JP2007509054A - Silylphenol promotes vascular health - Google Patents

Abstract

The present invention relates generally to therapeutic and prophylactic methods and compositions for improving vascular health. In one embodiment, the method of the invention comprises administering to a subject in need of treatment a therapeutically or prophylactically effective amount of at least one compound of the invention, wherein the amount is the major heart It is therapeutically or prophylactically effective in the treatment or prevention of adverse events, vascular access dysfunction or male erectile dysfunction.

Description

Detailed Description of the Invention

This application is related to US Provisional Patent Application No. 60 / 511,654, filed October 17, 2003, and US Provisional Patent Application No. 60 / 511,663, filed October 17, 2003. No., US Provisional Patent Application No. 60 / 511,670, filed Oct. 17, 2003, US Provisional Patent Application No. 60 / 537,233, filed Jan. 20, 2004, January 2004 U.S. Provisional Patent Application No. 60 / 537,250, filed on 20th, U.S. Provisional Patent Application No. 60 / 537,286, filed on Jan. 20, 2004 (each of which is hereby incorporated by reference) All of which are considered part of this specification).

FIELD OF THE INVENTION The present invention is for improving vascular health, including methods for treating and preventing major cardiac adverse events, methods for treating and preventing vascular access dysfunction, and methods for treating and preventing male erectile dysfunction. The present invention relates to therapeutic and preventive methods and compositions.

BACKGROUND OF THE INVENTION Vascular health is associated with a number of disease and disorder states and modes. Such diseases and disorders include major cardiac adverse events, vascular access dysfunction and male erectile dysfunction.

Major cardiac adverse events include, but are not limited to, cardiac death such as aortocoronary bypass grafting and percutaneous coronary intervention (PCI), nonfatal myocardial infarction, unstable angina, stroke or Major cardiac adverse events (MACE), including interventional procedures, are the leading cause of death in long-term hemodialysis patients. The annual mortality from MACE in end-stage renal disease (ESRD) patients treated with hemodialysis is 10-20 times higher when stratified by age than the mortality from such heart disease in the general population (not stratified) In some cases 30 times higher). Report by Levey AS et al. From the National Kidney Foundation, Expert Committee on Heart Disease, www.kidney.org/professionals/pysfile/cardiointro.cfm (October 1998), "Control of Heart Disease Epidemics in Chronic Kidney Disease" . Diabetes is also a major independent risk factor for heart disease and MACE. The overall prevalence of heart disease is as high as 55% among adult diabetics.

  Traditionally, the treatment of dyslipidemia is the primary target for the treatment and prevention of MACE. Nevertheless, despite the vastness of this problem, there is currently no effective therapy for the treatment or prevention of major cardiac adverse events in patients suffering from end-stage renal disease or diabetes. Traditional anti-atherosclerosis treatments such as statins and fibrates have proven to be largely ineffective at reducing the risk of MACE in these patient populations. This suggests that known mechanisms of atherosclerosis and vascular occlusive disease, such as elevated low density lipoprotein (LDL), are not the first risk factor in these populations. Thus, there remains a great need for effective therapies for the treatment and prevention of MACE.

Vascular access dysfunction Vascular access dysfunction is the single most important cause of morbidity in the hemodialysis population. United States Renal Data System: Annual Report, Minneapolis, MN (2002). More specifically, in the end-stage renal disease (ESRD) patient population, 50% of patients treated with hemodialysis experience vascular access failure within the first year of placement and 75% within 2 years of placement. Have experienced a failure. Roy-Chaudhury et al., Kidney International, 59: 2325-2334 (2001).

  In ESRD and chronic hemodialysis patients, the most common form of vascular access procedure performed in the United States is the placement of an arteriovenous shunt. Shunt thrombosis is responsible for the majority of vascular access dysfunction in this patient population, and in more than 90% of thrombosis transplants, the potential pathology is stenosis at the anastomosis of the vein or downstream (near) It is either stenosis in the vein. Same as above.

  Despite the vastness of this problem, there is currently no effective therapy for the treatment or prevention of vascular access dysfunction in this target population. Traditional anti-atherosclerosis treatments such as statins and fibrates have proven to be largely ineffective in treating the ESRD patient population. This is a proliferative and stenotic process in which known mechanisms of atherosclerosis and vascular dysfunction, such as elevated low density lipoprotein (LDL), are responsible for vascular access dysfunction observed in ESRD patient populations Suggests not to be involved.

  Recent studies have investigated the role of smooth muscle cells, intercellular matrix proteins, macrophages, and certain cytokines in transplant stenosis, but the potential mechanism of vascular access dysfunction in hemodialysis patients remains unclear . Thus, there remains a great need for effective therapies for the treatment and prevention of vascular access dysfunction.

Erectile dysfunction Erectile dysfunction refers to the inability of a medical condition to achieve penile erection sufficient for successful sexual intercourse. The term “impossible” is often used to describe this general condition. Erectile dysfunction can result from a variety of causes, including those secondary to clinical conditions such as hormonal insufficiency and diabetes. In addition, erectile dysfunction is associated with treatment of clinical conditions such as prostate cancer or side effects associated with the use of drugs, alcohol and other drugs, including, for example, clomipramine or selective serotonin resorption inhibitors (SSRIs). As a side effect. Around 140 million men worldwide and, according to National Institutes of Health studies, 30 million US men suffer from inability or erectile dysfunction. It is estimated that the latter number can rise to 47 million by 2000. See US 20030176413 A1.

  The Massachusetts Male Aging Study found that minimal, moderate and complete disability was 52% in men aged 40-70 years. In the same study, the prevalence of complete disability increased from 5% at 40 years to 15% at 70 years. See H.A. Feldman et al., “Impotence And Its Medical And Psychosocial Correlates: Results Of The Massachusetts Male Aging Study,” J. Urol. 151 (1): 54-61 (1994). In more recent studies, it has been estimated that the prevalence of erectile dysfunction is about 20% in men aged 50-59 years. See C. B. Johannes, et al., “Incidence of erectile dysfunction in men 40 to 69 years old: Longitudinal Results from The Massachusetts Male Aging Study,” J. Urol. 163: 460-63 (2000). Despite the frequent occurrence of this condition, only a small number of patients were treated because existing treatment alternatives were uniformly unfavorable (for discussion, see “ABC of Sexual Health,” Brit. Med. J 318: 387-390 (1999)).

  One vacuum pump of these minimally invasive treatment alternatives requires the use of a vacuum constriction device on the penis to produce an erection. The physiology of the penis is such that blood flows through a deep artery in the tissue while blood flows out through a vein near the skin surface. By placing a plastic cylinder on the penis shaft and using a vacuum pump to constrain venous blood flow from the penis, the corpus cavernosum penile tissue is congested with the trapped blood, then An erection is generated. A common patient complaint is that the device is destructive to sexual activity, has short-term effectiveness, and can cause tissue damage to the penis, including consequences such as penile ecchymosis. Severe tissue damage can occur with extended use due to penis such as necrosis.

  Artificial penile transplantation is an alternative treatment for erectile dysfunction, which requires surgical implantation of a mechanical device inside the penis (see, eg, US Pat. No. 5,065,744 to Zumanowshky). The implant can be a semi-rigid adaptive rod or a fluid expanded tube that can be manipulated by the patient to achieve an erection. Although this method does not affect the ability to have urination, ejaculation or orgasm, the surgery required to implant the prosthesis can lead to pain, infection and scarring.

  Recent insights into the physiological mechanism of penile erections have led to the development of other therapies for the treatment of erectile dysfunction. Studies have shown that during sexual arousal, nitric oxide (NO) molecules are released in the penis from nerve endings and endothelial cells to the surrounding tissue. Nitric oxide molecules affect the enzyme guanylate cyclase, reducing intracellular calcium levels and relaxing smooth muscle cells (cyclic guanosine monophosphate (cGMP). In the penis, cavernous smooth muscle Cell relaxation allows for increased blood flow into the sponge space, leading to intersponge pressure and penile stiffness.

Medicaments that inhibit cGMP degradation can enhance and prolong penile erection during sexual stimulation. Sildenafil (VIAGRA ^R, Pfizer Inc.), when taken orally, is one such pharmaceutical which shows such successful (Terrett, NK et al. Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824) . Sildenafil is a selective inhibitor of type V phosphodiesterase (PDE-5), a cyclic GMP-specific phosphodiesterase isozyme (RB Moreland et al., “Sildenafil: A Novel Inhibitor of Phosphodiesterase Type 5 in Human Corpus Cavernosum Smooth Muscle Cells, ”Life Sci., 62: 309-318 (1998)). Oral sildenafil has been reported to be effective in about 70% of men taking it. Several additional selective PDE-5 inhibitors are included, including UK-114542 (Pfizer), IC-351 (ICOS), M-54033 and M-54018 (Mochida Pharmaceutical Co.) and E-4010 (Eisai). Is in clinical trials.

Other pharmacological approaches to the treatment of erectile dysfunction have been described (“Latest Findings on the Diagnosis and Treatment of Erectile Dysfunction,” Drug News & Perspect., 9: 572-575 (1996); “Oral Pharmacotherapy in Erectile Dysfunction, ”Cur. Opin. In Urology, 7: 349-353 (1997)). For example, clinical development of a product according Zonagen is an oral formulation of phentolamine mesylate α- adrenergic receptor antagonists under the trademark Vasomax ^R.

SUMMARY OF THE INVENTION The present invention relates to therapeutic and prophylactic methods and compositions that improve vascular health. In one embodiment, a method is provided comprising administering to a subject in need of treatment a therapeutically or prophylactically effective amount of at least one compound of the invention, said amount comprising major cardiac adverse events, blood vessels It is therapeutically or prophylactically effective in treating or preventing access dysfunction or male erectile dysfunction.

  More particularly, in another certain embodiment, the present invention specifically relates to major cardiac adverse events (MACE) in patients with increased oxidative burden or increased oxidative stress, such as hemodialysis, ESRD and diabetic patients. Directed to methods for prophylactic or therapeutic treatment. The method of the invention is particularly suitable for therapeutic treatment and prevention of major cardiac adverse events in hemodialysis, ESRD and diabetic patients. In addition, the methods of the present invention are effective for prophylactic or therapeutic treatment of major cardiac adverse events without adverse side effects such as suppression of high density lipoprotein (HDL) cholesterol levels or QTc interval prolongation.

  In another embodiment, the invention relates to prophylactic or therapeutic treatment of vascular access dysfunction, particularly in patients refractory to statin and / or fibrate therapy, such as those suffering from ESRD. The method of the invention is particularly suitable for the treatment and prevention of arteriovenous shunt stenosis in subjects undergoing hemodialysis. In addition, the methods of the present invention are effective for prophylactic and therapeutic treatment of vascular access dysfunction without harmful side effects such as suppression of high density lipoprotein (HDL) cholesterol levels or QTc interval prolongation.

  In yet another embodiment, the present invention relates to prophylactic or therapeutic treatment of erectile dysfunction in male patients. Penile arterial and cavernous neurogenic disorders and endothelium-dependent relaxation are associated with diseases associated with vascular dysfunction such as diabetes. Multiple mechanisms include vascular functions associated with diabetes, including overproduction of reactive oxygen species that lead to the disappearance of nitric oxide (NO) released by endothelium and nitric oxidergic neurons in vascular tissue Associated with failure. The methods and compositions of the present invention are directed to limiting the adverse effects of mechanisms associated with erectile dysfunction, particularly those associated with diabetes.

  In one embodiment, the methods of the present invention may be used in subjects in need of treatment, such as subjects with increased oxidative burden or increased oxidative stress, thus subjects at risk for major cardiac adverse events, vascular access. Administering a therapeutically or prophylactically effective amount of a compound of formula (I) to a subject having a shunt or transplant, or suffering from diabetes and experiencing erectile dysfunction or seeking prophylactic treatment including:

Wherein X ₁ and X ₂ are independently selected from the group consisting of oxy and dialkyl substituted silyls,
R ₁ is alkyl;
R ₂ and R ₃ are independently selected from the group consisting of H and alkyl;
R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, methoxy and branched or straight chain alkyl; and R ₈ and R ₉ are independently hydrogen, hydroxy, tri Fluoromethyl, halide, amine, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, -O (alkyl), -OCO- (H or alkyl), -OCO- (alkenyl), -OCO- ( Aryl), -OCO- (heteroaryl),-(alkyl) -COOH,-(alkenyl) -COOH, -OCO- (alkyl) -COOH, -OCO- (alkenyl) -COOH, -CO- (alkyl)- Selected from the group consisting of COOH and -CO- (alkenyl) COOH;
Here, the substituent of R ₈ or R ₉ is alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (alkyl), —OCO— (H or alkyl), —OCO— (alkenyl). ), -OCO- (aryl), -OCO- (heteroaryl),-(alkyl) -COOH,-(alkenyl) -COOH, -OCO- (alkyl) -COOH, -OCO- (alkenyl) -COOH,- CO- (alkyl) when is -COOH or -CO- (alkenyl) -COOH, they are _{independently,} C 1 -C ₆ alkyl, _{halogen, -OH, -OCH 3, -OCH 2} CH 3, halomethyl, dihalomethyl, trihalomethyl, -NH _2, alkyl-substituted _{amino, -NO 2, -CN, -NC,} -C (= NH) (NH 2) ( i.e., amino Emissions), - SH, -COOH, it may be substituted with one or more functional groups independently selected from the group consisting -COOCH ₃ and -COOCH ₂ CH _3].

In a preferred embodiment, the method comprises a compound of formula (I) wherein X ₁ and X ₂ are independently selected from the group consisting of oxy and dialkyl substituted silyls;
R ₁ is C ₁ -C ₄ alkyl;
R ₂ and R ₃ are independently selected from the group consisting of H and C ₁ -C ₄ alkyl;
R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, methoxy and branched or straight chain C ₁ -C ₆ alkyl; and R ₈ and R ₉ are independently hydrogen, hydroxy, trifluoromethyl, halide, amine, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroarylthio acryloyl, -O _(C 1 -C ₆ alkyl), - OCO- (H or _C 1 -C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C _{8 alkyl) -COOH, - (C 2 -C} 8 _{alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH Oyo It is selected from -CO- _(C 2 -C ₆ alkenyl) group consisting of COOH;
Here, the substituent of R ₈ or R ₉ is alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (C ₁ -C ₆ alkyl), —OCO— (H or C ₁ — C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C ₈ alkyl) -COOH, - _(C 2 -C _{8 alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH or -CO - If it is _(C 2 -C ₆ alkenyl) -COOH, they are _{independently,} C 1 -C ₆ alkyl, _{halogen, -OH, -OCH 3, -OCH 2} CH 3, halomethyl (dihalomethyl, tri Halomethyl, —NH ₂ , alkyl-substituted amino, —NO ₂ , —CN, —NC, —C (═NH) (NH ₂ ) (ie, diamine), —SH, —COOH, —COOCH ₃ and —COOCH ₂ CH Administration of a compound represented by the formula: which may be substituted with one or more functional groups independently selected from the group consisting of ₃ to a subject in need of treatment.

  In another embodiment, the methods of the present invention may be used in subjects in need of treatment, such as subjects with increased oxidative burden or increased oxidative stress, thus subjects at risk for major cardiac adverse events, blood vessels Administration of a therapeutically or prophylactically effective amount of a compound of formula (II) to a subject who has an access shunt or transplant, or who suffers from diabetes and experiences erectile dysfunction or seeks prophylactic treatment Including:

Wherein X ₁ and X ₂ are independently selected from the group consisting of thio, oxy and dialkyl substituted silyl;
R ₁ is C ₁ -C ₄ alkyl;
R ₂ and R ₃ are independently selected from the group consisting of H and C ₁ -C ₄ alkyl;
R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, methoxy and branched or straight chain alkyl; and R ₈ and R ₉ are independently hydrogen, hydroxy, tri Fluoromethyl, halide, amine, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, -O (alkyl), -OCO- (H or alkyl), -OCO- (alkenyl), -OCO- ( Aryl), -OCO- (heteroaryl),-(alkyl) -COOH,-(alkenyl) -COOH, -OCO- (alkyl) -COOH, -OCO- (alkenyl) -COOH, -CO- (alkyl)- Selected from the group consisting of COOH and -CO- (alkenyl) -COOH;
Here, the substituent of R ₈ or R ₉ is alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (alkyl), —OCO— (H or alkyl), —OCO— (alkenyl). ), -OCO- (aryl), -OCO- (heteroaryl),-(alkyl) -COOH,-(alkenyl) -COOH, -OCO- (alkyl) -COOH, -OCO- (alkenyl) -COOH,- CO- (alkyl) when is -COOH and -CO- (alkenyl) -COOH, they are _{independently,} C 1 -C ₆ alkyl, _{halogen, -OH, -OCH 3, -OCH 2} CH 3, halomethyl, dihalomethyl, trihalomethyl, -NH _2, alkyl-substituted _{amino, -NO 2, -CN, -NC,} -C (= NH) (NH 2) ( i.e., amino Emissions), - SH, -COOH, it may be substituted with one or more functional groups independently selected from the group consisting -COOCH ₃ and -COOCH ₂ CH _3].

In a preferred embodiment, the process comprises formula (II) wherein X ₁ and X ₂ are independently selected from the group consisting of thio, oxy and dialkyl substituted silyls,
R ₁ is C ₁ -C ₄ alkyl;
R ₂ and R ₃ are independently selected from the group consisting of H and C ₁ -C ₄ alkyl;
R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, methoxy and branched or straight chain C ₁ -C ₆ alkyl; and R ₈ and R ₉ are independently hydrogen, hydroxy, trifluoromethyl, halide, amine, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroarylthio acryloyl, -O _(C 1 -C ₆ alkyl), - OCO- (H or _C 1 -C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C _{8 alkyl) -COOH, - (C 2 -C} 8 _{alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH Oyo It is selected from -CO- _(C 2 -C ₆ alkenyl) group consisting of COOH;
Here, the substituent of R ₈ or R ₉ is alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (C ₁ -C ₆ alkyl), —OCO— (H or C ₁ — C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C ₈ alkyl) -COOH, - _(C 2 -C _{8 alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH or -CO - If it is _(C 2 -C ₆ alkenyl) -COOH, they are _{independently,} C 1 -C ₆ alkyl, _{halogen, -OH, -OCH 3, -OCH 2} CH 3, halomethyl (dihalomethyl, tri Halomethyl, —NH ₂ , alkyl-substituted amino, —NO ₂ , —CN, —NC, —C (═NH) (NH ₂ ) (ie, amidine), —SH, —COOH, —COOCH ₃ and —COOCH ₂ CH Administration of a compound represented by the formula: which may be substituted with one or more functional groups independently selected from the group consisting of ₃ to a subject in need of treatment.

  In yet another embodiment, a subject in need of treatment, such as a subject with an increased oxidative burden or increased oxidative stress, thus a subject at risk of a major cardiac adverse event, a vascular access shunt or Administration of a therapeutically or prophylactically effective amount of a compound of formula (V) to a subject having a transplant, or suffering from diabetes and experiencing erectile dysfunction or seeking a prophylactic treatment. A method is provided:

[Where G is

Wherein Y ₁ is —H, C ₁ -C ₄ alkyl or C ₃ -C ₆ alkenyl;
Y ₂ is —H, C ₁ -C ₄ alkyl, or C ₃ -C ₆ alkenyl, aryl, heteroaryl, aryloyl, alkanoyl or heteroaryloyl;
Y ₃ is —H, —CN and C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl or heteroaryl;
Y ₄ is (CH ₂ ) _n (where n is 0 to 4) or C ₃ -C ₆ alkenyl;
Y ₅ is NH, (CH 2) _n (where n is 0 to 4) or C ₂ -C ₆ alkenyl;
Y ₆ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
Y ₇ is H, C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, or NH Y ₈ ;
Y ₈ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
Y ₉ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl or heteroaryl;
Y ₁₀ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
Y ₁₁ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, —O— or —N— (Y ₁ );
L is _C 1 -C ₆ alkyl or _C 2 -C ₆ alkenyl)
It is selected from the group consisting of; and G are independently, -F, -Cl, -Br, -I , -NH 2, alkyl-substituted _{amino, -OH, -CN, -SH, -CH} 3, -CH 2 (It may be further substituted with one or more substituents selected from the group consisting of CH ₃ , —CF ₃ , —OCH ₃ , —OCH ₂ CH ₃ , —COOH, —COOCH ₃ and —COOCH ₂ CH ₃ )
Selected from the group of].

  In another aspect of the invention, there are provided compounds of the invention useful in the methods of the invention, in particular compounds of formula V, and metabolites of such compounds and pharmaceutical compositions comprising such compounds.

  Aspects of the present invention will become apparent to those skilled in the art based on the following figures and detailed description.

  In another aspect of the invention, there are provided compounds of the invention useful in the methods of the invention, in particular compounds of formula V, and metabolites of such compounds and pharmaceutical compositions comprising such compounds.

  Aspects of the present invention will become apparent to those skilled in the art based on the following figures and detailed description.

Detailed Description of the Invention The present invention relates generally to therapeutic and prophylactic methods and compositions for improving vascular health. Factors contributing to vascular health according to the present invention include, but are not limited to, reduced expression of VCAM-1; TNF-α, quenching of ROS, or NO activity caused by inflammation and inflammatory cytokines Prevention of loss of blood; induction of heme oxygenase-1 (HMOX-1) expression; neointimal thickening after vascular injury and intimal-to-medial ratio after vascular injury May include reduction; or inhibition of leukocyte recruitment to sites of vascular injury or pain. Disease states and disorders associated with such vascular health factors include major cardiac adverse events, vascular access dysfunction and male erectile dysfunction.

  More specifically, major cardiac adverse events (MACE) are the leading cause of death in long-term hemodialysis patients, such as those suffering from ESRD. Diabetes is also a major independent risk factor for heart disease and MACE. While atherosclerosis contributes to the pathological mechanisms underlying the development of MACE in these patients, additional risk factors play an important role. This is supported by the fact that the risk of occurrence of MACE in hemodialysis, ESRD and diabetic patient populations is not significantly affected by traditional anti-atherosclerotic treatments such as statins and fibrates. Furthermore, conventional lipid risk factors such as LDL cholesterol do not adequately explain the overwhelming occurrence of MACE observed in these patient populations.

