KR20040067865A - Benzimidazoles that are useful in treating sexual dysfunction - Google Patents

Abstract

The present invention relates to the use of a compound of formula (I ') to treat sexual dysfunction and to a composition containing a compound of formula (I') to treat sexual dysfunction.

Formula I '

Description

Benzimidazoles that are useful in treating sexual dysfunction

Preclinical evidence indicates that dopamine (DA) plays an important role in mammalian penile erection. Sexual stimulation may be initiated by sensory (sexual desire) information leading to the cerebral cortex. The cerebral cortex has a wide range of neuronal connections with the hypothalamus and intermediate brain structures such as perianal gray matter (PAG) as well as edge structures such as tonsils. The two major nuclei of the hypothalamus are the MPOA and the ventricular nucleus (PVN). MPOA and PVN nuclei play an important role in sexual behavior because both lesions in these regions completely eliminate male sexual behavior. The incerto-hypothalamic dopamine pathway that stimulates PVN and MPOA nuclei has been associated with the early erectile effect of DA preparations. Apomorphine (6aR) 5,6,6a, 7-tetrahydro-6-methyl-4H-dibenzo [de, g] quinoline-10,11-diol), quinpyrrole and (-)-(3-hydroxy Systemic administration of DA receptor agonists such as phenyl) -N-propylpiperidine (3-PPP) promotes penile erection of rats, an effect blocked by the central DA antagonist haloperidol. Since the erectile effect cannot be blocked by the peripheral DA antagonist domperidone, the early erectile effect of DA agonists is centrally mediated. Andersson K and Wagner G, Physiology of penile erection, Physiol Rev (1995) 75 : 191-236; deGroat W and Booth A, Neural Control of Penile Erection, in: Nervous control of urogenital system, Vol. 3, (ed. Maggi, C) (1993) p. 467-524, Hardwood Academic Publishers, Chur, Switzerland; and Moreland RB, Nakane M, Hsieh G and Brioni JD, Prospectives for Pharmacotherapy of Male Erectile Dysfunction, Curr Opinion CPNS Invest Drugs (2000) 2: 283-302].

Clinical data also indicate that the DA system of the CNS plays an important role in the regulation of male sexual behavior, as indicated by the sexual stimulatory effect of L-dopa in Parkinson's disease and the early erectile effect of apomorphine in humans. Morales A, Geaton J, Johnston B and Adams M, Oral and Topical Treatment of Erectile Dysfunction: present and future, in: Urologic Clinics of North America, (1995) Vol. 22, p. 879-886; Padma-Nathan H, Auerbach S, Lewis R, Lewand M and Perdok R, Efficacy and safety of apomorphine SL vs. placebo for male erectile dysfunction (MED), Urology (1999) 161: 214 (abstract 821); and Dula E, Keating W, Siami P, Edmonds A, O'Neil J, Efficacy and safety of fixed-dose and dose-optimization regimens of sublingual apomorphine versus placebo in men with erectile dysfunction, Urology (2000) 56: 130-135 ].

DA receptors belong to a superfamily of protein receptors that couple across cellular membranes and signal across GTP-binding proteins. Several G proteins (including Gs, Gq and Gi) have been identified that induce specific intracellular events.Milligan G and Rees S, Chimaeric G proteins: their potential use in drug discovery, Trends Pharmacol Sci (1999) 20 : 118-124].

There are five known DA receptors, which are classified into two groups, type D _{1 and} type D ₂ . Type ₁ receptors include D ₁ and D ₅ . D type ₂ receptors include D ₂ , D ₃ and D _4. Missale C, Nash S, Robinson S, Jaber M and Caron M, Dopamine receptors: from structure to function, Physiol Rev (1998) 78: 189 -225]. The D ₁ type receptor subtype can be G _s coupled to activate adenylate cyclase. Type ₂ population receptor subtypes are Gi coupled to increase cellular calcium levels and inhibit adenylate cyclase.

Type ₁ population members are G _s coupled receptors capable of activating adenylate cyclase. D ₁ receptors are the most common DA receptors in the CNS according to mRNA expression and immunohistochemistry studies [Vallone D, Picetti R and Borreli E, Structure and function of dopamine receptors, Neurosci Biobehav Rev (2000) 24: 125 -132]. It is found in the limbic system, hypothalamus and thalamus, as well as in the striated body, nucleus accumbens and olfactory nodules. D1 receptor expression has been reported in the heart and kidneys, although the function of these peripheral D ₁ receptors is clear, but its role in the regulation of hemodynamic parameters has been confirmed. The D ₅ receptor has a higher affinity for DA than the D ₁ receptor and is rarely distributed in the CNS where no evidence of expression is seen outside the CNS.

Type ₂ population members are G _i coupled receptors that inhibit adenylate cyclase and increase intracellular calcium concentration. D ₂ receptors are the most common D ₂ type receptors, and are located in the brain parts such as striated and black matter and in the peripheral parts of the heart, pituitary gland and kidney. D ₃ receptors are found abundantly in the islands of Callefa, which have a clear population population in the fold stripe / lateral septal nucleus region, olfactory nodule, denitre neurus and ancestral cortex [Suzuki M, Hurd Y, Sokoloff P, Schwartz J and Sedwall G, D ₃ dopamine receptor mRNA is widely express in human brain, Brain Res (1998) 779: 58-74].

Expression of the D ₄ receptor has been documented by RNA hybridization and immunohistochemical studies. Recently, studies have shown that D ₄ expression is highest in the enterorhinal cortex, lateral septal nucleus, hippocampus, and anterior visual cross section [Primus R, Thurkauf A, Xu J, Yevich E, Mcinerney S, Shaw K, Tallman J and Gallagher D, Localization and characterization of dopamine D ₄ binding sites in rat andhuman brain by use of the novel D ₄ receptor-selective ligand [ ³ H] NGD 94-1, J Pharmacol Exp Ther (1997) 282 : 1020-1027]. Localization of D ₄ is evident from the distribution of D _{2 in} the brain, since D ₂ receptors are most common in the striatum. Expression of the D ₄ receptor in the hypothalamus MPOA is important for promoting penile erection in terms of the role of the hypothalamus as an integration region between the cortex and the spinal cord pathway. The involvement of D ₄ receptors in other DNS regions, thalamus, hypothalamus and spinal cord cannot be excluded.

US Pat. No. 3,472,854 (Sterling) describes benzimidazole compounds useful as antipsychotics, sedatives, skeletal muscle relaxants, antiadrenergics, hypothermia, anticonvulsants, hypotensives and cardiovascular agents.

Sule et al. Disclosed 2- (N4-substituted-N1-piperazinyl) methyl-5- (or 6) -substituted benzimidazoles as potentially antiparasitic activity. In particular, this document describes the synthesis of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, but the compound is not considered to be effective as an antiparasitic agent. : Bull. Haffkine Inst., 1978, 6 (2), 62-64]

US Patent No. 5,792,768 to Merck Sharp and Dome describes benzimidazole compounds as D ₄ antagonists and useful antipsychotics.

US 5,714,498 (Merck Sharp and Dome) includes schizophrenia, depression, vomiting, Parkinson's disease, dyskinesia, hypothalamic-pituitary dysfunction, upper gastrointestinal disorders, drug abuse, antipsychotics and cardiovascular disorders Benzimidazole compounds as D ₄ ligands for disorders of the dopamine system are described.

The present invention discloses the use of benzimidazole of formula (I) for the treatment of sexual dysfunction in mammals. More specifically, the compounds are not intended to be limiting, but are useful for the treatment of sexual dysfunction, including male erectile dysfunction.

Summary of the Invention

The present invention relates to a method of treating sexual dysfunction in a mammal, in particular a human, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. Will.

In Formula I above,

A is , , , , , , , , , , , , , , , , , , , or Is selected from,

X is selected from NH, O or S,

L is selected from CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ CH ₂ ,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ , (NZ ₁ Z ₂ ) carbonyl or (NZ ₁ Z ₂ ) sulfonyl, wherein Z ₁ and Z ₂ are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl or formyl;

R _A , R _B , R _C and R _D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ or (NZ ₁ Z ₂ ) carbonyl,

R _E is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl or (NZ ₁ Z ₂ ) carbonyl,

R _F is selected from hydrogen or alkyl,

Z is selected from N, C or CH,

--- is a bond when Z is C and absent when Z is N or CH.

The present invention relates to the use of benzimidazole and compositions containing the compound for the treatment of sexual dysfunction.

All patents, patent applications, and patent documents cited in this specification are herein incorporated by reference in their entirety.

In principle embodiments, the present invention comprises administering to a mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, in a mammal, in particular in humans It relates to a method for treating a disorder.

Formula I

In Formula I above,

A is , , , , , , , , , , , , , , , , , , , or Is selected from,

X is selected from NH, O or S,

L is selected from CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ CH ₂ ,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ , (NZ ₁ Z ₂ ) carbonyl or (NZ ₁ Z ₂ ) sulfonyl, wherein Z ₁ and Z ₂ are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl or formyl;

R _A , R _B , R _C and R _D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ or (NZ ₁ Z ₂ ) carbonyl,

R _E is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl or (NZ ₁ Z ₂ ) carbonyl,

R _F is selected from hydrogen or alkyl,

Z is selected from N, C or CH,

--- is a bond when Z is C and absent when Z is N or CH.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is N, --- is absent, L and A relates to a method of treating sexual dysfunction in a mammal in which a therapeutically effective amount of a compound of formula (I) as defined in formula (I) is administered to the mammal.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is N, --- is absent and A is And a method for treating sexual dysfunction in a mammal in which L, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are administered to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). will be.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH ₂ , Z is N; --- is absent, and A is R ₂ , R ₃ and R ₄ are each hydrogen, and R ₁ and R ₅ are each a method for treating sexual dysfunction in a mammal, wherein the mammal is administered a therapeutically effective amount of a compound of formula (I) It is about.

In another aspect, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH ₂ , Z is N , --- is absent, and A , R ₂ , R ₃ and R ₄ are each hydrogen, and R ₁ and R ₅ are each the treatment of sexual dysfunction in a mammal administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I) It is about a method.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is N, --- is absent, and A is And L, R ₁ , R ₂ , R ₃ and R ₄ are directed to a method of treating sexual dysfunction in a mammal in which a therapeutically effective amount of a compound of formula (I) is defined in formula (I) to a mammal.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH ₂ , Z is N , --- is absent, and A And R ₂ , R ₃ and R ₄ are each hydrogen and R ₁ is a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). .

In another embodiment, the invention provides that R _A , R _B , R _C , R _D , R _E and R _F are each hydrogen, L is CH ₂ , Z is N, --- is absent, and A is And a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) wherein R ₁ , R ₂ , R ₃ and R ₄ are each hydrogen.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, R _F is alkyl, L is CH ₂ , and Z is N, --- is absent, and A is And R ₂ , R ₃ and R ₄ are each hydrogen and R ₁ is a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). .

In another embodiment, the present invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, R _F is alkyl (where alkyl is methyl), L is CH ₂ , Z is N, --- is absent, and A is And a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) wherein R ₁ , R ₂ , R ₃ and R ₄ are each hydrogen.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is N, --- is absent, and A is R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from hydrogen or hydroxy and L is a mammal that administers to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). The present invention relates to a method for treating sexual dysfunction.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH ₂ , Z is N , --- is absent, and A And R ₁ , R ₂ and R ₄ are each hydrogen and R ₃ is hydroxy, and the method relates to a method for treating sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of the compound of formula (I).

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is N, --- is absent, and A is And L, R ₂ , R ₃ and R ₄ are directed to a method of treating sexual dysfunction in a mammal in which a therapeutically effective amount of a compound of formula (I) is defined as defined in formula (I).

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH ₂ , Z is N , --- is absent, and A And a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) wherein R ₂ , R ₃ and R ₄ are each hydrogen.

In another embodiment, the invention provides that R _A , R _B , R _C , R _D , R _E and R _F are each hydrogen, L is CH ₂ , Z is N, --- is absent, and A is And a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) wherein R ₂ , R ₃ and R ₄ are each hydrogen.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is N, --- is absent, and A is And X, L, R ₂ and R ₃ are directed to a method of treating sexual dysfunction in a mammal in which a therapeutically effective amount of a compound of formula (I) is defined as defined in formula (I) to the mammal.

In another aspect, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH ₂ , Z is N , --- is absent, and A And R ₂ and R ₃ are each hydrogen and X is S, the present invention relates to a method for the treatment of sexual dysfunction in a mammal by administering to said mammal a therapeutically effective amount.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen and halogen, and R _E is alkoxycarbonyl, alkylcarbonyl, alkyl, arylcarbonyl, cycloalkylcarbon Nyl, heterocyclecarbonyl or (NZ ₁ Z ₂ ) carbonyl, Z is N, --- is absent, and A is Treatment of sexual dysfunction in a mammal in which Z ₁ , Z ₂ , L, R ₁ , R ₂ , R ₃ and R ₄ are administered to the mammal a therapeutically effective amount of a compound of formula (I) as defined in Formula (I) It is about a method.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is alkoxycarbonyl, alkylcarbonyl, (NZ ₁ Z ₂ ) carbonyl or Heterocyclecarbonyl, wherein the heterocycle portion of heterocyclocarbonyl is pyrrolidinyl, R _F is hydrogen, L is CH ₂ , Z is N, --- is absent, and A end And R ₂ , R ₃ and R ₄ are each hydrogen and Z ₁ , Z ₂ and R ₁ are used for the sexual dysfunction of a mammal to administer to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). It relates to a method of treatment.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is CH, --- is absent and A is A method for treating sexual dysfunction in a mammal in which L, R ₁ , R ₂ , R ₄ , R ₄ and R ₅ are administered to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). will be.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH _2, and Absent, Z is CH and A is R ₂ , R ₃ and R ₄ are each hydrogen and R ₁ and R ₅ are each a method of treating sexual dysfunction in a mammal, wherein the mammal is administered a therapeutically effective amount of a compound of formula (I) as defined in formula (I). It is about.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is CH, --- is absent and A is And L, R ₁ , R ₂ , R ₃ and R ₄ are directed to a method of treating sexual dysfunction in a mammal in which a therapeutically effective amount of a compound of formula (I) is defined in formula (I) to a mammal.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH _2, and Absent, Z is CH and A is And R ₂ , R ₃ and R ₄ are each hydrogen and R ₁ is a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). .

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is C, --- is a bond, and A is A method for treating sexual dysfunction in a mammal in which L, R ₁ , R ₂ , R ₄ , R ₄ and R ₅ are administered to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). will be.

In another aspect, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH ₂ , Z is C , --- is a bond, and A is R ₂ , R ₃ and R ₄ are each hydrogen, and R ₁ and R ₅ are each a method of treating sexual dysfunction in a mammal, wherein the mammal is administered a therapeutically effective amount of a compound of formula (I) as defined in formula (I). It is about.

