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US 7,598,261 B2Granted
Spirocyclic heterocyclic derivatives and methods of their use
AssigneeAdolor Corporation
InventorsRoland E. Dolle, Bertrand Le Bourdonnec, Guo-Hua Chu
Life of this patent
Estimating the term…
Abstract
Spirocyclic heterocyclic derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the spirocyclic heterocyclic derivatives are ligands of the δ opioid receptor and may be useful, inter alia, for treating and/or preventing pain, anxiety, gastrointestinal disorders, and other δ opioid receptor-mediated conditions.
Claims93
A compound of formula XIV:
- wherein:
- W2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from hydroxy, aminocarbonyl (—C(═O)—NH2), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C═O)—N(alkyl)(alkyl));
- R23 and R24 are each independently H or alkyl, provided that at least one of R23 and R24 is alkyl;
- A2 and B2 are each H, or together form a double bond;
- and
- X2 is —CH2— or —O—;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
4 more elements
A compound of formula XXII:
- wherein:
- W2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from heteroaryl, hydroxy, carboxy (—COOH), —C(═O)-alkyl, —C(═O)-aryl, —C(═O)—O-alkyl, —S(═O)2—N(alkyl)(alkyl);
- aminocarbonyl (—C(═O)—NH2), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl) (alkyl));
- R23 and R24 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- and
- J2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from halo, heterocycloalkyl, hydroxy, alkoxy, —S(═O)2-alkyl, —S(═O)2—NH2, —S(═O)2—NH(alkyl), —S(═O)2—N(alkyl)(alkyl), carboxy (—COOH), —C(═O)—O-alkyl, and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl));
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
- provided that:
- when W2 is para-diethylaminocarbonylphenyl, para-prop-2-ylaminocarbonylphenyl, orpara-pent-3-ylaminocarbonylphenyl, R23 and R24 are each H, and A and B are each H or together form a double bond, then J2 is other than unsubstituted phenyl or anisyl;
- and
- when W2 is:
- R23 and R24 are each H, and A and B together form a double bond;
- then J2 is other than unsubstituted phenyl.
11 more elements
A compound of formula XXV:
- wherein:
- W2 is aryl optionally substituted with —C(═O)-alkyl or —C(═O)-aryl;
- R23 and R24 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- X2 is —CH2— or —O—;
- and
- J2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from hydroxy, alkoxy, —S(═O)2-alkyl, —S(═O)2—NH2, —S(═O)2—NH(alkyl), —S(═O)2—N(alkyl)(alkyl), —C(═O)—N(alkyl)(alkyl), carboxy (—COOH), and —C(═O)—O-alkyl;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
- provided that the compound of formula XXV is other than 4-phenyl-spiro[2H,1-benzopyran-2,4′-piperidine].
6 more elements
A compound of formula XXVII:
- wherein:
- W2 is para-dialkylaminocarbonylphenyl, the phenyl group of which is further optionally substituted with 1-2 groups independently selected from tetrazolyl, N-alkyltetrazolyl, hydroxy, carboxy (—COOH), and aminocarbonyl (—C(═O)—NH2);
- R23 and R24 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- Q1 and Q2 are each independently H, hydroxy, alkoxy, haloalkoxy, halo, or heterocycloalkyl;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
- provided that:
- when one of Q1 and Q2 is hydroxy and the other is H, or both Q1 and Q2 are hydroxy, then the phenyl group of W2 is further substituted with 1-2 groups selected from tetrazolyl, N-alkyltetrazolyl, hydroxy, carboxy (—COOH), and aminocarbonyl (—C(═O)—NH2);
- when Q1, Q2, R23, and R24 are each H and the phenyl group of W2 is further substituted with one hydroxy, then A2 and B2 are each H;
- when W2 is para-dialkylaminocarbonylphenyl, then at least one of Q1, Q2, R23, and R24 is other than H;
- when W2 is para-dialkylaminocarbonylphenyl, R23 and R24 are each H, and Q2 is halo, then Q1 is other than H or hydroxy;
- when W2 is para-dialkylaminocarbonylphenyl, R23 and R24 are each H, Q1 is methoxy, or cyclopropylmethoxy, and Q2 is H, then A2 and B2 are each H;
- and
- when W2 is para-dialkylaminocarbonylphenyl, R23 and R24 are each H, and Q1 is H or OH, then Q2 is other than methoxy, cyclopropylmethoxy.