  Another major cause of morbidity and hospitalization in hemodialysis populations, especially ESRD patients, is vascular access dysfunction. Vascular access dysfunction or stenosis is fundamentally different from atherosclerosis and can be characterized by very different hemodynamics, depending on the transplant (e.g., arterial shunts to veins are arterial From the source to the high pressure blood flow to the typically low pressure venous source). Atherosclerosis and vascular access dysfunction may share certain underlying pathological mechanisms such as inflammatory responses, but they are not mediated in the same physical context (e.g., vascular access transplantation or shunting). The inflammatory response in is different from the inflammatory response that occurs in atherosclerotic plaques). This is again supported by the fact that vascular access dysfunction in the hemodialysis patient population is not significantly affected by conventional anti-atherosclerosis treatments such as statins and fibrates. Furthermore, conventional lipid risk factors such as LDL cholesterol do not adequately explain the overwhelming occurrence of vascular access dysfunction observed in hemodialysis patient populations.

  Current studies show that hemodialysis patients exposed to increased oxidative stress that reduce lipoprotein resistance to oxidation have higher levels of plasma VCAM-1 compared to controls and exhibit vascular inflammation, It has reduced endothelium-dependent vasodilation, suggesting having low NO production. Annuk et al., J Am Soc Nephrol, 12: 2747-2752 (2001); Bolton et al., Nephrol Dial Transplant, 16: 1189-1197 (2001); Schmidt et al., Kidney Int, 58: 1261-1266 (2000). In atherosclerotic ducts, it has been suggested that the heme oxygenase-carbon monoxide signaling pathway plays a physiological role in maintaining vascular tone and health in atherosclerotic ducts. Siow, et al., Cardiovascular Res., 41: 385-94 (1999).

  According to the present invention, without being limited by theory, atherosclerosis is a causative factor for the morbidity of MACE in hemodialysis, ESRD and diabetic patients, but the non-LDL cholesterol-related mechanism is the MACE in this patient population. It is thought that it substantially promotes the occurrence of Furthermore, vascular access dysfunction and stenosis are different from atherosclerosis and, according to the present invention, without being limited by theory, the non-LDL cholesterol-related mechanism is substantially related to vascular access dysfunction in the ESRD patient population. It is thought that it contributes.

  Accordingly, in one aspect of the present invention, compounds and pharmaceutical compositions with specific pharmacological properties that target these mechanisms have been identified for use in combination with the methods of the present invention. More specifically, the compounds disclosed herein target these non-LDL cholesterol-related mechanisms, thereby increasing oxidative burden or increasing oxidative stress, such as in hemodialysis, ESRD and diabetic patients It has been shown to provide a novel approach for the treatment, prevention, and reduction of the risk of MACE and / or vascular access dysfunction in patients with AD.

In another embodiment of the present invention, the compounds and methods of the present invention provide a safe, effective and convenient method of treating erectile dysfunction secondary to diseases such as diabetes. The compound may be administered in combination with other active agents or devices known to increase the erectile response to achieve an additive or synergistic effect. Current research has led to the relaxation of penile smooth muscle cells, thereby dilating in arterial blood and secondary to various diseases through the use of drugs that directly affect the signal pathways that give rise to erectile responses Indicates that erectile dysfunction can be treated. The most prominent compounds used in the treatment of erectile dysfunction is sildenafil sold under trademark VIAGRA ^R. Sildenafil and other PDE-5 inhibitors act through inhibition of cGMP degradation.

  As used herein, “major cardiac adverse event” or “MACE” is, but not limited to, aortic coronary artery bypass graft surgery and percutaneous coronary angioplasty (PCI), as will be appreciated by those skilled in the art. Including cardiac death, non-fatal myocardial infarction, unstable angina, stroke or interventional procedures.

  As used herein, “vascular access” for hemodialysis means any in-line or arterial-to-venous communication used during hemodialysis, either with natural or artificial devices. “Shunt” in this context refers to a prosthetic vascular access implant or device made of natural or artificial materials (eg, often PTFE). “Vascular access dysfunction” functions properly during dialysis, including but not limited to narrowing, stenosis, occlusion, weakening, susceptibility to thrombus formation or infection, pain or discomfort, etc. Any defect that impairs the ability of the implant or device or increases the risk of a morbidity for the patient.

  “Erectile dysfunction” as used herein means sufficient stiffness, duration or inability to obtain sufficient stiffness and duration of erection. Sufficient stiffness and degree of duration are necessary to achieve a penile erection sufficient for successful sexual intercourse.

A. Methods of the Invention In one embodiment, the invention relates to major cardiac adverse events (MACE), particularly in patients with increased oxidative burden or increased oxidative stress, such as hemodialysis, ESRD and diabetic patients. Directed to methods for prophylactic or therapeutic treatment. The method of the invention is particularly suitable for therapeutic treatment and prevention of major cardiac adverse events in hemodialysis, ESRD and diabetic patients. In addition, the method of the present invention is effective for prophylactic and therapeutic treatment of major cardiac adverse events without adverse side effects such as suppression of high density lipoprotein (HDL) cholesterol levels or QTc interval prolongation.

  Such methods of the present invention generally involve treatment of major cardiac adverse events or subjects at risk of such occurrence (especially increased oxidative burden such as hemodialysis, ESRD and diabetic patients or Administration of a therapeutically or prophylactically effective amount of at least one compound of the present invention to those having elevated oxidative stress. Without being limited by theory, reduced expression of VCAM-1; TNF-α, quenching of ROS, or prevention of loss of NO activity caused by inflammation and inflammatory cytokines; heme oxygenase-1 (HMOX- 1) possible expression mechanisms, including neointimal thickening after vascular injury and decreased intima-to-media ratio after vascular injury; and inhibition of leukocyte recruitment to the site of vascular injury It is thought to act through the order.

  In another embodiment, such methods of the invention comprise identifying a subject with increased oxidative burden or increased oxidative stress and administering to the subject a compound of the invention. A skilled clinician will understand how to measure oxidative burden and stress levels. In the methods of the invention, the subject may optionally have normal lipid levels or standardized lipid levels (ie, standardized lipid levels through conventional drugs, diet and / or exercise).

  In another embodiment, the present invention is particularly directed to a method for the treatment and prevention of vascular access dysfunction in patients suffering from ESRD or refractory to statin and / or fibrate treatment. The method of the invention is particularly suitable for the treatment and prevention of arteriovenous shunt stenosis in subjects undergoing hemodialysis. In addition, the method of the present invention is effective in preventing or treating vascular access dysfunction without harmful side effects such as suppression of high density lipoprotein (HDL) cholesterol levels or QTc interval prolongation.

  Such methods of the invention generally require treatment for vascular access dysfunction or at risk for vascular access dysfunction (e.g., any having vascular access for hemodialysis, Or in particular having a previous history of vascular access dysfunction, stenosis or occlusion) comprising administering a therapeutically or prophylactically effective amount of at least one compound of the invention. Without being limited by theory, possibly reduced expression of VCAM-1; prevention of loss of NO activity caused by TNF-α; induction of heme oxygenase-1 (HMOX-1) expression; It is thought to act through a combination of mechanisms including membrane thickening and a decrease in intima-to-media ratio; and inhibition of leukocyte recruitment to sites of vascular injury.

  In yet another embodiment, the present invention is directed to a method for prophylactic and therapeutic treatment of erectile dysfunction, particularly in patients such as those suffering from diabetes. The method of the invention is particularly suitable for the prophylactic and therapeutic treatment of erectile dysfunction as a result of being convenient, effective, painless and inconspicuous. The mechanism of action associated with the method of the present invention is distinguished from known treatments such as PDE-5 inhibitors and is safe and absent from the potential for tissue damage associated with the use of devices such as vacuum contraction devices. In addition, the method of the present invention avoids the risks associated with surgical artificial penis transplantation.

  The methods of the present invention generally include at least a therapeutically or prophylactically effective amount for a subject in need of treatment for erectile dysfunction or at risk of developing erectile dysfunction (e.g., an individual suffering from diabetes). Administering one compound of the invention. Without being limited by theory, possibly reduced expression of VCAM-1; TNF-α, quenching of ROS, or prevention of loss of NO activity caused by inflammation and inflammatory cytokines; heme oxygenase-1 (HMOX It is believed to act through a combination of mechanisms that promote vascular health, including induction of expression of -1); and inhibition of leukocyte recruitment to sites of vascular injury or pain.

  In one embodiment, a method is provided for administering a therapeutically or prophylactically effective amount of at least one compound of the invention to a subject in need of treatment, wherein the amount is a major cardiac adverse event, vascular It is therapeutically or prophylactically effective in treating or preventing access dysfunction or male erectile dysfunction.

  The compounds of the present invention can be administered to a subject via any drug delivery route known in the art. Certain typical routes of administration include oral, intraocular, vaginal, rectal, buccal, topical, nasal, ocular, subcutaneous, intramuscular, intravenous (bolus and injection), intracerebral, transdermal and pulmonary. Including. A preferred formulation for administering such compounds is the international application number [Serial Number Undetermined] of Attorney Docket No. 18528.737 entitled Self-Emulsifying Drug Delivery Systems for Hydrophobic Therapeutic Compounds (hereby incorporated by reference) It is considered as a part of the present specification).

  In one embodiment, as determined by a skilled clinician, the compounds of the invention are prophylactically effective after determining an increased risk of developing MACE due to increased oxidative burden or increased oxidative stress. Administered in an amount. In another embodiment, the compounds of the invention are administered in a therapeutically effective amount during a first indication of MACE, such as a myocardial infarction or percutaneous coronary angioplasty (PCI) procedure.

  In another embodiment, the compounds of the invention can be administered at the same time, prior to, and subsequent to placement of the vascular access device, as determined by a skilled clinician. For example, pre-treat patients prior to vascular access device attachment for 1 day to 1 month or longer to reduce any local inflammation present at the site of the vascular access graft or device It would be desirable. Furthermore, it is believed that ongoing or chronic preventive treatment can be initiated as early as the initial shunt placement to prevent or reduce the occurrence of transplant / shunt stenosis. Alternatively, treatment can begin at any point on the sequence of shunt stenosis or dysfunction. More particularly, in one embodiment, the compounds of the invention are administered in a prophylactically effective amount immediately after initiation of hemodialysis (or other vascular access event). In other embodiments, the compounds of the invention are administered in a therapeutically effective amount upon the first indication of vascular access dysfunction, eg, stenosis, occlusion, disorder.

  In yet another embodiment, the compounds of the present invention may be used in patients suffering from a heart disease or disorder associated with vascular dysfunction such as diabetes at any time prior to the development of symptoms of erectile dysfunction. It can be administered prophylactically to individuals considered to be at risk. Prophylactic treatment can actually begin at the same time as the diagnosis and treatment of a disease that would put an individual at risk of suffering from erectile dysfunction. Alternatively, the individual can be treated following the development of symptoms of erectile dysfunction to improve the disease or prevent or reduce further loss of ability to achieve and sustain an erection. More particularly, in one embodiment, a compound of the invention is administered to an individual at risk for developing erectile dysfunction in an amount that is prophylactically effective prior to the onset of symptoms. In another embodiment, the compounds of the invention are administered in a therapeutically effective amount during the first indication of erectile dysfunction, for example, during the initial occurrence of disability by a diabetic patient to maintain penile erection .

  As used herein, the term therapeutically or prophylactically effective amount refers to the treatment, amelioration, or prevention of an identified disease or disorder, including a reduction in the risk of occurrence, or a detectable treatment. Refers to the amount of a medicament for exhibiting a therapeutic or prophylactic effect. The effect can be detected by, for example, chemical markers for measurable events such as MACE, shunt stenosis or injury, antigen level or time, or duration of erection or intracavernous pressure. The therapeutic effect also includes a decrease in physical symptoms such as vascular inflammation. The exact effective amount for a subject will depend on the weight, size, and health of the subject, the nature and extent of the disease, and the treatment or combination of treatments selected for administration. The therapeutically or prophylactically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

For any compound, the therapeutically or prophylactically effective amount can be estimated initially either in, for example, cell cultures of neoplastic cells, animal models, usually mice, rabbits, dogs, or pigs. An animal model can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 _(the dose therapeutically effective in 50% of the population), the dose lethal to 50% of the LD 50 _(the population ). The dose ratio between therapeutic and toxic effects is the therapeutic index and it can be expressed as the ED 50 _/ LD ₅₀ ratio. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. Data obtained from cell culture assays and animal studies may be used to formulate a dosage range for human use. The amount contained in such compositions is preferably within a range of circulating concentrations that include the ED ₅₀ with little or no toxicity. The dosage will vary within this range depending on the dosage form used, the sensitivity of the patient and the route of administration.

  More particularly, the observed concentration-biological effect relationship for the compounds of the present invention is from about 5 μg / mL to about 100 μg / mL, from about 10 μg / mL to about 50 μg / mL, or from about 10 μg / mL to about 25 μg. The initial target plasma concentration in the range of / mL is shown. In order to achieve such plasma concentrations, the compounds of the invention may be administered at doses varying from 0.1 [mu] g to 100,000 mg, depending on the route of administration. Guidance on specific methods of administration and delivery is provided in literature generally available to practitioners in the art. In general, however, dosages range from about 1 mg / day to about 10 g / day, or from about 0.1 g / day to about 3 g, in single, divided or continuous doses for patients weighing about 50 to about 100 kg. / Day, or about 0.3 g / day to about 3 g / day, or about 0.5 g / day to about 2 g / day (dose may be adjusted for patients over or below this weight range) .

  The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage forms and dosages are adjusted to provide sufficient levels of the active agent or to maintain the desired effect. Factors that may be considered include, for example, the severity of the disease state, the subject's general health, the subject's age, weight and sex, diet, timing and frequency of administration, drug combination, response sensitivity and tolerance to treatment / Contains a response. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance of the particular formulation.

B. Compounds of the Invention In another aspect of the invention, compounds useful for the prevention or treatment of MACE, vascular access dysfunction, or male erectile dysfunction are provided. The compounds of the present invention are generally effective in the prophylactic or therapeutic treatment of MACE, vascular access dysfunction, or male erectile dysfunction without adverse side effects such as suppression of HDL cholesterol levels or QTc interval prolongation t-Butylphenol compound.

  The compounds of the present invention appear to target multiple biochemical mechanisms associated with the treatment of vascular disorders, which can be used for MACE, vascular dysfunction due to vascular access device placement, or in particular The risk of developing male erectile dysfunction in patients with increased oxidative burden or increased oxidative stress may be treated or prevented or reduced prophylactically. More particularly, the compounds of the invention are particularly useful for the treatment of hemodialysis, ESRD and diabetic patients.

  The compounds of the present invention include probucol, 2, [3] -tert-butylhydroxyanisole (BHA), 2,6-di-tert-butylmethylphenol (BHT), and other 2,4 known in the art. Structurally related to 6-di-alkylphenols. Preferred compounds of the invention useful in the method of the invention are those of formula (I) shown below:

Wherein X ₁ and X ₂ are independently selected from the group consisting of oxy and dialkyl substituted silyls,
R ₁ is alkyl; R ₂ and R ₃ are independently selected from the group consisting of H and some alkyl;
R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, methoxy and branched or straight chain alkyl; and R ₈ and R ₉ are independently hydrogen, hydroxy, tri Fluoromethyl, halide, amine, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, -O (alkyl), -OCO- (H or alkyl), -OCO- (alkenyl), -OCO- ( Aryl), -OCO- (heteroaryl),-(alkyl) -COOH,-(alkenyl) -COOH, -OCO- (alkyl) -COOH, -OCO- (alkenyl) -COOH, -CO- (alkyl)- Selected from the group consisting of COOH and -CO- (alkenyl) COOH;
Here, the substituent of R ₈ or R ₉ is alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (alkyl), —OCO— (H or alkyl), —OCO— (alkenyl). ), -OCO- (aryl), -OCO- (heteroaryl),-(alkyl) -COOH,-(alkenyl) -COOH, -OCO- (alkyl) -COOH, -OCO- (alkenyl) -COOH,- CO- (alkyl) when is -COOH or -CO- (alkenyl) -COOH, they are _{independently,} C 1 -C ₆ alkyl, _{halogen, -OH, -OCH 3, -OCH 2} CH 3, halomethyl, dihalomethyl, trihalomethyl, -NH _2, alkyl-substituted _{amino, -NO 2, -CN, -NC,} -C (= NH) (NH 2) ( i.e., amino Emissions), - SH, -COOH, it may be substituted with one or more functional groups independently selected from the group consisting -COOCH ₃ and -COOCH ₂ CH _3].

In one embodiment, the method is directed to a subject in need of treatment for formula (I):
Wherein X ₁ and X ₂ are independently selected from the group consisting of oxy and dialkyl substituted silyls,
R ₁ is C ₁ -C ₄ alkyl;
R ₂ and R ₃ are independently selected from the group consisting of H and C ₁ -C ₄ alkyl;
R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, methoxy and branched or straight chain C ₁ -C ₆ alkyl; and R ₈ and R ₉ are independently hydrogen, hydroxy, trifluoromethyl, halide, amine, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroarylthio acryloyl, -O _(C 1 -C ₆ alkyl), - OCO- (H or _C 1 -C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C _{8 alkyl) -COOH, - (C 2 -C} 8 _{alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 3 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH Oyo It is selected from -CO- _(C 2 -C ₆ alkenyl) group consisting of COOH;
Here, the substituent of R ₈ or R ₉ is alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (C ₁ -C ₆ alkyl), —OCO— (H or C ₁ — C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C ₈ alkyl) -COOH, - _(C 2 -C _{8 alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH and -CO - If it is _(C 2 -C ₆ alkenyl) -COOH, they are _{independently,} C 1 -C ₆ alkyl, _{halogen, -OH, -OCH 3, -OCH 2} CH 3, halomethyl, dihalomethyl, DOO Halomethyl, -NH _2, alkyl-substituted _{amino, -NO 2, -CN, -NC,} -C (= NH) (NH 2) ( i.e., amidine), - SH, -COOH, -COOCH 3 and -COOCH ₂ CH May be substituted with one or more functional groups independently selected from the group consisting of ₃ ]
Administering a compound represented by:

Particular compounds of formula (I) are those wherein R ₄ and R ₅ are tert-butyl and R ₈ is hydroxy. Further compounds of formula (I) are independently selected from the group consisting of X ₁ and X ₂ consisting of oxy and dimethyl-silyl; R ₁ is methylene; R ₂ and R ₃ are hydrogen, R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of hydrogen and tert-butyl; R ₈ and R ₉ are independently selected from the group consisting of hydroxy and methoxy.

  In another embodiment, the compounds of the invention include those of formula (II) shown below.

Wherein X ₁ and X ₂ are independently selected from the group consisting of thio, oxy and dialkyl substituted silyl;
R ₁ is C ₁ -C ₄ alkyl;
R ₂ and R ₃ are independently selected from the group consisting of H and C ₁ -C ₄ alkyl;
R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, methoxy and branched or straight chain alkyl; and R ₈ and R ₉ are independently hydrogen, hydroxy, tri Fluoromethyl, halide, amine, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, -O (alkyl), -OCO- (H or alkyl), -OCO- (alkenyl), -OCO- ( Aryl), -OCO- (heteroaryl),-(alkyl) -COOH,-(alkenyl) -COOH, -OCO- (alkyl) -COOH, -OCO- (alkenyl) -COOH, -CO- (alkyl)- Selected from the group consisting of COOH and -CO- (alkenyl) COOH;
Here, the substituent of R ₈ or R ₉ is alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (alkyl), —OCO— (H or alkyl), —OCO— (alkenyl). ), -OCO- (aryl), -OCO- (heteroaryl),-(alkyl) -COOH,-(alkenyl) -COOH, -OCO- (alkyl) -COOH, -OCO- (alkenyl) -COOH,- CO- (alkyl) when is -COOH and -CO- (alkenyl) -COOH, they are _{independently,} C 1 -C ₆ alkyl, _{halogen, -OH, -OCH 3, -OCH 2} CH 3, halomethyl, dihalomethyl, trihalomethyl, -NH _2, alkyl-substituted _{amino, -NO 2, -CN, -NC,} -C (= NH) (NH 2) ( i.e., amino Emissions), - SH, -COOH, it may be substituted with one or more functional groups independently selected from the group consisting -COOCH ₃ and -COOCH ₂ CH _3].

In one embodiment, the method comprises formula (II) wherein X ₁ and X ₂ are independently selected from the group consisting of thio, oxy and dialkyl substituted silyls;
R ₁ is C ₁ -C ₄ alkyl;
R ₂ and R ₃ are independently selected from the group consisting of H and C ₁ -C ₄ alkyl;
R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, methoxy and branched or straight chain C ₁ -C ₆ alkyl; and R ₈ and R ₉ are independently hydrogen, hydroxy, trifluoromethyl, halide, amine, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroarylthio acryloyl, -O _(C 1 -C ₆ alkyl), - OCO- (H or _C 1 -C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C _{8 alkyl) -COOH, - (C 2 -C} 8 _{alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH Oyo It is selected from -CO- _(C 2 -C ₆ alkenyl) group consisting of COOH;
Here, the substituent of R ₈ or R ₉ is alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (C ₁ -C ₆ alkyl), —OCO— (H or C ₁ — C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C ₈ alkyl) -COOH, - _(C 2 -C _{8 alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH and -CO - If it is _(C 2 -C ₆ alkenyl) -COOH, they are _{independently,} C 1 -C ₆ alkyl, _{halogen, -OH, -OCH 3, -OCH 2} CH 3, halomethyl, dihalomethyl, DOO Halomethyl, -NH _2, alkyl-substituted _{amino, -NO 2, -CN, -NC,} -C (= NH) (NH 2) ( i.e., amidine), - SH, -COOH, -COOCH 3 and -COOCH ₂ CH Administration of a compound represented by the formula: which may be substituted with one or more functional groups independently selected from the group consisting of ₃ to a subject in need of treatment.

Again, particular compounds are those in which R ₄ and R ₅ are tert-butyl and R ₈ is hydroxy. More particularly, preferred compounds of formula (II) are those wherein X ₁ and X ₂ are thio; R ₁ is methylene; R ₂ and R ₃ are methyl; R ₄ , R ₅ , R ₆ and R ₇ are tert-butyl ; R ₈ is hydroxy; and R _9, what is butanedioate (i.e., succinic acid mono - {2,6-di -tert- butyl-4 [1- (3,5-di -tert- butyl -4-hydroxy-phenylsulfanyl) -1-methyl-ethylsulfanyl] phenyl} ester).

