Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-08-09
2001-03-13
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S587000
Reexamination Certificate
active
06201120
ABSTRACT:
BACKGROUND OF THE INVENTION
Compounds which inhibit the Ca
2+
-activated potassium channel (Gardos channel) of cells are useful in the treatment of a wide variety of diseases. For example, Sickle Cell Anemia can be treated with compounds which inhibit the Ca
2+
-activated potassium channel of erythrocytes (Stuart et al.,
J. Haematol
. 86:820 (1994). In addition, agents capable of inhibiting Ca
2+
-activated potassium channels have been shown to be useful in the treatment of arteriosclerosis (U.S. Pat. No. 5,358,959 to Halperin et al.) Moreover, cell proliferation is dependent on the regulated movement of ions across various cellular compartments, including activation of Ca
2+
-activated potassium channels (Magni et al.,
J. Biol. Chem
. 261:9321 (1991)). Thus, agents which inhibit Ca
2+
-activated potassium channels can be used in the treatment of proliferative diseases, including cancer, blood vessel proliferative disorders, fibrotic disorders and arteriosclerotic conditions.
SUMMARY OF THE INVENTION
The present invention is a method of preparing 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepines. The present invention also includes novel compounds which are intermediates in the preparation of 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepines and methods of preparing the intermediates.
In one embodiment, the present invention is a method of preparing an 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine represented by Structural Formula (I):
Phenyl Ring A, Phenyl Ring B and Phenyl Ring C are independently unsubstituted or substituted with one, two or three substituents. Each substituent on the 11-aryl-5,6-dihydro-11H-dibenzo[b,e]azepine is independently chosen.
R is —H, an aliphatic group, a substituted aliphatic group, an aryl group, a substituted aryl group, —C(O)—R′, —C(O)—H, —C(O)—NHR′, —S(O)
2
R′, —C(O)—C(O)—R′, —C(O)—C(O)—H, —C(S)—R′, —C(S)—H, —C(O)—OR′, —C(S)—OR′, —C(O)—SR′, —C(S)—SR′, —C(O)—NR′
2
or —C(O)—C(S)—R′. R′ is an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group.
The method of preparing an 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine represented by Structural Formula (I) comprises a first step in which a base, a substituted 2-aminobenzophenone and a starting material are reacted to form a diphenyl ketone. The 2-aminobenzophenone, the starting material and the diphenyl ketone are represented by Structural Formulas (II), (III) and (IV), respectively:
In Structural Formulas (II)-(IV), R
1
is a leaving group and R, Phenyl Ring A, Phenyl Ring B, and Phenyl Ring C are as described for Structural Formula (I).
The method of preparing an 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine represented by Structural Formula (I) comprises a second step in which the diphenyl ketone represented by Structural Formula (IV) is reacted with a ketone reducing agent to form an intermediate represented by Structural Formula (V):
In Structural Formula (V), R, Phenyl Ring A, Phenyl Ring B, and Phenyl Ring C are as described for Structural Formula (I).
The method of preparing an 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine represented by Structural Formula (I) comprises a third step in which the intermediate represented by Structural Formula (V) is reacted with one or more Lewis acids to form the 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine.
Another embodiment of the present invention is a method of forming a diphenyl ketone represented by Structural Formula (IV). The method comprises reacting a base, a 2-aminobenzophenone represented by Structural Formula (II) and a starting material represented by Structural Formula (III) to form the diphenyl ketone.
Another embodiment of the present invention is a method of forming an intermediate represented by Structural Formula (V). The method comprises reacting a diphenyl ketone represented by Structural Formula (IV) with a ketone reducing agent to form said intermediate.
Another embodiment of the present invention is a method of forming an intermediate represented by Structural Formula (V). The method comprises a first step of reacting a base, a 2-aminobenzophenone represented by Structural Formula (II) and a starting material represented by Structural Formula (III) to form a diphenyl ketone represented by Structural Formula (IV) and a second step of reacting the diphenyl ketone with a ketone reducing agent to form the intermediate represented by Structural Formula (V).
Another embodiment of the present invention is a method of forming a 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine from a diphenyl methanol. The 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine and the diphenyl methanol are represented by Structural Formulas (I) and (V), respectively, with the provisos that 1) at least one of Ring A, Ring B or Ring C is substituted; 2) when Ring B and Ring C are unsubstituted, Ring A is not substituted with —Cl para to the carbon atom bonded to the amino group; and 3) when Ring A and Ring C are unsubstituted, Ring B is not substituted with —OCH
3
at positions three, four and five with respect to the carbon bonded to the methyl amino group. Thus, 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepines and diphenyl methanols represented by Structural Formulas (VI)-(VIII) and (IX)-(XI), respectively, are excluded:
Another embodiment of the present invention is a method of forming a 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine represented by Structural Formula (I). The method comprises a first step of reacting a ketone reducing agent with a diphenyl ketone represented by Structural Formula (IV) to form an intermediate represented by Structural Formula (V) and reacting the intermediate with a Lewis acid to form the 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine.
Another embodiment of the present invention is a compound represented by Structural Formula (IV). Yet another embodiment of the present invention is a compound represented by Structural Formula (V) with the proviso that the compound is not represented by Structural Formulas (IX), (X) or (XI).
It is reported in co-pending U.S. patent applications that 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepines inhibit Ca
2+
-activated potassium channels and are therefore useful in treating sickle cell anemia, asteriosclerosis and proliferative diseases. The methods described herein can be used to prepare 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine in three reaction steps in overall yields of between about 10% and 35%. The starting materials and reagents are readily available and inexpensive. Thus, the present invention is an efficient and cost-effective method of preparing pharmacologically active agents useful in the treating sickle cell anemia, proliferative diseases such as cancer, blood vessel proliferative disorders, fibrotic disorders and arteriosclerotic conditions.
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Sasakura, K. and Sugasawa T., “Synthesis of 11-Phenyl-5, 6-Dihydro-11H-Dibenz(b,e)Azepine Derivatives,”Heterocycles, 15(1):421-425 (1981).
Brown, H.C. and Krishnamurthy S., “Boranes for Organic Reduction—A Forty-Year Odyssey1,”Aldrichimica Acta, 12(1):3-11 (1979).
Kisel, V.M., et al., “Condensed Isoquinolines. Part 6. Synthesis of 5-Aryl-7,12-Dihydroisoquino[2,3-a] Quinazolinium Salts,”Chemistry of Heterocyclic Compounds 31(5):586-587 (1995).
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Haider Reem M.
Lombardy Richard J.
Moussa Adel M.
Sun Minghua
Coleman Brenda
Hamilton Brook Smith & Reynolds P.C.
Pharm-Eco Laboratories, Inc.
Raymond Richard L.
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