Short-acting benzodiazepines Number:7,160,880 from the United States Patent and Trademark Office (PTO) owispatent The present invention provides a compound of formula (I): ##STR00001## wherein all variables are as defined herein, pharmaceutical formulations containing the same, processes for preparing the same and their use therapy.<H benzodiazepines, acting, Short, acting, be, 7160880.html, Patent, pto, 7160880

Title: Short-acting benzodiazepines

Abstract: The present invention provides a compound of formula (I): ##STR00001## wherein all variables are as defined herein, pharmaceutical formulations containing the same, processes for preparing the same and their use therapy.

Patent Number: 7,160,880 Issued on 01/09/2007 to Feldman, et al.

Inventors: Feldman; Paul L (Durham, NC), Jung; David Kendall (Durham, NC), Kaldor; Istvan (Durham, NC), Pacofsky; Gregory J. (Durham, NC), Stafford; Jeffrey A. (Durham, NC), Tidwell; Jeffrey H. (Durham, NC)
Assignee: CeNeS Limited (Cambridge, GB)

Appl. No.: 09/980,680

Filed: May 12, 2000

PCT Filed: May 12, 2000

PCT No.: PCT/US00/13134

371(c)(1),(2),(4) Date: October 31, 2001

PCT Pub. No.: WO00/69836

PCT Pub. Date: November 23, 2000

Foreign Application Priority Data


May 14, 1999 [GB]			9911152.8

Current U.S. Class: 514/221 ; 540/505; 540/509; 540/512; 540/572

Current International Class: A61P 25/20 (20060101); A61K 31/55 (20060101); C07D 243/14 (20060101); C07D 243/18 (20060101); C07D 243/24 (20060101)

Field of Search: 514/221 540/505,509,512,572

References Cited [Referenced By]

U.S. Patent Documents


4755508	July 1988	Bock et al.
5324726	June 1994	Bock et al.
5665718	September 1997	Godel et al.
5698691	December 1997	Yukimasa et al.
5834464	November 1998	Bock et al.
2002/0055500	May 2002	Wu et al.

Foreign Patent Documents


40183	Dec., 1959	DE
FR 2 034 577	Dec., 1970	EP
FR 2 115 265	Jul., 1972	EP
FR 2 183 716	Dec., 1973	EP
FR 2 231 385	Dec., 1974	EP
CH 608 234	Dec., 1978	EP
166356	Jan., 1986	EP
167919	Jan., 1986	EP
0 264 797	Apr., 1988	EP
284256	Sep., 1988	EP
434360	Jun., 1991	EP
434364	Jun., 1991	EP
0 508 798	Oct., 1992	EP
523845	Jan., 1993	EP
176 927	Sep., 1993	EP
727215	Aug., 1996	EP
881 235	Dec., 1998	EP
2259013	Mar., 1993	GB
7012813	Aug., 1970	NL
FR 2414043	Aug., 1979	WO
EP 0100 906	Feb., 1984	WO
EPO 122 889	Oct., 1984	WO
WO 91 05549	May., 1991	WO
WO 96 23790	Aug., 1995	WO
WO 96 20941	Jul., 1996	WO
WO 98 00405	Jan., 1998	WO
WO 98/38177	Sep., 1998	WO

Other References

Ichihara, Masato et al., "Preparation of diazepine derivatives as specific inhibitors of human renin", Database Chemabs Online!, Chemical Abstracts Service, (1995). cited by other .
Goumri-Magnet S. et al., "Free and Supported Phosphorus Ylides as Strong Neutral Bronsted Bases", Journal of Organic Chemistry, vol. 64, No. 10, (1999), pp. 3741-3744. cited by other .
Avdagic, Amir et al., "Lipase-catalyzed acetylation of 3-substituted 2,3-dihydro-1H-1,4-bezodiazepin-2-ones. Effect of temperature and conformation on enantioselectivity and configuration", Helv. Chim. Acta, vol. 81, No. 8, pp. 1567-1582, (1998). cited by other .
Heaney, Frances et al., "Steric control of reactivity: formation of oximes, benzodiazepinone N-oxides and isoxazoloquinolinones", Journal Chem. Soc., Perkin Trans. vol. 2, (3), (1998), pp. 547-559. cited by othe- r .
Bock, Mark G. et al., "Curtius rearrangement in the 5-phenyl-1,4-benzodiazepine series. Unprecendedted participation by an imine nitrogen", Journal Heterocycl. Chem., vol. 27, No. 3, (1990), pp. 631-636. cited by other .
Manghisi, E. et al., Synthesis and central nervous effects of some 3-substituted 1,4-benzodiazepin-2-ones, Boll. Chim. Farm., vol. 113, No. 12, (1974), pp. 642-644. cited by other .
Corbella, Attilio et al., "Stereochemistry of the enzymic 3-hydroxylation of 1,3-dihydro-22H-1,4-benzodiazepin-2-ones", J. Chem. Soc., Chem. Commun., No. 19, (1973), pp. 721-722. cited by other .
Walser, Armin et al., "Quinazolines and 1,4-benzodiazepines. LIX. Preparation of pyrrolo'2,1-c!-1,4-benzodiazepines", J. Org. Chem., vol. 38, No. 20, (1973), pp. 3502-3507. cited by other .
Shimamoto, Kiro et al., "Pharmaceutical screening of new benzodiazepines in mice", Takeda Kenkyusho Ho, vol. 29, No. 1, (1970) pp. 134-144. cited by other .
Gilman, A.G., et al. "Goodman and Gilman's The Pharmacological Basis of Therapeutics." Eighth Edition, Pergamon Press: New York, 1990; pp. 303-304, 346-358. cited by other .
Hering, W., et al. "CNS Effects of the New Benzodiazepines RO 48-6791 and RO 48-8684 Compared to Midazolam in Young and Elderly Volunteers." Anesthesiology 1996, 189, 85 (Suppl.). cited by other .
Dingemanse, J. et al. "Pharmacokinetic-Pharmacodynamic Modelling of the EEF Effects of RO 48-6791, a New Short-Acting Benzodiazepine, in Young and Elderly Subjects." Br. J. Anaesth. 1997, 79, pp. 567-574. cited by other .
Khan, W.A., et al. "Synthesis of 3-Substituted 1,4-Benzodiazepine2-Ones." Org. Prep. Proc. Int., 1978, 10, pp. 105-111. cited by other .
Hester, J.B., et al. "8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines with Substituents at C-4" J. Med. Chem., 1980, 23, 643-647. cited by other .
Bauer, T.M., et al. "Prolonged Sedation Due to Accumulation of Conjugated Metabolites of Midazolam." Lancet 1995, 346, pp. 145-147. cited by other .
Shafer, A., et al. "Complications of Sedation with Midazolam in the Intensive Care Unit and a Comparison wit Other Sedative Regimens." Crit. Care Med., 1998, 26, 947-956. cited by other.