Other embodiments are wherein X ₁ and X ₂ are independently selected from the group consisting of thio and dimethyl-silyl; R ₁ is methylene; R ₂ and R ₃ are independently selected from the group consisting of hydrogen and methyl R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of hydrogen and tert-butyl; and R ₈ and R ₉ are a group consisting of hydrogen, hydroxy, methoxy and butanedioate Except that when both X ₁ and X ₂ are thio, both R ₈ and R ₉ are not both hydroxy.

  In another embodiment of the present invention, compounds useful in the methods of the present invention include one or more of various phenolic antioxidants having the formula (III) shown below. Such phenolic compounds are described in U.S. Patent Nos. 5,155,250; 5,532,400; 5,962,435; and 5,677,291, all of which are incorporated herein by reference. Are considered part of this specification). Specifically, the phenolic antioxidant comprises 2,6-di-alkyl-4-silyl-phenol having the general formula (III).

[Wherein R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are each independently a C ₁ -C ₆ alkyl group;
Z is a thio, oxy or methylene group;
A is a C ₁ -C ₄ alkylene group; and R ₁₄ is C ₁ -C ₆ alkyl or — (CH ₂ ) _n — (Ar), where n is an integer 0, 1, 2, or 3;
Ar is phenyl or naphthyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, methoxy, ethoxyl, chloro, fluoro or C ₁ -C ₆ alkyl groups ].

  Compounds of formula (III) can be prepared by methods known to those skilled in the art and by the methods disclosed in US Pat. No. 5,155,250, particularly column 3, lines 12-8, line 44. . Such compounds have vascular protective properties, for example, other therapeutic uses where antioxidant properties are desirable.

Specific examples of 2,6-di-alkyl-4-silyl-phenol include, without limitation, the following:
2,6-di-t-butyl-4 [(triethylsilyl) methylthio] phenol 2,6-di-t-butyl-4 [(diethylphenylsilyl) methylthio] phenol 2,6-di-t-butyl-4 [{Diethyl- (4-methoxyphenyl) silyl} methylthio] phenol 2,6-di-t-butyl-4 [{Diethyl- (2-methoxyphenyl) silyl} methylthio] phenol 2,6-di-t-butyl -4 [(Tripropylsilyl) methylthio] phenol 2,6-di-t-butyl-4 [(dipropylphenylsilyl) methylthio] phenol 2,6-di-t-butyl-4 [{dipropyl (4-ethoxy Phenyl) silyl} methylthio] phenol 2,6-di-t-butyl-4 [{dipropyl (2-ethoxyphenyl) silyl} methylthio] phenol 2,6-di-t-butyl-4 [(triisopropylsilyl) methylthio ] Phenol 2,6-di-t-butyl-4 [(diisopropylphenol Rusilyl) methylthio] phenol 2,6-di-t-butyl-4 [{diisopropyl- (4-methoxyphenyl) silyl} methylthio] phenol 2,6-di-t-butyl-4 [{diisopropyl- (2-methoxy Phenyl) silyl} methylthio] phenol 2,6-di-t-butyl-4 [(tributylsilyl) methylthio] phenol 2,6-di-t-butyl-4 [(dibutylphenylsilyl) methylthio] phenol 2,6- Di-t-butyl-4 [{dibutyl- (4-ethoxyphenyl) silyl} methylthio] phenol 2,6-di-t-butyl-4 [{dibutyl- (2-ethoxyphenyl) silyl} methylthio] phenol 2, 6-di-t-butyl-4 [(triisobutylsilyl) methylthio] phenol 2,6-di-t-butyl-4 [(diisobutylphenylsilyl) methylthio] phenol 2,6-di-t-butyl-4 [ {Diisobutyl- (4-methoxyphenyl) silyl } Methylthio] phenol 2,6-di-t-butyl-4 [{diisobutyl- (2-methoxyphenyl) silyl} methylthio] phenol 2,6-di-t-butyl-4 [(tri-t-butylsilyl) methylthio ] Phenol 2,6-di-t-butyl-4 [(di-t-butylphenylsilyl) methylthio] phenol 2,6-di-t-butyl-4 [{di-t-butyl (4-ethoxyphenyl) Silyl} methylthio] phenol 2,6-di-t-butyl-4 [{di-t-butyl (2-ethoxyphenyl) silyl} methylthio] phenol 2,6-di-methyl-4 [(trimethylsilyl) methylthio] phenol 2,6-di-methyl-4 [(dimethylphenylsilyl) methylthio] phenol 2,6-di-methyl-4 [{dimethyl- (4-methoxyphenylsilyl)} methylthio] phenol 2,6-di-methyl- 4 [{Dimethyl- (2-methoxyphenylsilyl)} methylthio] phenol 2,6- -Methyl-4 [(dibutylphenylsilyl) methylthio] phenol 2,6-di-methyl-4 [{dibutyl- (4-ethoxyphenyl) silyl} methylthio] phenol 2,6-di-methyl-4 [{dibutyl- (2-Ethoxyphenyl) silyl} methylthio] phenol 2,6-di-methyl-4 [(tri-t-butylsilyl) methylthio] phenol 2,6-di-methyl-4 [(di-t-butylphenylsilyl) Methylthio] phenol 2,6-di-methyl-4 [{di-t-butyl- (4-methoxyphenyl) silyl} methylthio] phenol 2,6-di-methyl-4 [{di-t-butyl- (2 -Methoxyphenyl) silyl} methylthio] phenol 2,6-di-ethyl-4 [(trimethylsilyl) methylthio] phenol 2,6-di-ethyl-4 [(dimethylphenylsilyl) methylthio] phenol 2,6-di-ethyl -4 [(tri-t-butylsilyl) methylthio] phenol 2, -Di-ethyl-4 [(di-t-butylphenylsilyl) methylthio] phenol 2,6-di-ethyl-4 [{di-t-butyl- (4-methoxyphenyl) silyl} methylthio] phenol 2,6 -Di-ethyl-4 [{di-t-butyl- (2-methoxyphenyl) silyl} methylthio] phenol

2,6-di-propyl-4 [(trimethylsilyl) methylthio] phenol 2,6-di-propyl-4 [(dimethylphenylsilyl) methylthio] phenol 2,6-di-propyl-4 [(trimethylsilyl) methylthio] phenol 2,6-di-propyl-4 [(dimethylphenylsilyl) methylthio] phenol 2,6-di-propyl-4 [{dimethyl- (4-ethoxyphenyl) silyl} methylthio] phenol 2,6-di-propyl- 4 [{Dimethyl- (2-ethoxyphenyl) silyl} methylthio] phenol 2,6-di-butyl-4 [(trimethylsilyl) methylthio] phenol 2,6-di-butyl-4 [(dimethylphenylsilyl) methylthio] phenol 2,6-di-methyl-4 [(trimethylsilyl) methyloxy] phenol 2,6-di-methyl-4 [(dimethylphenylsilyl) methyloxy] phenol 2,6-di-methyl-4 [{dimethyl- ( 4 -Ethoxyphenyl) silyl} methyloxy] phenol 2,6-di-methyl-4 [{dimethyl- (2-ethoxyphenyl) silyl} methyloxy] phenol 2,6-di-butyl-4 [(triethylsilyl) methyl Oxy] phenol 2,6-di-butyl-4 [(diethylphenylsilyl) methyloxy] phenol 2,6-di-butyl-4 [{diethyl (4-methoxyphenyl) silyl} methyloxy] phenol 2,6- Di-butyl-4 [{diethyl (2-methoxyphenyl) silyl} methyloxy] phenol 2,6-di-t-butyl-4 [(trimethylsilyl) methyloxy] phenol 2,6-di-t-butyl-4 [(Dimethylphenylsilyl) methyloxy] phenol 2,6-di-t-butyl-4 [{dimethyl (4-methoxyphenyl) silyl} methyloxy] phenol 2,6-di-t-butyl-4 [{dimethyl (2-Methoxyphenyl) silyl} methyl Xyl] phenol 2,6-di-t-butyl-4 [{dimethyl- (4-ethoxyphenyl) silyl) methyloxy] phenol 2,6-di-t-butyl-4 [{dimethyl- (2-ethoxyphenyl) ) Silyl) methyloxy] phenol 2,6-di-methyl-4 [(trimethylsilyl) methyloxy] phenol 2,6-di-methyl-4 [(dimethylphenylsilyl) methyloxy] phenol 2,6-di-butyl -4 [(Triethylsilyl) methyloxy] phenol 2,6-di-butyl-4 [(diethylphenylsilyl) methyloxy] phenol.

  The foregoing compounds are listed merely to provide examples that may be used in the methods of the invention. Based on this disclosure, those skilled in the art will recognize that other compounds intended to be included within the scope of the presently claimed invention useful in the methods cited herein are included. Will.

  In an alternative process of the invention, it may be advantageous to use compounds of formula (I) or formula (II) which are not within the definition of compounds of formula (IV) shown below.

[Wherein R ₁₀ and R ₁₅ are each independently C ₁ -C ₆ alkyl;
R ₁₁ , R ₁₂ and R ₁₃ are each independently hydrogen or C ₁ -C ₆ alkyl;
R is hydrogen or —C (O) — (CH ₂ ) _m —Q (where Q is hydrogen or —COOH and m is an integer 1, 2, 3 or 4);
Z is a thio, oxy or methylene group;
A is _C 1 -C ₄ alkylene group;
R ₁₄ and R ₁₆ are each independently C ₁ -C ₆ alkyl or — (CH ₂ ) _n — (Ar), where n is an integer 0, 1, 2, or 3; and Ar is Hydroxy, methoxy, ethoxyl, halogen, trifluoromethyl, C ₁ -C ₆ alkyl or —NR ₁₇ R ₁₈ (where R ₁₇ and R ₁₈ are each independently hydrogen or C ₁ -C ₆ alkyl) Phenyl or naphthyl that is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of; provided that at least one of R ₁₁ or R ₁₄ or R ₁₆ is C ₁ -C ₆ an alkyl, when Ar is not substituted with trifluoromethyl or _-NR 17 _{R 18,} R is _{-C (O) - (CH 2} ) m -Q is a compound represented by or a Acceptable salts medicine.

In another embodiment, at least one of R ₈ or R ₉ is trifluoromethyl, Br, amino, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (C ₁ -C ₆ alkyl), - OCO- (H or _C 1 -C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C _{8 alkyl) -COOH, - (C 2 -C} 8 _{alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 alkenyl) -COOH, -CO- ( C ₀ -C ₆ alkyl) -COOH and -CO- _{(C 2} -C ₆ alkenyl) -COOH; or independently formula selected from the group consisting of any combination thereof (I) or formula (I Is be advantageous to use a compound of). In another alternative embodiment useful in the method of the invention, provided that when both X ₁ and X ₂ are both thio, both R ₈ and R ₉ are both independently selected from hydroxy, ester or ether It is advantageous to use a compound of formula (II) which is restricted if not, or where both X ₁ and X ₂ are both thio and where both R ₈ and R ₉ are not both hydroxy. It can be.

If it is not a compound of formula (IV) and both X ₁ and X ₂ are both thio, is it subject to the restriction that both R ₈ and R ₉ are not independently selected from hydroxy, ester or ether Alternatively, if both X ₁ and X ₂ are both thio, it may be further advantageous to use a compound of formula (II) subject to the restriction that both R ₈ and R ₉ are not both hydroxy. .

In another embodiment, at least one of R ₈ or R ₉ is trifluoromethyl, Br, amino, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (C ₁ -C ₆ alkyl), - OCO- (H or _C 1 -C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C _{8 alkyl) -COOH, - (C 2 -C} 8 _{alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 alkenyl) -COOH, -CO- ( C ₀ -C ₆ alkyl) -COOH and -CO- _{(C 2} -C ₆ alkenyl) -COOH; or subjected to restrictions are independently selected from the group consisting of any combination thereof; X _If both ₁ and X ₂ are both thio, either R ₈ and R ₉ are both subject to the restriction that they are not independently selected from hydroxy, ester or ether, or both X ₁ and X ₂ When is both thio, it may be advantageous to use a compound of formula (II) that is subject to the restriction that both R ₈ and R ₉ are not both hydroxy.

  In a further embodiment, there is provided a compound of formula (V) as shown below: The compounds of formula (V) are useful for the preparation of novel compositions that can be used in methods for the prophylactic or therapeutic treatment of vascular access dysfunction.

[Wherein G is

Wherein Y ₁ is —H, C ₁ -C ₄ alkyl or C ₃ -C ₆ alkenyl;
Y ₂ is —H, C ₁ -C ₄ alkyl, or C ₃ -C ₆ alkenyl, aryl, heteroaryl, aryloyl, alkanoyl or heteroaryloyl;
Y ₃ is —H, —CN and C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl or heteroaryl;
Y ₄ is (CH ₂ ) _n (where n is 0 to 4), or C ₃ -C ₆ alkenyl;
Y ₅ is NH (CH _{2) n (n} here is 0-4), or _{C 2} -C ₆ alkenyl;
Y ₆ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
Y ₇ is H, C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl or NH—Y ₈ ;
Y ₈ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
Y ₉ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl or heteroaryl;
Y ₁₀ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
Y ₁₁ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, —O— or —N— (Y ₁ );
L is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl)
Selected from the group consisting of;
Here, G is, -F, -Cl, -Br, -I , -NH 2, alkyl-substituted _{amino, -OH, -CN, -SH, -CH} 3, -CH 2 CH 3, -CF 3, - It may be further substituted with one or more substituents independently selected from the group consisting of OCH ₃ , —OCH ₂ CH ₃ , —COOH, —COOCH ₃ and —COOCH ₂ CH ₃ ].

  In one embodiment of formula (V), G does not contain any guanidine groups. Alternatively, in a preferred embodiment of formula (V), G is

Selected from.

  Certain preferred compounds of the present invention include:

  Other preferred compounds of the invention include the following:

For the purposes of the present invention, one or more functional groups including R _{1 to} R ₁₄ , Y _{1 to} Y ₁₀ , L, Z, A and Ar are incorporated into the molecules of formulas (I) to (V). Each functional group appearing at any position within the structure of formula (I)-(V) may be independently selected and may be independently substituted as appropriate.

Where a more general substituent is described at any position in a molecule of the invention, the general substituent may be replaced with a more specific substituent, and the resulting molecule is Is understood to be within the scope of the molecule. Thus, for example, when a substituent is cited as an alkyl group, it is understood that molecules and groups of molecules having substituents limited to C ₁ -C ₆ alkyl are part of the present invention. Similarly, where more than one substituent is commonly cited, each may be replaced with a more specifically cited substituent, and the resulting molecule is within the scope of the molecule of the invention. . Thus, for example, if the molecule to cite a second substituent as a first substituent and alkyl aryl alkenyl, first substituent, for example, - limited to (C ₅ -C ₁₀ alkenyl) It is understood that the second substituent may be limited to, for example, — (C ₁ -C ₆ alkyl) -naphthalene.

As used herein, the term “alkyl” generally refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclohexyl. , Saturated hydrocarbon groups in a linear, branched and cyclic arrangement including n-heptyl, octyl, n-octyl and the like. Disubstituted alkyl generally refers to a hydrocarbyl group substituted on a core with at least two substituents, R ₂ and R ₃ . In some embodiments, the alkyl _{substituents,} C 1 _{-C 20 alkyl,} C 1 _{-C 10 alkyl,} C 1 -C _{8 alkyl,} may include C 1 -C ₆ alkyl or _C 5 _{-C 10} alkyl.

  As used herein, the term halomethyl, dihalomethyl or trihalomethyl refers to a methyl group responsible for 1, 2 or 3 halogen substitutions, respectively.

The term “C ₁ -C ₄ alkylene” refers to a saturated hydrocarbyldiyl group of linear or branched configuration composed of 1 to 4 carbon atoms. Included within the scope of this term are methylene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propanediyl, 1,3-butane- Diyl, 1,4-butane-diyl and the like.

The term alkenyl as used herein is generally a straight, branched or cyclic having at least one carbon-carbon double bond in either the cis or trans sequence or as a mixture of cis and trans isomers. A hydrocarbyl group of the configuration (ie, an alkene group). Included in the scope of alkenyl, 3 to about 8 carbon atoms _(C 3 -C ₈ alkenyl), 4-6 carbon atoms _(C 4 -C ₆ alkenyl), or 5 to about 10 carbons It is a substituent having (C ₅ -C ₁₀ alkenyl). Examples of alkenyl substituents include —CHCH ₂ groups (ie, ethylene), propen-1-yl groups, propen-2-yl groups, and trans—CH ₂ CHCHCH ₃ groups (ie, trans-2-butene). .

  Aryl as used herein refers to a carbocyclic aromatic ring structure. Included within the scope of the aryl group are aromatic rings having 6 to 20 carbon atoms. In some embodiments, they may have 10-20 carbon atoms, and in others, they may have 14-24 carbon atoms. Examples of aryl groups that can be incorporated as substituents include phenyl, phenanthryl (ie, phenanthrene) and naphthyl (ie, naphthalene) ring structures.

  The heteroaryl used in the present specification refers to a cyclic aromatic ring structure, in which one or more atoms and heteroatoms in the ring are elements other than carbon. The heteroatom is typically an O, S or N atom. Included within the heteroaryl scope and which can be independently selected are O, N, S and P heteroaryl ring structures. In some embodiments, the heteroaryl group may be selected from two or more heteroatoms, three or more heteroatoms, or a heteroaryl group containing four or more heteroatoms. The heteroaryl ring structure may be selected from those containing 5 or more atoms, 6 or more atoms, or 8 or more atoms. Examples of heteroaromatic ring structures that can be incorporated as substituents include, but are not limited to: acridine, benzimidazole, benzoxazole, benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole 1,4-diazanaphthalene, furan, furazane, imidazole, indole, isoxazole, isoquinoline, isothiazole, oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, quinoline, quinoxaline, thiazole, thiophene, 1 , 3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazole and quinazoline.

As used herein, the structure —O (alkyl) represents an alkyl ether where alkyl is as defined above. Included within the scope of alkyl ether substituents are —O (C ₁ -C ₆ alkyl), —O (C ₂ -C ₈ alkyl) and —O (C ₄ -C ₁₀ alkyl). Examples of alkyl ethers include methoxy (ie, —OCH ₃ ), ethoxy (ie, —, —OCH ₂ CH ₃ ), and tert-butyl ether (ie, —OC (CH ₃ ) ₃ ).

The structure —OCO— (H or alkyl) used in the present specification represents an alkyl ester in which alkyl is the same as defined above. When the structure is -OCO- (H), the substituent will be a formate. Included within the scope of the alkyl ester is —OCO— (H or C ₁ -C ₇ alkyl), —OCO— (H or C ₃ -C ₉ alkyl), —OCO— (C ₁ -C ₇ alkyl) ), and -OCO- _(C 3 -C ₉ alkyl). Examples of alkyl esters include —OCOCH ₃ (ie, acetoxy), —OCOCH ₂ CH ₃ (ie, propionic acid ester).

The structure -OCO- (alkenyl) as used herein represents an alkenyl ester group wherein alkenyl is as defined above. Included within the scope of alkenyl esters are —OCO— (C ₂ -C ₈ alkenyl), —OCO— (C ₃ -C ₈ alkenyl) and —OCO— (C ₅ -C ₉ alkenyl). Alkenyl esters can be cis or trans isomers, or a mixture of both cis and trans isomers. Examples of alkenyl esters include —OCOCHCHCH ₃ (ie, 2-butenoate), —OCOCHCHCH ₂ CH ₃ (ie, 2-pentanoate).

The structure of-(alkyl) -COOH used in the specification of the present application generally refers to a saturated hydrocarboxyl group (alkyl carboxylic acid) in a linear, branched or cyclic arrangement, and-(C ₀ -C ₈ alkyl)- COOH groups have a total of 1 to 9 carbon atoms. Included in the scope of alkyl esters having 1 to 9 carbon atoms - (alkyl) of -COOH groups - having an _(C 0 -C ₈ alkyl) COOH or 5-12 carbon atoms, - ( a C ₄ -C ₁₁ alkyl) COOH. Such hydrocarboxyl groups include methanoic acid, ethanoic acid, propanoic acid, butanoic acid, 2-methylpropanoic acid, pentanoic acid, 3-methylbutanoic acid, 2,2-dimethylpropanoic acid and the like. Similarly, the structure-(alkenyl) -COOH generally refers to a saturated hydrocarboxyl group where alkenyl is as defined above. In addition to those alkyl esters cited as being included in the above-(alkyl) -COOH range, in some embodiments, the group is a structure having 3 to 9 carbon atoms-(C ₂ can be selected from -C ₈ alkenyl) -COOH, in another embodiment, the group structure having 5 to 10 carbon atoms - can be selected from _(C 4 -C ₉ alkenyl) -COOH.

The structure -OCO- (alkyl) -COOH (alkyldicarboxylic acid) used in the present specification generally refers to a saturated hydro-dicarboxyl group in a linear, branched or cyclic arrangement, and represents -OCO- (C ₀ -C ₆ alkyl) -COOH generally refers to dicarboxylic acids having 2 to 8 carbon atoms. Alkyl dicarboxylic acids have the structure -OCO _(C 0 -C _{6 alkyl) -COOH, -OCO- (C 0 -C} 8 alkyl) -COOH and --OCO _- including (C 5 _{-C 10} alkyl) -COOH - It may be selected from structures within the range of OCO (alkyl) -COOH. Alkyl dicarboxylic acids are ethanedioic acid, propanedioic acid, butanedioic acid (eg succinic acid, 2-methylpropanedioic acid, pentanedioic acid (ie glutaric acid), 3-methylbutanedioic acid, hexanedioic acid, etc.) including.

As used herein, the structure —OCO- (alkenyl) -COOH generally refers to a hydro-dicarboxyl group having at least one carbon-carbon double bond in a linear, branched or cyclic arrangement. The carbon-carbon double bond can be in the cis or trans configuration, or can exist as a mixture of cis and trans isomers. Alkenyloxycarbonyl dicarbonyl (alkenyl dicarboxylic acid) is, -OCO- having up to 8 carbon atoms _{(C 2} -C ₆ alkenyl) -OCO- having -COOH made structures and up to 12 carbon atoms _{(C 5} - C ₁₀ alkenyl) -COOH comprising structure including -OCO- (alkenyl) may be selected from include a structure in the range of -COOH. Alkenyloxydicarbonyl is trans-2-butanedioic acid (eg fumaric acid, cis-2-butenedioic acid (ie maleic acid), 2-pentenedioic acid, 3-methyl-2-pentene-2-pentene Dibutanedioic acid, hexanedioic acid, etc.).

