US 2006/0079557 A1 · Sulfamoyl benzamide derivatives and methods of their use

Abstract

Novel sulfamoyl benzamide compounds, pharmaceutical compositions containing the sulfamoyl benzamide compounds, and methods of their pharmaceutical use are disclosed. In certain embodiments, the sulfamoyl benzamide compounds are agonists and/or modulating ligands of cannabinoid receptors and may be useful, inter alia, for treating and/or preventing pain, gastrointestinal disorders, inflammation, auto-immune diseases, ischemic conditions, immune-related disorders, hypertension, neurological disorders, and neurodegenerative diseases, for providing cardioprotection against ischemic and reperfusion effects, for inducing apoptosis in malignant cells, for inhibiting mechanical hyperalgesia associated with nerve injury, and as an appetite stimulant.

Claims272

Dependent claims

A compound of formula I′:

wherein:
R1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, F, Cl, or Br;
R2 and R3 are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl, provided that at least one of R2 and R3 is other than H;
or R2 and R3 when taken together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocycloalkyl ring, wherein 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R9)—, —N(R10)—C(═O)—, or —C(═O)—N(R10)—;
R4 is H or alkyl;
R5 is:
Ra, Rb, and Rc are each independently H or alkyl;
Rd and Re taken together with the carbon atom to which they are attached form a carbocyclic ring;
R6, R7, and R8 are each independently H, F, Cl, Br, or alkyl;
R9 is H, alkyl, aryl, —C(═O)—R11, —C(═O)—OR11, —[C(R11)(R11)]s—C(═O)—OR11, —SO2R11, or —C(═O)N(R11)R11;
R10 is H, alkyl, or aryl;
each R11 is independently H or alkyl;
r is 0, 1, 2, or 3;
and
s is 1, 2, 3, or 4;
provided that:
(1) when Rd and Re taken together with the carbon atom to which they are attached form a monocyclic carbocyclic ring, then Rc is alkyl;
and
(2) when R5 is:
then R2 and R3 are taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocycloalkyl ring;
or a pharmaceutically acceptable salt thereof.

18 more elements

A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier;
and a compound of formula Ia:
wherein:
R1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, F, Cl, or Br;
R2 and R3 are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl, provided that at least one of R2 and R3 is other than H;
or R2 and R3 when taken together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocycloalkyl ring, wherein 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R9)—, —N(R10)—C(═O)—, or —C(═O)—N(R10)—;
R4 is H or alkyl;
R5 is:
each Ra, Rb, Rc, Rd, and Re are each independently H or alkyl;
or Rd and Re taken together with the carbon atom to which they are attached form a carbocyclic ring;
R6, R7, and R8 are each independently H, F, Cl, Br, or alkyl;
R9 is H, alkyl, aryl, —C(═O)—R11, —C(═O)—OR11, —[C(R11)(R11)]s—C(═O)—OR11, —SO2R11, or —C(═O)N(R11)R11;
R10 is H, alkyl, or aryl;
each R11 is independently H or alkyl;
r is 0, 1, 2, or 3;
and
s is 1, 2, 3, or 4;
provided that:
(1) when Rd and Re taken together with the carbon atom to which they are attached form a monocyclic carbocyclic ring, then Rc is alkyl or the monocyclic carbocyclic ring is an alkylcycloalkyl ring;
(2) at least two of Rc, Rd, and Re are other than H;
and
(3) when R1 is methyl or bromo, R2, R4, R6, R7, and R8 are each H, and R3 is methyl, then R5 is other than but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, 1,1,1-dimethyleth-1-yl, 1-dimethylprop-1-yl, 1,1-dimethylbut-1-yl, or 1,1-dimethylpent-1-yl;
or a pharmaceutically acceptable salt thereof.