Primary Examiner: Coleman; Brenda
Attorney, Agent or Firm: Corless; Peter F. Edwards Angell Palmer & Dodge LLP

Claims

What is claimed is:

1. A compound of formula (I): ##STR00094## wherein W is H, a C.sub.1 C.sub.4 branched alkyl, or straight chained alkyl; X is CH.sub.2, NH or NCH.sub.3; n is 1 or 2; Y is O or CH.sub.2; m is 0 or 1, provided that if X is CH.sub.2, n is 1 and m is 0, then R.sup.1 is not CH.sub.2CH.sub.3; R.sup.1 is H, a C.sub.1 C.sub.7 straight chain alkyl, a C.sub.3 C.sub.7 branched chain alkyl, a C.sub.1-4haloalkyl, a C.sub.3 C.sub.7 cycloalkyl, an aryl, a heteroaryl, an aralkyl, or a heteroaralkyl; R.sup.2 is phenyl, 2-halophenyl or 2-pyridyl, R.sup.3 is H, Cl, Br, F, I, CF.sub.3 or NO.sub.2; and wherein R.sup.4 and R.sup.5 together is a double bond in the diazepine ring and R.sup.6 represents the group NHR.sup.7 wherein R.sup.7 is H, C.sub.1-4 alkyl, benzyl, benzyl mono or disubstituted independently with halogen substituents, C.sub.1-4alkylpyridyl or C.sub.1-4 alkylimidazolyl; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound of formula (I): ##STR00095## wherein W is H; X is CH.sub.2 or NH; n is 1; Y is CH.sub.2; m is 0 or 1, provided that if X is CH.sub.2 and m is 0, then R.sup.1 is not CH.sub.2CH.sub.3; R.sup.1 is CH.sub.3, CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3, benzyl or 4-pyridylmethyl; provided that when R.sup.1 is CH.sub.3 or benzyl then m=1; R.sup.2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R.sup.3 is Cl, Br or NO.sub.2; R.sup.4 is H, CH.sub.3 or CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2; R.sup.5 and R.sup.6 together are O or S; or a pharmaceutically acceptable salt or solvate thereof.

3. A compound of formula (I): ##STR00096## wherein W is H; X is CH.sub.2 or NH; n is 1; Y is CH.sub.2; m is 0 or 1, provided that if X is CH.sub.2 and m is 0, then R.sup.1 is not CH.sub.2CH.sub.3; R.sup.1 is CH.sub.3, CH.sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3, benzyl or 4-pyridylmethyl; provided that when R.sup.1 is 4-pyridylmethyl, then X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl, R.sup.4 is H and R.sup.5 and R.sup.6 together are O; and further provided that when R.sup.1 is CH.sub.3 or benzyl then m=1; R.sup.2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R.sup.3 is Cl, Br or NO.sub.2; R.sup.4 is H, CH.sub.3 or CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2; provided that when R.sup.4 is CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3 or benzyl, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl and R.sup.5 and R.sup.6 together are O; R.sup.5 and R.sup.6 together are O or S; or a pharmaceutically acceptable salt or solvate thereof.

4. A compound of formula (I): ##STR00097## wherein W is H, and X, n, Y, m, R.sup.1-6 are as follows: TABLE-US-00008 R.sup.5 and X n Y m R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.6 CH.sub.2 1 CH.sub.2 1 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 CH.sub.3 2-fluorophenyl Br H O CH.sub.2 1 CH.sub.2 1 CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 CH.sub.3 2-fluorophenyl Cl CH.sub.3 O.

5. A compound of formula (I): ##STR00098## wherein W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl, R.sup.4 is H and R.sup.5 and R.sup.6 together are O.

6. A compound according to claim 1 wherein R.sup.4 and R.sup.5 together form a double bond in the diazepine ring, R.sup.6 is the group NHR.sup.7 and R.sup.1 is CH.sub.3.

7. A compound according to claim 6, wherein W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3, R.sup.2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R.sup.3 is Cl or Br and R.sup.7 is CH.sub.3, CH.sub.2CH.sub.3, benzyl, 4-pyridylmethyl-, 4-pyridylethyl, CH(CH.sub.3).sub.2, or 4-imidazolylethyl.

8. A compound according to claim 6, wherein W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3, and R.sup.2, R.sup.3 and R.sup.7 are as follows: TABLE-US-00009 R.sup.2 R.sup.3 R.sup.7 2-fluorophenyl Cl CH.sub.3 2-pyridyl Cl CH.sub.3 2-fluorophenyl Cl CH.sub.2CH.sub.3 2-fluorophenyl Cl benzyl 2-fluorophenyl Cl 4-pyridylmethyl 2-fluorophenyl Cl 4-pyridylethyl 2-fluorophenyl Cl CH.sub.2CH(CH.sub.3).sub.2 2-fluorophenyl Cl 2-(4-imidazolyl)ethyl 2-fluorophenyl Br CH.sub.3 2-chlorophenyl Cl CH.sub.3.

9. A compound according to claim 6, wherein W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3, R.sup.2 is 2-fluorophenyl, R.sup.3 is chlorine or bromine and R.sup.7 is methyl.

10. A compound according to claim 6, wherein W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl and R.sup.7 is CH.sub.3.

11. Methyl-3-[(3S)-7-chloro-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-1,4-b- enzodiazepin-3-yl]propanoate and pharmaceutically acceptable salts or solvates thereof.

12. Methyl-3-[(3S)-7-chloro-5-(2-fluorophenyl)-2-(methylamino)-3H-1,4-ben- zodiazepin-3-yl]propanoate and pharmaceutically acceptable salts or solvates thereof.