As used herein, -CO- (alkyl) -COOH and -CO- (alkenyl) -COOH are saturated, unsaturated and unsaturated ketocarboxylic acids in a linear, branched or cyclic configuration where alkyl and alkenyl are as defined above. Represents a group. The ketocarboxylic acid may be independently selected from structures contained within the structure of the structures -CO- (alkyl) -COOH and -CO- (alkenyl) -COOH. The alkyl ketocarboxylic acid can be selected from —CO— (C ₀ -C ₆ alkyl) —COOH and —CO— (C ₃ -C ₉ alkyl) COOH. The alkyl ketocarboxylic acid can be selected from —CO— (C ₀ -C ₆ alkyl) -COOH and —CO— (C ₃ -C ₉ alkyl) -COOH. Alkenyl keto carboxylic acid may be selected from -CO- _{(C 2} -C ₆ alkenyl) -COOH and -CO- _{(C 4} -C ₁₀ alkenyl) -COOH. Ketoalkylcarboxylic acids of the form -CO- (alkyl) -COOH are 6-keto-hexanoic acid, 5-keto-pentanoic acid, 5-keto-3-methyl-pentanoic acid, 3-keto-propanoic acid and 2- Contains keto-ethanoic acid. Ketoalkenylcarboxylic acids of the form -CO- (alkenyl) -COOH are 4-keto-2-butenoic acid, 5-keto-3-pentenoic acid, 6-keto-3-hexenoic acid and 6-keto-3-methyl. Contains -2,4-hexadienoic acid.

As used herein, alkanoyl generally refers to a group having the structure —CO— (H or alkyl) in which alkyl is as defined above. If the group is of the form —COH, the group will be an aldehyde. Alkanoyl groups included within the structure of —CO— (H or alkyl) include —CO— (C ₁ -C ₂₀ alkyl) having _{1 to 20} carbons. In other embodiments, the alkanoyl group has 3-20 carbon atoms, CO— (C ₃ -C ₂₀ alkyl), or CO— (C ₅ -C ₂₀ alkyl) of 5-20 carbon atoms. ), CO— (C ₇ -C ₂₀ alkyl) of _{7 to} 12 carbon atoms.

  As used herein, aryloyl refers to a structure of the form —CO— (aryl) where aryl is as defined above. Similarly, heteroaryloyl refers to a group of the formula —CO— (heteroaryl) where heteroaryl is as defined above. The aryloyl and heteroaryl groups can be independently selected to include the aryl and heteroaryl groups described above. Examples of aryloyl and heteroaryloyl groups include the following structures:

  As used herein, the structures -OCO- (aryl) and -OCO- (heteroaryl) are generally aromatic and heteroaromatic in which aryl and heteroaryl are present as ester substituents as defined above. Refers to the addition of carboxylic acid functional groups (aryloxy and heteroaryloxy). The —OCO— (aryl) and —OCO— (heteroaryl) groups may be independently selected to include the aryl and heteroaryl groups cited above. Aryl carboxylic acids include —OCO-phenyl (ie, benzoate ester) and the like. Heteroaromatic carboxylic acid functional groups include 2-carboxypyridine, 2-carboxypyrrole and 2-carboxyfuran.

  For the purposes of the present invention, halo substituents may be independently selected from halogens such as fluorine, chlorine, bromine, iodine and astatine.

  Also included within the scope of the invention are pharmaceutically acceptable salts, hydrates, solvates, clathrates, racemates, stereoisomers or polymorphs of the compounds of the invention.

C. Preparation of the Compounds of the Invention The compounds of the invention can be produced by any method known in the art. As noted above, the compounds of the present invention are structurally probucol, 2, [3] -tert-butylhydroxyanisole (BHA), 2,6-di-tert-butylmethylphenol (BHT) and in the art. Related to other known 2,6-di-alkylphenols. Accordingly, the compounds of the present invention may be synthesized by any method similar to those known in the art for the synthesis of 2,6-di-alkylphenols (see, eg, US Pat. No. 5,155,250). No. and 5,677,291 (the contents of which are hereby incorporated by reference in their entirety).

  By way of example, certain preferred compounds of the invention can be prepared according to the following general reaction scheme.

  The benzyl alcohol derivatives of the present invention can be generally synthesized as follows according to Reaction Schemes 1 and 2:

反応図式１

Reaction scheme 1

反応図式２

Reaction scheme 2

  The benzylamine derivatives of the present invention can be generally synthesized as follows according to Reaction Schemes 3, 4, 5 and 6:

反応図式３

Reaction scheme 3

反応図式５

反応図式６

Reaction scheme 5

Reaction scheme 6

  The N-methylbenzylamine derivatives of the present invention can be generally synthesized as follows according to Reaction Schemes 7, 8 and 9:

反応図式７

反応図式８

反応図式９

Reaction scheme 7

Reaction scheme 8

Reaction scheme 9

  The phenol derivatives of the present invention may be generally synthesized according to reaction schemes 10, 11, 12 and 13 as follows:

反応図式１０

反応図式１１

反応図式１２

反応図式１３

Reaction scheme 10

Reaction scheme 11

Reaction scheme 12

Reaction scheme 13

  The N-methylbenzylamide derivatives of the present invention can generally be synthesized according to Reaction Scheme 14 as follows:

反応図式１４

Reaction scheme 14

  The sulfonamide derivatives of the present invention can generally be synthesized according to Reaction Scheme 15 as follows:

反応図式１５

Reaction scheme 15

D. Metabolites of the Compounds of the Invention Also within the scope of the invention are in vivo metabolites of the compounds described herein. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily by enzymatic processes. Accordingly, the present invention includes compounds produced by a process comprising contacting a mammal with a compound of the present invention for a period of time sufficient to obtain its metabolite. Such products are typically prepared with radiolabeled (eg C ¹⁴ or H ³ ) compounds of the invention and doses detectable in mammals or humans such as rats, mice, guinea pigs, monkeys (eg In excess of about 0.5 mg / kg) to give sufficient time (typically about 30 seconds to 30 hours) for metabolism to occur, urine, blood or other living body It is identified by isolating the conversion product from the sample. These products are easily isolated because they are labeled (others are isolated by the use of antibodies capable of binding to epitopes remaining in the metabolite). The structure of the metabolite is determined by conventional methods such as MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well known to those skilled in the art. The conversion products are useful in diagnostic assays for therapeutic administration of the compounds of the present invention, even if they do not possess their own biological activity, unless they are found in vivo.

E. Pharmaceutical Compositions of the Invention While the compounds of the invention can be administered as such, it will be preferable to formulate the compounds as pharmaceutical compositions. Accordingly, in yet another aspect of the invention, pharmaceutical compositions useful for the prophylactic or therapeutic treatment of vascular access dysfunction are provided. The pharmaceutical compositions of the invention can be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, diluents, and the like, depending on the particular mode of administration and dosage form. The pharmaceutical composition should generally be formulated to achieve a physiologically compatible pH and can be in the range of about pH 3 to about pH 11, or about pH 3 to about pH 7, depending on the formulation and route of administration. . In an alternative embodiment, the pH is preferably adjusted to a range of about pH 5.0 to about pH 8.0.

  More particularly, the pharmaceutical composition of the present invention comprises a therapeutically or prophylactically effective amount of at least one compound of the present invention together with one or more pharmaceutically acceptable excipients. If desired, the pharmaceutical composition of the invention may comprise a combination of the compounds of the invention or may comprise a second active ingredient useful for the therapeutic or prophylactic treatment of vascular access dysfunction.

  For example, formulations of the present invention for parenteral or oral administration are most typically solids, solutions, emulsions or suspensions, while inhalable formulations for pulmonary administration are generally liquid or powder. Yes, a powder formulation is generally preferred. The pharmaceutical compositions of the invention may also be formulated as a lyophilized solid that is reconstituted with a physiologically compatible solvent prior to administration. Further pharmaceutical compositions of the invention can be formulated as syrups, creams, ointments, tablets, and the like.

  The term “pharmaceutically acceptable excipient” refers to an excipient for administration of a medicament, such as a compound of the present invention. The term refers to any pharmaceutical excipient that can be administered without undue toxicity. Pharmaceutically acceptable excipients are determined in part by the specific composition to which the composition is to be administered, as well as the specific method used to administer the composition. Consequently, there are a wide variety of suitable formulations of the pharmaceutical compositions of the present invention (see, eg, Remington's Pharmaceutical Sciences).

  Suitable excipients can be carrier molecules containing large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers and inactive virus particles. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose and stearic acid; oils, water, saline, glycerol and ethanol. Liquid; wetting or emulsifying agents; pH buffering substances and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions of the invention may be formulated in any manner suitable for the intended method of administration.
When intended for oral use, for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersed powders or granules (including micronized or nanoparticulate), emulsions, Hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use can be prepared by any method known in the art for the manufacture of pharmaceutical compositions, such compositions containing sweeteners, flavoring agents, One or more agents may be included, including colorants and preservatives.

  Pharmaceutically acceptable excipients particularly suitable for use in combination with tablets are, for example, inert diluents such as cellulose, calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; croscarmellose sodium, cross-linked Disintegrants such as povidone, corn starch or alginic acid; binders such as povidone, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques including microencapsulation that delays disintegration and adsorption in the gastrointestinal tract and thereby provides a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

  Formulations for oral use can also be formulated as hard gelatin capsules in which the active ingredient is an inert solid diluent such as cellulose, lactose, calcium phosphate, kaolin, or the active ingredient is glycerin, propylene glycol, polyethylene glycol, It can be shown as a soft gelatin capsule mixed with a non-aqueous or oil medium such as peanut oil, liquid paraffin or olive oil.

  In another embodiment, the pharmaceutical composition of the invention is formulated as a suspension comprising a compound of the invention in a mixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. Can do. In yet another embodiment, the pharmaceutical composition of the invention may be formulated as dispersed powders and granules suitable for preparation of a suspension by the addition of suitable excipients.

  Suitable excipients for use in connection with suspending agents include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; naturally occurring phospholipids (eg, Lecithin), condensation products of alkylene oxides with fatty acids (e.g. polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g. heptadecaethyleneoxycetanol), and fatty acids and hexitol anhydrides Dispersants or wetting agents such as condensation products of ethylene oxide with partial esters derived from (eg, polyoxyethylene sorbitan monooleate); and carbomers, beeswax, hard paraffin and cetyl Including such as alcohol thickener. The suspension may also be one or more preservatives such as acetic acid, methyl and / or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more such as sucrose or saccharin. Of sweeteners.

  The pharmaceutical composition of the present invention can be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil such as olive oil or arachis oil; a mineral oil such as liquid paraffin; or a mixture of these. Suitable emulsifiers include naturally occurring gums such as gum arabic and tragacanth; natural phospholipids such as soy lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides such as sorbitan monooleate; and polyoxyethylene It can be the condensation product of these esters with ethylene oxide such as sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

  In addition, the pharmaceutical compositions of the present invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oil suspension. This emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propanediol. Sterile injectable preparations can also be prepared as lyophilized powders. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can be used as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

  In general, the compounds of the invention useful in the methods of the invention are substantially insoluble in water and are slightly less soluble in most pharmaceutically acceptable protic solvents and vegetable oils. However, the compounds are generally soluble in medium chain fatty acids (eg, caprylic acid and capric acid) or triglycerides and have high solubility in propylene glycol esters of medium chain fatty acids. Also contemplated by the present invention are chemicals that are more suitable for delivery (eg, increased solubility, biological activity, palatability, reduced side effects), eg, by esterification, saccharification, PEGylation, etc. Or a compound modified by substitution or addition of a biological moiety.

  In one embodiment, the compounds of the invention may be formulated for oral administration in a self-emulsifying drug delivery system (SEDDS). Lipid-based formulations such as SEDDS are particularly suitable for low soluble compounds and can generally enhance the oral bioavailability of such compounds. Accordingly, the pharmaceutical compositions of the present invention provide a therapeutically or prophylactically effective amount of a compound of the present invention with medium chain fatty acids, propylene glycol esters thereof (eg, propylene glycol esters of edible fatty acids such as capryl and caprin fatty acids). And at least one pharmaceutically acceptable excipient selected from the group consisting of pharmaceutically acceptable surfactants such as polyoxyl 40 hydrogenated castor oil [eg as described in the SEDDS application above Prescription].

  In an alternative preferred embodiment, the cyclodextrin can be added as an aqueous soluble enhancer. Cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β- and γ-cyclodextrins. A particular cyclodextrin soluble enhancer is hydroxypropyl-β-cyclodextrin (HPBC), which can be added to any of the above compositions to further improve the water solubility properties of the compounds of the invention. In one embodiment, the composition comprises 0.1% to 20% hydroxypropyl-β-cyclodextrin, 1% to 15% hydroxypropyl-β-cyclodextrin or 2.5% to 10% hydroxy. Contains propyl-β-cyclodextrin. The amount of soluble enhancer used will depend on the amount of the compound of the invention in the composition.

F. Combination therapy Also, the compounds comprising MACE, vascular access dysfunction or male erectile dysfunction in a single or separate dosage form intended for simultaneous or subsequent administration to a subject in need of treatment, One or more other active ingredients useful for therapeutic treatment can be combined with the compounds of the present invention. When administered sequentially, the combination can be administered in two or more doses. In alternative embodiments, the compounds of the present invention and additional active ingredients can be administered by different routes.

  One skilled in the art will recognize that a variety of active ingredients can be administered in combination with a compound of the present invention that can act to increase or synergistically enhance a subject's response to the compound of the present invention. For example, the normal penile erection reaction results from a series of events that increase the activity of the enzymes NO synthase (NOS) and guanylyl cyclase, leading to an increase in NO and cyclic guanosine phosphate (cGMP). Either substrates for these enzymes or inhibitors of NO and cGMP degradation can be used to enhance the erectile response. Thus, the compounds of the present invention may be combined with sildenafil or similar compounds (vardenafil) that selectively inhibit phosphodiesterase type 5 (PDE5) and thus prevent the current state of cGMP, or for NO-synthesizing enzymes. It can be administered in combination with the substrate L-arginine, or both sildenafil and L-arginine. Other active ingredients that can be administered with the compounds of the present invention include NOS cofactor NAD (P) H or tetrahydrobiopterin; amino acids L-citrulline, L-ornithine, L-lysine, L-cysteine or salts or esters thereof; flavinoids Or including plant extracts including but not limited to ginkgo and bioflavonoids.

  According to the method of the present invention, combinations of active ingredients are: (1) co-formulation, co-administration or co-delivery in a combined formulation; (2) delivered alternately or in parallel as separate formulations; or (3) Delivered by any other combination therapy known in the art. When delivered by alternative therapies, the present invention provides for the active ingredient to be continuously administered, for example, in separate solutions, emulsions, suspensions, tablets, pills or capsules, or by different injections in separate syringes. Administration or delivery. In general, during an alternative therapy, an effective amount of each active ingredient is administered sequentially, i.e., sequentially, whereas an effective dosage of two or more active ingredients is administered together in a simultaneous therapy. The Also, various combinations of intermittent combination therapy may be used.

Examples Pharmacological studies focus on the mechanisms of action that are thought to be responsible for major cardiac adverse events in patients with increased oxidative burden and increased oxidative stress, such as hemodialysis, ESRD and diabetic patients. May be. Pharmacological tests may also be conducted focusing on the mechanisms of action that are believed to be responsible for refractive vascular occlusion of statins and fibrates, such as those observed in vascular access dysfunction. Furthermore, pharmacological studies may be conducted focusing on the mechanism of action that is thought to be responsible for erectile dysfunction. Potential mechanisms include, but are not limited to, increased serum antioxidant levels, inhibition of cytokine-induced expression of VCAM-1, retention of normal vasodilator response, tumor necrosis factor alpha (TNF-α Prevention of normal loss of NO activity initiated by or by ROS, induction of HMOX-1 expression, modulation of inflammation, and response to vascular injury or distress.

  Compositions containing the compounds of the present invention can be formulated as described herein and, where appropriate, compared to t-butylphenol compounds constructed similarly such as probucol.

  Animal tests that directly measure the effects of the compounds of the invention on erectile dysfunction and in a rat diabetic model may also be used. In addition, human cavernous tissue can be used to evaluate compounds of the present invention.

  Throughout these tests, pharmaceutical compositions containing the compounds of the invention can be formulated as described herein and, where appropriate, compared to t-butylphenol compounds similarly constructed such as probucol.

Example 1 In Vivo Antioxidant Activity After Oral Administration Also, the compounds of the present invention are subject to varying amounts of compounds of the present invention as a dietary mixture using a thiobarbituric acid reactant (TBARS) assay. It is shown to increase serum antioxidant activity through an in vivo test administered to the patient. TBARS is a qualitative indicator of lipid oxidation in a sample. In this assay, serum lipid oxidation is initiated with CuSO ₄ which results in the formation of aldehydes such as malondialdehyde (MDA). Upon incubation with thiobarbituric acid, the absorbance of the aldehyde can be detected at 530-540 nm. A TBARS value lower than the control serum value indicates the relative ability of the compounds of the invention to inhibit oxidation.

TBARS may be measured as follows: Rabbit serum (Hb 9.16 mg / dl) is purchased from Equitech-Bio (Kerrville, TX) and received as a frozen 50 mL aliquot. Serum is thawed upon arrival, separated into 5.0 mL aliquots, and stored at −20 ° C. until use. In the assay, 1.68 μl of 5 mM compound (in DMSO) is diluted with 1.6 mL of thawed rabbit serum contained in a round bottom glass flask. The mixture is spiked with 80 μL of 100 mM CuSO ₄ and vortexed briefly to bring CuSO ₄ into solution. The flask is opened to atmosphere and suspended in a 37 ° C. water bath and stirred at low speed to facilitate oxidation and mixing of the compound. Note that light exposure is limited during the assay period.

  At time 0 and subsequent time points, 26.5 μL aliquots are removed from the flasks and transferred to polypropylene eppendorf tubes, which are precipitated with 250 μL 20% (w / v) TCA, vortexed, and darkened at 4 ° C. Store in place. Once all the sample is collected, 25 μL of 10% SDS solution is added, the sample is vortexed again and then centrifuged at 13,200 rpm for 5 minutes into the pellet debris. Transfer the supernatant to a new polypropylene eppendorf tube and mix with 250 μL 0.67% TBA in 0.05 N NaOH. The sample is then incubated for 45 minutes at 85 ° C., cooled to room temperature, and then centrifuged to make any remaining debris into pellets. 200 microliters of the resulting supernatant is transferred to a clear bottom 96 well plate and the absorbance is read at 540 nm.

The TBARS values for certain preferred compounds of the present invention are shown in the following table (Δt _1/2 = t _{1/2 (cmpd)} t _{1/2 (DMSO)} : t _1/2 is the 2 with the highest TBARS formation. Is a fraction of a hour):

Alternatively, the TBARS value can be measured as follows. 100 μl of serum is mixed with 400 μl of 5 mM CuSO ₄ solution and incubated at 37 ° C. for 3 hours. The reaction is stopped by the addition of 1.0 mL of 20% trichloroacetic acid. Then 1.0 mL of 0.067% thiobarbituric acid in 0.05N sodium hydroxide is added and mixed, and the sample is incubated at 90 ° C. for 30 minutes. Samples are briefly centrifuged to pellet undissolved material and the supernatant is transferred to a 96 well plate. Absorbance is measured at 540 nm using a microplate reader. The nanomoles of MDA produced are calculated from a standard curve of 1-10 nanomoles of MDA prepared from malonaldehyde bis (dimethylacetal). Serum samples from the treated ratio are compared with serum samples from control rats.

  The TBARS values for certain compounds of the present invention are shown in the following table:

  In the specific example of the last 70 days of the in vivo study where preferred compounds were administered to rabbits via their diet, the compounds of the present invention were lag phase for copper-induced lipid peroxidation of serum lipids in a dose-dependent manner. Is shown to be extended. The increase in lag phase shown in FIG. 1 is proportional to the serum concentration of the preferred t-butylphenol compound of formula III, AC3056. Also, increased antioxidant activity in serum is observed in rats fed a diet containing AC3056, achieving an average serum concentration of 17.7 μg / mL.

Example 2: Inhibition of cytokine-induced VCAM-1 expression The compounds of the invention are also shown to inhibit cytokine-induced expression of VCAM-1 in cultured human vascular cells. In human coronary artery smooth muscle cells (CASMC), interleukin 4 (IL-4, 100 nmol / L) increases cell surface VCAM-1 to 538% of control. As shown in FIG. 2, the compounds of the present invention inhibited IL-4-induced VCAM-1 expression in a dose-dependent manner, with half-maximal inhibition observed at about 10 μmol / L. Probucol is generally less effective than the compounds of the present invention in this system (Figure 2).

Similarly, the compounds of the invention have been shown to inhibit cytokine induction (eg, tumor necrosis factor-α (TNF-α)) increase in VCAM-1 expression in human umbilical vein endothelial cells (HUVEC), Probucol is generally not effective over a similar concentration range (Figure 2). The overall effect of the compounds of the present invention on cytokine-induced VCAM-1 expression is a fairly high concentration that needs to inhibit cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1) (IC ₅₀ > 100 μmol / L) It appears to be relatively selective for this class of adhesion molecules, as demonstrated by this compound.

Example 3 Effect on Carbachol-Induced Vasodilation The effect of the compounds of the present invention on carbachol-induced vasodilation (endothelium-dependent increase in peripheral conductance) is investigated in atherosclerotic rabbits fed with cholesterol. Cholesterol supply will inhibit carbachol-induced vasodilation when compared to untreated animals fed a diet free of cholesterol. As shown in FIG. 3, treatment of rabbits fed with cholesterol containing 300 mg / day of a compound of the present invention for 70 days is shown to prevent loss of vasodilatory effects of carbachol. This suggests that the compounds of the invention improve endothelial function in animals exposed to a high cholesterol / high fat diet.

Example 4: Effect on NO activity elicited by TNF-α in porcine aortic endothelial cells The compounds of the present invention also prevent loss of NO activity elicited by tumor necrosis factor alpha (TNF-α) Is shown. For example, the compounds of the present invention prevent the loss of NO activity caused by TNF-α in porcine aortic endothelial cells in cultures stimulated with a Ca ²⁺ selective ion ionophore. NO activity is measured as an increase in cyclic guanosine monophosphate (cGMP) concentration. As shown in FIG. 4, inhibition of NO activity by 1 ng / mL TNF-α is blocked by 4 μg / mL (10 μmol / L) of the preferred compounds of the invention.