In another aspect, the present invention

2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;

N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;

2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;

2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;

2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;

2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;

2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide;

A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, A method of treating sexual dysfunction in humans, including male and female sexual dysfunctions, comprising administering to a human a therapeutically effective amount of an amide or prodrug.

In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating sexual dysfunction in humans, including male sexual dysfunction, comprising administering a therapeutically effective amount to a human, and female sexual dysfunction.

In another embodiment, the invention provides a therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) to a human The present invention relates to a method for treating sexual dysfunction of a person, including male sexual dysfunction, including female ham.

In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof The present invention relates to a method of treating sexual dysfunction in a human, including male sexual dysfunction and female sexual dysfunction comprising administering to a human a therapeutically effective amount of.

In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt, ester, amide or A method of treating sexual dysfunction in a person, including male sexual dysfunction and female sexual dysfunction, comprising administering to a human a therapeutically effective amount of a prodrug.

In another embodiment, the present invention provides a male comprising administering to a human a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, together with a pharmaceutically acceptable carrier and The present invention relates to a method for treating sexual dysfunction of a person including female sexual dysfunction.

In another aspect, the present invention

2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;

N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;

2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;

2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;

2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;

2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;

2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide;

A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, A method of treating sexual dysfunction in humans, including male and female sexual dysfunctions, comprising administering to a human a therapeutically effective amount of an amide or prodrug together with a pharmaceutically acceptable carrier.

In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating sexual dysfunction in humans comprising male sexual dysfunction and female sexual dysfunction comprising administering to a human a therapeutically effective amount with a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides a pharmaceutical composition for treating a therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate). A method of treating sexual dysfunction in a human, including male sexual dysfunction, comprising administering to a human with an acceptable carrier, and female sexual dysfunction.

In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating sexual dysfunction in a human, including male sexual dysfunction and female sexual dysfunction, comprising administering a therapeutically effective amount of to a human with a pharmaceutically acceptable carrier.

In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt, ester, amide or A method of treating sexual dysfunction in a human, including male sexual dysfunction and female sexual dysfunction, comprising administering a therapeutically effective amount of a prodrug to a human with a pharmaceutically acceptable carrier.

In another embodiment, the present invention is not intended to limit the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, but includes phosphodides, including sildenafil or vardenafil. The present invention relates to a method of treating sexual dysfunction in a human, including male sexual dysfunction, including administering to a human with a terase inhibitor, and female sexual dysfunction.

In another aspect, the present invention

2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;

N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;

2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;

2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;

2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;

2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;

2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide;

A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, Although not intended to limit the therapeutically effective amount of an amide or prodrug, it includes male sexual dysfunction and female sexual dysfunction, including administration to humans with phosphodiesterase 5 inhibitors including sildenafil or vardenafil The present invention relates to a method of treating sexual dysfunction of a person.

In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof Although not intended to limit the therapeutically effective amount, sexual function in humans, including male sexual dysfunction and female sexual dysfunction, including administration to humans with phosphodiesterase 5 inhibitors including sildenafil or vardenafil It relates to a method for treating a disorder.

In another embodiment, the present invention seeks to thereby limit the therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) But not, to a method of treating sexual dysfunction in humans, including male and female sexual dysfunctions, comprising administering to humans with phosphodiesterase 5 inhibitors including sildenafil or vardenafil. .

In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof It is not intended to thereby limit the therapeutically effective amount of to a sex of a person, including male sexual dysfunction and female sexual dysfunction, including administering to a human with a phosphodiesterase 5 inhibitor comprising sildenafil or vardenafil. It relates to a method of treating dysfunction.

In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt, ester, amide or It is not intended to limit the therapeutically effective amount of prodrugs to this, but humans including male sexual dysfunction and female sexual dysfunction, including administration to humans with phosphodiesterase 5 inhibitors, including sildenafil or vardenafil The present invention relates to a method for treating sexual dysfunction.

In another embodiment, the present invention is not intended to limit the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, but includes terrazocin, prazosin or tamsulosin The present invention relates to a method for treating sexual dysfunction in a human, including male and female sexual dysfunction, including administration to a human with an adrenergic receptor antagonist.

In another aspect, the present invention

2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;

N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;

2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;

2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;

2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;

2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;

2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide;

A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, It is not intended to limit the therapeutically effective amount of an amide or prodrug, but includes male sexual dysfunction and female sexual dysfunction, including administration to humans with adrenergic receptor antagonists including terrazocin, prazosin or tamsulosin The present invention relates to a method of treating sexual dysfunction of a person.

In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof Although not intended to limit the therapeutically effective amount, sexual function in humans, including male sexual dysfunction and female sexual dysfunction, including administration to humans with adrenergic receptor antagonists including terrazocin, prazosin or tamsulosin It relates to a method for treating a disorder.

In another embodiment, the present invention seeks to thereby limit the therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) But not, to a method of treating sexual dysfunction in humans, including male sexual dysfunction and female sexual dysfunction, comprising administering to a human with an adrenergic receptor antagonist comprising terrazosin, prazosin or tamsulosin .

In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof It is not intended to limit the therapeutically effective amount of to a sex of a person, including male sexual dysfunction and female sexual dysfunction, including administering to a human with an adrenergic receptor antagonist including terrazocin, prazosin or tamsulosin. The present invention relates to a method for treating dysfunction.

In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt, ester, amide or Although not intended to limit the therapeutically effective amount of prodrugs to this, persons including male sexual dysfunction and female sexual dysfunction, including administration to humans with adrenergic receptor antagonists including terrazosin, prazosin or tamsulosin The present invention relates to a method for treating sexual dysfunction.

In another embodiment, the present invention is not intended to limit the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, but in combination with a dopamine agonist comprising apomorphine. The present invention relates to a method for treating sexual dysfunction of a person, including male sexual dysfunction, including female administration.

In another aspect, the present invention

2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;

N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;

2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;

2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;

2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;

2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;

2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide;

A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, Although not intended to limit the therapeutically effective amount of an amide or prodrug, it may be possible to control sexual dysfunction in humans, including male sexual dysfunction and female sexual dysfunction, including administering to humans with a dopamine agonist comprising apomorphine. It relates to a method of treatment.

In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof Although not intended to limit the therapeutically effective amount thereto, the present invention relates to methods of treating sexual dysfunction in humans, including male sexual dysfunction and female sexual dysfunction, including administration to a human with a dopamine agonist comprising apomorphine. .

In another embodiment, the present invention seeks to thereby limit the therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) It is not, but it relates to a method for the treatment of sexual dysfunction in humans, including male and female sexual dysfunction, including administering to a human with a dopamine agonist comprising apomorphine.

In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof Although not intended to limit the therapeutically effective amount of to a method for treating sexual dysfunction in humans, including male sexual dysfunction and female sexual dysfunction, including administering to a human with a dopamine agonist comprising apomorphine. will be.

In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt, ester, amide or Although not intended to limit the therapeutically effective amount of prodrugs to this, methods of treating sexual dysfunction in humans, including male sexual dysfunction and female sexual dysfunction, including administration to humans with a dopamine agonist comprising apomorphine. It is about.

In another aspect, the invention provides an erection in a male comprising administering to a man in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof The present invention relates to a method for treating dysfunction.

In another aspect, the present invention

2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;

N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;

2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;

2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;

2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;

2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;

2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide;

A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, A method of treating erectile dysfunction in men, comprising administering a therapeutically effective amount of an amide or prodrug to a male in need thereof.

In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating erectile dysfunction in men, comprising administering a therapeutically effective amount to a man in need thereof.

In another embodiment, the invention provides a therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) of erectile dysfunction A method of treating erectile dysfunction in men, including administering to men in need thereof.

In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating erectile dysfunction in men, comprising administering a therapeutically effective amount of to a male in need thereof.

In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutical salt, ester, amide or prodrug of A method of treating erectile dysfunction in men, comprising administering a therapeutically effective amount of to a male in need thereof.

In another embodiment, the present invention provides a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, for treating insensitivity, clitoris impotence, vaginal hyperemia, dyspareunia or vaginal spasms. A method of treating insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasm in a woman, including administration to a woman in need thereof.

In another aspect, the present invention

2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;

N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;

2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;

2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;

2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;

2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;

2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide;

A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, Insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vagina in women, including administering a therapeutically effective amount of an amide or prodrug to a woman in need of treatment for insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasms It relates to a method of treating cramps.

In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasm in a woman, comprising administering a therapeutically effective amount to a woman in need of treatment for insensitivity, lack of clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasms. It is about.

In another embodiment, the invention provides a therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) insensitive, clitoris A method of treating insensitivity, clitoris erectile deficiency, vaginal hyperemia, dyspareunia or vaginal spasm in a woman, comprising administering to a woman in need of treatment for erectile dysfunction, vaginal hyperemia, dyspareunia or vaginal spasm.

In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasm in a woman comprising administering a therapeutically effective amount of to a woman in need of treatment for insensitivity, lack of clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasms It is about.

In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutical salt, ester, amide or prodrug of A method of treating insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasm in a woman comprising administering a therapeutically effective amount of to a woman in need of treatment for insensitivity, lack of clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasms It is about.

In another embodiment, the invention provides a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, for cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, gross Cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, gross abuse, Parkinson's disease in humans, including administration to a person in need of treatment of a disorder selected from abuse, Parkinson's disease, anxiety, mood disorders and depression, A method of treating disorders selected from anxiety, mood disorders and depression.

In another aspect, the present invention

2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;

N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;

2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;

2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;

2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;

2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;

2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;

N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide;

A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, A therapeutically effective amount of an amide or prodrug is administered to a person in need of treatment for a disorder selected from cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression. Cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, bad substance abuse, Parkinson's disease, anxiety, mood disorders, and depression in a person comprising.

In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A therapeutically effective amount of the heart of a person comprising administering a therapeutically effective amount to a person in need of treatment of a disorder selected from cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression It relates to a method for treating disorders selected from vascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression.

In another embodiment, the invention provides a therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) for cardiovascular disorders. Cardiovascular disorders, inflammatory disorders, attention in humans, including administration to persons in need of treatment of disorders selected from inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, pest abuse, Parkinson's disease, anxiety, mood disorders and depression And a method for treating a disorder selected from deficit hyperactivity disorder, Alzheimer's disease, bad substance abuse, Parkinson's disease, anxiety, mood disorders and depression.

In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof Administering a therapeutically effective amount of to a person in need thereof for treatment of a disorder selected from cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression. Cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression.

In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutical salt, ester, amide or prodrug of Administering a therapeutically effective amount of to a person in need thereof for treatment of a disorder selected from cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression. Cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression.

In another aspect, the invention relates to a compound of Formula (II), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof

A is , , , , , , , , , , , , , , , , , or Is selected from,

X is selected from NH, O or S,

L is selected from CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ CH ₂ ,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ or (NZ ₁ Z ₂ ) carbonyl, wherein Z ₁ and Z ₂ are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl or formyl),

R _A , R _B , R _C and R _D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ or (NZ ₁ Z ₂ ) carbonyl,

R _E is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl or (NZ ₁ Z ₂ ) carbonyl,

R _F is selected from the group consisting of hydrogen or alkyl,

A And X is S, then R ₂ or R ₃ is not hydrogen.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen and A is And L, R ₂ , R ₃ and R ₄ are directed to compounds of formula II as defined in formula II.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH 2, and A is And R ₂ , R ₃ and R ₄ are each hydrogen.

In another aspect, the invention relates to a compound of Formula III, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

In Formula III above,

R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from hydrogen, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylthio or hydroxy,

L is selected from CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ CH ₂ ,

R _A , R _B , R _C and R _D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ or (NZ ₁ Z ₂ ) carbonyl, wherein Z ₁ and Z ₂ are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl or formyl),

R _E is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl or (NZ ₁ Z ₂ ) carbonyl,

R _F is selected from the group consisting of hydrogen or alkyl,

If R _F is hydrogen, at least one of R ₁ , R ₂ , R ₃ and R ₄ is not hydrogen.

In another embodiment, the present invention provides that R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from hydrogen or hydroxy provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is hydroxy , R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, and L relates to compounds of formula III as defined in formula (I).

In another embodiment, the invention provides that R ₁ , R ₂ and R ₄ are each hydrogen, R ₃ is hydroxy, L is CH ₂ , and R _A , R _B , R _C and R _D are each independently hydrogen Or halogen, and R _E and R _F are each hydrogen.

In another embodiment, the invention provides that R ₁ , R ₂ , R ₃ and R ₄ are each hydrogen, L is CH ₂ , and R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen And R _E is hydrogen and R _F is alkyl.

In another embodiment, the present invention provides that R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from hydrogen or alkylsulfonylamino, provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is alkyl Sulfonylamino, R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, and R _F is directed to a compound of formula III as defined in formula III .

In another embodiment, the present invention provides that R ₁ , R ₃ and R ₄ are each hydrogen, R ₁ is alkylsulfonylamino, L is CH ₃ , and R _A , R _B , R _C and R _D are each independent And hydrogen or halogen, wherein R _E and R _F are each hydrogen.

In another aspect, the present invention relates to a compound of formula IV, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

In Formula IV above,

A is , , , , , , , , , , , , , , , , , , or Is selected from,

X is selected from NH, O or S,

L is selected from CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ CH ₂ ,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ or (NZ ₁ Z ₂ ) carbonyl, wherein Z ₁ and Z ₂ are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl or formyl),

R _A , R _B , R _C and R _D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ or (NZ ₁ Z ₂ ) carbonyl,

R _E is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl or (NZ ₁ Z ₂ ) carbonyl,

R _F is selected from hydrogen or alkyl,

Z is selected from C or CH,

--- is a bond when Z is C and absent when Z is CH.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is CH, --- is absent, and A is And L, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are directed to compounds of formula IV as defined in formula IV.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH ₂ , Z is CH , --- is absent, and A R ₂ , R ₃ and R ₄ are each hydrogen and R ₁ and R ₃ are directed to compounds of formula IV as defined in formula IV.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is CH, --- is absent and A is And L, R ₁ , R ₂ , R ₃ and R ₄ are directed to compounds of formula IV as defined in formula IV.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH ₂ , Z is CH , --- is absent, and A R ₂ , R ₃ and R ₄ are each hydrogen and R ₁ relates to a compound of formula IV as defined in formula IV.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E is hydrogen, Z is C, --- is a bond, and A is And L, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are directed to compounds of formula IV as defined in formula IV.