13. A compound of formula (I) ##STR00099## wherein W is H and X, n, Y, m, Z, p and R.sup.1-6 are as follows: TABLE-US-00010 R.sup.5 and X N Y m Z p R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.6 CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 -- 0 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Br H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-fluorophenyl Cl H O CH.sub.2 1 -- 0 -- 0 benzyl 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H O CH.sub.2 1 CH.sub.2 2 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Br H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 2 -- 0 C(CH.sub.3).sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl NO.sub.2 H O CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.2CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 4-pyridyl- 2-fluorophenyl Cl H O methyl CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.3CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.3CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.2CH(CH.sub.3).sub.2 2-pyridyl Cl H O CH.sub.2 1 -- 0 -- 0 CH.sub.2CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH(CH.sub.3).sub.2 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl CH.sub.2CH.sub.2N(CH- .sub.2CH.sub.3).sub.2 O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl CH.sub.3 O CH.sub.2 1 -- 0 -- 0 benzyl 2-fluorophenyl Cl CH.sub.3 O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-fluorophenyl Cl CH.sub.2CH.sub.2N(CH.s- ub.2CH.sub.3).sub.2 O NH 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl H S CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H S CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Cl H S CH.sub.2 1 CH.sub.2 1 O 1 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl phenyl NO.sub.2 H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl H H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl NO.sub.2 H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-pyridyl NO.sub.2 H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-fluorophenyl H H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 phenyl NO.sub.2 H O CH.sub.2 1 -- 0 -- 0 3-pyridyl- 2-fluorophenyl Cl H O methyl CH.sub.2 1 -- 0 -- 0 4-pyridyl- 2-fluorophenyl Cl H O methyl.

14. A compound of formula (I) ##STR00100## wherein W is H and X, n, Y, m, Z, p and R.sup.1-6 are as follows: TABLE-US-00011 R.sup.5 and X n Y m Z p R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.6 CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 -- 0 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Br H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-fluorophenyl Cl H O CH.sub.2 1 -- 0 -- 0 benzyl 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H O CH.sub.2 1 CH.sub.2 2 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Br H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 2 -- 0 C(CH.sub.3).sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl NO.sub.2 H O CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.2CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.2CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 4-pyridyl- 2-fluorophenyl Cl H O methyl CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.3CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.3CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.2CH(CH.sub.3).sub.2 2-pyridyl Cl H O CH.sub.2 1 -- 0 -- 0 CH.sub.2CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH(CH.sub.3).sub.2 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl CH.sub.2CH.sub.2N(CH- .sub.2CH.sub.3).sub.2 O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl CH.sub.3 O CH.sub.2 1 -- 0 -- 0 benzyl 2-fluorophenyl Cl CH.sub.3 O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-fluorophenyl Cl CH.sub.2CH.sub.2N(CH.s- ub.2CH.sub.3).sub.2 O NH 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl H S CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H S CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Cl H S CH.sub.2 1 CH.sub.2 1 O 1 CH.sub.3 2-fluorophenyl Cl H O.

15. A compound of formula (I): ##STR00101## wherein W is H; X is CH.sub.2 or NH; n is 1; Y is CH.sub.2; m is 0 or 1, provided that if X is CH.sub.2 and m is 0, then R.sup.1 is not CH.sub.2CH.sub.3; R.sup.1 is CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3, or 4-pyridylmethyl; R.sup.2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R.sup.3 is Cl, Br or NO.sub.2; R.sup.4 is H, CH.sub.3 or CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2; R.sup.5 and R.sup.6 together are O or S; or a pharmaceutically acceptable salt or solvate thereof.

16. A compound of formula (I): ##STR00102## wherein W is H; X is CH.sub.2 or NH; n is 1; Y is CH.sub.2; m is 0 or 1, provided that if X is CH.sub.2 and m is 0, then R.sup.1 is not CH.sub.2CH.sub.3; R.sup.1 is CH.sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3, or 4-pyridylmethyl; provided that when R.sup.1 is 4-pyridylmethyl, then X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl, R.sup.4 is H and R.sup.5 and R.sup.6 together are O; R.sup.2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R.sup.3 is Cl, Br or NO.sub.2; R.sup.4 is H, CH.sub.3 or CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2; provided that when R.sup.4 is CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3 or benzyl, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl and R.sup.5 and R.sup.6 together are O; R.sup.5 and R.sup.6 together are O or S; or a pharmaceutically acceptable salt or solvate thereof.

17. A pharmaceutical composition comprising a compound of claim 1.

18. A pharmaceutical composition comprising a compound of claim 11.

19. A pharmaceutical composition comprising a compound of claim 12.

20. A method of producing sedation or hypnosis, inducing anxiolysis, inducing muscle relaxation or treating convulsions in a mammal in need thereof which comprises administering to the mammal an effective amount of a compound of claim 1.

21. A method of producing sedation or hypnosis, inducing anxiolysis, inducing muscle relaxation or treating convulsions in a mammal in need thereof which comprises administering to the mammal an effective amount of a compound of claim 6.

Description

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a Rule 371 Application of PCT Application No. US00/13134, filed May 12, 2000, which claims priority to GB application Serial No. 9911152.8, filed May 14, 1999.

FIELD OF THE INVENTION

The present invention relates to benzodiazepine derivatives, to pharmaceutical compositions containing them and to their use in medicine. More particularly, the present invention relates to benzodiazepine derivatives suitable for therapeutic purposes, including sedative-hypnotic, anxiolytic, muscle relaxant and aticonvulsant purposes.

BACKGROUND OF THE INVENTION

The broad neuropharmacology elicited from the benzodiazepine class of compounds is generally attributed to their binding to a site on a specific receptor/chloride ion channel complex known as the GABA.sub.A receptor. Benzodiazepine-receptor binding potentiates the binding of the inhibitory neurotransmitter .gamma.-aminobutyric acid (GABA) to the complex, thereby leading to inhibition of normal neuronal function. In addition to the therapeutic purposes listed above, benzodiazepines have been used widely for anesthesia, particularly as a premedication or as a component in the induction and/or maintenance of anesthesia. See generally, Goodman and Gilman's The Pharmacological Basis of Therapeutics, Eighth Edition; Gilman, A. G.; Rall, T. W.; Nies, A. S.; Taylor, P., Eds.; Pergamon Press: New York, 1990; pp. 303 304, 346 358.