Example 5: Induced expression of heme oxygenase-1 (HMOX-1) The compounds of the invention are also shown to induce the expression of HMOX-1. More particularly, the compounds of the invention are tested for effects on gene expression using a number of methods known in the art, including whole blood nucleic acid extraction and QPCR after purification. For example, as shown in FIGS. 5 and 6, the compounds of the present invention expressed HMOX-1 in unstimulated and LPS-stimulated (1 ng / mL) whole blood for 6 hours at concentrations of 10 and 50 μg / mL. To induce.

Example 6: Modulation of inflammation and response to vascular injury Compounds of the invention are shown to affect neointimal thickening after experimental vascular injury. More particularly, the compounds of the invention can be tested to determine their effects on inhibition of leukocyte recruitment, cell proliferation and neointimal thickening after mouse carotid artery injury in a mouse model of mechanical injury as described below. .

  Utilizing a mouse model of mechanical injury designed to achieve complete endothelial erosion and controlled arterial stretching based on the air-dried rat model of Fishman et al., Lab Invest., 32: 339-351 (1975). Then, the effect of the compound of the present invention is examined. This mouse model shares much with the extensively tested and characterized experimental models of vascular injury and takes advantage of the genetic diversity of the mouse system. It reliably achieves both endothelial and medial damage via an endovascular approach, and in its ability to produce progressive intimal thickening over time (Lindner et al., Circ Res., 73 : 792-796 (1993)), perivascular cuffing (Moroi et al., J Clin Invest., 101: 1225-1232 (1998)), ipsilateral carotid artery ligation (Kumar et al., Arterioscler Thromb Vasc Biol., 17 : 2238-2244 (1997)) and electricity— (Carmeliet et al., Am J Pathol., 150: 761-776 (1997)) or Rose Bengal / green light— (Kikuchi et al., Atrioscler Thromb Vasc Bio., 18: 1069-1078 (1998)) is fundamentally different from the previously reported mouse model of arterial injury including induced injury.

In this mouse model, intimal and medial thickening is associated with progressive vasodilation or “positive remodeling” in the damaged vessel as determined by undamaged and radius measurement of the outer elastic lamina after 28 days. In addition, augmentation of neointimal thickening is associated with atherosclerosis using Apo E deficient (ApoE ^{− / −} ) mice fed a high fat diet supplemented with 1.25% cholesterol for 12 weeks of mechanical damage. It is obvious when done in the background. Inflammatory cells are an important component of this neovascular intima that comprises 34% of the total of day 28 cells.

The mouse model (described above) of endothelial erosion and carotid dilatation in ApoE ^{− / −} mice fed a high fat diet supplemented with 1.25% cholesterol for 12 weeks utilizes: A breeding colony of C57B1 / 6JApoE ^{− / −} mice in a pathogen removal barrier is established and mice of that colony receive compound or vehicle control of the present invention for 18 hours prior to injury and daily after injury. On days 1, 3, 7 and 28 after vascular injury, anesthesia is administered, the thoracic cavity is opened, and the animals are sacrificed by exsanguination of the right artery. A 22 gauge butterfly catheter was inserted into the left ventricle for in situ pressure perfusion at 100 mHg at 0.9% saline for 1 minute followed by 4 minutes in 0.1 M phosphate buffer, pH 7.3. Fix with% paraformaldehyde. The right and left common carotid arteries are excised and immersed in buffered paraformaldehyde. Also, spleen and small intestine from three compounds treated and from control animals are obtained as control tissues for immunohistochemistry. All animals preferably receive 50 mg / kg BrdU intraperitoneally 18 and 1 hour before sacrifice.

  The carotid artery is embedded and two cross sections are cut at 500 mm intervals. The sections are then stained with hematoxylin-eosin and Verhoeff tissue elastin staining. The histologist, who is not informed of animal genotype or drug therapy, then used a microscope equipped with a CCD camera connected to a computer running NIH image v1.60 software to determine the lumen, The membrane and media area are measured. Average the results for the two faces of each artery. For immunohistochemistry, standard avidin biotin procedures are used for mouse CD45 (lymphocyte common antigen, Pharmigen), MOMA-2 (mouse macrophages, Serotec) BrdU (DAKO) and SMC actin (DAKO). Immunostained parts are quantified as percent positive (number of immunostaining positive cells for related antigen / total number of nuclei).

  To assess the effect of the compounds of the invention on luminal platelet and leukocyte adhesion to the vessel wall, additional animals are prepared for scanning electron microscopy one day after injury. Vascular damage and tissues obtained in these mice are performed as described above except that modified Ito-Karovsky fixative can be used for perfusion and immersion fixation. The tissue is then rinsed overnight in 0.1 M cacodylate buffer at 4 ° C., subjected to rigorous drying and sputter coating with gold, and then imaged with a Cambridge Instruments StereoScan 240.

For example, FIG. 7 (a) shows typical quantitative morphometry in a mechanical injury model in ApoE ^{− / −} male males fed a high fat diet supplemented with 1.25% cholesterol for 12 weeks prior to injury. FIG. 7 (b) shows a typical intima-to-media ratio. Test mice receive a preferred t-butylphenol compound of the present invention (AC3056) or vehicle control 18 hours prior to 28 days of injury and daily after injury. IEL = inner elastic plate; EEL = outer elastic plate; I / M = intima-to-media ratio; NS = no significant difference. As shown in FIGS. 7 (a) and 7 (b), the compounds of the present invention decrease the average neovascular intima thickness, increase the average lumen thickness and increase the intima / media ratio. In terms of reduction, it affects the thickening of the new intima after experimental vascular injury.

FIG. 8 is representative of carotid neointima and media in a model of mechanical injury in ApoE ^{− / −} male mice fed a high fat diet supplemented with 1.25% cholesterol for 12 weeks prior to injury. Percent of CD45 positive cells (CD45 immunostained positive cells / total number of nuclei). Again, test mice receive the t-butylphenol compound of the invention (AC3056) or vehicle control 18 hours prior to 28 days of injury and daily after injury. NS = no significant difference. As shown in FIG. 8, the compounds of the present invention inhibit leukocyte recruitment to the neointimal space after vascular injury.

FIG. 9 shows in carotid neointima and media in a mechanical injury model in ApoE ^{− / −} male mice fed a high fat diet supplemented with 1.25% cholesterol for 12 weeks prior to injury. Typical percent Brdu positive cells (number of Brdu immunostained positive cells / total number of nuclei) are shown. Again, test mice receive the t-butylphenol compound of the invention (AC3056) or vehicle control 18 hours prior to 28 days of injury and daily after injury. NS = no significant difference.

  The pharmacological data provides evidence that the compounds of the invention act as potent antioxidants with anti-atherosclerotic properties. The compounds also reduce total and LDL cholesterol levels in rabbits, decrease VCAM-1 expression, increase HMOX-1 expression in human vascular cells, and reduce neointimal thickening after experimental vascular injury And inhibit lymphocyte recruitment. Thus, the compounds of the present invention have clinical utility in the treatment of vascular access dysfunction.

Example 7: Prevention and reversal of erectile dysfunction in male rats Male Sprague-Dawley rats are used as a model for testing diabetic erectile dysfunction. Non-insulin dependent diabetes is induced in 12 week old rats by a single injection of streptozotocin (40 mg / kg ip) dissolved in 0.1 M citrate / trisodium citrate buffer (pH 4-4.5). This low dose of streptozotocin has been shown to increase blood glucose without significantly affecting testosterone levels. Control (non-diabetic) animals receive an equivalent volume of citrate buffer. After one week, to give a tail blood samples, the glucose concentration ^{Acccutrend R glucometer (Boehringer Mannheim, Germany} ) is measured using a. If glycemia is higher than 200 mg / dl (11 mM), diabetes induction is considered successful.

  An erectile response to cavernous nerve stimulation is performed in rats anesthetized with ketamine (60 mg / kg) and diazepam (4 mg / kg). The surgical procedure consists of an incision and isolation of the right cavernous nerve through the transperineal incision through the midline abdominal incision and exposure of the penis cura (CNES). Intracavernous pressure (ICP) measurement is achieved by insertion of a 23 gauge needle connected to a disposable pressure transducer (Abbott, Sligo, Ireland) and a data acquisition system (AD Instruments, Castle Hill, Australia) into the right leg. A catheter is inserted into the left carotid artery and right external jugular vein, respectively, for constant blood pressure measurement and saline infusion. Electrical stimulation is applied by a sophisticated half-gold bipolar hook electrode connected to a stimulator and current amplifier (Cribertec CS-9, Madrid, Spain). The electrical stimulation parameters consist of a pulse with a duration of 1 minute, 1 millisecond, and a current intensity of 1.5 mA. Frequency response curves are performed by applying stimuli of 1, 3 and 10 Hz at 3 minute intervals.

  The erectile response to rat cavernous nerve stimulation is determined by measuring peak ICP increase normalized by mean arterial pressure (MAP) value, and the area under the curve (AUC) of that ICP increase is normalized by MAP value. Complete frequency response curves are compared by a two-way ANOVA test.

  A typical t-butylphenol compound is administered orally by the preparation of a rat diet containing 0.3% compound dissolved in corn oil. Rats have free access to this feed. Rats included in the prophylactic treatment group will receive a representative compound from the beginning of induction of the diabetic state and the erectile response will be measured 8 weeks later. Diabetic control animals are fed a normal rat diet supplemented with corn oil for a period of 8 weeks. Rats included in the recovery treatment group receive a normal diet for the first 8 weeks of diabetes and a further 4 weeks of a diet containing 0.3% of representative compounds of the present invention. Diabetic control animals for recovery treatment are fed normal rat diet supplemented with corn oil for 12 weeks.

  Induction of diabetes with streptozotocin causes a sustained increase in blood glucose concentration in rats, which is maintained throughout the study period. FIGS. 10 and 11 show that treatment with 0.3% of the compound does not modify blood glucose levels, whether prophylactic or reversible.

  The effect of prophylactic treatment with representative compounds of the present invention on cardiovascular parameters and erectile response is compared after 8 weeks of induction of diabetes with streptozotocin. Eight weeks of diabetes does not alter MAP levels in diabetic rats (FIG. 12A). There is a significant decrease in heart rate in diabetic rats. This effect is partially prevented by treatment with the compounds of the invention (FIG. 12B).

  Prophylactic treatment with the compounds of the present invention significantly improves the erectile response in diabetic rats. When compared to untreated diabetic rats, diabetic rats treated with representative compounds of the present invention show an increased erectile response. This enhancement effect is significant when the response is shown as the AUC of the ICP response to cavernous nerve stimulation (FIG. 13), and significant when the response is shown as a peak increase in ICP after each stimulation (FIG. 14). .

  The effects of recovery treatment and erectile response with the compounds of the invention on cardiovascular parameters are compared after 12 weeks of induction of diabetes with streptozotocin. 12 weeks of diabetes induction does not alter MAP levels. Recovery treatment with representative compounds of the invention does not modify MAP levels in diabetic rats (FIG. 15A). There is a significant decrease in heart rate in diabetic rats. This effect is not altered by recovery treatment with the compounds of the invention (FIG. 15B).

  Recovery treatment with the compounds of the present invention significantly improves the erectile response in diabetic rats. When compared to 12 weeks of untreated diabetic rats, diabetic rats treated with a representative compound of the invention for 4 weeks after 8 weeks of untreated diabetes show an increased erectile response. This enhancement effect is significant when the response is shown as the AUC of the ICP response to cavernous nerve stimulation (FIG. 16). There is no significant difference between untreated diabetic rats and rats treated with representative compounds of the present invention when the response is shown as peak increase in ICP after cavernosal nerve stimulation (FIG. 17).

Example 8: Endothelium-dependent relaxation of cavernous bodies from diabetic patients Human cavernous specimens are obtained from impotence men at the time of artificial penis transplantation as previously described (Angulo, et al., J. Pharm. Exp Ther., 295: 586-593 (2000)). Tissue at the time of the removal, ice cold M-400 solution (pH7.4;. 400mOsm / kg composition 4.19% _{mannitol, 0.2% KH 2 PO 4,} 0.97% of _K 2 _HPO 4 · 3 H ₂ O, 0.11% KCl and 0.08% NaHCO ₃ ) and transport to laboratory for use within 16 hours.

To assess the effect on trabecular tissue, human cavernous strips containing 8 ml of physiological saline continuously bubbled with a 95% O ₂ /5% CO ₂ mixture to maintain pH 7.4. Attach to pressure transducer in a tissue bath (37 ° C). Strips are contracted with 0.5 μM phenylephrine and the relaxation response is assessed by cumulative addition of test or vehicle control compounds to the chamber. Transmural electrical stimulation (TES) is applied by two electrodes on each side of the tissue connected to a stimulator and a current amplifier. The normal parameter for TES will be a 0.5 millisecond square wave for 20 seconds at a voltage adjusted to obtain a current of 75 mA.

  For the measurement of the acute effect of antioxidant treatment on endothelium-dependent relaxation of human corpus cavernosum, cavernosal strips are contracted with phenylephrine and exposed to cumulative concentrations of acetylcholine. Once a sufficient concentration-response curve is obtained, the tissue is extensively washed and exposed to vehicle or AC3056 antioxidant (10 μM) for 30 minutes. The tissue is contracted again and exposed to acetylcholine. (N = 6-8 for each group).

  The acute effect of antioxidant treatment on relaxation induced by transmural electrical stimulation of nitric oxide agonists is measured as follows. Strips treated with guanethidine (10 μM) and atropine (0.1 μM) are contracted and transmural electrical stimulation is applied at various frequencies (0.5, 1, 2, 6 and 12 Hz). The tissue is then washed for 30 minutes and exposed to vehicle control or AC3056 antioxidant. The tissue is contracted again and then the frequency-response curve is repeated. (N = 6-8 for each group).

Example 9: Preparation of compounds of the invention A Preparation of benzyl alcohol derivatives:
The following compounds and analogs of the present invention can be generally prepared according to Reaction Scheme 1.
Synthesis of (4-bromobenzyloxy) (tert-butyl) dimethylsilane (2) Imidazole (12 g, 0.182 mol) was added to (4-bromophenyl) methanol (1) (17 g in dry CH ₂ Cl ₂ (60 mL). , 0.091 mol) and the reaction is stirred at 0 ° C. A solution of TBDMSCl (20.87 g, 0.13 mol) in CH ₂ Cl ₂ (30 mL) is slowly added to the reaction over 30 minutes and stirred at the same temperature for an additional 4 hours. The reaction is quenched with water (50 mL) and extracted with CH ₂ Cl ₂ (3 × 50 mL). The combined organic layers are washed with saturated aqueous NaHCO ₃ (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified by silica gel column chromatography to give pure (4-bromobenzyloxy) (tert-butyl) dimethylsilane (2) as a colorless oil in 84% (23 g) yield.

(Chloromethyl) 4-(((tert-butyl) dimethylsilyl) benzyloxy) dimethylsilane (3)
Compound (2) (20 g, 0.067 mol) is dissolved in dry THF (70 mL) under N ₂ atmosphere and cooled to −78 ° C. using dry ice and ethanol bath. In a dropping funnel attached to the reaction flask, n-BuLi (62.5 mL of 1.6 M in hexane, 0.1 mol) was added slowly over 1 hour and the resulting solution was further brought to −78 ° C. for 1.5 hours. And stir. A solution of chloro (chloromethyl) dimethylsilane (9.7 mL, 0.073 mol) in THF (20 mL) is added slowly over 30 minutes and the reaction is stirred for an additional 2 hours. Saturated aqueous NH ₄ Cl (100 mL) is added and the reaction is allowed to warm to room temperature. The THF is evaporated under vacuum and the residue is dissolved in EtOAc (200 mL). The organic phase is washed with water (2 × 50 mL), brine (50 mL)), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The product is purified by a silica gel column using 5% EtOAc / hexane as eluent. The pure product is obtained as a colorless oil in 86% (19 gm) yield.

(Iodomethyl) 4-(((tert-butyl) dimethylsilyl) benzyloxy) dimethylsilane (4)
To a stirred solution of (chloromethyl) 4-(((tert-butyl) dimethylsilyl) benzyloxy) dimethylsilane (3) (14 g, 0.049 mol) in dry CH ₃ CN (30 mL) was added NaI (36.5 g). 0.25 mol) is added and the resulting solution is heated in a 70 ° C. oil bath.
After 6 hours, all CH ₃ CN is removed under reduced pressure and the residue is dissolved in CH ₂ Cl ₂ (100 mL), filtered and washed with CH ₂ Cl ₂ (3 × 20 mL). The combined organic portions are washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified by silica gel column with 5% EtOAc / hexane as eluent. The pure product is obtained as a pale yellow oil in 97% (20 gm) yield.

2,6-Di-tert-butyl-1,4-bisphenol (5)
Bisphenol (5) is synthesized from 2,6-di-tert-butylcyclohexa-2,5-diene-1,4-dione and Zn / HCl under the experimental conditions described above. The purification of bisphenol (5) is confirmed by TLC, dried completely under vacuum and stored under N ₂ atmosphere.

4-((((4- (hydroxybenzyl) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (C1)
Under N ₂ atmosphere, CS ₂ CO ₃ (8.78 g, 0.027 mol) is added to a stirred solution of bisphenol (5) (5 g, 0.023 mol) in dry DMF (15 mL). The heterogeneous reaction mixture is stirred at 60 ° C. for 1 hour. A solution of (iodomethyl) 4-(((tert-butyl) dimethylsilyl) benzyloxy) dimethylsilane (4) (11.4 g, 0.027 mol) in DMF (15 mL) was added slowly over 1 hour to obtain The reaction solution is stirred at 60 ° C. for 1 hour. All solvent is removed in vacuo and the residue is partitioned between EtOAc (100 mL) and saturated aqueous NH ₄ Cl (50 mL) solution. The organic phase is removed and washed thoroughly with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified by silica gel column using 5-10% EtOAc / hexane as eluent to give the product (6) as a semi-solid material of approximately 85% (13.5 g) purity.

To the product (13.5 g, ca. 85%) dissolved in MeOH (10 mL) is added dry HCl (33.5 mL of 2M in MeOH, 0.067 mol) and the solution is stirred for 2 h at 0 ° C. . All solvent is removed and the residue is dissolved in EtOAc (150 mL). The organic portion is washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column with 15-20% EtOAc / hexane as eluent. The pure product (C1) is obtained as a colorless solid in 73% (6.5 gm) yield in two steps.

¹ H NMR: (CDCl ₃ , 300 MHz) δ; 7.63 (d, J = 4.75 Hz, 2H), 7.39 (d, J = 4.84 Hz, 2H), 6.81 (s, 2H), 4.73 (s, 1H), 4.71 (s, 2H), 3.73 (s, 2H), 1.43 (s, 18H), 0.43 (s, 6H);
Analytical HPLC: (C ₁₈ , 20-90% CH ₃ CN in 0.1% TFA / H ₂ O for 15 min) R _t = 11.05;
LCMS: Calculated C ₂₄ H ₃₆ O ₃ Si = 400.24; Found = 401.2 [M + H] ⁺

The following compounds and similar compounds of the present invention may be prepared according to Reaction Scheme 2.
4-(((4-Benzyloxycarbonyl) propanoic acid) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (C2)
To a solution of 4-((((4- (hydroxybenzyl) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (I) (0.5 g, 0.0013 mol) in CH ₂ Cl ₂ (5 mL). , Pyridine (0.32 mL, 0.0043 mol), succinic anhydride (0.15 g, 0.0015 mol) and a catalytic amount of DMAP (4 mg) are added and the resulting solution is stirred at 0 ° C.
After 2 h, the reaction is quenched by adding water (30 mL) and diluted with CH ₂ Cl ₂ (50 mL). The organic phase is separated, washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column with 2-5% MeOH / CH ₂ Cl ₂ as eluent. The pure product (C2) is obtained as a colorless solid in 80% (0.5 g) yield.

¹ H NMR: (CDCl ₃ , 300 MHz) δ; 7.62 (d, J = 4.80 Hz, 2H), 7.36 (d, J = 4.80 Hz, 2H), 6.80 (s, 2H), 5.15 (s, 2H), 4.75 (s, 1H), 3.73 (s, 2H), 2.70 (m, 4H), 1.43 (s, 18H), 0.43 (s, 6H);
Analytical HPLC: (C ₁₈ , 20-90% CH ₃ CN in 0.1% TFA / H ₂ O for 15 min) R _t = 11.16;
LCMS: Calculated C ₂₈ H ₄₀ O ₆ Si = 500.26; Found = 501.3 [M + H] ⁺

4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl 2- (dimethylamino) acetate (C3)
4: 1 v / v CH ₂ Cl ₂ : Compound 4-((((4- (hydroxybenzyl) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (C1) (0) dissolved in DMF (5 mL) To .23 g, 0.575 mmol) was added DMAP (0.07 g, 0.58 mmol), N, N-dimethylglycine hydrochloride (0.121 g, 0.86 mmol) and DCC (0.355 g, 1.73 mmol). The resulting solution is stirred overnight at 0 ° C. The reaction is quenched with water (50 mL) and diluted with CH ₂ Cl ₂ (50 mL) The organic phase is separated and water (2 × 50 mL). , Washed with brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated The crude material is purified on a silica gel column with 30-60% EtOAc / hexanes as eluent. (C3) is 89% (0.25 g) In it obtained as a light colorless solid.