20 more elements

A method of binding cannabinoid receptors in a patient in need thereof, comprising the step of:

administering to said patient an effective amount of a compound of formula Ia:
wherein:
R1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, F, Cl, or Br;
R2 and R3 are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl, provided that at least one of R2 and R3 is other than H;
or R2 and R3 when taken together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocycloalkyl ring, wherein 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R9)—, —N(R10)—C(═O)—, or —C(═O)—N(R10)—;
R4 is H or alkyl;
R5 is:
each Ra, Rb, Rc, Rd, and Re is independently H or alkyl;
or Rd and Re taken together with the carbon atom to which they are attached form a carbocyclic ring;
R6, R7, and R8 are each independently H, F, Cl, Br, or alkyl;
R9 is H, alkyl, aryl, —C(═O)—R11, —C(═O)—OR11, —[C(R11)(R11)]s—C(═O)—OR11, —SO2R11, or —C(═O)N(R11)R11;
R10 is H, alkyl, or aryl;
each R11 is independently H or alkyl;
r is 0, 1, 2, or 3;
and
s is 1, 2, 3, or 4;
provided that:
(1) when Rd and Re taken together with the carbon atom to which they are attached form a monocyclic carbocyclic ring, then Rc is alkyl or the monocyclic carbocyclic ring is an alkylcycloalkyl ring;
and
(2) at least two of Rc, Rd, and Re are other than H;
or a pharmaceutically acceptable salt thereof.

18 more elements

A compound of formula IV:

wherein:
R1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, F, Cl, or Br;
R2 and R3 are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl, provided that at least one of R2 and R3 is other than H;
or R2 and R3 when taken together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocycloalkyl ring, wherein 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R9)—, —N(R10)—C(═O)—, or —C(═O)—N(R10)—;
R4 is H or alkyl;
R5 is:
each Ra, Rb, and Rc, is independently H or alkyl;
Rd and Re taken together with the carbon atom to which they are attached form a carbocyclic ring;
or Rc, Rd, and Re, taken together with the carbon atom to which they are attached, form a bicycloalkyl or tricycloalkyl ring;
R6, R7, and R8 are each independently H, F, Cl, Br, or alkyl;
R9 is H, alkyl, aryl, —C(═O)—R11, —C(═O)—OR11, —[C(R11)(R11)]s—C(═O)—OR11, —SO2R11, or —C(═O)N(R11)R11;
R10 is H, alkyl, or aryl;
each R11 is independently H or alkyl;
r is 0, 1, 2, or 3;
and
s is 1, 2, 3, or 4;
provided that:
(1) when Rd and Re taken together with the carbon atom to which they are attached form a monocyclic carbocyclic ring, then Rc is alkyl;
(2) when R5 is:
then R2 and R3 are taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocycloalkyl ring;
(3) when R1 is H or Cl, R2 and R3 are each independently cyclohexyl, 1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-on-4-yl, or substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenyl, or R2 and R3 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocycloalkyl ring, wherein 1 of the heterocycloalkyl ring carbon atoms may be optionally replaced by —O— or —N(R9)—, R6, R8, and Rb are H, and R7 is H or chloro, then R5 is other than 1-adamantyl, adamant-1-ylmethyl, or adamant-1-yleth-1-yl;
and
(4) the compound of formula IV is other than N-(2-adamantan-1-yl-ethyl)-2,4-dichloro-5-dimethylsulfamoyl-benzamide, N-(2-adamantan-1-yl-ethyl)-3-(morpholine-4-sulfonyl)-benzamide, N-adamantan-1-yl-4-methyl-3-(piperidine-1-sulfonyl)-benzamide, N-(1-adamantan-1-yl-ethyl)-4-methyl-3-(piperidine-1-sulfonyl)-benzamide, N-adamantan-1-ylmethyl-3-(ethyl-phenyl-sulfamoyl)-4-methyl-benzamide, N-adamantan-1-yl-4-bromo-3-(morpholine-4-sulfonyl)-benzamide, N-(1-adamantan-1-yl-ethyl)-4-fluoro-3-(morpholine-4-sulfonyl)-benzamide, 2,4-dichloro-N-(3,5-dimethyl-adamantan-1-yl)-5-dimethylsulfamoyl-benzamide, or N-cycloheptyl-4-methyl-3-(morpholinosulfonyl)benzamide;
or a pharmaceutically acceptable salt thereof.

