KR20100097098A - Methods and compounds for treating retinol-related diseases - Google Patents

Abstract

Compounds that reduce serum retinol levels are used to treat ophthalmic conditions that are associated with overproduction of waste products that accumulate during the visual cycle process. We describe for example methods, compounds and compositions for treating macular degeneration and dystrophies or for alleviating the symptoms associated with such ocular conditions.

Description

METHODS AND COMPOUNDS FOR TREATING RETINOL-RELATED DISEASES}

Cross Reference of Related Application

This application claims the benefit of US Provisional Application No. 60 / 975,765, entitled Methods and Compounds for Treating Retinol Related Diseases, filed September 27, 2007, the disclosure of which is incorporated herein by reference in its entirety.

The methods and compositions described herein are for treating retinol related diseases in a subject by modulating the activity or availability of serum retinol, retinol binding protein (RBP) and / or transthyretin (TTR) in the subject. .

Retinoids are essential for the maintenance of normal growth, development, immunity, reproduction, vision and other physiological processes. In contrast, abnormal production or processing of retinoids correlates with the manifestation of the disease.

For example, more than 100 million of the world's children are suffering from vitamin A deficiency and death. Accumulation of excess vitamin A in target organs and tissues, such as the eye, can also lead to blindness in many retinal diseases, including macular degeneration. Many pathologies commonly referred to as vitreoretinal diseases (eg, retinopathy, macular degeneration and dystrophies) affect the vitreous and retina that are present at the back of the eye. Macular degeneration is a group of eye diseases that are the leading cause of blindness in the population over the age of 55 in the United States, with more than 10 million Americans now suffering from this disease. According to some studies, judging from the epidemic of the disease, the number of patients with macular degeneration over the next decade will increase by six times. Age-related macular degeneration or dystrophy is a particularly debilitating disease, which leads to progressive loss of vision and eventually to severe damage to central vision.

There are two categories of age-related macular degeneration: wet and dry. Dry form of macular degeneration, which accounts for about 90% of all cases, is also known as atropic, nonexudative or drusenoid macular degeneration. In the dry form of macular degeneration, drusen typically accumulates under RPE tissue in the retina. Thereafter, vision loss can occur if drusen interferes with the function of the photoreceptor in the macula. As a result, this form of macular degeneration results in gradual loss of vision over the years.

Macular degeneration in wet form, which accounts for about 10% of cases, is also known as choroidal neovascularization, subretinal angiogenesis, exudative or discoid degeneration. In wet form of macular degeneration, abnormal blood vessel growth may form below the macular; These blood vessels can leak blood and enter body fluids into the macula, damaging photoreceptor cells. Studies have shown that dry macular degeneration can lead to wet macular degeneration. Wet form macular degeneration can proceed rapidly and cause serious damage to central vision.

Described herein are methods, compounds, and compositions for treating retinol related diseases in human subjects or patients. Such diseases include macular degeneration, macular dystrophy and retinal dystrophy, including dry form of macular degeneration, superficial atrophy and / or photoreceptor degeneration. Also described herein are methods, compounds, and compositions for treating hyperretinolemia (excess serum retinol levels) in human subjects or patients. Also described herein are methods, compounds and compositions for lowering levels of serum retinol, serum RBP (retinol binding protein) and / or serum TTR (transthyretin) in human subjects or patients. Also described herein are methods, compounds, and compositions for treating vitreoretinal diseases to lower the level of serum retinol in a patient's body. In some embodiments, the vitreoretinal disease is macular degeneration, macular dystrophy and retinal dystrophy. In some embodiments, the vitreoretinal disease is dry form macular degeneration, photoreceptor degeneration, superficial atrophy, macular dystrophy, diabetic retinopathy, wet form macular degeneration, prematurity retinopathy and / or pigmented retinitis.

In one aspect, a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof; And pharmaceutically acceptable excipients:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, sec-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisostere,-(C = O) -NR ¹ R, NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) -OR or-(C ₁ -C ₇ ) alkyl- (C═O) -NR ¹ R Is;

이고;R is H or

ego;

G is -OR ¹ ,-(C ₁ -C ₆ ) alkyl,-(C ₁ -C ₆ ) alkyl-OR ¹ , halogen, -CO ₂ R ¹ ,-(C ₁ -C ₆ ) alkyl-CO ₂ R ¹ , NHR ¹ ,-(C ₁ -C ₆ ) alkyl-NHR ¹ ,-(C = O) NHR ¹ ,-(C ₁ -C ₆ ) alkyl- (C = O) NHR ¹ , -NHR ¹ (C ═O) R ¹ , — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ;

R ¹ is H or (C ₁ -C ₆ ) alkyl;

X is halogen. In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition for systemic administration of a compound of formula (I).

In one embodiment, there is provided a compound having the structure of Formula (II): or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof; And pharmaceutically acceptable excipients:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

이며;R is H or

Is;

G is -OR ¹ ,-(C ₁ -C ₆ ) alkyl,-(C ₁ -C ₆ ) alkyl-OR ¹ , halogen, -CO ₂ R ¹ ,-(C ₁ -C ₆ ) alkyl-CO ₂ R ¹ , NHR ¹ ,-(C ₁ -C ₆ ) alkyl-NHR ¹ ,-(C = O) NHR ¹ ,-(C ₁ -C ₆ ) alkyl- (C = O) NHR ¹ , -NHR ¹ (C ═O) R ¹ , — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ;

R ¹ is H or (C ₁ -C ₆ ) alkyl. In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition for systemic administration of a compound of formula (II).

를 가진 화합물이다. 또 다른 구체예로는, 구조

를 가진 화합물이다.In another embodiment is a pharmaceutical composition comprising a compound having the structure of Formula (II) wherein A is O. In a further embodiment, a medicament comprising a compound having the structure of formula (II) wherein B is-(CH ₂ ) _n and n is 1-6 or B is-(C ₃ -C ₈ ) cycloalkyl Pharmaceutical composition. In yet another embodiment, E is (C═O) —OR, a carboxylic acid bioisotope, — (C═O) —NR ¹ R, — (C ₁ -C ₇ ) alkyl- (C═O) A pharmaceutical composition comprising a compound having the structure of Formula (II) wherein -OR or-(C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R. In one embodiment, a compound having the structure of Formula (II) wherein A is O, B is (C ₃ -C ₈ ) cycloalkyl, E is (C═O) —OR, and R is H It is a pharmaceutical composition comprising a. In a further embodiment, B is cyclohexyl and R is H. In yet further embodiments, B is cyclopentyl and R is H. In still further embodiments, the structure

It is a compound having. In another embodiment, the structure

It is a compound having.

인 일반식 (II)의 구조를 가진 화합물을 포함하는 약제학적 조성물이다.In one embodiment, R is

A pharmaceutical composition comprising a compound having the structure of phosphorus general formula (II).

In another embodiment is a pharmaceutical composition comprising a compound having the structure of Formula (II) wherein E is (C═O) —OR. In a further embodiment is a pharmaceutical composition comprising a compound having the structure of formula (II) wherein R is H. In yet further embodiments, 5- (2-tert-butyl-4-chlorophenoxy) -N- (4-hydroxyphenyl) pentanamide, 7- (2-tert-butyl-4-chlorophenoxy C) -N- (4-hydroxyphenyl) heptanamide, 4- (5- (2-tert-butyl-4-chlorophenoxy) pentaneamido) benzoic acid, 4- (3-((2-tert- Butyl-4-chlorophenoxy) methyl) cyclopentaneamido) benzoic acid, 5- (2-tert-butyl-4-chlorophenoxy) pentanoic acid, 4- (2-tert-butyl-4-chlorophenoxy) Butanoic acid, 2- (3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentyl) acetic acid, 7- (2-tert-butyl-4-chlorophenoxy) heptanoic acid, 4- ( 5- (2-tert-butyl-4-chlorophenoxy) pentaneamido) benzamide, 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclohexanecarboxylic acid, 3-((2- tert-butyl-4-chlorophenoxy) methyl) cyclopentanecarboxylic acid, 3-((2-tert-butyl-4-chlorophenylamino) methyl) cyclopentanamide, 4- (3-((2-tert-butyl 4-chlorophenoxy) methyl) cyclopentanecarboxamido) benzoic acid 5- (2-tert- butyl-4-chlorophenylthio) a composition comprising a compound of formula (I) selected from the group consisting of pentanoic acid.

In one embodiment is a pharmaceutical composition comprising a compound of formula (I) that inhibits the retinol-retinol binding protein-transtyretin complex formation, wherein the IC ₅₀ of inhibition is less than about 5 μM. In a further embodiment is a pharmaceutical composition comprising a compound of formula (I) wherein the IC ₅₀ of inhibition is less than about 1 μM. In another embodiment is a pharmaceutical composition comprising a compound of formula (I) that inhibits cytochrome P ₄₅₀ to less than about 50%. In yet another embodiment is a pharmaceutical composition comprising a compound of formula (I) that inhibits cytochrome P ₄₅₀ to less than about 10%. In another embodiment is a pharmaceutical composition comprising a compound of formula (I) for use in treating a vitreoretinal disease. In a further embodiment, the vitreoretinal disease is a group consisting of macular degeneration of the dry form, photoreceptor degeneration, superficial atrophy, macular dystrophy, diabetic retinopathy, macular degeneration of the wet form, prematurity retinopathy and retinitis pigmentosa. It is a pharmaceutical composition containing the compound of general formula (I) selected from.

In one aspect, a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof; And pharmaceutically acceptable excipients or carriers:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, sec-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl or optionally substituted heteroaryl;

X is halogen. In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition for systemic administration of a compound of formula (I).

In one embodiment, there is provided a compound having the structure of Formula (II): or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof; And pharmaceutically acceptable excipients or carriers:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl, (C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl or optionally substituted heteroaryl. In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition for systemic administration of a compound of formula (II).

를 가진 화합물 또는 그의 활성 대사산물 또는 약제학적으로 허용가능한 전구약물, 염 또는 용매화물; 및 약제학적으로 허용가능한 부형제 또는 담체를 포함하는 약제학적 조성물이다. 또 다른 구체예로는, 구조

를 가진 화합물 또는 그의 활성 대사산물 또는 약제학적으로 허용가능한 전구약물, 염 또는 용매화물; 및 약제학적으로 허용가능한 부형제 또는 담체를 포함하는 약제학적 조성물이다.In one embodiment, a compound having the structure of Formula (II) wherein A is O, B is (C ₃ -C ₈ ) cycloalkyl, E is (C═O) —OR, and R is H Or active metabolites or pharmaceutically acceptable prodrugs, salts or solvates thereof; And pharmaceutically acceptable excipients or carriers. In a further embodiment, a compound having the structure of formula (II) wherein A is O, B is cyclohexyl, and R is H, or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof ; And pharmaceutically acceptable excipients or carriers. In yet another embodiment, a compound having the structure of formula (II) wherein A is O, B is cyclopentyl, and R is H, or an active metabolite or pharmaceutically acceptable prodrug, salt or Solvates; And pharmaceutically acceptable excipients or carriers. In still further embodiments, the structure

A compound having or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof; And pharmaceutically acceptable excipients or carriers. In another embodiment, the structure

A compound having or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof; And pharmaceutically acceptable excipients or carriers.

In another embodiment is a pharmaceutical composition comprising a compound of formula (I) in an amount sufficient to modulate serum retinol or ocular retinol levels or activity in a mammal.

In one aspect, the method comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof, Treatment of dry macular degeneration, photoreceptor degeneration, superficial atrophy, macular dystrophies, diabetic retinopathy, wet macular degeneration, prematurity retinopathy or pigment retinopathy in patients:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

X is halogen. In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one embodiment, there is a need for administering to a patient a therapeutically effective amount of a compound of formula (II): or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof, Treatment of dry form macular degeneration, photoreceptor degeneration, superficial atrophy, macular dystrophies, diabetic retinopathy, wet form macular degeneration, prematurity retinopathy, or pigmented retinitis

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In one embodiment, a therapeutically effective amount of a compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one aspect, a mammal is provided with a therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof that modulates retinol binding protein levels or activity in a mammal. A method of treating vitreoretinal disease, comprising administering to an animal:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

X is halogen. In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one embodiment, there is provided a therapeutically effective amount of a compound of formula (II) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof that modulates retinol binding protein levels or activity in a mammal. A method of treating vitreoretinal disease, comprising administering to a mammal:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl, (C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In one embodiment, a therapeutically effective amount of a compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In another embodiment is a method of treating a vitreoretinal disease wherein a therapeutically effective amount of a compound of Formula (I) or (II) is administered to a mammal, wherein the retinol binding protein is RBP4. In a further embodiment, the method comprises administering to a mammal a therapeutically effective amount of a compound of formula (I) or (II) in dry form macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophy , Diabetic retinopathy, wet form macular degeneration, prematurity retinopathy and pigmented retinitis.

In one aspect, a therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvent thereof, that modulates serum retinol binding protein or transthyretin level or activity in a mammal A method of lowering serum retinol binding protein or transthyretin level or activity in a mammal, comprising administering a cargo:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

X is halogen. In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one aspect, a therapeutically effective amount of a compound of formula (II) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvent thereof that modulates serum retinol binding protein or transthyretin level or activity in a mammal A method of lowering serum retinol binding protein or transthyretin level or activity in a mammal, comprising administering a cargo:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl, (C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In one embodiment, a therapeutically effective amount of a compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In another embodiment, the method comprises administering a therapeutically effective amount of a compound of Formula (I) or (II), wherein the serum retinol binding protein or transthyretin level in a mammal wherein the serum retinol binding protein is RBP4. Or a method of lowering activity. In one embodiment, the method comprises administering a therapeutically effective amount of a compound of formula (I) or (II) to inhibit the transcription of a retinol binding protein or transthyretin in a mammal, the serum retinol in the mammal A method of lowering binding protein or transthyretin level or activity. In a further embodiment, the method comprises administering a therapeutically effective amount of a compound of formula (I) or (II) to inhibit the transcription of a retinol binding protein or transthyretin in a mammal, wherein the serum retinol in the mammal is A method of lowering binding protein or transthyretin level or activity. In another embodiment, the method comprises administering a therapeutically effective amount of a compound of Formula (I) or (II) to inhibit the binding of retinol to a retinol binding protein, wherein the serum retinol binding protein or trans in a mammal. It is a method of lowering tyretin level or activity. In one embodiment, the method comprises administering a therapeutically effective amount of a compound of formula (I) or (II) to inhibit the binding of a retinol binding protein to transtiren, or the serum retinol binding protein in a mammal. It is a method of lowering transthyretin level or activity. In another embodiment, serum retinol binding in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or (II) to increase the retinol binding protein or transthyretin removal rate in the mammal. A method of lowering protein or transthyretin levels or activity.

In one aspect, there is provided a method of treating a mammal in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof: Here's how to treat retinol-related diseases:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

X is halogen. In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one embodiment, retinol-associated in a mammal comprises administering a therapeutically effective amount of a compound of formula (II): or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof Here's how to treat a disease:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In one embodiment, a therapeutically effective amount of a compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In another embodiment, a method of treating a retinol related disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II), wherein the retinol related disease is Hyperostosis, idiopathic intracranial hypertension, amyloidosis, Alzheimer's disease and Alstrom-Halgren syndrome.

In one aspect, a therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof, which does not directly modulate the activity of an enzyme or protein in the visual cycle: A method of reducing serum retinol levels in a mammal with dry form of age related macular degeneration, comprising administering to the mammal:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

X is halogen. In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one embodiment, a therapeutically effective amount of a compound of formula (II) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvent thereof, which does not directly modulate the activity of an enzyme or protein in the visual cycle A method of reducing serum retinol levels in a mammal with dry form of age related macular degeneration, comprising administering a cargo:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In one embodiment, a therapeutically effective amount of a compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In another embodiment, age-related macular degeneration in dry form, comprising administering to a mammal a compound of formula (I) or (II) that does not directly inhibit or bind an enzyme or protein in the visual cycle. To reduce serum retinol levels in mammals with

In a further embodiment, serum retinol in a mammal having dry form of age-related macular degeneration, comprising administering to the mammal a compound of formula (I) or (II) that does not affect rhodopsin regeneration rate. It is a way to reduce the level.

In another embodiment, serum retinol levels in a mammal having dry form of age-related macular degeneration, comprising administering to the mammal a compound of Formula (I) or (II) that does not worsen delayed dark adaptation. It is a way to reduce.

In still further embodiments, dry age-related macular degeneration, comprising administering to a mammal a compound of formula (I) or (II) that limits the spread of geographic atrophy or photoreceptor degeneration To reduce serum retinol levels in mammals with

In one aspect, hyperretinolemia, comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof: Here's how to cure:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

X is halogen. In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In another embodiment is a method of treating hyperretinolemia comprising administering a therapeutically effective amount of a compound of Formula (II): or an active metabolite or pharmaceutically acceptable prodrug or solvate thereof:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In one embodiment, a therapeutically effective amount of a compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In a further embodiment, there is a method of treating hyperretinolemia associated with vitreoretinal disease, comprising administering a compound of formula (I) or (II) to a mammal.

In another embodiment is a method of treating hyperretinolemia associated with diabetes or Alzheimer's disease, comprising administering a compound of formula (I) or (II) to a mammal.

In one aspect, the method comprises administering to a mammal an effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof, wherein ) Is a method of treating retinol related diseases in mammals, wherein the retinol-retinol binding protein-transtyretin complex formation is inhibited and the IC _5O inhibition is less than about 5 μM:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

X is halogen. In one embodiment, an effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one embodiment, the method comprises administering to a mammal an effective amount of a compound of formula (II) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof, wherein Is a method of treating retinol related diseases in mammals wherein the compound of II) inhibits retinol-retinol binding protein-transtyretin complex formation and IC _5O inhibition is less than about 5 μM:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In one embodiment, an effective amount of a compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one embodiment, the method comprises administering to a mammal an effective amount of a compound of formula (I) or (II), wherein the compound of formula (I) or (II) is a retinol-retinol binding protein- A method of treating retinol related diseases in mammals that inhibits the formation of transtyretin complexes and wherein IC ₅₀ inhibition is less than about 1 μM.

In another embodiment, the method comprises administering to a mammal an effective amount of a compound of formula (I) or (II), wherein the compound of formula (I) or (II) is a retinol-retinol binding protein- A method of treating retinol-related diseases in a mammal, wherein the composition of the formula (I) or (II) further inhibits cytochrome P ₄₅₀ by less than about 50%.

In another embodiment, the method comprises administering to a mammal an effective amount of a compound of formula (I) or (II), wherein the compound of formula (I) or (II) is a retinol-retinol binding protein- A method of treating retinol-related diseases in a mammal, wherein the composition of the formula (I) or (II) further inhibits cytochrome P ₄₅₀ by less than about 10%.

In one aspect, a therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt thereof, which modulates retinol binding protein or transthyretin level or activity in a mammal, or A method of treating Type I or Type II diabetes in a mammal, comprising administering a solvate to the mammal:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

X is halogen. In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one embodiment, a therapeutically effective amount of a compound of formula (II) or an active metabolite or pharmaceutically acceptable prodrug, salt thereof, that modulates retinol binding protein or transthyretin level or activity in a mammal Or administering a solvate to the mammal, the method of treating type I or type II diabetes in a mammal:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In one embodiment, a therapeutically effective amount of a compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one aspect, a method of treating a mammal in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) and / or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof A method of reducing serum retinol or ocular retinol levels is:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

X is halogen. In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In one embodiment, the method comprises administering to a mammal a therapeutically effective amount of a compound of formula (II) and / or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof To reduce serum retinol or ocular retinol levels in:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In one embodiment, a therapeutically effective amount of a compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

In another embodiment, the method comprises administering to a mammal an effective amount of a compound of Formula (I) or (II), wherein the mammal is a human that reduces serum retinol or ocular retinol levels. It is a way.

A further embodiment comprises administering to the mammal an effective amount of a compound of Formula (I) or (II) and reducing serum retinol or ocular retinol levels by at least 20%. Retinol or eye tissue retinol levels are reduced.

Still further embodiments include administering to a mammal an effective amount of a compound of Formula (I) or (II), the method comprising inducing nitric oxide production inducing agents, anti-inflammatory agents, physiologically acceptable antioxidants, physiological At least one additional agent selected from the group consisting of acceptable minerals, negatively charged phospholipids, carotenoids, statins, angiogenesis inhibitors, matrix metalloproteinase inhibitors, resveratrol and other trans-stilbene compounds and 13-cis-retinoic acid A method for reducing serum retinol or ocular retinol levels in a mammal, further comprising administering a.

In one aspect, there is a composition comprising a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl, provided that-(C ₂ -C ₇ ) heteroalkyl is a nitrogen atom, -C (= O)-, -S-, -S (= O)-, -S (= O) _2- , -NR ¹ (C = O)-,-(C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -0 (C = O) NR ^1- , -NR ¹ (C = O) O-, -0 (C = O) O- , -NR ¹ (C═O) NR ¹ —, — (C═O) O—, —0 (C═O) — may not contain;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^1- (C = 0) -R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, - (C 1 -C 7) alkyl, ^{- (C = O) -NR 1} R, C 1 -C 4 Alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, heteroaryl, substituted heteroaryl, substituted aryl, arylalkyl, -C (O) R ² , hydroxy- (C ₁ -C ₆ Alkyl), aryloxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, —0-C (O) NR ² R ³ , -NR ² R ³ (C═O) OR ¹ , -SO ₂ NR ² R ³ , provided that heteroaryl cannot contain nitrogen atoms;

R ² and R ³ are each independently H, C ₁ -C ₆ alkyl and C ₃ -C ₆ Selected from cycloalkyl;

R is H, optionally substituted aryl or optionally substituted heteroaryl, provided that when B is -S-, R cannot be pyrimidine; When B is-(C ₂ -C ₇ ) alkyl R cannot be imidazole;

R ¹ is H or (C ₁ -C ₆ ) alkyl;

X is halogen,

일 수 없다.Where E is

Cannot be

In one embodiment is a composition comprising a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl; Provided that-(C ₂ -C ₇ ) heteroalkyl is a nitrogen atom, -C (= O)-, -S-, -S (= O)-, -S (= O) _2- , -NR ¹ (C = O)-,-(C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -0 (C = O) NR ^1- , -NR ¹ ( May contain C═O) O—, —0 (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O—, —0 (C═O) — No;

D is tert-butyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^1- (C = 0) -R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, - (C 1 -C 7) alkyl, ^{- (C = O) -NR 1} R, C 1 -C 4 Alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, substituted aryl, arylalkyl, -C (O) R ² , hydroxy- (C ₁ -C ₆ Alkyl), aryloxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, -OC (O) NR ² R ³ , -NR ² R ³ (C = O) OR ¹ , -SO ₂ NR ² R ³ ;

R ² and R ³ are each independently H, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Selected from cycloalkyl;

R is H, optionally substituted aryl or optionally substituted heteroaryl, provided that when B is -S-, R cannot be pyrimidine; When B is-(C ₂ -C ₇ ) alkyl R cannot be imidazole;

R ¹ is H or (C ₁ -C ₆ ) alkyl;

X is Cl;

However, the compound of general formula (I) cannot be a dimer.

The pharmaceutical composition comprises a compound of formula (I) and a pharmaceutically acceptable carrier or excipient:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl; Provided that-(C ₂ -C ₇ ) heteroalkyl is a nitrogen atom, -C (= O)-, -S-, -S (= O)-, -S (= O) _2- , -NR ¹ (C = O)-,-(C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -0 (C = O) NR ^1- , -NR ¹ ( May contain C═O) O—, —0 (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O—, —0 (C═O) — No;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^1- (C = 0) -R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, - (C 1 -C 7) alkyl, ^{- (C = O) -NR 1} R, C 1 -C 4 Alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, substituted aryl, arylalkyl, -C (O) R ² , hydroxy- (C ₁ -C ₆ Alkyl), aryloxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, -OC (O) NR ² R ³ , -NR ² R ³ (C = O) OR ¹ , -SO ₂ NR ² R ³ ;

R ² and R ³ are each independently H, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Selected from cycloalkyl;

R is H, optionally substituted aryl or optionally substituted heteroaryl, provided that when B is -S-, R cannot be pyrimidine; When B is-(C ₂ -C ₇ ) alkyl R cannot be imidazole;

R ¹ is H or (C ₁ -C ₆ ) alkyl;

X is halogen;

However, the compound of general formula (I) cannot be a dimer. In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition for systemic administration of a compound of formula (I).

In some embodiments, E is (C═O) —OR, —0- (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisotope, — (C═O) -NR ¹ R, NR ^1- (C═O) —R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, or - is a (C = O) -NR ¹ R composition - (C ₁ -C ₇₎ alkyl. In another embodiment, a composition wherein X is Cl and D is isopropyl, tert-butyl or cyclopropyl. In further embodiments are compositions wherein D is tert-butyl and X is Cl. In some embodiments, a composition wherein B is — (CH ₂ ) _n and n is 1-6 or B is — (C ₃ -C ₈ ) cycloalkyl. In some embodiments is a composition where A is zero. In another embodiment is a composition wherein A is NH or S.

