be prepared according to Reaction Scheme 1.

ＰＧは、ＣｂｚやＢｏｃなどの、アミンの保護に適する保護基である。

PG is a protecting group suitable for protecting amines, such as Cbz and Boc.

  PG 'is a protecting group suitable for protecting a hydroxy group, such as benzyl or acyl.

  When PG = t-Boc, compound (II) is commercially available.

  Compounds of general formula (III) are prepared from compounds of formula (II) by process step i, ie in the presence of a suitable base such as 2,6-lutidine, pyridine, triethylamine, etc., ethyl acetate, diethyl ether, dichloromethane, etc. Reaction with a suitable anhydride such as trifluoromethanesulfonic anhydride / chloride, mesyl anhydride / chloride, tosyl chloride or sulfonyl chloride in a suitable solvent, optionally at low temperature for 30-60 minutes Can be prepared by converting the alcohol to a suitable leaving group (LG) such as triflate, mesylate, tosylate. Typical conditions are: 1.0 equivalents of compound (II), 2.0 equivalents of 2,6-lutidine, and 1.0-1.1 equivalents of trifluoromethanesulfonic anhydride in dichloromethane at −30 ° C. Including 30 minutes.

  A compound of general formula (IV) is obtained from a compound of general formula (III) according to process step ii, i.e. in a suitable solvent such as N, N-dimethylformamide, water, acetone, etc. At a temperature of up to 18 hours by reacting with a suitable iodide source such as potassium iodide, sodium iodide, tetra-n-butylammonium iodide. Typical conditions include 18 equivalents in 1.0 equivalents of compound (III) and 5.0 equivalents of potassium iodide, N, N-dimethylformamide at a temperature between 0-25 ° C.

  The compound of formula (V) is obtained from the compound of formula (IV) by process step iii, i. It can be prepared by cross-coupling of compound (IV) and an appropriately protected iodophenol (X) using a method similar to that of Billotte (Synlett, 4, 379, 1998). Typical conditions are 0.08 equivalents of 1,2-dibromoethane and excess zinc dust in N, N-dimethylformamide at 70 ° C. for 10 minutes, followed by 0.08 equivalents of chlorotrimethylsilane (at room temperature). 1 hour stirring), 1.0 equivalent of compound (IV) (1 hour stirring at 40 ° C.), and 1.0-1.1 equivalents of iodophenol, tris (dibenzylideneacetone) dipalladium (0) (catalyst) And adding a suitable palladium catalyst such as, and tri (2-furyl) phosphine sequentially at 70 ° C. over 4 hours.

  The compound of formula (VI) is prepared from the compound of formula (V) by process step (iv), ie the hydroxyl protecting group (PG ') W. Greene and P.M. It can be prepared by removal using standard methods, as described in Wutz's “Protecting Groups in Organic Synthesis”. When PG ′ is benzyl, typical conditions are 1.0 equivalent of compound (V), 5.0 equivalents of ammonium formate, and 10% Pd / C (catalyst), heated to reflux in ethanol, 1 to Includes 4 hours.

  The compound of formula (I) is obtained from the compound of formula (VI) by process step (v), ie the amino protecting group (PG) W. Greene and P.M. It can be prepared by removal using standard methods, as described in Wutz's “Protecting Groups in Organic Synthesis”. When PG is BOC, typical conditions include 1.0 equivalent of compound (VI) and excess hydrogen chloride gas in dichloromethane at 0-25 ° C. for 1-18 hours.

Alternatively, when R ¹ is (C ₁ -C ₆ ) alkyl, R ² is H, and R ³ , R ⁴ , and R ⁵ are H or OH, R ³ , R ⁴ , and R Those in which one of ⁵ is OH can be prepared as described in Scheme 2.

式（Ｖ）の化合物は、スキーム１に記載のとおりに調製することができる。

Compounds of formula (V) can be prepared as described in Scheme 1.

  The compound of formula (VII) is prepared from the compound of formula (V) by process step v, ie the amino protecting group (PG) W. Greene and P.M. It can be prepared by removal using standard methods, as described in Wutz's “Protecting Groups in Organic Synthesis”. When PG is BOC, typical conditions include 1.0 equivalent of compound (VI) and excess trifluoroacetic acid in dichloromethane at 0-25 ° C. for 1-6 hours.

  The compound of general formula (VIII) is commercially available.

  Compounds of general formula (IX) are prepared from compounds of formulas (VII) and (VIII) according to process step vii, ie in the presence of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride. Can be prepared by carrying out the reductive amination in a suitable solvent such as dichloromethane, dioxane, etc. under ambient conditions for 1-48 hours. Typical conditions include 1.0 equivalents of compound (VII), 1.5 equivalents of compound (VIII), and 1.5 equivalents of sodium triacetoxyborohydride in dichloromethane for 18 hours.

  Compounds of formula (I) can be prepared from compounds of formula (IX) by process step iv described in Scheme 1.

  It will further be appreciated that a compound of formula (I) can be converted to another compound of formula (I) by a series of halogenation reactions.

For example, one of the groups R ³ , R ⁴ , and R ⁵ is H, one of the groups R ³ , R ⁴ , and R ⁵ is OH, and the groups R ³ , R ⁴ , and R ⁵ When one of is I, the compound of formula (I) ′ can be prepared by iodination of compound (I). Typical conditions include 1.0 equivalent of Compound (I) and 1.0-1.1 equivalents of iodine in dichloromethane at 0-25 ° C. for 24 hours.

One of the groups R ³ , R ⁴ , and R ⁵ is OH, one of the groups R ³ , R ⁴ , and R ⁵ is Br, and of the groups R ³ , R ⁴ , and R ⁵ When one of is selected from Br and H, the compound of formula (I) ′ can be prepared by bromination of compound (I). Typical conditions include 1.0 equivalents of Compound (I) and 1.0-1.1 equivalents of bromine in glacial acetic acid at 10-25 ° C. for 18 hours.

  All of the above reactions and the preparation of the new starting materials used in the above-described methods are conventional and the appropriate reagents and reaction conditions for their performance or preparation, as well as the procedure for isolating the desired product are: Those skilled in the art will be familiar with the literature precedents and the examples and preparations herein.

  The compounds of the present invention are useful as selective D3 agonists in the treatment of disease states. There are several compounds that have activity as both D2 and D3 agonists, but the use of such compounds has numerous side effects including nausea, vomiting, syncope, hypotension, and bradycardia And some of them cause serious concerns.

  It was previously thought that the effects of prior art compounds were due to their ability to show agonistic activity on D2, but D2 agonistic activity has been suggested to be responsible for the side effects detailed above. .

  The present invention provides a class of selective D3 agonists. Coincidentally, these agonists have been found to be effective but reduce the side effects associated with non-selective prior art compounds.

  Accordingly, another aspect of the present invention provides a compound of formula (I) for use as a medicament.

  The compounds of the present invention have sexual dysfunction, i.e. female sexual dysfunction, including hyposexual desire disorder, female sexual arousal disorder, female orgasmic disorder, and sexual pain disorder, male erectile dysfunction, hypertension, neurodegeneration, depression It is particularly useful in the treatment of pain, as well as psychiatric disorders.

  Accordingly, the present invention provides the use of a compound of formula (I) in the preparation of a medicament for treating or preventing a disease or condition involving dopamine D3 receptor.

  Furthermore, the present invention provides the use of a compound of formula (I) without preparation, in the preparation of a medicament for treating or preventing sexual dysfunction.

The compounds of the present invention are useful in male sexual dysfunction, particularly male erectile dysfunction. Male erectile dysfunction (MED), otherwise known as male erectile dysfunction, is defined as follows.
“A state in which an erection cannot be obtained and / or cannot be maintained to perform satisfactory sexual activity” (NIH Consensus Development Panel on Impotence, 1993)
The prevalence of erectile dysfunction (ED) of all degrees (minimal, moderate, and complete disability) is 52% in men aged 40-70 and higher in men older than 70 (Melman et al., 1999, J. Urology, 161, 5-11). This condition has a considerable negative impact on the quality of life of the individual and his partner, often resulting in increased anxiety and tension, which leads to depression and self-depression. Twenty years ago, MED was primarily regarded as a psychological disorder (Benet et al., 1994, Comp. Ther. 20: 669-673), but now it is characterized by the majority of individuals The root cause is known. As a result, great progress has been made in identifying the mechanism of normal penile erection and the pathophysiology of MED.

  Penile erection is a hemodynamic event determined by the balance between cavernous smooth muscle contraction and relaxation and penile vasculature (Lerner et al., 1993, J. Urology, 149, 1256- 1255). Corpus smooth muscle is also referred to herein as corporate smooth muscle, or, in the plural sense, corpus cavernosa. As the cavernous smooth muscle relaxes, blood flow into the trabecular space of the corpus cavernosum increases, causing the corpus cavernosum to fill the surrounding white membrane and compressing the drainage vein. As a result, the blood pressure increases greatly and an erection occurs (Naylor, 1998, Br. J. Urology, 81, 424-431).

The changes that occur during the process of erection are complex and require a high degree of coordinated control involving the peripheral and central nervous system and the endocrine system (Naylor, 1998, Br. J. Urology, 81, 424). ~ 431 pages). Cavernous smooth muscle contraction is modulated by noradrenergic innervation of the sympathetic nervous system through activation of post-synaptic α ₁ adrenergic receptors. MED can be associated with an increase in the intrinsic smooth muscle tone of the corpus cavernosum. However, the process of cavernous smooth muscle relaxation is mediated in part by non-adrenergic, non-cholinergic (NANC) neurotransmission. In the penis, there are several other NANC neurotransmitters other than NO, such as calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP). The main relaxing factor responsible for mediating this relaxation is nitric oxide (NO) synthesized from L-arginine by nitric oxide synthase (NOS) (Taub et al., 1993, Urology, Vol. 42, 698- Page 704). It is believed that reducing the cavernous smooth muscle tension may help NO induce relaxation of the corpus cavernosum. During male sexual arousal, NO is released from neurons and endothelium and binds to and activates soluble guanylate cyclase (sGC), which is located in smooth muscle cells and endothelium. Resulting in increased levels of cyclic guanosine 3 ′, 5′-monophosphate (cGMP). When cGMP is elevated in this way, an unknown mechanism (possibly due to activation of Ca ²⁺ pumps and potassium channels activated by Ca ²⁺ ) is thought to be involved in the cell. A decrease in the calcium concentration ([Ca ²⁺ ] _i ) results in relaxation of the corpus cavernosum.

  Multiple sites that may modulate sexual behavior have been identified in the central nervous system. The key neurotransmitters are thought to be serotonin, norepinephrine, oxytocin, nitric oxide, and dopamine. By mimicking the action of such key neurotransmitters, sexual function can be adjusted. Dopamine D3 receptors are expressed almost exclusively in the marginal area of the brain, an area involved in reward, emotion, and cognitive processes.

  Without being bound by a particular theory, “It appears that the integrity of the nigrostriatal dopaminergic pathway plays a role in the control of motor activity and is therefore essential for the display of sexual activity. In any case, in more detail about sexual function, dopamine acts on oxytocinergic neurons that are located in the paraventricular nucleus of the hypothalamus, possibly further in the erection-promoting sacral parasympathetic nucleus It seems that this can trigger a penile erection. ”At present, it is clear that the important site is D3 and not D2, as previously thought.

  In short, D3 is a trigger factor for sexual behavior.

  Accordingly, the present invention provides the use of a compound of formula (I) in the preparation of a medicament for treating or preventing male sexual dysfunction, particularly but not exclusively male erectile dysfunction.

  Mild to moderate MED patients should benefit from treatment with the compounds according to the invention and may be successful in patients with severe MED. However, early studies suggest that the proportion of responders in mild, moderate, and severe MED patients can be higher with selective D3 agonist / PDE5 inhibitor combinations. Mild, moderate and severe MED are terms known to those skilled in the art, but guidance can be found in The Journal of Urology, vol. 151, pages 54-61 (January 1994). .

  Early studies suggest that the MED patient population described below should benefit from treatment with selective D3 agonists and PDE5i (or other combinations described below). Such patient groups are described in I. Clinic Andrology Vol. 23, No. 4, pp. 773-782, and published by Mosby-Wolfe. Eardley and K.C. This is described in more detail in Chapter 3 of the book “Electile Dysfunction-Current Investigation and Management” by Setia, as follows: That is, sex related to psychogenic, organic, vascular, endocrine, neurogenic, arterial, drug-induced sexual dysfunction (breast irritation), and cavernous factors, particularly venous causes Dysfunction.

  Accordingly, the present invention provides the use of a compound of formula (I) without preparation, in the preparation of a medicament in combination with a PDE5 inhibitor for the treatment of erectile dysfunction.

