US 6,407,092 B1Granted

Tetracyclic azepinoindole compounds

AssigneePharmacia & Upjohn Company

InventorsJackson B. Hester, Bruce N. Rogers, Eric Jon Jacobsen, Michael D. Ennis, Brad A. Acker, Susan L. Vander Velde, Kristine E. Frank

Life of this patent

Estimating the term…

Abstract

The present invention provides compounds of formula I: wherein R1, R2, X and Y have any of the values defined in the specification, as well as pharmaceutical compositions comprising the compounds. The invention also provides therapeutic methods as well as processes and intermediates useful for preparing compounds of formula (I).

Claims38

Dependent claims

A compound of formula I:

wherein
each R1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, tifluoromethoxy, C1-7alkyl, C1-7alkoxy, C1-7alkanoyl, C1-7alkoxycarbonyl, C1-7alkanoyloxy, aryl, heteroaryl, —S(O)mNRaRb, NRc Rd, —S(O)mRe, or —C(═O)NRaRb, wherein any C1-7alkyl, C1-7alkoxy, C1-7alkanoyl, C1-7alkoxycarbonyl, or C1-7alkanoyloxy of R1 is optionally partially unsaturated and is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, balo, cyano, C1-7alkoxy, C1-7alkanoyl, C1-7alkoxycarbonyl, C1-7alkanoyloxy, —S(O)mRe, —S(O)mNRaRb, NRcRd, or —C(═O)NRaRb;
R2 is hydrogen, C1-7alkyl, C1-7alkanoyl, arylcarbonyl, aryl, (aryl)C1-7alkyl, C1-7alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or (aryl)C1-7alkoxycarbonyl;
X and Y together are a 2 or 3 membered saturated or partially unsaturated chain comprising one or more carbon atoms and one oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (S(O)2—), or NRf in the chain;
wherein the chain is optionally substituted on each carbon with oxo (═O), thioxo (═S), —NRqRr, —S(O)pRs, or —ORt, or with one or two substitutents independently selected from the group consisting of C1-7alkyl, (C1-7alkoxy)C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, heteroaryl)C1-7alkyl, and (aryl)oxyC1-7alkyl;
or wherein the chain is optionally substituted on a carbon with a 4, 5, or 6 membered spirocyclic carbon ring;
or wherein the chain is optionally substituted on two adjacent atoms with a 2, 3, or 4 membered alkylene chain forming a ring that is fused to the ring comprising X and Y;
each m is independently 0, 1, or 2;
n is 0, 1, 2, or 3;
p is 0, 1, or 2;
each Ra and Rb is independently hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
or Ra and Rb together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each Rc and Rd is independently hydrogen, C1-7alkyl, C1-7alkanoyl, C1-7alkoxycarbonyl, aryl, (aryl)C1-7alkyl, heteroaryl, (heteroaryl)C1-7alkyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl;
or Rc and Rd together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each Re is independently hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
Rf is hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, (heteroaryl)C1-7alkyl, or is a bond to a 2, 3, or 4 membered alkylene chain that forms a ring that is fused to the ring comprising X and Y;
each Rq and Rr is independently hydrogen, C1-7alkyl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
or Rq and Rr together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
Rs is C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
and
Rt is hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
wherein any aryl or heteroaryl ring of R1, R2, X, Y, Ra-Rf, or Rq-Rt is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-7alkyl, C1-7alkoxy, phenyl, sulfonyl, NRjRk, or —C(═O)NRjRk;
wherein each Rj and Rk is in independently hydrogen, C1-7alkyl, C1-7alkanoyl, C1-7alkoxycarbonyl, aryl, (aryl)C1-7alkyl, arylcarbonyl, or aryloxycarbonyl;
or Rj and Rk together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
and
wherein any heteroaryl is a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, C1-4alkyl, phenyl or benzyl, or a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom;
or a pharmaceutically acceptable salt thereof;
provided Y is not oxy, thio, sulfinyl, or NRf;
and
provided X and Y together are not a 2-membered unsaturated chain;
and
provided no carbon of X and Y is bonded to more than one oxy, thio, sulfinyl, or NRf.

29 more elements

The compound:

4-bromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
5-bromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
6-bromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
5,6-dibromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
4,6-dibromo-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
4-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
5-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
6-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
4-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
5-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
4-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
5-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
6-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole;
4-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
5-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
6-chloro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4,5-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
5,6-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4,6-difluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4-chloro-5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4-chloro-6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
5-chloro-6-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
6-chloro-5-fluoro-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
5-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
6-methyl-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
5-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
6-methoxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
5-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
6-(triflouromethyl)-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
4-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
5-benzyloxy-1,2,8,9,10,13-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
or
6-benzyloxy-1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole;
or a pharmaceutically acceptable salt thereof.

