Use of thyroid beta agonists

文档序号：1911391 发布日期：2021-12-03 浏览：14次中文

阅读说明：本技术 甲状腺β-激动剂的应用 (Use of thyroid beta agonists ) 是由 B·连 R·汉利 M·迪纳曼于 2017-04-24 设计创作，主要内容包括：本发明涉及甲状腺激素受体β激动剂及其应用。本发明公开了式I的甲状腺激素受体β激动剂及其在制造用于治疗X-连锁肾上腺脑白质营养不良的药物中的应用。(The invention relates to a thyroid hormone receptor beta agonist and application thereof. The invention discloses a thyroid hormone receptor beta agonist of a formula I and application thereof in preparing a medicament for treating X-linked adrenoleukodystrophy.)

1. Use of a thyroid hormone receptor beta agonist in the manufacture of a medicament for the treatment of X-linked adrenoleukodystrophy, wherein the thyroid hormone receptor beta agonist is a compound of formula I:

wherein:

g is selected from the group consisting of-O-, -S (O)_a-、-CH₂-、-CF₂-, -CHF-, -C (O) -, -CH (OH) -, -NH-and-N (C)₁-C₄Alkyl) -group(s);

a is an integer from 0 to 2;

t is selected from the group consisting of- (CR)^a ₂)_m-、-CH＝CH-、-O(CR^b ₂)(CR^a ₂)_p-、-S(CR^b ₂)(CR^a ₂)_p-、-N(R^b)(CR^b ₂)(CR^a ₂)_p-、-N(R^b)C(O)(CR^a ₂)_p-、-(CR^a ₂)_pCH(NR^c ₂)-、-C(O)(CR^a ₂)_n-、-(CR^a ₂)_nC(O)-、-(CR^a ₂)C(O)(CR^a ₂) and-C (O) NH (CR)^b ₂) -a group of compositions;

m＝0-3；

n＝0-2；

p＝0-1；

each R^aIndependently selected from hydrogen, optionally substituted-C₁-C₄Alkyl, halogen, -OH, optionally substituted-O-C₁-C₄Alkyl, -OCF₃Optionally substituted-S-C₁-C₄Alkyl, -NR^c ₂Optionally substituted-C₂-C₄Alkenyl and optionally substituted-C₂-C₄Alkynyl;

each R^bIndependently selected from hydrogen, optionally substituted-C₁-C₄Alkyl, optionally substituted-C₂-C₄Alkenyl and optionally substituted-C₂-C₄Alkynyl;

each R^cIndependently selected from hydrogen, optionally substituted-C₁-C₄Alkyl, optionally substituted-C₂-C₄Alkenyl, optionally substituted-C₂-C₄Alkynyl and optionally substituted-C (O) -C₁-C₄Alkyl groups;

R¹and R²Each independently selected from halogen, optionally substituted-C₁-C₄Alkyl, optionally substituted-S-C₁-C₃Alkyl, optionally substituted-C₂-C₄Alkenyl, optionally substituted-C₂-C₄Alkynyl, -CF₃、-OCF₃Optionally substituted-O-C₁-C₃Alkyl and cyano;

R³and R⁴Each independently selected from hydrogen, halogen, -CF₃、-OCF₃Cyano, optionally substituted-C₁-C₁₂Alkyl, optionally substituted-C₂-C₁₂Alkenyl, optionally substituted-C₂-C₁₂Alkynyl, optionally substituted- (CR)^a ₂)_mAryl, optionally substituted (CR)^a ₂)_mCycloalkyl, optionally substituted (CR)^a ₂)_mHeterocycloalkyl, -OR^d、-SR^d、-S(O)_1-2R^e、-S(O)₂NR^fR^g、-C(O)NR^fR^g、-C(O)OR^h、-C(O)R^e、-N(R^b)C(O)R^e、-N(R^b)C(O)NR^fR^g、-N(R^b)S(O)₂R^e、-N(R^b)S(O)₂NR^fR^gand-NR^fR^gA group of (a);

each R^dIs selected from optionally substituted-C₁-C₁₂Alkyl, optionally substituted-C₂-C₁₂Alkenyl, optionally substituted-C₂-C₁₂Alkynyl, optionally substituted- (CR)^b ₂)_nAryl, optionally substituted- (CR)^b ₂)_nCycloalkyl, optionally substituted- (CR)^b ₂)_nHeterocycloalkyl and-C (O) NR^fR^gA group of (a);

each R^eIs selected from optionally substituted-C₁-C₁₂Alkyl, optionally substituted-C₂-C₁₂Alkenyl, optionally substituted-C₂-C₁₂Alkynyl, optionally substituted- (CR)^a ₂)_nAryl, optionally substituted- (CR)^a ₂)_nCycloalkyl and optionally substituted- (CR)^a ₂)_nHeterocycloalkyl group;

R^fand R^gEach independently selected from hydrogen, optionally substituted-C₁-C₁₂Alkyl, optionally substituted-C₂-C₁₂Alkenyl, optionally substituted-C₂-C₁₂Alkynyl, optionally substituted- (CR)^b ₂)_nAryl, optionally substituted- (CR)^b ₂)_nCycloalkyl and optionally substituted- (CR)^b ₂)_nHeterocycloalkyl, or R^fAnd R^gMay be taken together to form an optionally substituted heterocycle which may contain a substituent selected from the group consisting of O, NR^bAnd S, wherein any up to four substituents are selected from the group consisting of optionally substituted-C₁-C₄Alkyl, -OR^bOxo, cyano, -CF₃Optionally substituted phenyl and-C (O) OR^hA group of (a);

each R^hIs optionally substituted-C₁-C₁₂Alkyl, optionally substituted-C₂-C₁₂Alkenyl, optionally substituted-C₂-C₁₂Alkynyl, optionally substituted- (CR)^b ₂)_nAryl, optionally substituted- (CR)^b ₂)_nCycloalkyl and optionally substituted- (CR)^b ₂)_nA heterocycloalkyl group;

R⁵is selected from the group consisting of-OH, optionally substituted-OC₁-C₆Alkyl, -OC (O) R^e、-F、-NHC(O)R^e、-NHS(O)_1-2R^e、-NHC(S)NH(R^h) and-NHC (O) NH (R)^h) A group of (a);

x is P (O) YR¹¹Y’R¹¹；

Y and Y' are each independently selected from the group consisting of-O-and-NR^v-a group of compositions;

when Y and Y' are-NR^vWhen is attached to-NR^vR of (A-C)¹¹Independently selected from the group consisting of-H, - [ C (R)^z)₂]_q-COOR^y、-C(R^x)₂COOR^y、-[C(R^z)₂]_q-C(O)SR^yand-cycloalkylene-COOR^yA group of (a);

when Y and Y' are-O-, are linked toR of-O-¹¹Independently selected from the group consisting of-H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH₂-heterocycloalkyl (wherein the cyclic moiety contains a carbonate or a thiocarbonate), optionally substituted-alkylaryl, -C (R)^z)₂OC(O)NR^z ₂、-NR^z-C(O)-R^y、-C(R^z)₂-OC(O)R^y、-C(R^z)₂-O-C(O)OR^y、-C(R^z)₂OC(O)SR^y-alkyl-S-C (O) R^y-alkyl-S-alkylhydroxy and-alkyl-S-alkylhydroxy; or

R¹¹And R¹¹Taken together is-alkyl-S-S-alkyl-to form a cyclic group, or R¹¹And R¹¹Taken together are the groups:

wherein:

v, W and W' are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or

V and Z are linked together via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, 0-1 of which is a heteroatom and the remaining atoms are carbon, the cyclic group being substituted with a hydroxyl, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy group linked to a carbon atom three atoms from the two Y groups linked to phosphorus; or

V and Z are linked together via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, the cyclic group being fused to an aryl group at the β -and γ -positions of Y linked to the phosphorus; or

V and W are linked together via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy, said substituent being attached to one of said carbon atoms that is three atoms away from Y attached to said phosphorus; or

Z and W are linked together via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or

W and W' are linked together via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

z is selected from the group consisting of-CHR^zOH、-CHR^zOC(O)R^y、-CHR^zOC(S)R^y、-CHR^zOC(S)OR^y、-CHR^zOC(O)SR^y、-CHR^zOCO₂R^y、-OR^z、-SR^z、-CHR^zN₃、-CH₂Aryl, -CH (aryl) OH, -CH (CH ═ CR)^z ₂)OH、-CH(C≡CR^z)OH、-R^z、-NR^z ₂、-OCOR^y、-OCO₂R^y、-SCOR^y、-SCO₂R^y、-NHCOR^z、-NHCO₂R^y、-CH₂NH aryl, - (CH)₂)_q-OR^zAnd- (CH)₂)_q-SR^zA group of (a);

q is an integer of 2 or 3;

each R^zIs selected from the group consisting of R^yand-H;

each R^ySelected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;

each R^xIndependently selected from the group consisting of-H and alkyl, or R^xAnd R^xTaken together to form a cyclic alkyl group; and is

Each R^vSelected from the group consisting of-H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

with the following conditions:

a) v, Z, W, W' is not all-H; and is

b) When Z is-R^zWhen then at least one of V, W and W' is not-H, alkyl, aralkyl, or heterocycloalkyl;

c) when G is-O-and T is-CH₂-、R¹And R²Is bromine, R³Is isopropyl, R⁴Is hydrogen and R⁵When is-OH, then X is not P (O) (OH)₂Or P (O) (OCH)₂CH₃)₂；

Or a salt, ester, or prodrug of said compound of formula I.