11 more elements
A compound of formula XXVIII:
- wherein:
- D is:
- K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O)2—N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH2), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));
- R23, R24, and R26 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- and
- X2 is —CH2— or —O—;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
5 more elements
A compound of formula XXIX:
- wherein:
- W2 is para-N(alkyl),N(alkyl-Z)aminocarbonylaryl or para-N(alkyl),N(alkyl-Z)aminocarbonylheteroaryl, wherein the aryl or heteroaryl ring of W2 is substituted with 0-2 groups selected independently from hydroxy and alkoxy;
- Z is alkoxy, alkylamino, or dialkylamino;
- R23 and R24 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- and
- X2 is —CH2— or —O—;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
5 more elements
A compound of formula XXX:
- wherein:
- W2 is:
- R23 and R24 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- X2 is —CH2— or —O—;
- and
- J2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 1-3 groups selected independently from halo and haloalkoxy;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
- provided that when W2 is:
- then the aryl ring of J2 is substituted with at least one haloalkoxy.
7 more elements
A compound of formula XXXII:
- wherein:
- D is N(alkyl),N(alkyl)aminocarbonylheteroaryl;
- R23, R24, and R26 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- and
- X2 is —CH2— or —O—;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
- provided that when D is:
- and X2 is —O—, then A2 and B2 are each H.
6 more elements
A pharmaceutical composition, comprising:
- a pharmaceutically acceptable carrier;
- and a compound of formula XIV:
- wherein:
- W2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from hydroxy, aminocarbonyl (—C(═O)—NH2), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl));
- R23 and R24 are each independently H or alkyl, provided that at least one of R23 and R24 is alkyl;
- A2 and B2 are each H, or together form a double bond;
- and
- X2 is —CH2— or —O—;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
6 more elements
A pharmaceutical composition, comprising:
- a pharmaceutically acceptable carrier;
- and a compound of formula XXII:
- wherein:
- W2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from heteroaryl, hydroxy, carboxy (—COOH), —C(═O)-alkyl, —C(═O)-aryl, —C(═O)—O-alkyl, —S(═O)2—N(alkyl)(alkyl);
- aminocarbonyl (—C(═O)—NH2), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl));
- R23 and R24 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- and
- J2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from halo, heterocycloalkyl, hydroxy, alkoxy, —S(═O)2-alkyl, —S(═O)2—NH2, —S(═O)2—NH(alkyl), —S(═O)2—N(alkyl)(alkyl), carboxy (—COOH), —C(═O)—O-alkyl, and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl));
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
- provided that:
- when W2 is para-diethylaminocarbonylphenyl, para-prop-2-ylaminocarbonylphenyl, or para-pent-3-ylaminocarbonylphenyl, R23 and R24 are each H, and A and B are each H or together form a double bond, then J2 is other than unsubstituted phenyl or anisyl;
- and
- when W2 is:
- R23 and R24 are each H, and A and B together form a double bond;
- then J2 is other than unsubstituted phenyl.
13 more elements
A pharmaceutical composition, comprising:
- a pharmaceutically acceptable carrier;
- and a compound of formula XXV:
- wherein:
- W2 is aryl optionally substituted with —C(═O)-alkyl or —C(═O)-aryl;
- R23 and R24 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- X2 is —CH2— or —O—;
- and
- J2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from hydroxy, alkoxy, —S(═O)2-alkyl, —S(═O)2—NH2, —S(═O)2—NH(alkyl), —S(═O)2—N(alkyl)(alkyl), —C(═O)—N(alkyl)(alkyl), carboxy (—COOH), and —C(═O)—O-alkyl;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
- provided that the compound of formula XXV is other than 4-phenyl-spiro[2H,1-benzopyran-2,4′-piperidine].