  Suitable PDE5 inhibitors are described herein.

  The compounds of the present invention have female sexual dysfunction (FSD), particularly female sexual arousal disorder (FSAD), hyposexual desire disorder (HSDD, lack of interest in sex), FSAD with HSDD, and female orgasmic disorder It is useful in the treatment or prevention of (FOD, orgasm cannot be obtained).

  According to the present invention, FSD can be defined as that a woman is less or less satisfied with sexual expression. FSD is a generic term for several diverse female sexual disorders (Leiblum, SR (1998)-"Definition and classification of female sex disorders", Int. J. Impotence Res., 10th. Vol., Pages S104-S106; Berman, JR, Berman, L., and Goldstein, I. (1999)-"Female sexity function: Incidence, pathology, evaluations and treatment, Volume 54". 385-391). Women may lack desire, have difficulty reaching sexual arousal or orgasm, have sexual pain, or have such problems. Some types of disease, drug application, injury, or psychological problems can cause FSD. The treatments under development are targeted at the treatment of specific FSD subtypes, primarily desire and sexual arousal disorders.

  The category of FSD is best defined by contrasting it with the normal female sexual response, ie, desire, sexual arousal, and orgasmic phases (Leiblum, SR (1998)-" "Definition and classification of female sex disorders", Int. J. Impression Res., Vol. 10, pages S104-S106). Desire or libido is an impulse to sexual expression. Their manifestations often include sexual thinking when dating with an interested partner or when exposed to other stimuli that inspire sexual desire. Sexual arousal is a vascular response to sexual stimulation, with genital hyperemia as a key component, including increased vaginal lubrication, vaginal elongation, and increased genital sensation / sensitivity. include. Orgasm is the release of sexual tension that has culminated during sexual arousal.

  Thus, FSD exists when a woman has an inadequate or unsatisfactory response in such a phase, usually either desire, sexual arousal, or orgasm. The categories of FSD include hyposexual desire disorder, sexual arousal disorder, orgasm disorder, and sexual pain disorder. The compounds of the present invention improve the genital response to sexual stimulation (as in female sexual arousal disorder), but also do the associated pain, sexual intercourse pain and discomfort. Can improve and treat other female sexual disorders as well.

  If a woman has no or little desire for sexual relations and little or no sexual thinking or imagination, then there is a sexual desire decline disorder. This type of FSD can be caused by low testosterone levels due to natural or surgical menopause. Other causes include illness, drug application, fatigue, depression, and anxiety.

  Female sexual arousal disorder (FSAD) is characterized by inadequate genital response to sexual stimulation. The genitals do not lead to hyperemia characterizing normal sexual arousal. Intercourse is painful because the vaginal wall is poorly lubricated. Orgasm may be disturbed. Sexual arousal disorder can be caused by estrogen loss during menopause or postpartum and during lactation, as well as by diseases with vascular components such as diabetes and atherosclerosis. Other causes arise as a result of treatment with diuretics, antihistamines, antidepressants such as selective serotonin reuptake inhibitors (SSRIs), or antihypertensive drugs.

  Sexual pain disorders (including sexual pain and vaginal spasticity) are characterized by pain resulting from insertion, drug application that reduces lubrication, endometriosis, pelvic infection, inflammatory bowel disease, or urinary system May be caused by problems.

  As previously discussed, D3 is believed to be a trigger for sexual behavior. The clitoris is regarded as a homolog of the penis (Levin, RJ (1991), Exp. Clin. Endocrinol., 98, 61-69), the same machine that produces an erectile response in men Introductory causes an increase in genital blood flow in women, with an effect on FSD. In addition, there are changes in active and passive sexual behavior.

  Thus, according to one aspect of the invention, in the preparation of a medicament for treating or preventing female sexual dysfunction, including hyposexual desire disorder, female sexual arousal disorder, female orgasm disorder, and sexual pain disorder Use of the compound of formula (I) without writing is provided.

  In one embodiment, the compound of formula (I) is useful in the treatment or prevention of sexual arousal disorder, orgasmic disorder, and hyposexual desire disorder, and in another embodiment, in the treatment or prevention of sexual arousal disorder. is there.

  In another embodiment, the compounds of formula (I) are useful in the treatment of subjects with female sexual arousal disorder and concomitant hyposexual desire disorder.

The American Psychiatric Association Diagnostic and Statistical Handbook (DSM) IV defines female sexual arousal disorder (FSAD) as follows:
“… Sufficient lubrication of sexual arousal—a condition that persists or frequently fails to achieve or maintain sexual activity until completion of sexual activity. This disorder causes significant distress or interpersonal entanglement No difference ... "

  The sexual arousal response consists of pelvic vascular hyperemia, vaginal lubrication and enlargement, and external genital swelling. The disorder causes significant distress and / or interpersonal entanglement.

  FSAD is a very widespread sexual disorder that affects women before menopause, near menopause, and after menopause (± hormone replacement therapy (HRT)). This disorder is associated with accompanying disorders such as depression, cardiovascular disease, diabetes, and genitourinary (UG) disorders.

  The main effects of FSAD are lack of hyperemia / inflation, lack of lubrication, and lack of satisfaction with genital sensations. The secondary effects of FSAD are reduced libido, pain during intercourse, and difficulty in obtaining orgasm.

  Recently, it has been hypothesized that there is a vascular basis for at least some patients with FSAD symptoms (Goldstein et al., Int. J. Impot. Res., Vol. 10, pages S84-S90, 1998). ), Animal data support this view (Park et al., Int. J. Impot. Res., Vol. 9, pages 27-37, 1997).

  R. J. et al. Levin states that “... male and female genitals arise from embryologically common tissue primordia, so that the male and female genital structures are homologous to each other. The penis is a homologue of the penis and the labia is a homologue of the scrotal sac ... "(Levin, RJ (1991), Exp. Clin. Endocrinol., 98, 61- 69 pages).

  Drug candidates for the treatment of FSAD that are under investigation are drugs for treating erectile dysfunction that naturally promote circulation to the male reproductive organs.

  The compounds of the present invention are advantageous by providing a means to restore a normal sexual arousal response, ie increased blood flow to the genitals resulting in redness of the vagina, clitoris, and labia. This increases vaginal lubrication by plasma exudates, increases vaginal extensibility, and increases genital sensitivity. Thus, the present invention provides a means to restore or enhance a normal sexual arousal response.

  Accordingly, in one embodiment of the present invention there is provided the use of a compound of formula (I) without preparation, in the preparation of a medicament for treating or preventing female sexual arousal disorder.

  As used herein, female genital organ means the following. “The genitals consist of internal and external groups. The internal genitalia is located in the pelvis and consists of the ovaries, fallopian tubes, uterus, and vagina. The external genitals are on the surface of the urogenital diaphragm and below the pelvic arch. The external genitalia includes the pubic hill, large and small labia, clitoris, vaginal vestibule, vestibular bulb, and large vestibular gland. ”(Gray's Anatomy, CD Clemente, 13th US Edition).

  The compounds of the invention can be applied to the following FSD patient subpopulations: young people who are or are not receiving hormone replacement therapy, the elderly, premenopausal, near menopause, postmenopausal women.

The compounds of the present invention can be applied to patients with FSD resulting from:
i) Angiogenic etiology such as cardiovascular or atherosclerotic disease, hypercholesterolemia, tobacco smoking, diabetes, hypertension, radiation injury and perineal trauma, traumatic to the subiliac abdominal vulva vasculature injury.
ii) Neurogenic etiology such as spinal cord injury, multiple sclerosis, diabetes, parkinsonism, cerebrovascular stroke, central nervous system diseases including peripheral neuropathy, trauma, or radical pelvic surgery.
iii) Hypothalamic / pituitary / gonadal dysfunction, or ovarian dysfunction, pancreatic dysfunction, surgical or medical castration, androgen deficiency, high circulating levels of prolactin such as hyperprolactinemia, nature Hormonal / endocrine etiology such as menopause, premature menopause, hyperthyroidism and decline.
iv) Depression, obsessive-compulsive disorder, anxiety disorder, postpartum depression / "Baby Blues", emotional and relationship problems, performance anxiety, marital imbalance, dysfunctional attitude, sexual fear, religion Psychogenic etiology such as suppression on top, or deeply injured past experience.
v) Results of treatment with selective serotonin reuptake inhibitors (SSRi) and other antidepressant treatments (tricyclic and major tranquilizers), antihypertensive treatments, sympatholytics, and long-term oral contraceptive treatments Drug sexual dysfunction that occurs as

  The compounds of the present invention are also useful in the treatment of depression.

  Dopamine D3 receptors are expressed almost exclusively in the marginal area of the brain, an area involved in reward, emotion, and cognitive processes. Long-term treatment with several classes of antidepressants has been shown to increase the expression of D3 in the marginal area, and the antidepressant effect of desipramine is due to sulpiride (D2 / D3 antagonist) It may be blocked when injected into the nucleus (region rich in D3), but not in the caudate nucleus-putamen (region rich in dopamine D2 receptor). Furthermore, antidepressant effects were observed in preclinical depression models and patients treated with pramipexole, a D2 / D3 agonist preferential to D3. Available information suggests that D3 receptors mediate antidepressant activity and that selective D3 receptor agonists represent a new class of antidepressants. Since antidepressants have been found to be effective in other psychiatric disorders, D3 agonists have the potential to treat psychiatric disorders.

  Appropriate conditions include depression (eg depression in cancer patients, depression in Parkinson's disease patients, post-myocardial infarction depression, subsymptomatic symptomatic depression, depression in infertile women, major depression, child abuse. -Induced depression, postpartum depression, and grumbling elderly syndrome), single episode or recurrent major depressive disorder, dysthymic disorder, depressive neurosis, and neurological depression, anorexia Melancholy-type depression, including insomnia, weight loss, insomnia, early morning awakenings, or psychomotor retardation; increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder, and childhood depression Including atypical depression (or reactive depression); bipolar disorder or manic depression, eg, bipolar I disorder, bipolar II disorder, and mood circulatory disorder; behavioral disorder; destructive behavioral abnormality; Stealing, note Deficit hyperactivity disorder (ADHD); behavioral disorders associated with intellectual and autistic disorders; borderline personality disorder; avoidance personality disorder; panic disorder with or without agoraphobia, agoraphobia without history of panic disorder , Specific phobias, eg, certain animal phobias, social anxiety, social phobia, obsessive compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, anxiety disorders such as generalized anxiety disorder; emotional instability, pathological Crying; schizophrenia and other psychotic disorders such as schizophrenia-like disorder, schizophrenic disorder, delusional disorder, short-term psychotic disorder, shared psychotic disorder, psychotic disorder with delusions or hallucinations, psychosis of anxiety Sexual episodes, anxiety related to psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders related to psychotic disorders such as acute madness, And depression related to bipolar disorder; mood disorders related to schizophrenia; eating disorders (eg, anorexia nervosa and bulimia nervosa), obesity; dyskinesias including akinesia, familial paroxysmal dyskinesia, spasticity, toe Motor disorders such as Rett Syndrome, Scott Syndrome, PALSYS, Immobility-Stiffness Syndrome; Motor disorders induced by drug application, eg Parkinsonism induced by neuroleptics, malignant syndromes, acute dystonia induced by neuroleptics Extrapyramidal movement disorders such as acute akathisia induced by neuroleptics, delayed dyskinesia induced by neuroleptics, postural tremor induced by drug application; chemical dependence and addiction (eg alcohol Heroin, cocaine, benzodiazepine, nicotine, or phenova Addictive or addiction to rubital) and behavioral addiction such as gambling addiction; eye disorders such as glaucoma and ischemic retinopathy; sleep disorders (weakness seizures) and shock.

  In another embodiment, the present invention provides the use of a compound of formula (I) in the preparation of a medicament for treating depression or psychiatric disorder.

  Suitable depression states and psychiatric disorders are those described above.

  The compounds of the present invention are also useful in the treatment of neurodegeneration, which may be caused by neurotoxin poisoning; visual pathways such as those caused by strokes in the retina, optic nerve, and / or occipital lobe. It includes vision loss caused by neurodegeneration; epileptic spasms; and those resulting from impaired glucose and / or oxygen supply to the brain.