In another embodiment, the invention provides that R _A , R _B , R _C and R _D are each independently selected from hydrogen or halogen, R _E and R _F are each hydrogen, L is CH ₂ , Z is C , --- is a bond, and A is R ₂ , R ₃ and R ₄ are each hydrogen, and R ₁ and R ₅ are directed to compounds of formula IV as defined in formula IV.

Definition of the present invention

As used throughout this specification and the appended claims, the following terms have the following meanings:

As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon of 2 to 10 carbon atoms containing one or more carbon-carbon double bonds formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3-decenyl are included.

The term "alkoxy" as used herein refers to an alkyl group as defined herein added to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy.

The term "alkoxyalkoxy" as used herein refers to an alkoxy group, as defined herein, added to a parent molecular moiety through another alkoxy group, as defined herein. Representative Examples of Alkoxy Alkoxy include, but are not limited to, tertiary butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy and methoxymethoxy.

The term "alkoxyalkyl" as used herein refers to an alkyl group as defined herein added to the parent molecular moiety through an alkyl group as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl and methoxymethyl.

The term "alkoxycarbonyl" as used herein refers to an alkoxy group, as defined herein, added to a parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.

The term "alkoxycarbonylalkyl" as used herein refers to an alkoxycarbonyl group as defined herein added to the parent molecular moiety through an alkyl group as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-3-butoxycarbonylethyl.

The term "alkoxysulfonyl" as used herein refers to an alkoxy group, as defined herein, added to a parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.

As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon of 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, secondary butyl, iso-butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

The term "alkylcarbonyl" as used herein refers to an alkyl group as defined herein added to a parent molecular moiety through a carbonyl group as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term "alkylcarbonylalkyl" as used herein refers to an alkylcarbonyl group as defined herein added to the parent molecular moiety through an alkyl group as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

The term "alkylcarbonyloxy" as used herein refers to an alkylcarbonyl group as defined herein added to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy and tertiary butylcarbonyloxy.

The term "alkylsulfinyl" as used herein refers to an alkyl group as defined herein added to a parent molecular moiety through a sulfinyl group as defined herein. Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfinyl.

The term "alkylsulfonyl" as used herein refers to an alkyl group as defined herein added to a parent molecular moiety through a sulfonyl group as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.

The term "alkylsulfonylamino" as used herein refers to an alkylsulfonyl group as defined herein added to the parent molecular moiety through an NH group. Representative examples of alkylsulfonylamino include, but are not limited to, methylsulfonylamino and ethylsulfonylamino.

The term "alkylthio" as used herein refers to an alkyl group as defined herein added to the parent molecular moiety through a sulfur atom. Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, tertiary butylsulfanyl and hexylsulfanyl.

The term "alkylthioalkyl" as used herein refers to an alkylthio group as defined herein added to the parent molecular moiety through an alkyl group as defined herein. Representative examples of alkyltaoalkyl include, but are not limited to, methylsulfanylmethyl and 2- (ethylsulfanyl) ethyl.

As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group of 2 to 10 carbon atoms containing one or more carbon-carbon triple bonds. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.

The term "aryl" as used herein refers to a monocyclic system or bicyclic system or tricyclic condensed cyclic system in which one or more condensed rings are aromatic. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl and tetrahydronaphthyl.

The aryl groups of the present invention are alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aroxulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkyl Thioalkyl, alkynyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro,- Or 1, 2, 3, 4 or 5 substituents independently selected from NZ ₁ Z ₂ and (NZ ₁ Z ₂ ) carbonyl.

The term "arylcarbonyl" as used herein refers to an aryl group as defined herein added to the parent molecular moiety through a carbonyl group as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.

The term "carbonyl" as used herein refers to a -C (O)-group.

The term "carboxy" as used herein refers to a -CO ₂ H group.

As used herein, the term “carboxyalkyl” refers to a carboxy group as defined herein added to a parent molecular moiety through an alkyl group as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl and 3-carboxypropyl.

As used herein, the term “cyano” refers to a —CN group.

The term "cyanoalkyl" as used herein refers to a cyano group as defined herein added to the parent molecular moiety through an alkyl group as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl and 3-cyanopropyl.

The term "cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group having 3 to 8 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, the term “cycloalkylcarbonyl” refers to a cycloalkyl group, as defined herein, appended to a parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, cyclobutylcarbonyl and cyclohexylcarbonyl.

As used herein, the term "ethylenedioxy" refers to a two-membered ring in which the oxygen atom of the ethylenedioxy group is bonded to a parent molecular moiety through a carbon atom forming a five-membered ring, or the oxygennerer of the ethylenedioxy group forms a six-membered ring. -O (CH ₂ ) ₂ O- group bonded to the parent molecular moiety through two adjacent carbon outer groups.

The term "formyl" as used herein refers to a -C (O) H group.

The term "halo" or "halogen" as used herein refers to -Cl, -Br, -I or F.

The term "haloalkoxy" as used herein refers to one or more halogens as defined herein added to the parent molecular moiety through an alkoxy group as defined herein. Representative examples of haloalkoxy include, but are not limited to, 2-fluoro-1-chloroethoxy, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy and pentafluoroethoxy.

As used herein, the term “haloalkyl” refers to one or more halogens as defined herein added to the parent molecular moiety through an alkyl group as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.

The term "heterocycle" or "heterocyclic" as used herein refers to a monocyclic, bicyclic or tricyclic ring system. Monocyclic ring systems include three or four membered rings containing heteroatoms independently selected from oxygen, nitrogen and sulfur, or one, two or three heteroatoms wherein heteroatoms are independently selected from nitrogen, oxygen and sulfur Five-, six- or seven-membered ring containing a. 5 membered rings have 0 to 2 double bonds and 6 and 7 membered rings have 0 to 3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, ditianyl, furyl, imida Zolyl, imidazolinyl, imidazolidinyl, isotrazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadia Zolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperazinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinin, pyridinyl, pyrimidinyl , Pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thia Zolinyl, thiazolidinyl, thienyl, thiomo Lepolynyl, 1,1-dioxydothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, thiazinyl, thiazolinyl and tritianyl. Bicyclic ring systems include any of the above monocyclic ring systems condensed with an aryl group as defined herein, a cycloalkyl group as defined herein or another monocyclic ring system. Representative examples of bicyclic ring systems include, but are not limited to, benzimidazolyl, benzodioxynyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, Benzothiopyranyl, cinnolinyl, indazolyl, indolyl, 2,3-dihydroindolyl, indolinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolinyl, isoquinolinyl Phthalazinyl, pyranopyridinyl, quinolinyl, quinolininyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and thiopyranopyridinyl. Tricyclic ring systems include any of the above acyclic ring systems condensed with aryl groups as defined herein, cycloalkyl groups as defined herein, or monocyclic ring systems. Representative examples of tricyclic ring systems include, but are not limited to, acridinyl, carbazolyl, carbolinyl, dibenzo [bd] furanyl, dibenzo [b, d] furan, naphtho [2,3 -b] thienyl, phenazinyl, phenothiazinyl, phenoxazinyl, thianthrenyl, thioxanthenyl and xanthenyl.

Heterocycles of the invention are alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkyl Thioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo , -NZ ₁ Z ₂ and (NZ ₁ Z ₂ ) carbonyl may be substituted with 1, 2 or 3 substituents independently selected.

The term “heterocyclecarbonyl” as used herein refers to a heterocycle as defined in Bonner, which is added to the parent molecular moiety through a carbonyl group as defined herein. Representative examples of heterocyclecarbonyl include, but are not limited to, pyridin-3-ylcarbonyl and quinolin-3-ylcarbonyl.

As used herein, the term "hydroxy" refers to an -OH group.

As used herein, the term "hydroxyalkyl" refers to one or more hydroxy groups as defined herein added to the parent molecular moiety through an alkyl group as defined herein. Representative examples of hydrogitalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl 2-ethyl-4-hydroxyheptyl, and 2,4-dihydroxybutyl .

The term "hydroxy protecting group" or "O protecting group" refers to a substituent that protects the hydroxyl group against unwanted reactions during the synthesis process. Examples of hydroxy protecting groups include, but are not limited to, substituted methyl ethers such as methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) -ethoxymethyl, Benzyl and triphenylmethyl; Tetrahydropyranyl ethers; Substituted ethyl ethers such as 2,2,2-trichloroethyl and t-butyl; Silyl ethers such as trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; Cyclic acetyls and ketals such as methylene acetyl, acetonide and benzylidene acetyl; Cyclic ortho esters such as methoxymethylene; Cyclic carbonates; And cyclic boronates.

The term "mercapto" as used herein refers to the -SH group.

As used herein, the term “methylenedioxy” refers to an —OCH ₂ O— group in which the oxygen atom of methylenedioxy is bonded to a molecular moiety through two adjacent carbon atoms.

As used herein, the term “nitro” refers to the —NO ₂ group.

The term "nitrogen protecting group" as used herein refers to a group that protects an amino group against unwanted reactions during the synthesis process. Nitrogen protecting groups include carbamates, amides, N-benzyl derivatives and imine derivatives. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc), tertiary butylacetyl, trifluoroacetyl and Triphenylmethyl (trityl).

The term "-NZ ₁ Z ₂ " as used herein refers to two groups Z ₁ and Z ₂ added to the parent molecular moiety through a nitrogen atom. Z ₁ and Z ₂ are each independently selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl. Representative examples of -NZ ₁ Z ₂ include, but are not limited to, amino, methylamino, dimethylamino, acetylamino, (acetyl) (methyl) amino and (methylsulfonyl) amino.

As used herein, the term “(NZ ₁ Z ₂ ) carbonyl” refers to the group —NZ ₁ Z ₂ as defined herein added to the parent molecular moiety through a carbonyl group as defined herein. Representative examples of (NZ ₁ Z ₂ ) carbonyl include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl, ((acetyl) (methyl) amino) carbonyl and ( Ethylmethylamino) carbonyl.

The term "(NZ ₁ Z ₂ ) sulfonyl" as used herein refers to the group -NZ ₁ Z ₂ as used herein added to the parent molecular moiety via a sulfonyl group as defined herein. Representative examples of (NZ ₁ Z ₂ ) sulfonyl include, but are not limited to, aminosulfonyl, (methylamino) sulfonyl, (dimethylamino) sulfonyl, ((acetyl) (methyl) amino) salfonyl and ( Ethylmethylamino) sulfonyl.

The term "oxo" as used herein refers to a = 0 moiety.

The term "sulfinyl" as used herein refers to the group -S (O)-.

The term "sulfonyl" as used herein refers to a -S (O) ₂ -group.

The term “sexual dysfunction” as used herein refers to sexual dysfunction of a mammal, including male and female sexual dysfunction.

The term “male dysfunction” as used herein includes, but is not limited to, erectile dysfunction and premature ejaculation.

The term “female sexual dysfunction” as used herein includes, but is not limited to, clitoris erectile dysfunction, vaginal hyperemia, dyspareunia and vaginal spasms.

The compounds of the present invention may exist as stereoisomers in which asymmetric or chiral centers exist. Such stereoisomers are "R" or "S" which are left in the form of substituents around chiral carbon atoms. The terms "R" and "S" as used herein are described in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present invention contemplates various stereoisomers and mixtures thereof and is specifically included within the scope of the present invention. Stereoisomers include enantiomers, diastereomers and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing racemic mixtures and then digesting as is well known to those skilled in the art. Can be. Such decomposition methods include (1) combining a mixture of enantiomers to a chiral assistant, separating the obtained mixture of diastereomers by recrystallization or chromatography, and releasing the optically pure product from the assistant, or ( 2) a method of directly separating a mixture of optical enantiomers on a chiral chromatography column.

As a preferable compound of this invention,

2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;

Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;

N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;

2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;

2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;

2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;

2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole; And

2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole; Or pharmaceutically acceptable salts, esters, amides or prodrugs thereof.

More preferred compound of the present invention,

6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol and

2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole.

Most preferred compounds of the present invention,

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole.

Abbreviation

The abbreviations used in the description of the following schemes and examples are as follows: BF3OEt2 boron trifluoride diethyl ether complex; BINAP 2,2'-bis (diphenylphosphino) -1,1'-binafyl; Boc tert-butoxycarbonyl; nBuLi n-butyllithium; dba dimenzylidene acetone; DME dimethoxyethane; DMF N, N-dimethylformamide; DMSO dimethylsulfoxide; EtOH ethanol; MeOH methanol; TEA triethylamine; TFA trifluoroacetic acid; THF tetrahydrofuran; THP tetrahydropyran; TLC thin layer chromatography.

Preparation of Compounds of the Invention

The compounds of the present invention can be prepared by various synthetic routes. Representative processes are described in Schemes 1-5.

Benzimidazole (4), wherein R _A , R _B , R _C , R _D , R _F , A, Z and --- are as defined in Formula (I), can be prepared as described in Scheme 1. Benzene-1,2-diamine (1) is treated with an acid such as chloroacetic acid and 6N HCl to give 2-chloromethylbenzimidazole (2). 2-chloromethylbenzimidazole (2) is treated with compound (3) in acetonitrile or a solvent such as N, N-dimethylformamide in the presence of a base such as triethylamine, potassium carbonate or cesium carbonate to form benzimidazole. (4) is obtained.

Benzimidazole (1) in which R _A , R _B , R _C , R _D , R _F and A are as defined in formula (I) can be prepared as described in Scheme 2. P is -C (O) OC (CH ₃ ) in a solvent such as ethanol or n-butanol while heat is applied to haloheterocycle (6) wherein Y is halogen in the presence of a base such as cesium carbonate (or in the absence of a base). N protected piperazine (8) can be obtained by treatment with an excess of N protected piperazine (7), which is a nitrogen protecting group such as) ₃ or -C (O) OCH ₂ Ph. Alternatively, haloheterocycle (6) and N protected piperazine are described in Wagaw and Buchwald, JOC 61 (1996) 7240-7241; Harris et al., JOC 64 (1999) 6019-6022; or Yang and Buchwald, J. of Organometallic Chem. 576 (1999) 125-146 can be treated with a transition metal catalyst to yield N protected piperazine (8). N protected piperazine 8 can be deprotected using conditions known to those skilled in the art. For example, acidic conditions can be used to remove -C (O) OC (CH ₃ ) ₃ , such as methylene chloride in 1,4-dioxane or trifluoroacetic acid in 4N HCl. -C (O) OCH ₂ Ph can be removed using hydrogenation conditions, such as using palladium on carbon under 1 to 4 pressures of hydrogen in a solvent such as methanol, ethanol or ethyl acetate. Deprotected piperazine (9) can be treated as described in Scheme 1 to obtain benzimidazole (10).