In some embodiments, herein comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) or an active metabolite or composition of a pharmaceutically acceptable prodrug, salt or solvate The disclosed methods of treatment are:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl; Provided that-(C ₂ -C ₇ ) heteroalkyl is a nitrogen atom, -C (= 0)-, -S-, -S (= 0)-, -S (= 0) _2- , -NR ¹ (C = O)-,-(C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -0 (C = O) NR ^1- , -NR ¹ (C Cannot contain -O-, -0 (C = O) O-, -NR ¹ (C = O) NR ¹ -,-(C = O) O-, -0 (C = O)- ;

D is tert-butyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^1- (C = 0) -R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, - (C 1 -C 7) alkyl, ^{- (C = O) -NR 1} R, C 1 -C 4 Alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ Alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, substituted aryl, arylalkyl, -C (O) R ² , hydroxy- (C ₁ -C ₆ Alkyl), aryloxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, -OC (O) NR ² R ³ , -NR ² R ³ (C = O) OR ¹ , -SO ₂ NR ² R ³ ;

R ² and R ³ are each independently H, C ₁ -C ₆ Alkyl and C ₃ -C ₆ cycloalkyl;

R is H, optionally substituted aryl or optionally substituted heteroaryl, provided that when B is -S-, R cannot be pyrimidine; When B is-(C ₂ -C ₇ ) alkyl R cannot be imidazole;

R ¹ is H or (C ₁ -C ₆ ) alkyl;

X is Cl; Provided that the compound of formula (I) may not be a dimer.

In one aspect, a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where

A is O;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl; Provided that-(C ₂ -C ₇ ) heteroalkyl is a nitrogen atom, -C (= 0)-, -S-, -S (= 0)-, -S (= 0) _2- , -NR ¹ (C = O)-,-(C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -0 (C = O) NR ^1- , -NR ¹ (C Cannot contain -O-, -0 (C = O) O-, -NR ¹ (C = O) NR ¹ -,-(C = O) O-, -0 (C = O)- ;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^1- (C = 0) -R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, - (C 1 -C 7) alkyl, ^{- (C = O) -NR 1} R, C 1 -C 4 Alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ Alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, substituted aryl, arylalkyl, -C (O) R ² , hydroxy- (C ₁ -C ₆ Alkyl), aryloxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, -OC (O) NR ² R ³ , -NR ² (C = O) OR ¹ or -SO ₂ NR ² R ³ ;

R ² and R ³ are each independently H, C ₁ -C ₆ Alkyl and C ₃ -C ₆ cycloalkyl;

R is H,-(C ₂ -C ₇ ) alkyl, optionally substituted aryl or optionally substituted heteroaryl, provided that when B is -S-, R cannot be pyrimidine; When B is-(C ₂ -C ₇ ) alkyl R cannot be imidazole;

R ¹ is H or (C ₁ -C ₆ ) alkyl;

X is halogen.

In some embodiments is a compound of Formula (I) wherein B is — (CH ₂ ) _n and n is 1-6 or B is — (C ₃ -C ₈ ) cycloalkyl. In another embodiment, E is (C═O) —OR, a carboxylic acid bioisotope, — (C═O) —NR ¹ R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR or — (C ₁ -C ₇ ) alkyl- (C═O) -NR ¹ R. In a further embodiment is a compound of formula (I) wherein D is isopropyl, tert-butyl or cyclopropyl. In some embodiments, X is Cl and D is tert-butyl.

In another embodiment, a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where

A is NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^1- (C = 0) -R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, - (C 1 -C 7) alkyl, ^{- (C = O) -NR 1} R, C 1 -C 4 Alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ Alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, substituted aryl, arylalkyl, -C (O) R ² , hydroxy- (C ₁ -C ₆ Alkyl), aryloxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, -OC (O) NR ² R ³ , -NR ² (C = O) OR ¹ or -SO ₂ NR ² R ³ ;

R ² and R ³ are each independently H, C ₁ -C ₆ Alkyl and C ₃ -C ₆ cycloalkyl;

R is H,-(C ₂ -C ₇ ) alkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ¹ is H or (C ₁ -C ₆ ) alkyl;

X is halogen.

In some embodiments is a compound of Formula (I) wherein B is — (CH ₂ ) _n and n is 1-6 or B is — (C ₃ -C ₈ ) cycloalkyl. In another embodiment, E is (C═O) —OR, a carboxylic acid bioisotope, — (C═O) —NR ¹ R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR or — (C ₁ -C ₇ ) alkyl- (C═O) -NR ¹ R. In a further embodiment is a compound of formula (I) wherein D is isopropyl, tert-butyl or cyclopropyl. In some embodiments, X is Cl and D is tert-butyl.

Other objects, features and advantages of the methods, compounds and compositions disclosed herein will become apparent from the following detailed description. However, it is to be understood that the description and the specific examples, although indicative of specific embodiments, are provided by way of illustration only.

Dose-response relationship of test compound compared to fenretinide (HPR). The data show that the test compound (having a chemical structure consistent with Formula (I)) interferes with RBP4-TTR interaction approximately seven times more strongly than HPR (IC 5 _O = 0.1 vs. IC _{50 O,} respectively). = 0.7).
HPLC analysis of serum retinol. Mice were treated with compounds having the structure of DMSO or general formula (I). Serum was prepared by collecting whole blood from the tail vein. Serum samples were analyzed by HPLC. Representative chromatographic tracing is shown for mice receiving DMSO (Panel A) and mice receiving test compound (Panel B). Retinol peaks and their absorbance spectra are shown in plots.
Steady state serum concentrations of retinol and test compounds. Mice were administered daily doses (20 mg / kg / day, intraperitoneally, in DMSO) of test compounds having the structure of Formula (I). After 28 days of treatment, blood samples were taken and serum prepared for analysis by HPLC. Representative chromatograms are provided which show the presence of test compound (detection at 280 nm, dashed line) and retinol (detection at 325 nm, solid line).
Figure 4. Concentration quantitation and immunotaxin detection of RBP4. Western blot detection of RBP4 in the serum of mice treated with DMSO (top panel, lanes 1-5) or test compounds having a structure consistent with Formula (I) (Panel A, lanes 6-10). The pixel density of the bands shown in lanes 1-5 of Panel A was determined and the average pixel density was taken as 100%. Relative levels of RBP4 in mice treated with test compounds were also determined by pixel densitometry. These data are shown in bar graphs.
5. Chromatographic separation and identification of toxic retinal fluorophores. Lipid soluble components were extracted from the eyecup of abca4 null mutant mice (BL6 / 129, 6 months old). Eyecup extracts were analyzed by HPLC with on-line absorbance (solid line) and fluorescence (dashed line) detection. The indicated fluorophores (A2E precursor and A2E) were not present in age-matched wild type mice.
6. Genetic regulation of RBP4 in abca4 mutant mice: effects on serum retinol, RBP4 and toxic retinal fluorophores. Mouse strains expressing heterozygous mutations in RBP4 and ABCA4 (RBP4 +/-, ABCA4 +/-) to determine if genetic reduction of RBP4 is sufficient to reduce serum levels of retinol, RBP4 and toxic retinal fluorophore in RPE Produced. Serum retinol concentrations in RBP4 +/-, ABCA4 +/- mice were reduced by at least 50% compared to mice with normal complement of RBP (RBP4 + / +, ABCA4-/-). The extent of this retinol reduction corresponded to that observed in HPR-treated RBP4 + / +, ABCA4-/-mice (Panel A). As determined by immunoassay analysis, the decrease in serum retinol correlated directly with the decrease in RBP4. Western blot identification of RBP4 in various mouse strains is shown in Panel B. Histological analysis was also performed. Tissue sections from RBP4 + / +, ABCA4 +/− mice (panel C), RBP4 +/−, ABCA4 +/− (panel D) and RBP4 + / +, ABCA4 + / + (panel E) were analyzed by fluorescence microscopy. It was evident from this analysis that the lipofuscin fluorophore (indicated by the white arrow) was significantly reduced in mice with low steady state levels of RBP4 and retinol.
Dose-response relationship of test compound for fenretinide (HPR). The data were obtained from test compound 2 with chemical name 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclohexanecarboxylic acid and chemical name 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclo Test compound 3 with pentanecarboxylic acid is shown to be effective in interfering with RBP4-TTR interaction (IC ₅₀ = 0.25-0.70 μm).
8. Cytochrome P ₄₅₀ inhibition profile for test compounds and fenretinide (HPR). A panel of six cytochrome P ₄₅₀ isoenzymes was screened to test compound 2 with chemical compound 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclohexanecarboxylic acid and chemical name 3-((2- The potent toxicity associated with test compound 3) with tert-butyl-4-chlorophenoxy) methyl) cyclopentanecarboxylic acid and HPR (denoted 2 μM in this assay) was analyzed. The data show very little inhibition of cytochrome P ₄₅₀ isoenzymes by the test compounds.
9. Quantification of intraocular retinoids after treatment with test compounds. ATRP (control) or ATRP + SIR-1047 was administered to ABCA4-/-mice daily for 20 days (n = 3 per group). On the last day of administration, traces of [ ³ H] ATROL (0.32 pmol, 8 μCi) in 100 μl corn oil were administered to all animals. After 5 hours, the eye was taken out. As described in this method, one eye of each animal was used for retinoid analysis and the other eye was used for analysis of A2E and related fluorophores. The data showed a significant decrease in [ ³ H] ATROL uptake in animals treated with the test compound. Analysis of each retinoid species reveals a significant reduction in precursor substrate (ATRE) for visual chromophore biosynthesis and immediate precursor (AT-Ox) for A2E biosynthesis.
10. Effect of test compounds to reduce total fluorophore levels in ABCA4-/-mice. Mice were treated as described in FIG. 1 (above). At the end of the study, one eye from each animal was used to measure total fluorophore levels. In summary, one whole eye was homogenized in 1 ml phosphate buffered saline (50 mM Na ₂ HPO ₄ , 150 mM NaCl, pH 7.8). After homogenization, 1 ml methanol was added and the samples mixed thoroughly. The mixture was incubated at room temperature for 5 minutes and extracted twice with 2 mL hexanes. The extract was concentrated to about 400 μl for fluorescence measurements. The collected fluorescence spectra were obtained using a Spex Fluorolog-3 spectrofluorometer (Jobin Yvon Horiba, Edison, NJ) operated in ratio mode. Samples were excited at 488 nm and monitored at 500-700 m. The data show a significant decrease in total fluorophore levels in mice treated with the test compound.
11. Effect of test compound on reducing A2E and A2E precursor A2PE-H2 in ABCA4-/-mice. Mice were treated as described in FIG. 1 (above). At the end of the study, one eye from each animal was used to measure A2E and A2PE-H2. In summary, one whole eye was homogenized in 1 ml phosphate buffered saline (50 mM Na ₂ HPO ₄ , 150 mM NaCl, pH 7.8). After homogenization, 1 ml methanol was added and the samples mixed thoroughly. The mixture was incubated at room temperature for 5 minutes and extracted twice with 2 mL hexanes. The solvent was evaporated under a stream of nitrogen and the sample residue was reconstituted in 200 μl isopropanol (IPA) for analysis by HPLC. Zorbax RX-Sil 5-μm equilibrated with phospholipid mobile phase (hexane: IPA: ethanol: 25 mM phosphate buffer: acetic acid 485: 376: 100: 37.5: 0.275 v: v) at a flow rate of 1 ml / min. Separate on column (250 x 4.6-mm). The data show that both A2E and its precursors were dramatically reduced in mice treated with test compounds as compared to vehicle-treated mice.

Details of the methods and compositions disclosed herein will be described for reference. Examples of embodiments are described in the following embodiments.

Interestingly, compounds of formulas (I) and (II) are used to provide benefits to patients suffering from or susceptible to various vitreoretinal diseases, including but not limited to macular degeneration and dystrophies. Compounds of Formulas (I) and (II) provide these patients with at least one of the following benefits: reduction in serum retinol or RBP levels, control of transthyretin levels, reduction in drusen formation, retinol-retinol Reduction of binding protein complex formation and reduction of retinol-binding protein-transtyretin complex formation. As used herein, RBP refers to protein RBP4.

Also included is the use of the compounds of formulas (I) and (II) as prophylactic treatment for wet form of age related macular degeneration. In addition, compounds of formulas (I) and (II) provide additional therapeutic effects on wet form of age-related macular degeneration because these compounds additionally have angiogenesis inhibitory activity.

Visual cycle

Vertebrate retinas have two types of photoreceptor cells: rods and abstracts. The rod is responsible for visual action under low light conditions. Abstracts are less sensitive and provide a high degree of temporal and spatial resolution and color perception. Under daylight conditions, the rod reaction is saturated so that vision is entirely mediated by the abstract. Both types of cells have a structure called extinction that includes stacked disc disks. The reaction of visual transmission takes place on the surface of these discs. The first stage of vision is photon absorption by opsin-pigment molecules (rhodosin), which is involved in the isomerization of chromophores from 11-cis to all-trans. Before the photosensitivity is recoverable, the produced all-trans-retinal must be converted back to 11-cis-retinal in a multi-enzymatic process that occurs in retinal epithelial cells, a cell monolayer adjacent to the retina.

Macular or retinal degeneration and dystrophy

Macular degeneration (also called retinal degeneration) is an ocular disease that involves the degeneration of the macula, the central part of the retina. Approximately 85 to 90% of cases of macular degeneration are in the "dry" (atrophic or non-angiogenic) form. In dry form of macular degeneration, retinal degeneration is associated with the formation of small yellow deposits known as drusen under the macula; The accumulation of lipofucin in RPE also leads to photoreceptor degeneration and geographic atrophy. This phenomenon causes thinning and drying of the macula. The location and extent of retinal thinning caused by drusen correlates directly with the degree of central vision loss. Degeneration of the photoreceptor covered with drusen and the pigment layer of the retina is atrophy and gradually loses central vision. As a result, damage to the retinal pigment epithelium and lower photoreceptor cells causes lead atrophy. Administering at least one compound having the structure of Formula (I) or (II) to a mammal reduces or limits the diffusion of photoreceptor degeneration and / or geographic atrophy in the mammal's eye. By way of example only, administration of a compound of formula (I) or (II) to a mammal can be used to treat photoreceptor degeneration and / or geographic atrophy in the mammal's eye.

In the case of “wet” form of macular degeneration, new blood vessels are formed (ie, angiogenesis) to improve blood supply to the retinal tissue, particularly the macula under which the retina is involved in keen central vision. These new blood vessels are susceptible to damage and are sometimes destroyed, causing bleeding and damaging surrounding tissues. Wet macular degeneration occurs in only about 10% of cases of macular degeneration, but accounts for about 90% of macular degeneration related blindness. Angiogenesis can lead to rapid vision loss and, optionally, scar formation and intraocular bleeding into the retinal tissue. Such scar tissue and bleeding blood form dark, distorted areas of vision and often lead to legal blindness. Macular degeneration in wet form primarily begins with distortion of the central field of view. Straight lines are also bent. Many people with macular degeneration have blurred vision and even blind spots. Growth promoter proteins called vascular endothelial growth factor or VEGF have been targeted to induce such abnormal vascular growth in the eye. These results enable aggressive research into experimental drugs that inhibit or block VEGF. Studies have shown that anti-VEGF agents can also be used to block and prevent abnormal blood vessel growth. These anti-VEGF agents stop or inhibit VEGF stimulation, allowing blood vessels to grow less. Such anti-VEGF agents may be successful in inhibiting angiogenesis or blocking vascular leakage and the ability of VEGF to induce blood vessel growth under the retina. In one embodiment, administering to the mammal at least one compound having the structure of Formula (I) or (II) reduces the formation or diffusion of wet form of age-related macular degeneration in the eye of the mammal. Limited. By way of example only, administration of a compound of formula (I) or (II) to a mammal is used to treat wet form of age related macular degeneration in the eye of a mammal. Likewise, the compounds of formula (I) or (II) are used to treat choroidal neovascularization and abnormal angiogenesis under the macular of the mammalian eye. In one embodiment, these therapeutic benefits include lowering serum retinol and intraocular retinol levels; Resulting from a number of effects, such as angiogenesis inhibitory activity and / or inhibition of directed atrophy.

Stargardt's disease is macular dystrophies that occur in childhood and manifest as degenerative macular degeneration. See, eg, Allikmets et al., Science, 277: 1805-07 (1997); Lewis et al., Am. J. Hum. Genet, 64: 422-34 (1999); Stone et al., Nature Genetics, 20: 328-29 (1998); Allikmets, Am. J. Hum. Gen., 67: 793-799 (2000); Klevering, et al., Ophthalmology, 111: 546-553 (2004). Stargardt's disease is characterized by a gradual loss of central vision clinically and by progressive atrophy of the RPE covering the macula. Mutations in the human ABCA4 gene for Rim Protein (RmP) are involved in Stargardt's disease. In the early stages of the disease, the patient is delayed in cancer adaptation but normal in rod function. Histologically, Stargardt's disease is associated with the deposition of lipofuscin pigment granules in RPE cells.

The prevalence of ABCA4 mutations in AMD is still unclear, but mutations in ABCA4 are also degenerative pigment retinitis (see, eg, Cremers et al., Hum. Mol. Genet., 7: 355-62 (1998)). , Degenerative abstract-interlaced dystrophies [Reference, Homologous] and non-exudative age-related macular degeneration [Reference, Allikmetset al., Science, 277: 1805-07 (1997)); Lewis et al., Am. J. Hum. Genet., 64: 422-34 (1999). Stone et al., Nature Genetics, 20: 328-29 (1998); Allikmets, Am. J. Hum. Gen., 67: 793-799 (2000); Klevering, et al., Ophthalmology, 111: 546-553 (2004). These diseases, like Stargard's disease, are associated with delayed adaptation of rods. See Steinmetz et al., Brit. J. Ophthalm., 77: 549-54 (1993). In addition, lipofuscin deposition in RPE cells is mainly referred to AMD (Kliffenet al., Microsc. Res. Tech., 36: 10622 (1997)) and for some pigmented retinitis (Bergsmaet). al., Nature, 265: 6267 (1977). In addition, an autosomal dominant form of Stargardt disease is caused by mutations in the ELOV4 gene. Karan, et al., Proc. Natl. Acad. Sci. (2005).

There are also several forms of macular degeneration that affect children, adolescents, or adults commonly known as early onset or juvenile macular degeneration. Most of these forms are genetic and appear to be macular dystrophies instead of degeneration. Some examples of macular dystrophies include star-gardert disease, as well as abstract-spinal dystrophies, corneal dystrophies, Fuch's dystrophies, Sorsby's macular dystrophies, Best Disease and childhood. Interretinal separation.

Regulation of vitamin A levels

Vitamin A (all-trans retinol) is an important cellular nutrient that cannot be synthesized in vivo and must be obtained from food. The name vitamin A is a generic name and can be attached to any compound having biological activity, including the binding activity of retinol. One equivalent of retinol (RE) refers to the specific biological activity of 1 μg of all-trans retinol (3.33 IU) or 6 μg of beta-carotene (10 IU). Beta-carotene, retinol and retinal (vitamin A aldehyde) all have effective and robust vitamin A activity. Each of these compounds is derived from carotene, a member of the molecular family known as carotenoids, which are plant precursor molecules. Beta-carotene, which consists of two retinol molecules, each linked to the aldehyde end, is also referred to as the provitamin form of vitamin A.

Ingested β-carotene is cleaved by β-carotene dioxygenase in the intestinal lumen to be retinal. Retinal is reduced to retinol in the intestine by retinaldehyde reductase (NADPH required enzyme) and then esterified with palmitic acid.

After digestion, retinol in the food is transported to the liver where the lipid aggregates are bound. Belovino et al., Mol. Aspects Med., 24: 411-20 (2003). Once transported to the liver, retinol complexes with the retinol binding protein (RBP) and is then secreted into the bloodstream. Retinol-RBP holo-protein must bind to transthyretin (TTR) before being transported to target tissue outside the liver, such as the eye [Zanotti and Berni, Vitam. Horm., 69: 271-95 (2004). This is a secondary complex that allows retinol to remain in the bloodstream for a long time. Binding to TTR promotes the release of RBP from hepatocytes, which prevents the RBP-retinol complex from being filtered by the kidneys. The retinol-RBP-TTR complex is delivered to target tissues that absorb retinol and use it for various intracellular processes. The process of transporting retinol cells through the bloodstream by the RBP-TTR complex is the main pathway where cells and tissues require retinol.

Retinol uptake into cells from the complexed retinol-RBP-TTR form occurs by binding of RBP to cellular receptors present on target cells. This interaction triggers the inclusion of the RBP-receptor complex, which results in retinol release from the complex or retinol binding to intracellular retinol binding protein (CRBP), which results in the release of apoRBP into the plasma by the cell. do. Another route is believed to be due to an alternative mechanism in which retinol is introduced into the cell, for example, an alternative mechanism in which only retinol is absorbed into the cell. See Blomhoff (1994) for reference.

The methods, compounds and compositions described herein are useful for modulating levels of vitamin A in mammalian subjects. In particular, the level of vitamin A can be regulated by modulating the availability or activity of retinol binding protein (RBP) and transthyretin (TTR) in mammals. The methods, compounds and compositions described herein modulate RBP and TTR levels or activity in mammalian subjects, and as a result, modulate levels of vitamin A. Increasing or decreasing the levels of vitamin A in a subject can affect the availability of retinol in target organs and tissues. Therefore, by providing a means of regulating the availability of retinol and retinol derivatives, it is possible to control the pathology of the disease caused by local or non-enriched retinol or retinol derivatives in target organs and tissues. In addition, the therapeutic methods described herein are used for the treatment of hyperretinolemia, where excess serum retinol levels are associated with symptoms related to vitreoretinal disease or vitreoretinal disease (eg, the formation of lipofucin or drusen). cause.

For example, A2E, the main fluorophore of lipofuscin, is due to overproduction of the visual cycle retinoid all-trans-retinaldehyde, A2E precursor, macular or retinal degeneration or dystrophies, eg age related macular degeneration and star It is formed in the case of Legard disease. Therefore, the reduction of vitamin A and all-trans retinaldehyde in the retina will be advantageous for the reduction of A2E and lipofucin accumulation and for the treatment of age-related macular degeneration.

Thus, modulators that inhibit retinol delivery to cells by disrupting the binding of apoRBP and retinol or the binding of holo-RBP (RBP + retinol) and its transport protein TTR or by increasing the kidney excretion of RBP and TTR (eg, Compounds of Formulas (I) and (II)) will be useful for reducing serum vitamin A levels and accumulation of retinol and derivatives thereof in target tissues such as the eye.

Similarly, modulators affecting the availability of retinol transport proteins, retinol binding proteins (RBPs) and transthyretin (TTR) may include serum vitamin A levels and accumulation and physical signs of retinol and its derivatives in target tissues such as the eye. It may be useful to reduce physical manifestation. For example, TTR is a component of the drusen construct, suggesting that TTR is directly involved in age-related macular degeneration [Mullins, RF, FASEB J. 14: 835-846 (2000); Pfeffer BA, et al., Molecular Vision 10: 23-30 (2004).

Through the same approach as regulating RBP and / or TTR levels or activity in mammals, metabolic disorders such as type I or type II diabetes (obesity and / or obesity), IIH, bone related disorders such as bone formation It is expected to find use in the treatment of hyperplasia, protein misfolding and aggregation disorders, such as systemic amyloidosis and Alzheimer's disease, and Alstrom-Halgren syndrome.

Thus, one embodiment of the methods, compounds and compositions described herein provides RBP or TTR levels in a mammal by administering to the mammal a therapeutically effective amount of at least one of the compounds of Formula (I) or Formula (II). Or to modulate activity.

Retinol binding protein ( RBP ) And transthyretin ( TTR )

The retinol binding protein RBP consists of a single polypeptide chain and has a molecular weight of about 21 kD. RBP is cloned and sequenced, as a result of which the amino acid sequence is determined [Colantuni et al., Nuc. Acids Res., 11: 7769-7776 (1983). Through the three-dimensional structure of RBP, its specialized hydrophobic pockets designed to bind and protect the fat-soluble vitamin retinol were identified (Newcomer et al., EMBO J., 3: 1451-1454 (1984)). In in vitro experiments, it was found that cultured hepatocytes synthesize and secrete RBP (Blaner, W.S., Endocrine Rev., 10: 308-316 (1989)). In subsequent experiments, it was demonstrated that many cells contain mRNA of RBP, suggesting that RBP is synthesized in various places in the body. See Blancer (1989). Most of the RBP secreted by the liver contains retinol in a molar ratio of 1: 1. In order for RBP to be secreted normally, retinol and RBP must be combined.

In cells, RBP binds firmly to retinol present in the endoplasmic reticulum, where RBP is found in high concentrations. When retinol binds to RBP, retinol-RBP begins to be translocated from the endoplasmic reticulum to the Golgi complex, thereby secreting retinol-RBP from the cells. RBP secreted from hepatocytes also helps transport retinol from hepatocytes to stellate cells, where retinol-RBP is directly secreted into the plasma.

In plasma, about 95% of plasma RBP binds to transthyretin (TTR) in a molar ratio of 1: 1, where almost all of the plasma vitamin A is bound to RBP. TTR consists of four identical subunits with a molecular weight of 54,980 Daltons and is a well characterized plasma protein. Through the full three-dimensional structure estimated by X-ray diffraction, it can be seen that the protein has an extended β-sheet structure arranged in tetrahedral form [Blake et al., J. Mol. Biol., 121: 339-356 (1978). There is a passage in the center of the tetramer where two thyroxine binding sites exist. However, due to negative cooperativity, it is understood that only one thyroxine molecule normally binds to TTR. The complexation process of TTR and RBP-retinol reduces the filtering of retinol through glomeruli, increasing the half-life of retinol and RBP in plasma by about three times.