2. The use of claim 1, wherein G is selected from the group consisting of-O-and-CH₂-the group of compositions.

3. The use of claim 1, wherein R⁵Selected from-OH, optionally substituted-OC₁-C₆Alkyl and-OC (O) R^e。

4. The use of claim 1, wherein R⁴Selected from hydrogen, halogen, -CF₃、-OCF₃Cyano, optionally substituted-C₁-C₁₂Alkyl, optionally substituted-C₂-C₁₂Alkenyl and optionally substituted-C₂-C₁₂Alkynyl.

5. The use of claim 1, wherein T is-O (CR)^b ₂)(CR^a ₂)_p-, and p is 0 or 1.

6. The method of claim 1Use, wherein Y and Y' are-O-and R linked to-O-)¹¹Independently selected from the group consisting of-H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and-C (R)^z)₂-OC(O)R^yGroup (d) of (a).

7. Use according to claim 1, wherein R is when Y and Y' are-O-)¹¹And R¹¹Taken together to form a radical

8. The use of claim 7, wherein V is substituted aryl and W' are hydrogen.

9. The use of claim 1, wherein the thyroid hormone receptor β agonist is to be administered at a dose of 5 mg/day, 10mg every other day, or 15mg every other day.

10. The use of claim 1, wherein the thyroid hormone receptor beta agonist is administered daily, every other day, or intermittently for three months, followed by a period of one month in which the thyroid hormone receptor beta agonist is not administered.

Technical Field

The present invention relates to thyroid beta agonists and methods, compositions and uses thereof for the treatment of X-linked adrenoleukodystrophy.

Background

Adrenoleukodystrophy (also known as X-linked adrenoleukodystrophy, X-ALD) is a disease of peroxisomal fatty acid beta oxidation that causes the accumulation of very long chain fatty acids in tissues throughout the body. The most severely affected tissues are myelin, adrenal cortex and Leydig cells (Leydig cells) in the central nervous system. As an X-linked disease, X-ALD is primarily manifested in men; however, approximately 50% of heterozygote women exhibit some symptoms later in life. The most severe form of X-ALD is known as brain ALD and is characterized by a rapidly progressing inflammatory demyelinating process in brain tissue. This form is more common in early childhood and is common in children under 12 years of age. Patients with brain-based ALD typically experience rapid regression to a vegetative state within 3 to 5 years. A more common form of X-ALD is known as Adrenomyeloneuropathy (AMN). This form of disease manifests late in life (usually between the ages of 25 and 45). AMN affects the spinal cord and motor neurons, but has no inflammatory component or brain involvement. Patients with AMN first develop difficulty walking, resulting in progressive dyskinesia with leg paralysis.

ALD is caused by mutations in the gene of ATP-binding cassette transporter d1(ABCD1) located on the X chromosome. ABCD1 acts to transport Very Long Chain Fatty Acids (VLCFA) into the peroxisomes for degradation. In X-ALD, defective ABCD1 leads to accumulation of VLCFA. Individuals with X-ALD exhibit very high levels of unbranched saturated very long chain fatty acids (in particular, wax acid (26: 0)). Treatment options for X-ALD are limited due to the absence of curative methods, nor approved therapies.

Accordingly, there is a need for improved methods for treating X-ALD.

Disclosure of Invention

Provided herein are methods for treating X-linked adrenoleukodystrophy, the methods comprising administering to a subject a pharmaceutical composition comprising a thyroid hormone receptor beta agonist of formula I

Wherein R is¹-R⁵G, T and X are as defined in the specification.

Certain aspects of the invention provide a method for treating X-linked adrenoleukodystrophy, the method comprising administering to a subject a thyroid hormone receptor beta agonist of formula I

Formula I

Wherein:

g is selected from the group consisting of-O-, -S (O)_a-、-CH₂-、-CF₂-, -CHF-, -C (O) -, -CH (OH) -, -NH-and-N (C)₁-C₄Alkyl) -group(s);

a is an integer from 0 to 2;

m＝0-3；

n＝0-2；

p＝0-1；

each R^bIndependently selected from hydrogen, optionally substituted-C₁-C₄Alkyl, optionally substituted-C₂-C₄Alkenyl and optionally substituted-C₂-C₄Alkynyl;

R³and R⁴Each independently selected from hydrogen, halogen, -CF₃、-OCF₃Cyano, optionally substituted-C₁-C₁₂Alkyl, optionally substituted-C₂-C₁₂Alkenyl, optionally substituted-C₂-C₁₂Alkynyl, optionally substituted- (CR)^a ₂)_mAryl, optionally substituted (CR)^a ₂)_mCycloalkyl, optionally substituted (CR)^a ₂)_mHeterocycloalkyl, -OR^d、-SR^d、-S(O)_1- ₂R^e、-S(O)₂NR^fR^g、-C(O)NR^fR^g、-C(O)OR^h、-C(O)R^e、-N(R^b)C(O)R^e、-N(R^b)C(O)NR^fR^g、-N(R^b)S(O)₂R^e、-N(R^b)S(O)₂NR^fR^gand-NR^fR^gA group of (a);

R^fand R^gEach independently selected from hydrogen, optionally substituted-C₁-C₁₂Alkyl, optionally substituted-C₂-C₁₂Alkenyl, optionally substituted-C₂-C₁₂Alkynyl, optionally substituted- (CR)^b ₂)_nAryl, optionally substitutedSubstituted- (CR)^b ₂)_nCycloalkyl and optionally substituted- (CR)^b ₂)_nHeterocycloalkyl, or R^fAnd R^gMay be taken together to form an optionally substituted heterocycle which may contain a substituent selected from the group consisting of O, NR^bAnd S, wherein any up to four substituents are selected from the group consisting of optionally substituted-C₁-C₄Alkyl, -OR^bOxo, cyano, -CF₃Optionally substituted phenyl and-C (O) OR^hA group of (a);

R⁵is selected from the group consisting of-OH, optionally substituted-OC₁-C₆Alkyl, -OC (O) R^e、-F、-NHC(O)R^e、-NHS(O)_1- ₂R^e、-NHC(S)NH(R^h) and-NHC (O) NH (R)^h) A group of (a);

x is P (O) YR¹¹Y’R¹¹；

Y and Y' are each independently selected from the group consisting of-O-and-NR^v-a group of compositions;

when Y and Y' are-O-, R attached to-O-¹¹Independently selected from the group consisting of-H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substitutedCH (A) of₂-heterocycloalkyl (wherein the cyclic moiety contains a carbonate or a thiocarbonate), optionally substituted-alkylaryl, -C (R)^z)₂OC(O)NR^z ₂、-NR^z-C(O)-R^y、-C(R^z)₂-OC(O)R^y、-C(R^z)₂-O-C(O)OR^y、-C(R^z)₂OC(O)SR^y-alkyl-S-C (O) R^y-alkyl-S-alkylhydroxy and-alkyl-S-alkylhydroxy; or

R¹¹And R¹¹Taken together is-alkyl-S-S-alkyl-to form a cyclic group, or R¹¹And R¹¹Taken together are the groups:

wherein:

or V and Z are linked together via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, of which 0-1 atom is a heteroatom and the remaining atoms are carbon, the cyclic group being substituted with a hydroxyl, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy group linked to a carbon atom three atoms from the two Y groups linked to phosphorus; or

v and W are linked together via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy, said substituent being attached to one of said carbon atoms that is three atoms away from Y attached to said phosphorus;

z and W are linked together via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

w and W' are linked together via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

p is an integer of 2 or 3;

with the following conditions:

a) v, Z, W, W' is not all-H; and is

b) When Z is-R^zWhen then at least one of V, W and W' is not-H, alkyl, aralkyl, or heterocycloalkyl;

each R^zIs selected from the group consisting of R^yand-H;

each R^ySelected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;

each R^xIndependently selected from the group consisting of-H and alkyl, or R^xAnd R^xTaken together to form a cyclic alkyl group;

each R^vSelected from the group consisting of-H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

and pharmaceutically acceptable salts and prodrugs of the thyroid hormone receptor beta agonists of formula I, and pharmaceutically acceptable salts of the prodrugs.