Benzimidazole (15), wherein R _A , R _B , R _C , R _D , R _F and A are as described in Formula I, can be prepared as described in Scheme 3. Tertiary butyl 4-oxopiperidine-1-carboxylate (Aldrich) can be treated with haloheterocycle (6) and organolithium reagent or Grignard reagent to give alcohol (13). Alcohol (13) can be treated with thionyl chloride to give tetrahydropyridine (14). Tetrahydropyridine (14) can be treated as described in Scheme 1 to yield benzimidazole (15).

Benzimidazole (21) in which R _A , R _B , R _C , R _D , R _F and A are as described in Formula (I) may be prepared as described in Scheme 4. Benzyl 4-oxopyridine-1-carboxylate (Aldrich) can be treated with haloheterocycle (6) and organolithium reagent or Grignard reagent to give alcohol (18). Alcohol 18 may be treated with thionyl chloride to give tetrahydropyridine 19. Tetrahydropyridine 19 can be treated with a transition metal catalyst such as palladium on carbon under hydrogen atmosphere to give piperidine 20. Piperidine 20 may be treated as described in Scheme 1 to yield benzimidazole 21.

Benzimidazole (23), wherein R _A , R _B , R _C , R _D and R _F are described in Formula I, can be prepared as described in Scheme 5. 5-amino-2-chloropyridine (Aldrich) was treated as described in Lynch et at., Tetrahedron Asymmetry 9 (1998) 2791-2794 and Koch and Schnatterer, Synthesis (1990) 499-501. 6-chloropyridin-3-yl acetate and 6-chloropyridin-3-ol can be obtained. 6-chloropyridin-3-ol or 6-chloropyridin-3-yl acetate can be prepared according to Schemes 1 and 2. The treatment can be carried out to obtain benzimidazole 23. Alternatively, 6-chloropyridin-3-ol can be treated with a hydroxy protective reagent such as benzyl bromide or benzyl chloride in DMF under a base such as cesium carbonate to obtain hydroxy protected chloropyridine with P 'benzyl. Can be. The hydroxy protected chloropyridine (22) was treated as described in Schemes 1 and 2 to obtain benzimidazole (23), followed by hydroxy protecting groups using standard deprotection methods known to those skilled in the art. Deprotection. For example, the benzyl hydroxy protecting group can be removed using a transition metal catalyst such as palladium on carbon under a hydrogen atmosphere in a solvent such as methanol, ethanol or ethyl acetate.

Example 1

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole maleate

Example 1A

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole

2-chloromethylbenzimidazole powder (6 g, 36 mmol) in a solution of 1- (2-pyridyl) piperazine (5.9 g, 36 mmol) in rapidly stirred DMF (15 mL) in a large round bottomed flask at 20 ° C. water bath. Add over 2 minutes. Triethylamine (7.5 mL, 1.5 equiv) is added and the reaction is stirred for 16 h until TLC indicates the starting material is consumed completely. The reaction is then treated with 5 ml of triethylamine and then slowly added dropwise water (70 ml). After 1 hour, the precipitate is recovered by suction filtration, 400 ml of water is added and dried to give 9 g of product. The solid is recrystallized twice from boiling n-butanol to give 7.6 g (72% purified yield) of the title compound as a buffer powder. Melting point 220-221 ° C. ¹ H NMR (d ₆ -DMSO, 300 MHz) d 2.55 (4H, J = 4.5 Hz), 3.52 (4H, J = 4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J = 6.6, 4.5 Hz ), 6.81 (1H, J = 8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J = 4.5, 1.8 Hz). MS (DCI / NH ₃ ) m / z 294 (M + H) ⁺ . Anal for C ₁₇ H ₁₉ N ₅ : C, 69.60; H, 6.53; N, 23.87. Found: C, 69.47; H, 6. 58; N, 23.87.

Example 1B

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole maleate

The product from Example 1A (1.66 g) and maleic acid (657 mg) were combined with sufficient ethanol and dissolved with mild heating. The mixture is cooled to room temperature and the solid obtained is recovered by filtration and crystallized from ethanol to give the maleate salt as a white powder. Melting point 189-190 ° C. Anal for C ₁₇ H ₁₉ N ₅ .C ₄ H ₄ O ₄ : C, 61.60; H, 5. 66; N, 17.10. Found: C, 61.42; H, 5.88; N, 17.12.

Example 2

2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole

The title compound was prepared according to the procedure of Example 1A, except that 1- (2-pyridyl) piperazine was replaced with 1- (2-pyrimidyl) piperazine and DMF was replaced with CH ₃ CN as solvent. Manufacture. Melting point 198-200 ° C. ¹ H NMR (CD ₃ OD, 300 MHz) d 2.60 (t, J = 6 Hz, 4H), 3.86 (t, J = 6 Hz, 4H), 3.85 (s, 2H), 6.58 (t, J = 5 Hz, 1H), 7.23 (m, 2H), 7.52 (brm, 2H), 8.30 (d, J = 5 Hz, 2H). MS (DCI / NH ₃ ) m / z 295 (M + H) ⁺ . Anal for C ₁₆ H ₁₈ N _6. (0.25 hexanes): C, 66.54; H, 6. 86; N, 26.60. Found: C, 66.41; H, 6.91; N, 26.41.

Example 3

2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole

The title compound is prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (6-methylpyridin-2-yl) piperazine. ¹ H NMR (CD ₃ OD, 300 MHz) d 2.55 (s, 3H), 2.86 (t, J = 5 Hz, 4H), 3.83 (t, J = 5 Hz, 4H), 4.22 (s, 2H), 6.84 (d, J = 7 Hz, 1H), 7.17 (d, J = 9 Hz, 1H), 7.59 (m, 2H), 7.79 (m, 2H), 7.92 (dd, J = 7, 9 Hz, 1H). MS (DCI / NH ₃ ) m / z 308 (M + H) ⁺

Example 4

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile

The title compound is prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (3-cyanopyridin-2-yl) piperazine. Melting point 208-210 ° C. ¹ H NMR (CD ₃ OD, 300 MHz) d 2.72 (t, J = 6 Hz, 4H), 3.74 (t, J = 6 Hz, 4H), 3.87 (s, 2H), 6.87 (dd, J = 7 , 6 Hz, 1H), 7.22 (2H, m), 7.54 (brm, 1H), 7.93 (dd, J = 7, 3 Hz, 1H), 8.35 (dd, J = 6, 3 Hz, 1H). MS (DCI / NH ₃ ) m / z 319 (M + H) ⁺ . Anal for C ₁₈ H ₁₈ N ₆ : C ,: 67.68; H, 5. 66; N, 26.22. Found: C, 67.91; H, 5. 70; N, 26.40.

Example 5

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole

Except for replacing the 4-fluoro-1,2-phenylenediamine of Example 6A with 4,6-dibromo-1,2-phenylenediamine, the process of Examples 6A and 6B was repeated. According to the title compound. ¹ H NMR (CDCl ₃ , 300 MHz) d 2.70 (t, J = 6 Hz, 4H), 3.58 (t, J = 6 Hz, 4H), 3.90 (s, 2H), 6.67 (m, 2H), 7.53 (m, 2H,), 7.65 (brm, 1H), 8.18 (m, 1H). MS (DCI / NH ₃ ) m / z 450, 452, 454 (M + H) ⁺ . Anal for C ₁₇ H ₁₇ Br ₂ N ₅ : C, 45.26; H, 3.80; N, 15.52. Found: C, 44.96; H, 3.87; N, 15.26.

Example 6

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole

Example 6A

5-fluoro-2-chloromethylbenzimidazole

To a 250 ml round bottom flask was added 4-fluoro-1,2-phenylenediamine (39.70 mmol, 5.0 g), chloroacetic acid (51.60 mmol, 4.87 g) and 6N HCl (25 ml) and the mixture was stirred at 95 ° C. Heat for hours. The mixture is cooled to rt, neutralized with K ₂ CO ₃ , extracted with ethyl acetate (5-500 mL), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The product is purified on SiO ₂ and eluted with 10% MeOH / CH ₂ Cl ₂ to give a brown foam (2.65 g) in 36% yield. ¹ H NMR (CD ₃ OD, 300 MHz) d 4.87 (br s, 2H), 7.05 (td, J = 3.0, 9.0 Hz, 1H), 7.27 (dd, J = 3.0, 9.0 Hz, 1H), 7.51-7.55 (m, 1 H). MS (DCI / NH ₃ ) m / z 185 (M + H) ⁺ .

Example 6B

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole

The title compound is prepared following the procedure of Example 1A, except that 2-chlorobenzimidazole is replaced with 5-fluoro-2-chlorobenzimidazole. ¹ H NMR (CD ₃ OD, 300 MHz) d 2.62-2.69 (t, J = 5.8 Hz, 4H), 3.52-3.59 (t, J = 6.0 Hz, 4H), 3.84 (s, 2H), 6.77 (dd, J = 2.0, 6.0 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 7.02 (dt, J = 3.0, 9.0 Hz, 1H), 7.24 (dd, J = 2.0, 9.0 Hz, 1H), 7.48-7.59 (m, 2 H), 8.05-8.10 (m, 1 H). MS (DCI / NH ₃ ) m / z 312 (M + H) ⁺ . Anal for C ₁₇ H ₁₈ N ₅ F · 0.20 MeOH: C, 65.01; H, 5.96; N, 22.04. Found: C, 64.79; H, 5.97; N, 22.17.

Example 7

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole

Example 7A

1- (2-thiazolyl) piperazine

2-bromothiazole (1.75 g, 10.74 mmol), cesium carbonate (6.65 g, 20.4 mmol), racemate BINAP (0.2 g) in a suspension of tertiary butyl 1-piperazinecarboxylate (2 g, 10.74 mmol) in toluene , 0.32 mmol) and tris (dibenzylideneacetone-dipalladium) (0) (0.2 g, 0.2 mmol) are added. The mixture is heated to reflux for 16 hours and cooled. The reaction mixture is partitioned between water and ethyl acetate. The organic layers are combined, dried (MgSO ₄ ) and concentrated under reduced pressure. Purification using a flash SiO ₂ column provides 0.45 g (16%) of the desired N-Boc piperazine derivative as a yellow solid. Boc-piperazine derivative (0.45 g, 1.68 mmol) is stirred with concentrated HCl (8 mL) for 10 minutes at room temperature. The reaction mixture is diluted with water, neutralized with solid Na ₂ CO ₃ to pH 8-9 and extracted with ethyl acetate. The organic layers are combined, washed with brine and dried (Na ₂ CO ₃ ) and the filtrate is concentrated under reduced pressure to give the title compound as a yellow solid (0.33 g) which is used without further purification.

Example 7B

2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole

The title compound is prepared following the procedure of Example 1A, except that 1- (2-pyridyl) piperazine is replaced with 1- (2-thiazolyl) piperazine. Melting point 203-205 ° C. ¹ H NMR (d ₆ -DMSO, 300 MHz) d 2.58-2.62 (t, J = 5.8 Hz, 4H), 3.42-3.46 (t, J = 6.0 Hz, 4H), 3.79 (s, 2H), 6.84 ( d, J = 3.0 Hz, 1H), 7.11-7.15 (m, 2H), 6.18 (d, J = 3.0 Hz, 1H), 7.42-7-46 (m, 1H), 7.53-7.57 (m, 1H) . MS (DCI / NH ₃ ) m / z 300 (M + H) ⁺ .C ₁₅ H ₁₇ N ₅ S.0.25H ₂ O Anal. For C: 59.31; H, 5.77; N, 23.06. Found: C, 59.60; H, 5.97; N, 23.17

Example 8

Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate

To the stirred solution of Example 1A (0.77 g, 2.6 mmol) in dichloromethane (7 mL) isobutyl chloroformate (0.375 mL, 2.9 mmol) was added. The mixture is stirred at rt for 16 h, concentrated under reduced pressure and the residue is purified by flash column on SiO ₂ by eluting with 1.3% methanol / dichloromethane to afford 0.5 g (49%) of the title compound as an oil. ¹ H NMR (CDCl ₃ , 300 MHz) d 1.10 (d, J = 6 Hz, 6H), 2.22 (m, 1H), 2.86 (bm, 4H), 3.67 (bm, 4H), 4.18 (bs, 2H) , 4.33 (d, J = 7 Hz, 2H), 6.66 (m, 2H), 7.35 (m, 2H), 7.53 (m, 1H), 7.76 (m, 1H), 7.93 (m, 1H), 8.19 ( m, 1 H). MS (DCI / NH ₃ ) m / z 394 (M + H) ⁺ .

Example 9

2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole

To the stirred solution of Example 1A (0.66 g, 2.2 mmol) in dichloromethane (7 mL) was added 1-pyrrolidinecarbonyl chloride (0.28 mL, 2.2 mmol) and triethylamine (0.625 mL, 4.5 mmol). do. The mixture is heated in a sealed vial for 17 hours, cooled to room temperature, diluted with dichloromethane, washed with 5% NaHCO ₃ , dried and concentrated under reduced pressure. The residue is purified by flash column on SiO ₂ eluting with 20% hexanes / ethyl acetate to afford 0.4 g (40%) of the title compound. Melting point 120-121 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) d 1.79-2.10 (m, 4H), 2.70 (m, 4H), 3.13 (m, 1H), 3.35-3.78 (bm, 8H), 4.32 (m, 1H), 6.65 (m, 2H), 7.30 (m, 3H), 7.49 (m, 1H), 7.76 (m, 1H), 8.28 (m, 1H). MS (DCI / NH ₃ ) m / z 391 (M + H) ⁺ . Anal for C ₂₂ H ₂₆ N ₆ O.½H ₂ O: C, 66.14; H, 6.81; N, 21.04. Found: C 66.22, H 6.68, N 21.11.

Example 10

N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide

The title compound is prepared according to the process of Example 9, except that 1-pyrrolidinecarbonyl chloride is replaced with N, N-dimethylcarbamoyl. Melting point 174-176 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) d 2.68 (bm, 4H), 2.93 (bm, 3H), 3.21 (bm, 3H), 3.48 (bm, 4H), 3.71 (bm, 1H), 4.25 (bm, 1H), 6.64 (m, 2H), 7.29 (m, 3H), 7.48 (m, 1H), 7.76 (m, 1H), 8.18 (m, 1H). MS (DCI / NH ₃ ) m / z 365 (M + H) ⁺ . Anal for C ₂₀ H ₂₄ N ₆ O: C, 65.91; H, 6. 64; N, 23.06. Found: C 65.28, H 6.56, N 22.97.

Example 11

2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole

The title compound is prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1-phenylpiperazine. Melting point 285-260 ° C. ¹ H NMR (CD ₃ OD, 300 MHz) d 3.01 (m, 4H), 3.39 (m, 4H), 4.28 (s, 2H), 6.97 (m, 1H), 7.08 (m, 2H), 7.31 (m , 2H), 7.57 (m, 2H), 7.78 (m, 2H). MS (DCI / NH ₃ ) m / z 393 (M + H) ⁺ . Anal for C ₁₈ H ₂₀ N ₄ : C, 73.94; H, 6.89; N, 19.16. Found: C, 73.76; H, 6. 99; N, 19.23.