On target RBP  or TTR  Control of binding or removal rate

Retinol bound to RBP must complex with TTR before being transported into the bloodstream for delivery to the eye. By forming such secondary complexes, retinol can remain in the bloodstream for a long time. Without TTR, the retinol-RBP complex is rapidly excreted in the urine. Similarly, without RBP, the retinol transport in the bloodstream and the uptake by cells will be reduced.

Thus, another embodiment described herein is to modulate the availability of RBP or TTR in the blood stream to complex with retinol or retinol-RBP by modulating RBP or TTR binding properties or clearance. As mentioned above, when TTR binds to RBP holo-protein, the removal rate of RBP and retinol is reduced. Thus, by modulating the availability or activity of RBP or TTR, retinol levels will also be regulated in subjects in need thereof.

For example, antagonists for the binding of retinol to RBP are used in the methods, compounds and compositions described herein. Antagonists for the binding of retinol to RBP include compounds of general formula (I) or (II) that compete with the binding of retinol and RBP.

As mentioned herein, one means of regulating the binding of retinol to RBP is to competitively bind a compound of formula (I) or (II). Thus, one embodiment of the methods and compositions described herein is a compound having a structure of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvent thereof that modulates RBP levels or activity Decreases RBP levels or activity through cargo:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl or optionally substituted heteroaryl;

X is halogen.

Another embodiment of the methods and compositions described herein comprises a compound having a structure of formula (II) below or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof that modulates RBP levels or activity. Decreases RBP levels or activity through:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ¹ - (O = C) -R, - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

이며;R is H or

Is;

G is -OR ¹ ,-(C ₁ -C ₆ ) alkyl,-(C ₁ -C ₆ ) alkyl-OR ¹ , halogen, -CO ₂ R ¹ ,-(C ₁ -C ₆ ) alkyl-CO ₂ R ¹ , NHR ¹ ,-(C ₁ -C ₆ ) alkyl-NHR ¹ ,-(C = O) NHR ¹ ,-(C ₁ -C ₆ ) alkyl- (C = O) NHR ¹ , -NHR ¹ (C ═O) R ¹ , — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ;

R ¹ is H or (C ₁ -C ₆ ) alkyl.

Detection of Modulator Activity

In some embodiments, the compounds and compositions described herein can also be used in assays to detect disruptions in RBP or TTR availability via conventional means. For example, a subject can be treated with any of the compounds or compositions described herein, and conventional assay techniques can be used to quantify RBP or TTR levels. See Sundaram, M., et al., Biochem. J. 362: 265-271 (2002). For example, typical noncompetitive sandwich assays include those disclosed in US Pat. No. 4,486,530, which is incorporated herein by reference. In this method, a sandwich complex, eg an immune complex, is formed in an assay medium. The complex includes a binding member that binds to the first antibody, or analyte, and the second antibody, or a binding agent that binds to the complex of the analyte or analyte and the first antibody, or a binding agent. do. A sandwich complex is then detected, which is related to the presence and / or amount of the analyte in the sample. The sandwich complex is detected due to the presence of a label complex, wherein either or both of the first and second antibodies, or binding agents, contain a label or a substituent capable of binding to the label. For example, a sample for detecting control of RBP or TTR clearance may be plasma, blood, stool, tissue, mucus, tears, saliva or urine. For a more detailed description of this approach, see US Pat. Nos. 29,169 and 4,474,878, the disclosures of which are incorporated herein by reference.

In a variation of the sandwich assay, a sample in a suitable medium is contacted with a labeled antibody or binding agent for the analyte and incubated for a period of time. The medium is then contacted with a support to which the second antibody or binding source for the analyte is bound. After the incubation period, the unbound reagent is removed by washing the support off the medium. Investigate whether a label is present on the support or medium, wherein the presence of the label is related to the presence or amount of the analyte. For a more detailed description of this approach, see US Pat. No. 4,098,876, the relevant disclosure of which is incorporated herein by reference.

In some embodiments, the modulators described herein can also be used in in vitro assays for detecting the rate of change in RBP or TTR activity. For example, modulators are added to samples that include RBP, TTR and retinol. Labeling of components, such as RBP, TTR, retinol or modulators, can be used to detect whether the complex formation has collapsed. Complex formation and subsequent complex destruction can be detected and / or measured through conventional means, eg, sandwich assays as described above. In addition, other detection systems, such as FRET detection methods for RBP-TTR-retinol complex formation, can also be used to detect modulators of RBP or TTR binding. See U.S. Provisional Patent Application 60 / 625,532 ("Fluorescence Assay for Modulators of Retinol Binding"), which is incorporated herein by reference.

In addition, other potent modulators, including but not limited to small molecules, polypeptides, nucleic acids, and antibodies, may also be screened using the in vitro detection methods described above. For example, the methods and compositions described herein may be used to screen small molecule libraries, nucleic acid libraries, peptide libraries or antibody libraries as described herein. Methods for screening libraries, such as the combinatorial and other libraries disclosed above, are described, for example, in US Pat. No. 5,591,646; 5,866,341; 5,866,341; And 6,343,257, which are incorporated herein by reference.

Adjuster activity In vivo  detection

In addition to the in vitro methods described above, in some embodiments, the methods and compositions described herein are also used in conjunction with in vivo detection and / or quantification of modulator activity on TTR or RBP availability. For example, labeled TTR or RBP can be injected into a subject, where candidate modulators can be added before, during or after injection of the labeled TTR or RBP. The subject may be a mammal, eg, a human; Other mammals such as primates, horses, dogs, sheep, goats, rabbits, mice or rats are also additional examples. The biological sample is then removed from the detected label and subject to determine TTR or RBP availability. Biological samples may include, but are not limited to, plasma, blood, urine, feces, mucus, tissue, tears or saliva. Detection of labeled reagents described herein can be carried out using any of the conventional methods known to those skilled in the art, depending on the nature of the label. Examples of devices for monitoring chemi-luminescence, radiolabel and other labeling compounds are described in US Pat. No. 4,618,485, the disclosure of which is incorporated herein by reference in its entirety; 5,981,202.

Hyperretinolemia

Retinol is a fat-soluble sulfate agent vitamin. Retinol at an appropriate level is important for vision and bone growth, but can be a problem if present in excess. Hyperretinolemia is the presence of synergistic or abnormal levels of retinol in the blood, including type I and type II diabetes, hyperostosis, such as diffuse idiopathic skeletal hyperostosis (DISH), and vitreoretinal disease It is thought to be related to diseases and conditions such as macular degeneration. The methods, compounds, and compositions described herein that reduce levels of retinol in the blood are used to treat such diseases and conditions. In addition, the methods, compounds, and compositions disclosed herein are effective in reducing retinol availability in target organs and tissues, such as the eye. By decreasing blood retinol concentrations, the availability of retinol in organs such as the liver can regulate the formation of retinol-retinol-binding protein complexes and / or the formation of retinol-retinol-binding protein-transtyretin complexes. In one embodiment, a method of treating a patient with hyperretinolemia, comprising administering a therapeutically effective amount of a compound of Formula (I) or (II) to reduce serum levels or activity of retinol .

Metabolic disorders

Metabolic disorders, including type I and type II diabetes (obesity and / or obesity) are also associated with abnormal retinol levels.

Type I diabetes (insulin-dependent diabetes)

Type I diabetes is severe among diabetes. If left untreated, patients with type I diabetes develop ketosis and rapid degeneration. Approximately 10 to 20% of diabetics, primarily composed of young people, are classified as type I diabetes. A small but non-obese adult may develop type I diabetes.

Type I diabetes is a catabolic disease in which there is little insulin in the bloodstream and elevated levels of glucagon in plasma. Type I diabetes is thought to be an autoimmune disease, possibly caused by infection of the pancreatic B cells of the affected individual or by an attack of a harmful environment. In support of the theory of autoimmunity, autoantibodies against insulin and islet cells are detected in patients with type I diabetes, unlike individuals without diabetes.

In children with type I diabetes, retinol binding protein (RBP) levels decrease, the amount of RBP released into the urine increases, and retinol levels decrease. See Basu, TK, et al., Am. J. Clin. Nutr. 50: 329-331 (1989); Durbey, SW et al., Diabetes Care 20: 84-89 (1997). Lower retinol and RBP levels also reduce zinc metabolism, an essential factor in the synthesis of RBP in hepatocytes. See Cunningham, JJ, et al., Metabolism 42: 1558-1562 (1994). In contrast, there is no change in tocopherol or vitamin E levels in patients with type I diabetes. See Basu, TK et al (1989).

Although the level of vitamin A in liver storage cells is increased, the level of retinol is lowered. Tuitoek PJ, et al., Br. J. Nutr. 75: 615-622 (1996). Studies demonstrating the association between vitamin A status and insulin secretion have shown that only insulin treatment can restore the level of vitamin A that has been reduced in type I diabetes patients [Tuitoek, PJ et al., J. Clin . Biochem. Nutr. 19: 165-169 (1996). Conversely, nutritional supplementation of vitamin A may not normalize the metabolic availability of vitamin A.

These studies demonstrate that there is a correlation between vitamin A and insulin-controlled glucose transported to muscle and adipocytes. Further studies have underlined this correlation by demonstrating the need for vitamin A for normal insulin secretion. See Chertow, BS, et al., J. Clin. Invest. 79: 163-169 (1987). Retinol was found to be required to release insulin from vitamin A deficient perfusion islet cells. In vivo experiments showed that vitamin A-deficient rats impaired the glucose-induced acute insulin release process, which was improved only by feeding vitamin A. Vitamin A can secrete insulin by promoting transglutaminase activity in islet and insulin-secreting cells [Driscoll HK, et al., Pancreas 15: 69-77 (1997)], and this vitamin A is fetal Is not only required for islet cell differentiation, but also to prevent glucose intolerance in adults [Matthews, KA et al., J. Nutr. 134: 1958-1963 (2004)], which is also required to enhance the role of vitamin A and retinol in the regulation of blood glucose levels and insulin release in diabetic patients. Disclosed herein are methods, compounds, and compositions for treating type I diabetes using compounds of formula (I) or (II) that modulate the levels and activities of retinol and / or RBP.

II Type Diabetes (Insulin- Independence  diabetes)

Type II diabetes is a heterogeneous group of diabetes with milder symptoms. Type II diabetes usually occurs in adults, but can sometimes occur in childhood.

Type II diabetes is usually insensitive to insulin as glucose levels in the plasma rise. Less than 85% of patients with type II diabetes are obese and are insensitive to endogenous insulin in proportion to the presence of fat in the abdomen. The cause of insulin insensitivity is the lack of post-receptors involved in insulin action. This is associated with a decrease in the ability to remove nutrients from the expanded cellular storage depots (eg, expanded adipocytes and overnourished liver and muscle cells) and the post-prandial blood stream. If insulin is oversecreted then intracellular insulin receptors may be further downregulated. In addition, glucose transport proteins (eg, GLUT4) are also downregulated with sustained activation, which further exacerbates the patient's condition due to hyperglycemic symptoms.

In contrast to patients with type I diabetes, the level of RBP is selectively elevated in patients with type II diabetes, with elevated levels of observed retinol also common. Sasaki, H et al., “Am. J. Med. Sci. 310: 177-82 (1995); Basualdo CG, et al., J. Am Coll. Nutr. 16: 39-45 (1997); Abahausain, MA et al., Eur. J. Clin. Nutr. 53: 630-635 (1999), and retinoic acid (all-trans RA and 13-cis in patients with type II diabetes). RA) levels were also reduced [Yamakoshi, Y et al., Biol. Pharm. Bull 25: 1268-1271 (2002)] Levels of vitamin E (tocopherol) and other vitamins, including carotenoids, and zinc, albumin and TTR ( Levels of vitamin A, known to affect the metabolism of vitamin A, were unchanged in both diabetic and control groups.

This selective increase in RBP levels in type II diabetes is associated with the selective decrease in RBP in type I diabetes, which supports the role of RBP and vitamin A in regulating blood glucose levels by insulin. Increasing insulin levels (hyperinsulinemia) in diabetics also increases levels of RBP [Basualdo et al. (1997). RBP levels are also associated with hyperglycemia in patients. Retinoids have already been shown to increase insulin sensitivity in humans. See Hartmann, D. et al., Eur. J. Clin. Pharmacol. 42: 523-8 (1992). The inverse correlation between RBP levels and insulin sensitivity in type I diabetes and type II diabetes suggests a therapeutic tool for controlling insulin sensitivity in mammalian subjects.

Retinol binding protein 4 ( RBP  4)

Retinol binding protein 4 (RBP4) is a protein secreted from adipocytes, known to transport vitamin A. Studies have shown that elevated serum RBP4 levels can help mark early stages of development of insulin resistance, a major cause of type II diabetes. Kahn et al., 354 New Eng. J. Med. 2552-63 (2006). In addition, experiments in mice have shown that elevated RBP4 levels cause insulin resistance. In addition, serum RBP4 levels correlate with the magnitude of insulin resistance in patients with obesity or type II diabetes with impaired glucose tolerance and in obese nondiabetic patients with a rich family history of type II diabetes. Elevated serum RBP4 is associated with components of metabolic syndrome, including body-mass index, waist-to-hip ratio, increased serum triglyceride levels and systolic blood pressure, and decreased high-density lipoprotein cholesterol levels.

In addition, studies have suggested that the amount of RBP4 in the blood reflects the amount of fat around the abdominal organs, which can be used as a biomarker of cardiovascular risk. As the level of RBP4 increases, the level of "abdominal fat" leads to an increased risk for heart disease and type II diabetes, because the increase in "abdominal fat" is associated with cardiovascular risk. In addition, studies have shown that gene expression of RBP4 is more increased in visceral adipose tissue (adipose tissue surrounding internal organs) than in subcutaneous adipose tissue. Thus, the level of RPB4 is higher in people with "built-in" obesity than those with subcutaneous obesity.

Provided herein are compounds of Formulas (I) and (II) that reduce excess serum levels of RBP4. In one embodiment is a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof which reduces serum levels of RBP4:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

이고;R is H or

ego;

G is -OR ¹ ,-(C ₁ -C ₆ ) alkyl,-(C ₁ -C ₆ ) alkyl-OR ¹ , halogen, -CO ₂ R ¹ ,-(C ₁ -C ₆ ) alkyl-CO ₂ R ¹ , NHR ¹ ,-(C ₁ -C ₆ ) alkyl-NHR ¹ ,-(C = O) NHR ¹ ,-(C ₁ -C ₆ ) alkyl- (C = O) NHR ¹ , -NHR ₁ (C ═O) R ¹ , — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O);

R ¹ is H or (C ₁ -C ₆ ) alkyl;

X is halogen.

In another embodiment is a compound of formula (II) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof that reduces serum levels of RBP4:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl, (C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

이며;R is H or

Is;

G is -OR ¹ ,-(C ₁ -C ₆ ) alkyl,-(C ₁ -C ₆ ) alkyl-OR ¹ , halogen, -CO ₂ R ¹ ,-(C ₁ -C ₆ ) alkyl-CO ₂ R ¹ , NHR ¹ ,-(C ₁ -C ₆ ) alkyl-NHR ¹ ,-(C = O) NHR ¹ ,-(C ₁ -C ₆ ) alkyl- (C = O) NHR ¹ , -NHR ¹ (C ═O) R ¹ , — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ;

R ¹ is H or (C ₁ -C ₆ ) alkyl.

In another embodiment, administering to the patient a therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof that reduces serum levels of RBP4: Including, the method of treating diabetes in a patient:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl or optionally substituted heteroaryl;

X is halogen. In another embodiment, an ophthalmic condition in a patient, such as, for example, macular degeneration, is only included by administering to the patient a therapeutically effective amount of a compound of formula (I) or (II) to reduce the level of RBP4. How to treat it. In a further embodiment, a method of lowering RBP4 in serum, including administering a compound of Formula (I) or (II). Another further embodiment is a method of lowering RBP4 in a tissue such as adipose tissue, by way of example only, comprising administering a compound of Formula (I) or (II).

In one embodiment, treating a patient with type I or type II diabetes in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or (II) that modulates RBP4 in adipose tissue. It is a way. In a further embodiment, administering to the patient a therapeutically effective amount of a compound of formula (I) or (II) that reduces RBP4 levels such that a decrease in RBP4 levels increases insulin sensitization. This is a method for treating type I or type II diabetes. In another embodiment, a therapeutically effective amount of a compound of formula (II) or an active metabolite or pharmaceutically acceptable prodrug, salt thereof, wherein the RBP4 level is reduced such that a decrease in RBP4 level increases insulin sensitization Or administering a solvate to the patient, the method of treating type I or type II diabetes in the patient:

Where

A is O, NH or S;

B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl,-(C ₃ -C ₈ ) heterocycloalkenyl;

E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;

R is H, optionally substituted aryl or optionally substituted heteroaryl.

Idiopathic Cranial  High blood pressure ( IIH )

IIH, also known as pseudo brain tumor (PTC), is a condition in which high pressure is applied to the fluid surrounding the brain without a clear cause. This condition is most common in women of childbearing age. Symptoms begin or worsen with weight gain. Common symptoms include headache, pulse synchronous tinnitus and vision impairment (congestive papilla), which, if untreated, can cause serious and permanent blindness.

Although the etiology of IIH is not known, the excess of vitamin A may be due to the similar symptoms and signs of IIH when the dose of vitamin A is administered to subjects. The study showed that serum retinol levels were higher in IIH patients than in the control group, although there were no significant differences in vitamin A intake and retinyl ester concentrations in both IIH patients and controls. See Jacobson, DM et al, Neurology, 54: 2192-3 (1999). Included herein are methods, compounds, and compositions for treating IIH using compounds of formulas (I) and (II).

Bone Related Disorders

Hyperplasia is a condition in which bone grows excessively. This bed can form a large amount of protrusions in the normal bone that can be seen in many musculoskeletal disorders. Diffuse idiopathic skeletal hyperplasia (DISH) is a type of hyperplasia that is characterized by fluid lime deposition and bone formation in vertebrates. In patients with DISH, abnormalities, ie, radiodense shields are formed on the front of the spine, are observed mainly on the thoracic spine. Ossification of posterior longitudinal ligament (OPPL) is also a common phenomenon in DISH patients, and the cervical spine is damaged as a result of spinal ligament hyperplasia or bone formation. Other diseases that develop in patients with hyperplasia or DISH include acute fractures of the spine and pseudojoints.

The pathogenesis of DISH and OPLL is currently unknown, but these two diseases are associated with high levels of serum retinol and RBP. Predicting what role vitamin A might play in the pathogenesis of DISH and OPLL (Kodama, T et al., In vivo 12: 339-344 (1998); Kilcoyne, RF, J. Am. Acad. Dermatol. 19: 212-216 (1988). Other studies have shown that retinol and RBP levels are abnormal when congenital RBP deficiency develops in patients with hyperplasia. DeBandt, M., et al., J. Rheumatol. 22: 1395-8 (1995). According to the medical evaluation, degenerative joint disease was also reported in elderly people with vitamin A hyperactivity. See Roomero, JB et al., Bull Hosp. Jt. Dis. 54: 169-174 (1996). Thus, the methods, compounds and compositions described herein utilize compounds of the general formula (I) or (II) that modulate the levels of serum retinol and RBP, for example only to treat bone related disorders such as hyperplasia. Used.

protein Misfolding  And flocculation disease

Misfolding and aggregation of proteins are commonly associated with amyloidosis, for example Alzheimer's disease, Parkinson's disease and several diseases known as systemic amyloidosis. These diseases are caused when the secondary structure of a protein is misfolded, usually soluble proteins form insoluble extracellular fibrils deposits of β-sheet-rich structures, also known as amyloid fibrils, which cause dysfunction of organs. Cause Twenty different fibril proteins, such as transthyretin (TTR), are observed as different clinical forms in human amyloidosis, respectively.

Wild type TTR protein is involved in the development of sporadic impaired senile systemic amyloidosis caused by accumulation of TTR fibrils in heart tissue. In contrast, mutant TTR proteins are associated with familial amyloid polyneuropathy and cardiomyopathy, where the deposits primarily affect the peripheral and autonomic nervous system and heart. The mechanisms involved in tissue selective deposition are currently unknown. In the development of amyloidosis, TTR is associated with fibril formation in its monomeric form. Compounds that promote stabilization of TTR tetramers, such as small molecule resveratrol and biarylamines, inhibit amyloid fibril formation in vitro. Reixach, N. et al., PNAS 101: 2817-2822 (2004).

Transthyretin is also involved in Alzheimer's disease, but in contrast to forming amyloid fibrils in amyloidosis, TTR inhibits the formation of amyloid beta proteins in vitro and in vivo. Schwartzman, AL et al., Amyloid. 11: 1-9 (2004); Stein, TD and Johnson, JA, J. Neurosci. 22: 7380-7388 (2002). Vitamin A has also been shown to exhibit amyloidogenic and amyloid-beta fibril destabilizing effects in vitro. See Ono, K., et al., Exp. Neurol. 189: 380-392 (2004).

Cystic  fibrosis

Cystic fibrosis is the primary cause of death of pseudomonas aeruginosa ) is a lethal genetic disease caused by excess lung infections associated with recurrent bacterial infections. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The products of these genes are chloride ion channels that are important for producing sweat, digestive fluid and mucus. The CFTR gene is located at q31.2 of chromosome 7 and produces a protein of 1,480 amino acids in length. The common mutation, ΔF508, is a deletion of three nucleotides that lose the amino acid phenylalanine at position 508 of the protein. Subsequently, ΔF508 produces proteins that normally do not fold and are degraded by the cell. In addition, the protein produced by the CFTR gene acts as a chloride ion channel that connects the cytoplasm to the surrounding fluid. Mutations in the CFTR protein trap chloride ions outside the cell. The exclusion of chloride ions into the cytoplasm attracts sodium ions, and these bonds form salts that are lost in large quantities in the sweat of cystic fibrosis individuals. Some studies suggest that loss of CFTR protein increases sodium and chloride uptake, which increases resorption of moisture, leading to dehydration and large amounts of mucus.

The treatment of cystic fibrosis is focused on the treatment of lung damage caused by large amounts of mucus and infection. Antibiotics such as vancomycin and tobramycin are used when lung function is reduced. Nose steroids such as fluticasone have been used to reduce rhinitis. In other cases, sinus surgery is used to relieve nasal obstruction and limit further infection.

Control of ceramide levels appears to be important for the effective removal of bacteria from infected lungs. Disclosed herein is a method of treating cystic fibrosis comprising administering a compound of Formula (I) or Formula (II) to aid in the removal of loaded bacteria through the mediation of ceramide production. In some embodiments, a method of treating bacterial infections associated with cystic fibrosis, comprising administering a compound of Formula (I) or Formula (II) to assist in the removal of bacteria from an infected lung. In other embodiments, the bacteria are Gram-negative bacteria. In a further embodiment, the Gram-negative bacterium is pseudomonas aeruginosa . In another embodiment, a method of treating cystic fibrosis, comprising administering a compound of Formula (I) or Formula (II) to correct ceramide deficiency in a cystic fibrosis related organ. In another embodiment, the cystic fibrosis related organ is lung.

Alstrom - Hallgren  syndrome

Alstrom-Halgren's syndrome (also known as Alstrom's syndrome) is a rare autosomal degenerative disease that occurs in children at very young ages. Symptoms include: abstract-rod dystrophies, deafness, obesity in the first year of life, progression of type II diabetes and severe insulin resistance, melanoma (the appearance of dark patches on the skin), hypergonadal gonadotropia Childhood blindness or severe vision impairment, associated with hypergonadotrophic hypogonadism and thyroid deficiencies.

Mutations associated with Alstrom syndrome were ubiquitous in the 14.9 cM region on chromosome 2p [Collin, GB et al., Hum. Mol. Gen. 6: 213-219 (1997). Aside from treating the individual symptomatic symptoms of the disease, there are currently no therapeutic methods available for Alstrom syndrome patients. In some embodiments are methods, compounds, and compositions used to treat Alstrom-Halgren syndrome using compounds having the structures of Formulas (I) and (II).

Justice

An "alkoxy" group refers to a (alkyl) O- group where alkyl is as defined herein.

"Alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" group, meaning that it does not contain any alkene or alkyne moieties. The alkyl moiety may also be an "unsaturated alkyl" moiety, meaning that it contains at least one alkene or alkyne moiety. "Alkene" moiety means a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety means a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Whether saturated or unsaturated, the alkyl moiety can be branched, straight chain or cyclic.

"Alkyl" moieties may have from 1 to 10 carbon atoms (herein, numerical ranges such as "1 to 10" are each given as an integer; for example, "1 to 10 carbon atoms" is an alkyl group of up to 10 carbon atoms). Meaning that it may consist of one carbon atom, two carbon atoms, three carbon atoms, etc., up to and including carbon atoms, but the definitions given also include "alkyl" where the numerical range is not specified). The alkyl group may also be "lower alkyl" having 1 to 5 carbon atoms. The alkyl group of the compounds described herein may be represented by "C ₁ -C ₄ alkyl" or similar notation. By way of example only, "C ₁ -C ₄ Alkyl "means that there is 1 to 4 carbon atoms in the alkyl chain, ie the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Included but not limited to these.

The term "alkenyl" refers to the form of an alkyl group in which the first two atoms of the alkyl group form a double bond rather than an aromatic group portion. That is, the alkenyl group starts with the atom -C (R) = CR, where R refers to the remainder of the alkenyl group and can be the same or different. Non-limiting examples of alkenyl groups include -CH = CH, -C (CH ₃ ) = CH, -CH = CCH ₃ and -C (CH ₃ ) = CCH ₃ . The alkenyl moiety can be branched, straight or cyclic (also known as a "cycloalkenyl" group in this case).