37 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/553,246Filed 20 Apr 2000 · us provisional application
Priority: 23 Apr 1999
Granted: 18 Jun 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 471/16
In which the condensed system contains three hetero rings: peri-condensed systems
A61P 25/18
Drugs for disorders of the nervous system: antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
A61P 25/22
Drugs for disorders of the nervous system: anxiolytics
A61P 25/24
Drugs for disorders of the nervous system: antidepressants

Family

Application60/130,881Us provisional application · filed 23 Apr 1999
US 6,407,092 B1This patent

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

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Abstract

A compound of formula I:

wherein
each R1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, tifluoromethoxy, C1-7alkyl, C1-7alkoxy, C1-7alkanoyl, C1-7alkoxycarbonyl, C1-7alkanoyloxy, aryl, heteroaryl, —S(O)mNRaRb, NRc Rd, —S(O)mRe, or —C(═O)NRaRb, wherein any C1-7alkyl, C1-7alkoxy, C1-7alkanoyl, C1-7alkoxycarbonyl, or C1-7alkanoyloxy of R1 is optionally partially unsaturated and is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, balo, cyano, C1-7alkoxy, C1-7alkanoyl, C1-7alkoxycarbonyl, C1-7alkanoyloxy, —S(O)mRe, —S(O)mNRaRb, NRcRd, or —C(═O)NRaRb;
R2 is hydrogen, C1-7alkyl, C1-7alkanoyl, arylcarbonyl, aryl, (aryl)C1-7alkyl, C1-7alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or (aryl)C1-7alkoxycarbonyl;
X and Y together are a 2 or 3 membered saturated or partially unsaturated chain comprising one or more carbon atoms and one oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (S(O)2—), or NRf in the chain;
wherein the chain is optionally substituted on each carbon with oxo (═O), thioxo (═S), —NRqRr, —S(O)pRs, or —ORt, or with one or two substitutents independently selected from the group consisting of C1-7alkyl, (C1-7alkoxy)C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, heteroaryl)C1-7alkyl, and (aryl)oxyC1-7alkyl;
or wherein the chain is optionally substituted on a carbon with a 4, 5, or 6 membered spirocyclic carbon ring;
or wherein the chain is optionally substituted on two adjacent atoms with a 2, 3, or 4 membered alkylene chain forming a ring that is fused to the ring comprising X and Y;
each m is independently 0, 1, or 2;
n is 0, 1, 2, or 3;
p is 0, 1, or 2;
each Ra and Rb is independently hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
or Ra and Rb together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each Rc and Rd is independently hydrogen, C1-7alkyl, C1-7alkanoyl, C1-7alkoxycarbonyl, aryl, (aryl)C1-7alkyl, heteroaryl, (heteroaryl)C1-7alkyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl;
or Rc and Rd together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each Re is independently hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
Rf is hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, (heteroaryl)C1-7alkyl, or is a bond to a 2, 3, or 4 membered alkylene chain that forms a ring that is fused to the ring comprising X and Y;
each Rq and Rr is independently hydrogen, C1-7alkyl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
or Rq and Rr together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
Rs is C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
and
Rt is hydrogen, C1-7alkyl, aryl, (aryl)C1-7alkyl, heteroaryl, or (heteroaryl)C1-7alkyl;
wherein any aryl or heteroaryl ring of R1, R2, X, Y, Ra-Rf, or Rq-Rt is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-7alkyl, C1-7alkoxy, phenyl, sulfonyl, NRjRk, or —C(═O)NRjRk;
wherein each Rj and Rk is in independently hydrogen, C1-7alkyl, C1-7alkanoyl, C1-7alkoxycarbonyl, aryl, (aryl)C1-7alkyl, arylcarbonyl, or aryloxycarbonyl;
or Rj and Rk together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
and
wherein any heteroaryl is a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, C1-4alkyl, phenyl or benzyl, or a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom;
or a pharmaceutically acceptable salt thereof;
provided Y is not oxy, thio, sulfinyl, or NRf;
and
provided X and Y together are not a 2-membered unsaturated chain;
and
provided no carbon of X and Y is bonded to more than one oxy, thio, sulfinyl, or NRf.

29 more elements

Facts

Application

09/553,246Filed 20 Apr 2000 · us provisional application

Priority

23 Apr 1999

Granted

18 Jun 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 471/16
In which the condensed system contains three hetero rings: peri-condensed systems
A61P 25/18
Drugs for disorders of the nervous system: antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
A61P 25/22
Drugs for disorders of the nervous system: anxiolytics
A61P 25/24
Drugs for disorders of the nervous system: antidepressants