Example 12

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile

The title compound is prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (2-cyanophenyl) piperazine. Melting point 236-237 ° C. ¹ H NMR (CD ₃ OD, 300 MHz) d 2.77 (m, 4H), 3.27 (m, 4H), 3.89 (s, 2H), 7.07 (m, 1H), 7.15 (m, 1H), 7.23 (m , 2H), 7.56 (m, 4H). MS (DCI / NH ₃ ) m / z 318 (M + H) ⁺ . Found for C ₁₉ H ₁₉ N ₅ : C, 71.90; H, 6 .03; N, 22.07. Found: C, 71.76; H, 6.03; N, 22.16.

Example 13

2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole

The title compound is prepared following the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (2-chlorophenyl) piperazine. Melting point 245-246 ° C. ¹ H NMR (CD ₃ OD, 300 MHz) d 3.02 (m, 4H), 3.20 (m, 4H), 4.29 (s, 2H), 7.04 (m, 1H), 7.17 (dd, J = 9, 2 Hz , 1H), 7.28 (m, 1H), 7.47 (dd, J = 9, 2 Hz, 1H), 7.55 (m, 2H), 7.75 (m, 2H). MS (DCI / NH ₃ ) m / z 327 (M + H) ⁺ . Anal for C ₁₈ H ₁₉ ClN ₄ : C, 66.15; H, 5.86; N, 17.14. Found: C, 66.07; H, 5.95; N, 17.15.

Example 14

2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole

The title compound is prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (2-fluorophenyl) piperazine. Melting point 262-264 ° C. ¹ H NMR (CD ₃ OD, 300 MHz) d 2.96 (m, 4H), 3.24 (m, 4H), 4.26 (s, 2H), 7.06 (m, 4H), 7.55 (m, 2H), 7.66 (m , 2H). MS (DCI / NH ₃ ) m / z 311 (M + H) ⁺ . Anal for C ₁₈ H ₁₉ FN ₄ : C, 69.66; H, 6. 17; N, 18.05. Found: C, 69.51; H, 6. 19; N, 18.12.

Example 15

2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole

The title compound is prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (2-nitrophenyl) piperazine. Purification using acetonitrile / TFA as eluent as the reverse phase support affords the title compound as the TFA salt. ¹ H NMR (CD ₃ OD, 300 MHz) d 2.89 (m, 4H), 3.20 (m, 4H), 4.22 (s, 2H), 7.17 (m, 1H), 7.24 (m, 1H), 7.57 (m , 3H), 7.77 (m, 3H). MS (DCI / NH ₃ ) m / z 338 (M + H) ⁺ .

Example 16

2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole

The title compound is prepared according to the process of Example 15 except that 1- (2-nitrophenyl) piperazine is replaced with 1- (2-methoxyphenyl) piperazine. ¹ H NMR (CD ₃ OD, 300 MHz) d 3.13 (m, 4H), 3.46 (m, 4H), 3.93 (s, 3H), 4.33 (s, 2H), 7.03 (m, 1H), 7.12 (m , 1H), 7.35 (m, 2H), 7.55 (m, 2H), 7.76 (m, 2H). MS (DCI / NH ₃ ) m / z 323 (M + H) ⁺ .

Example 17

4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol

The title compound is prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (4-hydroxyphenyl) piperazine. Melting point 206-209 ° C. ¹ H NMR (CD ₃ OD, 300 MHz) d 3.12 (m, 4H), 3.55 (m, 4H), 4.32 (s, 2H), 6.93 (m, 2H), 7.32 (m, 2H), 7.60 (m , 2H), 7.80 (m, 2H). MS (DCI / NH 3) m / z 309 (M + H) ⁺ .

Example 18

2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole

The title compound is prepared following the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (2-methylthiophenyl) piperazine. Melting point 214-216 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) d 2.14 (s, 3H), 2.77 (m, 4H), 3.07 (m, 4H), 3.94 (s, 2H), 7.06 (m, 1H), 7.12 (m, 3H), 7.25 (m, 2H), 7.59 (m, 2H). MS (DCI / NH ₃ ) m / z 339 (M + H) ⁺ . Anal for C ₁₉ H ₂₂ N ₄ O. 1/4 H ₂ 0: C, 66.54; H, 6. 61; N, 16.34. Found: C 66.23, H 6.54, N 16.36.

Example 19

2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole

The title compound is prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (2-ethoxyphenyl) piperazine. Melting point 95-100 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) d 1.45 (t, J = 6 Hz, 3H), 2.39 (m, 4H), 3.33 (m, 4H), 4.03 (s, 2H), 4.07 (q, J = 6 Hz, 2H), 6.83-7.03 (m, 3H), 7.26 (m, 3H), 7.60 (m, 2H). MS (DCI / NH ₃ ) m / z 337 (M + H) ⁺ . Anal for C ₂₀ H ₂₄ N ₄ O: C, 71.40; H, 7. 19; N, 16.65. Found: C 68.97, H 6.90, N 16.01.

Example 20

2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol

The title compound is prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (2-hydroxyphenyl) piperazine. Melting point 208-216 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) d 2.78 (m, 4H), 2.97 (m, 4H), 3.93 (s, 2H), 6.83-6.95 (m, 2H), 7.05 (m, 1H), 7.14 ( dd, J = 7, 2 Hz, 1 H), 7.59 (m, 2 H). MS (DCI / NH ₃ ) m / z 309 (M + H) ⁺ . Anal for C ₁₈ H ₂₀ N ₄ O · ½H ₂ O: C, 68.12; H, 6.67; N, 17.65. Found: C 68.34, H 6.53, N 17.28.

Example 21

2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole

4- (2-methoxyphenyl) piperidine (0.2 g, 1.06 mmol), 2-chloromethyl-benzimidazole (186, 1.1 mmol) and Cs ₂ CO ₃ (0.36 g, 0.36 in DMF (8 mL) mmol) is stirred at rt for 18 h. The reaction mixture is decanted with water (30 mL) and extracted with ethyl acetate (20 mL). The organic phase is washed with brine (2 x 30 mL), dried over MgSO ₄ , filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography, eluting with 5% methanol in dichloromethane to afford the title compound (82 mg, 25%). ¹ H NMR (CDCl _3, 300 MHz) d 1.69 (m, 4H), 2.19 (m, 2H), 2.87 (m, 1H), 2.96 (m, 2H), 3.75 (s, 2H), 3.77 (s, 3H), 6.92 (m, 2H), 7.15 (m, 4H), 7.45 (m, 1H), 7.55 (m, 1H), 12.26 (s, 1H). MS (DCI-NH ₃ ) m / z 322 (M + H) ⁺ .

Example 22

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole

Example 22A

Benzyl 4-hydroxy-4-pyridin-2-ylpiperidine-1-carboxylate

A solution of 2-bromopyridine (0.47 mL, 5 mmol) in THF (20 mL) is cooled to -60 ° C and treated dropwise with nBuLi (1.6 M in hexane, 5.2 mL, 5.2 mmol). The reaction mixture is stirred at −60 ° C. for 30 minutes, then benzyl 4-oxo-1-piperidine carboxylate (1.14 g, 4.9 mmol) in THF (10 mL) is slowly added to the reaction mixture. The reaction mixture is stirred at −60 ° C. for 15 minutes and then quenched with saturated NH ₄ Cl. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature. The mixture is extracted with CH ₂ Cl ₂ and the organics are dried (MgSO ₄ ), filtered and the filtrate is concentrated under reduced pressure. The residue was purified by flash chromatography using hexanes: ethyl acetate (1: 1) to give 400 mg (27%) of the title compound. ¹ H NMR (d ₆ -DMSO, 300 MHz) d 1.54 (m, 4H), 2.05 (m, 4 H), 3.25 (m, 4H), 3.95 (m, 4H), 5.11 (s, 2H), 5.35 (s, 1H), 7.25 (m, 2H), 7.35 (m, 5H), 7.68 (m, 1H), 7.79 (m, 1H), 8.5 (m, 1H); MS (DCI / NH ₃ ) m / z 313 (M + H) ⁺ .

Example 22B

4- (pyrid-2-yl) piperidine

The product from Example 22A (0.4 g, 1.28 mmol) in thionyl chloride (6 mL) was refluxed for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue is treated with ice and 40% NaOH and extracted with CH ₂ Cl ₂ . The organics are separated, washed with brine, dried (Na ₂ SO ₄ ), filtered and the filtrate is concentrated to give 332 mg of dehydration product.

The crude dehydration product is then hydrogenated at 60 ° C. with 10% Pd / C (250 mg) for 40 hours at 50 ° C. to afford the title compound (150 mg, 88%). MS (DCI / NH ₃ ) m / z 163 (M + H) ⁺ .

Example 22C

2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole

Product from Example 22B (0.6 g, 0.36 mmol), 2-chloromethyl-benzimidazole (0.62 g, 0.36 mmol) and Cs ₂ CO ₃ (0.12 g, 0.36 mmol) in DMF (8 mL) at room temperature Stir for 18 hours. The reaction mixture is decanted with water (30 mL) and extracted with acetate (20 mL). The organic layer is washed with brine (2 × 30 mL), dried over MgSO ₄ , filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography, eluting with 5% MeOH / CH ₂ Cl ₂ to afford the title compound (11.2 mg, 11%). ¹ H NMR (CDCl ₃ , 300 MHz) d 2.0 (m, 5H), 2.51 (m, 2H), 2.79 (m, 1H), 3.14 (m, 2H), 4.01 (s, 2H), 7.09 (m, 3H), 7.29 (m, 1 H), 7.55 (m, 3 H), 8.49 (m, 1 H). MS (DCI / NH ₃ ) m / z 293 (M + H) ⁺ .

Example 23

2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole

The title compound is prepared as described in Example 22C, except the 4- (pyridin-2-yl) piperidine is replaced with 4-phenyl-1,2,3,6-tetrahydropyridine. ¹ H NMR (CD ₃ OD + 1 drop of CDCl ₃ + 1 drop of TFA, 300 MHz) d 2.90 (m, 2H), 3.52 (t, 2H), 3.92 (m, 2H), 4.7 (s, 2H), 6.14 (m, 1H), 7.34 (m, 3H), 7.46 (m, 2H), 7.52 (m, 2H), 7.78 (m, 2H). MS (DCI / NH ₃ ) m / z 290 (M + H) ⁺ .

Example 24

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole

Example 24A

3-methyl-1-pyridin-2-ylpiperazine hydrobromide

2-Methylpiperazine (1.0 g, 0.01 mol, racemic mixture) and 2-bromopyridine (10 mL, 0.1 mol) were combined and heated at 120 ° C. for 16 hours. The reaction mixture is cooled to 23 ° C. and partitioned between ethyl acetate and water. The layers are separated and the aqueous layer is concentrated under reduced pressure. The residue is triturated with ethyl acetate, dichloromethane and methanol to yield 460 mg (26% yield) of the title compound as an off-white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 1.27 (d, J = 6.6 Hz, 3H), 2.90 (dd, J = 10.5, 14.1 Hz, 1H), 3.10 (m, 2H), 3.40 (m, 2H), 4.32 (m, 2H), 6.77 (dd, J = 4.8, 6.9 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 7.64 (m, 1H), 8.15 (m, 1H), 8.63 (bs, 1 H), 8.92 (bs, 1 H); MS (APCI) m / e 178 (M + H) ⁺ .

Example 24B

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole

The product from Example 24A (0.50 g, 1.93 mmol) in N, N-dimethylformamide (10 mL) was added 2-chloromethyl-1H-benzimidazole (0.31 in N, N-dimethylformamide (10 mL). g, 1.83 mmol) solution slowly. After 5 minutes, the mixture is treated with cesium carbonate (0.60 mmol, 1.83 mmol) and the cooling bath is removed. After 1 h, the reaction mixture is diluted with ethyl acetate, washed with water (3 ×) and brine, dried over Na ₂ SO ₄ , filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed with flash silica gel (2% methanol / dichloromethane) to give 201 mg (36% yield) of the title compound. Melting point 207-209 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) d 1.18 (d, J = 6.0 Hz, 3H), 2.38 (m, 1H), 2.52 (m, 1H), 2.78 (m, 2H), 3.02 (m, 1H), 3.67 (d, J = 14.4 Hz, 1H), 3.97 (m, 2H), 4.08 (d, J = 14.4 Hz, 1H), 6.62 (dd, J = 5.1, 6.9 Hz, 1H), 6.81 ( d, J = 8.4 Hz, 1H), 7.14 (m, 2H), 7.50 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m / e 308 (M + H) ⁺ ; Anal for C ₁₈ H ₂₁ N ₅ : C, 70.33; H, 6.89; N, 22.78. Found: C, 70.15; H, 6.92; N, 22.46.

Example 25

2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole

Example 25A

(3S) -3-methyl-1-pyridin-2-ylpiperazine

(S)-(+)-2-methylpiperazine (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120 ° C. for 14 hours. The reaction mixture is cooled to 23 ° C. and partitioned between ethyl acetate and water. The layers are separated and the aqueous layer is extracted twice with ethyl acetate. The aqueous phase is brought to pH 11 with saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride is added and the saturated aqueous solution is extracted with ethyl acetate (2 ×) and dichloromethane (2 ×). The combined organic extracts are dried over Na ₂ SO ₄ , filtered and the filtrate is concentrated under reduced pressure to give 0.6 g (67% yield) of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) d 1.02 (d, J = 6.0 Hz, 3H), 2.27 (dd, J = 10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J = 6, 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m / e 178 (M + H) ⁺ .

Example 25B

2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole

The product of Example 25B (0.24 g, 1.33 mmol) in N, N-dimethylformamide (10 mL) was stirred at 23 ° C. for 2 hours with 2-chloromethyl-1H-benzimidazole (0.21 g, 1.27 mmol). And cesium carbonate (0.41 mmol, 1.27 mmol). The reaction mixture is diluted with ethyl acetate and washed with water (3 ×) and brine, dried over Na ₂ SO ₄ , filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on flash silica gel (1-3% methanol / dichloromethane gradient) to give 178 mg (46% yield) of the title compound as a pale yellow solid. Melting point 149-151 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) d 1.18 (d, J = 6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J = 8, 11.2 Hz, 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J = 14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J = 14 Hz, 1H), 6.60 (dd, J = 4.8, 6.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H ), 12.22 (bs, 1 H); MS (ESI) m / e 308 (M + H) ⁺ ; Anal. calcd for C ₁₈ H ₂₁ N ₅ : C, 70.33; H, 6.89; N, 22.78. Found: C, 70.21; H, 6. 77; N, 22.62.