  Conditions associated with neurodegeneration include non-hidden leg syndrome, Huntington's disease, multiple sclerosis, mild cognitive impairment, Down syndrome, stroke, Dutch hereditary amyloid cerebral hemorrhage, cerebral amyloid angiopathy, delirium, dementia, aging Associated cognitive decline (ARCD) and Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's dementia, memory impairment, loss of executive function, cerebrovascular dementia, mixed vascular degeneration Types of dementia, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal ganglia degeneration, multiple infarct dementia, alcohol-dependent dementia or other Drug-related dementia, dementia related to intracranial tumor or brain trauma, Huntington's disease, Pick's disease, dementia related to Creutzfeldt-Jakob disease, H Dementia associated with V or AIDS, Alzheimer's disease with diffuse Lewy bodies, frontotemporal dementia with parkinsonism (FTDP), head trauma, spinal cord injury, demyelinating disease of the nervous system, peripheral neuropathy , Pain, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, multiple sclerosis, dyskinesia associated with dopamine agonist treatment, intellectual disability; learning disabilities, including reading disabilities, mathematical disabilities, or written expression disabilities, aging Amnestic and other cognitive or neurodegenerative disorders, including related cognitive decline, amnestic disorders, parkinsonism induced by neuroleptics, tardive dyskinesia, acute and chronic neurodegenerative disorders are included.

  Accordingly, the present invention provides the use of a compound of formula (I) in the preparation of a medicament for treating neurodegeneration.

  The compounds of the present invention are also useful in the treatment of pain, particularly but not limited to chronic nociceptive pain.

  Physiological pain is an important defense mechanism designed to warn of potentially harmful stimuli from the outside environment. This lineage operates through a specific set of primary sensory neurons and is activated by nociceptive stimuli via peripheral transduction mechanisms (for review see Milian, 1999, Prog. Neurobiol., 57, 1 See page 164). Such sensory fibers are known as nociceptors and are characterized by small diameter axons with slow conduction velocities. A nociceptor encodes the location of the stimulus by the intensity, duration, and quality of the nociceptive stimulus, as well as its projection onto the tissue-distributed spinal cord. Nociceptors are found on nociceptive nerve fibers of two major types, Aδ fibers (myelinated) and C fibers (indefinite). The activity generated by nociceptor input is transmitted to the thalamic base bilaterally and then onto the cortex, either directly or via the brainstem relay nucleus, after complex processing in the dorsal horn, where pain sensation occurs .

  Pain is generally classified as acute or chronic. Acute pain begins suddenly and is temporary (usually in 12 weeks or less). Acute pain is usually associated with a specific cause, such as a specific injury, and is often sharp and severe. Acute pain is a type of pain that can exist after undergoing certain injuries that occur as a result of surgery, dental work, a strain or a sprain. Acute pain generally does not result in any persistent psychological response. In contrast, chronic pain is long-lasting pain that usually lasts longer than 3 months, and is a significant psychological and emotional problem. Common examples of chronic pain are neuropathic pain (eg, painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain, and chronic postoperative Pain.

  When there is substantial damage to body tissue due to disease or trauma, the properties of nociceptor activation are altered, sensitizing at the periphery, locally around the lesion, and at the center where the nociceptors terminate. Such an effect reinforces the sense of pain. In acute pain, such a mechanism may be useful in promoting protective behavior that may make it possible to perform the repair process. The normal expectation is that sensitivity should return to normal once the injury has healed. However, in many chronic pain states, hypersensitivity remains much longer than the healing process, often due to nervous system damage. This damage often results in abnormalities in sensory nerve fibers associated with maladaptation and abnormal activity (Woolf and Salter, 2000, Science, 288, 1765-1768).

  Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be very uneven and may be difficult to see with various pain symptoms. The symptoms include: 1) spontaneous pain that can be dull, burning, or stinging, 2) a worsened pain response to noxious stimuli (hyperalgesia), and 3) pain caused by normally harmless stimuli ( Allodynia-Meyer et al., 1994, Textbook of Pain, pages 13-44). Patients suffering from various forms of acute and chronic pain may have similar symptoms, but the underlying mechanisms may be different and thus require different treatment strategies. Thus, pain can also be divided into a number of different subtypes that follow different pathophysiology, including nociceptive, inflammatory, and neuropathic pain.

  Nociceptive pain is induced by tissue damage or intense stimulation that can cause damage. Pain afferents are activated by the transmission of stimuli by nociceptors at the site of injury, activating neurons at the level of the spinal cord where they terminate. This is then relayed up the spinal tract to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, pages 13-44). When nociceptors are activated, two types of afferent nerve fibers are activated. Myelinated Aδ fibers provide rapid transmission and a sharp stinging sensation, while unmyelinated C fibers transmit at a slower rate and transmit dull or tingling pain. Moderate to severe acute nociceptive pain includes pain from central nervous system trauma, contusion / sprain, burns, myocardial infarction, and acute pancreatitis, postoperative pain (pain after any type of surgical procedure), It is a prominent feature of posttraumatic pain, renal colic, cancer pain, and back pain. Cancer pain is pain associated with a tumor (eg, bone pain, headache, facial pain, or visceral pain), or pain associated with cancer treatment (eg, post-chemotherapy syndrome, chronic postoperative pain syndrome, or radiation). It may be chronic pain such as post syndrome. Cancer pain may occur in response to chemotherapy, immunotherapy, hormone therapy, or radiation therapy. Back pain may be due to disc herniation or disc rupture or abnormalities in the lumbar facet joint, sacroiliac joint, paravertebral muscle, or posterior longitudinal ligament. Back pain may resolve spontaneously, but in some patients it becomes a chronic condition that can be particularly debilitating if it persists beyond 12 weeks.

  Neuropathic pain is currently defined as pain that begins or is caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease, so the term “neuropathic pain” includes many disorders of diverse etiology. These include peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancerous neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain, and chronic alcoholism, This includes but is not limited to pain associated with hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. Neuropathic pain is often present even after the original cause has disappeared and generally remains for many years, significantly reducing the patient's quality of life (Woolf and Mannion, 1999, Lancet, Vol. 353, 1959-1964). Symptoms of neuropathic pain are often difficult to treat because they are not uniform even among patients with the same disease (Woolf and Decostard, 1999, Pain Sup., Vol. 6, pages S141-S147; Woolf and Mannion, 1999) Lancet, 353, 1959-1964). They include spontaneous pain that can be persistent, as well as paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally harmless stimuli) Is included.

  The process of inflammation is a series of complex biochemical and cellular events that are activated in response to tissue damage or the presence of foreign bodies, resulting in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, pages 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the most common chronic inflammatory conditions in developed countries, and rheumatoid arthritis is a common cause of disability. Although the exact etiology of rheumatoid arthritis is unknown, current hypotheses suggest that both genetic and microbiological factors may be important (Grennan and Jayson, 1994, Textbook of Pain, 397- 407). It is estimated that nearly 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of which are over 60 years of age, which is 40 million as the age of the population increases It is a very serious public health problem because it is expected to increase to humans (Houge and Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, pages 387-395). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has been shown to have a significant impact on psychosocial and physical functioning and become a major cause of disability later in life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. The disease ranges from an intermittent onset of back pain that occurs throughout life to a severe chronic disease that attacks the spine, peripheral joints, and other body organs.

  Another type of inflammatory pain is visceral pain, including pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, including organs of the abdominal cavity. These organs include the genitals, spleen, and parts of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (GI) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These GI disorders include gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS), and functional abdominal pain syndrome (FAPS) for FBD, Crohn's disease, ileitis, and ulcerative colitis for IBD This includes a wide range of disease states that are currently only moderately controlled, all of which cause visceral pain on a regular basis. Other types of visceral pain include pain associated with dysmenorrhea, cystitis, and pancreatitis, and pelvic pain.

  Some types of pain have multiple etiologies and may therefore be classified into multiple areas, for example, back pain and cancer pain are both nociceptive and neuropathic components. Note that you have.

Other types of pain include the following:
The consequences of musculoskeletal disorders, including myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, and purulent myositis Pain that occurs as
Cardiac and vascular pain, including pain caused by angina, myocardial infarction, mitral stenosis, epicarditis, Reino phenomenon, edematous sclerosis, and skeletal muscle ischemia,
• Headaches, including migraines (including migraines with and without aura), cluster headaches, muscle headaches, mixed headaches, and headaches related to vascular disorders,
Orofacial pain, including toothache, ear pain, intraoral burning syndrome, and temporal mandibular myofascial pain.

  Accordingly, the present invention provides the use of a compound of formula (I) without preparation, however, in the preparation of a medicament for treating or preventing pain. In another embodiment, the present invention provides the use of a compound of formula (I) without preparation, in the preparation of a medicament for treating or preventing chronic nociceptive pain.

  In addition to its role in the treatment of sexual dysfunction, depression, neurodegeneration, pain, and psychiatric disorders, the compounds of the present invention are likely to be effective in several additional indications. Thus, the present invention provides high blood pressure, premature ejaculation, obesity, cluster headache, migraine, pain, endocrine disorders (eg hyperprolactinemia), vasospasm (especially of the cerebral vasculature), cerebellar ataxia, (motility And in the preparation of medications to treat gastrointestinal disorders (including changes in secretion), premenstrual syndrome, fibromyalgia syndrome, stress incontinence, chronic paroxysmal unilateral headache, and headache (related to vascular disorders) There is provided the use of a compound of formula (I).

  In another embodiment, the present invention provides a method of treating or preventing a condition, disease or disorder as described herein above, in a mammalian subject, including a human in need thereof, in an effective amount of formula (I) Or a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof.

  It should be understood that all references to treatment herein include therapeutic, palliative and prophylactic treatment.

D3 / D2 Agonist Binding Assay Gonazalez et al. (Eup. J Pharmacology 272 (1995) pages R1-R3) is the ability of compounds to bind at the D3 and / or D2 dopamine receptors, and thus the binding selection of such compounds. An assay for determining sex is disclosed. This assay is therefore referred to herein as a binding assay.

D3 / D2 Agonist Functional Assay A suitable assay is disclosed in WO 2004/052372.

  Using the assays described above, all of the compounds of the invention have <2 μM binding Ki at the D3 receptor and / or a functional effect, expressed as EC50, at the D3 receptor of less than 200 nM. None of the compounds showed a detectable EC50 in the D2 functional assay.

  Illustratively, the compound of Example 2 has a functional effect shown as an EC50 at the D3 receptor of 61 nM, but an Emax (maximum response value) of 77% (based on the maximum effect of the standard drug pramipexole). It is. In the D2 receptor functional assay described above, this compound showed only a 24% response at 10,000 nM (based on the maximum effect of pramipexole).

Pain Assays Described below are assays suitable for determining the utility of the compounds of the invention in various pain conditions.

Neuropathic pain The activity of a compound in the treatment of neuropathic pain can be measured according to the following test protocol.

  Animals: Male Sprague Dawley rats are housed in groups. All animals are placed in a 12 hour light / dark cycle (lights on at 07:00) and food and water are given ad libitum. All experiments were performed by observers who were unaware of the treatment in accordance with the 1986 UK Home Office Animals (Scientific Procedures) Act 1986.

Chronic Constriction Injury (CCI) Rat Model of Neuropathic Pain Sciatic nerve CCI was performed as previously described by Bennett and Xie (Bennett GJ, Xie YK, “A peripheral monotherapy in rat products”. pain sensation like sein in man ", Pain: 33: 87-107, 1988). The animals were anesthetized with a 2% isoflurane / O ₂ mixture. The right rear thigh was shaved and wiped with 1% iodine. The animals were then transferred to a thermostatic blanket for the duration of the procedure, and anesthesia was maintained through the nose cone during surgery. The skin was removed along the femoral line. The common sciatic nerve was exposed in the middle of the thigh by blunt dissection of the biceps femoris. Forceps were inserted under the nerve to release the approximately 7 mm nerve proximal to the sciatic trifurcation and the nerve was gently lifted off the thigh. Using forceps, the suture was passed under the nerve and tied with a single knot until a slight resistance was felt, then double tied. This procedure was repeated until the nerves were loosely tied at approximately 1 mm intervals by 4 ligatures (4-0 silk). The incisions were overlaid and the wound was treated with topical antibiotics.

Streptozocin (STZ) Diabetes Neuropathy in Rats Diabetes was induced by a single intraperitoneal administration of streptozotocin (50 mg / kg) freshly dissolved in 0.9% sterile saline. Streptozotocin injection induces reproducible mechanical allodynia that lasts for at least 7 weeks within 3 weeks (Chen and Pan, (Chen SR and Pan HL, “Hypersensitive of Spinothalotropic Neurons Associated Associated Rats ", J Neurophysiol 87: 2726-2733, 2002).

Assessment of static and dynamic allodynia Static allodynia Prior to the assessment of allodynia, animals were habituated to a test cage with a bottom wire. Static allodynia (von 1, 1.4, 2, 4, 6, 8, 10, 15, and 26 grams in order of von Frey hair (Stoelting, Wood Dale, Ill.) From weak to strong. ) Evaluation was applied to the sole of the hind paw. Each von Frey hair was applied to the paw for a maximum of 6 seconds or until a withdrawal response occurred. Once the withdrawal response to von Frey hair was established, the legs were retested starting with a filament that was thinner than the one that caused the withdrawal action, and then in order of increasing force with the remaining filaments until no withdrawal action occurred. The maximum force of 26 g not only elicited a response but also lifted the foot, so it was taken as a cut-off point. Both hind paws of each animal were tested in this way.