When G is-O-and T is-CH₂-、R¹And R²Is bromine, R³Is isopropyl, R⁴Is hydrogen and R⁵When is-OH, then X is not P (O) (OH)₂Or P (O) (OCH)₂CH₃)₂；

Or a salt, ester, or prodrug of said thyroid hormone receptor beta agonist of formula I.

In certain embodiments, G is selected from the group consisting of-O-and-CH₂-the group of compositions.

In certain embodiments, R⁵Selected from-OH, optionally substituted-OC₁-C₆Alkyl and-OC (O) R^e。

In certain embodiments, R⁴Selected from hydrogen, halogen, -CF₃、-OCF₃Cyano, optionally substituted-C₁-C₁₂Alkyl, optionally substituted-C₂-C₁₂Alkenyl and optionally substituted-C₂-C₁₂Alkynyl.

In certain embodiments, T is-O (CR)^b ₂)(CR^a ₂)_p-, and p is 0 or 1.

In certain embodiments, Y and Y' are-O-, R attached to-O-¹¹Independently selected from the group consisting of-H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and-C (R)^z)₂-OC(O)R^yGroup (d) of (a).

In certain embodiments, when Y and Y' are-O-, R¹¹And R¹¹Taken together to form the group:

wherein:

q is an integer of 2 or 3;

with the following conditions:

a) v, Z, W, W' is not all-H; and is

b) When Z is-R^zWhen then at least one of V, W and W' is not-H, alkyl, aralkyl, or heterocycloalkyl;

each R^zIs selected from the group consisting of R^yand-H;

each R^ySelected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;

each R^xIndependently selected from the group consisting of-H and alkyl, or R^xAnd R^xTaken together to form a cyclic alkyl group;

each R^vSelected from the group consisting of-H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl.

In certain embodiments, V is substituted aryl and W' are hydrogen.

In certain embodiments, the thyroid hormone receptor beta agonist is administered at a dose of 5 mg/day, 10mg every other day, or 15mg every other day.

In certain embodiments, the pharmaceutical composition is administered daily, every other day, or intermittently for a period of three months, followed by a period of one month where the pharmaceutical composition is not administered.

In certain embodiments, the thyroid hormone receptor beta agonist is administered daily, every other day, or intermittently for three months, followed by a period of one month in which the thyroid hormone receptor beta agonist is not administered.

Drawings

Figure 1 is a bar graph showing the effect of compounds assayed on ABCD2 expression. The numbers in parentheses indicate the concentration of each compound in μ M. Figure 2 is a graph showing qPCR analysis of compounds determined at 3 and 10 days of incubation.

Figure 3 contains three panels (panel a-panel C) showing the effect of incubation of X-ALD cell lines with compound 2 and compound 4 on VLCFA β -oxidation (panel a), D3C26:0 synthesis (panel B), and ABCD2 induction (panel C).

Figure 4 contains two panels (panel a and panel B) showing the effect of incubating X-ALD cell lines with compound 1, compound 2, compound 3 and compound 4, and 4-PBA and sobetirome for 10 days on VLCFA β -oxidation (panel a) and on de novo synthesis of VLCFA (panel B).

Figure 5 contains three panels (panel a-panel C) showing the effect of incubating X-ALD cell lines with compound 1, compound 2, compound 3 and compound 4, and 4-PBA and sobetirome for 3 days on ABCD2 induction (panel a), VLCFA β -oxidation (panel B), and VLCFA de novo synthesis (panel C).

Fig. 6 is a line graph depicting data showing the time course of C26:0-LPC levels in whole blood from the initial cohort.

FIG. 7 is a line graph depicting data for a time course of C26:0-LPC levels in whole blood from a second cohort.

Fig. 8 is a bar graph depicting data showing the change from baseline in C26:0 for compound 3 in whole blood.

Figure 9 is a bar graph depicting data showing the time course of C26:0-LPC levels in plasma from the initial cohort.

Detailed Description

In certain aspects, provided herein are methods related to the treatment of X-linked adrenoleukodystrophy (X-ALD). In certain aspects, the invention provides methods of treating X-ALD comprising, for example, administering to a subject a thyroid hormone receptor beta agonist in a therapeutically effective amount.

In certain embodiments, the thyroid receptor β agonist is a phosphonic acid-containing compound or a salt, ester, or prodrug of the phosphonic acid-containing compound (such as those disclosed in U.S. patent 7,829,552 and U.S. patent publication 2009-0232879, which are hereby incorporated by reference in their entirety), and specifically relates to the compounds and prodrugs disclosed herein. In certain embodiments, the thyroid receptor β agonist is a compound of formula I:

wherein:

g is selected from the group consisting of-O-, -S (O)_a-、-CH₂-、-CF₂-, -CHF-, -C (O) -, -CH (OH) -, -NH-and-N (C)₁-C₄Alkyl) -group(s);

a is an integer from 0 to 2;

m＝0-3；

n＝0-2；

p＝0-1；

each R^bIndependently selected from hydrogen, optionally substituted-C₁-C₄Alkyl, optionally substituted-C₂-C₄Alkenyl and optionally substituted-C₂-C₄Alkynyl;

R³and R⁴Each independently selected from hydrogen, halogen, -CF₃、-OCF₃Cyano, optionally substituted-C₁-C₁₂Alkyl, optionally substituted-C₂-C₁₂Alkenyl, optionally substituted-C₂-C₁₂Alkynyl, optionally substituted- (CR)^a ₂)_mAryl, optionally substituted (CR)^a ₂)_mCycloalkyl, optionally substituted (CR)^a ₂)_mHeterocycloalkyl, -OR^d、-SR^d、-S(O)_1- ₂R^e、-S(O)₂NR^fR^g、-C(O)NR^fR^g、-C(O)OR^h、-C(O)R^e、-N(R^b)C(O)R^e、-N(R^b)C(O)NR^fR^g、-N(R^b)S(O)₂R^e、-N(R^b)S(O)₂NR^fR^gand-NR^fR^gA group of (a);

R⁵is selected from the group consisting of-OH, optionally substituted-OC₁-C₆Alkyl, -OC (O) R^e、-F、-NHC(O)R^e、-NHS(O)_1- ₂R^e、-NHC(S)NH(R^h) and-NHC (O) NH (R)^h) A group of (a);

x is P (O) YR¹¹Y’R¹¹；

Y and Y' are each independently selected from the group consisting of-O-and-NR^v-a group of compositions;

when Y and Y' are-O-, R attached to-O-¹¹Independently selected from the group consisting of-H, alkyl, optionally substituted aryl, optionally substitutedOptionally substituted heterocycloalkyl, optionally substituted CH₂-heterocycloalkyl (wherein the cyclic moiety contains a carbonate or a thiocarbonate), optionally substituted-alkylaryl, -C (R)^z)₂OC(O)NR^z ₂、-NR^z-C(O)-R^y、-C(R^z)₂-OC(O)R^y、-C(R^z)₂-O-C(O)OR^y、-C(R^z)₂OC(O)SR^y-alkyl-S-C (O) R^y-alkyl-S-alkylhydroxy and-alkyl-S-alkylhydroxy; or

R¹¹And R¹¹Taken together is-alkyl-S-S-alkyl-to form a cyclic group, or R¹¹And R¹¹Taken together are the groups:

wherein:

p is an integer of 2 or 3;

optionally with the proviso that:

a) v, Z, W, W' is not all-H; and is

b) When Z is-R^zWhen then at least one of V, W and W' is not-H, alkyl, aralkyl, or heterocycloalkyl;

each R^zIs selected from the group consisting of R^yand-H;

each R^ySelected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;

each R^xIndependently selected from the group consisting of-H and alkyl, or R^xAnd R^xTaken together to form a cyclic alkyl group;

each R^vSelected from the group consisting of-H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl;

and pharmaceutically acceptable salts and prodrugs of the compounds of formula I, and pharmaceutically acceptable salts of the prodrugs.

When G is-O-and T is-CH₂-、R¹And R²Is bromine, R³Is isopropyl, R⁴Is hydrogen and R⁵When is-OH, then X is not P (O) (OH)₂Or P (O) (OCH)₂CH₃)₂；

Or a salt, ester, or prodrug of said compound of formula I.

In certain embodiments, G is selected from the group consisting of-O-and-CH₂-the group of compositions.

In certain embodiments, R⁵Selected from-OH, optionally substituted-OC₁-C₆Alkyl and-OC (O) R^e。

In certain embodiments, wherein T is-O (CR)^b ₂)(CR^a ₂)_p-, and p is 0 or 1.

In certain embodiments, when Y and Y' are-O-, R¹¹And R¹¹Taken together to form the group:

wherein:

q is an integer of 2 or 3;

optionally with the proviso that:

a) v, Z, W, W' is not all-H; and is

b) When Z is-R^zWhen then at least one of V, W and W' is not-H, alkyl, aralkyl, or heterocycloalkyl;

each R^zIs selected from the group consisting of R^yand-H;

each R^ySelected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;

each R^xIndependently selected from the group consisting of-H and alkyl, or R^xAnd R^xTaken together to form a cyclic alkyl group;

each R^vSelected from the group consisting of-H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl and lower acyl.