Example 26

2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole

Example 26A

(3R) -3-methyl-1-pyridin-2-ylpiperazine

Combine (R)-(-)-2-methylpiperazine (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) and combine at 120 ° C. for 14 hours. The reaction mixture is cooled to 23 ° C. and partitioned between a large volume of ethyl acetate and water. After separating the layers, additional water is added to the ethyl acetate solution. A few drops of 1N HCl solution are added to the water / ethyl acetate mixture and mixed vigorously. The layers are separated and the combined aqueous phases are basified to pH 11 with saturated sodium bicarbonate and solid sodium carbonate solution. Sodium chloride is added and the saturated aqueous solution is extracted with chloroform containing a few drops of isopropyl alcohol (5 ×). The combined organic extracts are dried over Na ₂ S0 ₄ , filtered and the filtrate is concentrated under reduced pressure to yield 0.79 g (89% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 1.02 (d, J = 6.0 Hz, 3H), 2.27 (dd, J = 10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J = 6, 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m / e 178 (M + H) ⁺ .

Example 26B

2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole

The product of Example 26A (0.79 g, 4.43 mmol) and N, N-dimethylformamide (15 mL) were 2-chloromethyl-1H-benzimidazole in N, N-dimethylformamide (15 mL) at 0 ° C. (0.70 g, 4.21 mmol) solution. After 10 minutes, the mixture is treated with cesium carbonate (1.37 mmol, 4.21 mmol) and the cooling bath is removed. After 1 h, the reaction mixture is diluted with ethyl acetate and washed with water (3 ×) and brine, dried over Na ₂ SO ₄ , filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on flash silica gel (1-3% methanol / dichloromethane gradient) to yield 0.50 g (39% yield) of the title compound as a light yellow solid. Melting point 151-153 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) d 1.18 (d, J = 6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J = 8, 11.2 Hz, 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J = 14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J = 14 Hz, 1H), 6.60 (dd, J = 4.8, 6.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H ), 12.22 (bs, 1 H); MS (ESI) m / e 308 (M + H) ⁺ ; Anal. calcd for C ₁₈ H ₂₁ N ₅ : C, 70.33; H, 6.89; N, 22.78. Found: C, 70.10; H, 7.03; N, 22.63.

Example 27

N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide

Example 27A

N- (2-chloropyridin-3-yl) methanesulfonamide

2-chloro-pyridin-3-ylamine (1.00 g, 7.75 mmol) in dichloromethane (20 mL) at 23 ° C. was treated with methane sulfonyl chloride (2.23 g, 19.4 mmol) and triethylamine (1.96 g, 19.4 mmol). To be processed. After stirring for 48 hours, the reaction mixture is diluted with water, the layers are separated and the aqueous phase is extracted with dichloromethane (2x). The organic layers are combined, dried over MgSO ₄ , filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on flash silica gel (20% ethyl acetate: hexanes), concentrated under reduced pressure and added with 10% aqueous sodium hydroxide solution (32 mL). Stir vigorously for 0.5 hours until the solution is homogeneous. The solution is then neutralized with 2N HCl to pH 7, saturated with Na ₂ SO ₄ and extracted with ethyl acetate (3 ×). The combined extracts are dried over Na ₂ S0 ₄ , filtered and the filtrate is concentrated under reduced pressure to yield 1.5 g (93% yield) of the title compound. See Tetrahedron Letters 38, 26, 4667-4670, 1997; Eur. J. Org. Chem. 2000, 1263-1270. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 3.12 (s, 3H), 7.46 (dd, J = 4.5, 8.4 Hz, 1H), 7.89 (dd, J = 1.5, 8.4 Hz, 1H), 8.27 ( dd, J = 1.5, 4.5 Hz, 1 H), 9.72 (bs, 1 H); MS (ESI) m / e 205 (M) ^- .

Example 27B

N- (2-piperazin-1-ylpyridin-3-yl) methanesulfonamide

Piperazine (5.2 g, 60.2 mmol), the product from Example 27A (1.24 g, 6.02 mmol) and n-butanol (90 mL) were combined and refluxed for 3 days. The reaction mixture is cooled to 23 ° C. and concentrated under reduced pressure. The residue is chromatographed on flash silica gel (33% methanol / dichloromethane and 1% acetic acid) to give 2.0 g (yield up to 88%) of the title compound. ¹ H NMR (300 MHz, CD ₃ OD) d 1.97 (s, CH ₃ from CH ₃ CO ₂ H), 3.13 (s, 3H), 3.42 (m, 8H), 7.13 (dd, J = 4.5, 8.4 Hz , 1H), 7.78 (dd, J = 1.5, 8.4 Hz, 1H), 8.12 (dd, J = 1.5, 4.5 Hz, 1H); MS (DCI / NH ₃ ) m / e 257 (M + H) ⁺ .

Example 27C

N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide

The product from Example 27B (0.066 g, 0.21 mmol) and cesium carbonate (0.137 g, 0.42 mmol) were combined in N, N-dimethylformamide (2 mL) at 23 ° C. and stirred for 5 minutes. The mixture is then treated with 2-chloromethyl-1H-benzimidazole (0.035 g, 0.21 mmol). After 1 hour, the reaction mixture is concentrated under reduced pressure. The residue is impregnated with flash silica gel and chromatographed on flash silica gel (10% methanol / dichloromethane) to give 22 mg (27% yield) of the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ ) d 2.64 (m, 4H), 3.12 (s, 3H), 3.23 (m, 4H), 3.79 (s, 2H), 5.75 (s, 2H), 6.98 ( dd, J = 5, 8.5 Hz, 1H), 7.14 (m, 2H), 7.44 (bd, J = 7.5 Hz, 1H), 7.57 (bd, J = 7.5 Hz, 1H), 7.58 (dd, J = 1 , 7 Hz, 1H), 8.08 (dd, J = 1, 5 Hz, 1H), 8.76 (bs, 1H); MS (ESI) m / e 387 (M + H) ⁺ .

Example 28

2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole

Example 28A

2-chloro-3-fluoropyridine

1,4-diazabicyclo [2.2.2] octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was n-butyllithium (32.2 mL, 51.5 mmol, 1.6 M solution in hexane) at −78 ° C. Drop by the deal. The reaction mixture is warmed to -20 ° C for 1 hour and then recooled to -78 ° C. The recooled mixture is treated with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL). After stirring at −78 ° C. for 2 hours, the mixture is treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring at −78 ° C. for 1 hour, the reaction mixture is treated with water (15 mL) and tetrahydrofuran (25 mL) solution. The reaction mixture is warmed to 0 ° C. and after 30 minutes additional water and diethyl ether are added to the mixture. The layers are separated and the aqueous phase is extracted with diethyl ether (2 ×). The combined ether layers are dried over Na ₂ S0 ₄ , filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on flash silica gel (10% ethyl acetate / hexanes) to yield 3.5 g (52% yield) of the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m / e 154 (M + Na) ⁺ .

Example 28B

1- (3-fluoropyridin-2-yl) piperazine

The product of Example 28A (3.3 g, 0.025 mol) in n-butanol (150 mL) at 23 ° C. was treated with piperazine (21.5 g, 0.25 mol) and then refluxed for 3 days. The reaction mixture is cooled to 23 ° C. and concentrated under reduced pressure. The residue is slurried with water and ethyl acetate. The ethyl acetate solution is separated, dried over Na ₂ SO ₄ , filtered and the filtrate is concentrated under reduced pressure to give 3.3 g (73% yield) of the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ ) d 2.80 (m, 4H), 3.38 (m, 4H), 6.84 (m, 1H), 7.47 (m, 1H), 7.98 (m, 1H); MS (ESI) m / e 182 (M + H) ⁺ .

Example 28C

2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole

The product of Example 28B (0.50 g, 2.76 mmol), 2-chloromethyl-1H-benzimidazole (0.48 g, 2.90 mmol), and cesium carbonate (1.8 g, 5.52 mmol) were added N, N-dimethyl at 23 ° C. Combine in formamide (28 mL) and stir for 1.25 h. The mixture is concentrated under reduced pressure and rinsed with 10% methanol / dichloromethane. The solid is filtered off and the filtrate is concentrated under reduced pressure. The residue is impregnated with flash silica gel and chromatographed on flash silica gel (10% methanol / dichloromethane) to give 311 mg (36% yield) of the title compound. Melting point 210-212 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) d 2.62 (m, 4H), 3.43 (m, 4H), 3.78 (s, 2H), 6.87 (m, 1H), 7.14 (m, 2H), 7.50 ( m, 3H), 8.00 (m, 1H); MS (APCI) m / e 312 (M + H) ⁺ ; Anal for C ₁₇ H ₁₈ FN ₅ .0.4 H ₂ O: C, 64.10; H, 5.95; N, 21.98. Found: C, 64.16; H, 5.86; N, 21.95.

Example 29

6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol

Example 29A

5- (benzyloxy) -2-chloropyridine

2-chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After the reaction product is stirred at 23 ° C. for 6 hours, the reaction mixture is diluted with water, adjusted to pH 7 with saturated aqueous NaH ₂ PO ₄ and extracted with dichloromethane. The organic extract is dried over Na ₂ S0 ₄ , filtered and the filtrate is concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with CH ₂ Cl ₂ ) to provide the title compound as a white solid (3.44 g, 79%). Melting point <50 ° C; R _f = 0.4 (CH ₂ Cl ₂ ); MS 220 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) d 8.20 (d, 1H, J = 2.7 Hz), 7.55 (dd, 1H, J = 9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 ( s, 2H).

Example 29B

Tert-Butyl 4- [5- (benzyloxy) pyridin-2-yl] piperazin-1-carboxylate

Product from Example 29A (2.63 g), Pd ₂ (dba) ₃ (0.33 g), racemate BINAP (0.45 g), sodium tert-butoxide (2.3 g) and tert-butyl piperazine-1-carboxyl The rate (4.46 g) is combined in toluene (80 mL) and heated at 95 ° C for 3 hours. The reaction mixture is treated with toluene (50 mL) and with diethyl ether (200 mL). The mixture is washed with water, the organic phase is dried over Na ₂ SO ₄ , filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography, eluting with 1: 4 ethyl acetate / hexanes to give the title compound (4.06 g, 92%). Melting point 93-94 ° C; R _f = 0.21 (1: 4 ethyl acetate / hexane); MS 370 (M + H) ⁺ .

Example 29C

1- [5- (benzyloxy) pyridin-2-yl] piperazine

The product from Example 29B (1.96 g) was treated with trifluoroacetic acid (3.5 mL) at 23 ° C. for 2 hours with stirring. The mixture is partitioned between CH ₂ Cl ₂ (100 mL) / n-butanol (5 mL) and water (400 mL) / NH ₄ OH (5 mL). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and the filtrate is concentrated under reduced pressure to give the title compound as a white powder which is used in the next step without further purification.

Example 29D

2-({4- [5- (benzyloxy) pyridin-2-yl] piperazin-1-yl} methyl) -1H-benzimidazole

The product from Example 29C and 2-chloromethyl-1H-benzoimidazole (0.88 mg) were combined and dissolved in DMF (7 mL) / triethylamine (1.5 mL). After stirring at 23 ° C. for 2 hours, the mixture is treated with acetonitrile (20 mL) and then stirred for 24 hours. The reaction mixture is partitioned between CH ₂ Cl ₂ (100 mL) / n-butanol (5 mL) and water (800 mL) / NH ₄ OH (5 mL). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography to give the title compound as a white solid (1.169 g, 55%). Melting point 62-64 ° C .; R _f = 0.26 (95: 5 CH ₂ Cl ₂ : methanol: 0.1% NH ₄ OH); MS 400 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) d 12.3 (bs, NH, 1H), 7.90 (d, 1H, J = 3 Hz), 7.55 (m, 1H), 7.3-7.5 (m, 8H), 7.15 (m, 2H), 6.80 (d, 1H, J = 9 Hz), 5.05 (s, 2H), 3.76 (s, 2H), 3.39 (t, 4H, J = 5.1 Hz), 2.57 (t, 4H , J = 5.1 Hz).

Example 29E

6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol

The product from Example 29D (800 mg) in ethyl acetate (35 mL) was treated with palladium on carbon (85 mg) at 10 ° C. at 23 ° C. under a blanket of hydrogen gas until TLC showed consumption of starting material. The mixture is filtered and the filter cake is washed with methanol and CH ₂ Cl ₂ . The filtrates are combined and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with 90: 10: 0.1 CH ₂ Cl ₂ : methanol: NH ₄ OH) to afford the pure title compound as a white solid (566 mg, 92%). Melting point 144-145 ° C .; R _f = 0.08; (95: 5 CH ₂ Cl ₂ : methanol: 0.1% NH ₄ OH); MS 310 (M + H) ⁺ ; ¹ H NMR (300 MHz, MeOD) d 7.72 (d, 1H, J = 2.7 Hz), 7.53 (m, 2H), 7.21 (m, 2H), 7.12 (dd, 1H, J = 9, 3 Hz), 6.75 (d, 1H, J = 9 Hz), 3.85 (s, 2H), 3.40 (t, 4H, J = 5.1 Hz), 2.69 (t, 4H, J = 5.1 Hz); C ₁₇ H ₁₉ N ₅ O Analytical values for 1.0 equivalent of methanol, 0.1 equivalent of dichloromethane: C 62.13; H 6.68; N 20.01. Found: C 62.04; H 6.57; N 19.67.

Example 30

2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole

The title compound can be prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (3-methylpyridin-2-yl) piperazine.

In vivo data

Rat penis erection model

In vivo penile erection is studied using Wistar rat as the main animal model. All experiments are conducted from 9 am to 3 pm in a diffused light laboratory with red light. Animals are weighed and acclimated to the laboratory for 60 minutes before starting the experiment. Rats are individually placed in clear cages (20 × 30 × 30 cm) after drug injection. The penile erection number is recorded by direct observation for 60 minutes after drug administration, and the number of animals showing one or more erections is expressed as the percentage of occurrence.

Induced penile erection of rats against 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole Capacity (μmol / kg) Incidence rate (%) Vehicle 25 0.003 25 0.01 50 0.03 83 0.10 58

As vehicle, (L) -ascorbic acid (1 mg / ml) in saline is used. 12 animals are used per dose. As a positive control, apomorphine is used at a dose of 0.1 μmol / kg which produces 83% incidence of rat penile erection.

The data in Table 1 shows the statistical significance of rats after subcutaneous administration of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole to doses of 0.01 to 0.10 μmol / kg. Induces significant penile erection.