  The minimum amount of force required to elicit a response was recorded in grams as the paw withdrawal threshold (PWT). Static allodynia was defined as present when animals responded to 4 g or less of a stimulus that was non-noxious in untreated rats (Field MJ, Bramwell S, Hughes J, Singh L, “Detection of static and ”dynamic components of mechanical allodynia in rat models of neuropathic pain:” are the “significant by distinct primary sensor”, pp.

Dynamic allodynia Dynamic allodynia was assessed by lightly stroking the plantar surface of the hind paw with a cotton swab. Care was taken to follow this procedure in fully habituated rats that were not active to avoid recording general motor activity. At least two measurements were performed at each time point, and the average value was defined as a paw withdrawal operation waiting time (PWL). If no response was shown within 15 seconds, the procedure was terminated and the animal was assigned to its withdrawal operation time. Pain withdrawal responses were often accompanied by repeated buttocks or licking movements. Dynamic allodynia was considered to be present if the animal responded to a cotton swab stimulus within 8 seconds of starting stroking (Field et al., 1999).

Nociceptive pain The activity of a compound in the treatment of nociceptive pain can be measured according to the following test protocol.

Hot Plate Experimental Procedure: Male Sprague Dawley rats are placed on a hot plate (Ugo Basile, Italy) maintained at 55 ± 5 ° C. The time between when the animal is placed on the hot plate and when any of the movements of licking the front paws or hind legs, trembling or jumping off the surface is measured. Baseline measurements will be taken and animals will be re-evaluated after drug administration. The cut-off time of the hot plate waiting time is set to 20 seconds in order to prevent tissue damage.

Ovarian hysterectomy (OVX)
Experimental procedure: Female Sprague Dawley rats are placed in an anesthesia chamber and anesthetized with a 2% isoflurane / O ₂ mixture. During surgery, anesthesia is maintained from the nose cone. OVX is performed by a midline incision (2 cm in length) with a white line, during which animals are placed on an electric blanket. The ovarian mesenchyme and cervix are ligated with 5-0 silk using a single clamp technique. The ovaries and uterus are then removed. The abdominal wall is closed using a 4-needle simple interrupted suture and the skin is closed using 4 wound clips. Immediately after surgery, animals are placed in individual resin glass chambers. Once the animal has recovered from anesthesia, abdominal posture is recorded at various times, twice every 30 minutes. The scoring posture is the back posture, abdominal muscle contraction associated with inward movement of the hind limbs, body stretching, and pressing the lower abdomen against the floor. Each of these behaviors is scored as one posture.

Brennan
Experimental Procedure: Male Sprague Dawley rats are placed in an anesthesia chamber and anesthetized with a 2% isoflurane / O ₂ mixture. During surgery, anesthesia is maintained from the nose cone. Clean the bottom of the right hind paw with 50% ethanol. A 1 cm long longitudinal incision is made on the skin and fascia of the sole of the foot with a No. 11 blade, starting from 0.5 cm inside the heel edge and extending to the toes. Use forceps to lift the plantar muscle and make a longitudinal incision, leaving the muscle's origin and landing intact. After hemostasis by applying a weak pressure, the skin is closed by simple stitching of two needles with twisted silk.

OA model induced by monoiodoacetate (MIA) Male 6 week old Sprague-Dawley rats (SD, Japan SLC or Charles River Japan) are anesthetized with pentobarbital. The injection site is shaved and cleaned with 70% ethanol. Using a 29G needle, the right knee joint is injected with 25 μl of MIA solution or saline. At 7, 14, 19, and 20 days after the injection of MIA, the rats are trained and the weight bearing (WB) is measured without stress. 21 days after MIA injection, the WB on each hind leg is measured and the decrease in WB is calculated as 10.2. The WB decrease value is defined as “pre value”. Consider the pre-value and pre-pre-value, and prepare the experimental group equally. After administration of the test compound or vehicle, the WB of each hind paw was measured.

Cancer Pain Model In these experiments, male adult C3H / HeN mice (Japan SLC, Shizuoka Prefecture) were used. Mice were housed in an incubator maintained at 22 ° C. in an alternating 12 hour light / dark cycle according to National Institutes of Health guidelines and were given food and water ad libitum. The sarcoma injection protocol used is that described. After inhalation of isoflurane (2%) to induce general anesthesia, a surface incision was made in the skin overlying the patella using Mora scissors. The patella was then incised to expose the distal femoral condyle. A 30 gauge needle is inserted into the medullary canal at the level of the intercondylar notch to create the first core path. After making the initial core, a 29 gauge needle is used to make the final path to the bone. A 0.5 mm indentation was then made using a semi-circular bar drill on a dental high speed air handpiece to serve as a mechanical retention of the dental resin filling. Then 20 μl of α-minimal essential medium (Sigma; sham injection) or 20 μl of medium containing 1 × 10 ⁵ 2472 osteolytic sarcoma cells (American Type Culture Collection, Rockville, MD, USA). The injection was made using a 29 gauge needle and a 25 cc syringe. In order to prevent leakage of cells out of the bone, the injection site was closed with a dental resin and then thoroughly washed with filtered water. Automatic wound clips (Becton Dickinson, San Jose, CA) were used to close the wound. Wound clips were removed on the 5th day so as not to interfere with behavioral testing.

Assessment of static and dynamic allodynia Static allodynia The procedure described above for neuropathic pain.

Dynamic allodynia The procedure described above for neuropathic pain.

Radiant heat paw withdrawal behavior Experimental procedure: Rat foot sole test (Ugo Basile, Italy) according to a modification of Hargreaves et al., 1988 is used to evaluate thermal paw withdrawal behavior. Rats are habituated to an apparatus consisting of three individual perspex boxes on an elevated glass table. A movable radiant heat source is placed under the table, focused on the hind legs, and the paw withdrawal waiting time (PWL) is recorded. In order to prevent tissue damage, the automatic cut-off point is 22.5. PWL is measured 2-3 times for both hind paws of each animal, and the average is the baseline for the left and right hind paws. Calibrate the device to obtain a PWL of approximately 10 seconds.

Body weight load Experimental procedure: The "Incapastance Tester" (Linton Instruments, Diss, UK) is used to examine the sensitivity of animals in a weight bearing test. Rats were placed with their forelimbs placed on a perspex hill, and the weight distribution of the hind limbs was measured with a force transducer under each hind paw. Each animal is placed in the device and the weight load applied by the hind paw is noted. Subtract the same (injured) foot from the opposite foot (normal) to calculate the difference in weight bearing, and use this as raw data.

Inflammatory pain The activity of a compound in the treatment of inflammatory pain can be measured according to the following test protocol.

Weight Loss Reduction of Rats Induced by CFA Male 7 week old SD rats were fasted overnight. CFA (300 μg of Mycobacterium tuberculosis H37RA (Difco Laboratories) in 100 μL of liquid paraffin (Wako)) is injected into the right hind footpad of rats. Two days after the administration of CFA, changes in hindlimb weight distribution in the left (ipsilateral) and right (opposite) limbs are measured as an indicator of pain using the Linton Incapacitance Tester (Linton Instrumentation, UK) . Test compounds suspended in 0.1% MC (Wako) are orally administered in a volume of 1 mL per 100 g body weight. Each animal is placed in the device and the weight load exerted by the hind paw is measured before drug administration, 1, 2, and 4 hours after drug administration.

Rat mechanical hyperalgesia induced by carrageenan Male 4-week-old SD rats were fasted overnight. Hyperalgesia is induced by intraplantar injection of λ carrageenan (0.1 ml of a 1% w / v solution in saline, Choshi Kagaku). The test compound (0.1 ml of 0.1% methylcellulose / 100 g body weight) is given orally 5.5 hours after the carrageenin injection. The paw withdrawal threshold (grams) is measured by an analgesimeter (Ugo Basile) at 3.5, 4.5, 6.5, and 7.5 hours after carrageenin injection. (Randall L.O. and Selitto I.J., Arch. Int. Pharmacodyn. 111, 409-419, 1957)

Thermal hyperalgesia in rats induced by carrageenan (CITH)
Thermal hyperalgesia was assessed using the rat plantar test (Ugo Basile, Italy Comerio) according to a modification by Hargreaves et al. (1988). Briefly, rats were habituated to a device consisting of three individual perspex boxes on a glass table. A movable radiant heat source was placed under the table and focused on the desired foot. Paw withdrawal waiting time (PWL) was recorded three times for both hind paws of each animal, and the average was taken as the baseline for the left and right hind paws. The device was calibrated to obtain a PWL of approximately 10 seconds in an untreated rat. A 22.5 second cut-off was observed to prevent plantar band tissue damage. Lambda carrageenan was injected into the plantar of the right hind paw (100 μl, 20 mg / ml) and a baseline record of PWT was taken 2 hours after dosing.

Visceral pain The activity of a compound in the treatment of visceral pain can be measured according to the following test protocol.

  Several models are available for determining whether a compound is effective in treating visceral disorders. These models include the LPS model (Eutamene H et al., J Pharmacol Exp Ther 2000, 295 (1): 162-7), the TNBS model (Diop L. et al., Gastroenterology 1999, 116th vol. 4). (2): A986 page), IBD model (Clemett D, Markham A, Drugs April 2000, Vol. 59 (4): 929-56), pancreatic pain model (Isla AM, Hosp Med June 2000) 61 (6): 386-9), and visceral non-digestive pain models (Boucher M et al., J Urol July 2000, 164 (1): 203-8).

Chronic visceral allodynia in rats induced by TNBS In this experimental model of colonic distension in conscious rats, pre-injection of trinitrobenzenesulfonic acid (TNBS) into the proximal colon reduced the visceral pain threshold.

  Materials and Methods: Male Sprague-Dawley rats are used. 3 animals per cage are housed in a controlled environment (20 ± 1 ° C., humidity 50 ± 5%, 8:00 am to 8:00 pm lighting). On day 0 under anesthesia (ketamine 80 mg / kg ip, acepromazine 12 mg / kg ip) TNBS (50 mg / kg, 30% in ethanol) or saline (1.5 ml / kg) versus control rats Was injected into the proximal colon wall (1 cm from the cecum). After surgery, animals are individually housed in polypropylene cages and placed in a controlled environment (20 ± 1 ° C., humidity 50 ± 5%, 8:00 am. To 8:00 pm lighting) for 7 days. . Seven days after administration of TNBS, a balloon (5-6 cm in length) is inserted from the anus and the catheter is taped to the base of the tail (the balloon tip is 5 cm from the anus) and kept in position. One hour after oral administration of the test compound, a colonic bloating cycle is applied, ie the balloon is inflated in steps of 5 mmHg (0.667 kPa) from 0 mmHg to 75 mmHg, each inflation step lasting 30 seconds. . Each colonic bloating cycle is controlled by a standard pressure regulator. The threshold (mmHg) is taken to correspond to the pressure that initially caused abdominal contraction, where the bloating cycle is stopped. After 4 cycles of bloating in the same animal, the colon threshold is determined.

Rat Rectal Hypersensitivity Induced by LPS Intraperitoneal administration of bacterial lipopolysaccharide (LPS) has been shown to induce rectal hyperalgesia in conscious rats.

  Materials and Methods: Animals are surgically prepared for electromyography. That is, rats are anesthetized by intraperitoneal administration of acepromazine (0.6 mg / kg) and ketamine (120 mg / kg). Three groups of three electrodes, each in triplicate, are implanted just above the external oblique musculature, ie, the inguinal ligament. The electrode is exposed at the back of the neck and protected by a glass tube attached to the skin. Animals were individually housed in polypropylene cages and placed in a temperature controlled room (21 ° C.). Food (UAR pellets, French Epinay) and water were given ad libitum.

  Electromyogram recording begins 5 days after surgery. 2. The electrical activity of the abdominal striated muscle was measured using an electroencephalograph (Mini VIII Alvar, Paris, France) and using a short time constant (0.03 seconds) to remove the low frequency signal (<3 Hz). Record using a paper speed of 6 cm / min. Record spike burst as an index of abdominal contraction.

  Dwelling procedure: Rats are placed in a plastic tunnel (6 cm diameter x 25 cm long) where animals cannot move, escape or turn to prevent balloon breakage. To minimize stress responses during the experiment, animals are habituated to this procedure for 4 days before the rectum is full. The balloon used for distension is an arterial embolectomy catheter (Fogarty, Edwards Laboratories Inc.). The rectification of the rectum is performed by inserting a balloon (diameter 2 mm x length 2 cm) 1 cm from the rectal anus and fixing the catheter at the base of the tail. The balloon is inflated gradually with warm water from 0 ml to 1.2 ml in steps of 0.4 ml with each inflation step lasting 5 minutes. In order to detect possible leaks, the volume of water introduced into the balloon is confirmed by removing it completely with a syringe at the end of the bloating period.