"Amide" is the chemical moiety of the formula -C (O) NHR or -NHC (O) R, wherein R is alkyl, cycloalkyl, aryl, heteroaryl (bonded via ring carbon) and heteroalicyclic (ring carbon Combined through). Amides may be amino acid or peptide molecules that bind to compounds of formula (I) to form prodrugs. Any amine, hydroxy or carboxy side chain on the compounds described herein may be amidated. Processes and specific groups for preparing such amides are known to those skilled in the art and are described herein by Greene and Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New York, NY, 1999].

The term “aromatic” or “aryl” refers to an aromatic group containing at least one ring having a conjugated pi electronic system, and refers to carbocyclic aryl (eg phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic” ") Groups such as pyridine. The term includes monocyclic or fused-ring polycyclic (ie, rings which share adjacent pairs of carbon atoms) groups. The term "carbocyclic" refers to a compound having one or more covalently ringed structures and wherein the atoms that form the backbone of the ring are all carbon atoms. Thus, the term distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom other than carbon.

The term "cycloalkyl" refers to monocyclic or polycyclic radicals containing only carbon and hydrogen and which may be saturated, partially unsaturated or fully unsaturated. Cycloalkyl groups include groups having 3 to 10 reducers. Illustrative examples of cycloalkyl groups include the following moieties, and the like:

The term "halo" alternatively "halogen" means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.

The terms "heteroalkyl", "heteroalkenyl" and "heteroalkynyl" refer to optionally substituted atoms having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Alkyl, alkenyl and alkynyl radicals are included.

The term “heteroaryl” alternatively “heteroaromatic” refers to an aryl group comprising one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group wherein at least one of the ring backbone atoms is a nitrogen atom. Polycyclic heteroaryl groups may or may not be fused. Illustrative examples of heteroaryl groups include the following moieties and the like:

The term "part" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized as chemical entities attached to or within a molecule.

The term "bond" or "single bond" refers to a chemical bond between two atoms or two parts when the atoms connected by the bond are considered to be part of a larger infrastructure.

The term "carboxylic acid bioisotope" means a moiety capable of replacing carboxylic acid groups. Bioisotopes contain exchanges of other generally similar atoms or groups of atoms and maintain similar biological activity by mimicking spatial arrangement, electronic properties, or some other physicochemical properties of carboxylic acid groups. Thus, for example, tetrazole, sulfonic acid and sulfonamide are carboxylic acid bioisotopes.

The term “optionally substituted” means that the groups mentioned are alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, Amino and protected derivatives thereof, including thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, silyl and mono- and di-substituted amino groups It can be substituted by one or more additional group (s) selected individually and independently. Examples of protecting groups can be found in references such as Greene and Wuts, supra.

In some embodiments, a compound disclosed herein can have one or more chiral centers, each center can exist in an R or S configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, for example, by separation of the stereoisomers, for example by chiral chromatography columns.

The methods and formulations described herein include N-oxides, crystalline forms (also known as polymorphs) or pharmaceutically acceptable salts of compounds having the structure of formula (I) as well as those compounds having the same active form. The use of active metabolites. In some situations, compounds exist as tautomers. All tautomers are included within the scope of the compounds disclosed herein. In addition, the compounds disclosed herein may exist in unsolvated or solvated form with a pharmaceutically acceptable solvent such as water, ethanol, and the like. It is contemplated that the solvated forms of the compounds described herein will also be presented herein.

Pharmaceutical composition

Another aspect is a pharmaceutical composition comprising a compound of formula (I) or (II) and a pharmaceutically acceptable diluent, excipient or carrier.

The term "pharmaceutical composition" refers to a mixture of a compound of formula (I) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. The pharmaceutical composition facilitates the administration of the compound to the organism. Techniques for administering the compounds include intravenous, oral, aerosol, parenteral, eye, lung and topical administration.

The term "carrier" refers to a relatively non-toxic chemical compound or agent that promotes compound introduction into a cell or tissue.

The term "diluent" refers to a chemical compound used to dilute a compound of interest before delivery. Diluents are also used to stabilize compounds, as they can provide a more stable environment. Salts dissolved in buffers (which may also be provided to adjust or maintain pH) are used as diluents, including but not limited to phosphate buffered saline.

The term "physiologically acceptable" means a non-toxic material, such as a carrier or diluent, without disrupting the biological activity or properties of the compound.

The term "pharmaceutically acceptable salt" means a compound formulation that does not disrupt biological activity or properties without causing significant irritation to the organism to be administered. In one embodiment, the pharmaceutically acceptable salts include compounds of formula (I) such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. It can be obtained by reacting an acid. Pharmaceutically acceptable salts can also be prepared by reacting a compound of general formula (I) with a base, such as ammonium salts, alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases, Such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, and salts with amino acids such as arginine, lysine and the like.

A “metabolite” of a compound described herein is a derivative of a compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized" refers to all processes in which a particular substance is changed by an organism, including but not limited to hydrolysis reactions and enzyme catalyzed reactions. Thus, enzymes can cause certain structural alterations in a compound. For example, cytochrome P ₄₅₀ catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyltransferases can be used in the presence of activated glucuronic acid molecules such as aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhi. Catalyze the transition to a drill. Further information on metabolism is obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).

In some embodiments, metabolites of a compound described herein are identified by administering the compound to a host and analyzing a tissue sample from the host, or incubating the compound with liver cells in vitro and analyzing the produced compound.

"Prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because, in certain circumstances, they may be easier to administer than the parent drug. In some embodiments, they are bioavailable, for example by oral administration, but the parent drug is not. For example, prodrugs also have improved solubility in pharmaceutical compositions than parent drugs. Examples of prodrugs are administered as esters (“prodrugs”) to promote permeation through the cell membrane when water-solubility is disadvantageous to mobility, and metabolically hydrolyzed to the active entity carboxylic acid when introduced into cells where water solubility is favorable. Included but are not limited to compounds of formula (I) that decompose. Further examples of prodrugs may be short peptides (polyamino acids) bound to acid groups, in which case the peptides are metabolized to reveal the active moiety.

In some embodiments, the compounds described herein may be administered to a human patient, either by themselves or in combination therapy, in a pharmaceutical composition in admixture with other active ingredients or appropriate carrier (s) or excipient (s). Techniques for formulating and administering compounds of the present application are described in "Remington: The Science and Practice of Pharmacy," 20th ed. (2000).

Route of administration

Suitable routes of administration include, for example, oral, rectal, transmucosal, transdermal, intrapulmonary or intestinal administration; Intramuscular, subcutaneous, intravenous, intramedullary injections, and parenteral delivery, including intradural, direct intraventricular, intraperitoneal, intranasal or injection.

Alternatively, the compound may also be administered topically rather than in a systemic manner, for example by injecting the compound directly into an organ, often in a depot or sustained release formulation. In addition, liposomes will be targeted and selectively absorbed by the organ. In addition, the drug is provided in the form of a rapid release formulation, in the form of a sustained release formulation or in the form of an intermediate release formulation.

Composition / Formulation

Pharmaceutical compositions comprising a compound of formula (I) can be prepared by known methods, for example, by conventional mixing, dissolving, granulating, preparing a dragee, levigating, emulsifying, encapsulating, entrapping or It can be produced by a compression process.

For example, pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that are easy to process the active compounds into formulations that can be used pharmaceutically. . Proper formulation is dependent upon the route of administration chosen.

In some embodiments, compounds of Formula (I) or (II) may be administered in a variety of ways, including systemically, such as orally or intravenously.

Useful compositions may also include solubilizers that aid in dissolution of the compound of formula (I) or (II). The term “solubilizer” generally includes formulations that allow a colloidal or true solution of the formulation to form. Certain acceptable nonionic surfactants such as polysorbate 80 may be useful as solubilizers such as acceptable glycols, polyglycols such as polyethylene glycol 400 and glycol ethers.

Useful compositions also include acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; Bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; And one or more acceptable pH adjusting or buffering agents including buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in the amounts necessary to maintain the pH of the composition in an acceptable range.

Useful compositions may also include one or more acceptable salts in amounts necessary to provide osmotic pressure in the composition in an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chlorides, citrates, ascorbates, borates, phosphates, bicarbonates, sulfates, thiosulfates or bisulfite anions; Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

Other useful compositions may also include one or more acceptable preservatives to inhibit bacterial activity. Suitable preservatives include mercury-containing materials such as merpenes and thiomesal; Stabilized chlorine dioxide; And quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

In some embodiments, the aqueous suspension composition may be packed in a single non-resealable container. Multiple doses of resealable containers may also be used, in which case it is common to include a preservative in the composition.

Pharmaceutical carriers for the hydrophobic compounds of formula (I) or (II) are cosolvent systems comprising benzyl alcohol, nonpolar surfactants, water miscible organic polymers and aqueous phases. The cosolvent system may be 10% ethanol, 10% polyethylene glycol 300, 10% polyethylene glycol 40 castor oil (PEG-40 castor oil) and 70% aqueous solution. This cosolvent system dissolves hydrophobic compounds well and is itself low toxicity upon systemic administration. For example, the proportion of cosolvent system can vary greatly without destroying its solubility and toxicity characteristics. In addition, the nature of the cosolvent component may vary: For example, other low toxicity nonpolar surfactants may be used in place of PEG-40 castor oil, and the fraction size of polyethylene glycol 300 may vary; In some embodiments, other biocompatible polymers may replace polyethylene glycol, such as polyvinylpyrrolidone; Other sugars or polysaccharides may be included in the aqueous solution.

Alternatively, other delivery systems of hydrophobic pharmaceutical compounds can be used. Liposomes and emulsions are well known as examples of delivery vehicles or carriers for hydrophobic drugs. Typically more toxic, but in some embodiments, certain organic solvents such as N-methylpyrrolidone are also used. In addition, the compounds are delivered using, for example, sustained release systems such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Sustained release capsules release the compound for weeks to 100 days, depending on its chemistry. Depending on the chemical nature and biological stability of the therapeutic agent, additional methods for protein stabilization can be used.

All formulations described herein can benefit from antioxidants, metal chelating agents, thiol containing compounds and other common stabilizers. Examples of such stabilizers include, but are not limited to, the following: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) About 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02 % w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, ( l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; Or (n) combinations thereof.

In some embodiments, compounds of Formula (I) or (II) may also be provided as salts with pharmaceutically suitable counter ions. In some embodiments, pharmaceutically suitable salts may be formed with a number of acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to dissolve better in aqueous or other protic solvents than the corresponding free acid or base forms.

Oral administration

In some embodiments, the pharmaceutical compositions provided herein are provided in solid, semisolid or liquid dosage forms. Oral administration as used herein also includes oral, tongue and sublingual administration. Suitable oral dosage forms include tablets, capsules, pills, troches, lozenges, flavors, cachets, pills, drug addition chewing gums, granules, bulk powders, effervescent or non-foamable powders or granules, solutions, emulsions, suspensions, Solutions include, but are not limited to, wafers, sprinkles, elixirs and syrups. In addition to the active ingredient (s), in some embodiments, the pharmaceutical composition includes, but is not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, and flavoring agents. It contains one or more pharmaceutically acceptable carriers or excipients.

Binders or granulating agents provide adhesion to the tablets to ensure that the tablets remain intact after compression. Suitable binders or granulating agents include starch such as corn starch, potato starch, and pre-gelatinized starch (eg starch 1500); gelatin; Sugars such as sucrose, glucose, dextrose, molasses and lactose; Natural and synthetic gums such as acacia, alginic acid, alginate, extracts of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxy Methylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch arabogalactan, powdered tragacanth (tragacanth), and guar gum; Celluloses such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); Microcrystalline celluloses such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pennsylvania); And mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dexrate, kaolin, mannitol, salicylic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. In some embodiments, the binder or filler is present in about 50 to about 99 weight percent of the pharmaceutical composition provided herein.

Suitable diluents include, but are not limited to, calcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugars. Certain diluents such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient amounts, characterize some compressed tablets that disintegrate in the mouth by chewing. In some embodiments, such compressed tablets are used as chewable tablets.

Suitable disintegrants include agar; Bentonite; Celluloses such as methylcellulose and carboxymethylcellulose; Wood products; Natural sponge; Cation exchange resins; Alginic acid; Gums such as guar gum and Veegum HV; Citrus pulp; Crosslinked celluloses such as croscarmellose; Crosslinked polymers such as crospovidone; Crosslinked starch; Calcium carbonate; Microcrystalline celluloses such as sodium starch glycolate; Polyacrine potassium; Starch such as corn starch, potato starch, tapioca starch and pregelatinized starch; clay; Aligns; And mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein can vary depending on the form of the formulation. In some embodiments, it contains about 0.5 to about 15 weight percent or about 1 to about 5 weight percent disintegrant of the pharmaceutical composition provided herein.

Suitable lubricants include calcium stearate; Magnesium stearate; Mineral oil; White mineral oil; glycerin; Sorbitol; Mannitol; Glycols such as glycerol behenate and polyethylene glycol (PEG); Stearic acid; Sodium lauryl sulfate; talc; Hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; Zinc stearate; Ethyl oleate; Ethyl laurate; Agar; Starch; Lycopodium; Silica or silica gel such as AEROSIL 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL ^® (Cabot Co., Boston, Mass.) And mixtures thereof Include but are not limited to these. In some embodiments, the pharmaceutical compositions provided herein contain about 0.1 to about 5 weight percent lubricant.

Suitable fluidizing agents include colloidal silicon dioxide, CAB-O-SIL ^® (Cabot Co., Boston, Mass.), And asbestos-free talc. Colorants include approved and certified water soluble FD & C dyes, and water insoluble FD & C dyes suspended on alumina hydrate, and any of pigment lakes and mixtures thereof. Pigment lakes are combinations that produce dyes in insoluble form by adsorbing a water soluble dye on a hydrated oxide of a heavy metal. Flavorants include natural flavors derived from plants, such as fruits, and synthetic blends of compounds that produce good taste sensations such as peppermint and methyl salicylate and peppermint. Sweetening agents include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include gelatin, acacia, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN ^® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ^® 80) and triethanolamine Oleate is included. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate and alcohols. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of non-aqueous liquids used in the emulsion include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

In some embodiments, orally used pharmaceutical preparations include orally used pharmaceutical preparations include push-fit capsules made of gelatin, which are only examples of glycerol or sorbitol, and Sealed soft capsules made of the same plasticizer and gelatin; Or hard gel capsules or tablets. In some embodiments, the indentable capsules contain the active ingredient in admixture with fillers such as lactose, binders such as starch and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In some embodiments, for soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, in some embodiments, stabilizers are added. All oral dosage forms should be present in dosages suitable for such administration.

For oral or sublingual administration, in some embodiments, the composition may take the form of a tablet, lozenge or gel formulated in a conventional manner.

In some embodiments, it should be understood that multiple carriers and excipients provide several functions even within the same formulation.

In some embodiments, the pharmaceutical compositions provided herein are provided as compressed tablets, humectant tablets, chewable lozenges, rapid solvents, multiple compressed tablets or enteric coated tablets, dragees or film coated tablets. Enteric coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenylsalicylates, waxes, shellac, ammonia shellac and ammonia shellac, and cellulose acetate phthalate. Dragees are, in some embodiments, enclosed compressed tablets with a sugar coating that completely covers the unpleasant taste or aroma and is beneficial in protecting the oxidation of the tablets. Film coated tablets are compression tablets covered with a water soluble thin layer or film. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by one or more compression cycles, including layered tablets and compressed-coated or dry-coated tablets.

In some embodiments, the tablet dosage form is provided with one or more carriers or excipients disclosed herein, including the active ingredient alone or as a binder, disintegrant, controlled release polymer, lubricant, diluent and / or colorant in powder, crystal or granular form. . Flavoring sweeteners are particularly useful for the formation of chewable tablets and lozenges.

In some embodiments, the pharmaceutical compositions provided herein are provided as soft or hard capsules made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin, also known as dry-filled capsule (DFC), consists of two parts, one covering the other and completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft spherical shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol or similar polyols. In some embodiments, the soft gelatin shell contains a preservative to prevent the growth of microorganisms. Suitable preservatives are those described herein, including methyl- and propyl-parabens and sorbic acid. In some embodiments, liquid, semisolid and solid dosage forms provided herein are encapsulated in a capsule. Suitable liquid and semisolid dosage forms include suspensions and solutions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions are described, for example, in US Pat. No. 4,328,245; No. 4,409,239; And 4,410,545. In some embodiments, the capsule is coated to adjust or maintain dissolution of the active ingredient (s).

In some embodiments, the pharmaceutical compositions provided herein are provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Latex is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid, including oil-in-water or water-in-oil. Latexes include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers and preservatives. Suspensions include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcohol solutions are pharmaceutically acceptable acetals such as di (lower alkyl) acetals of lower alkyl aldehydes (the term "lower" means alkyl having from 1 to 6 carbon atoms), for example acetaldehyde diethyl acetal ; And water miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Ericsir is a clear, sweet solution of hydrous alcohol. The syrup is a concentrated aqueous solution of sugar, for example sucrose, and also contains a preservative. In the case of liquid dosage forms, for example a solution of polyethylene glycol is diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, for example water, to be evaluated for ease of administration.

Other useful liquid and semisolid dosage forms include 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether Including, but not limited to, dialkylated mono- or poly-alkylene glycols and those containing the active ingredient (s) provided herein, where 350, 550, and 750 refer to approximate average molecular weights of polyethylene glycol. In some embodiments, these formulations contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine , Lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and esters thereof, and dithiocarbamate.

In some embodiments, the pharmaceutical compositions provided herein for oral administration are also provided in the form of liposomes, micelles, microspheres or nanosystems. In some embodiments, the micelle dosage form is prepared as described in US Pat. No. 6,350,458.

In some embodiments, the pharmaceutical compositions provided herein are provided as non-bubble and foamy granules and powders to be reconstituted into liquid dosage forms. In some embodiments, pharmaceutically acceptable carriers and excipients used in non-bubble granules or powders include diluents, sweeteners, and wetting agents. In some embodiments, pharmaceutically acceptable carriers and excipients used in aerated granules or powders include sources of carbon dioxide and organic acids.

In some embodiments, colorants and flavoring agents are used in both of the above dosage forms.

In some embodiments, the pharmaceutical compositions provided herein are formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted- and planned-release forms.

Parenteral  administration

In some embodiments, the pharmaceutical compositions provided herein are administered parenterally by injection, infusion or implantation for topical or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, urethral, intrasternal, intracranial, intramuscular, intravitreal and subcutaneous administration.

In some embodiments, the pharmaceutical compositions provided herein are any administration suitable for parenteral administration, including solid forms suitable for suspensions or solutions in solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanobased, and pre-injection solutions. Formulated in the form. In some embodiments, such dosage forms are prepared according to conventional methods (see, eg, Remington: The Science and Practice of Pharmacy).

In some embodiments, pharmaceutical compositions intended for parenteral administration include aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial or microbial growth preservatives, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, topical Include, but are not limited to, anesthetics, suspensions and dispersing agents, wetting or emulsifying agents, complexing agents, metal ion-blocking or latent agents, penetration enhancers, cell cryoprotectants, lyophilizers, thickeners, pH adjusters and inert gases And one or more pharmaceutically acceptable carriers.

Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injections, Ringer's injections, isotonic dextrose injections, sterile water injections, dextrose and Hartmann Ringer's solutions. It is not limited. Non-aqueous vehicles include plant-derived fixed oil, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain triglycerides of coconut and palm kernel oils. It is not limited to these. Water-miscible vehicles include ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g. polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide and dimethyl sulfoxy Include, but are not limited to these.

Suitable antimicrobial agents or preservatives include phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride, benzethonium chloride, methyl- and propyl-paraben and Sorbic acid is included but is not limited thereto. Suitable isotonic agents include but are not limited to sodium chloride, glycerin and dextrose. Suitable buffers include, but are not limited to, phosphates and citrate. Suitable antioxidants are those described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include but are not limited to procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable metalion blockade or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin and sulfobutylether 7-β-cyclodextrin (CAPTISOL ^® , CyDex, Lenexa, KS Cyclodextrins, including), but are not limited to these.

In some embodiments, the pharmaceutical compositions provided herein are formulated for single or multiple administration. Single dose formulations are filled in ampoules, vials or syringes. Parenteral formulations for multiple administration should contain antimicrobial agents at bacteriostatic or bacteriostatic concentrations. All parenteral formulations must be sterile.

In one embodiment, the pharmaceutical composition is provided in a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided in a sterile soluble dry product, including lyophilized powder and subcutaneous tablet, to be reconstituted with the vehicle prior to use. In another embodiment, the pharmaceutical composition is provided in a ready-to-use sterile suspension. In another embodiment, the pharmaceutical composition is provided as a sterile soluble dry product to be reconstituted with the vehicle prior to use. In another embodiment, the pharmaceutical composition is provided in a ready-to-use sterile milk.

In some embodiments, the pharmaceutical compositions provided herein are formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted- and planned-release forms.

In some embodiments, the pharmaceutical composition is formulated as a suspension that is a solid, semisolid or thixotropic liquid for administration as a transplant depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that allows the active ingredient (s) to diffuse in the pharmaceutical composition.

Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene polyisobutylene, polybutadiene, polyethylene , Ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels, collagen, crosslinked polyvinyl alcohols of acrylic and methacrylic esters, and partially hydrolyzed crosslinks Polyvinyl acetate is included.

Suitable outer polymer membranes include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinylacetate copolymers, silicone rubber, polydimethyl siloxane, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl Vinyl chloride copolymer with acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer and ethylene / vinyl oxy Ethanol copolymers are included.

In some embodiments, for intravenous injection, the compounds of formula (I) or (II) are formulated in aqueous solutions, preferably in physiologically suitable buffers such as Hank's solution, Ringer's solution or physiological saline buffer. For transmucosal administration, penetrants suitable for the barrier to penetrate are used in the formulation. For other parenteral injections, in some embodiments, a suitable formulation comprises an aqueous or nonaqueous solution, preferably with a physiologically suitable buffer or excipient.

The compounds are formulated for parenteral administration in some embodiments by injection, for example by bolus injection or continuous infusion. In some embodiments, the injectable formulation is in unit dosage form, eg, in ampoules or in multi-dose containers, with additional preservatives. In some embodiments, the composition takes the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and contains a formulation formulation, such as a suspension, stabilization and / or dispersing formulation.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, in some embodiments, suspensions of the active compounds are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions, in some embodiments, contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension also contains an agent which increases the solubility of the compound to produce a suitable stabilizer or high concentration solution.

Alternatively, the active ingredient (s) are in powder form for constitution with a suitable vehicle, eg pyrogen-free sterile water, before use.

In some embodiments, the compounds are formulated in rectal compositions containing conventional suppository bases, such as cocoa butter or other glycerides, such as rectal gels, rectal foams, rectal aerosols, suppositories, or retention enemas.

In addition to the formulations described above, in some embodiments the compound is formulated as a depot preparation. Such long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds are formulated with suitable polymers or hydrophobic materials (eg as emulsions in acceptable oils) or ion exchange resins or with poorly soluble derivatives such as poorly soluble salts.

Injectable depot formulations are prepared in some embodiments by forming microencapsulation matrices (also known as microcapsule matrices) of compounds of formula (I) or (II) in biodegradable polymers. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release is controlled. Injectable depot formulations are prepared in some embodiments by entrapping the drug in microfluidic or liposomes. By way of example only, a posterior juxtascleral depot can be used as the mode of administration of a compound having the structure of Formula (I) or (II). The sclera is a thin, avascular layer composed of a highly oriented collagen network that wraps the eyes of most vertebrates. Because the sclera is bloodless, it is used as a natural storage depot that the injected material does not quickly remove or disappear from the eye. In some embodiments, the formulation of the compound used for administration to the sclera of the eye is in any form suitable for application to the sclera by injection through a small diameter cannula suitable for scleral layer injection. Examples of injectable application forms are solutions, suspensions or colloidal suspensions.

Topical administration

The pharmaceutical compositions provided herein are administered topically to the skin, openings or mucous membranes in some embodiments. Topical administration as used herein includes dermal (intra), conjunctival, corneal, intraocular, ophthalmic, ear, transdermal, nasal, vaginal, urethral, respiratory and rectal administration.

The pharmaceutical compositions provided herein may, in some embodiments, be emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dispersants, dressings, elixirs, lotions, suspensions, dikes, pastes, foams, films, aerosols, It is formulated in any dosage form suitable for topical or systemic administration, including washes, sprays, suppositories, bandages, transdermal patches. In some embodiments, topical formulations of the pharmaceutical compositions provided herein also include liposomes, micelles, microspheres, nanospheres or nanoparticles and mixtures thereof.

As another useful formulation for administering a compound having the structure of Formula (I) or (II), transdermal delivery devices (“patches”) are used. Such transdermal patch agents may be used in some embodiments to inject continuously or discontinuously in a controlled amount of a compound of this disclosure. Examples of the structure and use of transdermal patches for the delivery of pharmaceutical preparations can be found in US Pat. No. 5,023,252. In some embodiments, such patches can be made continuously, pulsed or as required for delivery of the pharmaceutical formulation. In yet another additional embodiment, transdermal delivery of a compound of formula (I) or (II) is achieved by means such as iontophoretic patching agents. Transdermal patch agents can control delivery of the compound. In some embodiments, the rate of absorption can be slowed by using a rate-controlling membrane or by entrapping the compound in a polymer matrix or gel. Conversely, in some embodiments, absorption accelerators may be used to increase the absorption rate. In some embodiments, formulations suitable for transdermal administration may be in separate patches and may be lipophilic emulsions or aqueous buffers dissolved and / or dispersed in a polymer or tackifier.

Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial agents or growth preservatives, stabilizers, solubilizers, isotonic agents, buffers, Antioxidants, local anesthetics, suspending and dispersing preparations, wetting or emulsifying preparations, complexing agents, metal ion block or rate preparations, penetration enhancers, cell cryoprotectants, lyophilizers, thickeners and inert gases. Do not.

In some embodiments, the pharmaceutical compositions are electroporation, iontophoresis, negative electrophoresis, ultrasonography and microneedle or needleless injection methods such as POWDERJECT ^™ (Chiron Corp., Emeryville, CA) and BIOJECT ^™ (Bioject Medical Technologies Inc., Tualatin, Oregon).

In some embodiments, the pharmaceutical compositions provided herein are provided in the form of ointments, creams and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles such as lard, benzoinated lard, olive oil, cottonseed oil and other oils, white petrolatum; Emulsifiable or absorbent vehicles such as hydrophilic petrolatum, hydroxystealine sulfate and anhydrous lanolin; Dehydrated vehicles, such as hydrophilic ointments; Water soluble ointment vehicles including polyethylene glycols of various molecular weights; Emulsion vehicles of water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin and stearic acid are described (The Science and Practice of Pharmacy, supra). See). These vehicles are softeners but generally require the addition of antioxidants and preservatives.

In some embodiments, a suitable cream base is oil-in-water or water-in-oil. In some embodiments, the cream vehicle is flushable and contains an oil phase, an emulsifier and an aqueous phase. The oil phase is also commonly referred to as the "inner" phase, consisting of petrolatum and fatty alcohols, such as cetyl or stearyl alcohol. The aqueous phase is not essential but mainly exceeds the oil phase in large quantities and generally contains a humectant. Emulsifiers in cream formulations include nonionic, anionic, cationic or amphoteric surfactants.

Gels are systems in the form of semisolid suspensions. Single-phase gels contain organic polymers that are substantially uniformly distributed throughout the liquid carrier. Suitable gelling agents include crosslinked acrylic acid polymers, Carbomer For instance, carboxy polyalkylene, Carbopol (Carbopol ^®); Hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymer and polyvinyl alcohol; Cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and methylcellulose; Gums such as tragacanth and xanthan gum; Sodium alginate; And gelatin. In some embodiments, dispersants such as alcohols or glycerin are added or gelling agents dispersed by grinding, mechanical mixing and / or stirring to prepare a uniform gel.

In some embodiments, the pharmaceutical compositions provided herein comprise suppositories, vaginal suppositories, urethral suppositories, poultices or poultices, pastes, powders, dressings, creams, gypsum, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams Rectal, urethral, vaginal or vaginal administration, in the form of a spray or enema. In some embodiments, these dosage forms are prepared using conventional processes as disclosed in Remington: The Science and Practice of Pharmacy, supra.

Rectal, urethral, and vaginal suppositories are solids for insertion into the body openings, which melt or soften at room temperature or soften at body temperature to release the active ingredient (s) into the openings. Pharmaceutically acceptable carriers for use in rectal and vaginal suppositories include bases or vehicles, such as an upright formulation, which when formulated with the pharmaceutical compositions provided herein produce a melting point close to body temperature; And antioxidants described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), mercury, paraffin, white and yellow waxes, suitable mixtures of mono-, di- and triglycerides of fatty acids, hydrogels Such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; Glycerylated gelatin is included, but is not limited to these. In some embodiments combinations of various vehicles are used. Rectal and vaginal suppositories are prepared in some embodiments by compression methods or molding. Typical weights of rectal and vaginal suppositories are about 2 to about 3 g.

In some embodiments, the pharmaceutical compositions provided herein are administered to the eye in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, intraocular inserts and implants.

In some embodiments, the pharmaceutical compositions provided herein are administered by inhalation intranasally or by airway. In some embodiments, the pharmaceutical composition may be a pressurized container, a pump, a spray, an atomizer, such as an atomizer, a nebulizer alone or a suitable propellant, such as an electrohydraulic, to produce a fine spray. It is provided in the form of an aerosol or solution for delivery using 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical composition may, in some embodiments, be a dry powder for inhalation alone or in combination with an inert carrier such as lactose or phospholipids; And nasal drops. For intranasal use, in some embodiments the powder comprises biobinding agents including chitosan or cyclodextrins.

In some embodiments, solutions or suspensions for use in pressurized vessels, pumps, sprays, atomizers and nebulizers are used to disperse, solubilize or expand the release of ethanol, aqueous ethanol, or the active ingredient (s) provided herein. Other suitable agents, propellants as solvents; And / or surfactants such as sorbitan trioleate, oleic acid or oligolactic acid.

In some embodiments, the pharmaceutical compositions provided herein are micronized to a size suitable for administration by inhalation, such as 50 micrometers or less, or about 10 micrometers or less. Particles of this size may, in some embodiments, be pulverized, such as spiral jet milling, fluid bed jet mills, supercritical fluid processing for nanoparticle formation, high pressure homogenization or spray drying. It is prepared using.

In some embodiments, capsules, blisters and cartridges for use in an inhaler or blower comprise a powder mix of a pharmaceutical composition provided herein; Suitable powder bases such as lactose or starch; And performance modifiers such as l-leucine, mannitol or magnesium stearate. Lactose includes anhydrous forms or monohydrate forms. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. In some embodiments, the pharmaceutical compositions provided herein for inhalation / intranasal administration further comprise suitable flavoring agents, such as menthol and levomenthol, or sweetening agents, such as saccharin or saccharin sodium.

In some embodiments, the pharmaceutical compositions provided herein for topical administration are formulated for immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, target- and scheduled-release.

Strain release

The pharmaceutical compositions provided herein are formulated in a modified release dosage form in some embodiments. As used herein, the term “modified release” refers to a dosage form that is different from that of an immediate dosage form when the rate or site of release of the active ingredient (s) is administered by the same route. Modified release dosage forms include delayed-, extended-, long-term, sustained-, pulsed-, controlled-, accelerated- and rapid-, target-, planned-release, and intragastric retention dosage forms. Pharmaceutical compositions of modified release dosage forms include, but are not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. And various modified release devices and methods. In some embodiments, the release rate of the active ingredient (s) is modified by changing the particle size and polymorphism of the active ingredient (s).

Examples of modified releases include US Pat. No. 3,845,770; 3,916,899; 3,536,809; 3,536,809; 3,598,123; 3,598,123; 4,008,719; 4,008,719; No. 5,674,533; 5,059,595; 5,059,595; 5,591,767; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,639,476; 5,354,556; 5,354,556; 5,639,480; 5,639,480; 5,733,566; 5,739,108; 5,739,108; 5,891,474; 5,891,474; 5,922,356; 5,922,356; 5,972,891; 5,972,891; 5,980,945; 5,980,945; 5,993,855; 5,993,855; 6,045,830; 6,045,830; 6,087,324; 6,087,324; No. 6,113,943; No. 6,197,350; 6,248,363; 6,248,363; 6,264,970; 6,264,970; 6,267,981; 6,267,981; 6,376,461; 6,376,461; 6,419,961; 6,419,961; No. 6,589,548; No. 6,613,358; And 6,699,500, including, but not limited to.

1. Matrix controlled release device

Pharmaceutical compositions provided herein of modified release dosage forms are, in some embodiments, made using matrix controlled release devices (eg, Takada et al in "Encyclopedia of Controlled Drug Delivery," Vol. 2 , Mathiowitz ed., Wiley, 1999).

In one embodiment, a pharmaceutical composition provided herein of a modified release dosage form uses an erosive matrix device that is a water-swellable, erosive or soluble polymer, including synthetic polymers and naturally occurring polymers and derivatives such as polysaccharides and proteins. Formulated.

Materials useful for forming an erosive matrix include chitin, chitosan, dextran, and pullulan; Gum agar, gum arabian, gum karaya, locust bean gum, gum tragacanth, carrageenan, gum gatti, guar gum, xanthan gum, and scleroglucan; Starch such as dextrin and maltodextrin; Hydrophilic colloids such as pectin; Phosphatides such as lecithin; Alginate; Propylene glycol alginate; gelatin; Collagen; And cellulose, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), Cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT) And ethyl hydroxy ethyl cellulose (EHEC); Polyvinyl pyrrolidone; Polyvinyl alcohol; Polyvinyl acetate; Glycerol fatty acid esters; Polyacrylamide; Polyacrylic acid; Copolymers of etacrylic acid or methacrylic acid (EUDRAGIT ^® , Rohm America, Inc., Piscataway, NJ); Poly (2-hydroxyethyl-methacrylate); Polylactide; Copolymers of L-glutamic acid and ethyl-L-glutamate; Degradable lactic acid-glycolic acid copolymers; Poly-D-(-)-3-hydroxybutyric acid; And other acrylic acid derivatives such as butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate and (trimethylaminoethyl) methacrylate chloride and Copolymers are included, but are not limited to these.

In a further embodiment, the pharmaceutical composition is formulated with a non-erosive matrix device. The active ingredient (s) are dissolved or dispersed in an inert matrix and are primarily released by diffusion through the inert matrix once administered. Suitable materials for use as non-erosive matrix devices include insoluble plasticizers, such as polyethylene, polypropylene, polyisoprene polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinyl Chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinylacetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl acetate, vinylidene chloride, vinyl chloride copolymer with ethylene and propylene , Ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyl oxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticization Polyethylene Les terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, and; Hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and crosslinked partially hydrolyzed polyvinyl acetate; And fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

In matrix controlled release systems, the desired release kinetics are, for example, the polymer form used, the polymer viscosity, the particle size of the polymer and / or active ingredient (s), the ratio of active ingredient (s) to polymer and other excipients in the composition or Controllable via a carrier.

The pharmaceutical compositions provided herein of the modified release dosage forms are prepared in some embodiments by methods including direct compression, dry or wet granulation and then compression, and melt granulation and compression.

2. Osmotic  Controlled release device

The pharmaceutical compositions provided herein of modified release dosage forms, in some embodiments, are osmotic, including single chamber systems, dual chamber systems, asymmetric membrane technology (AMT), and extruding core systems (ECS). It was made using a controlled release device. Such devices generally have at least two parts: (a) a core containing the active ingredient (s); And (b) a semipermeable membrane having at least one delivery port that surrounds this core. The semipermeable membrane regulates the ingress of water from the aqueous use environment into the core to release the drug by ejection through the delivery port (s).

In addition to the active ingredient (s), the center of the osmotic device optionally includes an osmotic agent that generates a driving force for delivery from the environment of use to the center of the device. One class of osmotic agents are water-swellable hydrophilic polymers, also referred to as "osmopolymers" and "hydrogels", including hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide ( PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic) acid, poly (methacrylic) acid, polyvinylpyrrolidone (PVP), PVA / PVP copolymer with hydrophobic monomers such as crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymer, vinyl acetate and methyl methacrylate, hydrophilic polyurethanes containing large amounts of PEO blocks, sodium croscarmellose , Carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulite Agarose (CEC), sodium alginate, but contains a polycarbophil, gelatin, xanthan gum, and sodium starch glycolate is not limited to these.

Another class of osmotic agents are osmogens that can absorb water and cause an invasive pressure gradient to act across the barrier of the surrounding coating. Suitable osmogens include inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulfate; Sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; Organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; Urea; And mixtures thereof.

Osmotic agents with different dissolution rates are used in some embodiments to determine how quickly the active ingredient (s) are delivered early from the dosage form. For example, using amorphous sugars, such as Mannogeme EZ (SPI Pharma, Lewes, DE), allows for faster delivery during the first 2-3 hours, resulting in faster production of the desired therapeutic effect and slowing down of the remaining amounts. And continuous release to maintain the therapeutic or prophylactic effect at the desired level over an extended period of time. In this case, the active ingredient (s) are released at a rate that replaces the amount of active ingredient (s) that is metabolized and excreted.

In some embodiments, the core also includes various other excipients and carriers described herein to enhance the performance of the dosage form and enhance stability or throughput.

Materials useful for forming semipermeable membranes include various grades of acrylic, vinyl, ethers, polyamides, polyesters, water-insoluble and water-insoluble at physiologically appropriate pH or by chemical alteration such as crosslinking. Easy cellulose derivatives are included. Examples of suitable polymers useful for forming coatings are plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose discetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carba Mate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of low-cursor bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG / PPG copolymer, PV P, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (acrylic) acids and esters and poly- (methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, Collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

In some embodiments, the semipermeable membrane is a hydrophobic microporous membrane, as disclosed in US Pat. No. 5,798,119, which is substantially filled with pores and not wetted by an aqueous medium but is permeable to water vapor. Such hydrophobic or water vapor permeable membranes are typically hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene Fluoride, polyvinyl esters and ethers, natural waxes and synthetic waxes.

The delivery port (s) on the semipermeable membrane is formed in some embodiments after coating by mechanical or laser drilling. The delivery port (s) is formed in some embodiments in situ due to corrosion of the plug of water soluble material or tearing of a thin portion of the membrane above the indentation in the core. In addition, as in the case of asymmetric membrane coatings of the type disclosed in US Pat. Nos. 5,612,059 and 5,698,220, delivery ports are formed during the coating process.

The total amount and release rate of the active ingredient (s) released are substantially controlled in some embodiments through the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and location of the delivery ports.

The pharmaceutical composition of the osmotic controlled release dosage form further comprises, in some embodiments, additional conventional excipients or carriers as described herein to promote the performance or processability of the formulation.

In some embodiments, osmotic controlled release dosage forms are prepared according to conventional methods and techniques (see, eg, Remington: The Science and Practice of Pharmacy; Santus and Baker, J. Controlled Release 1995, 35, 1-). 21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided herein are formulated as an AMT controlled release dosage form comprising an asymmetric osmotic membrane coating a core comprising the active ingredient (s) and other pharmaceutically acceptable excipients or carriers. . See US Pat. No. 5,612,059 and WO2002 / 17918. In some embodiments, AMT controlled release dosage forms are prepared using methods such as integrated compression, dry granules, wet granules, and dip-coating processes.

In certain embodiments, the pharmaceutical compositions provided herein are formulated in an ESC controlled release dosage form comprising an osmotic membrane coating a core comprising the active ingredient (s), hydroxyethyl cellulose and other pharmaceutically acceptable excipients or carriers. Become

3. Multiparticulate Controlled Release Device

The pharmaceutical compositions provided herein of the modified release dosage forms can, in some embodiments, comprise a variety of particles, granules or particles having a diameter ranging from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm, or It is made of a multiparticulate controlled release device comprising pellets. Such multiparticulates are prepared in some embodiments by processes such as wet- and dry-granulation, extrusion / sphering, roller-consolidation, melt-coagulation, and spray-coating seed cores. . See, eg, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; And Pharmaceutical Pelletization Technology; Marcel Dekker: 1989).

For administration by aspiration, the compounds of formula (I) or (II) are usually suitable propellants, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable The gas is used to deliver in the form of an aerosol spray delivery from a pressurized pack or nebulizer. In the case of a pressurized aerosol, the dosage unit is determined in some embodiments by providing a valve to deliver a metered amount. Formulated into capsules or cartridges, for example gelatin, for use in an inhaler or blower containing a suitable powder base such as lactose or starch.

Method of treatment, dosage and combination therapy

The term "mammal" means all mammalian fluids, including humans. Mammals include, by way of example only, humans, non-human primates, cattle, dogs, cats, goats, sheep, pigs, rats, mice, and rabbits.

As used herein, the term “effective amount” means the amount of a compound administered to alleviate to some extent one or more of the symptoms of the disease, condition or disorder being treated.

As used herein, the term “indirectly regulates” refers to an agent that reduces serum retinol levels in a mammal to reduce retinol levels in the mammal's eye. Modulating these intraocular retinol levels can modulate the activity of visual cycle proteins. This form of regulation (which occurs through the reduction of intracellular serum retinol levels) is referred to herein as indirect regulation.

In some embodiments, a composition containing a compound (s) described herein can be administered for prophylactic and / or therapeutic treatment. The term "treatment" is used for the purpose of referring to prophylactic and / or therapeutic treatments. In therapeutic applications, the composition is administered to a patient already suffering from a disease, condition or disorder in an amount sufficient to cure or at least partially arrest the condition, condition or condition. The amount effective for such use will vary depending on the severity and course of the disease, disorder or condition, previous treatment, the patient's health and adverse reactions, and the judgment of the treating physician.

In prophylactic applications, a composition containing a compound disclosed herein is administered to a patient susceptible to or at risk of a particular disease, disorder or condition. This amount is defined as "prophylactically effective amount or dose." In its use, the exact amount also depends on the patient's state of health, weight, and the like.

The term "increasing" or "increasing" means increasing or prolonging the efficacy or duration of a given effect. That is, in increasing the effectiveness of a therapeutic agent, the term “increasing” means the ability to increase or prolong the efficacy or duration of the effect of another therapeutic agent on the system. As used herein, “increasing effective amount” refers to an amount sufficient to enhance the effectiveness of other therapeutic agents in a given system. When used with a patient, the amount effective for such use will depend on the severity and course of the disease, disorder or condition, previous treatment, the patient's health and adverse reactions, and the judgment of the treating physician.

If the patient's condition does not improve, at the physician's discretion, the compound may be administered for an extended period of time, i.e., throughout the patient's survival, to alleviate, control or limit the patient's disease or condition. .

If the patient's condition improves, administration of the compound may be provided continuously at the discretion of the physician; It may be temporarily suspended for a period of time (ie, a "drug holiday").

When the patient's bed improves, a maintenance dose is administered as needed. The dose or frequency of administration, or both, can then be reduced as a function of symptoms for the level at which the improved disease, disorder or condition is maintained. In some embodiments, patients may require long-term intermittent treatment based on any symptom recurrence.

The amount of a given agent that will correspond to this amount will vary depending on factors such as the particular compound, disease state and severity thereof, the specificity of the subject or host to be treated (eg, body weight), but for example, the specific therapeutic agent, route of administration, It may also be routinely determined by methods known in the art depending on the particular situation of the case, including the condition and the subject or host to be treated. Generally, however, the dose used for adult treatment will typically be about 0.02 to about 5000 mg per day, preferably about 1 to about 1500 mg per day. The predetermined dose is, in some embodiments, conveniently administered in a single dose or simultaneously (or over a short period of time) or in sub-dose at appropriate intervals, such as twice, three, four or more times daily. May be given in divided doses.

In certain cases, it may be appropriate to administer at least one of the compounds (or pharmaceutically acceptable salts, esters, amides, prodrugs or solvates) disclosed herein in combination with other therapeutic agents. Also, by way of example only, if one of the side effects a patient experiences when receiving one of the compounds disclosed herein is inflammation, it may be appropriate to administer the anti-inflammatory agent in combination with the initial therapeutic agent. Also, by way of example only, the therapeutic effect of one of the compounds disclosed herein can be augmented by administering an adjuvant (ie, the adjuvant alone will yield minimal therapeutic benefit, but in combination with other therapeutic agents, the total therapeutic benefit for the patient). Is improved). In addition, by way of example only, one of the compounds disclosed herein may be administered with other therapeutic agents (also including other therapeutic regimens) that also have a therapeutic effect to increase the benefit experienced by the patient. By way of example only, in the treatment of macular degeneration comprising administering one of the compounds disclosed herein, the therapeutic benefit can be increased by providing the patient with another macular degeneration treatment or therapy. In any case, regardless of the disease, disorder or condition to be treated, the total benefit experienced by the patient may be a simple sum of the two therapeutic agents or the patient may experience a synergistic benefit.

Also disclosed herein are combination therapies comprising the use of a compound of formula (I) or (II) with modulators of serum retinol levels or activity. In one embodiment, the combination comprises a compound of formula (I) or (II) above and a compound of formula (III) or an active metabolite or pharmaceutically acceptable prodrug or solvate thereof:

또는 그의 활성 대사산물 또는 약제학적으로 허용가능한 전구약물 또는 용매화물이다. 하나의 구체예로는, 일반식 (I) 또는 (II)의 화합물 및 일반식 (III)의 화합물을 포함하는 병용제이며, 여기서 일반식 (III)의 화합물은 4-하이드록시페닐레틴아미드이다.Wherein X ¹ is selected from the group consisting of NR ² , O, S, CHR ² ; R ¹ is (CHR ² ) _x -L ¹ -R ³ , where x is 0, 1, 2 or 3; L ¹ is a single bond or -C (O)-; R ² is H, (C ₁ -C ₄ ) alkyl, F, (C ₁ -C ₄ ) fluoroalkyl, (C ₁ -C ₄ ) alkoxy, -C (O) OH, -C (O) -NH ₂ ,-(C ₁ -C ₄ ) alkylamine, -C (O)-(C ₁ -C ₄ ) alkyl, -C (O)-(C ₁ -C ₄ ) fluoroalkyl, -C (O) - (C ₁ -C ₄₎ alkylamine, and _{-C (O) - (C 1} -C 4) is a moiety selected from the group consisting of alkoxy; R ³ is H or (C ₂ -C ₇ ) alkenyl, (C ₂ -C ₇ ) alkynyl, aryl, (C ₃ -C ₇ ) cycloalkyl, (C ₅ -C ₇ ) cycloalkenyl and heterocyclo Optionally substituted with 1-3 substituents independently selected from the group consisting of: In another embodiment, the combination comprises a compound of Formula (I) or (II) and a compound of Formula (III), wherein the combination modulates serum retinol levels or activity. In a further embodiment, a combination comprising a compound of formula (I) or (II) and a compound of formula (III) wherein X ¹ is NR ² and R ² is H or (C ₁ -C ₄ ) alkyl Jay. Another further embodiment is a combination comprising a compound of formula (I) or (II) and a compound of formula (III) wherein x is O. In another embodiment, there is a combination comprising a compound of formula (I) or (II) and a compound of formula (III) wherein x is 1 and -C (O)-which is L ¹ . In another embodiment is a combination comprising a compound of formula (I) or (II) and a compound of formula (III) wherein R ³ is optionally substituted heteroaryl. In a further embodiment, there is a combination comprising a compound of formula (I) or (II) and a compound of formula (III), wherein the compound of formula (III)

Or an active metabolite or pharmaceutically acceptable prodrug or solvate thereof. In one embodiment, there is a combination comprising a compound of formula (I) or (II) and a compound of formula (III), wherein the compound of formula (III) is 4-hydroxyphenylretinamide .

Specific non-limiting examples of combination regimens include at least one of the compounds of formula (I) or (II): nitric oxide (NO) production inducers, statins, negatively charged phospholipids, antioxidants, minerals, anti-inflammatory agents, angiogenesis inhibitors, matrices Use with metalloproteinase inhibitors and carotenoids. In some cases, suitable combination agents may fall within several categories (for example, lutein is an antioxidant and a carotenoid). In addition, the compounds of formula (I) or (II) may be administered with additives that may provide an advantage to the patient in some embodiments, by way of example only cyclosporin A may be exemplified.

In addition, in some embodiments, compounds of Formulas (I) and (II) are used in combination with methods that may provide additional or synergistic benefits to a patient, which is merely an example of in vitro leoparesis (also called membrane). The use of known differential filtration), the use of an implantable miniature telescope, the laser light coagulation of drusen and the microstimulation regimen.

The use of antioxidants has been found to be beneficial for patients with macular degeneration and dystrophy. For example, Arch. Ophthalmol, 119: 1417-36 (2001); Sparrow, et al., J. Biol. Chem., 278: 18207-13 (2003). Examples of suitable antioxidants that can be used in combination with at least one compound having the structure of Formula (I) or (II) include vitamin C, vitamin E, beta-carotene and other carotenoids, coenzyme Q, 4-hydroxy- 2,2,6,6-tetramethylpiperidine-N-oxyl (also known as Tempol), lutein, butylated hydroxytoluene, resveratrol, trolox analogs (PNU-83836-E) And bilberry extracts.

The use of certain minerals has also been found to be beneficial for patients with macular degeneration and dystrophy. See, eg, Arch. Ophthalmol, 119: 1417-36 (2001). Examples of suitable minerals that can be used in combination with at least one compound having the structure of formula (I) or (II) include copper-containing minerals such as cupric oxide (as an example only); Zinc-containing minerals such as zinc oxide (only by way of example); And selenium-containing compounds.

The use of certain negatively charged phospholipids has also been found to be beneficial for patients with macular degeneration and dystrophy. See, eg, Shaban & Richter, Biol. Chem., 383: 537-45 (2002); Shaban, et al., Exp. Eye Res., 75: 99108 (2002). Examples of suitable negatively charged phospholipids that can be used in combination with at least one compound having the structure of Formula (I) or (II) include cardiolipin and phosphatidylglycerol. When positively charged and / or neutral phospholipids are also used in combination with a compound having the structure of Formula (I) or (II), it may be beneficial to patients with macular degeneration and dystrophicity.

The use of certain carotenoids is correlated with the maintenance of photoprotection required for photoreceptor cells. Carotenoids are naturally occurring yellow-red pigments of terpenoid groups present in plants, algae, bacteria and certain animals such as algae and shellfish. Carotenoids are known as large class molecules of more than 600 naturally occurring carotenoids. Carotenoids include hydrocarbons (carotene) and their oxygenates, alcohol derivatives (xanthophylls). These include actinioerysrol, astaxanthin, canthaxanthin, capxanthine, capsorubine, β-8'-apo-carotenal, β-12'-apo-carotenal, α-carotene. , β-carotene, “carotene” (mixture of α- and β-carotene), γ-carotene, β-kryptoxanthin, lutein, lycopene, violeryline, zeaxanthin and their hydroxyl- or carboxy-containing Esters of members. Many carotenoids are actually present in cis- and trans-isomer forms, while synthetic compounds are often racemic mixtures.

In humans, the retina primarily accumulates two carotenoids, namely zeaxanthin and lutein. These two carotenoids are powerful antioxidants and absorb blue light, which may help protect the retina. The group that provided the carotenoid-deficient diet in a study of quails had a low concentration of zeaxanthin and was significantly damaged by light, as evidenced by a very large number of apoptotic photoreceptor cells. The highest levels of zeaxanthin were found to show minimal damage. Examples of carotenoids suitable for use with at least one compound having the structure of Formula (I) include lutein and zeaxanthin as well as any of the carotenoids mentioned above.

Suitable nitric oxide production inducers include compounds that stimulate internal NO, raise levels of endothelial cell-induced relaxation factors (EDRF) in vivo, or which are substrates for nitric oxide synthase. Such compounds include, for example, L-arginine, L-homoarginine and N-hydroxy-L-arginine, nitration and nitration analogs thereof (e.g., nitrated L-arginine, nitrated L-arginine, nitro) N-hydroxy-L-arginine, nitrated N-hydroxy-L-arginine, nitrated L-homoarginine and nitrated L-homoarginine), precursors of L-arginine and / or physiologically acceptable thereof Possible salts such as citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids, arginase enzyme inhibitors (eg N-hydroxy-L-arginine and 2 (S) -amino-6 -Boronohexanoic acid) and nitric oxide synthase substrates, cytokines, adenosine, bradykinin, caleticulin, bisaccordyl and phenolphthalein. EDRF is a vascular relaxation factor secreted by endothelial cells and has been identified as nitric oxide or a closely related derivative thereof (Palmer et al., Nature, 327: 524-526 (1987); Ignarro et al., Proc. Natl. Acad. Sci. USA, 84: 9265-9269 (1987).

Statins serve as lipid lowering agents and / or suitable nitric oxide production inducers. In addition, the relationship between statin use and delayed onset or development of macular degeneration has been demonstrated. G. McGwin, et al., British Journal of Ophthalmology, 87: 112125 (2003). Thus, statins can provide benefits to patients suffering from ocular conditions (such as macular degeneration, macular dystrophies and retinal dystrophies) when administered in combination with a compound of formula (I) or (II). Suitable statins include, by way of example only rosuvastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, belosstatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, atorvastatin, atorvastatin calcium ( Semicalcium salts of atorvastatin) and dihydrocompactin.

Suitable anti-inflammatory agents that can be used with the compounds of general formula (I) or (II) include, by way of example only, aspirin and other salicylates, chromolines, nedocromil, theophylline, zileuton, zafirlukast, montelukast , Pralulucaste, indomethacin and lipoxygenase inhibitors; Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxine; Prednisone, dexamethasone, cyclooxygenase inhibitors (ie, COX-1 and / or COX-2 inhibitors such as Naproxen ^™ or Celebrex ^™ ); Statins (for example, rosuvastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, belostatin, fluvastatin, compactin, lovastatin, dalvastatin, fludodostatin, atorvastatin, atorvastatin calcium (atorvastatin Semicalcium salts) and dihydrocompactin); And dissociated steroids.

In some embodiments, a suitable matrix metalloproteinase (MMP) inhibitor may be administered in combination with a compound of formula (I) or (II) to treat an ocular condition or condition associated with macular or retinal degeneration. MMPs are known to hydrolyze most extracellular matrix components. These proteases play important roles in many biological processes such as normal tissue remodeling, embryonic formation, wound healing and angiogenesis. However, overexpression of MMP has been observed in many disease states, including macular degeneration. MMP was mostly identified as multidomain zinc endopeptidase. Many metalloproteinase inhibitors are known (see, for example, Whittaker M. et al., Chemical Reviews 99 (9): 27352776 (1999)), which evaluated MMP inhibitors. Representative examples of MMP inhibitors are tissue inhibitors of metalloproteinases (TIMPs) (eg TIMP-1, TIMP-2, TIMP-3 or TIMP-4), α ₂ -macroglobulin, tetracycline (eg tetracycline, minocycline And doxycycline), hydroxamate (eg BATIMASTAT, MARIMISTAT and TROCADE), chelating agents (eg EDTA, cysteine, acetylcysteine, D-phenicylamine and gold salt), synthetic MMP fragments, succinylmercaptopurine, phosphonami Date and hydroxamic acid. MMP inhibitors that may be used in combination with a compound of formula (I) or (II) include, by way of example only, any of the inhibitors mentioned above.

The use of angiogenesis inhibitors or VEGF inhibitory drugs may also provide benefits for patients suffering from macular degeneration and dystrophies. Suitable angiogenesis inhibiting or VEGF inhibitory drugs that can be used in combination with at least one compound having the structure of Formula (I) or (II) include, for example, Rhufab V2 (Lucentis ^™ ), tryptophanyl-tRNA Synthetase (TrpRS), EyeOO1 (anti-VEGF PEGylated aptamer), squalane, Retaane ^™ 15 mg (Anecotab acetate for depot suspension; Alcon, Inc.), combretastatin A4 Prodrugs (CA4P), Macugen ^TM , Mifeprex ^TM (Mifeprex ^TM ) (ru486), Subtenon Triamcinolone Acetonide, Intravitreal Crystalline Triamcinolone Acetonide, Prinostat (AG3340-Synthetic Substrate) Metalloproteinase inhibitors, Pfizers), fluorosinolone acetonides (including Fluocinolone Guided Transplantation, Bausch & Lomb / Control Delivery System)), VEGFR inhibitors (Sugen) and VEGF-Trap (Regeneron / Aventis). Resveratrol, which can be extracted from walnut or red grape husks, has been demonstrated to have angiogenesis inhibitory activity, and in some embodiments may be used as a second or additional agent for the combination therapy disclosed herein. In addition, other trans-stilbene compounds are expected to exhibit similar activity.

In some embodiments, other pharmaceutical therapies that have been used to alleviate vision disorders can be used in combination with at least one compound of Formula (I) or (II). Such therapies include agents such as Visudyne ^™ , specific heat lasers, PKC 412, Endovion (NeuroSearch A / S), neurotrophic factors such as glial cell derived neurotrophic factors and ciliary nerves. Nutritional Factors, Diatagem, Dorzolamide, Phototrop, 9-cis-Retinal, Eye Drops (including Echo Therapy), eg, phospholine iodide or ecothioate or carbonic anhydride Enzyme inhibitors, AE941 from AEterna Laboratories, Inc., Sirna-027 from Sirna Therapeutics, Inc., pegaptanib (NeXstar Pharmaceuticals / Gilead Sciences), neurotropins (eg NT-4 / 5, Genentech ), Cand 5 (Acuity Pharmaceuticals), ranibizumab (Genentech), INS-37217 (Inspire Pharmaceuticals), integrin antagonists (e.g. from Jerini AG and Abbott Laboratories), EG-3306 from Ark Therapeutics Ltd., BDM- E (BioDiem Ltd.), thalidomide (eg, used by EntreMed, Inc.), cardiotropin-1 (Genen tech), 2-methoxyestradiol (Allergan / Oculex), DL-8234 (Toray Industries), NTC-200 (Neurotech), tetrathiomolybdate (University of Michigan), LYN-002 (Lynkeus Biotech), microalgae Microalgal compound (Aquasearch / Albany, Mera Pharmaceuticals), D-9120 (Celltech Group plc), ATX-S1O (Hamamatsu Photonics), TGF-beta2 (Genzyme / Celtrix), tyrosine kinase inhibitors (Allergan, SUGEN, Pfizer ), NX-278-L (NeXstar Pharmaceuticals / Gilead Sciences), Opt-24 (OPTIS France SA), Retinal Cell Ganglion Neuroprotectors (CogentNeurosciences), N-Nitropyrazole Derivatives (Texas A & M University System), KP-102 ( Krenitsky Pharmaceuticals) and cyclosporin A are used together, but are not limited to these. See US Patent Application Publication No. 20040092435.

In any case, in some embodiments multiple therapeutic agents, one of which is one of the compounds described herein, are administered in any order or even simultaneously. When administered concurrently, the multiple therapeutic agents are in some embodiments single, in some cases, multiple therapeutic agents, one of which is one of the compounds described herein, in some embodiments in any order or simultaneously. May be administered. When administered concurrently, the plurality of therapeutic agents may be provided in a single integrated form or may be provided in multiple forms (eg, a single pill or two separate pills). One of the therapeutic agents may be administered in multiple doses, or both therapeutic agents may be administered in multiple doses. If not administered at the same time, the time interval between multiple administrations may vary from more than zero weeks to less than four weeks. In addition, the combination methods, compositions and formulations are not limited to the use of only two agents; That is, multiple therapeutic agents can be administered in combination. By way of example only, a compound having a structure of Formula (I) or (II) may be provided with at least one sulfate agent and at least one nitric oxide production inducing agent; Compounds having the structure of formula (I) or (II) may be provided with at least one nitric oxide production inducer and at least one negatively charged phospholipid.

In addition, the compounds of formula (I) or (II) may be used in some embodiments with methods that may provide additional or synergistic benefits to the patient. Methods known, suggested or considered to alleviate visual impairment include, but are not limited to, limiting retinal translocation, photodynamic therapy (e.g., receptor-targeting PDT, Bristol-Myers Squibb, Co .; Porformer sodium for PDT injections). Berteporphine, QLT Inc., PDT and Lostaporphine, Miravent Medical Technologies; PDT and Talaphorpine Sodium, Nippon Petroleum; Motexapine Lutetium, Pharmacyclics, Inc.), antisense oligonucleotide methods [e.g., Nova Products validated by Novagali PharmaSA and using ISIS-13650 (Isis Pharmaceuticals), laser photocoagulation therapy, drusen laser method, macular hole surgery, macular displacement surgery, implantable miniature telescopes Method, pi-kinetic cardiovascular imaging (also known as Micro-Laser Therapy and Feeder Vessel Treatment), proton beam therapy, micro ruler Extreme therapy, retinal detachment and vitreous surgery, scleral swelling, submacular surgery, carotid hyperthermia, I phototherapy, RNA interference, in vitro blood filtration [also known as membrane differential filtration and rheotherapy ], Microchip transplantation, stem cell therapy, gene replacement therapy, ribozyme gene therapy [eg, hypoxia response element (Oxford Biomedica); Lentipak (Genetix); PDEF Gene Therapy (GenVec)], photoreceptor / retinal cell transplantation (eg, transplantable retinal epithelial cells (Diacrin, Inc.); Retinal cell transplantation (CellGenesys, Inc.) and acupuncture.

Additional combinations that can be used to benefit an individual include using genetic tests to determine whether the individual is a carrier of a mutant gene known to be associated with a particular ophthalmic condition. By way of example only, the human ABCA4 gene deficiency is believed to be associated with five different retinal phenotypes, including Stargardt's disease, abstract-antibody dystrophies, age-related macular degeneration and retinitis pigmentosa. See, eg, Allikmets et al., Science, 277: 1805-07 (1997); Lewis et al., Am. J. Hum. Genet, 64: 422-34 (1999); Stone et al., Nature Genetics, 20: 328-29 (1998); Allikmets, Am. J. Hum. Gen., 67: 793-799 (2000); Klevering, et al., Ophthalmology, 111: 546-553 (2004). In addition, an autosomal dominant form of Stargardt disease is caused by mutations in the ELOV4 gene. See, eg, Karan, et al., Proc. Natl. Acad. Sci. (2005). Patients with any of these mutations are expected to benefit therapeutically and / or prophylactically with the methods disclosed herein.

In addition, in some embodiments, a compound of Formula (I) or (II) or another agent that reduces serum retinol levels is combined with an agent that treats or alleviates the side effects resulting from serum retinol reduction (prior to, during or After administration). These side effects include dry skin and dry eyes. Thus, agents that alleviate or treat skin dryness or eye dry may be administered in some embodiments with a compound of Formula (I) or (II) or another agent that reduces serum retinol levels.

Example

The following examples provide exemplary methods for synthesizing compounds of formula (I) or (II). These examples are provided for illustrative purposes only and do not limit the claims provided herein.

Analytic LC Of MS  Way:

Method A:

Instrument: Waters UPLC / MS with UV detector (220 nM) and MS detector (ESI).

HPLC column: Waters Acquity BEH C18 1.7 μm 2.1 mm × 50 mm.

HPLC gradient: 0.6 mL / min, 95: 5 20 mM ammonium formate buffer (to pH 7.4 using ammonium hydroxide): From acetonitrile 20:80 ammonium formate buffer: 1.5 min with acetonitrile, 1.3 Keep for a minute.

Method B:

Instrument: Waters LC / MS with DAD detectors 220 and 254 nM and MS detector (ESI).

HPLC column: Merck LiChroCART 30-4 Purospher STAR RP-18, endcapped, 3 μm, 4.6 mm × 50 mm.

HPLC gradient: 1.5 mL / min, 95: 5 20 mM ammonium formate buffer (to pH 7.4 using ammonium hydroxide): 5:95 ammonium formate buffer from acetonitrile: 2.5 min with acetonitrile, 1.8 Keep for minutes

Method C:

Instrument: Waters Alliance with UV detector 220 nM and MS detector (ESI).

HPLC column: Waters XTerra MS C18, 5 μm, 4.6 mm × 50 mm.

HPLC gradient: 2 ml / min, 95: 5 water + 5% formic acid: acetonitrile + 5% formic acid for 0.5 minutes, followed by 5:95 aqueous: organic for 5 minutes, 0.5 minutes

Example  1: 5- (2- tert -Butyl-4- Chlorophenoxy ) Pentanic  synthesis

Methyl 5-bromovalerate (1.52 mL, 2.09 g, 10.7 mmol), 2-tert-butyl-4-chloro-phenol (2.4 g, 13 mmol) and calcium carbonate (1.4 g, 10.1 mmol) were added to anhydrous DMF ( 10 mL) and stirred at 120 ° C. for 2 hours. Water was added to the resulting mixture (80 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed twice with 10% sodium hydroxide (2 x 20 mL), water (1 x 20 mL), dried over sodium sulphate and evaporated in vacuo. 3.46 g (quant) of crude 1a were obtained and used in the next step without further purification.

A mixture of 10% sodium hydroxide (10 mL) and 1a (3.46 g) in dioxane (50 mL) was stirred overnight at room temperature. Dioxane was removed in vacuo and the remaining mixture was diluted with water and then extracted with ethyl acetate (2 x 20 mL). The pH of the aqueous layer was adjusted to 4 with concentrated hydrochloric acid and extracted with chloroform (1 × 20 mL). The organic layers were combined, dried over sodium sulfate and evaporated in vacuo. The product was triturated with hexane to give 1.87 g (61%, calculated from methyl 5-bromovaleric) white crystals 1-1. mp. 95.4-96.4 ℃

The following compounds were prepared by the above procedure using 2-tert-butyl-4-chlorophenol and the appropriate methanesulfonyl esters.

 The following compounds were prepared by the above procedure using 2-tert-butyl-4-chlorophenol, appropriate bromoester and cesium carbonate as the base of the first stage and lithium hydroxide as the base of the second stage.

Example  2: 5- (2- tert -Butyl-4- Chlorophenoxy ) -N- (4- Hydroxyphenyl ) Pentanamide Synthesis of

A mixture of carbonyl diimidazole (0.18 g, 1.11 mmol) and 1-1 (0.3 g, 1.05 mmol) was stirred in dichloroethane (2.5 mL) for 30 minutes, then 4-aminophenol (0.136 g, 1.25 mmol) ) And N, N-diisopropylethylamine (220 μl, 1.25 mmol) were added. The resulting solution was stirred for a further 4 hours. The solvent was evaporated and the remaining mixture was diluted with 20 mL ether and then washed with 1M hydrochloric acid (1 × 20 mL), the organic layer was dried over sodium sulphate and the solvent was evaporated. The product was triturated with diisopropyl ether to give 2-1 (6 mg, 25%).

Example  3: methyl  4- (5- (2- tert -Butyl-4- Chlorophenoxy ) Pentanamido ) Benzoate  synthesis

A mixture of oxalyl chloride (0.12 g, 0.95 mmol) and 1-1 (0.25 g, 0.88 mmol) in dichloroethane (5 mL) was stirred for 48 h at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in dichloroethane. To this solution was added methyl 4-aminobenzoate (0.146 g, 0.96 mmol) and N, N-diisopropylethylamine (350 μL, 2.0 mmol) and stirred overnight at room temperature. The mixture was washed with 20 mL 10% hydrochloric acid, the organic layer was dried over sodium sulfate and the solvent removed in vacuo to give 0.25 g (69%) of 3-1. LCMS: Method A, Rt: 1.85 min, M + H = 418.

The following compounds were prepared by the above procedure using oxalyl chloride or thionyl chloride.

Example  4: methyl  3- (3-((2- tert -Butyl-4- Chlorophenoxy ) methyl ) Cyclopentane - Carr Copying) Of cyclohexanecarboxylate  synthesis

A solution of EDC HCl (0.067 g, 0.35 mmol), N-hydroxybenzotriazole (0.053 g, 0.35 mmol) and 1-2 (0.109 g, 0.354 mmol) in anhydrous DMF was stirred at room temperature for 40 minutes and then methyl 3-aminocyclohexanecarboxylate hydrochloride (0.075 g, 0.385 mmol) and triethylamine (54 μL, 0.385 mmol) were added and stirring continued for 4 hours. The reaction mixture was diluted with 5% sodium bicarbonate (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with 10% hydrochloric acid (1 x 20 mL), brine (2 x 20 mL) and dried over sodium sulfate. The solvent was removed in vacuo and the oil residue was purified by flash chromatography on Kieselgel 6OH using chloroform as eluent to yield 0.1 g (63%) of 4-1 as a pale yellow oil. LCMS: Method A, Rt: 1.98 min, M + H = 450).

The following compounds were prepared by the above procedure using the appropriate amine.

Example  5: 4- (5- (2- tert -Butyl-4- Chlorophenoxy ) Pentanamido Synthesis of benzoic acid

A mixture of sodium hydroxide (1M, 3 mL) and 3-1 (0.25 g, 0.59 mmol) in dioxane (4 mL) was stirred at rt overnight. Adjust to pH 4 with 1M hydrochloric acid and extract the solution with 20 mL dichloromethane. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo to give 5-1 (0.2 g, 83%). LCMS: Method B, Rt: 2.08 min, M + H ₂ O = 421.

The following compounds were prepared by the above procedure from the appropriate esters.

The following compounds were prepared by the above procedure from a suitable ester and heated to 50 ° C. during the hydrolysis step.

Example  6: N- (4- (2- tert -Butyl-4- Chlorophenoxy ) Butyl) -4- Hydroxy -3- ( Morphol Linomethyl)- Benjamid  synthesis

To a solution of triethylamine (7.5 mL, 53.6 mol) and Boc-4-aminobutanol (5.07 g, 26.8 mmol) in dichloroethane (60 mL) was added methanesulfonyl chloride (2.3 mL, 29.5 mmol) at 0 ° C. It was. After the addition was completed, the mixture was stirred for a further 10 minutes. The reaction mixture was washed with 30 ml of cold saturated sodium bicarbonate and the organic layer was dried over magnesium sulfate. The solvent was evaporated to give 9.9 g of crude 6a as a yellow oil. This crude product was used in the next step.

24a (9.9 g, mmol) in anhydrous DMF (40 mL) in a mixture of potassium carbonate (6.0 g, 43.4 mol) and 2-tert-butyl-4-chlorophenol (4.0 g, 21.7 mmol) in anhydrous DMF (40 mL) ) Was added dropwise at 60 ° C. The resulting mixture was stirred at 60 ° C. overnight. The mixture was poured into water and extracted with 20 mL ethyl acetate and the organic layer was dried over sodium sulfate and the solvent removed in vacuo. The crude product (8.3 g) was purified by column chromatography using hexane / dichloromethane (1: 1) followed by dichloromethane using a gradient elution to give 2.41 g (31%) 6b.

A mixture of HCl (15 mL, 6.5 M) and 6b (2.41 g, 6.8 mmol) in dioxane was stirred overnight in ethyl acetate. The mixture was evaporated and the residue was recrystallized from a mixture of diethyl ether and ethyl acetate to give 1.41 g (81%) of 6c.

EDC HCl (0.074 g, 0.385 mmol), N-hydroxybenzotriazole (0.059 g, 0.385 mmol) in anhydrous DMF, triethylamine (54 μL, 0.385 mmol), 4-hydroxy-3-morpholine-4 A mixture of -ylmethyl-benzoic acid (0.091 g, 0.385 mmol) and 4- (2-tert-butyl-4-chloro-phenoxy) -butylamine hydrochloride (0.102 g, 0.35 mmol) was stirred at room temperature for 3 hours. It was. 20 mL of 5% sodium bicarbonate solution was added and the reaction was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with 10% hydrochloric acid (1 x 20 mL), brine (2 x 20 mL) and dried over sodium sulfate. The solvent was removed in vacuo and the residue was triturated with a mixture of diethyl ether and ethyl acetate. The crude product was purified by flash chromatography (Kieselgel 60H) using chloroform: methanol (10: 3) as eluent. Yield: 0.070 g (42%) 6-1. LCMS: Method A, Rt: 1.80 min, M + H = 475).

The following compounds were prepared by the above procedure using the appropriate acid.

Example  7: 4- (4- (2- tert -Butyl-4- Chlorophenoxy ) Butyl Carbamoyl Synthesis of benzoic acid

EDC HCl (0.084 g, 0.44 mmol), N-hydroxybenzotriazole (0.067 g, 0.44 mmol) in anhydrous DMF (5 mL), triethylamine (62 μL, 0.44 mmol), terephthalic acid mono-tert-butyl ester (0.098 g, 0.44 mmol) and 6c (0.117 g, 0.40 mmol) were stirred at room temperature for 1 hour. 5% sodium bicarbonate solution was added (20 mL) and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with 10% hydrochloric acid (1 x 20 mL), brine (2 x 20 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give 0.246 g of crude 7a.

Ester 7a was dissolved in 5 mL of dioxane, 4 mL of 6.5 M hydrogen chloride in dioxane was added and the mixture was stirred at rt for 24 h. The reaction mixture was poured into water and extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with water (1 x 20 mL), dried over sodium sulphate and the solvent was evaporated. Product 7-1 was crystallized from ether / hexanes, filtered and washed several times with ether / hexanes to give 0.127 (59%) of white crystals 25-1. LCMS: Method A, Rt: 1.36 min, M + H = 404.

The following compound was prepared by the above procedure.

Example  8

The following compounds were prepared by the procedures described herein.

The following examples provide exemplary methods for testing the efficacy and stability of the compounds of formula (I) or (II). These examples are provided for illustrative purposes only and are not intended to limit the claims provided herein.

Mouse and Rat  Research

The optimal dose of a compound of formula (I) or (II) to block the formation of A2E in abca4-/-mice can be determined using standard dose escalation studies. To determine the dose range to be used, a high productivity in vitro assay is developed that detects modulators that inhibit RBP-TTR interaction. Drug concentrations (IC ₅₀ values) that inhibit 50% of RBP-TTR interactions are calculated from the data. In these experiments, fenretinide, known as a potent inhibitor of RBP-TTR interaction, is used as a positive control. Representative data of a typical dose-response experiment is shown in FIG. 1. Examples of in vivo approaches using compounds having the structure of Formula (I) or (II) are disclosed below.

The effect of the compound of formula (I) or (II) on intraretinal all-trans-retinal from bright mice is determined by the dose dealing with the therapeutic dose in humans. The method includes treating mice with a single intraperitoneal dose in the morning. In some embodiments, an increase in the number of injections may be necessary to keep all-trans-retinal in the retina at reduced levels throughout the day.

ABCA4 knockout mouse. ABCA4 encodes a rim protein (RmP), an ATP-binding cassette (ABC) transporter in the extremity discs of rods and abstract photoreceptors. The transport substrate for RmP is unknown. Mice produced with knockout mutations in the abca4 gene (see Weng et al., Cell, 98: 13-23 (1999)) are useful for studying RmP function as well as the efficacy of candidates. It is useful for screening in vivo. These animals have complex ocular phenotypes: (i) slow photoreceptor degeneration, (ii) delayed recovery of rod sensitivity following photoexposure, (iii) increased atRAL and decreased atROL at photoreceptor disruption after photobleaching, (iv) structurally increased phosphatidylethanolamine (PE) and (v) lipofucin accumulation in RPE cells at the extremities. See Weng et al., Cell, 98: 13-23 (1999).

The denaturation rate of photoreceptors is monitored in treated and untreated wild-type and abca4-/-mice using two techniques. One is to study mice by ERG analysis at another time and is employed in the clinical diagnostic process. See Weng et al., Cell, 98: 13-23 (1999). An electrode was placed on the corneal surface of the anesthetized mouse, and the electrical response to light flash was recorded from the retina. The α-wave amplitude resulting from photoinduced hyperpolarization of the photoreceptor is a sensitive indicator of photoreceptor degeneration. Kezierski et al., Invest. Ophthalmol. Vis. Sci., 38: 498-509 (1997). ERG is performed in live animals. In some embodiments, the same mouse is analyzed repeatedly during the study. A clear technique for quantifying photoreceptor degeneration is histological analysis of retinal sections. At each time point, the number of photoreceptors remaining in the retina will be determined by counting the rows of photoreceptor nuclei in the outer nuclear layer.