Shorter-acting benzodiazepines that may provide faster recovery profiles have been the subject of recent clinical investigations (W. Hering et al., Anesthesiology 1996, 189, 85 (Suppl.); J. Dingemanse et al., Br. J. Anaesth 1997, 79, 567 574.) Recent patent filings also describe benzodiazepines of interest. (WO 96/23790; WO 96/20941; U.S. Pat. No. 5,665,718). Other publications that describe benzodiazepinones include E. Manghisi and A. Salimbemi, Boll. Chim. Farm. 1974, 113, 642 644), W. A. Khan and P. Singh, Org. Prep. Proc. Int. 1978, 10, 105 111 and J. B. Hester, Jr, et al. J. Med. Chem. 1980, 23, 643 647. Benzodiazepines in present practice, such as diazepam, lorazepam, and midazolam all undergo metabolism by hepatic-dependent processes. Active metabolites, which are often much more slowly metabolized than the parent drug, can be generated by these hepatic mechanisms in effect prolonging the duration of action of many benzodiazepines (T. M. Bauer et al., Lancet 1995, 346, 145 7). Inadvertent oversedation has been associated with the use of benzodiazepines (A. Shafer, Crit Care Med 1998, 26, 947 956), particularly in the ICU, where benzodiazepines, such as midazolam, enjoy frequent use. However, the benzodiazepine compounds of this invention differ from benzodiazepines in present-day clinical practice.

SUMMARY OF THE INVENTION

It has now been found that compounds of the present invention as described in Formula (I) possess certain advantages because of their structural design. The benzodiazepines described by this invention all contain a carboxylic ester moiety and are inactivated by nonspecific tissue esterases. An organ-independent elimination mechanism is predicted to be characteristic of the benzodiazepines of this invention, providing a more predictable and reproducible pharmacodynamic profile.

The compounds of the present invention are suitable for therapeutic purposes, including sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant purposes. The compounds of the present invention are short-acting CNS depressants that are useful to be administered intravenously in the following clinical settings: preoperative sedation, anxiolysis, and amnestic use for perioperative events; conscious sedation during short diagnostic, operative or endoscopic procedures; as a component for the induction and maintenance of general anesthesia, prior and/or concomitant to the administration of other anesthetic agents; ICU sedation.

DETAILED DESCRIPTION OF THE INVENTION

Thus it is provided according to a first aspect of the present invention compounds of Formula (I):

##STR00002## wherein W is H or C.sub.1 C.sub.4 branched alkyl or straight chained alkyl; X is CH.sub.2, NH, or NCH.sub.3; n is 1 or 2; Y is O or CH.sub.2; m is 0 or 1, provided that if X is CH.sub.2, n is 1 and m is 0, then R.sup.1 is not CH.sub.2CH.sub.3; Z is O; p is 0 or 1; R.sup.1 is H, a C.sub.1 C.sub.7 straight chain alkyl, a C.sub.3 C.sub.7 branched chain alkyl, a C.sub.1 C.sub.4 haloalkyl, a C.sub.3 C.sub.7 cycloalkyl, an aryl, a heteroaryl, an aralkyl, or a heteroarylalkyl; R.sup.2 is phenyl, 2-halophenyl, or 2-pyridyl, R.sup.3 is H, Cl, Br, F, I, CF.sub.3 or NO.sub.2; (1) R.sup.4 is H, C.sub.1 C.sub.4 alkyl, or dialkylaminoalkyl and R.sup.5 and R.sup.6 together represent a single oxygen or S atom which is linked to the diazepine ring by a double bond and p is zero or 1 (as depicted in formula Ia); or (2) R.sup.4 and R.sup.5 together form a double bond in the diazepine ring and R.sup.6 represents the group NHR.sup.7 wherein R.sup.7 is H, C.sub.1-4 alkyl, C.sub.1-4 hydroxylalkyl, benzyl, or benzyl mono or disubstituted independently with halogen substituents, C.sub.1-4alkylpyridyl or C.sub.1-4 alkylimidazolyl and p is zero (as depicted in formula Ib); or (3) R.sup.4, and R.sup.6 form the group --CR.sup.8.dbd.U--V.dbd. wherein R.sup.8 is hydrogen, C.sub.1-4 alkyl, or C.sub.1-3 hydroxyalkyl, U is N or CR.sup.9 wherein R.sup.9 is H, C.sub.1-4alkyl, C.sub.1-3hydroxyalkyl or C.sub.1-4alkoxy-C.sub.1-4alkyl, V is N or CH and p is zero (as depicted in formula Ic); or pharmaceutically acceptable salts or solvates thereof.

The term "aryl," alone or in combination, is defined herein as a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group, e.g., phenyl or naphthyl, which can be unsubstituted or substituted, for example, with one or more and, in particular, one to three substituents selected from halogen, C.sub.1 C.sub.4 branched or straight chained alkyl, C.sub.1 C.sub.4 alkoxy, C.sub.1 C.sub.4 haloalkyl, hydroxy, nitro, amino, and the like. The term "heteroaryl" is defined herein as a 5-membered or 6-membered heterocyclic aromatic group which can optionally carry a fused benzene ring and wherein said 5-membered or 6-membered heterocyclic aromatic group can be unsubstituted or substituted, for example, with one or more and, in particular, one to three substituents selected from halogen, C.sub.1 C.sub.4 branched or straight chained alkyl, C.sub.1 C.sub.4 alkoxy, C.sub.1 C.sub.4 haloalkyl, hydroxy, nitro, amino, and the like. The term "alkoxy," alone or in combination, is defined herein to include an alkyl group, as defined earlier, which is attached through an oxygen atom to the parent molecular subunit. Exemplary alkoxy groups include but are not necessarily limited to methoxy, ethoxy and isopropoxy. The term "aralkyl" is defined herein as an alkyl group, as defined earlier, in which one of the hydrogen atoms is replaced by an aryl group. The term "heteroaralkyl" is defined herein as an alkyl group, as defined earlier, in which one of the hydrogen atoms is replaced by a heteroaryl group.

Exemplary branched or straight chained C.sub.1 C.sub.4 alkyl groups include but are not necessarily limited to methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl. Exemplary C.sub.1 C.sub.7 straight chain alkyl groups include, but are not necessarily limited to, methyl, ethyl, propyl, n-butyl, n-hexyl and n-heptyl. Exemplary C.sub.3 C.sub.7 branched chain alkyl groups include, but are not necessarily limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and isohexyl. Exemplary C.sub.3 C.sub.7 cycloalkyl groups include, but are not necessarily limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Exemplary C.sub.1 C.sub.4 haloalkyl groups include, but are not necessarily limited, to methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo and iodo.