Supplementary active agents suitable for use in the combinations of the present invention include the following.
1) Natural or synthetic prostaglandins or esters thereof. Suitable prostaglandins for use herein include alprostadil, prostaglandin E ₁ , prostaglandin E ₀ , 13,14-dihydroprostaglandin E ₁ , prostaglandin E ₂ , eprostinol. ); Natural, synthetic, and semi-synthetic prostaglandins and derivatives thereof, including those described in WO00033825 and / or US6037346, issued March 14, 2000, all incorporated herein by reference; PGE ₀ , PGE ₁ , PGA ₁ , PGB ₁ , PGF ₁ α, 19-hydroxy PGA ₁ , 19-hydroxy-PGB ₁ , PGE ₂ , PGB ₂ , 19-hydroxy-PGA ₂ , 19-hydroxy-PGB ₂ , PGE ₃ α, carbo Prostotromethamine, Ginop Examples include compounds such as lost, tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostane, thiaprost, moxisylate.
2) α-Adrenergic receptor antagonist compounds also known as α-adrenergic receptors or α-receptors or α-blockers. Suitable compounds for use herein include the disclosure thereof relating to α-adrenergic receptors, incorporated herein by reference, and selective α _1- adrenergic receptor or α _2- adrenergic receptor blockers and non-selectives. Α-adrenergic receptor blockers described in PCT application WO 99/30697 published on June 14, 1998, including adrenergic receptor blockers, are included, and suitable α ₁ adrenergic receptor blockers include: Phentolamine, phentolamine mesylate, trazodone, alfuzosin, indolamine, naphthopidyl, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohimbine, lauwolfa alkaloid, Recorda 15/2739, SNAP1 069, SNAP5089, RS17053, SL89.0591, doxazosin, terazosin, Abanokiru, and prazosin; US6037346 [3 May 14, 2000] of the α ₂ blocker blockers, Jibenarunin (dibenarnine), tolazoline, trimazosin, and Jibenarunin (dibenarnine); Described in U.S. Pat. Nos. 4,188,390, 4,026,894, 3511836, 431,507, 3,277,661, 2,973,666, 2503059, 4,703,063, 3381009, 4,252,721, and 259,000, each incorporated herein by reference. include alpha-adrenergic receptor, the alpha ₂ adrenergic receptor blockers, optionally a Pirukisamin (pirxamine) Clonidine in the presence cardiotonics of include papaverine, and papaverine.
3) NO donor (NO agonist) compound. NO-donor compounds suitable for use herein include organic nitrates such as mono-, di-, or tri-nitrates, or glyceryl trinitrate (also known as nitroglycerin), 5-isosorbide mononitrate, di- Isosorbide nitrate, pentaerythritol tetranitrate, erythritol tetranitrate, sodium nitroprusside (SNP), 3-morpholinoside nominin molsidomine, S-nitroso-N-acetylpenicillamine (SNAP) S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L-arginine, amyl nitrate, phosphosidemine, chlorohydrate, (SIN-1) S-nitroso-N-cysteine, diazeniumdiolate (NONOates), 1,5-pentanedinitrate, L-Arginine , Ginseng, Daegu, Molsidomine, Re-2047; organic nitrates containing nitrosylated moxysylate derivatives such as NMI-678-11 and NMI-937 described in published PCT application WO0012075.
4) Potassium channel opener or modulator. Potassium channel openers / modulators suitable for use herein include nicorandil, cromokalim, lebucromacarim, remakalim, pinacidil, clearazoxide, minoxidil, caribodotoxin, glyburide, 4-aminipyridine, ₂ is included.
5) Vasodilator. Vasodilators suitable for use herein include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroplumazine, Rec 15/2739, trazodone.
6) thromboxane A2 agonist,
7) CNS active agent,
8) Ergot alkaloids. Suitable ergot alkaloids are described in US Pat. No. 6,037,346, issued March 14, 2000, and include acetergamin, brazergoline, bromerguride, cyanergoline, derolgotril, derolgotril. , Dyslergin, ergonobine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, tergoline, tergotamine, tergotamine Gurido, and terguride are included.
9) Compounds that modulate the action of natriuretic factor, in particular B type and C type natriuretic factor such as atrial natriuretic factor (also known as atrial natriuretic peptide), neutral endopeptidase inhibitor,
10) A compound that inhibits angiotensin converting enzyme such as enapril, and a combined inhibitor of angiotensin converting enzyme and neutral endopeptidase such as omapatrilato,
11) Angiotensin receptor antagonists such as losartan,
12) a substrate for NO synthase, such as L-arginine,
13) Calcium channel blockers such as amlodipine,
14) an endothelin receptor antagonist and an endothelin converting enzyme inhibitor;
15) cholesterol-lowering drugs such as statins (eg atorvastatin / Lipitor ™) and fibrates,
16) antiplatelet and antithrombotic agents, such as tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activator inhibitors,
17) Insulin sensitizers such as resulin and hypoglycemic agents such as glipizide,
18) an acetylcholinesterase inhibitor such as donezipil;
19) steroidal or non-steroidal anti-inflammatory agent,
20) Estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists, preferably raloxifene or lasofoxifene, ie the preparation thereof is detailed in WO 96/21656 (−)-cis-6 -Phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol and pharmaceutically acceptable salts thereof,
21) a PDE inhibitor, more particularly a PDE2, 3, 4, 5, 7, or 8 inhibitor, preferably a PDE2 or PDE5 inhibitor, most preferably a PDE5 inhibitor (see below), Preferably, the IC50 for each enzyme is less than 100 nM (provided that PDE3 and PDE4 inhibitors are administered topically or only by injection into the penis),
22) One or more of vasoactive intestinal protein (VIP), VIP mimetics, VIP analogs, more particularly VIP receptor subtype VPAC1, VPAC, or PACAP (pituitary adenylate cyclase activating peptide) One or more of a VIP receptor agonist or VIP analog (eg, Ro-125-1553) or VIP fragment, one or more of an alpha adrenergic receptor antagonist (eg, Invicorp, Avaptadil) in combination with VIP What is mediated,
23) as claimed in Melanotan II, PT-14, PT-141, or WO-09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361, WO-00114879, WO-00113112, WO-0995358 Melanocortin receptor agonists or modulators or melanocortin activators (especially of the MC3 or MC4 subtype), such as
24) Serotonin receptor agonists, antagonists or modulators, more particularly 5HT1A (including VML670), 5HT2A, including those described in WO-09902159, WO-0000002550, and / or WO-00028993 Agonists, antagonists, or modulators of 5HT2C, 5HT3, and / or 5HT6 receptors,
25) Testosterone supplements (including dehydroandrostenedione), testosterone (Tostrelle), dihydrotestosterone, or testosterone implants,
26) Estrogens, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie, as a combination), or hormone replacement therapy of estrogen and methyltestosterone (eg, HRT, especially Premarin, Cenestein, Oestrofeminal, Equine, Estrace, Elleste Solo, Estring, Eastraderm TTS, Eastrader Matrix, Dermstril, Premphase, Preempro, Prepak, Prequeque, Estratest, EstratestHS, Tibole)
27) modulators of noradrenaline, dopamine and / or serotonin transporters, such as bupropion, GW-320659,
28) Purine receptor agonists and / or modulators,
29) neurokinin (NK) receptor antagonists, including those described in WO-09964008,
30) an opioid receptor agonist, antagonist or modulator, preferably an agonist of the ORL-1 receptor,
31) Oxytocin receptor agonists, antagonists or modulators, preferably selective oxytocin agonists or modulators,
32) Cannabinoid receptor modulators,
33) SEP inhibitors (SEPi), eg, SEPi having an IC ₅₀ of less than 100 nanomolar, more preferably less than 50 nanomolar.
The SEP inhibitor according to the present invention preferably has a selectivity to SEP of more than 30 times, more than 50 times compared to neutral endopeptidase NEP EC 3.4.24.11 and angiotensin converting enzyme (ACE). More preferred. SEPi also preferably has a selectivity greater than 100 times compared to endothelin converting enzyme (ECE).
34) NPY (especially Y1 and Y5 subtype) receptor antagonists or modulators,
35) a sex hormone binding globulin antagonist or modulator that inhibits the binding of estrogens and / or androgens,
36) Arginase II inhibitor,
37) Vasopressin receptor agonists, antagonists or modulators, preferably selective for the V1a receptor,
38) PDE5 inhibitor. Suitable PDE5 inhibitors include
5- [2-Ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] Pyrimidin-7-one (sildenafil), especially sildenafil citrate; (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) Pyrazino [2 ′, 1 ′: 6,1] pyrido [3,4-b] indole-1,4-dione (IC-351 or tadalafil); 2- [2-ethoxy-5- (4-ethyl-piperazine) -1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one (Vardenafil); 5- ( 5-acetyl- -Butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- (5 -Acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one; 4-[(3-chloro-4-methoxybenzyl) amino] -2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- (Pyrimidin-2-yl Methyl) pyrimidine-5-carboxamide (TA-1790); 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- [2- (1-Methylpyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide (DA8159), and pharmaceutically acceptable salts thereof are included.
39) Selective dopamine D4 receptor agonists such as 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole (ABT724),
40) dapoxetine, paroxetine, 3-[(dimethylamino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 28, WO0172687), 3-[(dimethylamino) methyl] -4- [3-Methyl-4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 12, WO0218333), N-methyl-N-({3- [3-methyl-4- (methylsulfanyl) phenoxy] -4- One or more selective serotonin reuptake inhibitors (SSRIs), such as pyridinyl} methyl) amine (Example 38, PCT application PCT / IB02 / 01032),
41) One or more NEP inhibitors. The NEP is preferably EC 3.4.24.11, the NEP inhibitor is more preferably a selective inhibitor of EC 3.4.24.11, and the selective NEP inhibitor has an IC ₅₀ More preferably, it is a selective inhibitor of EC 3.4.24.11 (e.g. ompatrilat, sampatrilat) with a NEP of less than 100 nM, and a suitable NEP inhibitor compound is EP-A-1097719 IC50 values for NEP and ACE can be determined using the methods described in published patent application EP 1097719-A1, paragraphs [0368]-[0376].
42) Melanocortin receptor agonists (eg melanotan II and PT141) and selective MC3 and MC4 agonists (eg THIQ),
43) Monoamine transport inhibitors, in particular noradrenaline reuptake inhibitors (NRI) (eg reboxetine).

  Patents and patent applications that can be used in accordance with the invention are referred to by cross-reference herein to the therapeutically active compounds described in the claims (especially claim 1) and specific examples. (All of which are incorporated herein by reference).

  When administering a combination of active agents, they can be administered simultaneously, separately or sequentially.

  The compounds of formula (I) can be administered alone, but with an appropriate pharmaceutical excipient, diluent or carrier generally selected in light of the intended route of administration and standard pharmaceutical practice. It is administered as a mixture.

  Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.

  For example, tablets of formula (I), which may contain flavoring or coloring agents; soft or hard capsules containing multiparticulate or nanoparticulate, liquid or powder; (including liquid-filled forms) Lozenges; chews; gels; rapid dispersion dosage forms; films; vaginal suppositories; sprays; and in the form of buccal / mucoadhesive patches, when administered orally, buccal, or sublingually Release, delayed release, modified release, sustained release, pulsed release, or controlled release can be applied.

  Such tablets include excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, glycine, starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarme May contain disintegrants such as sodium loose, certain complex silicates, and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, acacia . Further, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

  A similar type of solid composition can also be used as a filler in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, lactose, or high molecular weight polyethylene glycols. In aqueous suspensions and / or elixirs, the compounds of formula (I), various sweetening or flavoring agents, coloring substances or pigments, emulsifiers and / or suspending agents, and water, ethanol, propylene glycol, glycerin Can be combined with diluents such as combinations thereof.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules (eg made of gelatin or hydroxypropylmethylcellulose) and are usually carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose Or a suitable oil and one or more emulsifiers and / or suspending agents. A liquid formulation can also be prepared, for example, by reforming a solid from a sachet.

  The compounds of the present invention are used in rapidly dissolving and rapidly disintegrating dosage forms such as those described in Liang and Chen (2001) Expert Opinion in Therapeutic Patents, Volume 11 (6), pages 981-986. You can also

  Ingestible oral films for use in humans or animals are usually flexible, water-soluble or water-swellable thin film dosage forms that can be rapidly dissolving or mucoadhesive and are usually of formula (I) And a film forming polymer, a binder, a solvent, a wetting agent, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the formulation may perform more than one function.