Induced penile erection of rats for 6- [4- (1H-benzimidazol-2-ylmethyl) piperidin-1-yl] pyridin-3-ol Capacity (μmol / kg) Incidence rate (%) Vehicle 25 0.01 42 0.03 58 0.1 58 0.3 33

(L) -ascorbic acid (1 mg / ml) in brine is used as the vehicle. 12 animals are used per dose. As a positive control, apomorphine is used at a dose of 0.1 μmol / kg which produces 93% incidence of rat penile erection.

The data in Table 2 shows statistics after subcutaneous administration of 6- [4- (1H-benzimidazol-2-ylmethyl) piperidin-1-yl] pyridin-3-ol for doses of 0.01 to 0.10 μmol / kg Academically significant induction of penile erection.

Preferred compounds of the invention induce at least 50% incidence of penile erection of rats at doses of about 0.003 to 0.10 μmol / kg.

Ferret's Vomiting Model

Male pitch ferrets (weight 1.0-1.5 kg) are purchased (Marshall Farms). Fast the ferrets overnight before the experiment. Subcutaneous administration of apomorphine or a compound of the present invention; Animals are placed individually in the observation cage and drug-induced vomiting and nausea signals are measured (observed directly) for 90 minutes after drug infusion. Nausea is characterized by behaviors such as licks, nausea, retreat, hair buring, and strong abdominal grooming. Vomiting is usually characterized by periodic abdominal contractions associated with exercise that precedes these behaviors and vomits or nausea.

Induced vomiting of rats against 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole Capacity μmol / kg Incidence rate (%) Vehicle 0 0.03 0 0.3 0 3.0 0

Sterile saline is used as the vehicle. Six animals are used per dose. As a positive control in Table 3, apomorphine is used at a dose of 0.3 μmol / kg which generates 100% incidence of ferrets showing vomiting.

As shown in Table 3, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole does not induce vomiting of ferrets after subcutaneous administration.

Apomorphine is included as a positive control in these studies. These data show that 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole provides significant benefits over apomorphine because it promotes penile erection without inducing vomiting. Indicates.

Compounds of the invention, particularly 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are not intended to be limited to these as a method of treating sexual dysfunction in mammals. It can be used in combination with phosphodiesterase 5 inhibitors including cdenafil or vardenafil.

Compounds of the invention, particularly 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are not intended to be limited to these as a method of treating sexual dysfunction in mammals. It can be used in combination with an adrenergic receptor antagonist including terrazocin, prazosin or tamsulosin.

Compounds of the invention, particularly 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are not intended to be limited to these as a method of treating sexual dysfunction in mammals. It can be used in combination with a dopamine agonist including apomorphine.

Compounds of the invention, in particular 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are dopamine agonists and are therefore described in N.J. Hrib. Drugs of the future 25: 587-611 (2000); Dopamine and sexual behavior. M. Melis and A. Argiolas. Neuroscience and Biobehavioral Reviews 19: 19-38 (1995); and Dopaminereceptors: from structure to function. C. Missale, S.R. Nash, S. Robinson, M. Jabber and M. Caron. Physiological Reviews 78: 189-225 (1998), which are useful for the treatment of female sexual dysfunction, attention deficit hyperactivity disorder, Alzheimer's disease, drug abuse, Parkinson's disease, anxiety, schizophrenia, mood disorders and depression.

Compounds of the invention, in particular 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are dopamine agonists and are therefore useful for the treatment of cardiovascular disorders. Dopamine and dopamine have been reported to be useful in the treatment of cardiovascular disorders by exerting pharmacologically contributing cardiovascular effects on blood pressure and heart rate [Chen FF, and Lin MT, Effects of dopamine, apomorphine gamma-]. hydroxybutyric acid, haloperidol, and pimozide on reflex bradycardia in rats, Journal of Pharmacology and Experimental Therapeutics (1980) 214: 427-432], data from primates suggest potential clinical potential of dopamine receptor agonists for treating cardiovascular disease. Support utility (Hahn, RA and MacDonald BR, Primate cardiovascular responses meditated by dopaminine receptors: effects of N, N-dipropyldopamine and LY171555, Journal of Phamacology and Experimental Therapeutics (1984) 229: 132-138).

Compounds of the invention, in particular 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are dopamine agonists and are therefore useful for the treatment of inflammation. Dopamine may have an anti-inflammatory effect and may be useful in the treatment of diseases in which inflammation plays a detrimental role [Bendele AM, Spaethe SM, Benslay DN, and Bryant HU, Anti-inflammatory activity of pergolide, a dopamine receptor agonist, in Journal of Pharmacology of Pharmacology and Experimental Therapeutics (1991) 259: 169-175]. Dopamine may also be useful in the treatment of cancer. See Lissoni P, Mandala M, Giani L, Malugani F, Secondino S, Zonato S, Rocco F, Gardani G, Efficacy of Bromocriptine in the Treatment of Metastatic Breast Cancer and Prostate Cancer-related Hyperprolactinemia, Neuroendocrinology Letters (2000) 21: 405-408].

The term agonist as used herein refers to a compound that interacts with one or more dopamine receptor subtypes and induces observable intracellular biochemical responses. Response is measured for total agonists such as dopamine.

As used herein, the term "pharmaceutically acceptable carrier" means any type of nontoxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation aid. Examples of some materials that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; Starches such as starch and potato starch; Cellulose and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Tragacanth powder; malt; gelatin; Talc; Excipients such as cocoa butter and suppository waxes; Oils such as sweet bean oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols such as propylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Unheated water; Isotonic saline; Ringer's solution; Ethyl alcohol and phosphate buffer solutions, and other nontoxic miscible lubricants such as sodium lauryl sulfate and magnesium stearate, and colorants, mold release agents, coatings, sweeteners, flavoring and fragrances, preservatives and antioxidants It may be present in the composition at its discretion.

The present invention provides a pharmaceutical composition comprising a compound of the present invention in combination with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be formulated for oral administration, parenteral injection or enteral administration in solid or liquid form.

Further included within the scope of this invention are pharmaceutical compositions comprising one or more dopamine agonists prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable compositions. The pharmaceutical compositions can be formulated for oral administration, parenteral injection or disorder administration in solid or liquid form.

The pharmaceutical composition of the present invention is directed to humans and other mammals as oral, sublingual, enteral, parenteral, intracranial, urethra, intravaginal, intraperitoneal, topical (powder, ointment or drops), cheek or oral or nasal sprays. May be administered. The term “parenteral” as used herein refers to dosage forms including intravenous, intramuscular, intraperitoneal, subcutaneous, intraarticular injection and infusion.

Preferred administration to humans is oral or sublingual.

Oral injectable pharmaceutical compositions of the present invention include sterile powders for reconstitution into pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersants, suspensions or emulsions and sterile injectable solutions or dispersants. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include injectable organics such as water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g. olive oil) and ethyl oleate. Esters are included. For example, proper fluidity can be maintained by using a coating such as lecithin, maintaining the required particle size in the case of a dispersant, and using a surfactant.

Such compositions may contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of the action of microorganisms can be ensured by various antibacterial and antibacterial agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. It may be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Pharmaceutical forms for injection can be delayed with agents that delay absorption, such as aluminum monostearate and gelatin.

In some cases, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection, in order to prolong the effect of the drug. This can be achieved using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

In addition to the active compounds, suspensions may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth and mixtures thereof It may contain

If desired, for more effective distribution, the compounds of the present invention can be incorporated into sustained or targeted delivery systems such as polymeric matrices, liposomes and microspheres. It may be sterilized by incorporating a sterilizing agent, for example, in the form of a sterile solid composition that can be filtered through a bacterial retention filter or dissolved in sterile water or other sterile injectable media immediately prior to use.

The compounds of the present invention may also be in microencapsulated form with one or more excipients as noted above, if necessary. Solid dosage forms in the form of tablets, tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical compounding arts. In such solid dosage forms the active compound may be mixed with one or more inert diluents such as sucrose, lactose or starch. Such dosage forms may also include additional materials other than inert diluents, such as tableting lubricants and other tableting aids, such as, for example, magnesium stearate and microcrystalline cellulose, as is commonly practiced. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer. It may optionally contain a contrast agent and may also be such a composition which releases only the active ingredient (s) or preferentially to a particular part of the intestinal pathway in a delayed manner. Examples of visceral compositions that can be used include polymeric substances and waxes.

Injectable depot forms are made by forming microencapsulated matrices of the compounds of the invention in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compound of the invention to the polymer and the nature of the particular polymer used, the ratio of the compound of the invention can be adjusted. Examples of biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the agent in liposomes or microemulsions which can be mixed with living tissue.

Injectable formulations can be sterilized by incorporating a sterilizing agent in the form of a sterile solid composition that can be, for example, filtered through a bacterial retention filter or dissolved or dispersed immediately prior to use in sterile water or other sterile injectable media. have.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in a non-toxic, parenterally acceptable solution such as 1,3-butanediol or a diluent. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, U.S.P. And sodium chloride isotonic solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound or compounds of the present invention may contain one or more inert, pharmaceutically acceptable excipients or carriers, such as sodium citrate or sodium phosphate and / or a) starch, lactose, sucrose, glucose, Fillers or extenders such as mannitol and silicic acid; b) carboxymethylcellulose, alginate, gelatin. Binders such as polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retardants such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; And i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof.

Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or lactose, such as high molecular weight polyethylene glycols.

Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric and other coatings well known in the pharmaceutical compounding arts. It may optionally contain a contrast agent and may be a composition which releases only or preferentially the active ingredient (s) in a particular part of the intestinal pathway in a delayed manner. Examples of visceral compositions that can be used include polymeric substances and waxes.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds of the present invention, liquid dosage forms include, for example, water and other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, Fatty acids of 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germinated oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan Esters, and mixtures thereof.

In addition to inert diluents, oral compositions may include wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with any pharmaceutically acceptable carrier to the extent necessary and any necessary preservatives or buffers. Ocular formulations, ear drops, ointments, powders and solutions are also contemplated as being within the scope of this invention.

Ointments, pastes, creams and gels, in addition to the compounds of the present invention, include excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxide Or mixtures thereof.

Powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these materials. The spray contains conventional propellants such as chlorofluorohydrocarbons.

The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term “pharmaceutically acceptable salts” is a salt that is suitable for use in contact with the masonry of a mammal, especially a human, and with a reasonable benefit / risk ratio, without undue toxicity, irritation, allergic reactions, etc. within the safe medical judgment area Means. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, J. Pharmaceutical Sciences, 1977, 66: 1 et seq, describes pharmaceutically acceptable compositions in detail. The salts can be prepared separately, either in the reaction system or by reacting the free base functional groups with a suitable organic acid during the final isolation or purification of the compounds of the present invention. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate , Glycerophosphate, heavy sulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, heavy sulfate, heptanoate, hexanoate, fumarate, hydrochloride, dihydrochloride, trihydrochloride, Hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isetheonate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, Persulfate, 3-phenylpropionate, picrate, pivalate, Propionate, succinate, sulfate, bis (tartrate), tartrate, (L) -tartrate, bis ((L) tartrate), (D) tartrate, bis ((L) tartrate), ( DL) tartrate, bis ((DL) tartrate), meso-tartrate, bis (metho tartrate), tyrocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.

Preferred pharmaceutically acceptable salts of the present invention are bis ((D) tartrate), bis ((DL) tartrate), bis (bromide), bis (sulfate), bis (phosphate), fumarate and tris (hydro Chloride).

The most preferred pharmaceutically acceptable salt of the present invention is bis ((L) tartrate).

As used herein, the term “pharmaceutically acceptable prodrug” or “prodrug” refers to contacting a mammal, in particular a human tissue, within the scope of safe medical judgment, without excessive toxicity, irritation, allergic reactions, or the like. To show a prodrug of a compound of the invention that is suitable for use, balanced at a reasonable benefit / risk ratio and effective for its intended use. Prodrugs of the compounds of the invention can be converted in vivo to the compounds of the invention, for example, by blood hydrolysis. See T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the ACS Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). For example, a compound of Formula I wherein R _E is substituted with alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclocarbonyl or (NZ ₁ Z ₂ ) carbonyl is a prodrug . In particular, isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate; 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole; And N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide is a representative example of a prodrug of a compound of formula (I) to be.

As used herein, the term “pharmaceutically acceptable ester” or “ester” refers to an ester of a compound of the invention that hydrolyzes in vivo, and that is rapidly destroyed in the human body leaving the compound of the invention or a salt thereof. It includes. Examples of pharmaceutically acceptable, non-toxic esters of the invention include C ₁ to C ₆ alkyl esters and C ₅ to C ₇ cycloalkyl esters, but C ₁ to C ₄ alkyl esters are preferred. Esters of compounds of formula (I) can be prepared according to conventional methods.

As used herein, the term "pharmaceutically acceptable amide" or "amide" is a nontoxic of the present invention derived from ammonia, primary C ₁ to C ₆ alkyl amines and secondary C ₁ to C ₆ dialkyl amines. Refers to amide. In the case of secondary amines, the amine may be in the form of a five or six membered heterocycle containing a nitrogen atom. Preferred are ammonia, C ₁ to C ₃ alkyl primary amides and C ₁ to C ₂ dialkyl secondary amides. Amides of compounds of formula (I) may be prepared according to conventional methods.

Dosage forms for topical administration of a compound of this invention may include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives. Ocular formulations, ophthalmic ointments, powders and solvents are also contemplated within the scope of the present invention.

The actual level of administration of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of the compound or compounds of the present invention effective to achieve the desired therapeutic response for a particular patient, composition and dosage form. . The dosage level chosen depends on the activity of the particular compound, the route of administration, the severity of the condition of treatment and the condition and previous history of the patient being treated. However, it is within the skill in the art to start with a dose of a compound of the present invention at a lower level than necessary to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

The present invention contemplates a compound of the invention that has been chemically synthesized or formed, for example, by administering a prodrug to the compound of the invention and subsequently biotransforming it.

When used in the above treatments or other therapies, therapeutically effective amounts of the compounds of the invention may be used in pure form or in the form in which these forms are in the form of pharmaceutically acceptable salts or prodrugs. Alternatively, the compounds of the present invention may be administered in combination with one or more pharmaceutically acceptable excipients as a pharmaceutical composition containing the compound or compounds of the present invention. The phrase “therapeutically effective amount” of a compound of the present invention means that the compound or amount of compounds of the present invention is sufficient to treat sexual dysfunction at a reasonable benefit / risk ratio applicable to any medical treatment. However, the total daily usage of the compound or compounds of the present invention and compositions thereof is determined by the attending physician within the scope of safe medical judgment. Specific therapeutically effective dose levels for any particular patient may include the severity of the sexual dysfunction and sexual dysfunction being treated; The activity of the compound or compounds of the invention used; The specific composition employed; The age, body weight, general health, sex and diet of the patient; The time of administration, route of administration, and rate of excretion of the compound or compounds of the invention; Duration of treatment; Medicaments used in combination or coincidental with the compound or compounds of the present invention; And various factors including factors well known in the medical arts. For example, it is well known in the art to start a dose of agonist at a level lower than necessary to achieve the desired therapeutic effect and to gradually increase administration until the desired effect is achieved.

