US 6,320,074 B1Granted

Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors

AssigneeLigand Pharmaceuticals Incorporated

InventorsMarcus F. Boehm, Richard A. Heyman, Lin Zhi, Stacie Canan Koch

Life of this patent

Estimating the term…

Abstract

Compounds, compositions, and methods for modulating processes mediated by Retinoid X Receptors using retinoid-like compounds which have activity selective for members of the subclass of Retinoid X Receptors (RXRs), in preference to members of the subclass of Retinoic Acid Receptors (RARs). Examples of such compounds are bicyclic benzyl, pyridinyl, thiophene, furanyl, and pyrrole derivatives. The disclosed methods employ compounds for modulating processes selectively mediated by Retinoid X Receptors.

Claims41

Dependent claims

A compound having the formula:

wherein
R1 and R2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms;
Y represents C, O, S, N, CHOH, CO, SO, SO2 or a pharmaceutically acceptable salt;
R3 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N;
R4 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C, but R4 does not exist if Y is N, and neither R3 or R4 exist if Y is S, O, CHOH, CO, SO, or SO2;
R′ and R″ represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino,
or R′ and R″ taken together form an oxo (keto), methano, thioketo, HO—N═, NC—N═, (R7R8)N—N═, R17O—N═, R17N═, epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen;
R′″ and R″″ represent hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkyl amino,
or R′″ and R″″ taken together form a cycloalkyl group having 3-10 carbons, and wherein the cycloalkyl group can be substituted with lower alkyl having 1-4 carbons or halogen;
R5 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR7, SR7, NR7R8,
R6, R10, R11, R12, R13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR7, SR7, NR7R8, or (CF2)nCF3, and exist only if the Z, Z′, Z″, Z′″, or Z″″, from which it originates is C, or each independently represent hydrogen or a lower alkyl having 1-4 carbons if the Z, Z′, Z″, Z′″, or Z″″ from which it originates is N, and where one of R6, R10, R11, R12 or R13 is X;
R7 represents hydrogen or a lower alkyl having 1-6 carbons;
R8 represents hydrogen or a lower alkyl having 1-6 carbons;
R9 represents a-lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-carboxyphenyl q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-florophenyl, or q-iodophenyl, where q=2-4;
R14 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone;
R17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR7 and SR7 substituted alkenes) R9, alkyl carboxylic acid (including halogen, acyl, OR7 and SR7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR7 and SR7 substituted alkenes), alkyl amines (including halogen, acyl, OR7 and SR7 substituted alkyls), and alkenyl amines (including halogen, acyl, OR7 and SR7 substituted alkenes);
X is COOH, tetrazole, PO3H, SO3H, CHO, CH2OH, CONH2, COSH, COOR9, COSR9, CONHR9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring;
one of Z, Z′, Z″, Z′″ and Z″″, each independently, represent O, N, or a pharmaceutically acceptable salt, and the rest are C, however, all Z's may represent C in the second structure but one of Z,Z′,Z″,Z′″ and Z″″ is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N and is not O or S in any of the six-membered rings containing them;
n=0-3;
and
the dashed lines in the fourth structure shown depicts optional double bonds.

18 more elements

A method for modulating a process mediated by one or more Retinoid X Receptors, said method comprising causing said process to be conducted in the presence of at least one compound of the formula:

wherein
R1 and R2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms;
Y represents C, O, S, N, CHOH, CO, SO, SO2 or a pharmaceutically acceptable salt;
R3 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N;
R4 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C, but R4 does not exist if Y is N, and neither R3 or R4 exist if Y is S, O, CHOH, CO, SO, or SO2;
R′ and R″ represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino,
or R′ and R″0 taken together form an oxo (keto), methano, thioketo, HO—N═, NC—N═, (R7R8)N—N═, R17O—N═, R17N═, epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen;
R′″ and R″″ represent hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkyl amino,
or R′″ and R″″ taken together form a cycloalkyl group having 3-10 carbons, and wherein the cycloalkyl group can be substituted with lower alkyl having 1-4 carbons or halogen;
R5 represents hydrogen a lower alkyl having 1-4 carbons, halogen, nitro, OR7, SR7, NR7R8, or (CF2)nCF3;
R6, R10, R11, R12, R13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR7, SR7, NR7R8, or (CF2)nCF3, and exist only if the Z, Z′, Z″, Z′″, or Z″″, from which it originates is C, or each independently represent hydrogen or a lower alkyl having 1-4 carbons if the Z, Z′, Z″, Z′″, or Z″″ from which it originates is N, and where one of R6, R10, R11, R12 or R13 is X;
R7 represents hydrogen or a lower alkyl having 1-6 carbons;
R8 represents hydrogen or a lower alkyl having 1-6 carbons;
R9 represents a-lower alkyl having 1-4 carbons, phenyl, aromatic alkyl or q-carboxyphenyl, q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-florophenyl, or q-iodophenyl, where q=2-4;
R14 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone;
R17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR7 and SR7 substituted alkenes) R9, alkyl carboxylic acid (including halogen, acyl, OR7 and SR7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR7 and SR7 substituted alkenes), alkyl amines (including halogen acyl, OR7 and SR7 substituted alkyls), and alkenyl amines (including halogen, acyl, OR7 and SR7 substituted alkenes);
X is COOH, tetrazole, PO3H, SO3H, CHO, CH2OH, CONH2, COSH COOR9, COSR9, CONHR9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring;
one of Z,Z′,Z″,Z′″ and Z″″, each independently, represent O, N, or a pharmaceutically acceptable salt, and the rest are C, however, all Z's may represent C in the second structure but one of Z,Z′,Z″, Z′″ and Z″″ is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N and is not O or S in any of the six-membered rings containing them;
n=0-3:
and
the dashed lines in fourth structure shown depicts optional double bonds.