  The compound of formula (I) may be water-soluble or insoluble. Water-soluble compounds usually contain 1% to 80% by weight of solute, more typically 20% to 50% by weight. Less soluble compounds may contain a higher percentage of the composition, usually up to 88% by weight of solute. Alternatively, the compound of formula (I) may be in the form of multiparticulate beads.

  The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids, usually in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight. Exists.

  Other possible ingredients include antioxidants, coloring agents, flavoring and flavoring agents, preservatives, salivary gland stimulants, cooling agents, co-solvents (including oils), relaxation agents, bulking agents, antifoaming agents, Surfactants and flavoring agents are included.

  Films according to the present invention are usually prepared by evaporating and drying a thin water-soluble film coated on a peelable backing or paper. This can be done in a drying oven or drying tunnel, usually a composite coating dryer, or by freeze drying or vacuum drying.

  The compounds of formula (I) may also be administered parenterally, for example intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracerebrally, intramuscularly or subcutaneously. Or can be administered by infusion techniques. For such parenteral administration, the compound is best used in the form of a sterile aqueous solution, which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. . The aqueous solution should be buffered appropriately (preferably to pH 3-9) if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

  The compound of formula (I) is usually from a dry powder inhaler in the form of a dry powder (alone, for example, as a dry blend with lactose or as a mixed component particle mixed with phospholipids, for example). Or as an aerosol spray, with or without an appropriate propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, It can also be administered intranasally or by inhalation from a pressurized container, pump, spray, atomizer (preferably an atomizer that produces a fine mist using electrohydraulics), or a nebulizer, or as a nasal solution. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, atomizers, or nebulizers are, for example, ethanol, aqueous ethanol, or other chemicals suitable for dispersing, solubilizing, or extending the release of actives, propellants as solvents As well as solutions or suspensions of the active compound, including optional surfactants such as sorbitan trioleate, oleic acid, oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminuting method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to produce nanoparticles, high pressure homogenization, or spray drying.

  Capsules (eg, made of gelatin or hydroxypropylmethylcellulose), blisters, and cartridges for use in an inhaler or insufflator are suitable powder bases such as powder mixtures of the compounds of the invention, lactose and starch , And performance regulators such as l-leucine, mannitol, magnesium stearate. Lactose may be anhydrous or in the monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

  A solution formulation suitable for use in an atomizer that generates a fine mist using electrohydraulic may contain 1 μg to 20 mg of the compound of the present invention per actuation, and the working volume may vary from 1 μl to 100 μl. . A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Other solvents that can be used in place of propylene glycol include glycerin and polyethylene glycol.

  A suitable flavoring agent such as menthol or l-menthol, or a suitable sweetening agent such as saccharin or saccharin sodium can also be added to the formulations of the invention intended for inhalation / intranasal administration.

  Formulations for inhalation / intranasal administration can be formulated for immediate and / or modified release, for example using PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, vaginal suppository, or enema. Cocoa butter is a traditional suppository base, but various alternative materials may be used as appropriate.

  Formulations for rectal / vaginal administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  The compounds of the present invention may be administered by the ocular route. For ophthalmic use, the compound may optionally be benzal chloride as a finely divided suspension in pH adjusted isotonic sterile saline, or preferably as a solution in pH adjusted isotonic sterile saline. It can be formulated in combination with a preservative such as Luconium. Alternatively, the compound of the present invention can be formulated as an ointment such as petrolatum.

  For topical application to the skin, the compound of formula (I) is, for example, one of mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene-polyoxypropylene compound, emulsifying wax, and water or Formulation as a suitable ointment containing the active compound suspended or dissolved in a mixture with the plural. Or, for example, a mixture of one or more of mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. It can be formulated as a suitable turbid or dissolved lotion or cream.

  The compounds of formula (I) can also be used in combination with cyclodextrins. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Generating a drug-cyclodextrin complex can alter the solubility, dissolution rate, bioavailability, and / or stability properties of the drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug, cyclodextrins can also be used as auxiliary additives, such as carriers, diluents, or solubilizers. α, β, and γ cyclodextrins are most commonly used and suitable examples are described in WO-A-91 / 11172, WO-A-94 / 02518, and WO-A-98 / 55148. .

  For example, since it may be desirable to administer a combination of active compounds for the purpose of treating a particular disease or condition, two or more pharmaceutical compositions, at least one of which comprises a compound according to the invention, may be formulated It is within the scope of the present invention that they may be conveniently combined in the form of a kit suitable for co-administration of products.

  Thus, a kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula I according to the invention, and a container, a divided bottle, or a divided foil bag, etc. Means for holding the compositions separately. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

  The kits of the invention are particularly suitable for administering different oral and parenteral dosage forms, for administering separate compositions at different dosing intervals, or for titrating separate compositions against each other. To assist compliance, kits usually include directions for administration and may be provided with a so-called memory aid.

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used.
Optical rotation at αD 587 nm Ac ₂ O Acetic anhydride APCI Atmospheric pressure chemical ionization Arbacel® filter agent br Broad Boc t-butoxycarbonyl Bu butyl CDCl ₃ chloroform-d1
CD ₃ OD methanol-d4
δ chemical shift d double line dd double double line DCM dichloromethane DMF N, N-dimethylformamide DMSO dimethyl sulfoxide eq (mole) equivalent ESI electrospray ionization Et ethyl EtOAc ethyl acetate h time HCl hydrogen chloride HPLC high performance liquid chromatography HR M / S High resolution mass spectrum IPA Isopropyl alcohol KOAc Potassium acetate m Multi-line Me Methyl MeCN Acetonitrile M / S Mass spectrum min Minute NMR Nuclear magnetic resonance q Quadruple r. t. Room temperature s singlet sat saturated t triplet td doublet triplet Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography

¹ H nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structure. The characteristic chemical shift (δ) is the usual abbreviation representing the main peak, ie s: singlet, d: doublet, t: triplet, q: quadruple, m: multiplet, br : Using broad, ppm _H from tetramethylsilane toward low magnetic field. The following abbreviations were used for common solvents. That is, CDCl ₃ : deuterated chloroform, DMSO: dimethyl sulfoxide. The abbreviation psi means pounds per square inch, and LRMS means low resolution mass spectrometry. When thin layer chromatography (TLC) is used, it refers to silica gel TLC using silica gel 60F ₂₅₄ plates, where R _f is the first of the solvent advanced the length of the compound on the TLC plate. Divided by length.

Example 1
3-Azetidin-3-ylphenol hydrochloride

調製例５の生成物（８８ｍｇ、０．３５ｍｍｏｌ）をジクロロメタン（５ｍＬ）に溶かした氷冷溶液に、塩化水素ガスを１５分間バブルした。次いで混合物を室温に温め、１８時間攪拌した。反応混合物を真空中で濃縮し、残渣をジエチルエーテルで摩砕して、表題化合物を白色固体として収率８２％で５４．１ｍｇ得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ：４．２０（ｍ，３Ｈ）、４．３５（ｍ，２Ｈ）、６．７５（ｍ，２Ｈ）、６．８５（ｄ，１Ｈ）、７．２０（ｔ，１Ｈ）。ＭＳ ＡＰＣＩ ｍ／ｚ １５０［ＭＨ］^＋ 微量分析：Ｃ_９Ｈ_１１ＮＯの計算値（％）：Ｃ ５６．４２；Ｈ ６．６６；Ｎ ７．３１；実測値（％）Ｃ ５６．２１；Ｈ ６．３８，Ｎ ７．３０

Hydrogen chloride gas was bubbled into an ice-cold solution of the product of Preparation Example 5 (88 mg, 0.35 mmol) in dichloromethane (5 mL) for 15 minutes. The mixture was then warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether to give 54.1 mg of the title compound as a white solid in 82% yield.
¹ H NMR (400 MHz, CD ₃ OD) δ: 4.20 (m, 3H), 4.35 (m, 2H), 6.75 (m, 2H), 6.85 (d, 1H), 7. 20 (t, 1H). MS APCI m / z 150 [MH] ⁺ trace analysis: calculated C ₉ H ₁₁ NO (%): C 56.42; H 6.66; N 7.31; found (%) C 56.21; H 6.38, N 7.30

(Example 2)
3- (1-propylazetidin-3-yl) phenol trifluoroacetate

表題化合物は、調製例８の生成物から、調製例５と同様の方法を使用して調製した。粗製の化合物を、１００：０〜９５：５のジクロロメタン：メタノールを溶離液とするシリカゲルカラムクロマトグラフィーによって精製して、所望の生成物を淡黄色の油状物として収率８０％で得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．００（ｔ，３Ｈ）、１．６５（ｍ，２Ｈ）、３．０５（ｔ，２Ｈ）、３．３５（ｂｍ，２Ｈ）、４．００（ｍ，３Ｈ）、６．６０（ｍ，２Ｈ）、６．８０（ｄ，１Ｈ）、７．１５（ｔ，１Ｈ）。ＭＳ ＡＰＣＩ ｍ／ｚ １９２［ＭＨ］^＋ 微量分析：Ｃ_１２Ｈ_１７ＮＯ．ＣＦ_３ＣＯ_２Ｈ ０．２ ＣＨ_３ＯＨの計算値（％）：Ｃ ５４．７２；Ｈ ６．０８；Ｎ ４．４９；実測値（％）Ｃ ５４．５０；Ｈ ６．２５，Ｎ ４．５２

The title compound was prepared from the product of Preparation Example 8 using a method similar to that of Preparation Example 5. The crude compound was purified by silica gel column chromatography eluting with 100: 0 to 95: 5 dichloromethane: methanol to give the desired product as a pale yellow oil in 80% yield.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.00 (t, 3H), 1.65 (m, 2H), 3.05 (t, 2H), 3.35 (bm, 2H), 4.00 (M, 3H), 6.60 (m, 2H), 6.80 (d, 1H), 7.15 (t, 1H). MS APCI m / z 192 [MH] ⁺ trace analysis: C ₁₂ H ₁₇ NO. Calculated value for CF ₃ CO ₂ H 0.2 CH ₃ OH (%): C 54.72; H 6.08; N 4.49; Found (%) C 54.50; H 6.25, N 4 .52

(Example 3)
2-Iodo-5- (1-propylazetidin-3-yl) phenol

実施例２の生成物をジクロロメタンに溶解させ、炭酸カリウム溶液で洗浄した。有機溶液を硫酸マグネシウムで乾燥させ、真空中で濃縮して、遊離のアミンを得た。アミンのサンプル（１．５ｇ、７．８５ｍｍｏｌ）をジクロロメタン（４０ｍＬ）に溶解させ、溶液を０℃に冷却した。次いで、ヨウ素（２．０９ｇ、８．２５ｍｍｏｌ）のジクロロメタン（５０ｍＬ）溶液を１時間かけて滴下した。混合物を室温に温め、２４時間攪拌を続けた。次いで、反応液を炭酸カリウム溶液（５０ｍＬ）および１０％チオ硫酸ナトリウム水溶液（８０ｍＬ）で洗浄し、有機溶液を硫酸マグネシウムで乾燥させ、真空中で濃縮した。残渣を、９０：１０：０〜９０：１０：１の酢酸エチル：メタノール：０．８８アンモニアを溶離液とするシリカゲルカラムクロマトグラフィーによって精製した後、Ｐｈｅｎｏｍｅｎｅｘ ＬｕｎａＣ１８システムを使用し、５０：５０〜２６：７４の１０ｍＭ酢酸アンモニウム（水性）：１０ｍＭ酢酸アンモニウム（メタノール性）を溶離液とするＨＰＬＣによってさらに精製して、表題化合物をゴム質として得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：０．９８（ｔ，３Ｈ）、１．４５（ｍ，２Ｈ）、２．５５（ｔ，２Ｈ）、３．２２（ｄｄ，２Ｈ）、３．７２（ｍ，１Ｈ）、３．８０（ｄｄ，２Ｈ）、６．５５（ｄ，１Ｈ）、６．８２（ｓ，１Ｈ）、７．６０（ｄ，１Ｈ）。ＭＳ ＡＰＣＩ ｍ／ｚ ３１８［ＭＨ］^＋

The product of Example 2 was dissolved in dichloromethane and washed with potassium carbonate solution. The organic solution was dried over magnesium sulfate and concentrated in vacuo to give the free amine. A sample of amine (1.5 g, 7.85 mmol) was dissolved in dichloromethane (40 mL) and the solution was cooled to 0 ° C. Then, a solution of iodine (2.09 g, 8.25 mmol) in dichloromethane (50 mL) was added dropwise over 1 hour. The mixture was allowed to warm to room temperature and stirring was continued for 24 hours. The reaction was then washed with potassium carbonate solution (50 mL) and 10% aqueous sodium thiosulfate (80 mL) and the organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 90: 10: 0 to 90: 10: 1 ethyl acetate: methanol: 0.88 ammonia, then using a Phenomenex Luna C18 system, 50: 50-26 Further purification by HPLC eluting with: 74 10 mM ammonium acetate (aq): 10 mM ammonium acetate (methanolic) gave the title compound as a gum.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.98 (t, 3H), 1.45 (m, 2H), 2.55 (t, 2H), 3.22 (dd, 2H), 3.72 (M, 1H), 3.80 (dd, 2H), 6.55 (d, 1H), 6.82 (s, 1H), 7.60 (d, 1H). MS APCI m / z 318 [MH] ⁺

(Examples 4 and 5)
A solution of the product of Preparation Example 10 (1.98 g, 10.34 mmol) in glacial acetic acid (30 mL) was cooled to 10 ° C. A solution of bromine (558 μL, 10.85 mmol) in glacial acetic acid (30 mL) was added dropwise and the mixture was stirred at room temperature for 18 hours. A few drops of 10% sodium thiosulfate solution were added and then the mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and sodium bicarbonate solution and the aqueous layer was extracted with dichloromethane (twice). The combined organic solution was then dried over magnesium sulfate and concentrated in vacuo to give a light brown foam. The foam was purified by silica gel column chromatography eluting with 100: 0 to 90:10 dichloromethane: methanol to obtain the product of Example 4 first, followed by the product of Example 5. .