¹ H NMR: (CDCl ₃ , 300 MHz) δ; 7.62 (d, J = 4.79 Hz, 2H), 7.37 (d, J = 4.80 Hz, 2H), 6.80 (s, 2H), 5.18 (s, 2H), 4.75 (s, 1H), 3.73 (s, 2H), 3.23 (s, 2H), 2.37 (s, 6H), 1.43 (s, 18H), 0.42 (s, 6H);
Analytical HPLC: (C ₁₈ , 20-90% CH ₃ CN in 0.1% TFA / H ₂ O for 15 min) R _t = 9.42;
LCMS: Calculated C ₂₈ H ₄₃ NO ₄ Si = 485.3; Found = 486.3 [M + H] ⁺

B. Preparation of Benzylamine Derivatives The following compounds and similar compounds of the present invention may be prepared according to Reaction Scheme 3.
4-((((3,5-di-tert-4-hydroxyphenoxy) methyl) dimethylsilyl) benzylmethanesulfonate (7)
To a stirred solution of alcohol (I) (4.2 g, 0.0105 mol) in dry CH ₂ Cl ₂ (10 mL) at 0 ° C. under N ₂ atmosphere was added Et ₃ N (4.4 mL, 0.031 mol) and DMAP. (0.256 g, 0.0021 mol) is added. A solution of MeSO ₂ Cl (1.26 mL, 0.0158 mol) in dry CH ₂ Cl ₂ (5 mL) is added slowly over 10 minutes and stirred for another 2 hours. The reaction is diluted with CH ₂ Cl ₂ (50 mL) and quenched with water (20 mL). The organic phase is separated, washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified by silica gel column with 5% EtOAc / hexane as eluent. The pure mesylation product (7) is obtained as a light colorless solid in 80% (4.0 g) yield.
LCMS: Calculated C ₂₅ H ₃₈ O ₅ SSi = 478.22; Found = 479.3 [M + H] ⁺

4-(((4-Azidomethyl) phenyl) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (8)
Mesylate (7) (3 g, 0.0063 mol) was dissolved in CH ₃ CN (10 mL) and NaN ₃ (1.63 g, 0.0251 mol) was added. The heterogeneous reaction mixture is heated in an 80 ° C. oil bath for 6 hours. Remove all solvent and dry. Dissolve the residue in CH ₂ Cl ₂ (50 mL), filter and wash repeatedly with CH ₂ Cl ₂ (5 × 20 mL). The combined organic portions are washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude azide compound is purified on a silica gel column using 5-10% EtOAc / hexane as eluent. Pure material (8) is obtained as a colorless solid in 96% (2.55 g) yield.
LCMS: Calculated C ₂₄ H ₃₅ N ₃ O ₂ Si = 425.25; Found = 426.2 [M + H] ⁺

4-(((4-Aminomethyl) phenyl) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (9)
To a solution of the azide compound (8) (2.2 g, 0.052 mol) in THF (10 mL), 5% H ₂ O, triphenylphosphine (1.63 g, 0.0068 mol) was added and the resulting solution The mixture is first stirred at 0 ° C. for 2 hours and then at room temperature overnight. All solvent was removed in vacuo and the residue was loaded directly onto a silica gel column and eluted with 50-90% EtOAc / hexanes to remove all nonpolar impurities before 5-10% The product is isolated using MeOH / CH ₂ Cl ₂ . Pure amine (9) is obtained as a colorless light solid in 95% (1.95 g) yield.
LCMS: Calculated C ₂₄ H ₃₇ NO ₂ Si = 399.26; Found = 400.2 [M + H] ⁺

(4-(((3,5-di-tert-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) (N, N, di-tert-butyloxycarbonyl) guanidine (11)
Amine (9) (0.6 g, 0.0015 mol), DMF (10 mL) and Et ₃ N (0.62 mL, 0.0045 mol) were taken in a flask under N ₂ atmosphere and a catalytic amount of HgCl ₂ (20 mg). This is followed by the addition of 1,3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseurea (10) (0.654 g, 0.0027 mol). The heterogeneous reaction is stirred for 4 hours. The reaction is quenched with H ₂ O (20 mL) and DMF is removed in vacuo. The residue is filtered and washed repeatedly with CH ₂ Cl ₂ (4 × 10 mL). The combined organic portions are washed with water (50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column using 5-10% EtOAc / hexane as eluent. The pure guanidine derivative (11) is obtained as a white solid in 94% (0.9 g) yield.
LCMS: Calculated C ₃₅ H ₅₅ N ₃ O ₆ Si = 641.39; Found = 642.4 [M + H] ⁺

(4-(((3,5-di-tert-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) guanidine (C9)
To a stirred solution of compound (11) (0.45 g, 0.72 mmol) in CH ₂ Cl ₂ (2 mL) at 0 ° C. was added TFA (2.8 mL, 0.014 mol) and the solution was at 0 ° C. Stir for 2 hours. All solvent is removed under vacuum and the residue is dissolved in CH ₂ Cl ₂ (30 mL).
The organic portion is washed with saturated aqueous NaHCO ₃ (2 × 20 mL), water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column using 5-10% MeOH / CH ₂ Cl ₂ as the eluent.
Pure guanidine (C9) is obtained as a colorless light solid in 86% (0.26 g) yield.

¹ H NMR: (CDCl ₃ , 300 MHz) δ; 8.36 (m, 1H), 7.60 (d, J = 4.76 Hz, 2H), 7.24 (d, J = 4.73 Hz, 2H), 6.79 (s, 2H), 4.74 (s, 1H), 4.27 (d, J = 3.48 Hz, 2H), 3.72 (s, 2H), 1.41 (s, 18H), 0.40 (s, 6H);
Analytical HPLC: (C ₁₈ , 15-90% CH ₃ CN in 0.1% TFA / H ₂ O for 15 min) R _t = 9.39;
LCMS: Calculated C ₂₅ H ₃₉ N ₃ O ₂ Si = 441.28; Found = 442.2 [M + H] ⁺

The following compounds and similar compounds of the present invention may be prepared according to Reaction Scheme 4.
(4-(((3,5-di-tert-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) 2-cyanoguanidine (C10)
Amine hydrochloride (12) (0.45 g, 1 mmol) (dry HCl / MeOH, prepared from the corresponding amine using drying in vacuo) and sodium dicyanamide (0.12 g, 1.34 mmol) in iPrOH (5 mL) Dissolve in 5% H ₂ O. The solution is thoroughly flushed with N ₂ and heated in a sealed tube at 120 ° C. for 5 hours. After cooling to room temperature, all solvent is removed in vacuo and the residue is dissolved in EtOAc (50 mL). The organic portion is washed with saturated aqueous NH ₄ Cl (2 × 20 mL), water (2 × 20 mL), brine (30 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column using 5-10% MeOH / CH ₂ Cl ₂ as the eluent. The pure product (C10) is obtained in 62% (0.3 g) yield as a colorless light solid.

¹ H NMR: (CDCl ₃ , 300 MHz) δ; 7.60 (d, J = 4.67 Hz, 2H), 7.26 (d, J = 4.62 Hz, 2H), 6.79 (s, 2H), 5.18 (bd, s, 2H ), 4.75 (s, 1H), 4.35 (d, J = 3.38 Hz, 2H), 3.72 (s, 2H), 1.40 (s, 18H), 0.41 (s, 6H);
Analytical HPLC: (C ₁₈ , 15-90% CH ₃ CN in 0.1% TFA / H ₂ O for 15 min) R _t = 10.52;
LCMS: Calculated C ₂₆ H ₃₈ N ₄ O ₂ Si = 466.28; Found = 467.3 [M + H] ⁺

(Chloromethyl) (4- (diethoxymethyl) phenyl) dimethylsilane (14)
Compound (13) (25 g, 0.097 mol) is dissolved in dry THF (70 mL) under N ₂ atmosphere and cooled to −78 ° C. using a dry ice / ethanol bath. In a dropping funnel attached to the reaction flask, n-BuLi (121.1 mL of 1.6M in hexane, 0.195 mol) was added slowly over 1 hour and the resulting solution was further added for 1.5 hours at -78 ° C. Stir. A solution of chloro (chloromethyl) dimethylsilane (16.6 mL, 0.116 mol) in THF (10 mL) is added slowly over 30 minutes and the reaction is stirred at −78 ° C. for an additional 2 hours. Saturated aqueous NH ₄ Cl (100 mL) is added and the reaction is allowed to warm to room temperature. The THF is evaporated under vacuum and the residue is dissolved in EtOAc (200 mL). The organic phase is washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The product is purified by silica gel column using 3-10% EtOAc / hexane as eluent. The pure product (14) is obtained as a colorless oil in 65% (18 gm) yield.

The following compounds and similar compounds of the present invention may be prepared according to Reaction Scheme 5.
(Iodomethyl) (4- (diethoxymethyl) phenyl) dimethylsilane (15)
To a stirred solution of (chloromethyl) (4- (diethoxymethyl) phenyl) dimethylsilane (14) (19 g, 0.066 mol) in dry CH ₃ CN (30 mL) was added NaI (49.5 g, 0.33 mol). And the resulting solution is heated to 70 ° C. in an oil bath. After 6 hours, all CH ₃ CN is removed under reduced pressure and the residue is dissolved in CH ₂ Cl ₂ (100 mL), filtered and washed with CH ₂ Cl ₂ (3 × 20 mL). The combined organic portions are washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column with 5% EtOAc / hexane as eluent. The pure iodo product (15) is obtained as a pale yellow oil in 96% (24 gm) yield.

4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) benzaldehyde (17)
Under N ₂ atmosphere, CS ₂ CO ₃ (10.54 g, 0.032 mol) was added to a stirred solution of bisphenol (5) (6 g, 0.027 mol) in dry DMF (15 mL) and the heterogeneous reaction mixture was added. Stir at 60 ° C. for 1 hour. A solution of (iodomethyl) (4- (diethoxymethyl) phenyl) dimethylsilane (15) (12.55 g, 0.032 mol) in DMF (5 mL) was added slowly over 1 hour and the resulting reaction was added to 60 mL. Stir for 1 hour at ° C. All solvent is removed in vacuo and the resulting reaction mixture is stirred at 60 ° C. for 1 hour. All solvent is removed in vacuo and the residue is partitioned between 100 mL EtOAc and aqueous NH ₄ Cl (50 mL). The organic phase is removed and washed thoroughly with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material was purified by silica gel column using 5-10% EtOAc / hexane as eluent. The product is isolated with a purity of about 94% (13.5 g).

To the above mixture in MeOH (15 mL) (13.5 g in MeOH (15 mL), ca. 94% purity) was added dry HCl (85 mL of 2M in MeOH, 0.17 mol) and the resulting solution was 12 Stir at 0 ° C. for hours. All solvent is removed and the residue is dissolved in EtOAc (150 mL). The organic portion is washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified by silica gel column with 15-20% EtOAc / hexane as eluent. Pure product (17) is obtained as a colorless solid in 71% (7.6 g).

LCMS: Calculated C ₂₄ H ₃₄ O ₃ Si = 398.23; Found = 399.2 [M + H ⁺ ]

The following compounds and similar compounds of the invention may be prepared according to Reaction Scheme 6.
(4-(((3,5-di-tert-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) aminoguanidine (C5)
To the refrigerated (0 ° C.) and stirred solution of aldehyde (17) (0.05 g, 0.126 mol) in MeOH (5 mL) is added sodium triacetoxyborohydride (0.08 g, 0.377 mol). After 5 minutes, aminoguanidine (0.021 g, 1.88 mmol) is added, stirred at 0 ° C. for 2 hours and warmed to room temperature overnight. All solvent is removed in vacuo and the residue is dissolved in EtOAc (50 mL) and treated with saturated aqueous NH ₄ Cl (50 mL). The organic phase is separated, washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column using 5% MeOH / CH ₂ Cl ₂ as the eluent. The pure amino guanidine product (C5) is obtained as a pale yellow oil in 67% (0.038 gm) yield.

¹ H NMR: (CDCl ₃ , 300 MHz) δ; 7.67 (s, 1H), 7.64 (d, J = 4.73 Hz, 2H), 7.31 (d, J = 4.73 Hz, 2H), 6.80 (s, 2H), 6.37 (bd. S, 2H), 6.04 (bd. S, 2H), 4.75 (s, 1H), 4.23 (t, J = 3.38 HZ, 1H), 3.96 (d, J = 3.4 HZ, 2H), 3.74 (s, 2H), 1.43 (s, 18H), 0.43 (s, 6H);
Analytical HPLC: (C ₁₈ , 20-90% CH ₃ CN in 0.1% TFA / H ₂ O for 15 min) R _t = 9.18;
LCMS: Calculated C ₂₅ H ₄₀ N ₄ O ₂ Si = 456.29; Found = 457.3 [M + H] ⁺

(4-(((3,5-di-tert-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) N-hydroxyaminobenzylidene (C6)
To a refrigerated (0 ° C.) and stirred solution of aldehyde (17) (0.05 g, 0.126 mol) in MeOH (5 mL) is added sodium triacetoxyborohydride (0.08 g, 3.77 mmol). After 5 minutes, hydroxylamine hydrochloride (0.013 g, 1.88 mmol) is added, stirred at 0 ° C. for 2 hours and warmed to room temperature overnight. All solvent is removed in vacuo and the residue is dissolved in EtOAc (50 mL) and treated with saturated aqueous NH ₄ Cl (50 mL). The organic phase is separated, washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The product is purified through a silica gel column using 2-5% MeOH / CH ₂ Cl ₂ as the eluent. The pure product (C6) is obtained as a white solid in 60% (0.03 gm) yield.

¹ H NMR (CDCl ₃ , 300 MHz) δ; (CDCl ₃ , 300 MHz) δ; 8.13 (s, 1H), 7.63 (d, J = 4.85 Hz, 2H), 7.56 (d, J = 4.81 Hz, 2H), 6.79 (s, 2H), 4.73 (s, 1H), 3.73 (s, 2H), 1.43 (s, 18H), 0.43 (s, 6H);
Analytical HPLC: (C ₁₈ 15 min 15-90% CH ₃ CN in 0.1% TFA / H ₂ O) R _t = 11.41;
LCMS: Calculated C ₂₄ H ₃₅ NO ₃ Si = 413.24; Found = 414.2 [M + H] ⁺

C. Preparation of N-Methylbenzylamine Derivatives The following compounds and similar compounds of the invention may be prepared according to Reaction Scheme 7.
4-((Dimethyl (4-((methylamino) methyl) phenyl) silyl) methoxy) -2,6-di-tert-butylphenol (18)
To a refrigerated (0 ° C.) and stirred solution of aldehyde (17) (4.0 g, 0.010 mol) in MeOH (20 mL) was added sodium triacetoxyborohydride (6.36 g, 0.030 mol) and 0. Stir at ° C. After 5 minutes, methylamine hydrochloride (1.02 g, 0.015 mol) is added and stirred at 0 ° C. for 2 hours and allowed to reach room temperature overnight. All solvent is removed in vacuo and the residue is dissolved in EtOAc (100 mL) and treated with saturated aqueous NH ₄ Cl (50 mL). The organic phase is separated, washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The product is purified through a silica gel column using 5-10% MeOH / CH ₂ Cl ₂ as the eluent. The pure methylamine derivative is obtained as a purple light solid in 95% (3.95 gm) yield.
LCMS: Calculated C ₂₅ H ₃₉ NO ₂ Si = 413.28; Found = 414.2 [M + H] ⁺

(4-(((3,5-di-tert-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) (1,3-bis (tert-butoxycarbonyl) (methyl) guanidine (19)
A solution of amine (18) (0.5 g, 1.21 mmol), DMF (10 mL) and Et ₃ N (0.49 mL, 3.63 mmol) under N ₂ atmosphere is followed by a catalytic amount of HgCl ₂ (20 mg). 1,3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseurea (10) (0.53 g, 1.82 mmol) is added. The heterogeneous reaction is stirred for 4 hours. The reaction is quenched with H ₂ O (20 mL) and DMF is removed in vacuo. The residue is triturated with CH ₂ Cl ₂ (4 × 10 mL), filtered and washed repeatedly with CH ₂ Cl ₂ (20 mL). The combined organic portions are washed with water (50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column using 5-10% EtOAc / hexane as eluent. The pure product (19) is obtained as a colorless solid in 86% (0.68 g) yield.
LCMS: Calculated C ₃₆ H ₅₇ N ₃ O ₆ Si = 655.4; Found = 656.4 [M + H] ⁺

(4-(((3,5-di-tert-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) (methyl) guanidine (C4)
To a chilled (0 ° C.) solution of compound (19) (0.45 g, 0.68 mmol) in CH ₂ Cl ₂ (2 mL) was added TFA (2.8 mL, 0.014 mol) and the solution was stirred for 2 h. To do. All solvent is removed under vacuum and the remaining residue is dissolved in CH ₂ Cl ₂ (30 mL). The organic portion is washed with saturated aqueous NaHCO ₃ (2 × 20 mL), water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column using 5-10% MeOH / CH ₂ Cl ₂ as the eluent. The pure product (C4) is obtained as a colorless light solid in 94% (0.29 g) yield.

¹ H NMR: (5% CD ₃ OD in CDCl ₃ , 300MHz) δ; 7.61 (d, J = 4.76 Hz, 2H), 7.16 (d, J = 4.80 Hz, 2H), 6.76 (s, 2H), 4.47 (s, 2H), 3.70 (s, 2H), 3.00 (s, 3H), 1.39 (s, 18H), 0.39 (s, 6H);
Analytical HPLC: (C ₁₈ , 20-90% CH ₃ CN in 0.1% TFA / H ₂ O for 15 min) R _t = 9.17;
LCMS: Calculated C ₂₆ H ₄₁ N ₃ O ₂ Si = 455.3; Found = 456.3 [M + H] ⁺

(4-(((3,5-di-tert-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) -2-cyano (methyl) guanidine (C7)
Amine hydrochloride (20) (0.3 g, 0.67 mmol) (prepared from the corresponding amine by drying in vacuo with dry HCl / MeOH) and sodium dicyanamide (0.0773 g, 0.87 mmol) were added to iPrOH. Dissolve in 5% H ₂ O in (5 mL). The solution is thoroughly flushed with N ₂ and heated in a sealed tube at 120 ° C. for 5 hours. After cooling to room temperature, all solvent is removed in vacuo and the residue is dissolved in EtOAc (50 mL).
The organic portion is washed with saturated aqueous NH ₄ Cl (2 × 20 mL), water (2 × 20 mL), brine (30 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column using 5-10% MeOH / CH ₂ Cl ₂ as the eluent. The pure product (C7) is obtained as a colorless light solid in 63% (0.2 g) yield.

¹ H NMR: (CDCl ₃ , 300 MHz) δ; 7.61 (d, J = 4.78 Hz, 2H), 7.23 (d, J = 4.82 Hz, 2H), 6.79 (s, 2H), 5.27 (bd.S, 2H ), 4.73 (s, 1H), 4.58 (s, 2H), 3.72 (s, 2H), 3.00 (s, 3H), 1.42 (s, 18H), 0.41 (s, 6H);
Analytical HPLC: (C ₁₈ , 15-90% CH ₃ CN in 0.1% TFA / H ₂ O for 15 min) R _t = 10.91;
LCMS: Calculated C ₂₇ H ₄₀ N ₄ O ₂ Si = 480.29; Found = 481.3 [M + H] ⁺

The following compounds and similar compounds of the invention may be prepared according to Reaction Scheme 8.
(4-(((3,5-di-tert-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) (methyl) biguanidine (C8)
Amine hydrochloride (20) (0.3 g, 0.67 mmol) (prepared from the corresponding amine by drying in vacuo with dry HCl / MeOH) and dicyanadimide (0.073 g, 0.87 mmol) were added to iPrOH ( Dissolve in 5% H ₂ O in 5 mL). The solution is thoroughly flushed with N ₂ and heated at 120 ° C. in a sealed tube for 4 hours. After cooling to room temperature, all solvent is removed in vacuo and the remaining residue is dissolved in EtOAc (50 mL). The organic portion is washed with saturated aqueous NH ₄ Cl (2 × 20 mL), water (20 mL), brine (30 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column using 10-20% MeOH / CH ₂ Cl ₂ as the eluent. The pure product (C8) is obtained as a colorless light solid in 46% (0.15 g) yield.

¹ H NMR: (5% CD ₃ OD in CDCl ₃ , 300MHz) δ; 7.56 (d, J = 4.80 Hz, 2H), 7.18 (d, J = 4.78 Hz, 2H), 6.75 (s, 2H), 4.60 (s, 2H), 3.68 (s, 2H), 2.96 (s, 3H), 1.37 (s, 18H), 0.37 (s, 6H);
Analytical HPLC: (C ₁₈ , 15-90% CH ₃ CN in 0.1% TFA / H ₂ O for 15 min) R _t = 9.41;
LCMS: Calculated C ₂₇ H ₄₃ N ₅ O ₂ Si = 497.32; Found = 498.3 [M + H] ⁺

3- (N- (4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) -N-methylcarbamoyl) propanoic acid (C11)
To a solution of amine (18) (0.2 g, 0.484 mmol) in CH ₂ Cl ₂ (5 mL) was added DMAP (0.059 g, 0.48 mmol) and succinic anhydride (0.058 g, 0.58 mmol). Add and stir the resulting solution at 0 ° C. After 2 hours, the reaction is quenched by adding water (20 mL) and diluted with CH ₂ Cl ₂ (40 mL). The organic phase is separated, washed with water (50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The crude material is purified on a silica gel column with 5-10% MeOH / CH ₂ Cl ₂ as eluent. The pure product (C11) is obtained as a colorless solid in 63% (0.15 g) yield.

¹ H NMR: (CDCl ₃ , 300 MHz) (most NMR signals are divided into two theoretical sets with an intensity ratio of 1: 1.4) δ; 7.62 and 7.57 (d, J = 4.73 Hz, 2H), 7.23 and 7.17 (d, J = 4.80 Hz, 2H), 6.79 (s, 2H), 4.75 (bd. S, 1H), 4.60 and 4.56 (s, 2H), 3.73 and 3.71 (s, 2H), 2.99 and 2.97 (s, 3H), 2.73 and 2.71 (m, 4H), 1.42 (s, 18H), 0.41 (s, 6H);
Analytical HPLC: (C ₁₈ , 15-90% CH ₃ CN in 0.1% TFA / H ₂ O for 15 min) R _t = 10.8;
LCMS: Calculated C ₂₉ H ₄₃ NO ₅ Si = 513.29; Found = 514.3 [M + H] ⁺

D. Preparation of phenol derivatives:
The following compounds and analogs of the invention can be prepared according to Reaction Schemes 9, 10, 11 and 12.
1-Bromo-4- (methoxymethoxy) benzene (22)
500-mL Soxhlet containing 4-bromophenol (8.65 g, 50 mmol), dimethoxymethane (40 mL (450 mmol)), monohydrate of p-toluenesulfonic acid (100 mg) with 50 g of type 3A molecular sieve Dissolve in 200 mL anhydrous CH ₂ Cl ₂ in the extractor and reflux the solution overnight under argon. The reaction was allowed to cool, concentrated under reduced pressure and purified via flash chromatography (SiO ₂ , 3% EtOAc / hexanes) to give the desired product (22) as a colorless oil (5.78 g, 53 %): ¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.38 (d, J = 5.4 Hz, 2H), 6.92 (d, J = 5.4 Hz, 2H), 5.14 (s, 2H), 3.47 (s , 3H).