21 more elements

A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier;
and a compound of formula VI:
wherein:
R1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, F, Cl, or Br;
R2 and R3 are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl, provided that at least one of R2 and R3 is other than H;
or R2 and R3 when taken together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocycloalkyl ring, wherein 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R9)—, —N(R10)—C(═O)—, or —C(═O)—N(R10)—;
R4 is H or alkyl;
R5 is:
each Ra, Rb, Rc, Rd, and Re is independently H or alkyl;
or Rd and R1 taken together with the carbon atom to which they are attached form a carbocyclic ring;
or Rc, Rd, and Re, taken together with the carbon atom to which they are attached, form a bicycloalkyl or tricycloalkyl ring;
R6, R6, and R8 are each independently H, F, Cl, Br, or alkyl;
R9 is H, alkyl, aryl, —C(═O)—R11, —C(═O)—OR11, —[C(R11)(R11)]s—C(═O)—OR11, —SO2R11, or —C(═O)N(R11)R11;
R10 is H, alkyl, or aryl;
each R11 is independently H or alkyl;
r is 0, 1, 2, or 3;
and
s is 1, 2, 3, or 4;
provided that:
(1) when Rd and Re taken together with the carbon atom to which they are attached form a monocyclic carbocyclic ring, then Rc is alkyl or the monocyclic carbocyclic ring is an alkylcycloalkyl ring;
(2) at least two of Rc, Rd, and Re are other than H;
and
(3) when R1 is methyl or bromo, R2, R4, R6, R7, and R8 are each H, and R3 is methyl, then R5 is other than but-2-yl, pent-2-yl, hex-2-yl, hept-2-yl, 1,1,1-dimethyleth-1-yl, 1-dimethylprop-1-yl, 1,1-dimethylbut-1-yl, or 1,1-dimethylpent-1-yl;
or a pharmaceutically acceptable salt thereof.

21 more elements

A method of binding cannabinoid receptors in a patient in need thereof, comprising the step of:

administering to said patient an effective amount of a compound of formula VI:
wherein:
R1 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroaralkyl, F, Cl, or Br;
R2 and R3 are each independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl, provided that at least one of R2 and R3 is other than H;
or R2 and R3 when taken together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocycloalkyl ring, wherein 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R9)—, —N(R10)—C(═O)—, or —C(═O)—N(R10)—;
R4 is H or alkyl;
R5 is:
each Ra, Rb, Rc, Rd, and Re is independently H or alkyl;
or Rd and Re taken together with the carbon atom to which they are attached form a carbocyclic ring;
or Rc, Rd, and Re, taken together with the carbon atom to which they are attached, form a bicycloalkyl or tricycloalkyl ring;
R6, R7, and R8 are each independently H, F, Cl, Br, or alkyl;
R9 is H, alkyl, aryl, —C(═O)—R11, —C(═O)—OR11, —[C(R11)(R11)]s—C(═O)—OR11, —SO2R11, or —C(═O)N(R11)R11;
R10 is H, alkyl, or aryl;
each R11 is independently H or alkyl;
r is 0, 1, 2, or 3;
and
s is 1, 2, 3, or 4;
provided that:
(1) when Rd and Re taken together with the carbon atom to which they are attached form a monocyclic carbocyclic ring, then Rc is alkyl or the monocyclic carbocyclic ring is an alkylcycloalkyl ring;
and
(2) at least two of Rc, Rd, and Re are other than H;
or a pharmaceutically acceptable salt thereof.

19 more elements

Dependencies are inferred from the claim text.

Sulfamoyl benzamide derivatives and methods of their use

Life of this patent

Sulfamoyl benzamide derivatives and methods of their use

Life of this patent

Abstract

Claims272