Example 4
2,6-Dibromo-4- (1-propylazetidin-3-yl) phenol

^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：０．９１（ｔ，３Ｈ）、１．３０（ｍ，２Ｈ）、２．３８（ｍ，２Ｈ）、３．０１（ｍ，２Ｈ）、３．７５（ｍ，１Ｈ）、３．８２（ｍ，２Ｈ）、７．４４（ｓ，２Ｈ）ＭＳ ＡＰＣＩ ｍ／ｚ ３４８／３５０［ＭＨ］^＋；微量分析：Ｃ_１２Ｈ_１５ＮＯＢｒ_２の計算値（％）：Ｃ ４１．２９；Ｈ ４．３３；Ｎ ４．０１；実測値（％）Ｃ ４１．１３；Ｈ ４．６１，Ｎ ３．７１；収量：７０ｍｇ（３％）

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 0.91 (t, 3H), 1.30 (m, 2H), 2.38 (m, 2H), 3.01 (m, 2H), 3 .75 (m, 1H), 3.82 (m, 2H), 7.44 (s, 2H) MS APCI m / z 348/350 [MH] ⁺ ; microanalysis: calculated for C ₁₂ H ₁₅ NOBr ₂ (%): C 41.29; H 4.33; N 4.01; Found (%) C 41.13; H 4.61, N 3.71; Yield: 70 mg (3%)

(Example 5)
2-Bromo-4- (1-propylazetidin-3-yl) phenol

^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：０．９５（ｔ，３Ｈ）、１．４５（ｍ，２Ｈ）、２．５５（ｍ，２Ｈ）、３．２２（ｍ，２Ｈ）、３．７０（ｍ，１Ｈ）、３．８８（ｍ，２Ｈ）、６．９０（ｄ，１Ｈ）、７．１０（ｄ，１Ｈ）、７．３９（ｓ，１Ｈ）ＭＳ ＡＰＣＩ ｍ／ｚ ２７２［ＭＨ］^＋；微量分析：Ｃ_１２Ｈ_１６ＮＯＢｒ ０．４ ＤＣＭの計算値（％）：Ｃ ４８．９９；Ｈ ５．５７；Ｎ ４．６１；実測値（％）Ｃ ４８．９４；Ｈ ５．６０，Ｎ ４．５９；収量：４５０ｍｇ（１６％）

¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.95 (t, 3H), 1.45 (m, 2H), 2.55 (m, 2H), 3.22 (m, 2H), 3.70 (M, 1H), 3.88 (m, 2H), 6.90 (d, 1H), 7.10 (d, 1H), 7.39 (s, 1H) MS APCI m / z 272 [MH] ⁺ ; Microanalysis: C ₁₂ H ₁₆ NOBr 0.4 Calculated DCM (%): C 48.99; H 5.57; N 4.61; Found (%) C 48.94; H 5.60 , N 4.59; Yield: 450 mg (16%)

(Preparation Example 1)
3-{[(trifluoromethyl) sulfonyl] oxy} azetidine-1-carboxylate t-butyl

１−ｂｏｃ−３−（ヒドロキシ）アゼチジン（１０ｇ、５７．８ｍｍｏｌ）のジクロロメタン（１００ｍＬ）溶液に、２，６−ルチジン（１３．４ｍＬ、１１５．６１ｍｍｏｌ）を加え、溶液を−３０℃に冷却した。次いで、トリフルオロメタンスルホン酸無水物（１２．７ｍＬ、６０．６９ｍｍｏｌ）を滴下し、混合物を−３０℃で３０分間攪拌した。次いで、混合物を室温に温め、ジクロロメタン（５０ｍＬ）で希釈し、１Ｍ塩酸（１００ｍＬ）および水（１００ｍＬ）で洗浄した。有機溶液を硫酸マグネシウムで乾燥させ、真空中で濃縮して、表題化合物を赤色の油状物として定量的収率で得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（ｓ，９Ｈ）、４．１５（ｍ，２Ｈ）、４．３２（ｍ，２Ｈ）、５．４０（ｍ，１Ｈ）

To a solution of 1-boc-3- (hydroxy) azetidine (10 g, 57.8 mmol) in dichloromethane (100 mL) was added 2,6-lutidine (13.4 mL, 115.61 mmol) and the solution was cooled to −30 ° C. . Then trifluoromethanesulfonic anhydride (12.7 mL, 60.69 mmol) was added dropwise and the mixture was stirred at −30 ° C. for 30 minutes. The mixture was then warmed to room temperature, diluted with dichloromethane (50 mL) and washed with 1M hydrochloric acid (100 mL) and water (100 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a red oil in quantitative yield.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.45 (s, 9H), 4.15 (m, 2H), 4.32 (m, 2H), 5.40 (m, 1H)

(Preparation Example 2)
3-iodoazetidine-1-tert-butyl carboxylate

調製例１の生成物（５７．８ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１５０ｍＬ）に溶かした氷冷溶液に、ヨウ化カリウム（５５．１１ｇ、３３２．０４ｍｍｏｌ）を加え、混合物を室温で１８時間攪拌した。次いで、混合物を水（３０ｍＬ）で希釈し、ジエチルエーテル（２×２００ｍＬ）で抽出した。有機溶液を合わせて水（２×２００ｍＬ）で洗浄し、硫酸マグネシウムで乾燥させ、真空中で濃縮して、橙色の油状物を得た。油状物を、９５：５のペンタン：酢酸エチルを溶離液とするシリカゲルカラムクロマトグラフィーによって精製して、表題化合物１２．２ｇを得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．４３（ｓ，９Ｈ）、４．２５（ｍ，２Ｈ）、４．４５（ｍ，１Ｈ）、４．６５（ｍ，２Ｈ）

To an ice-cooled solution of the product of Preparation Example 1 (57.8 mmol) in N, N-dimethylformamide (150 mL) was added potassium iodide (55.11 g, 332.04 mmol), and the mixture was stirred at room temperature for 18 hours. Stir. The mixture was then diluted with water (30 mL) and extracted with diethyl ether (2 × 200 mL). The combined organic solutions were washed with water (2 × 200 mL), dried over magnesium sulfate and concentrated in vacuo to give an orange oil. The oil was purified by silica gel column chromatography eluting with 95: 5 pentane: ethyl acetate to give 12.2 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.43 (s, 9H), 4.25 (m, 2H), 4.45 (m, 1H), 4.65 (m, 2H)

(Preparation Example 3)
3- [4- (Benzyloxy) phenyl] azetidine-1-carboxylate t-butyl

亜鉛末（１．３９ｇ、２１．２ｍｍｏｌ）を１００℃の真空オーブンで１８時間乾燥させ、窒素でパージし、１，２−ジブロモエタン（０．１２ｍＬ、１．４１ｍｍｏｌ）の入った無水Ｎ，Ｎ−ジメチルホルムアミド（２５ｍＬ）で懸濁させた。反応混合物を７０℃で１０分間加熱し、次いで室温に冷却した。クロロトリメチルシラン（０．１８ｍＬ、１．４１ｍｍｏｌ）を滴下し、攪拌を１時間続けた。次いで、調製例２の生成物（５ｇ、１７．６６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２０ｍＬ）溶液を加え、混合物を４０℃で１時間加熱した後、１−（ベンジルオキシ）−３−ヨードベンゼン（５．７５ｇ、１８．５５ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（３２４ｍｇ、０．３５ｍｍｏｌ）、およびトリ（２−フリル）ホスフィン（１６４ｍｇ、０．７１ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（５０ｍＬ）中混合物を加えた。反応混合物を７０℃に温め、４時間攪拌した。次いで、混合物を室温に冷却し、ジエチルエーテルと飽和塩化アンモニウム溶液とに分配した。水層を分離し、別のジエチルエーテルで抽出した。有機溶液を合わせて硫酸マグネシウムで乾燥させ、真空中で濃縮した。残渣を、９５：５〜９０：１０のペンタン：酢酸エチルを溶離液とするシリカゲルカラムクロマトグラフィーによって精製すると、表題化合物が黄色の油状物として収率６０％で３．６ｇ得られた。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（ｓ，９Ｈ）、３．７０（ｍ，１Ｈ）、３．９５（ｍ，２Ｈ）、４．３０（ｄｄ，２Ｈ）、５．０５（ｓ，２Ｈ）、６．９０（ｂｒｍ，３Ｈ）、７．２７（ｍ，１Ｈ）、７．３５（ｍ，１Ｈ）７．４０（ｂｒｍ，４Ｈ）。

Zinc dust (1.39 g, 21.2 mmol) was dried in a vacuum oven at 100 ° C. for 18 hours, purged with nitrogen, and anhydrous N, N containing 1,2-dibromoethane (0.12 mL, 1.41 mmol). -Suspended with dimethylformamide (25 mL). The reaction mixture was heated at 70 ° C. for 10 minutes and then cooled to room temperature. Chlorotrimethylsilane (0.18 mL, 1.41 mmol) was added dropwise and stirring was continued for 1 hour. Then, a solution of the product of Preparation 2 (5 g, 17.66 mmol) in N, N-dimethylformamide (20 mL) was added and the mixture was heated at 40 ° C. for 1 hour, after which 1- (benzyloxy) -3-iodo N, N- of benzene (5.75 g, 18.55 mmol), tris (dibenzylideneacetone) dipalladium (0) (324 mg, 0.35 mmol), and tri (2-furyl) phosphine (164 mg, 0.71 mmol) A mixture in dimethylformamide (50 mL) was added. The reaction mixture was warmed to 70 ° C. and stirred for 4 hours. The mixture was then cooled to room temperature and partitioned between diethyl ether and saturated ammonium chloride solution. The aqueous layer was separated and extracted with another diethyl ether. The organic solutions were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 95: 5-90: 10 pentane: ethyl acetate to give 3.6 g of the title compound as a yellow oil in 60% yield.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.45 (s, 9H), 3.70 (m, 1H), 3.95 (m, 2H), 4.30 (dd, 2H), 5.05 (S, 2H), 6.90 (brm, 3H), 7.27 (m, 1H), 7.35 (m, 1H) 7.40 (brm, 4H).