The compounds of formula (I) wherein R.sup.5 and R.sup.6 together represent an oxygen or sulphur atom linked to the diazepine ring via a double bond represent a first embodiment of a first aspect of the present invention and are conveniently represented by the formula (1a):

##STR00003## wherein R.sup.1, R.sup.2, R.sup.3, W, X, Y, Z, p, n and m have the meanings defined in formula (I).

In one embodiment of the compounds of formula (1a) there are provided compounds wherein W is H; X is CH.sub.2 or NH; n is 1; Y is CH.sub.2; m is 0 or 1, provided that if X is CH.sub.2, n is 1 and m is 0, then R.sup.1 is not CH.sub.2CH.sub.3; Z is O; p is 0 or 1; R.sup.1 is H, CH.sub.3, CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3, benzyl, 4-pyridylmethyl or 3-pyridylmethyl; R.sup.2 is phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl; R.sup.3 is Cl, Br or NO.sub.2; R.sup.4 is H, CH.sub.3 or CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2; R.sup.5 and R.sup.6 together are O or S; or pharmaceutically acceptable salts and solvates thereof.

A further embodiment of the compounds of formula (Ia) is that wherein: W is H; X is CH.sub.2 or NH; n is 1; Y is CH.sub.2; m is 1; p is 0; R.sup.1 is H, CH.sub.3, CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, [CH.sub.2(CH.sub.3).sub.2] CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3, benzyl or 4-pyridylmethyl or 3-pyridylmethyl; provided that if R.sup.1 is 3-pyridylmethyl or 4-pyridylmethyl, then X is CH.sub.2, n is 1, Y is CH.sub.2, m is 0 or 1, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl, R.sup.4 is H and R.sup.5 and R.sup.6 together is oxygen; R.sup.2 is phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R.sup.3 is Cl, Br or NO.sub.2; R.sup.4 is H, CH.sub.3 or CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2; provided that when R.sup.4 is CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2, then X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3 or benzyl, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl and R.sup.5 and R.sup.6 together represent O; R.sup.5 and R.sup.6 together are O or S; or pharmaceutically acceptable salts and solvates thereof.

In yet a further embodiment of the present invention are the compounds of formula (1a) wherein W is H; X is CH.sub.2 or NH; n is 1; Y is CH.sub.2; m is 0 or 1, provided that if X is CH.sub.2 and m is 0, then R.sup.1 is not CH.sub.2CH.sub.3; p is 0; R.sup.1 is CH.sub.3, CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3, benzyl or 4-pyridylmethyl; R.sup.2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R.sup.3 is Cl, Br or NO.sub.2; R.sup.4 is H, CH.sub.3 or CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2; R.sup.5 and R.sup.6 together are O or S; or pharmaceutically acceptable salts and solvates thereof.

Yet another embodiment of the present invention are compounds of formula (Ia) wherein W is H; X is CH.sub.2 or NH; n is 1; Y is CH.sub.2; m is 0 or 1, provided that if X is CH.sub.2 and m is 0, then R.sup.1 is not CH.sub.2CH.sub.3; p is 0; R.sup.1 is CH.sub.3, CH.sub.2CH.sub.3, (CH.sub.2).sub.2CH.sub.3, (CH.sub.2).sub.3CH.sub.3, [CH.sub.2(CH.sub.3).sub.2] CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3, benzyl or 4-pyridylmethyl; provided that when R.sup.1 is 4-pyridylmethyl, then X is CH.sub.2, Y is CH.sub.2, m is 1, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl, R.sup.4 is H and R.sup.5 and R.sup.6 together represent oxygen; R.sup.2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R.sup.3 is Cl, Br or NO.sub.2; R.sup.4 is H, CH.sub.3 or CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2; provided that when R.sup.4 is CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2, then X is CH.sub.2, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3 or benzyl, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl and R.sup.5 and R.sup.6 together represent O; R.sup.5 and R.sup.6 together represent O or S; or pharmaceutically acceptable salts and solvates thereof.

Yet another embodiment of the first aspect of the invention are compounds of formula (Ia) or pharmaceutically acceptable salts and solvates thereof wherein in each compound W is H and wherein X, n, Y, m, Z, p and R.sup.1-6 for each compound are as follows:

TABLE-US-00001 R.sup.5 and X n Y m Z p R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.6 CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 -- 0 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Br H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-fluorophenyl Cl H O CH.sub.2 1 -- 0 -- 0 benzyl 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H O CH.sub.2 1 CH.sub.2 2 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Br H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 2 -- 0 C(CH.sub.3).sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl NO.sub.2 H O CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.2CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.2CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 4-pyridyl- 2-fluorophenyl Cl H O methyl CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.3CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.3CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.2CH(CH.sub.3).sub.2 2-pyridyl Cl H O CH.sub.2 1 -- 0 -- 0 CH.sub.2CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH(CH.sub.3).sub.2 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl CH.sub.2CH.sub.2N(CH- .sub.2CH.sub.3).sub.2 O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl CH.sub.3 O CH.sub.2 1 -- 0 -- 0 benzyl 2-fluorophenyl Cl CH.sub.3 O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-fluorophenyl Cl CH.sub.2CH.sub.2N(CH.s- ub.2CH.sub.3).sub.2 O NH 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H O NH 1 CH.sub.2 2 -- 0 CH.sub.3 2-chlorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl H S CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H S CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Cl H S CH.sub.2 1 CH.sub.2 1 O 1 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl phenyl NO.sub.2 H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl H H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl NO.sub.2 H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-pyridyl NO.sub.2 H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-fluorophenyl H H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 phenyl NO.sub.2 H O NH 1 CH.sub.2 2 -- 0 (CH.sub.2).sub.3CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 -- 0 -- 0 3-pyridyl- 2-fluorophenyl Cl H O methyl CH.sub.2 1 -- 0 -- 0 4-pyridyl- 2-fluorophenyl Cl H O methyl

Yet another embodiment of the first aspect of the invention are compounds of formula (Ia) or pharmaceutically acceptable salts and solvates thereof wherein in each compound W is H and wherein X, n, Y, m, Z, p and R.sup.1-6 for each compound are as follows:

TABLE-US-00002 R.sup.5 and X n Y m Z p R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.6 CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 -- 0 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Br H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-fluorophenyl Cl H O CH.sub.2 1 -- 0 -- 0 benzyl 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H O CH.sub.2 1 CH.sub.2 2 -- 0 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Br H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 2 -- 0 C(CH.sub.3).sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl NO.sub.2 H O CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.2CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.2CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 4-pyridyl- 2-fluorophenyl Cl H O methyl CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.3CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 (CH.sub.2).sub.3CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.2CH(CH.sub.3).sub.2 2-pyridyl Cl H O CH.sub.2 1 -- 0 -- 0 CH.sub.2CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH(CH.sub.3).sub.2 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl CH.sub.2CH.sub.2N(CH- .sub.2CH.sub.3).sub.2 O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl CH.sub.3 O CH.sub.2 1 -- 0 -- 0 benzyl 2-fluorophenyl Cl CH.sub.3 O CH.sub.2 1 CH.sub.2 1 -- 0 benzyl 2-fluorophenyl Cl CH.sub.2CH.sub.2N(CH.s- ub.2CH.sub.3).sub.2 O NH 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H O NH 1 CH.sub.2 2 -- 0 CH.sub.3 2-chlorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-fluorophenyl Cl H S CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-chlorophenyl Cl H S CH.sub.2 1 CH.sub.2 1 -- 0 CH.sub.3 2-pyridyl Cl H S CH.sub.2 1 CH.sub.2 1 O 1 CH.sub.3 2-fluorophenyl Cl H O

Yet another embodiment of the first aspect of the invention are compounds of formula (Ia) or pharmaceutically acceptable salts and solvates thereof wherein in each compound W is H, and p is 0, and wherein X, n, Y, m, R.sup.1-6 for each compound are as follows:

TABLE-US-00003 R.sup.5 and X n Y m R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.6 CH.sub.2 1 CH.sub.2 1 CH.sub.3 2-fluorophenyl Cl H O CH.sub.2 1 CH.sub.2 1 CH.sub.3 2-fluorophenyl Br H O CH.sub.2 1 CH.sub.2 1 CH.sub.3 2-pyridyl Cl H O CH.sub.2 1 CH.sub.2 1 CH.sub.3 2-fluorophenyl Cl CH.sub.3 O

Yet another embodiment of the first aspect of the invention is a compound of formula (Ia) or a pharmaceutically acceptable salt and solvate thereof wherein W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, p is 0, R.sup.1 is CH.sub.3, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl, R.sup.4 is H and R.sup.5 and R.sup.6 together represent oxygen.

The compounds of formula (I) wherein R.sup.4 and R.sup.5 together form a double bond in the diazepine ring and wherein R.sup.6 is the group NHR.sup.7 represent a further embodiment of the first aspect of the invention and are conveniently represented by formula (1b).

##STR00004## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.7, W, X, Y, n and m have the meanings defined in formula (I).

In a further embodiment of the first aspect of the invention are compounds of formula (Ib) or pharmaceutically acceptable salts and solvates thereof wherein W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3, R.sup.2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R.sup.3 is Cl or Br and R.sup.7 is CH.sub.3, CH.sub.2CH.sub.3, benzyl, 4-pyridylmethyl-, 4-pyridylethyl, CH(CH.sub.3).sub.2, 4-imidazolylethyl or CH.sub.2CH.sub.2OH.

In yet another embodiment of the first aspect of the invention are compounds of formula (Ib) or pharmaceutically acceptable salts and solvates thereof wherein in each compound W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3, and wherein R.sup.2, R.sup.3 and R.sup.7 for each compound are as follows:

TABLE-US-00004 R.sup.2 R.sup.3 R.sup.7 2-fluorophenyl Cl CH.sub.3 2-pyridyl Cl CH.sub.3 2-fluorophenyl Cl CH.sub.2CH.sub.3 2-fluorophenyl Cl benzyl 2-fluorophenyl Cl 4-pyridylmethyl 2-fluorophenyl Cl 4-pyridylethyl 2-fluorophenyl Cl CH.sub.2CH(CH.sub.3).sub.2 2-fluorophenyl Cl 2-(4-imidazolyl)ethyl 2-fluorophenyl Cl CH.sub.2CH.sub.2OH 2-fluorophenyl Br CH.sub.3 2-chlorophenyl Cl CH.sub.3

Yet another embodiment of the first aspect of the invention are compounds of formula (Ib) or pharmaceutically acceptable salts and solvates thereof wherein in each compound W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3, R.sup.2 is 2-fluorophenyl, R.sup.3 is chlorine or bromine and R.sup.7 is methyl.

Yet another embodiment of the first aspect of the invention is a compound of formula (Ib) or a pharmaceutically acceptable salt and solvate thereof wherein W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3, R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl and R.sup.4 is CH.sub.3.

The compounds of formula (I) where the groups R.sup.4 and R.sup.5 and R.sup.6 together form the group --CR.sup.8.dbd.U--V.dbd. represent a further embodiment of the first aspect of the invention and may be conveniently represented by the compound of formula (1c):

##STR00005## wherein R.sup.1, R.sup.2, R.sup.8, U, V, W, X, Y, n and m have the meanings given in formula (I).

In yet another embodiment of the first aspect of the invention are compounds of formula (Ic) or pharmaceutically acceptable salts and solvates thereof wherein W is H, X is CH.sub.2, n is 1; Y is CH.sub.2, m is 1; R.sup.1 is CH.sub.3 or CH.sub.2CH(CH.sub.3).sub.2; R.sup.2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl; R.sup.3 is Cl or Br; R.sup.8 is H, CH.sub.3 or CH.sub.2OH; R.sup.9 is H, CH.sub.3, CH.sub.2OH or CH.sub.2O-t-butyl; U is CR.sup.9 or N; and V is N or CH.

Yet another embodiment of the first aspect of the invention are compounds of formula (Ic) or pharmaceutically acceptable salts and solvates thereof wherein W is H, X is CH.sub.2, n is 1; Y is CH.sub.2, m is 1; R.sup.1 is CH.sub.3 or CH.sub.2CH(CH.sub.3).sub.2; provided that when R.sup.1 is CH.sub.2CH(CH.sub.3).sub.2, then R.sup.2 is 2-fluorophenyl, R.sup.3 is Cl, R.sup.8 is CH.sub.3, U is N and V is N; R.sup.2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl; R.sup.3 is Cl or Br; R.sup.8 is H, CH.sub.3 or CH.sub.2OH; R.sup.9 is H, CH.sub.3, CH.sub.2OH or CH.sub.2O-t-butyl; U is CR.sup.9 or N; and V is N or CH.

Yet another embodiment of the first aspect of the invention are compounds of formula (Ic) or pharmaceutically acceptable salts and solvates thereof wherein in each compound W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1 and wherein R.sup.1, R.sup.2, R.sup.3, R.sup.8, U and V for each compound are as follows:

TABLE-US-00005 R.sup.1 R.sup.2 R.sup.3 R.sup.8 U V CH.sub.3 2-fluorophenyl Cl H CH N CH.sub.3 2-fluorophenyl Cl CH.sub.3 CH N CH.sub.3 2-fluorophenyl Cl H C--CH.sub.3 N CH.sub.3 2-fluorophenyl Cl H C--CH.sub.2OH N CH.sub.3 2-fluorophenyl Cl CH.sub.2OH CH N CH.sub.3 2-pyridyl Cl H CH N CH.sub.3 2-pyridyl Cl CH.sub.3 CH N CH.sub.3 2-pyridyl Br CH.sub.3 CH N CH.sub.3 2-pyridyl Br H C--CH.sub.3 N CH.sub.3 2-pyridyl Cl H C--CH.sub.3 N CH.sub.3 2-pyridyl Cl H C--CH.sub.2OH N CH.sub.3 2-pyridyl Cl CH.sub.2OH CH N CH.sub.3 2-pyridyl Cl CH.sub.3 C--CH.sub.3 N CH.sub.3 2-chlorophenyl Cl CH.sub.3 N N CH.sub.3 2-fluorophenyl Cl CH.sub.3 N N CH.sub.2CH(CH.sub.3).sub.2 2-fluorophenyl Cl CH.sub.3 N N CH.sub.3 2-fluorophenyl Cl H N CH CH.sub.3 2-fluorophenyl Cl CH.sub.3 N CH CH.sub.3 2-fluorophenyl Cl H C--CH.sub.2O-t- N butyl CH.sub.3 2-pyridyl Cl CH.sub.3 C--CH.sub.2OH N

Yet another embodiment of the first aspect of the invention are compounds of formula (1c) or pharmaceutically acceptable salts and solvates thereof wherein in each compound W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1 and wherein R.sup.1, R.sup.2, R.sup.3, R.sup.8, U and V for each compound are as follows:

TABLE-US-00006 R.sup.1 R.sup.2 R.sup.3 R.sup.8 U V CH.sub.3 2-pyridyl Br CH.sub.3 CH N CH.sub.3 2-pyridyl Cl CH.sub.3 CH N CH.sub.3 2-fluorophenyl Cl CH.sub.3 N CH CH.sub.3 2-pyridyl Br H C--CH.sub.3 N

Yet another embodiment of the first aspect of the invention is a compound of formula (Ic) or a pharmaceutically acceptable salt and solvate thereof wherein in W is H, X is CH.sub.2, n is 1, Y is CH.sub.2, m is 1, R.sup.1 is CH.sub.3, R.sup.2 is 2-pyridyl, R.sup.3 is Br, R.sup.8 is CH.sub.3, U is CH and V is N.

Those skilled in the art will recognize that a stereocenter exists in compounds of Formula (I). Accordingly, the present invention includes individual enantiomers of the compounds of Formula (I) substantially free of the other enantiomer, as well as in racemic or other admixture with the other enantiomer.

General Procedures

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); .mu.L (microliters); psi (pounds per square inch); M (molar); mM (millimolar); i. v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); RT (room temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); T.sub.r (retention time); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (N,N-dimethylformamide); DMPU (N,N'-dimethylpropyleneurea); (CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); mCPBA (meta-chloroperbenzoic acid; EDC (ethylcarbodiimide hydrochloride); BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TBAF (tetra-n-butylammonium fluoride); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP (4-dimethylaminopyridine). All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in .degree. C. (degrees Centigrade). All reactions conducted under an inert atmosphere at room temperature unless otherwise noted.

.sup.1H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, a Varian Unity-400 instrument, or a General Electric QE-300. Chemical shifts are expressed in parts per million (ppm, .delta. units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA, JOEL SX-102, or a SCIEX-APIiii spectrometer; high resolution MS were obtained using a JOEL SX-102A spectrometer. All mass spectra were taken under electrospray ionization (ESI), chemical ionization (CI), electron impact (EI) or by fast atom bombardment (FAB) methods. Infrared (IR) spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1-mm NaCl cell. Rotations were recorded on a Perkin-Elmer 241 polarimeter. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230 400 mesh, Merck). Optical rotations were obtained using a Perkin Elmer Model 241 Polarimeter. Melting points were determined using a Mel-Temp II apparatus and are uncorrected.

Compounds of general formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula I. Those skilled in the art will recognize that a stereocenter exists in compounds of Formula I. Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

Compounds of Formula (Ia, wherein X.dbd.CH.sub.2, R.sup.4.dbd.H, R.sup.5 and R.sup.6.dbd.O, p=0) can be prepared according to the synthetic sequence shown in Scheme 1a and further detailed in the Examples section (vide infra). An appropriate aminobenzophenone (A) is coupled to a suitably protected (e.g., FMOC) amino acid chloride (B) in a suitable solvent, e.g., chloroform, to provide amide (C) (J. Org. Chem. 1986, 51, 3732 3734). Carbodiimide-mediated coupling (such as with DCC or EDC) can also be used for this condensation. Base-mediated removal of the amine protecting group (e.g., triethylamine, DCM) and subsequent cyclization (acetic acid, DCE) provides (D), which are compounds of formula Ia wherein R.sup.5 and R.sup.6 together represent O for compounds wherein R.sup.4 is a substituent other than hydrogen, the anilide nitrogen can be alkylated by deprotonation with a base such as NaH in a suitable solvent (e.g. DMF), followed by addition of an alkylating agent such R.sup.4I, thereby providing the N-alkylated compounds (E), which are also represented by formula (Ia).