(Chloromethyl) (4- (methoxymethoxy) phenyl) dimethylsilane (23)
1-Bromo-4- (methoxymethoxy) benzene (22) (9.51 g, 44 mmol) is dissolved in 150 mL anhydrous ethyl ether in a 500-mL round bottom flask and the solution is cooled to -78 ° C. With continuous stirring under argon, 75 mL tert-butyllithium (1.7 M in hexane, 127 mmol) is added dropwise via syringe and the reaction is kept at −78 ° C. for an additional 30 minutes. 18 mL chloro (chloromethyl) dimethylsilane (133 mmol) is carefully added dropwise to the reaction flask via syringe and the reaction mixture is slowly warmed to room temperature overnight. The reaction is quenched with 100 mL saturated NH ₄ Cl and the organic phase is separated and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated and the residue is purified by flash chromatography _(SiO 2, 3% EtOAc / hexanes) to give the desired product (23) as a colorless oil ^{(10.57g, 98%): 1} H- NMR (CDCl ₃ , 300MHz) δ 7.48 (d, J = 5.1Hz, 2H), 7.06 (d, J = 5.1Hz, 2H), 5.20 (s, 2H), 3.48 (s, 3H), 2.93 (s, 2H), 0.40 (s, 6H).

(Iodomethyl) (4- (methoxymethoxy) phenyl) dimethylsilane (24)
A 500-mL round bottom flask was charged with (chloromethyl) (4- (methoxymethoxy) phenyl) dimethylsilane (23) (10.57 g, 43 mmol), NaI (19.4 g, 130 mmol), 200 mL anhydrous CH ₃ CN. And the reaction mixture is refluxed overnight under argon. The solution is allowed to cool to room temperature and the precipitate formed on cooling is filtered off. The filtrate is evaporated under vacuum and the residue is purified by flash chromatography (SiO ₂ , 5% EtOAc / hexanes) to give the desired product (24) as a colorless oil (10.68 g, 74%):
¹ H-NMR (CDCl ₃ , 300MHz) δ 7.47 (d, J = 5.1Hz, 2H), 7.06 (d, J = 5.1Hz, 2H), 5.20 (s, 2H), 3.48 (s, 3H), 2.16 (s, 2H), 0.42 (s, 6H)

4-((((4- (methoxymethoxy) phenyl) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (C12)
In a 250-mL flask, 2,6-di-tert-butyl-1,4-bisphenol (5) (6.93 g, 31 mmol), (iodomethyl) (4- (methoxymethoxy) phenyl) dimethylsilane (24) ( 10.60 g, 31 mmol), CS ₂ CO ₃ (11.25 g, 35 mmol), anhydrous CH ₃ CN are added and the mixture is stirred overnight at 80 ° C. under a constant stream of argon. Quench the reaction with 50 mL saturated NH ₄ Cl and extract with 100 mL CH ₂ Cl ₂ . The organic phase is separated, washed with 100 mL brine and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated and the residue purified by flash chromatography (SiO _2, hexanes) to give a slightly yellow solid (11.35 g, 85%) desired product as an (C12):

¹ H-NMR (CDCl ₃ , 300MHz) δ 7.54 (d, J = 5.1Hz, 2H), 7.06 (d, J = 5.1Hz, 2H), 6.80 (s, 2H), 5.20 (s, 2H), 4.72 (s, 1H), 3.70 (s, 2H), 3.48 (s, 3H), 1.43 (s, 18H), 0.40 (s, 6H); retention time in RP-HPLC (C ₁₈ , 0.1% TFA over 7 minutes 30-95% CH ₃ CN in / H ₂ O) is 5.02; calculated mass for C ₂₅ H ₄₃ O ₆ Si (M + 2H ₂ O + H) ⁺ 467.3, found by LC-MS 467.3; element Analysis for C ₂₅ H ₃₈ O ₄ Si Calculated: C, 69.72; H, 8.89; O, 14.86; Si, 6.52; Found: C, 69.35; H, 8.64; N, 0.20.

4-(((4-Phenol) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (25)
4-((((4- (methoxymethoxy) phenyl) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (C12) (6.23 g, 14 mmol) in 200 mL p-dioxane in a 500-mL round bottom flask. ) Is added, and the mixture is stirred at room temperature under argon for 3 days. The solution is extracted with 200 mL EtOAc and the solvent is evaporated under reduced pressure. The residue was purified by flash chromatography _(SiO 2, 5% EtOAc / hexanes followed by 10% EtOAc / hexane) to give the desired product as a colorless liquid (2.73 g) (25) and slightly yellow solid The recovered starting material is obtained as (2.70 g). The colorless liquid turns into a white solid upon standing at room temperature. The calculated yield is 50%: ¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.49 (d, J = 5.1 Hz, 2H), 6.86 (d, J = 5.1 Hz, 2H), 6.80 (s, 2H), 4.81 (s, 1H), 4.72 (s, 1H), 3.70 (s, 2H), 1.43 (s, 18H), 0.39 (s, 6H); elemental analysis C ₂₃ H ₃₄ O ₃ Si, calculated : C, 71.46; H, 8.86; O, 12.42; Si, 7.26; Found: C, 70.33; H, 8.96; N, 0.08.

Succinic acid 4-((((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) phenol ester (C13)
To a 10-mL round bottom flask was added 4-((((4-phenol) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (25) (0.150 g, 0.388 mmol), succinic anhydride (0 .388 g, 3.88 mmol), N-methylmorpholine (0.645 mL, 5.82 mmol), 5 mL anhydrous CH ₂ Cl ₂ are added and the resulting mixture is stirred at room temperature overnight. The solution is evaporated to dryness under reduced pressure. The residue was redissolved in 8 mL CH ₃ CN and then applied to a reverse phase HPLC column (C18, 10-95% CH ₃ CN / 0.1% TFA water gradient) to give a white powder (110 mg, 60% Yield) as the desired product (C13): ¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.62 (d, J = 5.0 Hz, 2H), 7.10 (d, J = 5.0 Hz, 2H), 6.80 (s, 2H), 4.74 (s, 1H), 3.72 (s, 2H), 2.89 (t, J = 3.9Hz, 2H), 2.81 (t, J = 3.9Hz, 2H), 1.43 (s, 18H) , 0.41 (s, 6H); retention time in RP-HPLC (C ₁₈ , 30-95% CH ₃ CN in 0.1% TFA / H ₂ O over 7 minutes) is 4.54; calculated mass C ₂₇ H ₃₉ O ₆ Si (M + H) ⁺ 487.3, LC-MS measured 487.3; Elemental analysis C ₂₇ H ₃₈ O ₆ Si Calculated: C, 66.63; H, 7.87; O, 19.73; Si, 5.77; Found: C, 66.23; H, 7.48; N, 0.15.

4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) phenyl 2- (dimethylamino) acetate (C14)
To a 15-mL round bottom flask was added 4-(((4-phenol) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (25) (0.200 g, 0.52 mmol), N, N-dimethyl. Glycine HCl salt (0.109 g, 0.78 mmol), PS-carbodiimide (2.1 mmol / g, 0.37 g 0.78 mmol, N-methylmorpholine (0.087 mL (0.78 mmol)), DMAP (6. 5 mg, 0.052 mmol), 10 mL anhydrous CH ₂ Cl ₂ is added and the resulting mixture is stirred overnight at room temperature The resin is filtered off and the solution is evaporated to dryness under reduced pressure. Redissolved in 8 mL CH ₃ CN and then applied to a reverse phase HPLC column (C18, 10-95% CH ₃ CN / 0.1% TFA water gradient) to give a white powder (205 mg, 76% yield). ) To give the desired product (C14): ¹ H—N MR (CDCl ₃ , 300MHz) δ 7.66 (d, J = 5.0Hz, 2H), 7.13 (d, J = 5.0Hz, 2H), 6.79 (s, 2H), 4.73 (s, b, 1H), 4.18 ( s, 2H), 3.72 (s, 2H), 3.05 (s, 6H), 1.43 (s, 18H), 0.42 (s, 6H); retention time in RP-HPLC (C ₁₈ , 0.1% TFA / 30-95% CH ₃ CN in H ₂ O) is 3.94; calculated mass for C ₂₇ H ₄₂ O ₄ Si (M + H) ⁺ 472.3, found by LC-MS 472.3; elemental analysis C ₂₉ H ₄₂ F ₃ NO ₆ Si (M + TFA) Calculated: C, 59.47; H, 7.23; F, 9.73; N, 2.39; O, 16.39; Si, 4.79; Found: C, 58.46; H, 6.30; N, 2.42.

4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) phenyl 4-methylpiperazine-1-carboxylate (C15)
To a 10-mL round bottom flask was added 4-(((4-phenol) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (25) (0.250 g, 0.65 mmol), p-nitrophenol chloro. Formate (0.203 g, 0.97 mmol), N-methylmorpholine (0.216 mL (1.95 mmol)), 5 mL anhydrous CH ₂ Cl ₂ are added and the resulting mixture is stirred for 3 hours at room temperature. 1-Methylpiperazine (0.22 mL, 1.95 mmol) is subsequently added and stirring is continued overnight. The reaction is evaporated to dryness under reduced pressure. The residue was redissolved in 8 mL CH ₃ CN and applied to a reverse phase HPLC column (C18, 10-95% CH ₃ CN / 0.1% TFA water gradient) to give a light white powder (211 mg, 64% yield). Ratio) to obtain the desired product (C15):

¹ H-NMR (CDCl ₃ , 300MHz) δ 7.62 (d, J = 5.0Hz, 2H), 7.10 (d, J = 5.0Hz, 2H), 6.90 (s, 2H), 4.72 (s, b, 1H) , 4.41 (s, b, 2H), 3.71 (s, 2H), 2.92 (s, 3H), 2.88 (s, b, 2H), 2.63 (s, b, 4H), 1.43 (s, 18H), 0.41 (s, 6H); retention time in RP-HPLC (C ₁₈ , 30-95% CH ₃ CN in 0.1% TFA / H ₂ O over 7 minutes) is 4.04; calculated mass C ₂₉ H ₄₅ N ₂ O ₄ Si (M + H) ⁺ 513.3, Measured by LC-MS 513.3 .; Elemental analysis C ₃₁ H ₄₅ F ₃ N ₂ O ₆ Si (M + TFA) Calculated: C, 59.40; H, 7.24; F , 9.09; N, 4.47; O, 15.32; Si, 4.48; Found: C, 58.25; H, 6.67; N, 4.57.

Methyl 2- (4-((3,5-di-tert-butyl-4-hydroxyphenoxy) dimethylsilyl) phenoxy) acetate (C16)
A 15-mL round bottom flask was charged with 4-(((4-phenol) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (25) (0.120 g, 0.31 mmol), methyl bromoacetate (0 .60 mL, 0.62 mmol), CS ₂ CO ₃ (0.202 g, 0.62 mmol), 5 mL anhydrous CH ₃ CN are added and the resulting mixture is stirred at room temperature overnight. The solution is evaporated to dryness under reduced pressure and the residue is first applied to a silica gel column eluted with hexane followed by 5% EtOAc / hexane to give the desired product as a white powder (87 mg, 61% yield). Get the object (C16):

¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.54 (d, J = 5.1 Hz, 2H), 6.92 (d, J = 5.1 Hz, 2H), 6.80 (s, 2H), 4.72 (s, 1H), 4.75 (s, 2H), 3.81 (s, 3H), 3.69 (s, 2H), 1.42 (s, 18H), 0.40 (s, 6H); retention time in RP-HPLC (C ₁₈ , 0.1% TFA over 7 minutes 30-95% CH ₃ CN in / H ₂ O) is 4.82; calculated mass for C ₂₆ H ₃₉ O ₅ Si (M + H) ⁺ 459.3, found by LC-MS 459.3; elemental analysis C ₂₆ H ₃₈ O ₅ Si Calculated: C, 68.08; H, 8.35; O, 17.44; Si, 6.12; Found: C, 67.70; H, 8.04; N, 0.11.

Isopropyl 2- (4-((3,5-di-tert-butyl-4-hydroxyphenoxy) dimethylsilyl) phenoxy) -2-methylpropionate (C17)
In a 5-mL reaction glass vial, 4- (4-phenol) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (25) (0.220 g, 0.57 mmol), isopropyl 2-bromo-2- Methyl propionate (1.0 mL, 5.65 mmol), CS ₂ CO ₃ (0.375 g, 1.14 mmol) is added, the glass vial is capped and the resulting mixture is heated to 145 ° C. overnight. After cooling to room temperature, the solution is extracted with 50 mL EtOAc, washed with saturated NH ₄ Cl, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness under reduced pressure. The residue is first applied to a silica gel column eluting with 2% EtOAc / hexane followed by 5% EtOAc / hexane to give the desired product (C17) as a slightly yellow oil (172 mg, 59% yield). :

¹ H-NMR (CDCl ₃ , 300MHz) δ 7.46 (d, J = 5.0Hz, 2H), 6.83 (d, J = 5.0Hz, 2H), 6.80 (s, 2H), 5.08 (p, J = 3.8Hz , 1H), 4.72 (s, 1H), 3.68 (s, 2H), 1.60 (s, 6H), 1.43 (s, 18H), 1.21 (d, J = 3.8Hz, 6H), 0.38 (s, 6H) ; Retention time in RP-HPLC (C ₁₈ , 5-100% CH ₃ CN in 0.1% TFA / H ₂ O over 12 min) is 11.20; calculated mass for C ₃₀ H ₄₇ O ₅ Si (M + H ) ⁺ 515.3, Measured by LC-MS 515.3; Elemental analysis C ₃₀ H ₄₈ O ₆ Si (M + H ₂ O) Calculated: C, 67.63; H, 9.08; O, 18.02; Si, 5.27; Measured: C, 66.22; H, 7.28; N, 0.34.

The following compounds and similar compounds of the invention may be prepared according to Reaction Scheme 13.
4-(((4- (2- (2-methoxyethoxy) ethoxy) phenyl) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (C18)
In a 10-mL glass vial, 4-(((4-phenol) dimethylsilyl) methoxy) -2,6-di-tert-butylphenol (25) (0.33 g, 0.85 mmol), 2- (2-methoxy Ethoxy) ethyl tosylate (1.16 g, 4.25 mmol), CS ₂ CO ₃ (0.277 g, 0.85 mmol), 2 mL anhydrous DMF were added and the resulting mixture was capped and stirred at 60 ° C. for 2 h. To do. 50 mL saturated NH ₄ Cl solution is added and the mixture is extracted with 75 mL EtOAc. The organic phase is separated, washed with brine and dried over anhydrous Na ₂ SO ₄ . The solution was then evaporated to dryness under reduced pressure and the residue applied to a silica gel column eluting first with 20% EtOAc / hexane followed by 10% EtOAc / hexane to give a white crystalline solid (251 mg, The desired product (C18) is obtained as 61% yield):

¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.52 (d, J = 4.1 Hz, 2H), 6.94 (d, J = 4.1 Hz, 2H), 6.80 (s, 2H), 4.72 (s, 1H), 4.16 (t, J = 3.0Hz, 2H), 3.87 (t, J = 3.0Hz, 2H), 3.73 (t, J = 2.8Hz, 2H), 3.70 (s, 2H), 3.58 (t, J = 2.8Hz , 2H), 3.39 (s, 3H), 1.43 (s, 18H), 0.39 (s, 6H); retention time in RP-HPLC (C _18, over in 0.1% TFA / H ₂ O 5 minutes 30-95 % CH ₃ CN) is 4.29; calculated mass for C ₂₈ H ₄₅ O ₅ Si (M + H) ⁺ 489.3, found by LC-MS 489.3; elemental analysis for C ₂₈ H ₄₄ O ₅ Si calculated: C , 68.81; H, 9.07; O, 16.37; Si, 5.75; Found: C, 67.50; H, 8.92.

E. Preparation of N-methylbenzylamide derivatives:
The following compounds and analogs of the invention may be prepared according to Reaction Scheme 14.
2- (2-methoxyethoxy) -N-4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) -N-methylacetamide (C20)
A solution of HOBt (35 mg, 0.25 mmol), HBTU (98 mg, 0.25 mmol), DIEA (0.090 mL, 0.516 mmol), 2- (2-methoxyethoxy) acetic acid (35 mg, 26 mmol) and DMF (4 mL) Is added to a solution of 18 (0.035 g, 0.086 mmol) in DMF (1 mL). The homogeneous solution is stirred overnight and quenched with water (50 mL). The organic material is extracted with EtOAc (3 × 20 mL), washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The product is purified by silica gel column using 30-50% EtOAc / hexane as eluent. The pure product (C20) is obtained as a pale yellow oil in 78% (0.035 gm) yield.

¹ H NMR: (CDCl ₃ , 300 MHz) (most NMR signals are divided into two theoretical sets with an intensity ratio of 1: 1.4) δ; 7.59 and 7.56 (d, J = 4.60 Hz, 2H), 7.24 and 7.18 (d, J = 4.70 Hz, 2H), 6.79 (s, 2H), 4.73 (s, 1H), 4.58 and 4.49 (s, 2H), 4.27 and 4.26 (s, 2H), 3.70 (m, 3H), 3.60 (m, 2H), 3.59 (m, 1H), 3.38 and 3.33 (s, 3H), 2.93 and 2.91 (s, 3H), 1.42 (s, 18H), 0.41 (s, 6H);
Analytical HPLC: (C ₁₈ 15 min 20-90% CH ₃ CN in 0.1% TFA / H ₂ O) R _t = 10.91;
LCMS: Calculated C ₃₀ H ₄₇ NO ₅ Si = 529.32; Found = 530.3 [M + H] ⁺

2- (2- (2-methoxyethoxy) ethoxy) -N- (4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) -N-methylacetamide ( C19)
Following the same procedure described in the synthesis of C20, 18 (0.035 g, 0.086 mmol), HOBt (35 mg, 0.25 mmol), HBTU (98 mg, 0.25 mmol, DIEA (0.090 mL) in DMF (5 mL). (0.516 mmol)) and 2- [2- (2-methoxyethoxy) ethoxy] acetic acid (46 mg, 26 mmol) gave the desired amide (C19 as a pale yellow oil in 74% yield (0.036 g)). ).

¹ H NMR (CDCl ₃ , 300 MHz) (most NMR signals are divided into two theoretical sets with an intensity ratio of 1: 1.4) δ; 7.59 and 7.56 (d, J = 4.60 Hz, 2H), 7.24 And 7.18 (d, J = 4.70 Hz, 2H), 6.79 (s, 2H), 4.73 (s, 1H), 4.58 and 4.55 (s, 2H), 4.27 and 4.26 (s, 2H), 3.76 (m, 1H ), 3.71 (m, 3H), 3.65 (m, 2H), 3.64 (m, 2H), 3.54 (m, 1H), 3.38 and 3.36 (m, 1H), 3.34 (m, 1H), 2.93 and 2.91 ( s, 3H), 1.42 (s, 18H), 0.41 (s, 6H);
Analytical HPLC: (C ₁₈ 15 min 20-90% CH ₃ CN in 0.1% TFA / H ₂ O) R _t = 10.89;
LCMS: Calculated C ₃₂ H ₅₁ NO ₆ Si = 573.35; Found = 574.3 [M + H] ⁺

F. Preparation of sulfonamide derivatives:
The following compounds and similar compounds of the invention may be prepared according to Reaction Scheme 15.
N- (4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) -4-methoxy-N-methylbenzenesulfonamide (C21)
To a solution of compound 18 (0.035 g, 0.086 mmol) in dry CH ₂ Cl ₂ (4 mL) is added Et ₃ N (0.024 mL, 0.172 mmol) and the reaction is cooled to 0 ° C. A solution of 4-methoxybenzenesulfonyl chloride (0.022 mg, 0.106 mmol) in CH ₂ Cl ₂ (1 mL) is added slowly and the solution is stirred for 6 hours. All solvent is removed in vacuo and the residue is dissolved in EtOAc (50 mL) and treated with saturated aqueous NH ₄ Cl (50 mL). The organic phase is separated, washed with water (2 × 50 mL), brine (50 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated. The product is purified by silica gel column using 20-50% EtOAc / hexane as eluent. The pure product (C21) is obtained as a colorless solid in 70% (0.035 gm) yield.

¹ H NMR (CDCl ₃ , 300 MHz) δ; (CDCl ₃ , 300 MHz) δ; 7.78 (d, J = 6 Hz, 2H), 7.56 (d, J = 4.81 Hz, 2H), 7.31 (d, J = 4.8 Hz, 2H), 7.03 (d, J = 5.7 Hz, 2H), 6.79 (s, 2H), 4.73 (s, 1H), 4.12 (s, 2H), 3.89 (s, 3H), 3.71 (s, 2H ), 2.58 (s, 3H), 1.42 (s, 18H), 0.41 (s, 6H);
Analytical HPLC: (C ₁₈ 15 min 20-90% CH ₃ CN in 0.1% TFA / H ₂ O) R _t = 12.73;
LCMS: Calculated value C ₃₂ H ₄₅ NO ₅ SSi = 583.3; Found value = 584.3 [M + H] ⁺

N- (4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) -2,4-dichloro-N-methylbenzenesulfonamide (C22)
Following the same procedure described in the synthesis of C21, 18 (0.035 g, 0.086 mmol), Et ₃ N (0.024 mL, 0.172 mmol), 2,4-dichlorobenzenesulfonyl chloride (0.026 mg, 0.026 mmol). 106 mmol) and CH ₂ Cl ₂ (5 mL) gave the desired sulfonamide (C22) as a semi-solid in 94% yield (0.050 g).

¹ H NMR δ; 8.04 (d, J = 5.1 Hz, 1H), 7.56 (d, J = 4.81 Hz, 2H), 7.55 (s, 1H), 7.38 (m, 1H), 7.34 (m, 2H), 6.79 (s, 2H), 4.73 (s, 1H), 4.40 (s, 2H), 3.72 (s, 2H), 2.76 (s, 3H), 1.42 (s, 18H), 0.41 (s, 6H);
Analytical HPLC: (C ₁₈ 40-90% CH ₃ CN in 0.1% TFA / H ₂ O over 15 min) R _t = 11.76;
LCMS: Calculated C ₃₁ H ₄₁ Cl ₂ NO ₄ SSi = 621.19; Found = 622.3 [M + H] ⁺

N- (4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) -4-fluoro-N-methylbenzenesulfonamide (C23)
Following the same procedure described in the synthesis of XXI, 18 (0.035 g, 0.086 mmol), Et ₃ N (0.024 mL, 0.172 mmol), 4-fluorobenzenesulfonyl chloride (0.020 mg, 0.106 mmol) And the reaction between CH ₂ Cl ₂ (5 mL) gave the desired sulfonamide (C23) as a colorless solid in 62% yield (0.030 g).