The total daily dose of a compound of the invention administered to a human or other mammal may range from about 0.001 to about 30 mg / kg / day. For oral administration, more preferred doses may range from about 0.01 to about 10 mg / kg / day. For sublingual administration, more preferred doses may range from about 0.001 mg to about 0.15 mg / kg / day. If necessary, the effective daily dose can be divided into multiple doses for the purpose of administration, and consequently a single dose composition can contain such amounts or portions thereof to supplement the daily dose.

Claims (112)

A method of treating sexual dysfunction in a mammal, comprising administering a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, ester, amide, or prodrug thereof to a mammal in need thereof. . Formula I In Formula I above, A is , , , , , , , , , , , , , , , , , , , And Is selected from the group consisting of X is selected from the group consisting of NH, O and S, L is selected from the group consisting of CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ and CH ₂ CH ₂ CH ₂ CH ₂ , R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ , (NZ ₁ Z ₂ ) carbonyl and (NZ ₁ Z ₂ ) sulfonyl, wherein Z ₁ and Z ₂ are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl; R _A , R _B , R _C and R _D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ and (NZ ₁ Z ₂ ) carbonyl, R _E is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl and (NZ ₁ Z ₂ ) carbonyl, R _F is selected from the group consisting of hydrogen and alkyl, Z is selected from the group consisting of N, C and CH, --- is a bond when Z is C and absent when Z is N or CH. The method of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is N, and --- is absent. The compound of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is N, --- is absent, and A end How to be. The compound of claim 1, wherein L is CH ₂ , R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, Z Is N, --- is absent, and A is And R ₂ , R ₃ and R ₄ are each hydrogen. The compound of claim 4, wherein the compound of formula I is 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile, 2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole, 2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole and The process is selected from the group consisting of 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol. The compound of claim 1, wherein L is CH ₂ , R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, Z Is N, --- is absent, and A is And R ₁ , R ₂ , R ₄ and R ₅ are each hydrogen. The method of claim 6, wherein the compound of formula I is 4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol. The compound of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is N, --- is absent, and A end How to be. The compound of claim 1, wherein L is CH ₂ , R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, Z Is N, --- is absent, and A is And R ₂ , R ₃ and R ₄ are each hydrogen. The compound of claim 9, wherein the compound of formula I is used. 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile, 5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide and 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. The method of claim 9, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. The compound of claim 1, wherein L is CH ₂ , R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is alkyl, Z Is N, --- is absent, and A is And R ₂ , R ₃ and R ₄ are each hydrogen. The compound of claim 12, wherein the compound of formula I is 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole and 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole. The compound of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is N, --- is absent, and A end R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen and hydroxy. The compound of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, L is CH ₂ , Z Is N, --- is absent, and A is And R ₁ , R ₂ and R ₄ are each hydrogen and R ₃ is hydroxy. The method of claim 15, wherein the compound of formula I is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol. The compound of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is N, --- is absent, and A end How to be. The compound of claim 1, wherein L is CH ₂ , R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, Z Is N, --- is absent, and A is And R ₂ , R ₃ and R ₄ are each hydrogen. The method of claim 18, wherein the compound of formula I is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. The compound of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is N, --- is absent, and A end How to be. The compound of claim 1, wherein L is CH ₂ , R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, Z Is N, --- is absent, and A is And R ₂ and R ₃ are each hydrogen and X is S. The method of claim 21, wherein the compound of formula I is 2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. The compound of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, and R _E is alkoxycarbonyl, alkylcarbonyl, alkyl, arylcarbonyl, cycloalkyl Is selected from the group consisting of carbonyl, heterocyclecarbonyl and (NZ ₁ Z ₂ ) carbonyl, Z is N, --- is absent, and A is How to be. The compound of claim 1, wherein L is CH ₂ , R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is alkoxycarbonyl, alkylcarbonyl, (NZ ₁ Z ₂ ) carbonyl and heterocyclecarbonyl, wherein the heterocycle portion of heterocyclecarbonyl is pyrrolidinyl, R _F is hydrogen, Z is N, --- is absent and A is And R ₂ , R ₃ and R ₄ are each hydrogen. The compound of claim 24, wherein the compound of formula I is Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole and N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide. The compound of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is CH, --- is absent, and A end How to be. The compound of claim 1, wherein L is CH ₂ , R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, Z Is CH, --- is absent, and A is And R ₂ , R ₃ and R ₄ are each hydrogen. The method of claim 27, wherein the compound of formula I is 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole. The compound of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is CH, --- is absent, and A end How to be. The compound of claim 1, wherein L is CH ₂ , R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, Z Is CH, --- is absent, and A is And R ₂ , R ₃ and R ₄ are each hydrogen. The method of claim 30, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole. The compound of claim 1, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is C, --- is a bond, A end How to be. The compound of claim 1, wherein L is CH ₂ , R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, Z Is C, --- is a bond, and A is And R ₂ , R ₃ and R ₄ are each hydrogen. The method of claim 33, wherein the compound of formula I is 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole. Treatment of sexual dysfunction in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof in combination with a pharmaceutically acceptable carrier Way. The compound of claim 35, wherein the compound of formula I is 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile, 5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole, N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide, 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile, 2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole, 2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole, 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole, 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole, 2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide and 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. The method of claim 35, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. The method of claim 35, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate). The method of claim 35, wherein the compound of formula I is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. 36. The method of claim 35, wherein the compound of formula I is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol. Sexual dysfunction of a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof in combination with a phosphodiesterase 5 inhibitor Treatment method. The compound of claim 41, wherein the compound of formula I is 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile, 5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole, N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide, 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile, 2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole, 2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole, 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole, 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole, 2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide and 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. The method of claim 41, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. The method of claim 41, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) 42. The method of claim 41, wherein the compound of formula I is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1 H-benzimidazole. 42. The method of claim 41, wherein the compound of formula (I) is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol. A method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof in combination with an adrenergic receptor antagonist. 48. The compound of claim 47, wherein the compound of formula 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile, 5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole, N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide, 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile, 2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole, 2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole, 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole, 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole, 2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide and 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. 48. The method of claim 47, wherein the compound of Formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. 48. The method of claim 47, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate). 48. The method of claim 47, wherein the compound of formula I is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. 48. The method of claim 47, wherein the compound of formula I is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol. A method of treating sexual dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof in combination with a dopamine agonist. The compound of claim 53, wherein the compound of formula I is 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile, 5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole, N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide, 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile, 2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole, 2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole, 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole, 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole, 2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide and 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. The method of claim 53, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. The method of claim 53, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate). The method of claim 53, wherein the compound of formula I is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. The method of claim 53, wherein the compound of formula I is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol. A method of treating erectile dysfunction in a male, comprising administering to a man in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. 60. The compound of claim 59, wherein the compound of formula 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile, 5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole, N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide, 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile, 2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole, 2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole, 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole, 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole, 2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide and 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. 60. The method of claim 59, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt or prodrug thereof. . 60. The method of claim 59, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate). 60. The compound of claim 59, wherein the compound of formula I is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt or prodrug thereof Way. 60. The compound of claim 59, wherein the compound of Formula I is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt or pro- cess thereof How to be a drug. A method of treating sexual dysfunction in a woman comprising administering to a woman in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. 67. The compound of claim 65, wherein the compound of formula I is 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile, 5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole, N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide, 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile, 2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole, 2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole, 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole, 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole, 2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide and 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. 67. The method of claim 65, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt thereof. 66. The method of claim 65, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate). 66. The compound of claim 65, wherein the compound of formula I is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt or prodrug thereof Way. 67. The compound of claim 65, wherein the compound of formula I is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt or pro How to be a drug. A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof may be formulated with attention deficit hyperactivity disorder, Alzheimer's disease, evil abuse, Parkinson's disease, schizophrenia, anxiety, mood disorders and depression Selected from the group consisting of attention deficit hyperactivity disorder, Alzheimer's disease, evil abuse, Parkinson's disease, schizophrenia, anxiety, mood disorder and depression, including administering to a mammal in need of treatment for a disorder selected from the group How to treat a disorder. The compound of claim 71, wherein the compound of formula I is 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile, 5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole, N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide, 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile, 2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole, 2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide and 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. The compound of claim 71, wherein the compound of formula I is 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole, 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole and 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole. The method of claim 71, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. The method of claim 71, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate). The method of claim 71, wherein the compound of formula I is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. The method of claim 71, wherein the compound of formula I is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol. A method of treating a cardiovascular disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. 79. The compound of claim 78, wherein the compound of formula 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile, 5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole, N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide, 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile, 2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole, 2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole, 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole, 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole, 2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide and 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. 79. The method of claim 78, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1 H-benzimidazole. 79. The method of claim 78, wherein the compound of Formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate). 79. The method of claim 78, wherein the compound of formula I is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. 79. The method of claim 78, wherein the compound of formula I is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol. A method of treating an inflammatory disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. 85. The compound of claim 84, wherein 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile, 5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole, N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide, 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile, 2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole, 2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole, 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol, 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole, 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole, 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole, 2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole, N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide and 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole. 85. The method of claim 84, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. 85. The method of claim 84, wherein the compound of formula I is 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate). 85. The method of claim 84, wherein the compound of formula I is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. 85. The method of claim 84, wherein the compound of formula I is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol. A compound of formula (II) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. Formula II In Formula II above, A is , , , , , , , , , , , , , , , , , And Is selected from the group consisting of X is selected from the group consisting of NH, O and S, L is selected from the group consisting of CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ and CH ₂ CH ₂ CH ₂ CH ₂ , R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ and (NZ ₁ Z ₂ ) carbonyl, wherein Z ₁ and Z ₂ are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl), R _A , R _B , R _C and R _D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ and (NZ ₁ Z ₂ ) carbonyl, R _E is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl and (NZ ₁ Z ₂ ) carbonyl, R _F is selected from the group consisting of hydrogen and alkyl, A And X is S, then R ₂ or R ₃ is not hydrogen. 91. The compound of claim 90, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, and A is Phosphorus compounds. 91. The compound of claim 90, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, L is CH ₂ , and A end And R ₂ , R ₃ and R ₄ are each hydrogen. 93. The compound of claim 92, which is 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole. A compound of formula III or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. Formula III In Formula III above, R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylthio and hydroxy, L is selected from the group consisting of CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ and CH ₂ CH ₂ CH ₂ CH ₂ , R _A , R _B , R _C and R _D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ and (NZ ₁ Z ₂ ) carbonyl, wherein Z ₁ and Z ₂ are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl), R _E is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl and (NZ ₁ Z ₂ ) carbonyl, R _F is selected from the group consisting of hydrogen and alkyl, If R _F is hydrogen, at least one of R ₁ , R ₂ , R ₃ and R ₄ is not hydrogen. 95. The compound of claim 94, wherein R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen and hydroxy, and R _A , R _B , R _C and R _D are each independently hydrogen and halogen And R _E is hydrogen. 95. The compound of claim 94 wherein R ₁ , R ₂ and R ₄ are each hydrogen, R ₃ is hydroxy, L is CH ₂ , and R _A , R _B , R _C and R _D are each independently hydrogen and halogen are selected from the group consisting of, and R _E is hydrogen, R _F is a hydrogen compound. 97. The compound of claim 96, which is 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol. 95. The compound of claim 94 wherein R ₁ , R ₂ , R ₃ and R ₄ are each hydrogen, L is CH ₂ and R _A , R _B , R _C and R _D are each independently from the group consisting of hydrogen and halogen Wherein R _E is hydrogen and R _F is alkyl. 99. The method of claim 98, 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole and 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole. 95. The compound of claim 94, wherein R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen and alkylsulfonylamino, and R _A , R _B , R _C and R _D are each independently hydrogen And halogen, wherein R _E is hydrogen. 95. The compound of claim 94, wherein R ₂ , R ₃ and R ₄ are each hydrogen, R ₁ is alkylsulfonylamino, L is CH ₂ , and R _A , R _B , R _C and R _D are each independently hydrogen And halogen, wherein R _E is hydrogen and R _F is hydrogen. 102. The compound of claim 101, which is N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide. A compound of formula IV or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. Formula IV In Formula IV above, A is , , , , , , , , , , , , , , , , , , , And Is selected from the group consisting of X is selected from the group consisting of NH, O and S, L is selected from the group consisting of CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ and CH ₂ CH ₂ CH ₂ CH ₂ , R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ and (NZ ₁ Z ₂ ) carbonyl, wherein Z ₁ and Z ₂ are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl), R _A , R _B , R _C and R _D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ ₁ Z ₂ and (NZ ₁ Z ₂ ) carbonyl [where Z ₁ and Z ₂ are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl; R _E is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl and (NZ ₁ Z ₂ ) carbonyl, R _F is selected from the group consisting of hydrogen and alkyl, Z is selected from the group consisting of C and CH, --- is a bond when Z is C and absent when Z is CH. 103. The compound of claim 103, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is CH, and Z is CH --- Is absent, A is Phosphorus compounds. 103. The compound of claim 103, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, L is CH ₂ , Z Is CH and Z is CH, --- is absent and A is And R ₂ , R ₃ and R ₄ are each hydrogen. 105. The compound of claim 105, which is 2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole. 103. The compound of claim 103, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is CH, and Z is CH --- Is absent, A is Phosphorus compounds. 103. The compound of claim 103, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, L is CH ₂ , Z Is CH and Z is CH, --- is absent and A is And R ₂ , R ₃ and R ₄ are each hydrogen. 109. The compound of claim 108, which is 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole. 103. The compound of claim 103, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, Z is C, --- is a bond, and A end Phosphorus compounds. 103. The compound of claim 103, wherein R _A , R _B , R _C and R _D are each independently selected from the group consisting of hydrogen and halogen, R _E is hydrogen, R _F is hydrogen, L is CH ₂ , Z Is C, --- is a bond, and A is And R ₂ , R ₃ and R ₄ are each hydrogen. 112. The compound of claim 111, which is 2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole.