US2004157871A1PendingUtilityA1

Yohimbine dimers exhibiting binding selectivities for alpha2 adrenergic receptors

45
Priority: Mar 23, 2001Filed: Oct 6, 2003Published: Aug 12, 2004
Est. expiryMar 23, 2021(expired)· nominal 20-yr term from priority
Inventors:Duane D. MillerWeiping ZhengBob M. Moore, IiSuni MustafaDennis R. FellerLongping LeiShilpa Lalchandani
C07D 519/00
45
PatentIndex Score
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Cited by
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References
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Claims

Abstract

The present invention relates to yohimbine dimer compounds, pharmaceutical compositions containing such dimer compounds, methods of making such dimer compounds, and uses thereof. The yohimbine dimer compounds include compounds of formula (I): where R is any linker molecule which affords a yohimbine dimer that has activity as an α 2 -AR antagonist and has selectivity for an α 2 -AR subtype over another α 2 -AR subtype.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A method of treating or preventing an α 2  adrenergic receptor mediated condition or disorder comprising: 
 providing a compound according to formula (I)  
                     
 wherein R is a linker molecule that affords activity of the compound as an α 2  adrenergic receptor antagonist; and  
 administering to a patient an effective amount of the compound to treat or prevent the α 2  adrenergic receptor mediated condition or disorder.  
 
     
     
         2 . The method according to  claim 1 , wherein the α 2  adrenergic receptor mediated condition or disorder is an α 2a  adrenergic receptor mediated condition or disorder.  
     
     
         3 . The method according to  claim 2 , wherein the α 2a  adrenergic receptor mediated condition or disorder is selected from the group consisting of hypertension, hypotension, erectile dysfunction, pain, glaucoma, alcohol and drug withdrawal, rheumatoid arthritis, ischemia, migraine, cognitive deficiency, spasticity, diarrhea, and nasal congestion.  
     
     
         4 . The compound according to  claim 2 , wherein the compound exhibits selectivity in binding an α 2a  adrenergic receptor over an α 2b  adrenergic receptor.  
     
     
         5 . The method according to  claim 1 , wherein the α 2  adrenergic receptor mediated condition or disorder is an α 2c  adrenergic receptor mediated condition or disorder.  
     
     
         6 . The method according to  claim 5 , wherein the α 2c  adrenergic receptor mediated condition or disorder is Raynaud's disease.  
     
     
         7 . The method according to  claim 5 , wherein the compound exhibits selectivity in binding an α 2c  adrenergic receptor over an α 2b  adrenergic receptor.  
     
     
         8 . The method according to  claim 1 , wherein R has a length of about 2.5 Å to about 45 Å.  
     
     
         9 . The method according to  claim 8  wherein R has a length of about 2.5 Å to about 5 Å.  
     
     
         10 . The method according to  claim 8  wherein R has a length of about 23 Å to about 29 Å.  
     
     
         11 . The method according to  claim 1 , wherein R is either: 
 (i) a straight or branched chain alkyl, alkenyl, alkynyl comprising at least 2 carbon atoms in a main chain thereof, or    (ii) a straight or branched chain alkyl, alkenyl, alkynyl comprising at least 2 carbon atoms in a main chain thereof and an X group within the main chain and/or a Y group as a substituent linked to a carbon atom in the main chain,    with X being —O—, carbonyl, —NR 1 — with R 1  being H or an alkyl, —C(O)NHR 1 — with R 1  being an alkyl, —S—, sulfoxide, sulfonyl, or a cyclic or multicyclic ring with or without hetero atoms as ring members and including, optionally, one or more substitutions on the ring structure, and    with Y being —OH, —NO 2 , —CN, —C(O)H, —SH, a primary, secondary, or tertiary amine, a carboxylic acid, an ester, a keto group, —SO 2 NH 2 , or —SO 2 NHR 2  with R 2  being an alkyl, or    (iii) a cyclic or multicyclic ring with or without hetero atoms as ring members and including, optionally, one or more substitutions on the ring structure(s).    
     
     
         12 . The method according to  claim 11 , wherein R is a straight chain alkyl.  
     
     
         13 . The method according to  claim 12 , wherein R is a straight chain C2 to C36 alkyl.  
     
     
         14 . The method according to  claim 12 , wherein R is a straight chain C3 to C24 alkyl.  
     
     
         15 . The method according to  claim 11 , wherein R is a straight chain alkyl comprising at least 4 carbon atoms and an X group within the straight chain, wherein X is a —O—.  
     
     
         16 . The method according to  claim 15 , wherein R is —(CH 2 CH 2 —O—CH 2 CH 2 ) n  wherein n is an integer from 1 to 6.  
     
     
         17 . The method according to  claim 15 , wherein R is —(CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 ) n — wherein n is an integer from 1 to 4.  
     
     
         18 . The method according to  claim 11 , wherein R is a straight chain alkyl comprising at least 5 carbon atoms and an X group within the straight chain, wherein X is —C(O)NHR 1 — with R 1  being an alkyl.  
     
     
         19 . The method according to  claim 11 , wherein R is —(CH 2 —NHC(O)) n —CH 2 —CH 2 —CH 2 —CH 2 —(C(O)NH—CH 2 ) n — wherein each n is independently an integer from 1 to 3.  
     
     
         20 . The method according to  claim 11 , wherein R is a straight chain alkenyl comprising at least 5 carbon atoms in a main chain thereof and an X group within the main chain, wherein X is —C(O)NHR 1 — with R 1  being an alkyl.  
     
     
         21 . The method according to  claim 20 , wherein R is a cis isomer or a trans isomer of —(CH 2 —NHC(O)) n —CH 2 —CH═CH—CH 2 —(C(O)NH—CH 2 ) n — wherein each n is independently an integer from 1 to 3.  
     
     
         22 . The method according to  claim 21 , wherein R is a cis isomer.  
     
     
         23 . The method according to  claim 21 , wherein R is a trans isomer.  
     
     
         24 . A method of modulating the activity of an α 2a  adrenergic receptor comprising: 
 providing a compound according to formula (I)  
                     
 wherein R is a linker molecule that affords activity of the compound as an α 2a  adrenergic receptor antagonist; and  
 contacting an α 2a  adrenergic receptor with the compound under conditions effective to modulate the activity of the α 2a  adrenergic receptor.  
 
     
     
         25 . The method according to  claim 24 , wherein the compound exhibits selectivity in binding an α 2a  adrenergic receptor over an α 2b  adrenergic receptor.  
     
     
         26 . The method according to  claim 24 , wherein R has a length of about 2.5 Å to about 45 Å.  
     
     
         27 . The method according to  claim 24 , wherein R is either: 
 (i) a straight or branched chain alkyl, alkenyl, alkynyl comprising at least 2 carbon atoms in a main chain thereof, or    (ii) a straight or branched chain alkyl, alkenyl, alkynyl comprising at least 2 carbon atoms in a main chain thereof and an X group within the main chain and/or a Y group as a substituent linked to a carbon atom in the main chain,    with X being —O—, carbonyl, —NR 1 — with R 1  being H or an alkyl, —C(O)NHR 1 — with R 1  being an alkyl, —S—, sulfoxide, sulfonyl, or a cyclic or multicyclic ring with or without hetero atoms as ring members and including, optionally, one or more substitutions on the ring structure, and    with Y being —OH, —NO 2 , —CN, —C(O)H, —SH, a primary, secondary, or tertiary amine, a carboxylic acid, an ester, a keto group, —SO 2 NH 2 , or —SO 2 NHR 2  with R 2  being an alkyl, or    (iii) a cyclic or multicyclic ring with or without hetero atoms as ring members and including, optionally, one or more substitutions on the ring structure(s).    
     
     
         28 . The method according to  claim 27 , wherein R is a straight chain alkyl.  
     
     
         29 . The method according to  claim 27 , wherein R is a straight chain alkyl comprising at least 4 carbon atoms and an X group within the straight chain, wherein X is a —O—.  
     
     
         30 . The method according to  claim 27 , wherein R is a straight chain alkyl comprising at least 5 carbon atoms and an X group within the straight chain, wherein X is —C(O)NHR 1 — with R 1  being an alkyl.  
     
     
         31 . The method according to  claim 27 , wherein R is —(CH 2 —NHC(O)) n —CH 2 —CH 2 —CH 2 —CH 2 —(C(O)NH—CH 2 ) n — wherein each n is independently an integer from 1 to 3.  
     
     
         32 . The method according to  claim 27 , wherein R is a straight chain alkenyl comprising at least 5 carbon atoms in a main chain thereof and an X group within the main chain, wherein X is —C(O)NHR 1 — with R 1  being an alkyl.  
     
     
         33 . The method according to  claim 32 , wherein R is a cis isomer or a trans isomer of —CH 2 —NHC(O)) n —CH 2 —CH═CH—CH 2 —(C(O)NH—CH 2 ) n —wherein each n is independently an integer from 1 to 3.  
     
     
         34 . A method of modulating the activity of an α 2c  adrenergic receptor comprising: 
 providing a compound according to formula (I)  
                     
 wherein R is a linker molecule that affords activity of the compound as an α 2c  adrenergic receptor antagonist; and  
 contacting an α 2c  adrenergic receptor with the compound under conditions effective to modulate the activity of the α 2c  adrenergic receptor.  
 
     
     
         35 . The compound according to  claim 34 , wherein the yohimbine dimer exhibits selectivity in binding an α 2c  adrenergic receptor over an α 2b  adrenergic receptor.  
     
     
         36 . The method according to  claim 34 , wherein the compound exhibits selectivity in binding an α 2c  adrenergic receptor over an (α 2a  adrenergic receptor.  
     
     
         37 . The method according to  claim 34 , wherein R has a length of about 2.5 Å to about 45 Å.  
     
     
         38 . The method according to  claim 34 , wherein R is either: 
 (i) a straight or branched chain alkyl, alkenyl, alkynyl comprising at least 2 carbon atoms in a main chain thereof, or    (ii) a straight or branched chain alkyl, alkenyl, alkynyl comprising at least 2 carbon atoms in a main chain thereof and an X group within the main chain and/or a Y group as a substituent linked to a carbon atom in the main chain,    with X being —O—, carbonyl, —NR 1 — with R 1  being H or an alkyl, —C(O)NHR 1 — with R 1  being an alkyl, —S—, sulfoxide, sulfonyl, or a cyclic or multicyclic ring with or without hetero atoms as ring members and including, optionally, one or more substitutions on the ring structure, and    with Y being —OH, —NO 2 , —CN, —C(O)H, —SH, a primary, secondary, or tertiary amine, a carboxylic acid, an ester, a keto group, —SO 2 NH 2 , or —SO 2 NHR 2  with R 2  being an alkyl, or    (iii) a cyclic or multicyclic ring with or without hetero atoms as ring members and including, optionally, one or more substitutions on the ring structure(s).    
     
     
         39 . The method according to  claim 38 , wherein R is a straight chain alkyl.  
     
     
         40 . The method according to  claim 38 , wherein R is a straight chain alkyl comprising at least 4 carbon atoms and an X group within the straight chain, wherein X is a —O—.  
     
     
         41 . The method according to  claim 38 , wherein R is a straight chain alkyl comprising at least 5 carbon atoms and an X group within the straight chain, wherein X is —C(O)NHR 1 — with R 1  being an alkyl.  
     
     
         42 . The method according to  claim 38 , wherein R is —(CH 2 —NHC(O)) n —CH 2 —CH 2 —CH 2 —CH 2 —(C(O)NH—CH 2 ) n — wherein each n is independently an integer from 1 to 3.  
     
     
         43 . The method according to  claim 38 , wherein R is a straight chain alkenyl comprising at least 5 carbon atoms in a main chain thereof and an X group within the main chain, wherein X is —C(O)NHR 1 — with R 1  being an alkyl.  
     
     
         44 . The method according to  claim 43 , wherein R is a cis isomer or a trans isomer of —(CH 2 —NHC(O)) n —CH 2 —CH═CH—CH 2 —(C(O)NH—CH 2 ) n — wherein each n is independently an integer from 1 to 3.

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