¹ H NMR δ; (CDCl ₃ , 300 MHz) δ; 7.58 (d, J = 6.0 Hz, 2H), 7.30 (d, J = 4.5 Hz, 2H), 7.23 (m, 4H), 6.79 (s, 2H) , 4.73 (s, 1H), 4.15 (s, 2H), 3.71 (s, 2H), 2.60 (s, 3H), 1.42 (s, 18H), 0.41 (s, 6H);
Analytical HPLC: (C ₁₈ 15 min 20-90% CH ₃ CN in 0.1% TFA / H ₂ O) R _t = 12.45;
LCMS: Calculated C ₃₁ H ₄₂ FNO ₄ SSi = 571.26; Found = 572.3 [M + H] ⁺

N- (4-(((3,5-di-tert-butyl-4-hydroxyphenoxy) methyl) dimethylsilyl) benzyl) -N-methylmethylsulfonamide (C24)
Following the same procedure described in the synthesis of XXI, 18 (0.035 g, 0.086 mmol), Et ₃ N (0.024 mL, 0.172 mmol), methanesulfonyl chloride (0.00085 mg, 0.106 mmol) and CH ₂ Reaction between Cl ₂ (5 mL) gave the desired sulfonamide (XXIV) as a pale yellow oil in 48% yield (0.020 g).

¹ H NMR (CDCl ₃ , 300 MHz) (most NMR signals are divided into two theoretical sets with an intensity ratio of 1: 1.4) δ; 7.61 and 7.56 (d, J = 4.60 Hz, 2H), 7.22 And 7.04 (d, J = 4.70 Hz, 2H), 6.79 (s, 2H), 4.73 and 4.72 (s, 1H), 4.58 and 4.52 (s, 2H), 3.72 and 3.71 (s, 2H), 2.95 and 2.93 (s, 3H), 2.18 and 2.15 (s, 3H), 1.42 (s, 18H), 0.41 (s, 6H);
Analytical HPLC: (C ₁₈ 15-minute 12-90% CH ₃ CN in 0.1% TFA / H ₂ O) R _t = 12.46;
LCMS: Calculated C ₂₆ H ₄₁ NO ₄ SSi = 491.25; Found = 492.3 [M + H] ⁺

  All publications and patent applications cited herein are to the same extent as specifically and individually indicated as if each individual publication and patent application were cited as part of this specification. The source is clearly indicated and considered as part of this specification.

  While certain embodiments have been described in detail above, those skilled in the art will clearly understand that numerous modifications are possible in embodiments without departing from the teachings thereof. All such modifications are intended to be included within the claimed invention.

FIG. 1 shows ex vivo antioxidant activity after oral administration of the t-butylphenol compound of the present invention: copper-induced oxidation of serum isolated from rabbits fed a 0.5% cholesterol / 10% corn oil diet for 70 days Indicates. FIG. 2 shows the inhibition of cytokine-induced VCAM-1 expression in human coronary artery smooth muscle cells (CASMC) and human umbilical vein endothelial cells (HUVEC) by t-butylphenol compounds of the present invention compared to probucol. FIG. 3 shows intravenous carbachol (1, 5, 10, 20 mg / kg) in control and test rabbits treated with a t-butylphenol compound of the present invention (at 300 mg / day for 70 days). Shows the change in total peripheral conductance (TPC) in response. FIG. 4 shows endothelial cell NO activity as a function of t-butylphenol compound and TNF-α. FIG. 5 shows induction of HMOX-1 expression by t-butylphenol compounds of the present invention in unstimulated whole blood. FIG. 6 shows the induction of HMOX-1 expression by t-butylphenol compounds of the present invention in LPS stimulated whole blood. FIG. 7 shows mechanical injury in ApoE ^{− / −} male mice treated with placebo or a representative compound of the present invention and fed a high fat diet supplemented with 1.25% cholesterol for 12 weeks prior to injury. (A) Quantitative morphometry and (b) neointimal-to-media ratio in model. FIG. 8 shows a mechanical injury model in ApoE ^{− / −} male mice treated with placebo or a representative compound of the invention and fed a high fat diet supplemented with 1.25% cholesterol for 12 weeks prior to injury. The percent CD45 positive cells (number of CD45 immunostained positive cells / total number of nuclei) in the neointima and media of the carotid artery in FIG. FIG. 9 shows mechanical damage in ApoE ^{− / −} male mice treated with placebo or a representative compound of the invention and fed a high fat diet supplemented with 1.25% cholesterol for 12 weeks prior to injury. Percent Brdu positive cells (number of Brdu immunostained positive cells / total number of nuclei) in the neointima and media of the carotid artery in the model are shown. FIG. 10 shows the time course of blood glucose levels in diabetic rats, as well as 8-week streptozotocin-induced rats treated (0.3% in rat diet) or not treated with representative compounds of the present invention. Morning blood glucose levels are determined using tail vein blood samples obtained from awake rats. Data are expressed as mean ± SEM (standard error of the mean). The number of animals used is indicated by n. Blood glucose levels are significantly increased in treated and untreated diabetic animals. No significant difference is observed between treated and untreated diabetic animals. FIG. 11 shows non-diabetic rats, diabetic rats not treated with streptozotocin induction for 12 weeks, and untreated for 8 weeks and treated with a representative compound of the invention for an additional 4 weeks (0.3% in rat diet). 2 shows the time course of blood glucose levels in the treated diabetic rats. Morning blood glucose levels are determined using tail vein blood samples obtained from awake rats. Data are expressed as mean ± SEM (standard error of the mean). The number of animals used is indicated by n. Blood glucose levels are significantly increased in diabetic animals. No significant difference is observed between treated and untreated diabetic animals. FIG. 12 shows the mean arterial pressure (MAP) in panel A of non-diabetic rats and diabetic rats treated with a representative compound of the invention (0.3% in rat diet) and untreated 8-week streptozotocin-induced diabetic rats. ) Values and heart rate (HR) in panel B. MAP and HR were measured in anesthetized rats prior to evaluation of erectile response to cavernous nerve stimulation. Data are shown as mean ± SEM. The number of animals used is indicated by n. *** p <0.005 for no diabetes by Student-Newman-Keuls post hoc test after one-way ANOVA. FIG. 13 shows the effect of prophylactic treatment with a representative compound of the invention (0.3% in rat diet) on erectile response in anesthetized 8-week streptozotocin-induced diabetic male rats. Data are shown as mean ± SEM of area under the curve (mm Hg × sec) of intracavernous pressure (ICP) increase in cavernous nerve electrical stimulation normalized by the MAP value at the time of each stimulus. *** p <0.005 versus frequency response curve in naïve diabetic rats by two-way ANOVA test. FIG. 14 shows the effect of prophylactic treatment with a representative compound of the invention (0.3% in rat diet) on the erectile response in anesthetized 8-week streptozotocin-induced diabetic male rats. Data are presented as mean ± SEM of peak increments (mm Hg) of ICP increase for cavernous nerve electrical stimulation normalized by MAP values at the time of each stimulus. *** p <0.005 versus frequency response curve in naïve diabetic rats by two-way ANOVA test. FIG. 15 shows non-diabetic rats, 12-week streptozotocin-induced untreated diabetic rats, and diabetic rats that were untreated for 8 weeks and treated with a representative compound of the present invention (0.3% in rat diet) for an additional 4 weeks. Mean arterial pressure (MAP) values (left panel) and heart rate (HR) levels (right panel) are shown. MAP and HR were measured in anesthetized rats prior to evaluation of erectile response to cavernous nerve stimulation. Data are shown as mean ± SEM. The number of animals used is indicated by n. *** p <0.005 for no diabetes by Student-Newman-Keuls post hoc test after one-way ANOVA. FIG. 16 shows erections in anesthetized 12-week streptozotocin-induced untreated rats and diabetic rats treated for 8 weeks untreated and then for another 4 weeks with a representative compound of the invention (0.3% in rat diet). Shows sexual response. Data are presented as the mean ± SEM of the area under the curve (mm Hg × sec) of ICP increase for cavernous electrical stimulation normalized by the MAP value at the time of each stimulation. ** p <0.01 vs frequency response curve in untreated diabetic rats by two-way ANOVA test. FIG. 17 shows anesthetized 12-week streptozotocin-induced untreated diabetic male rats and diabetes treated for 8 weeks untreated and then for another 4 weeks with a representative compound of the invention (0.3% in rat diet). Figure 2 shows an erectile response in rats. Data are presented as mean ± SEM of peak increments (mm Hg) of ICP increase for cavernous nerve electrical stimulation normalized by the MAP value at the time of each stimulation. ** p <0.01 vs frequency response curve in untreated diabetic rats by two-way ANOVA test.

Claims (34)

An effective amount of formula (I) for treating a disease or disorder associated with vascular health:

Wherein X ₁ and X ₂ are independently selected from the group consisting of oxy and dialkyl substituted silyls;
R ₁ is C ₁ -C ₄ alkyl;
R ₂ and R ₃ are independently selected from the group consisting of H and C ₁ -C ₄ alkyl;
R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, methoxy and branched or straight chain C ₁ -C ₆ alkyl; and R ₈ and R ₉ are independently hydrogen, hydroxy, trifluoromethyl, halide, amine, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroarylthio acryloyl, -O _(C 1 -C ₆ alkyl), - OCO- (H or _C 1 -C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C _{8 alkyl) -COOH, - (C 2 -C} 8 _{alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH Oyo It is selected from -CO- _(C 2 -C ₆ alkenyl) group consisting of COOH;
Here, the substituent of R ₈ or R ₉ is alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (C ₁ -C ₆ alkyl), —OCO— (H or C ₁ — C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C ₈ alkyl) -COOH, - _(C 2 -C _{8 alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH or -CO - If it is _(C 2 -C ₆ alkenyl) -COOH, they are _{independently,} C 1 -C ₆ alkyl, _{halogen, -OH, -OCH 3, -OCH 2} CH 3, halomethyl (dihalomethyl, tri _{Halomethyl, -NH 2, -NO 2, -CN} , -NC, -C (= NH) (NH 2), - SH, -COOH, independently from the group consisting -COOCH ₃ and -COOCH ₂ CH ₃ Selection Optionally substituted with one or more functional groups;
However, the compound represented by the formula (I) is represented by the formula (IV):

Wherein R ₁₀ and R ₁₅ are each independently C ₁ -C ₆ alkyl;
R ₁₁ , R ₁₂ and R ₁₃ are each independently hydrogen or C ₁ -C ₆ alkyl;
R is hydrogen or —C (O) — (CH ₂ ) _m —Q (where Q is hydrogen or —COOH and m is an integer 1, 2, 3 or 4);
Z is a thio, oxy or methylene group;
A is _C 1 -C ₄ alkylene group;
R ₁₄ and R ₁₆ are each independently C ₁ -C ₆ alkyl or — (CH ₂ ) _n — (Ar) (where n is an integer 0, 1, 2 or 3; and Ar is hydroxy, methoxy , Ethoxyl, halogen, trifluoromethyl, C ₁ -C ₆ alkyl or —NR ₁₇ R _18, wherein R ₁₇ and R ₁₈ are each independently hydrogen or C ₁ -C ₆ alkyl. Is unsubstituted or substituted phenyl or naphthyl with 1 to 3 substituents selected from: provided that at least one of R ₁₁ or R ₁₄ or R ₁₆ is C ₁ -C ₆ alkyl And when Ar is not substituted with trifluoromethyl or —NR ₁₇ R ₁₈ , R is not a compound represented by —C (O) — (CH ₂ ) _m —Q)]. Ru A method for the prophylactic or therapeutic treatment of a disease or disorder related to vascular health comprising administering a compound or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. X ₁ and X ₂ are independently selected from the group consisting of oxy and dimethyl-silyl; R ₁ is methylene; R ₂ and R ₃ are hydrogen, R ₄ , R ₅ , R ₆ and R ₇ are independently It is selected from the group consisting of hydrogen and tert- butyl; and R ₈ and R ₉ are independently method of claim 1, wherein a is selected from the group consisting of hydroxy and methoxy. The method of claim 1 wherein R ₄ and R ₅ are tert-butyl and R ₈ is hydroxy. An effective amount of formula (II) for treating a disease or disorder associated with vascular health:

Wherein X ₁ and X ₂ are independently selected from the group consisting of thio, oxy and dialkyl substituted silyl;
R ₁ is C ₁ -C ₄ alkyl;
R ₂ and R ₃ are independently selected from the group consisting of H and C ₁ -C ₄ alkyl;
R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of H, methoxy and branched or straight chain C ₁ -C ₆ alkyl; and R ₈ and R ₉ are independently hydrogen, hydroxy, trifluoromethyl, halide, amine, alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroarylthio acryloyl, -O _(C 1 -C ₆ alkyl), - OCO- (H or _C 1 -C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C _{8 alkyl) -COOH, - (C 2 -C} 8 _{alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH Oyo It is selected from -CO- _(C 2 -C ₆ alkenyl) group consisting of -COOH;
Here, the substituent of R ₈ or R ₉ is alkyl, alkenyl, aryl, heteroaryl, alkanoyl, aryloyl, heteroaryloyl, —O (C ₁ -C ₆ alkyl), —OCO— (H or C ₁ — C _{7 alkyl), - OCO- (C 3 -C} 7 alkenyl), - OCO- (aryl), - OCO- (heteroaryl), - _(C 0 -C ₈ alkyl) -COOH, - _(C 2 -C _{8 alkenyl) -COOH, -OCO- (C 0 -C} 6 _{alkyl) -COOH, -OCO- (C 2 -C} 6 _{alkenyl) -COOH, -CO- (C 0 -C} 6 alkyl) -COOH or -CO - If it is _(C 2 -C ₆ alkenyl) -COOH, they are _{independently,} C 1 -C ₆ alkyl, _{halogen, -OH, -OCH 3, -OCH 2} CH 3, halomethyl (dihalomethyl, tri _{Halomethyl, -NH 2, -NO 2, -CN} , -NC, -C (= NH) (NH 2), - SH, -COOH, independently from the group consisting -COOCH ₃ and -COOCH ₂ CH ₃ Selection Optionally substituted with one or more functional groups;
However, the compound represented by the formula (I) is represented by the formula (IV):

Wherein R ₁₀ and R ₁₅ are each independently C ₁ -C ₆ alkyl;
R ₁₁ , R ₁₂ and R ₁₃ are each independently hydrogen or C ₁ -C ₆ alkyl;
R is hydrogen or —C (O) — (CH ₂ ) _m —Q (where Q is hydrogen or —COOH and m is an integer 1, 2, 3 or 4);
Z is a thio, oxy or methylene group;
A is _C 1 -C ₄ alkylene group;
R ₁₄ and R ₁₆ are each independently C ₁ -C ₆ alkyl or — (CH ₂ ) _n — (Ar), where n is an integer 0, 1, 2, or 3; and Ar is hydroxy, methoxy , Ethoxyl, halogen, trifluoromethyl, C ₁ -C ₆ alkyl or —NR ₁₇ R _18, wherein R ₁₇ and R ₁₈ are each independently hydrogen or C ₁ -C ₆ alkyl. Is unsubstituted or substituted phenyl or naphthyl with 1 to 3 substituents selected from: provided that at least one of R ₁₁ or R ₁₄ or R ₁₆ is C ₁ -C ₆ alkyl In the case where Ar is not substituted with trifluoromethyl or —NR ₁₇ R ₁₈ , R is not a compound represented by —C (O) — (CH ₂ ) _m —Q]
A method for prophylactic or therapeutic treatment of a disease or disorder related to vascular health, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of such treatment: . X ₁ and X ₂ are independently selected from the group consisting of thio and dimethyl-silyl; R ₁ is methylene; R ₂ and R ₃ are independently selected from the group consisting of hydrogen and methyl; R ₄ , R ₅ , R ₆ and R ₇ are independently selected from the group consisting of hydrogen and tert-butyl; and R ₈ and R ₉ are independently selected from the group consisting of hydrogen, hydroxy, methoxy and butanedioate And wherein R ₈ and R ₉ are not both hydroxy when X ₁ and X ₂ are both thio. The method of claim 4 wherein R ₄ and R ₅ are tert-butyl and R ₈ is hydroxy. X ₁ and X ₂ are thio; R ₁ is methylene; R ₂ and R ₃ are methyl; R ₄ , R ₅ , R ₆ and R ₇ are tert-butyl; R ₈ is hydroxy; R ₉ is butanedio 5. The method of claim 4, wherein the method is art. An effective amount of formula (V) for treating a disease or disorder associated with vascular health:

[Where G is:

Wherein Y ₁ is —H, C ₁ -C ₄ alkyl or C ₃ -C ₆ alkenyl;
Y ₂ is —H, C ₁ -C ₄ alkyl, or C ₃ -C ₆ alkenyl, aryl, heteroaryl, aryloyl, alkanoyl or heteroaryloyl;
Y ₃ is —H, —CN and C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl or heteroaryl;
Y ₄ represents (CH ₂ ) _n (where n is 0 to 4) or C ₂ -C ₆ alkenyl;
Y ₅ is NH, (CH 2) _n (where n is 0 to 4) or C ₂ -C ₆ alkenyl;
Y ₆ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
Y ₇ is H, C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, or NH Y ₈ ;
Y ₈ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
Y ₉ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl or heteroaryl;
Y ₁₀ is alkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
L is _C 1 -C ₆ alkyl or _C 2 -C ₆ alkenyl)
Is selected from the group consisting of; and G are _{independently, -F, -Cl, -Br, -I} , -NH 2, -OH, -CN, -SH, -CH 3, -CH 2 CH 3, - It may be further substituted with one or more substituents selected from the group consisting of CF ₃ , —OCH ₃ , —OCH ₂ CH ₃ , —COOH, —COOCH ₃ and —COOCH ₂ CH ₃ ]
A method for prophylactic or therapeutic treatment of a disease or disorder related to vascular health, comprising administering to a subject in need of such treatment a compound represented by:   9. The method according to any one of claims 1 to 8, wherein the disease or disorder associated with vascular health is selected from the group consisting of major cardiac adverse events, vascular access dysfunction and male erectile dysfunction.   The method according to any one of claims 1 to 9, wherein the subject is selected from the group consisting of hemodialysis patients, end-stage renal disease patients or diabetic patients.   The subject has an increased oxidative burden or increased oxidative stress, a subject with a vascular access shunt or transplant, or a subject suffering from diabetes and experiencing erectile dysfunction or seeking prophylactic therapy 11. A method according to any one of the preceding claims, characterized in that it is.   12. The method according to any one of claims 1 to 11, wherein the subject is a human.   13. The method according to any one of claims 1 to 12, wherein the compound is administered orally to the subject.   About 1 mg to about 10 g of the compound is administered to the subject per day in single, divided or continuous doses to achieve a plasma concentration of the compound that is therapeutically effective for the treatment 14. A method according to any one of claims 1-13.   About 0.1 g to about 3 g of the compound is administered to the subject per day in single, divided or sequential doses to achieve a plasma concentration of the compound that is therapeutically effective for the treatment. The method according to any one of claims 1 to 13.   9. The method of any one of claims 1 to 8, wherein the disease or disorder associated with vascular health is a major cardiac adverse event.   17. The method of claim 16, wherein the subject is a subject with increased oxidative burden or increased oxidative stress.   The method of claim 16, wherein treatment comprises reducing the risk of occurrence of the major cardiac adverse event.   17. The method of claim 16, wherein the method identifies the subject as having an increased oxidative burden or increased oxidative stress.   17. The method of claim 16, wherein the subject has a normal lipid level or a normalized lipid level.   9. The method of any one of claims 1 to 8, wherein the disease or disorder associated with vascular health is vascular access dysfunction.   22. The method of claim 21, wherein the subject is a hemodialysis patient and the compound is administered directly after hemodialysis.   24. The method of claim 21, wherein the subject suffers from end stage renal disease.   23. The method of claim 21, wherein the vascular access dysfunction is associated with arteriovenous shunt stenosis.   9. The method of any one of claims 1 to 8, wherein the disease or disorder associated with vascular health is erectile dysfunction.   26. The method of claim 25, wherein the subject is diabetic distress from erectile dysfunction.   26. The method of claim 25, wherein the treatment is given prophylactically.   26. The method of claim 25, wherein the treatment is a combination treatment comprising a phosphodiesterase inhibitor as the second active ingredient. Formula (V):

[Where G is:

Wherein Y ₁ is —H, C ₁ -C ₄ alkyl or C ₃ -C ₆ alkenyl;
Y ₂ is —H, C ₁ -C ₄ alkyl, or C ₃ -C ₆ alkenyl, aryl, heteroaryl, aryloyl, alkanoyl or heteroaryloyl;
Y ₃ is —H, —CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl or heteroaryl;
Y ₄ is (CH ₂ ) _n (where n is 0 to 4) or C ₂ -C ₆ alkenyl;
Y ₅ is NH, (CH 2) _n (where n is 0 to 4) or C ₂ -C ₆ alkenyl;
Y ₆ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
Y ₇ is H, C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, or NH Y ₈ ;
Y ₈ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
Y ₉ is C ₁ -C ₄ alkyl, C ₃ -C ₆ alkenyl, aryl or heteroaryl;
Y ₁₀ is alkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl;
L _is, C 1 -C ₆ alkyl or _C 2 -C ₆ alkenyl; and G are _{independently, -F, -Cl, -Br, -I} , -NH 2, -OH, -CN, -SH, - _{CH 3, -CH 2 CH 3,} -CF 3, -OCH 3, -OCH 2 CH 3, -COOH, further with one or more substituents selected from the group consisting -COOCH ₃ and -COOCH ₂ CH ₃ substituents Or a salt or hydrochloride thereof and a pharmaceutically acceptable excipient.   30. A pharmaceutical composition according to claim 29, wherein said compound of formula (V) is formulated for oral administration in a self-emulsifying drug delivery system.   Lactose, calcium phosphate, kaolin, glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin, olive oil, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, gum arabic, dispersant, wetting agent and augmentation 30. The pharmaceutical composition according to claim 29, further comprising one or a member of the group consisting of a viscous agent.   32. A pharmaceutical composition according to any one of claims 29 to 31 further comprising one or more other active ingredients useful for the prophylactic or therapeutic treatment of major cardiac adverse events.   32. The pharmaceutical composition according to any one of claims 29 to 31, further comprising one or more other active ingredients useful for prophylactic or therapeutic treatment of vascular access dysfunction. 32. The pharmaceutical composition according to any one of claims 29 to 31, further comprising one or more other active ingredients useful for preventive or therapeutic treatment of erectile dysfunction.

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