Tissue extraction. Eye samples were thawed on ice in 1 ml PBS at pH 7.2 and homogenized by hand using a double glass-glass homogenizer. The sample was further homogenized after addition of 1 ml chloroform / methanol (2: 1, v / v). The sample was transferred to a borosilicate tube and the lipid was extracted with 4 ml of chloroform. The organic extract was washed with 3 ml of water and then the sample was centrifuged at 3,000 x g for 10 minutes. The chloroform phase was decanted and the aqueous phase was reextracted with an additional 4 mL chloroform. After centrifugation, the chloroform phases were combined and the sample was dried under nitrogen gas. Sample residue was resuspended in 200 μl 2-propanol and analyzed by HPLC as described below.

HPLC analysis. Chromatographic separations were performed on an Agilent Zorbax Rx-Sil column (5 μm, 4.6 × 250 mm) using Agilent 1100 series liquid chromatography with fluorescence and diode array detectors. The mobile phase was moved at a desired volume of volume per minute. Sample peaks were identified by comparison with retention time and absorption spectra of an authentic standard. Data was recorded as peak fluorescence (LU) obtained from the fluorescence detector.

Experimental mice received a compound of formula (I) or (II), and control mice received DMSO only and were then analyzed for A2E accumulation. The experimental group received from about 2.5 to about 20 mg / kg of the compound of formula (I) or (II) in about 10 to about 25 μl of DMSO per day. If no effect was observed even at the highest dose of about 50 mg / kg, the higher dose was tested. The control group was injected with 10-25 μl DMSO alone. Experimental or control substances were administered to mice by intraperitoneal (i.p.) injections during long term administration.

abca4-/-To assess the accumulation of A2E in mouse RPE, a compound of formula (I) or (II) of about 2.5 to about 20 mg / kg per day intraperitoneally injected into two-month-old abca4-/-mice Provided. After a predetermined period, both experimental and control mice were sacrificed and A2E levels in RPE were measured by HPLC.

Example  9: Rod Cell death  or Rod  Effect of Test Compounds on Functional Impairment

Experimental mice were administered a compound of formula (I) or (II), and control mice were administered DMSO alone, and the effects of test compounds on rod cell death or impaired rod function were analyzed. The experimental group received from about 2.5 to about 20 mg / kg of the compound of formula (I) or (II) in about 10 to about 25 μl of DMSO daily. If no effect was observed even at the highest dose of about 50 mg / kg, the higher dose was tested. The control group was injected with about 10 to about 25 μl of DMSO alone. Mice were administered to the experiment or control material by intraperitoneal injection for various durations of the experiment. Alternatively, mice were implanted with a pump that delivered the test or control material at a rate of about 0.25 μl / hr for various durations of the experiment.

Formulas for rod cell death or rod function impairment by monitoring ERG recordings and performing retinal histology for mice treated with compounds of Formula (I) or (II) at about 2.5 to about 20 mg / kg daily for about 8 weeks The effect of the compound of (I) or (II) was analyzed.

Example  10: Test for protection from light damage

The following study is described in Sieving, P.A., et al, Proc. Natl. Acad. Sci, 98: 1835-40 (2001). For chronic light-exposure studies, Sprague-Dawley male 7-week-old albino rats were acclimated to a 12:12 hour light / dark cycle of 5 lux fluorescent white light. About 20 to about 50 mg / kg compound of formula (I) or (II) in 0.18 ml DMSO was administered to chronic rats three times a day for 8 weeks by intraperitoneal injection. The control group was injected intraperitoneally with 0.18 ml DMSO. Rats were sacrificed two days after the last injection. If no effect was observed even at the highest dose of about 50 mg / kg, the higher dose was tested.

For acute light-exposure studies, rats were cancer-adjusted overnight, followed by a single intraperitoneal injection of a compound of formula (I) or (II) with about 20 to about 50 mg / kg in 0.18 ml DMSO under dark red light and ERG It remained dark for 1 hour prior to exposure to bleached light prior to measurement. Rats were exposed to 2,000 lux white fluorescent light for 48 hours. ERGs were recorded after 7 days and tissue structures examined immediately.

Rats were euthanized and eyeballs were extracted. The circumferential cell number of the outer nuclear layer thickness and rod rupture length (ROS) length was measured every 200 μm over the hemisphere, and the values were averaged to obtain a measure of cellular change over the entire retina. ERGs were recorded from chronic rats at 4 and 8 weeks of treatment. In acute rodents, rod recovery from bleaching light was tracked by cancer-compliant ERG by using stimuli that did not cause abstract contribution. Abstraction recovery was tracked by photocompliant EGG. Prior to ERG, animals were prepared and euthanized under dark red light. The pupils were expanded and ERGs were simultaneously recorded from both eyes using a gold-wire corneal loop.

Example  11: Fenretinide  Combination Therapies Included

Except for two additional treatment groups, mice and / or rats were tested by the methods described in Examples 8 and 9. In one of the additional treatment groups, mice and / or rats were treated with fenretinide increasing from about 5 mg / kg per day to about 50 mg / kg per day. In the second additional treatment group, mice and / or rat groups were treated with a combination of about 20 mg / kg of test compound per day and fenretinide increasing from about 5 mg / kg to about 50 mg / kg per day. The benefits for the combination therapy were analyzed as disclosed in Examples 8 and 9.

Example  12: abca4  In null mutant mice Of lipofucin (and / or A2E)  Effect of test compound on accumulation: step ( Phase ) I-dose response and effect on serum retinol

The effect of the compounds of formula (I) or (II) on serum retinol reduction in animal and human subjects has made it possible for the inventors to see if reduction of lipofucin and toxic bis-retinoid conjugate A2E can also be realized. To search. The rationale for this approach is based on two independent scientific evidences: 1) Reduction of intraocular vitamin A concentrations through inhibition of known visual cycle enzymes (11-cis retinol dehydrogenase) significantly reduces lipofucin and A2E. To make; And 2) animals maintained on a vitamin A deficient diet show a significant decrease in lipofuscin accumulation. Therefore, the purpose of this example was to investigate the effect of compounds of formula (I) or (II) in abca4 null mutant mice, an animal model in which large amounts of lipofucin and A2E accumulate in ocular tissues.

Initial studies were initiated by testing the effect of compounds of formula (I) or (II) on serum retinol. The animals were divided into groups, and DMSO, about 20 mg / kg of the compound of general formula (I) or (II), respectively, was administered for 14 days. At the end of the study period, blood was taken from the animals to prepare serum and the acetonitrile extract of the serum was analyzed by reverse phase LC / MS. UV-visible spectra and mass / charge analysis were performed to identify eluted peaks. Representative chromatographic data showing serum retinol levels in mice treated with DMSO or a compound having formula (I) are shown in FIG. 9. Steady state serum concentrations of test compounds (structures consistent with formula (I)) were also determined by HPLC (see FIG. 3). In addition, serum RBP levels were quantified by immunoassay (see FIG. 4).

Administration of an agent or agents that lower serum retinol levels in a patient without modulating at least one enzyme in the visual cycle is expected to treat macular and / or retinal dystrophy and degeneration or symptoms associated therewith. Assays, such as those disclosed herein, may be used in some embodiments to select additional agents having this activity, including agents selected from compounds having the structure of Formula (I) or (II).

Example  13: abca4  In null mutant mice Lipofucin  Effect of test compound on accumulation of (and / or A2E): step II  - abca4  Chronic Treatment of Null Mutant Mice

Abca4 null mutant mice were studied to evaluate the effect of compounds of formula (I) or (II) on A2E and A2E precursor reduction. Compounds of Formula (I) or (II) in DMSO (about 20 mg / kg, intraperitoneal) were administered to abca4 null mutant mice (BL6 / 129, 2 months old) daily for at least 28 days. Age / cell line-matched control mice received DMSO vehicle only. Mouse samples were taken on days 0, 14 and 28 (n = 3 per group) to extract eye and extract chloroform-soluble components (lipid, retinoid and lipid-retinoid conjugates). Mice were sacrificed by cervical dislocation, eyeballs were extracted and each snap snapped into a frozen vial. Sample extracts were then analyzed by HPLC with on-line fluorescence detection. Representative chromatographic traces obtained from eyecup extraction of abca4 null mutant mice are shown in FIG. 5. Similar studies were conducted to determine the effect of compound treatment of Formula (I) or (II) on retinal potential and morphological phenotype.

Example  14: Combination Therapies Including Test Compounds and Statins

Except for two additional treatment groups, mice and / or rats were tested in the manner described in Examples 8 and 9. In one of the additional treatment groups, mice and / or rats were treated at the optimal dose based on body weight: Lipitor ^® (atorvastatin), Mevacor ^® (lovastatin), Pravachol ^® (sodium pravastatin), Zocor ^TM (simvastatin), Leschol (flu) Treatment with appropriate statins). In the second additional treatment group, mice and / or rat groups were co-treated with about 20 mg / kg of compound of formula (I) or (II) per day and increasing doses of statin used in the previous step. Suggested human dosages for such statins are, for example: Lipitor ^® (atorvastatin) about 10 to about 80 mg / day, Mevacor ^® (lovastatin) about 10 to about 80 mg / day, Pravachol ^® (pravastatin sodium ) About 10 to about 40 mg / day, Zocor ^™ (simvastatin) about 5 to about 80 mg / day, Leschol (fluvastatin sodium) about 20 to about 80 mg / day. Dosages of statins for mice and / or rat subjects should be calculated based on body weight. The benefits of the combination therapy were analyzed as described in Examples 8 and 9.

Example  15: Combination Therapies Including Test Compounds, Vitamins, and Minerals

Mice and / or rats were tested according to the manner described in Example 13 except that selected vitamins and minerals were used. Compounds of formula (I) or (II) were administered orally or parenterally in combination with vitamins and minerals in an amount effective to inhibit the development and recurrence of macular degeneration. The test administration initially comprises about 20 mg / kg / day of a compound of formula (I) or (II) with about 100 to about 1000 mg of vitamin C, about 100 to about 600 mg of vitamin E, about 10,000 to about 40,000 With vitamin A of IU, about 50 to about 200 mg zinc and about 1 to about 5 mg copper for 15-20 weeks. The benefits of the combination therapy were analyzed as described in Examples 8 and 9.

Example  16: Analysis of Serum Retinol as a Function of Test Compound Concentration

ABCA4 null mutant mice were given daily for 28 days at the indicated dose (intraperitoneal) of the compound of formula (I) or (II) in DMSO (n = 4 per dose group). At the end of the study period, blood was drawn to prepare serum. After acetonitrile precipitation of serum proteins, the concentration of retinol and the compound of formula (I) or (II) were determined from the soluble phase by LC / MS. Identification of the eluted compound was confirmed by co-extraction of the same peak with UV-visible absorption spectrum and certification standard (see FIG. 2).

Example  17: TTR To / and to TTR Of compounds that inhibit gene expression in humans

Pure TTR polypeptides containing glutathione-S-transferase proteins and adsorbed to glutathione-induced wells in 96-well microtiter plates were contacted with test compounds from small molecule libraries in a buffer solution at physiological pH 7.0. Pure TTR polypeptides are disclosed in the art. See US Patent Application No. 20020160394, which is incorporated herein by reference. Test compounds included fluorescent tags in some embodiments. Samples were incubated for 5 minutes to 1 hour. Control samples were incubated in the absence of test compounds.

Buffer solutions containing test compounds were washed from the wells. Binding of test compounds to TTR polypeptide was detected by fluorescence measurement of well content. Test compounds that increase the fluorescence of the wells by at least 15% relative to the fluorescence of the wells where the test compounds were not incubated were identified as compounds that bind to the TTR polypeptide.

The identified test compounds were administered to human cell cultures transfected with TTR expression constructs in some embodiments and incubated at 37 ° C. for 10-45 minutes. Cell cultures of the same type that were not transfected were incubated for the same time without the addition of test compounds to serve as negative controls.

Then, Chirgwin et al., Biochem. 18, 5294-99, 1979 RNA was isolated from the two cultures described. Northern blots were prepared using 20-30 μg total RNA and hybridized with ³² P-labeled TTR-specific probes. Probes for detecting TTR mRNA transcription have already been disclosed. Test compounds that reduce TTR-specific signals compared to the signals obtained in the absence of test compounds have been identified as inhibitors of TTR gene expression.

Example  18: RBP To / and to RBP Of compounds that inhibit gene expression in humans

Pure apoRBP was contacted with test compound from small molecule library in physiological buffer solution at pH 7.0. Pure apoRBPs are disclosed in the art. See US Patent Application Publication No. 20030119715, which is incorporated herein by reference. Test compounds included fluorescent tags in some embodiments. Samples were incubated for 5 minutes to 1 hour. Control samples were incubated in the absence of test compounds. A competitive assay was also performed in the presence of holoRBP (RBP complexed with retinol).

Buffer solutions containing test compounds were washed from the wells. Binding of test compounds to apoRBP was detected by fluorescence measurement of well content. Test compounds that increase the fluorescence of the wells by at least 15% relative to the fluorescence of the wells where the test compounds were not incubated were identified as compounds that bind apoRBP.

Identified test compounds were administered to human cell cultures transfected with RBP expression constructs and incubated at 37 ° C. for 10-45 minutes. Cell cultures of the same type that were not transfected were incubated for the same time without the addition of test compounds to serve as negative controls.

Then, Chirgwin et al., Biochem. 18, 5294-99, 1979 RNA was isolated from the two cultures described. Northern blots were prepared using about 20 to about 30 μg total RNA and hybridized with ³² P-labeled RBP-specific probes. Test compounds that reduce RBP-specific signals relative to signals obtained in the absence of test compounds have been identified as inhibitors of RBP gene expression.

Example  19: serum retinol, Eye Cup Retinoid  Analysis of test compound effects on A2E and A2E levels

Compound Treatment of Formula (I) or ( II ). ABCA4-/-mice were given a compound of Formula (I) or (II) daily for 28 days (about 1.5 to about 15 μg / μl in 25 μl DMSO, intraperitoneally). At the start of the study mice were 1-2 months old and were either pigment (129 / SV) or albino (BALB / c) cell lines. Mice were bred under a 12 hour cycle of light / dark (30-50 lux) during the treatment period, and were anesthetized by intraperitoneal injection of ketamine (200 mg / kg) and xylazine (about 10 mg / kg), followed by cervical dislocation. To sacrifice.

Analysis of Serum Retinol. Whole blood was collected from the tail vein of the test compound-treated mice 18 hours after the last test compound administration (ie, on day 28). Serum was obtained from whole blood after centrifugation at 1,500 × g for 10 minutes. Serum protein was precipitated by addition of ice cold equilibrium volume of acetonitrile and centrifugation (10,000 × g, 10 minutes). The mother liquor was removed from the soluble phase and analyzed by HPLC using Agilent 1100 series capillary liquid chromatography with a diode-array detector. Chromatography was performed as described above.

Extraction and Analysis of Retinoids and A2E. After daily administration of a compound of Formula (I) or (II) (28 days), steady state levels of retinoids and A2E in the eyecups of ABCA4-/-mice were measured. Mice were sacrificed and eyeballs were extracted, then the retinoid or A2E was extracted using the posterior part of each eye. Methods and HPLC analysis techniques used to extract retinoids and A2E from eye tissue are disclosed. See, eg, Mata NL, Weng J, Travis GH. Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci USA. 2000; 97: 7154-7159; Weng J, et al .; Cell. 1999; 98: 13-23; Mata NL, et al .; Invest. Ophthalmol. Visual Sci. 2001; 42: 1685-1690. All samples were analyzed by HPLC using absorbance and fluorescence detection. In these analyses, column incubators were used to maintain the solvent and column temperatures at 40 ° C. Identification of the indicated compounds was confirmed by online spectrum analysis and co-extraction with certification standards.

Correlation between Serum Retinol, Intraocular Retinoid and A2E. From the collected data there was a direct correlation between the reduction of serum retinol and the reduction of retinoid levels and A2E levels in the eye cups of mammals. In particular, serum retinol reduction proceeded in a dose-dependent manner for both intraocular retinoid levels and intraocular A2E levels. For example, compounds of formula (I) or (II) have lowered serum retinol levels in mammals, which are substances in which reduction in serum retinol is associated with retinopathy and macular degeneration / ditrophy (eg A2E Affects the level of). Thus, agents such as those described herein that cause serum retinol reduction are also used in some embodiments to reduce intraocular A2E and retinoid levels, and furthermore, retinal diseases, such as retinopathy, based on lipofuscin in mammals. And macular degeneration / ditrophy.

Example  20: As a therapeutic target to arrest the accumulation of A2E RBP Validation of

Non-pharmacologic methods of reducing the lipofuscin fluorophore will be investigated to validate the therapeutic approach based on reducing RBP levels in patients. In this study, RBP protein levels will be reduced through genetic engineering. Two strains of mice expressing a heterozygous mutant in the retinol binding protein (RBP4) were generated. The first line has heterozygous mutations only at the RBP locus (RBP +/-); The second line carries heterozygous mutations at both the ABC4 and RBP4 loci (RBP4 +/-, ABC4 +/-). RBP +/− mice will be wild type at the ABC4 locus and therefore will not accumulate excess A2E fluorophores. However, ABC4 +/− mice will accumulate A2E fluorophores at levels that are approximately 50% of the levels observed in ABC4-/-(null homozygous) mice. The question is whether reduced RBP expression in RBP4 +/-, ABC4 +/- mice will affect the accumulation of toxic retinal fluorophores (eg A2E). FIG. 6 (Panel A) shows that serum retinol was dramatically reduced (> 50%) in RBP4 +/−, ABCA4 +/− mice compared to RBP4 + / +, ABCA4-/ − mice. The extent of retinol reduction in RBP4 +/-, ABCA4 +/- mice was compared to that observed in RBP4 + / +, ABCA4-/-mice receiving HPR over a 28-day period. Immunoassay analysis of RBP4 levels in the serum of these mice was consistent with retinol data (FIG. 6, Panel B).

A2E and precursor fluorophores (A2PE and A2PE-H ₂ ) levels in these mice with genetically reduced expression of RBP4 (RBP4 +/-, ABCA4 +/-) were monitored monthly over a period of 3 months, which was RBP4 +/- , Compared with fluorophore levels in ABCA4 +/− mice. Overall, it was demonstrated that the total fluorophore levels of RBP +/-, ABCA4 +/- mice were reduced by about 70% relative to the total fluorophore levels seen in ABCA4 +/- mice (Panels D and C, respectively). Indeed, fluorophore levels measured in RBP4 +/−, ABCA4 +/− mice approached the levels observed in wild type mice (compare Panels D and E). These data demonstrate that RBP is a therapeutic target for reducing fluorophore levels in the eye. Furthermore, through the data, an agent or method for inhibiting RBP transcription or translation in a patient can also (a) reduce serum retinol levels in that patient, and (b) provide therapeutic benefit to the retinol related diseases described herein. Proven to provide. In addition, agents or methods that increase RBP clearance in patients will also produce these effects and benefits.

Example  21: Guide Retinoid  dose

ABCA4-/-mice received ATRP (control) or ATRP + test compounds daily for 20 days (n = 3 mice per group). On the last day of administration, traces of [ ³ H] ATROL (0.32 pmol, 8 μCi) in 100 μl corn oil were administered to all animals. After 5 hours, the eye was taken out. As disclosed herein, one eye of each animal was used for retinoid analysis and the other eye was used for analysis of A2E and related fluorophores. The data showed a significant reduction in [ ³ H] ATROL uptake in animals treated with the test compound [FIG. 9]. Analysis of each retinoid species reveals a significant reduction in precursor substrate (ATRE) for visual chromophore biosynthesis and immediate precursor (AT-Ox) for A2E biosynthesis.

Example  22: gun Fluorophores  Effect of Test Compounds on Reduced Levels

Effect of test compound on decreasing total fluorophore levels in ABCA4-/-mice. Mice were treated as described in Example 13 above. At the end of the study, one eye from each animal was used to measure total fluorophore levels. In summary, one whole eye was homogenized in 1 ml phosphate buffered saline (50 mM Na ₂ HPO ₄ , 150 mM NaCl, pH 7.8). After homogenization, 1 ml methanol was added and the samples mixed thoroughly. The mixture was incubated at room temperature for 5 minutes and extracted twice with 2 mL hexanes. The extract was concentrated to about 400 μl for fluorescence measurements. The collected fluorescence spectra were obtained using a Spex Fluorolog-3 spectrofluorometer (Jobin Yvon Horiba, Edison, NJ) operated in ratio mode. Samples were excited at 488 nm and monitored at 500-700 m. The data show that the total fluorophore levels were significantly reduced in mice treated with the test compound [FIG. 10].

Example 23: Effect of Test Compounds on A2E and A2E Precursor Reduction

Mice were treated as described in Example 13 above. At the end of the study, one eye from each animal was used to measure A2E and A2PE-H2. In summary, one whole eye was homogenized in 1 ml phosphate buffered saline (50 mM Na ₂ HPO ₄ , 150 mM NaCl, pH 7.8). After homogenization, 1 ml methanol was added and the samples mixed thoroughly. The mixture was incubated at room temperature for 5 minutes and extracted twice with 2 mL hexanes. The solvent was evaporated under a stream of nitrogen and the sample residue was reconstituted in 200 μl isopropanol (IPA) for analysis by HPLC. Zorbax RX-Sil 5-μm equilibrated with phospholipid mobile phase (hexane: IPA: ethanol: 25 mM phosphate buffer: acetic acid 485: 376: 100: 37.5: 0.275 v: v) at a flow rate of 1 ml / min. Separate on column (250 x 4.6-mm). The data show that both A2E and its precursors were dramatically reduced in mice treated with the test compound compared to vehicle-treated mice (FIG. 11).

Human subject research

Detection of macular or retinal degeneration. The identification of abnormal blood vessels in the eye was performed, for example, by angiography. This identification helps to determine whether the patient is a candidate to use the candidate substance and whether to use other treatment methods for the patient to prevent or block further visual impairment. Angiography can be used to follow up treatment and further assess any new blood vessel growth.

Fluorescence angiography (fluorescence angiography, fluorescence angiography) is a technique for visualizing the choroid and retinal circulation on the eye side. After intravenous infusion of fluorescent dyes, multiframe photography (angiography), ophthalmoscope evaluation (vascular endoscopy), or Heidelberg retinal angiography (confocal injection laser system) were performed. Additionally, the retina can be examined in an OCT non-invasive manner to obtain cross-sectional images of the retina in high resolution. Fluorescent angiography is used to assess a wide range of retinal and choroidal diseases by analyzing leakage or possible damage to blood vessels feeding the retina. See also Berkow et al., Am. J. Ophthalmol. 97: 143-7 (1984)] was used to determine the abnormalities of the visual nerve and iris.

Similarly, angiography with indocyanine green is used to visualize the blood flow circulation in the posterior part of the eye. Fluorescence is more effective in the study of retinal circulation, and indocyanine is more effective in viewing deeper choroidal vascular layers. The use of indocyanine angiography is helpful when angiogenesis is not observed with fluorescein dye alone.

Appropriate human doses for compounds having the structure of formula (I) will be determined using standard dose escalation studies.

Example  24: Clinical trial to test the efficacy of test compounds for treating macular degeneration

As a preliminary test, all ophthalmic examinations, including fluorescence angiography, visual acuity, electrophysiological parameters, and biochemical and rheological parameters, were performed on all human patients. Inclusion criteria include: At least one eye has a visual acuity between 20/160 and 20/32, and drusen, areolar atrophy, pigment aggregation, pigment epithelial detachment or subretinal angiogenesis. AMD symptoms such as. Pregnant or lactating patients were excluded from the study. Other exclusion criteria include previous vitrectomy or other AMD surgical procedures, severe scarring or severe concurrent ocular disease (uncontrolled glaucoma).

Groups of patients diagnosed with macular degeneration or undergoing A2E, lipofucin or drusen formation in the eye were divided into control and experimental groups. Compounds of formula (I) or (II) were administered to the experimental group daily. Placebo was administered to the control group in the same regime as the test compound was administered to the experimental group.

Administration of a compound of formula (I) or (II) or placebo to a patient may be administered orally or parenterally in an amount effective to inhibit the progression or recurrence of macular degeneration. The effective dose ranges from about 1 to about 4000 mg / m 2 up to 3 times a day.

One method of measuring progression of macular degeneration in both the control and experimental groups is the line assessment and forced choice method (Ferris et al. Am J Ophthalmol, 94: 97-98 (1982)). The highest corrected visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) chart (Long Island Lighthouse, NY). Visual acuity is recorded in logMAR. One line change on the ETDRS chart corresponds to 0.1 logMAR. Common additional methods for measuring the progression of macular degeneration in control and experimental groups include Humphrey visual field examination, microfield of view (eg using Micro Perimeter MP-1 from NIDEK) and measuring the autofluorescence of certain compounds in the patient's eyes. The use of visual field inspection, including but not limited to monitoring.

