US 7,888,384 B2Granted

Heterocyclic derivatives for modulation of calcium channels

AssigneeVertex Pharmaceuticals Incorporated

InventorsAndreas Termin, Esther Martinborough, Nicole Zimmerman, Charles Cohen, Corey Gutierrez

Life of this patent

Estimating the term…

Abstract

Heterocyclic derivatives act as Ca channel antagonists. The compositions are useful for treating or relieving Ca channel mediated conditions.

Claims29

Dependent claims

A compound having formula I-A, or formula I-B:

or a pharmaceutically acceptable salt thereof, wherein:
R5 and R7 are independently defined by —ZR6, wherein Z is a bond or is an optionally substituted C1-C6 alkyl, alkenyl, or alkynyl, chain wherein up to two carbon units of Z are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—;
wherein R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, polycyclic hydrocarbon, substituted polycyclic hydrocarbon;
or
R1 and R2 together form an unsubstituted or substituted 3 to 7-membered ring, wherein the members of the ring contain 0-4 heteroatoms selected from nitrogen, oxygen, and sulfur;
R3 and R4 together form an unsubstituted or substituted 3 to 7-membered ring, wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulfur;
the group SO2NR3R4 is linked to the phenyl ring either at position 5 or 6;
X is N—Z—R6;
n is 0-3;
R6 is independently R′, halogen, NO2, CN, CF3, or OCF3;
R′ is independently selected from hydrogen or an optionally substituted group selected from a C1-C8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
provided that in compounds of formula I-A:
when R3 and R4, together with the intervening nitrogen atom, form a 4-benzyl-piperidin-1-yl ring, R5 is hydrogen, then R1 and R2 are not simultaneously hydrogen.

11 more elements

A compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein:
R3 is C1-C6 aliphatic, C5-C10 cycloaliphatic, or arylakyl, wherein R3 has 0-4 substituents selected from Z—R6;
and
RS is aryl optionally substituted with 0-4 substituents selected from Z—R6;
X is N—Z—R6;
R5 is hydrogen, or C1-C6 alkyl;
R7 is defined by —ZR6, wherein Z is a bond or is an optionally substituted C1-C6 alkyl, alkenyl, or alkynyl, chain wherein up to two carbon units of Z are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—;
wherein R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, polycyclic hydrocarbon, substituted polycyclic hydrocarbon;
or
R1 and R2 together form an unsubstituted or substituted 3 to 7-membered ring, wherein the members of the ring contain 0-4 heteroatoms selected from nitrogen, oxygen, and sulfur;
n is 0-3;
R6 is independently R′, halogen, NO2, CN, CF3, or OCF3;
R′ is independently selected from hydrogen or an optionally substituted group selected from a C1-C8aliphatic group, a 3-8-membered saturated or partially unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

11 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/424,883Filed 16 Apr 2009 · division
Priority: 22 Jun 2004
Published: US 2009/0253682 A18 Oct 2009
Granted: 15 Feb 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification25 codes

A61K 31/405
Indoles, e.g. pindolol: indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
A61K 31/343
Having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide: condensed with a carbocyclic ring, e.g. coumaran,…
A61K 31/381
Having sulfur as a ring hetero atom: having five-membered rings
A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol

Family

Application60/582,013Us provisional application · filed 22 Jun 2004
Application11/165,254Parent of this division · filed 22 Jun 2005
US 2009/0253682 A1Pre-grant publication · published 8 Oct 2009
US 7,569,604 B2Parent of this division
US 2006/0074076 A1Published application
US 7,888,384 B2This patent

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

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Abstract

Heterocyclic derivatives act as Ca channel antagonists. The compositions are useful for treating or relieving Ca channel mediated conditions.

A compound having formula I-A, or formula I-B:

or a pharmaceutically acceptable salt thereof, wherein:
R5 and R7 are independently defined by —ZR6, wherein Z is a bond or is an optionally substituted C1-C6 alkyl, alkenyl, or alkynyl, chain wherein up to two carbon units of Z are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—;
wherein R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, polycyclic hydrocarbon, substituted polycyclic hydrocarbon;
or
R1 and R2 together form an unsubstituted or substituted 3 to 7-membered ring, wherein the members of the ring contain 0-4 heteroatoms selected from nitrogen, oxygen, and sulfur;
R3 and R4 together form an unsubstituted or substituted 3 to 7-membered ring, wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulfur;
the group SO2NR3R4 is linked to the phenyl ring either at position 5 or 6;
X is N—Z—R6;
n is 0-3;
R6 is independently R′, halogen, NO2, CN, CF3, or OCF3;
R′ is independently selected from hydrogen or an optionally substituted group selected from a C1-C8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
provided that in compounds of formula I-A:
when R3 and R4, together with the intervening nitrogen atom, form a 4-benzyl-piperidin-1-yl ring, R5 is hydrogen, then R1 and R2 are not simultaneously hydrogen.

11 more elements

Facts

Application

12/424,883Filed 16 Apr 2009 · division

Priority

22 Jun 2004

Published

US 2009/0253682 A18 Oct 2009

Granted

15 Feb 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification25 codes

A61K 31/405
Indoles, e.g. pindolol: indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
A61K 31/343
Having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide: condensed with a carbocyclic ring, e.g. coumaran,…
A61K 31/381
Having sulfur as a ring hetero atom: having five-membered rings
A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol

Family

Application60/582,013Us provisional application · filed 22 Jun 2004

Application11/165,254Parent of this division · filed 22 Jun 2005

US 2009/0253682 A1Pre-grant publication · published 8 Oct 2009

US 7,569,604 B2Parent of this division

US 2006/0074076 A1Published application

US 7,888,384 B2This patent

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