In certain embodiments, V is substituted aryl and W' are hydrogen.

In certain preferred embodiments, the thyroid hormone receptor β agonist is a compound as shown in table 1 or a salt, ester or prodrug of said compound.

TABLE 1 exemplary thyroid receptor beta agonists

In certain embodiments, the present invention provides a pharmaceutical formulation for the treatment of X-ALD in a human patient, comprising an effective amount of a compound of formula I and one or more pharmaceutically acceptable excipients.

In certain embodiments, the subject is a mammal (e.g., a human).

Exemplary pharmaceutical compositions

In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of any preceding claim and a pharmaceutically acceptable carrier.

The compositions and methods of the invention can be employed to treat an individual in need thereof. In certain embodiments, the subject is a mammal, such as a human or non-human mammal. When administered to an animal (e.g., a human), the composition or compound is preferably administered as a pharmaceutical composition that includes, for example, a compound of the invention or a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions (such as water or physiological buffered saline) or other solvents or carriers (vehicles) such as glycols, glycerol, oils (such as olive oil) or injectable organic esters. In a preferred embodiment, when such a pharmaceutical composition is for human administration, particularly for invasive routes of administration (i.e., routes that circumvent transport or diffusion through epithelial barriers such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient may be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in the form of dosage units such as tablets, capsules (including dispersion capsules and gelatin capsules), granules, lyophils for reconstitution, powders, solutions, syrups, suppositories, injections and the like. The composition may also be present in a transdermal delivery system, for example, a skin patch. The composition may also be present in a solution suitable for topical administration (e.g., eye drops).

The pharmaceutically acceptable carrier may contain a physiologically acceptable agent that acts, for example, to stabilize, increase solubility, or to increase absorption of a compound, such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier (including physiologically acceptable agents) depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymeric matrix into which the compound of the invention may be incorporated (e.g., a compound of the invention). For example, liposomes comprising phospholipids or other lipids are relatively simple nontoxic, physiologically acceptable and metabolizable carriers to manufacture and administer.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier (vehicle) (e.g., a liquid or solid filler, diluent, excipient, solvent, or encapsulating material). Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the dosage form and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars (such as lactose, glucose and sucrose); (2) starches (e.g., corn starch and potato starch); (3) cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients (such as cocoa butter and suppository waxes); (9) oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); (10) glycols (e.g., propylene glycol); (11) polyols (such as glycerol, sorbitol, mannitol, and polyethylene glycol); (12) esters (e.g., ethyl oleate and ethyl dodecanoate); (13) agar; (14) buffering agents (such as magnesium hydroxide and aluminum hydroxide); (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) a ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible materials employed in pharmaceutical dosage forms.

The pharmaceutical composition (formulation) may be administered to a subject by any of a number of routes of administration, including, for example, orally (e.g., as drenches in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including dispersible capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anal, rectal, or vaginal (e.g., as pessaries, creams, or foams); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally, e.g. as sterile solutions or suspensions); a nasal ground; intraperitoneally; the ground under the skin; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compounds may also be formulated for inhalation. In certain embodiments, the compound may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable for use in such routes of administration can be found, for example, in U.S. Pat. nos. 6,110,973, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, as well as in the patents cited in these patents.

The dosage forms may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Typically, this amount will vary from about 1% to about 99%, preferably from about 5% to about 70%, most preferably from about 10% to about 30% of the active ingredient in one hundred percent.

The process for preparing these dosage forms or compositions comprises the step of bringing into association the active compound (e.g. a compound of the invention) with the carrier and optionally one or more accessory ingredients. In general, the dosage forms are prepared by uniformly and intimately bringing into association the compounds of the invention with liquid carriers or finely divided solid carriers or both, and then shaping the product, if necessary.

Dosage forms of the invention suitable for oral administration may be in the form of: capsules (including dispersible capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, typically sucrose and acacia or tragacanth), lyophilic gels, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia)) and/or as a mouthwash, and the like, each containing a predetermined amount of a compound of the invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules (including dispersion and gelatin capsules), tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and/or any of the following: (1) fillers or extenders (e.g., starch, lactose, sucrose, glucose, mannitol, and/or silicic acid); (2) binders (such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia); (3) humectants (such as glycerol); (4) disintegrating agents (such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate); (5) solution retarders (e.g., paraffin); (6) absorption accelerators (such as quaternary ammonium compounds); (7) wetting agents (such as, for example, cetyl alcohol and glycerol monostearate); (8) absorbents (such as kaolin and bentonite); (9) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof); (10) complexing agents (e.g., modified or unmodified cyclodextrins); and (11) a colorant. In the case of capsules (including dispersion-type capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

Tablets may optionally be manufactured by compression or moulding with one or more accessory ingredients. Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions (e.g., dragees, capsules (including dispersible capsules and gelatin capsules), pills, and granules) can optionally be scored or prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulating art). Using, for example, hydroxypropylmethylcellulose in varying proportions to provide a desired release profile, other polymer matrices, liposomes and/or microspheres, which may also be formulated to provide slow or controlled release of the active ingredient therein. They may be sterilized by, for example, filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient or ingredients only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes. The active ingredient may also be in microencapsulated form with one or more, if appropriate, of the above-mentioned excipients.

Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilic colloids for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art (such as, for example, water or other solvents, cyclodextrins, and derivatives thereof), solubilizing agents and emulsifiers (such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof).

In addition to inert diluents, the oral compositions can also contain adjuvants (such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents).

Suspensions, in addition to the active compounds, may contain suspending agents (such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof).

Dosage forms of pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as suppositories which can be prepared by mixing the active compound(s) with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or salicylate, and which are solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound(s).

The dosage form of the pharmaceutical composition for administration to the mouth may be in the form of a mouthwash, or a mouth spray, or a mouth ointment.

Alternatively or additionally, the composition may be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

Dosage forms suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray dosage forms containing such carriers as are known in the art to be appropriate.

Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

Ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons (e.g. butane and propane).

Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms may be manufactured by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic dosage forms, ophthalmic ointments, powders, solutions, and the like are also contemplated within the scope of the present invention. Exemplary ophthalmic dosage forms are described in U.S. publication nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, the liquid ophthalmic dosage form has properties similar to, or compatible with, tear fluid, aqueous humor, or vitreous humor. A preferred route of administration is topical administration (e.g., topical administration (such as eye drops or administration via an implant)).

As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, typically by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solubilizers or suspending or thickening agents, which render the dosage form isotonic with the blood of the intended recipient.

Examples of suitable aqueous and nonaqueous carriers that can be employed in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size for the dispersion and by the use of surfactants.

These compositions may also contain adjuvants (such as preserving, wetting, emulsifying, and dispersing agents). Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents (e.g., methylparaben, chlorobutanol, phenol sorbic acid, and the like). It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

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

Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable dosage forms are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

For use in the methods of the invention, the active compound may be administered by itself or as a pharmaceutical composition containing, for example, from 0.1% to 99.5% (more preferably from 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

The introduction method may also be provided by a rechargeable or biodegradable device. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including protein biopharmaceuticals. Various biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

The actual dosage level of the active ingredient in the pharmaceutical composition can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds being employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound or compounds being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound or compounds being employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician of ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician may start with a dose of a pharmaceutical composition or compound that is at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. By "therapeutically effective amount" is meant a concentration of the compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age and medical history of the subject. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent that is administered with the compound of the invention. A larger total dose may be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al (1996) Harrison's Principles of Internal Medicine 13ed., 1814-.

In general, a suitable dosage of active compound for use in the compositions and methods of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above.

In certain embodiments, the thyroid hormone receptor beta agonist may be administered daily. If desired, an effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered alone, optionally in unit dosage form, at appropriate intervals throughout the day. In certain embodiments of the invention, the active compound may be administered twice or three times daily. In certain embodiments, the thyroid hormone receptor β agonist may be administered every other day.

In some embodiments, the thyroid hormone receptor β agonist is administered to the subject intermittently according to a multiple-dosing regimen per day. In such embodiments, the compound is administered on at least two days and on up to five different days. In one aspect of a multiple-dose-per-day regimen, the compound is administered to the subject on consecutive days (e.g., consecutive days from two to five days). In certain embodiments, the compound is administered to the subject for 3 consecutive days, wherein no administration is made one day prior to repeating the dosing cycle.

In certain embodiments, the thyroid hormone receptor beta agonist may be administered daily, every other day, or intermittently for two, three, or four months, followed by a period of time (e.g., drug holiday) during which the thyroid hormone receptor beta agonist is not administered. In some embodiments, the period of time during which the thyroid hormone receptor beta agonist is not administered may be from about 56 days to about 5 days (e.g., about 49 days, such as about 42 days, such as about 35 days, such as about 28 days, such as about 21 days, such as about 14 days, or such as about 7 days), preferably 28 days. In some embodiments, the period of time during which the thyroid hormone receptor β agonist is not administered may be from about 2 months to about 1 week (e.g., 1 month).