(Preparation Example 4)
3- [4- (Benzyloxy) phenyl] azetidine-1-carboxylate t-butyl

表題化合物は、調製例２の生成物と１−（ベンジルオキシ）−４−ヨードベンゼンから、調製例３に類似した方法を使用して、白色固体として収率５７％で調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（ｓ，９Ｈ）、３．６５（ｍ，１Ｈ）、３．９０（ｍ，２Ｈ）、４．３０（ｍ，２Ｈ）、５．０５（ｓ，２Ｈ）、６．９５（ｄ，２Ｈ）、７．２２（ｄ，２Ｈ）、７．２９〜７．４５（ｍ，５Ｈ）

The title compound was prepared from the product of Preparation Example 2 and 1- (benzyloxy) -4-iodobenzene as a white solid in 57% yield using a method similar to Preparation Example 3.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.45 (s, 9H), 3.65 (m, 1H), 3.90 (m, 2H), 4.30 (m, 2H), 5.05 (S, 2H), 6.95 (d, 2H), 7.22 (d, 2H), 7.29-7.45 (m, 5H)

(Preparation Example 5)
3- (3-hydroxyphenyl) azetidine-1-carboxylate t-butyl

調製例３の生成物（１００ｍｇ、０．２９ｍｍｏｌ）のエタノール（５ｍＬ）溶液に、１０％Ｐｄ／Ｃ（１０ｍｇ）およびギ酸アンモニウム（９３ｍｇ、１．４８ｍｍｏｌ）を加え、混合物を４時間加熱還流した。次いで、反応混合物を室温に冷却し、終始エタノールで洗浄しながらＡｒｂｏｃｅｌ（登録商標）で濾過した。濾液を真空中で濃縮すると、表題化合物が透明な油状物として定量的収率で８８ｍｇ得られた。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．４７（ｓ，９Ｈ）、３．５９（ｍ，１Ｈ）、４．００（ｄｄ，２Ｈ）、４．３５（ｄｄ，２Ｈ）、６．７５（ｍ，２Ｈ）、６．９５（ｓ，１Ｈ）、７．１５（ｍ，１Ｈ）

To a solution of the product of Preparation 3 (100 mg, 0.29 mmol) in ethanol (5 mL) was added 10% Pd / C (10 mg) and ammonium formate (93 mg, 1.48 mmol), and the mixture was heated to reflux for 4 hours. The reaction mixture was then cooled to room temperature and filtered through Arbocel® with an ethanol wash throughout. The filtrate was concentrated in vacuo to give 88 mg of the title compound as a clear oil in quantitative yield.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.47 (s, 9H), 3.59 (m, 1H), 4.00 (dd, 2H), 4.35 (dd, 2H), 6.75 (M, 2H), 6.95 (s, 1H), 7.15 (m, 1H)

(Preparation Example 6)
3- [3- (Benzyloxy) phenyl] azetidine trifluoroacetate

調製例３の生成物（１０．６３ｇ、３１．３５ｍｍｏｌ）をジクロロメタン（５０ｍＬ）に溶かした氷冷溶液に、トリフルオロ酢酸（５０ｍＬ、６２７ｍｍｏｌ）を滴下し、混合物を０℃で４５分間攪拌した。混合物を室温に温め、さらに４時間攪拌を続けた。次いで、反応混合物を真空中で濃縮して、表題化合物を固体として定量的収率で１０ｇ得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：４．２０〜４．６５（ｂｒｍ，５Ｈ）、５．０５（ｓ，２Ｈ）、６．９５（ｍ，３Ｈ）、７．３０〜７．５０（ｍ，６Ｈ）ＭＳ ＥＳ ｍ／ｚ ２４０［ＭＨ］^＋

Trifluoroacetic acid (50 mL, 627 mmol) was added dropwise to an ice-cooled solution of the product of Preparation Example 3 (10.63 g, 31.35 mmol) in dichloromethane (50 mL), and the mixture was stirred at 0 ° C. for 45 minutes. The mixture was allowed to warm to room temperature and stirring was continued for an additional 4 hours. The reaction mixture was then concentrated in vacuo to give 10 g of the title compound as a solid in quantitative yield.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 4.20 to 4.65 (brm, 5H), 5.05 (s, 2H), 6.95 (m, 3H), 7.30 to 7.50 ( m, 6H) MS ES m / z 240 [MH] ⁺

(Preparation Example 7)
3- [4- (Benzyloxy) phenyl] azetidine trifluoroacetate

表題化合物は、調製例４の生成物とトリフルオロ酢酸から、調製例６と同様の方法を使用して、白色固体として定量的収率で調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：４．１０〜４．３０（ｂｒｍ，３Ｈ）、４．３５〜４．４０（ｂｒｍ，２Ｈ）、５．００（ｓ，２Ｈ）、７．００（ｄ，２Ｈ）、７．２５（ｍ，２Ｈ）、７．３０〜７．４０（ｂｒｍ，５Ｈ）ＭＳ ＡＰＣＩ ｍ／ｚ ２４０［ＭＨ］^＋

The title compound was prepared from the product of Preparation Example 4 and trifluoroacetic acid as a white solid in quantitative yield using the same method as Preparation Example 6.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 4.10 to 4.30 (brm, 3H), 4.35 to 4.40 (brm, 2H), 5.00 (s, 2H), 7.00 ( d, 2H), 7.25 (m, 2H), 7.30-7.40 (brm, 5H) MS APCI m / z 240 [MH] ⁺

(Preparation Example 8)
3- [3- (Benzyloxy) phenyl] -1-propylazetidine trifluoroacetate

調製例６の生成物（７．９４ｇ、３１．３４ｍｍｏｌ）のジクロロメタン（５０ｍＬ）溶液に、プロピオンアルデヒド（３．４ｍＬ、４７．０１ｍｍｏｌ）を加え、混合物を５分間攪拌した。反応混合物を０℃に冷却し、次いでトリアセトキシ水素化ホウ素ナトリウム（９．９６ｇ、４７．０１ｍｍｏｌ）を少量ずつ加えた。混合物を１８時間攪拌する間、温度が２５℃になった。反応を水（５ｍＬ）で失活させ、ジクロロメタンと炭酸カリウム溶液とに分配した。有機層を分離し、硫酸マグネシウムで乾燥させ、真空中で濃縮して、褐色の油状物を得た。この油状物を、１００：０〜９６：４のジクロロメタン：メタノールを溶離液とするシリカゲルカラムクロマトグラフィーによって精製すると、表題化合物が黄色の油状物として収率９６％で８．４３ｇ得られた。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：１．００（ｔ，３Ｈ）、１．６５（ｍ，２Ｈ）、３．００（ｍ，２Ｈ）、３．８０（ｂｒｍ，２Ｈ）、４．２２（ｍ，１Ｈ）、４．５０（ｂｒｍ，２Ｈ）、５．０５（ｓ，２Ｈ）、６．８０〜６．９５（ｂｒｍ，３Ｈ）、７．２５〜７．４５（ｍ，６Ｈ）ＭＳ ＥＳ ｍ／ｚ ２８２［ＭＨ］^＋

To a solution of the product of Preparation 6 (7.94 g, 31.34 mmol) in dichloromethane (50 mL) was added propionaldehyde (3.4 mL, 47.01 mmol) and the mixture was stirred for 5 minutes. The reaction mixture was cooled to 0 ° C. and then sodium triacetoxyborohydride (9.96 g, 47.01 mmol) was added in small portions. The temperature was 25 ° C. while the mixture was stirred for 18 hours. The reaction was quenched with water (5 mL) and partitioned between dichloromethane and potassium carbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give a brown oil. The oil was purified by silica gel column chromatography eluting with 100: 0 to 96: 4 dichloromethane: methanol to give 8.43 g of the title compound as a yellow oil in 96% yield.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.00 (t, 3H), 1.65 (m, 2H), 3.00 (m, 2H), 3.80 (brm, 2H), 4.22 (M, 1H), 4.50 (brm, 2H), 5.05 (s, 2H), 6.80-6.95 (brm, 3H), 7.25-7.45 (m, 6H) MS ES m / z 282 [MH] ⁺

(Preparation Example 9)
3- [4- (Benzyloxy) phenyl] -1-propylazetidine

表題化合物は、調製例７の生成物とプロピオンアルデヒドから、調製例８に類似した方法を使用して、黄色の油状物として収率６６％で調製した。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：０．９０（ｔ，３Ｈ）、１．４０（ｍ，２Ｈ）、２．４５（ｔ，２Ｈ）、３．０５（ｍ，２Ｈ）３．６５〜３．８０（ｂｒｍ，３Ｈ）、５．０５（ｓ，２Ｈ）、６．９５（ｄ，２Ｈ）、７．２０（ｄ，２Ｈ）、７．３０〜７．４５（ｂｒｍ，５Ｈ）ＭＳ ＡＰＣＩ ｍ／ｚ ２８２［ＭＨ］^＋

The title compound was prepared from the product of Preparation 7 and propionaldehyde as a yellow oil in 66% yield using a method analogous to Preparation 8.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.90 (t, 3H), 1.40 (m, 2H), 2.45 (t, 2H), 3.05 (m, 2H) 3.65 3.80 (brm, 3H), 5.05 (s, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 7.30-7.45 (brm, 5H) MS APCI m / z 282 [MH] ⁺

(Preparation Example 10)
4- (1-propylazetidin-3-yl) phenol

表題化合物は、調製例９の生成物から、調製例５に類似した方法を使用して調製した。粗製の化合物をジエチルエーテルで摩砕して、所望の生成物をクリーム色の固体（ｃｒｅａｍ ｓｏｌｉｄ）として収率９５％で得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９５（ｔ，３Ｈ）、１．４２（ｍ，２Ｈ）、２．５１（ｔ，２Ｈ）、３．０９（ｍ，２Ｈ）、３．７５（ｍ，１Ｈ）、３．８２（ｍ，２Ｈ）、６．７８（ｄ，２Ｈ）、７．１１（ｄ，２Ｈ）ＭＳ ＡＰＣＩ ｍ／ｚ １９２［ＭＨ］^＋ 微量分析：Ｃ_１２Ｈ_１７ＮＯ ０．１Ｈ_２Ｏの計算値（％）：Ｃ ７４．６５；Ｈ ８．９８；Ｎ ７．２５；実測値（％）Ｃ ７４．５８；Ｈ ９．０２，Ｎ ７．０２

The title compound was prepared from the product of Preparation Example 9 using a method analogous to Preparation Example 5. The crude compound was triturated with diethyl ether to give the desired product as a cream solid in 95% yield.
¹ H NMR (400 MHz, CDCl 3) δ: 0.95 (t, 3 H), 1.42 (m, 2 H), 2.51 (t, 2 H), 3.09 (m, 2 H), 3.75 ( m, 1H), 3.82 (m, 2H), 6.78 (d, 2H), 7.11 (d, 2H) MS APCI m / z 192 [MH] ⁺ microanalysis: C ₁₂ H ₁₇ NO 0 Calculated (%) for 1 H ₂ O: C 74.65; H 8.98; N 7.25; Found (%) C 74.58; H 9.02, N 7.02

Claims (15)

Compound of formula (I)

[Where:
R ¹ is selected from H and (C ₁ -C ₆ ) alkyl;
R ² is selected from H, halo, and C (O) NH ₂ ;
R ³ is selected from H, C (O) OH, C (O) NH ₂ , C (O) O (C ₁ -C ₆ ) alkyl, OH, and halo;
R ⁴ is NH ₂ , O (C ₁ -C ₆ ) alkyl, OCH ₂ Ph, C (O) OH, C (O) NH ₂ , C (O) (C ₁ -C ₆ ) alkyl, C (O ) O (C ₁ -C ₆ ) alkyl, OH, halo, and (C ₁ -C ₆ ) alkyl, wherein the alkyl may be substituted with OH;
R ⁵ is selected from H, CN, and C (O) NH ₂ ;
However, when R ⁴ is NH ₂ and R ¹ , R ² , and R ⁵ are all H, R ³ cannot be OH or Cl, R ⁴ is Cl, and R ¹ is H or CH _When R ² and R ⁵ are H, R ³ cannot be Cl. ]
And pharmaceutically acceptable salts, solvates, polymorphs, and prodrugs thereof. The compound of claim 1, wherein R ¹ is selected from H and propyl. ^3. A compound according to claim 1 or claim 2 wherein R2 is selected from H and halo. R ³ is H, are selected I, and from OH, A compound according to any one of claims 1 to 3. R ⁴ is selected from OH and Br, the compound according to any one of claims 1 to 4. The compound according to any one of claims 1 to 5, wherein R ⁵ is H. The compound according to any one of claims 1 to 6, wherein at least one of R ³ and R ⁴ is OH. 3-azetidin-3-ylphenol hydrochloride,
3- (1-propylazetidin-3-yl) phenol trifluoroacetate,
2-iodo-5- (1-propylazetidin-3-yl) phenol,
2,6-dibromo-4- (1-propylazetidin-3-yl) phenol,
2-bromo-4- (1-propylazetidin-3-yl) phenol,
And a pharmaceutically acceptable salt, solvate, polymorph, and prodrug thereof.   9. A compound of formula (I) according to any of claims 1 to 8 for use as a medicament.   Use of a compound of formula (I) according to any of claims 1 to 8, in the preparation of a medicament for treating or preventing sexual dysfunction.   Use according to claim 10, wherein the sexual dysfunction is male erectile dysfunction.   Use according to claim 10, wherein the sexual dysfunction is female sexual dysfunction.   13. Use according to claim 12, wherein the female sexual dysfunction is selected from impaired sexual desire, sexual arousal disorder, orgasmic disorder, or sexual pain disorder.   Use of a compound of formula (I) according to any of claims 1 to 8, in the preparation of a medicament for treating or preventing pain, without proviso. A pharmaceutical composition comprising a compound of formula (I) according to any of claims 1 to 8 and a pharmaceutically acceptable diluent or carrier.