18 more elements

A compound of the formula

wherein
R1 and R2, independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms;
Y represents C, O, S, N, CHOH, CO, SO, SO2 or a pharmaceutically acceptable salt;
R3 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N;
R4 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C, but R4 does not exist if Y is N, and neither R3 or R4 exist if Y is S, O, CHOH, CO, SO, or SO2;
R′ and R″ represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino,
or R′ and R″ taken together form an oxo (keto), methano, thioketo, HO—N═, NC—N═, (R7R8)N—N═, R17O—N═, R17N═, epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen;
R′″ and R″″ represent hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkyl, amino,
or R′″ and R″″ taken together form a cycloalkyl group having 3-10 carbons, and wherein the cycloalkyl group can be substituted with lower alkyl having 1-4 carbons or halogen;
R5 represents halogen, nitro, SR7, NR7R8, or (CF2)nCF3;
R6, R10, R11, R12, R13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR7, SR7, NR7R8, or (CF2)nCF3, or X;
R7 represents hydrogen or a lower alkyl having 1-6 carbons;
R8 represents hydrogen or a lower alkyl having 1-6 carbons;
R9 represents a-lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-carboxyphenyl, q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-florophenyl, or q-iodophenyl, where q=2-4;
R14 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone;
R17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR7 and SR7 substituted alkenes) R9, alkyl carboxylic acid (including halogen, acyl, OR7 and SR7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR7 and SR7 substituted alkenes), alkyl amines (including halogen, acyl, OR7 and SR7 substituted alkyls), and alkenyl amines (including halogen, acyl, OR7 and SR7 substituted alkenes);
X is COOH, tetrazole, PO3H, SO3H, CHO, CH2OH, CONH2, COSH, COOR9, COSR9, CONHR9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C on the ring, provided however, that X cannot be COOH, CHO, CH2OH, CONH2, COOR9, or COOW where W is a pharmaceutically acceptable salt when X originates from a C in the 2 or 6 position on the ring;
and
n=0-3.

16 more elements

A method for modulating a process mediated by one or more Retinoid X Receptors, said method comprising causing said process to be conducted in the presence of at least one compound of the formula:

wherein
R1 and R2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms;
Y represents C, O, S, N, CHOH, CO, SO, SO2 or a pharmaceutically acceptable salt;
R3 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N;
R4 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C, but R4 does not exist if Y is N, and neither R3 or R4 exist if Y is S, O, CHOH, CO, SO, or SO2;
R′ and R″ represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino,
or R′ and R″ taken together form an oxo (keto), methano, thioketo, HO—N═, NC—N═, (R7R8)N—N═, R17O—N═, R17N═, epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen;
R′″ and R″″ represent hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkyl, amino,
or R′″ and R″″ taken together form a cycloalkyl group having 3-10 carbons, and wherein the cycloalkyl group can be substituted with lower alkyl having 1-4 carbons or halogen;
R5 represents halogen, nitro, SR7, NR7R8, or (CF2)nCF3;
R6, R10, R11, R12, R13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR7, SR7, NR7R9, or (CF2)nCF3, or X;
R7 represents hydrogen or a lower alkyl having 1-6 carbons;
R8 represents hydrogen or a lower alkyl having 1-6 carbons;
R9 represents a-lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-carboxyphenyl, q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-florophenyl, or q-iodophenyl, where q=2-4;
R14 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone;
R17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR7 and SR7 substituted alkenes) R9, alkyl carboxylic acid (including halogen, acyl, OR7 and SR7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR7 and SR7 substituted alkenes), alkyl amines (including halogen, acyl, OR7 and SR7 substituted alkyls), and alkenyl amines (including halogen, acyl, OR7 and SR7 substituted alkenes);
X is COOH, tetrazole, PO3H, SO3H, CHO, CH2OH, CONH2, COSH, COOR9, COSR9, CONHR9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C on the ring, provided however, that X cannot be COOH, CHO, CH2OH, CONH2, COOR9, or COOW where W is a pharmaceutically acceptable salt when X originates from a C in the 2 or 6 position on the ring;
and
n=0-3.