In certain embodiments, the thyroid hormone receptor beta agonist can be administered at a dose of between about 1mg and about 100mg per day (such as between about 1mg and about 50mg per day, such as between about 1mg and about 25mg per day, such as between about 1mg and about 20mg per day, such as between about 5mg and 25mg per day, such as between about 5mg and about 20mg per day, or between about 5mg and about 15mg per day). In certain embodiments, the thyroid hormone receptor beta agonist can be administered at a dose of 100 mg/day, 50 mg/day, 25 mg/day, 20 mg/day, 15 mg/day, 10 mg/day, 5 mg/day, or 1 mg/day.

In certain embodiments, the thyroid hormone receptor beta agonist can be administered at a dose of between about 1mg and about 100mg every other day (such as between about 1mg and about 50mg every other day, such as between about 1mg and about 25mg every other day, such as between about 1mg and about 20mg every other day, such as between about 5mg and 25mg every other day, such as between about 5mg and about 20mg every other day, or between about 5mg and about 15mg every other day). In certain embodiments, the thyroid hormone receptor beta agonist can be administered at a dose of 100mg every other day, 50mg every other day, 25mg every other day, 20mg every other day, 15mg every other day, 10mg every other day, 5mg every other day, or 1mg every other day.

The invention encompasses the use of pharmaceutically acceptable salts of the compounds of the invention in the compositions and methods of the invention. As used herein, the term "pharmaceutically acceptable salt" encompasses salts derived from inorganic or organic acids including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, 2-naphthalenesulfonic acid, and others. Pharmaceutically acceptable salt forms may comprise forms in which the ratio of molecules comprising the salt is not 1: 1. For example, a salt may comprise more than one molecule of an inorganic or organic acid per molecule of base (e.g., two molecules of hydrochloric acid per molecule of a compound of formula I). As another example, a salt may include less than one molecule of an inorganic or organic acid per molecule of base (e.g., two molecules of the compound of formula I per molecule of tartaric acid).

In further embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benzphetamine, benzathine, betaine, calcium hydroxide, choline, dandol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4- (2-hydroxyethyl) morpholine, piperazine, potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

The pharmaceutically acceptable acid addition salts may also be present as various solvates (e.g. with water, methanol, ethanol, dimethylformamide, etc.). Mixtures of such solvates may also be prepared. The source of such solvates may be inherent in the solvent from crystallization, the solvent from preparation or crystallization, or extrinsic to such solvents.

Wetting agents, emulsifying agents, and lubricating agents (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, partitioning agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants (e.g., ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.); (2) oil-soluble antioxidants (e.g., ascorbyl palmitate, t-Butylparacresol (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.); and (3) metal-chelating agents (e.g., citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like).

Definition of

The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbyl C (O) - (preferably alkyl C (O) -).

The term "amido" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl c (o) NH-.

The term "acyloxy" is art recognized and refers to a group represented by the general formula hydrocarbyl C (O) O- (preferably alkyl C (O) O-).

The term "alkoxy" refers to an alkyl group (preferably a lower alkyl group) having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one double bond, and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls," where the latter refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may be present on one or more carbons that are or are not included in one or more double bonds. Further, such substituents include all those contemplated for alkyl groups as discussed below, except where stability is prohibitive. For example, it is contemplated that an alkenyl group is substituted with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups.

An "alkyl" group or "alkane" is a straight or branched chain nonaromatic hydrocarbon that is fully saturated. Typically, unless otherwise specified, a linear or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10. Examples of linear and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C₁-C₆Straight or branched alkyl groups are also referred to as "lower alkyl" groups.

Furthermore, as used throughout the specification, examples and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyls" and "substituted alkyls", wherein the latter refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. If not otherwise specified, such substituents can comprise, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the substituted moiety on the hydrocarbon chain may itself be substituted (if appropriate). For example, substituents of substituted alkyl groups may include amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF₃And substituted or unsubstituted forms of, -CN, and the like. Exemplary substituted alkyl groups are described below. Alkyl groups which may be substituted by alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl, -CF₃and-CN, etc. further substituted cycloalkyl.

The term "C" when used in conjunction with a chemical moiety, such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy_x-y"means comprising a group containing from x to y carbons in the chain. For example, the term "C_x-yAlkyl "refers to a substituted or unsubstituted saturated hydrocarbon group (containing straight and branched alkyl groups containing from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2, 2-trifluoroethyl, and the like). When the radical is in the terminal position, C₀Alkyl represents hydrogen, if the radical is internal, C₀Alkyl represents a bond. The term "C_2-yAlkenyl "and" C_2-yAlkynyl "refers to a substituted or unsubstituted unsaturated aliphatic hydrocarbon group similar in length and possible substituents to the alkane described aboveBut containing at least one double or triple bond, respectively.

As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group, and may be represented by the general formula alkyl S-.

As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group containing at least one triple bond and is intended to encompass both "unsubstituted alkynyls" and "substituted alkynyls" wherein the latter refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are or are not contained in one or more triple bonds. Further, such substituents include all those intended for alkyl groups as described above, except where stability is prohibitive. For example, it is contemplated that the alkynyl group is substituted with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups.

As used herein, the term "amide" refers to a group

Wherein each R¹⁰Independently represent hydrogen or a hydrocarbyl group, or two R¹⁰And two R¹⁰The attached N atoms combine to form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., moieties that can be represented by the following formula:

wherein each R¹⁰Independently represent hydrogen or a hydrocarbyl group, or two R¹⁰And two R¹⁰The attached N atoms combine to form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

As used herein, the term "aryl" comprises a substituted or unsubstituted, monocyclic aromatic group, wherein each atom of the ring is carbon. Preferably, the ring is a 5-to 7-membered ring, more preferably, a 6-membered ring. The term "aryl" also encompasses polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term "carbamate" is art-recognized and refers to the following groups:

wherein R is⁹And R¹⁰Independently represent hydrogen or a hydrocarbyl group (e.g. an alkyl group), or R⁹And R¹⁰Together with one or more intervening atoms to form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

As used herein, the terms "carbocycle" and "carbocyclic" refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings (in which all carbon atoms are saturated) and cycloalkene rings (which contain at least one double bond). "carbocycle" includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of the bicyclic carbocycle may be selected from the group consisting of saturated rings, unsaturated rings and aromatic rings. Carbocycles comprise bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two contiguous atoms with the other ring. Each of the fused carbon rings may be selected from saturated rings, unsaturated rings, and aromatic rings. In exemplary embodiments, an aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated bicyclic rings, unsaturated bicyclic rings, and aromatic bicyclic rings that is valency allowed is encompassed within the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo [2.2.1] heptane, 1, 5-cyclooctadiene, 1,2,3, 4-tetrahydronaphthalene, bicyclo [4.2.0] oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decahydronaphthalene, naphthalene, 1,2,3, 4-tetrahydronaphthalene, bicyclo [4.2.0] octane, 4,5,6, 7-tetrahydro-1H-indene and bicyclo [4.1.0] hept-3-ene. The "carbocycle" may be substituted at any one or more positions capable of carrying a hydrogen atom.

A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "cycloalkyl" includes monocyclic and bicyclic rings. Typically, monocyclic cycloalkyl groups have from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of the bicyclic cycloalkyl can be selected from the group consisting of a saturated ring, an unsaturated ring, and an aromatic ring. Cycloalkyl groups comprise bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to bicyclic cycloalkyl groups in which each of the rings shares two contiguous atoms with the other ring. The second ring of the fused bicyclic cycloalkyl can be selected from the group consisting of a saturated ring, an unsaturated ring, and an aromatic ring. "cycloalkenyl" groups are cyclic hydrocarbons containing one or more double bonds.

As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocyclic group.

The term "carbonate" is art recognized and refers to the group-OCO₂-R¹⁰Wherein R is¹⁰Represents a hydrocarbyl group.

As used herein, the term "carboxy" refers to a compound of the formula-CO₂And H represents a group.

As used herein, the term "ester" refers to the group-C (O) OR¹⁰Wherein R is¹⁰Represents a hydrocarbyl group.

As used herein, the term "ether" refers to a hydrocarbyl group that is linked to another hydrocarbyl group through an oxygen. Accordingly, the ether substituent of the hydrocarbyl group may be hydrocarbyl-O-. The ethers may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers comprise an "alkoxyalkyl" group, which may be represented by the general formula alkyl-O-alkyl.

As used herein, the terms "halogen (halo)" and "halogen (halo)" mean halogen and include chloro, fluoro, bromo, and iodo.

As used herein, the terms "heteroaralkyl" and "heteroaralkyl" refer to an alkyl group substituted with a heteroaryl group.

As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are contiguous.