8 more elements
A pharmaceutical composition, comprising:
- a pharmaceutically acceptable carrier;
- and a compound of formula XXVIIA:
- wherein:
- W2 is para-dialkylaminocarbonylphenyl, the phenyl group of which is further optionally substituted with 1-2 groups independently selected from tetrazolyl, N-alkyltetrazolyl, hydroxy, carboxy (—COOH), and aminocarbonyl (—C(═O)—NH2);
- R23 and R24 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- Q1 and Q2 are each independently H, hydroxy, alkoxy, haloalkoxy, halo, or heterocycloalkyl;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
- provided that:
- when one of Q1 and Q2 is hydroxy and the other is H, then the phenyl group of W2 is further substituted with 1-2 groups selected from tetrazolyl, N-alkyltetrazolyl, hydroxy, carboxy (—COOH), and aminocarbonyl (—C(═O)—NH2);
- when Q1, Q2, R23, and R24 are each H and the phenyl group of W2 is further substituted with one hydroxy, then A2 and B2 are each H;
- when W2 is para-dialkylaminocarbonylphenyl, then at least one of Q1, Q2, R23, and R24 is other than H;
- when W2 is para-dialkylaminocarbonylphenyl, R23 and R24 are each H, and Q2 is halo, then Q1 is other than H;
- when W2 is para-dialkylaminocarbonylphenyl, R23 and R24 are each H, Q1 is methoxy, cyclopropylmethoxy, and Q2 is H, then A2 and B2 are each H;
- and
- when W2 is para-dialkylaminocarbonylphenyl, R23 and R24 are each H, and Q1 is H, or OH, then Q2 is other than methoxy, cyclopropylmethoxy.
13 more elements
A pharmaceutical composition, comprising:
- a pharmaceutically acceptable carrier;
- and a compound of formula XXVIII:
- wherein:
- D is:
- K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O)2—N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH2), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));
- R23, R24, and R26 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- and
- X2 is —CH2— or —O—;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
7 more elements
A pharmaceutical composition, comprising:
- a pharmaceutically acceptable carrier;
- and a compound of formula XXIX:
- wherein:
- W2 is para-N(alkyl),N(alkyl-Z)aminocarbonylaryl or para-N(alkyl),N(alkyl-Z)aminocarbonylheteroaryl, wherein the aryl or heteroaryl ring of W2 is substituted with 0-2 groups selected independently from hydroxy and alkoxy;
- Z is alkoxy, alkylamino, or dialkylamino;
- R23 and R24 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- and
- X2 is —CH2— or —O—;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
7 more elements
A pharmaceutical composition, comprising:
- a pharmaceutically acceptable carrier;
- and a compound of formula XXX:
- wherein:
- W2 is:
- R23 and R24 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- X2 is —CH2— or —O—;
- and
- J2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 1-3 groups selected independently from halo or haloalkoxy;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
- provided that when W2 is:
- then the aryl ring of J2 is substituted with at least one haloalkoxy.
9 more elements
A pharmaceutical composition, comprising:
- a pharmaceutically acceptable carrier;
- and a compound of formula XXXII:
- wherein:
- D is N(alkyl),N(alkyl)aminocarbonylheteroaryl;
- R23, R24, and R26 are each independently H or alkyl;
- A2 and B2 are each H, or together form a double bond;
- and
- X2 is —CH2— or —O—;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
- provided that when D is:
- and X2 is —O—, then A2 and B2 are each H.
8 more elements
A compound of formula XXXIII:
- wherein:
- F1 is heteroaryl;
- and
- G is C1-6alkylene substituted with NH2, NHC(═O)alkyl, NH(C(O)N(H)alkyl, or NHS(═O)2alkyl;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
2 more elements
A compound of formula XXXIV:
- wherein:
- F2 is aryl or heteroaryl;
- and
- Q3 is hydroxy or alkoxy;
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
2 more elements
A compound selected from the group consisting of:
- or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
Dependencies are inferred from the claim text.