16 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/179,674Filed 27 Oct 1998 · continuation
Priority: 22 Apr 1992
Granted: 20 Nov 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification29 codes

C07D 303/38
Compounds containing oxirane rings: with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one…
A61P 3/02
Drugs for disorders of the metabolism: nutrients, e.g. vitamins, minerals
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 17/00
Drugs for dermatological disorders

Family

Application07/872,707Parent of this continuation-in-part · filed 22 Apr 1992
Application07/944,783Parent of this continuation-in-part · filed 11 Sep 1992
Application08/003,223Parent of this continuation-in-part · filed 11 Jan 1993
Application08/027,747Parent of this continuation-in-part · filed 5 Mar 1993
Application08/052,051Parent of this continuation-in-part · filed 21 Apr 1993
Application08/141,496Parent of this continuation · filed 22 Oct 1993
Application08/479,920Parent of this continuation · filed 7 Jun 1995
Application08/141,496Parent of this continuation-in-part
US 6,320,074 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound having the formula:

wherein
R1 and R2, each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms;
Y represents C, O, S, N, CHOH, CO, SO, SO2 or a pharmaceutically acceptable salt;
R3 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N;
R4 represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C, but R4 does not exist if Y is N, and neither R3 or R4 exist if Y is S, O, CHOH, CO, SO, or SO2;
R′ and R″ represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino,
or R′ and R″ taken together form an oxo (keto), methano, thioketo, HO—N═, NC—N═, (R7R8)N—N═, R17O—N═, R17N═, epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen;
R′″ and R″″ represent hydrogen, halogen, lower alkyl or acyl having 1-4 carbon atoms, alkyl amino,
or R′″ and R″″ taken together form a cycloalkyl group having 3-10 carbons, and wherein the cycloalkyl group can be substituted with lower alkyl having 1-4 carbons or halogen;
R5 represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR7, SR7, NR7R8,
R6, R10, R11, R12, R13 each independently represent hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR7, SR7, NR7R8, or (CF2)nCF3, and exist only if the Z, Z′, Z″, Z′″, or Z″″, from which it originates is C, or each independently represent hydrogen or a lower alkyl having 1-4 carbons if the Z, Z′, Z″, Z′″, or Z″″ from which it originates is N, and where one of R6, R10, R11, R12 or R13 is X;
R7 represents hydrogen or a lower alkyl having 1-6 carbons;
R8 represents hydrogen or a lower alkyl having 1-6 carbons;
R9 represents a-lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-carboxyphenyl q-hydroxyphenyl, q-bromophenyl, q-chlorophenyl, q-florophenyl, or q-iodophenyl, where q=2-4;
R14 represents hydrogen, a lower alkyl having 1-4 carbons, oxo, hydroxy, acyl having 1-4 carbons, halogen, thiol, or thioketone;
R17 represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR7 and SR7 substituted alkenes) R9, alkyl carboxylic acid (including halogen, acyl, OR7 and SR7 substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR7 and SR7 substituted alkenes), alkyl amines (including halogen, acyl, OR7 and SR7 substituted alkyls), and alkenyl amines (including halogen, acyl, OR7 and SR7 substituted alkenes);
X is COOH, tetrazole, PO3H, SO3H, CHO, CH2OH, CONH2, COSH, COOR9, COSR9, CONHR9, or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring;
one of Z, Z′, Z″, Z′″ and Z″″, each independently, represent O, N, or a pharmaceutically acceptable salt, and the rest are C, however, all Z's may represent C in the second structure but one of Z,Z′,Z″,Z′″ and Z″″ is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N and is not O or S in any of the six-membered rings containing them;
n=0-3;
and
the dashed lines in the fourth structure shown depicts optional double bonds.

18 more elements

Facts

Application

09/179,674Filed 27 Oct 1998 · continuation

Priority

22 Apr 1992

Granted

20 Nov 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification29 codes

C07D 303/38
Compounds containing oxirane rings: with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one…
A61P 3/02
Drugs for disorders of the metabolism: nutrients, e.g. vitamins, minerals
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 17/00
Drugs for dermatological disorders

Family

Application07/872,707Parent of this continuation-in-part · filed 22 Apr 1992

Application07/944,783Parent of this continuation-in-part · filed 11 Sep 1992

Application08/003,223Parent of this continuation-in-part · filed 11 Jan 1993

Application08/027,747Parent of this continuation-in-part · filed 5 Mar 1993

Application08/052,051Parent of this continuation-in-part · filed 21 Apr 1993

Application08/141,496Parent of this continuation · filed 22 Oct 1993

Application08/479,920Parent of this continuation · filed 7 Jun 1995

Application08/141,496Parent of this continuation-in-part

US 6,320,074 B1This patent

From the US filing history. Foreign family members aren’t listed.