The terms "heteroaryl" and "heteroaryl" comprise a substituted or unsubstituted aromatic monocyclic ring structure (preferably a 5-to 7-membered ring, more preferably a 5-to 6-membered ring) the ring structure of which comprises at least one heteroatom (preferably one to four heteroatoms, more preferably one or two heteroatoms). The terms "heteroaryl" and "heteroaryl" also encompass polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

The terms "heterocyclyl", "heterocycle" and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure (preferably a 3-to 10-membered ring, more preferably a 3-to 7-membered ring) whose ring structure contains at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also encompass polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings, wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. The heterocyclyl group may also be substituted with an oxo group. For example, "heterocyclyl" includes both pyrrolidine and pyrrolidone.

As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclic group.

As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom without an ═ O or ═ S substituent, and typically has at least one carbon-hydrogen bond and a predominant carbon backbone, but may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl groups for the purposes of this application, but substituents such as acetyl (which has an ═ O substituent on the connecting carbon) and ethoxy (which is connected through oxygen, but not carbon) are not hydrocarbyl groups for the purposes of this application. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group.

The term "lower", when used in conjunction with a chemical moiety (e.g., acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy), means a group containing ten or fewer non-hydrogen atoms (preferably six or fewer) in the substituent. For example, "lower alkyl" refers to an alkyl group containing ten or fewer carbon atoms (preferably six or fewer). In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituent as defined herein is lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy, respectively, whether occurring alone or in combination with other substituents, as in the recitation of hydroxyalkyl and aralkyl (in the case of aralkyl, for example, when calculating the carbon atoms in an alkyl substituent, atoms within the aryl group are not calculated).

As used herein, the term "oxo" refers to a carbonyl group. When an oxo substituent is present on an otherwise saturated group, such as a cycloalkyl group substituted with an oxo group (e.g., 3-oxo-cyclobutyl), the substituted group still means a saturated group. When a group is said to be substituted with a "oxo" group, this may mean that the carbonyl moiety (i.e., -C (═ O) -) replaces the methylene unit (i.e., -CH)₂-)。

The terms "polycyclyl," polycyclyl, "and" polycyclic "refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are" fused rings. Each of the rings of the polycyclic rings may be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with …" includes such substitution being according to the allowed valences of the atoms and substituents being substituted, as well as the implicit proviso that the substitution results in a stable compound (e.g., the compound does not spontaneously undergo a transformation, such as by rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" is intended to encompass all permissible substituents of organic compounds. In a broader aspect, the permissible substituents include acyclic and cyclic substituents of organic compounds, branched and unbranched substituents, carbocyclic and heterocyclic substituents, aromatic and nonaromatic substituents. For suitable organic compounds, the permissible substituents can be one or more and can be the same or different. For the purposes of the present invention, a heteroatom, such as nitrogen, may have a hydrogen substituent and/or any permissible substituents of organic compounds described herein that satisfy the valencies of the heteroatom. The substituent may comprise any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be appreciated by those skilled in the art that the substituents may themselves be substituted (if appropriate). Unless explicitly stated as "unsubstituted," references herein to chemical moieties are understood to encompass substituted variants. For example, reference to an "aryl" group or moiety implicitly encompasses both substituted and unsubstituted variants.

The term "sulfate" is art-recognized and refers to the group-OSO₃H or a radical-OSO₃H, a pharmaceutically acceptable salt thereof.

The term "sulfonamide" is art recognized and refers to a group represented by the general formula

Wherein R is⁹And R¹⁰Independently represent hydrogen or a hydrocarbyl group (e.g. alkyl), or R⁹And R¹⁰Together with one or more intervening atoms to form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

The term "sulfoxide" is art-recognized and refers to a radicalThe group-S (O) -R¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

The term "sulfonate" is art-recognized and refers to the group SO₃H or a group SO₃H, a pharmaceutically acceptable salt thereof.

The term "sulfone" is art-recognized and refers to the group-S (O)₂-R¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

As used herein, the term "thioester" refers to the group-C (O) SR¹⁰or-SC (O) R¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

As used herein, the term "thioether" corresponds to an ether, wherein sulfur is substituted for oxygen.

The term "urea" is art recognized and may be represented by the following general formula

Wherein R is⁹And R¹⁰Independently represents hydrogen or a hydrocarbyl group (e.g. alkyl), or R in either occurrence⁹And R¹⁰And one or more intervening atoms to form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

"protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or hinders the reactivity of the functional group. Typically, the protecting group may be selectively removed during the synthesis, as desired. Examples of protecting Groups are found in Greene and Wuts, Protective Groups in Organic Chemistry,3^rdEd.,1999,John Wiley&Sons, NY and Harrison et al, Compendium of Synthetic Organic Methods, Vols.1-8,1971-1996, John Wiley&Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl (C:)"TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitroveratroxycarbonyl ("NVOC"), and the like. Representative hydrocarbyl protecting groups include, but are not limited to, those in which the hydrocarbyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives, and allyl ethers.

The term "treatment" encompasses prophylactic and/or therapeutic treatment of a disease. The term "prophylactic or therapeutic" treatment is art-recognized and encompasses administration of one or more of the subject compositions to a host. If administered prior to clinical manifestation of a deleterious condition (e.g., disease or other deleterious state of the host animal), the treatment is prophylactic (i.e., it protects the host from developing a deleterious condition), whereas if administered after manifestation of a deleterious condition, the treatment is therapeutic (i.e., it is intended to reduce, alleviate, or stabilize an existing deleterious condition or side effects thereof).

The term "prodrug" is intended to encompass compounds that are converted under physiological conditions to the therapeutically active agents of the invention (e.g., compounds of formula I). A common method for making prodrugs is to include one or more selected moieties that are hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the invention. In certain embodiments, some or all of the compounds of formula I in the above dosage forms may be replaced with the corresponding suitable prodrugs, for example, wherein hydroxy groups in the parent compound are present as esters, or carbonate or carboxylic acid groups present in the parent compound are present as esters.

Using groups attached to functional groups (e.g., HO-, HS-, HOOC-, R)₂N-) form standard prodrugs, said groups being conjugated to formazanAdenosine receptor beta agonists, the group is cleaved in vivo. Standard prodrugs include, but are not limited to, carboxylic acid esters (where the groups are alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl), and esters of hydroxy, mercapto and amines (where the attached group is an acyl group, alkoxycarbonyl, aminocarbonyl), phosphate esters or sulfate esters. Standard prodrugs of phosphonic acids are also included and may be represented by R in formula I¹And (4) showing. The groups illustrated are exemplary, not exhaustive, and those skilled in the art can prepare other known various prodrugs. Such prodrugs of compounds of formula I are within the scope of the present invention. A prodrug must undergo some form of chemical transformation to produce a compound that is biologically active or a precursor of a biologically active compound. In some cases, prodrugs are generally less biologically active than the drug itself and are used to improve efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, and the like.

As used herein, the term "prodrug ester" includes (but is not limited to) the following groups and combinations of these groups:

[1]acyloxyalkyl esters, which are described in the literature (Farquhar et al,J.Pharm.Sci72,324-325(1983)) and represented by the formula A

Wherein R, R' and R "are independently H, alkyl, aryl, alkylaryl, and cycloaliphatic; (see WO 90/08155; WO 90/10636).

[2]Other acyloxyalkyl esters are possible in which an alicyclic ring is formed, as shown in formula B. These esters have been shown to produce phosphorus-containing nucleotides inside the cell by a hypothetical reaction sequence starting with a deesterification reaction followed by a series of elimination reactions (e.g., free et al,Biochem.Pharm.38:3193-3198(1989))。

wherein R is-H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, cycloalkyl or cycloaliphatic.

[3] Another class of these diesters, known as alkoxycarbonyloxymethyl esters, has been studied in the field of β -lactam antibiotics, as shown in formula a, wherein R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino; r' and R "are independently H, alkyl, aryl, alkylaryl and cycloaliphatic (Tatsuo Nishimura et al J. antibiotics,1987,40(1), 81-90; for review see Ferres, H., Drugs of Today,1983,19, 499.). More recently, Cathy, m.s. et al (abstracts from AAPS Western Regional Meeting, 4 months 1997) demonstrated bioavailability of these alkoxycarbonyloxymethyl ester prodrugs on (9- [ (R) -2-phosphonomethoxy) propyl ] adenine (PMPA) in dogs as high as 30%.

[4]Aryl esters have also been used as phosphonate prodrugs (e.g., Erion, DeLambert et al,J.Med.Chem.37:498,1994；Serafinowska et al.,J.Med.Chem.38:1372,1995). Phenyl and mono-and poly-substituted phenyl pro-esters have yielded the parent phosphonic acid (formula C) in studies conducted in animals and in humans. Another process has been described in which Y is a carboxylic ester ortho to the phosphate. Khamnei and Torrence,J.Med.Chem.；39:4109-4115(1996)。

wherein Y is H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, and cycloaliphatic.