Additional methods for measuring the progression of macular degeneration in both control and experimental groups include fundus photography, Heidelberg retinal angiography (or M. Hammer, et al., Ophthalmologe 2004 Apr. Observation of autofluorescence changes over time using the technique described in [Epub ahead of patent]], and fluorescence angiography taken at baseline, 3 months, 6 months, 9 months and 12 months. Investigations of morphological changes include (a) the size, characteristics and distribution of drusen; (b) development and progression of choroidal neovascularization; (c) other interval fundus changes or abnormalities; (d) read speed and / or read accuracy; (e) dark spot size; Or (f) changes in the size and number of the mapped atrophic lesions. In addition, Amsler Grid Test and color testing are optionally performed.

To statistically evaluate visual improvement during drug administration, the examiner uses an ETDRS (LogMAR) chart and standardized refractive and visual acuity protocols. Evaluating the mean ETDRS (LogMAR) best corrected visual acuity (BCVA) from baseline by the post-treatment visit interval obtained can help statistically determine vision improvement.

To assess ANOVA (group difference analysis) between control and experimental groups, using two groups of ANOVA, SAS / STAT software (SAS Institutes Inc., Cary, NC) The results of repeated measures analysis by unstructured covariance were compared with the average change in ETDRS (LogMAR) visual acuity from baseline through available post treatment interval visits.

Serum retinol levels were evaluated as follows: After acetonitrile precipitation of serum proteins, the concentration of retinol was determined from the soluble phase by LC / MS. Alternatively, serum retinol levels are reported in Drrikell et al., J Chromatogr, 1982, 231, 439-444 or Futterman et al., Invest. Ophthalmol Vis Sci, 1975, 14, 125, were evaluated as described.

Toxicity assessments after the start of the study were evaluated every three months in the following year, every four months in the following year, and every six months in the following year. Plasma levels of test compounds and their metabolites, serum retinol and / or RBP were also assessed during this visit. Toxicity assessments include patients using the compounds of formula (I) or (II) and control patients.

Example  25: RBP - TTR  And CYP ₄₅₀ For Non-retinoid  Adjuster's Activity

Compound of formula (I) surface
IC ₅₀ CYP
Suppression rate 5- (2-tert-butyl-4-chlorophenoxy) -N- (4-hydroxyphenyl) pentanamide 1 μM About 50% 7- (2-tert-butyl-4-chlorophenoxy) -N- (4-hydroxyphenyl) heptanamide 1 μM About 40% 2- (4- (5- (2-tert-butyl-4-chlorophenoxy) pentaneamido) phenyl) acetic acid 1 μM <10% 3-((2-tert-butyl-4-chlorophenoxy) methyl) -N- (4-hydroxyphenyl) cyclopentanecarboxamide 5 μM <10% 4- (5- (2-tert-butyl-4-chlorophenoxy) pentaneamido) benzoic acid 5 μM <10% 4- (3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentaneamido) benzoic acid 5 μM <10% 5- (2-tert-butyl-4-chlorophenoxy) pentanoic acid 0.1 μM ≤10% 4- (2-tert-butyl-4-chlorophenoxy) butanoic acid 1 μM About 15% 2- (3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentyl) acetic acid NT NT 7- (2-tert-butyl-4-chlorophenoxy) heptanoic acid 0.5 μM About 15% 4- (5- (2-tert-butyl-4-chlorophenoxy) pentaneamido) benzamide NT NT 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclohexanecarboxylic acid 0.16 μM <10% 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentanecarboxylic acid 0.4 μM <10% 3-((2-tert-butyl-4-chlorophenylamino) methyl) cyclopentanamide NT NT 5- (2-tert-butyl-4-chlorophenylthio) pentanoic acid NT NT NT: Not tested

Table 1 shows the IC ₅₀ values and cytochrome P ₄₅₀ inhibition of representative compounds having the structures of formulas (I) and (II).

Example  26: general formula (I) or (2) to reduce A2E production II Test for the efficacy of the compound of

In addition, compounds of formula (I) or (II) in reducing or limiting A2E production in the patient eye using the same protocol design, including the pre-test, administration, dose and toxicity assessment protocols described in Example 24. Was tested for efficacy.

Methods for measuring or monitoring the formation of A2E include the measurement / monitoring of autofluorescence of certain compounds in the patient's eye, the use of visual acuity and visual field tests (e.g. including microscopic fields), reading speed and / or as described in Example 23. Or read accuracy tests, measurements of the size and number of dark spots and / or superficial atrophic lesions. The statistical analysis described in Example 23 was used.

Example  27: Lipofucin  General formula (I) or ( II Test for the efficacy of the compound of

In addition, using the same protocol design, including the pre-test, dosing, dose and toxicity assessment protocols described in Example 24, the formula (I) or (II) of formula (I) or (II) in reducing or limiting Compounds were tested for efficacy. The statistical analysis described in Example 24 was used.

Tests used as surrogate markers for specific therapeutic efficacy include visual and visual field tests (eg, microscopic field), reading speed and / or reading accuracy tests, dark spots and / or in the patient's eye as disclosed in Example 24. Measurement of the size and number of geographic atrophy lesions, and the use of autofluorescence measurements / monitoring of certain compounds.

Example  28: Drusen  General formula (I) or ( II Test for the efficacy of the compound of

In addition, general formula (I) or (II) in reducing or limiting drusen production and formation in the patient eye using the same protocol design, including the pre-test, administration, dose and toxicity assessment protocols described in Example 24. ) Compounds were tested for efficacy. The statistical analysis described in Example 24 was used.

Methods for measuring the progression of drusen formation in both the control and experimental groups include fundus photography and baseline, followed by fluorescein angiography visited at 3, 6, 9, and 12 months. Investigation of morphological changes includes (a) drusen size, properties and distribution; (b) development and progression of choroidal neovascularization; (c) may include changes in fundus changes or abnormalities in other sections. Other tests that can be used as surrogate markers for specific therapeutic efficacy include visual and visual field examinations (including microscopic field) in the patient's eye as described in Example 23; Read speed and / or read accuracy checks; Measuring size and number of dark spots and / or geographic atrophy lesions; And the use of autofluorescence measurement / monitoring of certain compounds.

Example  29: macula In this nutrition  Genetic testing

Deletion of the human ABCA4 gene is thought to be associated with five unique retinal phenotypes, including Stargardt's disease, abstractor-antibody dystrophies, age-related macular degeneration (both dry and wet form) and pigmented retinitis. . See, eg, Allikmets et al., Science, 277: 1805-07 (1997); Lewis et al., Am. J. Hum. Genet, 64: 422-34 (1999); Stone et al., Nature Genetics, 20: 328-29 (1998); Allikmets, Am. J. Hum. Gen., 67: 793-799 (2000); Klevering, et al., Ophthalmology, 111: 546-553 (2004). In addition, an autosomal dominant form of Stargardt disease is caused by mutations in the ELOV4 gene. Karan, et al., Proc. Natl. Acad. Sci. (2005). Patients can be diagnosed with Stargardt's disease by any of the following analyzes:

For sequence mutation (s), a direct-sequencing mutation detection strategy that may comprise sequencing all exons and adjacent intron regions of ABCA4 or ELOV4;

-Genomic southern analysis;

Microarray analysis including all known ABCA4 or ELOV4 variants; And

Analysis by liquid chromatography tandem mass spectrometry combined with immunocytochemical analysis using antibodies and Western assay.

Diagnosis can be predicted and / or ascertained by fundus imaging, fluorescein angiography, and scanning laser ophthalmoscope images along with the patient and his family history.

Example  30: Formulation

Example  30a: oral composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of any compound of Formula (I) or Formula (II) was mixed with 750 mg of starch. The mixture was incorporated into an oral dosage form suitable for oral administration such as hard gelatin capsules.

Example  30b: Parenteral  Composition

To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of any compound of formula (I) or formula (II) are dissolved in DMSO and then 10 ml of 0.9% sterile saline and Mixed. The mixture was incorporated into a dosage unit form suitable for administration by injection.

Example  30c: Sublingual  (reshuffle Lozenge Composition

To prepare pharmaceutical compositions for oral delivery, such as hard lozenges, 100 mg of any compound mix of Formula (I) or Formula (II) is added to 420 mg of powdered sugar, 1.6 ml of white corn syrup, 2.4 Ml of distilled water and 0.42 ml of peppermint extract were mixed. The mixture was kneaded gently and poured into a mold to form a lozenge suitable for oral administration.

Example  30d: composition for inhalation

To prepare a pharmaceutical composition for inhalation delivery, 20 mg of any compound of Formula (I) or Formula (II) was mixed with 50 mg of citric anhydride and 100 ml of 0.9% sodium chloride solution. The mixture was incorporated into an inhalation delivery unit such as a nebulizer suitable for inhalation administration.

Example  30e: rectal gel composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of any compound of Formula (I) or Formula (II) was added 2.5 g of methylcellulose (1500 mPa), 100 mg of methylparaben, 5 g of glycerin And 100 ml of purified water. The resulting gel mixture was then incorporated into a rectal delivery unit such as a syringe suitable for rectal administration.

Example  30f: topical gel composition

To prepare a pharmaceutical topical gel composition, 100 mg of any compound of formula (I) or formula (II) were added with 1.75 g of hydroxypropyl cellulose, 10 ml of propylene glycol, 10 ml of isopropyl myristate. And 100 ml of purified alcohol USP. The resulting gel mixture was then incorporated into a container such as a tube suitable for topical administration.

Example  30g: for eye drops Liquid  Composition

To prepare a pharmaceutical eye drop formulation, 100 mg of any compound of Formula (I) or Formula (II) was mixed with 0.9 g of NaCl in 100 ml of purified water and then filtered using a 0.2 micron filter. The resulting isotonic solution was then incorporated into an eye drop delivery unit such as an eyecup container suitable for eye drop administration.

The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes shown are intended to be included within the spirit and scope of the present application and the appended claims.

Claims (74)

A compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof; And pharmaceutically acceptable excipients:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisostere,-(C = O) -NR ¹ R, NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) -OR or-(C ₁ -C ₇ ) alkyl- (C═O) -NR ¹ R Is;
R is H or

ego;
G is -OR ¹ ,-(C ₁ -C ₆ ) alkyl,-(C ₁ -C ₆ ) alkyl-OR ¹ , halogen, -CO ₂ R ¹ ,-(C ₁ -C ₆ ) alkyl-CO ₂ R ¹ , NHR ¹ ,-(C ₁ -C ₆ ) alkyl-NHR ¹ ,-(C = O) NHR ¹ ,-(C ₁ -C ₆ ) alkyl- (C = O) NHR ¹ , -NHR ¹ (C ═O) R ¹ or — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ;
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is halogen. The pharmaceutical composition according to claim 1, wherein the compound has a structure of formula (II) or an active metabolite or a pharmaceutically acceptable prodrug, salt or solvate thereof:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H or

Is;
G is -OR ¹ ,-(C ₁ -C ₆ ) alkyl,-(C ₁ -C ₆ ) alkyl-OR ¹ , halogen, -CO ₂ R ¹ ,-(C ₁ -C ₆ ) alkyl-CO ₂ R ¹ , NHR ¹ ,-(C ₁ -C ₆ ) alkyl-NHR ¹ ,-(C = O) NHR ¹ ,-(C ₁ -C ₆ ) alkyl- (C = O) NHR ¹ , -NHR ¹ (C ═O) R ¹ or — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ;
R ¹ is H or (C ₁ -C ₆ ) alkyl. The pharmaceutical composition of claim 2, wherein A is O. 4. The pharmaceutical composition of claim 3, wherein B is — (CH ₂ ) _n and n is 1-6 or B is — (C ₃ -C ₈ ) cycloalkyl. The compound of claim 4, wherein E is (C═O) —OR, a carboxylic acid bioisotope, — (C═O) —NR ¹ R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR or Pharmaceutical composition wherein-(C ₁ -C ₇ ) alkyl- (C═O) -NR ¹ R. The compound of claim 5, wherein R is

Phosphorus pharmaceutical composition. The pharmaceutical composition of claim 4, wherein E is (C═O) —OR. 8. The pharmaceutical composition of claim 7, wherein R is H. The compound of claim 1, wherein 5- (2-tert-butyl-4-chlorophenoxy) -N- (4-hydroxyphenyl) pentanamide, 7- (2-tert-butyl-4-chlorophenoxy)- N- (4-hydroxyphenyl) heptanamide, 4- (5- (2-tert-butyl-4-chlorophenoxy) pentaneamido) benzoic acid, 4- (3-((2-tert-butyl-4 -Chlorophenoxy) methyl) cyclopentaneamido) benzoic acid, 5- (2-tert-butyl-4-chlorophenoxy) pentanoic acid, 4- (2-tert-butyl-4-chlorophenoxy) butanoic acid, 2- (3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentyl) acetic acid, 7- (2-tert-butyl-4-chlorophenoxy) heptanoic acid, 4- (5- ( 2-tert-butyl-4-chlorophenoxy) pentaneamido) benzamide, 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclohexanecarboxylic acid, 3-((2-tert-butyl 4-chlorophenoxy) methyl) cyclopentanecarboxylic acid, 3-((2-tert-butyl-4-chlorophenylamino) methyl) cyclopentanamide, 4- (3-((2-tert-butyl-4- Chlorophenoxy) methyl) cyclopentanecarboxamido) benzoic acid and 5- (2-tert-part Pharmaceutical composition selected from the group consisting of methyl-4-chlorophenylthio) pentanoic acid. The pharmaceutical composition of claim 1, which inhibits retinol-retinol binding protein-transtyretin complex formation, wherein the IC ₅₀ of inhibition is less than about 5 μM. The pharmaceutical composition of claim 10, wherein the IC ₅₀ of inhibition is less than about 1 μM. The pharmaceutical composition of claim 1, wherein the composition inhibits cytochrome P ₄₅₀ to less than about 50%. The pharmaceutical composition of claim 12, wherein the composition inhibits cytochrome P ₄₅₀ to less than about 10%. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is used for the treatment of vitreoretinal disease. The method of claim 1, wherein the vitreoretinal disease is selected from the group consisting of dry macular degeneration, photoreceptor degeneration, superficial atrophy, macular dystrophy, diabetic retinopathy, wet macular degeneration, prematurity retinopathy, and pigmented retinitis. Pharmaceutical Compositions Selected. A compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof; And pharmaceutically acceptable excipients or carriers:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl or optionally substituted heteroaryl;
X is halogen. The compound of claim 16, further comprising a compound having the structure of formula (II): or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof; And pharmaceutical compositions with pharmaceutically acceptable excipients or carriers:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl, (C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl or optionally substituted heteroaryl. The pharmaceutical composition of claim 16, wherein the composition is present in an amount sufficient to reduce serum retinol or ocular retinol levels or activity in a mammal. A method of treating vitreoretinal disease, comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
X is halogen. The method of claim 19, comprising administering to the mammal a therapeutically effective amount of a compound of formula (II) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl, (C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. The method of claim 19 or 20, wherein the compound modulates retinol binding protein level or activity in a mammal and the retinol binding protein is RBP4. 20. The method of claim 19, wherein the vitreoretinal disease is selected from dry macular degeneration, photoreceptor degeneration, superficial atrophy, macular dystrophy, diabetic retinopathy, wet macular degeneration, prematurity retinopathy, or pigmented retinitis. . Mammalians have therapeutically effective amounts of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof that modulates serum retinol binding protein or transthyretin level or activity in a mammal. A method of lowering serum retinol binding protein or transthyretin level or activity in a mammal, the method comprising administering to:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
X is halogen. The method of claim 23, wherein the therapeutically effective amount of a compound of formula (II) or an active metabolite or pharmaceutically acceptable prodrug, salt thereof, that modulates serum retinol binding protein or transthyretin level or activity in a mammal Or administering a solvate:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl, (C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. The method of claim 23, wherein the serum retinol binding protein is RBP4. The method of claim 23, wherein the compound of formula (I) inhibits transcription of a retinol binding protein or transthyretin in a mammal. The method of claim 23, wherein the compound of formula (I) inhibits transcription of a retinol binding protein or transthyretin in a mammal. The method of claim 23, wherein the compound of formula (I) inhibits the binding of retinol to the retinol binding protein. The method of claim 23, wherein the compound of formula (I) inhibits binding of the retinol binding protein to transthyretin. The method of claim 23, wherein the compound of formula (I) increases the retinol binding protein or transthyretin removal rate in a mammal. Treating a retinol related disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof: Way:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
X is halogen. 32. The method of claim 31 comprising administering a therapeutically effective amount of a compound of formula (II): or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. 32. The method of claim 31, wherein the retinol related disease is hyperplasia, idiopathic intracranial hypertension, amyloidosis, Alzheimer's disease or Alstrom-Halgren syndrome. Administering to the mammal a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof that does not directly modulate the activity of the enzyme or protein in the visual cycle: To reduce serum retinol levels in mammals with dry form of age-related macular degeneration:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
X is halogen. 35. The therapeutically effective amount of a compound of formula (II) below or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof according to claim 34, which does not directly modulate the activity of the enzyme or protein in the visual cycle. A method comprising administering:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. The method of claim 34, wherein the compound of formula (I) does not directly inhibit or bind to the enzyme or protein in the visual cycle. The method of claim 34, wherein the compound of formula (I) does not affect rhodopsin regeneration rate. The method of claim 34, wherein the compound of formula (I) does not essentially exacerbate delayed dark adaptation. 35. The method of claim 34, wherein the compound of formula (I) limits the diffusion of autofluorescence around map atrophy, dark spots, dark spots or lesions, or photoreceptor degeneration. A method of treating hyperretinolemia comprising administering to a mammal a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
X is halogen. The method of claim 40 comprising administering a therapeutically effective amount of a compound of formula (II): or an active metabolite or pharmaceutically acceptable prodrug or solvate thereof:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. 41. The method of claim 40, wherein hyperretinolemia is associated with vitreoretinal disease. 41. The method of claim 40, wherein the hyperretinolemia is associated with diabetes or Alzheimer's disease. Administering to a mammal an effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof, wherein the compound of formula (I) is a retinol- Methods of treating retinol related diseases in mammals that inhibit retinol binding protein-transtyretin complex formation and IC ₅₀ inhibition is less than about 5 μM:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
X is halogen. 45. The method of claim 44, comprising administering to the mammal an effective amount of a compound of formula (II) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof: ) Compound inhibits retinol-retinol binding protein-transtyretin complex formation, and IC _5O inhibition is less than about 5 μM:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. The method of claim 44, wherein the IC ₅₀ inhibition is less than about 1 μM. 45. The method of claim 44, wherein the compound of formula (I) further inhibits cytochrome P ₄₅₀ to less than about 50%. 48. The method of claim 47, wherein the compound of formula (I) further inhibits cytochrome P ₄₅₀ to less than about 10%. A therapeutically effective amount of a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof, which modulates retinol binding protein or transthyretin level or activity in a mammal, A method of treating type I or type II diabetes in a mammal, comprising administering:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
X is halogen. 50. An effective amount of a compound of formula (II) below or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof according to claim 49 which modulates retinol binding protein or transthyretin level or activity in a mammal. A method comprising administering to a mammal:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. Serum retinol or ocular tissue in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) and / or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof: How to reduce retinol levels:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
X is halogen. The method of claim 51, comprising administering to the mammal an effective amount of a compound of formula (II): and / or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof.

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl, or-(C ₃ -C ₈ ) heterocycloalkenyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^{1 - (C = O) -R} , - (C 1 -C 7) alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R a;
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. The method of claim 51, wherein the mammal is a human. The method of claim 51, wherein the serum retinol or ocular tissue retinol level is reduced by at least 20%. 52. The method of claim 51, wherein nitric oxide production inducers, anti-inflammatory agents, physiologically acceptable antioxidants, physiologically acceptable minerals, negatively charged phospholipids, carotenoids, statins, angiogenesis inhibitors, matrix metalloproteinase inhibitors, resveratrol and other Further comprising administering at least one additional agent selected from the group consisting of a trans-stilbene compound and 13-cis-retinoic acid. A composition comprising a compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where
A is O, NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl, or-(C ₃ -C ₈ ) heterocycloalkenyl; Provided that-(C ₂ -C ₇ ) heteroalkyl is a nitrogen atom, -C (= O)-, -S-, -S (= O)-, -S (= O) _2- , -NR ¹ (C = O)-,-(C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -0 (C = O) NR ^1- , -NR ¹ ( May contain C═O) O—, —0 (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O— or —0 (C═O) — No;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^1- (C = 0) -R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, - (C 1 -C 7) alkyl, ^{- (C = O) -NR 1} R, C 1 -C 4 Alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, substituted aryl, arylalkyl, -C (O) R ² , hydroxy- (C ₁ -C ₆ Alkyl), aryloxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, -0-C (O) NR ² R ³ , -NR ² R ³ (C = O) OR ¹ or -SO ₂ NR ² R ³ ;
R ² and R ³ are each independently H, C ₁ -C ₆ alkyl and C ₃ -C ₆ Selected from cycloalkyl;
R is H, optionally substituted aryl or optionally substituted heteroaryl, provided that when B is -S-, R cannot be pyrimidine; When B is-(C ₂ -C ₇ ) alkyl R cannot be imidazole;
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is halogen;
Provided that the compound of Formula (I) cannot be a dimer. The compound of claim 56, wherein E is (C═O) —OR, —0- (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisotope, — (C═O) -NR ¹ R, NR ^1- (C═O) —R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R composition. The composition of claim 56 wherein X is Cl and D is isopropyl, tert-butyl or cyclopropyl. 57. The composition of claim 56, wherein A is O. The composition of claim 56, wherein B is-(CH ₂ ) _n and n is 1-6 or B is-(C ₃ -C ₈ ) cycloalkyl. A pharmaceutical composition comprising the compound of claim 56 and a pharmaceutically acceptable carrier or excipient. A method of treating vitreoretinal disease, comprising administering to a mammal a therapeutically effective amount of the composition of claim 56. A compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where
A is O;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl; Provided that-(C ₂ -C ₇ ) heteroalkyl is a nitrogen atom, -C (= O)-, -S-, -S (= O)-, -S (= O) _2- , -NR ¹ (C = O)-,-(C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -0 (C = O) NR ^1- , -NR ¹ ( May contain C═O) O—, —0 (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O— or —0 (C═O) — No;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^1- (C = 0) -R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, - (C 1 -C 7) alkyl, ^{- (C = O) -NR 1} R, C 1 -C 4 Alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, substituted aryl, arylalkyl, -C (O) R ² , hydroxy- (C ₁ -C ₆ Alkyl), aryloxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, -0-C (O) NR ² R ³ , -NR ² (C = O) OR ¹ or -SO ₂ NR ² R ³ ;
R ² and R ³ are each independently H, C ₁ -C ₆ alkyl and C ₃ -C ₆ Selected from cycloalkyl;
R is H,-(C ₂ -C ₇ ) alkyl, optionally substituted aryl or optionally substituted heteroaryl, provided that when B is -S-, R cannot be pyrimidine; When B is-(C ₂ -C ₇ ) alkyl R cannot be imidazole;
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is halogen. 64. The compound of claim 63, wherein B is-(CH ₂ ) _n and n is 1-6 or B is-(C ₃ -C ₈ ) cycloalkyl. The compound of claim 64, wherein E is (C═O) —OR, a carboxylic acid bioisotope, — (C═O) —NR ¹ R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R compounds. 67. The compound of claim 65, wherein E is (C = O) -OR. 67. The compound of claim 66, wherein D is isopropyl, tert-butyl or cyclopropyl. 68. The compound of claim 67, wherein X is Cl and D is tert-butyl. A compound of formula (I) or an active metabolite or pharmaceutically acceptable prodrug, salt or solvate thereof:

Where
A is NH or S;
B is a bond,-(C ₂ -C ₇ ) alkyl,-(C ₂ -C ₇ ) alkenyl,-(C ₃ -C ₈ ) cycloalkyl,-(C ₂ -C ₇ ) heteroalkyl,-(C ₃ -C ₈ ) heterocycloalkyl,-(C ₃ -C ₈ ) cycloalkenyl or-(C ₃ -C ₈ ) heterocycloalkenyl;
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl or methylenecyclopentyl;
E is (C = O) -OR, -0- (C = O) -R,-(C = O) -R, -OR, carboxylic acid bioisotope,-(C = O) -NR ¹ R, NR ^1- (C = 0) -R; - (C ₁ -C ₇₎ alkyl, - (C = O) -OR, - (C 1 -C 7) alkyl, ^{- (C = O) -NR 1} R, C 1 -C 4 Alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ Alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, substituted aryl, arylalkyl, -C (O) R ² , hydroxy- (C ₁ -C ₆ Alkyl), aryloxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, -OC (O) NR ² R ³ , -NR ² (C = O) OR ¹ or -SO ₂ NR ² R ³ ;
R ² and R ³ are each independently H, C ₁ -C ₆ Alkyl and C ₃ -C ₆ cycloalkyl;
R is H,-(C ₂ -C ₇ ) alkyl, optionally substituted aryl or optionally substituted heteroaryl;
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is halogen. The compound of claim 69, wherein B is — (CH ₂ ) _n and n is 1-6 or B is — (C ₃ -C ₈ ) cycloalkyl. The compound of claim 70, wherein E is (C═O) —OR, a carboxylic acid bioisotope, — (C═O) —NR ¹ R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR or - (C ₁ -C ₇₎ alkyl, ^{- (C = O) -NR 1} R compounds. The compound of claim 71, wherein E is (C═O) —OR. 73. The compound of claim 72, wherein D is isopropyl, tert-butyl or cyclopropyl. 75. The compound of claim 73, wherein X is Cl and D is tert-butyl.

Images