[5]Benzyl esters have also been reported to produce the parent phosphonic acid. In some cases, the use of a substituent at the para position may accelerate hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkoxy groups [ formula D, X ═ H, OR or O (CO) ROR O (CO) OR]The 4-hydroxy compound can be more easily produced by the action of an enzyme (e.g., oxidase, esterase, etc.). Mitchell et al,J.Chem.Soc.Perkin Transi2345 (1992); examples of such prodrugs are described in Brook, et al, wo 91/19721.

Wherein X and Y are independently H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halogen, or alkoxycarbonyl; and R' are independently H, alkyl, aryl, alkylaryl, halogen, and cycloaliphatic.

[6]Phosphonate containing pre-esters have been described which are useful in the delivery of fbpase inhibitors to hepatocytes. These pro-esters contain a protected thioethyl moiety as shown in formula E. One or more of the oxygens of the phosphonate ester may be esterified. Various thiol protecting groups are possible due to the mechanism leading to the deesterification which requires the generation of free thiolates. For example, disulfides are reduced by a reductase-mediated process (Puech et al,Antiviral Res.,22:155-174(1993)). Thioesters will also produce free mercaptides following esterase-mediated hydrolysis. Benzaria, et al.,J.Med.Chem.,39:4958(1996). Cyclic analogs are also possible and demonstrated to release phosphonate in isolated rat hepatocytes.

Wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio.

Other examples of suitable prodrugs include the prodrugs exemplified by the following references: biller and Magnin (U.S. patent No. 5,157,027); serafiowska et al (J.Med.Chem38,1372 (1995); starrett et al (J.Med.Chem.37,1857(1994))；Martin et al.J.Pharm.Sci.76,180(1987)；Alexander et al.,Collect.Czech.Chem.Commun59,1853 (1994); and EPO patent application 0632048 a 1. Some of the structural classes described are optionally substituted, including fused lactones (formula E-1 and E-2) attached at the ω -position and optionally substituted 2-oxo-1, 3-dioxoles (formula E-3) linked to the phosphorus oxygen through a methylene group, such as:

wherein R is-H, alkyl, cycloalkyl or cycloaliphatic; and is

Wherein Y is-H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy, halogen, amino, alicyclic, and alkoxycarbonyl.

Prodrugs of formula E-3 are examples of "optionally substituted alicyclic, wherein the cyclic moiety contains a carbonate or thiocarbonate".

[7] Propyl phosphonate monoesters can also be used to deliver fbpase inhibitors to hepatocytes. As shown in formula F, these esters may contain a hydroxyl group and a derivative of the hydroxyl group at the 3-position of the propyl group. As shown in formula F, the R and X groups may form a cyclic ring system. One or more of the oxygens of the phosphonate ester may be esterified.

Wherein R is alkyl, aryl, heteroaryl;

x is hydrogen, alkylcarbonyloxy, alkoxycarbonyloxy; and is

Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy, amino.

[8] Phosphoramidate derivatives have been explored as phosphate prodrugs as shown in formulas G and H (e.g., McGuigan et al, j.med.chem.,1999,42:393 and references cited therein).

Cyclic phosphoramidates have also been investigated as phosphonate prodrugs due to their putative higher stability compared to non-cyclic phosphoramidates (e.g., Starrett et al, j.med.chem.,1994,37: 1857).

Another type of nucleotide prodrug is reported as S-acyl-2-thioethyl ester in combination with phosphoramidates as shown in formula K (Egron et al, Nucleotides & Nucleotides,1999,18, 981).

Based on literature reports, other prodrugs are possible, such as substituted by ethyl, e.g., as by McGuigan, et al.BioorgMed.Chem.Lett.3:1207-1210(1993), and by Meier, C.et al.Bioorg.Med.Chem.Lett.7:99-104(1997) combinations of phenyl and benzyl nucleotide esters.

When R is⁶＝R⁶When V ═ W, W ═ H, and V and W both point up or both point down, structureHaving a plane of symmetry through the phosphorus-oxygen double bond. Wherein each-NR is replaced by-O-⁶The same is true of the structure of (1).

Examples

The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.

Experimental procedures

Human primary fibroblasts. Human skin fibroblasts were obtained from X-ALD patients by a neurological clinic at the academic medical center. Written informed consent was received from each patient. The X-ALD diagnosis was confirmed by VLCFA and ABCD1 mutation analysis. Control fibroblasts were obtained from male anonymous volunteers with written informed consent. Fibroblasts were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum, 2.5mM HEPES, 100U/ml penicillin and 100U/ml streptomycin with L-glutamine and 4.5g/L glucose. At wet 5% CO₂Cells were cultured at 37 ℃ in an atmosphere. All fibroblast lines used were routinely tested for mycoplasma. All tests were negative.

Preparation of stock solutions. Stock solutions of 10mM in DMSO were prepared by weighing the amount of compounds (1 and 3 and their respective active metabolites, 2 and 4) as shown in table 2. The stock solution was stored at room temperature in the dark. For each incubation, the amount of tissue culture medium required was calculated and a stock solution of tissue culture medium with the final concentration of the compound to be tested was prepared. Tissue culture medium was removed from the cells, the cells were washed once with PBS, and tissue culture medium with compound was added. If the experiment lasted more than three days, the tissue culture medium and compounds (using fresh formulation) were renewed after three days until the end of the experiment.

TABLE 2

Quantitative pcr (qpcr) analysis. Total RNA was isolated using TRIreagen (Sigma-Aldrich) and additional DNase treatment (Promega) was added according to the manufacturer's instructions. Nanodrop 2000(Thermo Fisher Scientific) was used for the quantification and characterization of RNA samples. The cDNA was synthesized using a first strand cDNA synthesis kit (Roche). LightCycler 480 SYBR Green I Master (Roche) was used for qPCR analysis. For data analysis, Light Cycler 480 software version 1.5.0 and LinRegPCR version 2014.5(Ramakers et al, neurosciences Letters 339:62-66(2003)) were used. The geometric mean of the expression levels of the two validated housekeeping genes RPS14 and H3F3A (whose expression levels were not affected by treatment) was used for normalization of the qPCR data.

Treatment of D in intact cells₃-C22: 0. beta. -oxidation. Peroxisomal β -oxidation activity was measured essentially as described by incubating the cells with 30 μ M deuterium-labeled C22:0(D3-C22:0) (Kemp et al, Clinical Chemistry 50:1824-1826 (2004)). Cells were seeded at approximately 40% confluence in DMEM in T75 flasks. The following day, the medium was replaced with medium containing 30 μ M D3-C22:0 and the compound being assayed at its final concentration. The final DMSO concentration in the tissue culture medium did not exceed 1%. Every 72 hours, the tissue culture medium and compounds were renewed. At the end of the experiment, cells were harvested and analyzed for VLCFA as described (Valianbour et al, Molecular Genetics and Metabolism,79:189-196 (2003)).

Effect of treatment on D3-C26:0 Synthesis in intact cells. The effect of certain compounds of the invention on the synthesis of D3-C26:0 from D3-C22:0 was measured in cultured skin fibroblasts from control and X-ALD patients. Cells were seeded at approximately 40% confluence in DMEM in T75 flasks. The following day, the medium was replaced with medium containing 30 μ M D3-C22:0 and the compound tested at its final concentration. The final DMSO concentration in the tissue culture medium did not exceed 1%. Every 72 hours, the tissue culture medium and compounds were renewed. At the end of the experiment, cells were harvested and analyzed for VLCFA as described (Valianbour et al, Molecular Genetics and Metabolism,79:189-196 (2003)).

VLCFA measurements. VLCFA was analyzed by electrospray ionization mass spectrometry (ESI-MS) as described (Valianbour et al, Molecular Genetics and Metabolism,79:189-196 (2003)).

Example 1 evaluation of different treatment doses

Two different X-ALD fibroblast lines were incubated in duplicate with four compounds at three doses as indicated in table 3.

TABLE 3

Compound (I)	Is low in	In	Height of
				2	100nM	1μM	10μM
4	100nM	1μM	10μM
				1	1μM	10μM	100μM
3	1μM	10μM	100μM

Two X-ALD cell lines incubated with 100. mu.M of 1 and 3 died within 24 hours. This strongly suggests that 1 and 3 are toxic at 100. mu.M. After 72 hours, cells that have received 0.1. mu.M, 1. mu.M or 10. mu.M of 2 or 4, or 0.1. mu.M or 10. mu.M of 1 or 3 appear healthy by judging their proliferation and morphology.

After 72h, cells were harvested and mRNA was isolated for QPCR analysis. As shown in figure 1, the effect of compounds on ABCD2 expression was compared to the expression level of ABCD2 in untreated (DMSO) cell lines. For all 4 compounds tested, 10 μ M was most effective. At this concentration, no negative effects of proliferation and cell morphology were observed.

Example 2 evaluation after prolonged culture

4X-ALD cell lines were incubated with 10. mu.M of 4 compounds 1,2,3 and 4. The effect of treatment on ABCD2 expression was analyzed on days 3 and 10. For 10 days incubation, tissue culture media and compounds were refreshed on days 3 and 6.

Day 3, day 6 and day 10: all cells appeared healthy, proliferation was normal, and morphology was normal. No abnormalities were noted. After 3 days, cells were harvested and mRNA was isolated for QPCR analysis. After 10 days, cells were harvested and mRNA was isolated for QPCR analysis. For all samples, cDNA synthesis and QPCR were done on the same day.

As shown in figure 2, the effect of compound treatment on ABCD2 expression was compared to ABCD2 expression levels in untreated (DMSO) cell lines at day 3 and day 10. Prolonged exposure resulted in comparable effects on ABCD2 induction.

Example 3-10 day treatment of the de novo Synthesis of VLCFA

5 different X-ALD cell lines were incubated with 10. mu.M of Compound 1, Compound 2, Compound 3 and Compound 4, 5mM 4PBA (sodium 4-phenylbutyrate) or 0.1. mu.M sobetierome for 6 days. On day 6, 30 μ M D3C22:0 was added to evaluate the effect of treatment on β -oxidation and de novo D3C26:0 synthesis. 6 untreated control cells and 5 different untreated X-ALD cells were included to allow evaluation of treatment effects. The total consisted of 41 experiments.

As shown in FIG. 4, in untreated X-ALD cells, the β -oxidation capacity decreased by-80%, and C26:0 increased by-4-fold de novo synthesis. The positive control (4PBA) restored β -oxidation to-50% of the control and normalized VLCFA synthesis to near normal levels. The positive control (sobetirome) did not show any beneficial effect on VLCFA β -oxidation or de novo synthesis.

Compound 1 (which was also the most active in experiment 3) caused a-40% reduction in de novo synthesis of D3C26: 0.

Example 4-treatment of VLCFA for 3 days de novo Synthesis

3 different X-ALD cell lines were incubated with 10. mu.M of Compound 1, Compound 2, Compound 3 and Compound 4, 5mM 4PBA or 0.1. mu.M sobetirome overnight for 16 hours. After 16 hours, the tissue culture medium was replaced with medium containing the above compound and 30 μ M D3C22:0 was added to evaluate the effect of treatment on β -oxidation and de novo synthesis of D3C26: 0. 6 untreated control cells and 3 different untreated X-ALD cells were included to allow evaluation of treatment effects. In total, it consisted of 27 experiments. At the same time, cells were cultured for QPCR analysis receiving the same treatment. See fig. 5.

Example 5-multiple dose assessment in rodents (prophetic)

Compound 1 or compound 3 will be administered to two to four groups of 12 ABCD1 knockout male mice aged at least 6 weeks at doses of 3-5mg/kg and 10mg/kg in a formulation comprising 0.5% carboxymethylcellulose and water. A homogeneous suspension was obtained by sonication in a water bath sonicator for about 20 minutes at room temperature. Mice will be administered the homogeneous suspension by intraperitoneal injection daily for 6 weeks.

After 6 weeks, changes in ABCD2 expression levels and VLCFA levels, as well as plasma and tissue levels, will be assessed.

Example 6 evaluation of Compound 3 in an in vivo model of X-ALD

Materials and methods

An animal. Male ABCD 1-/-mice were developed using the Taconic 129SvEv background strain. In a rodent setting, animals were housed at 3-4 per cage under a 12 hour lighting period (7AM-7PM lighting) and controlled temperature (22 ℃). They were fed standard mouse chow and drinking water was obtained ad libitum. At the beginning of each study, mice were between 2 months and 3 months of age.

Study protocol. Mice were injected intraperitoneally once daily with drug or vehicle (vehicle). For blood collection, — 50 μ Ι _ of blood was obtained by facial venipuncture using a sterile lancet. Blood was collected in 1.5ml microcentrifuge tubes containing dried dipotassium EDTA and mixed by gentle inversion at least ten times before being stored at-20 ℃. Blood was obtained in this manner after two, four and six weeks of treatment. After six weeks blood was collected, the animals were sacrificed by cervical dislocation. Additional blood for preparing plasma was obtained via cardiac puncture and placed in Microtainer tubes. The brain, spinal cord, adrenal gland, testis, and liver were excised and snap frozen in liquid nitrogen for future analysis.

Results

An initial cohort of 16 mice was randomized into 3:1 to receive compound 3 or placebo once daily for six weeks. The results of this initial cohort are presented in fig. 6 and summarized in table 4. Mice receiving compound 3 showed a rapid decrease in whole blood C26:0-LPC levels shortly after the start of dosing. Treated animals continued to experience a gradual decline in C26:0-LPC over six weeks. In contrast, control animals showed no decrease in mean C26:0-LPC at any time point. After a six week treatment period, animals receiving compound 3 showed a 40% reduction in whole blood C26:0-LPC levels (p < 0.0001) relative to vehicle (vehicle) control.

TABLE 4 mean blood levels of C26:0-LPC

Similar results were obtained with other VLCFA-LPC measurements; a highly statistically significant reduction in the mean levels of C20:0-LPC, C22:0-LPC, and C24:0-LPC was observed.

Based on the encouraging results of the initial cohort, the second larger cohort was evaluated. A total of 20 mice were randomly divided into 1:1 to receive compound 3 or vehicle (vehicle) daily for six weeks by IP administration.

The results from the second group confirm the initial data, where the treated mice exhibited a significant and gradual reduction in whole blood VLCFA levels relative to the control. FIG. 7 shows the time course of the change in C26:0-LPC level over the course of the process. Animals receiving compound 3 showed a statistically significant decrease in VLCFA both in comparison to vehicle (vehicle) at week six and in change from baseline (see figure 8 and table 5). Similar changes were noted for the other VLCFAs analyzed (C20:0, C22:0, C24: 0). Interestingly, the effect of vector (vehicle) not observed in previous experiments was observed in this group. This may be due to the lipid-based nature of the carrier (vehicle), via a mechanism similar to that observed with drugs such as Lorenzo's Oil.

Animals receiving compound 3 showed a decrease in whole blood C26:0-LPC levels of approximately 0.11 μ M after six weeks of treatment (fig. 8). At weeks four and six, the change from baseline was significant. Treatment with compound 3 resulted in a 52% reduction in C26:0-LPC at six weeks (p < 0.005, table 5) relative to vehicle (vehicle) treated animals.

Table 5: least squares mean change from baseline in whole blood C26:0-LPC levels in compound 3-treated mice compared to vehicle (vehicle)

During the second cohort study, blood was obtained as described in the methods section. At the sixth week time point, sufficient blood was collected to allow plasma VLCFA analysis at weeks two, four, and six. The results of the plasma analysis are presented in fig. 7 and table 6. Due to reduced analytical interference from other analytes, and reduced measurement variability, plasma is considered by many to be a more reliable measure of VLCFA levels.

As shown in fig. 9 and table 6, exposure to compound 3 resulted in a reduction in VLCFA (including C26:0, C24:0, C22:0, and C20:0) across a wide range. These effects were highly statistically significant relative to vehicle (vehicle) -treated mice, and were used to confirm observations from whole blood and initial data generated in the first treatment cohort. Interestingly, the trend of reduced effect on longer chain analytes may indicate that the effect of compound 3 on shorter chain VLCFA results in a reduced substrate pool for the elongase.

Table 6: percent change in mean plasma LPC levels compared to vehicle (vehicle) in compound 3-treated mice at week six.

Discussion of the related Art

Treatment of ABCD1 knockout mice with compound 3 for six weeks resulted in a reduction in the total VLCFA-lyso-PC analyte measured in this experiment. The difference in the key C26:0-LPC analyte between compound 3-treated and vehicle (vehicle) -treated animals was significant at both the fourth and sixth week time points, and effects were observed in both whole blood and plasma. The response to compound 3 appeared to be progressive; the difference between the effect of treatment and vector (vehicle) on C26:0-LPC generally increased with the progress of the study.

A significant decrease was also observed in the change from baseline analysis. Treatment with compound 3 resulted in a significant reduction in whole blood VLCFA from baseline relative to vehicle (vehicle) at the fourth and sixth week time points. In addition to the progressive treatment effect, the difference with respect to the vector (vehicle) became more statistically significant over time.

Exposure to compound 3 caused a significant effect on VLCFA levels. After six weeks of treatment, significant reductions were observed for C20:0-LPC, C22:0-LPC, and C24: 0-LPC. The trend towards greater effect on shorter VLCFA chain length may indicate depletion of the extended enzyme substrate pool, which may lead to a reduction in the enhancement of longer chain VLCFAs (e.g., C26:0) over time.

Is incorporated by reference

All publications and patents mentioned herein are incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents of

While specific embodiments of the subject invention have been discussed, the foregoing description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims that follow. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and to the specification, along with such variations.

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