##STR00006##

N4-oxide derivatives of compounds of Formula (I) (Z.dbd.O, p=1) can be prepared from compounds of formula (1a) wherein p is zero according to the synthetic sequence shown in Scheme 1b. It is readily apparent to one skilled in the art that benzodiazepinones represented by structure (E) can be oxidized by treatment with mCPBA or other oxidant in a suitable solvent (e.g., DCM).

##STR00007##

Compounds of Formula Ia wherein X is NH and p=0 may be prepared from the appropriate 3-aminobenzodiazepine F, which can be readily prepared by methods previously described (R. G. Sherrill et al., J. Org. Chem. 1995, 60, 730). The 3-amino-1,4-benzodiazepine thus obtained can be manipulated according to the sequence set forth in Scheme 2 and further detailed in the Examples section (vide infra). Alkylation of the 3-amino can be achieved by treatment with a 2-haloacetate (e.g. 2-bromoacetate) or conjugate addition to an appropriate unsaturated ester (e.g. methyl acrylate), providing derivatives G.

##STR00008##

Compounds of Formula Ia (wherein R.sup.5R.sup.6.dbd.O) can be converted to their corresponding wherein R.sup.5R.sup.6.dbd.S with Lawesson's reagent in toluene or other suitable solvent (J. Org. Chem. 1964, 29, 231 233).

Compounds of formula Ib may be synthesized as shown in Scheme 3 and further detailed in the Examples section (vide infra). Thus reaction of a compound of formula (1a) wherein R.sup.4 is hydrogen, R.sup.5R.sup.6.dbd.O and p is zero (D) with Lawesson's reagent as described above gives the thiolactam (H).

##STR00009##

Condensation of the thiolactam (H) with an amine R.sup.7NH.sub.2 in tetrahydrofuran affords the corresponding compounds of Formula (1b). Alternatively, compounds of Formula (1b) can be prepared by addition of an amine R.sup.7NH.sub.2 to the iminophosphate (I) in THF, which is prepared by reaction of compound (D) with an appropriate phosphoryl chloride reagent, preferably the bis-morpholinophosphoryl chloride (Ning et al., J. Org. Chem. 1976, 41, 2720 2724; Ning et al., J. Org. Chem. 1976, 41, 2724 2727).

A method of preparation of compounds of formula (1c; U.dbd.CR.sup.9; V.dbd.N), is set forth in Scheme 4 and further detailed in the Examples section (vide infra).

##STR00010##

These methods are analogous to those described (WO 96/20941, WO 96/23790). Reaction between either the thiolactam (H) or iminophosphate (I) and an appropriate an amino alcohol HOCH(R.sup.8)--CH(R.sup.9)NH.sub.2 provides adduct (J). Swern oxidation (i. DMSO, TFAA or (COCl).sub.2; TEA) of the hydroxyl group provides an intermediate ketone or aldehyde that undergoes cyclodehydration, spontaneously or under appropriate acidic conditions (e.g. p-toluenesulfonic acid, DMF), to provide compounds of formula (1c; U.dbd.CR.sup.9; V.dbd.N).

As set forth in Scheme 5, reaction of (I) (J. Med. Chem. 1993, 36, 479 490; J. Med. Chem. 1993, 36, 1001 1006) with the anion of isonitrile ester (K) delivers imidazole (L) as the product; subsequent removal of the ester functionality by methods set forth in the examples (vide infra) provides compounds of formula 1c; U.dbd.N; V.dbd.CH).

##STR00011##

An alternative method for the preparation of compounds of formula (1c; wherein X is CH.sub.2, n is Z, m=0, U.dbd.N; V.dbd.CH), is set forth in Scheme 6 and further detailed in the Examples section (vide infra). C4-unsubstituted imidazobenzodiazepine (M) is treated with a strong base (preferably potassium t-butoxide) and the anion is treated with a suitable Michael acceptor, such as t-butyl acrylate. The resultant ester adduct (N) is treated with a strong acid (e.g., TFA) to remove the t-butyl group and the carboxylic acid (O) is esterified to provide compounds of Formula (1c) by base-mediated alkylation with an alkyl halide.

##STR00012##

Alternative methods to prepare these compounds have also been described (e.g. J. Org. Chem. 1978, 43, 936 944).

Compounds of formula 1c (U.dbd.N; V.dbd.N), may be prepared as set forth in Scheme 7 and further detailed in the Examples section (vide infra). Thiolactam (H) is converted to its corresponding methylthioimidate (P), which then undergoes condensation and cyclodehydration to provide the desired triazolobenzodiazepine.

##STR00013##

Synthesis of Key Intermediates

The following section describes the preparation of intermediates that may be used in the synthesis of compounds of Formula I. There may be examples wherein the starting material can be prepared according to the methods set forth in the synthesis of an intermediate. It should be readily apparent to one skilled in the art how these methods can be applied to include all compounds of Formula I.

##STR00014##

The synthesis of the FMOC-Glu(OMe)-OH was carried out as described in Int. J. Peptide Protein Res. 1989, 33, 353.

##STR00015##

FMOC-Glu(OMe)-OH (80 g, 0.21 mol) was dissolved in CH.sub.2Cl.sub.2 (523 mL). DMF (1 mL) was added followed by dropwise addition of oxalyl chloride (19 mL, 0.22 mol). The solution was stirred at room temperature for 4 h, and concentrated in vacuo to a volume of ca. 200 mL. To this stirring concentrate was added hexanes by rapid dropwise addition. The resulting slurry was stirred for 30 min and filtered to provide the required acid chloride as a white solid (83 g, 98%).

##STR00016##

To a -40.degree. C. solution of 2.5 M n-butyllithium in hexane (400 mL, 1000 mmol, 4 eq) and diethyl ether (1 L) was added 2-bromopyridine (173.93 g, 1101 mmol, 4.4 eq) over approximately 30 min. The reaction was stirred for 1 h at -40.degree. C., and then treated with 5-bromoanthranilic acid (54.14 g, 250.6 mmol, 1 eq) in THF (1 L). The reaction was warmed to 0.degree. C. and stirred 2 h at 0.degree. C., then quenched with chlorotrimethylsilane (625 mL, 4924 mmol, 20 eq). The reaction was stirred 30 min at ambient temperature, then cooled to 0.degree. C. and quenched with 3N HCl (625 mL). The aqueous layer was separated, and the organic layer was extracted once with 3N HCl. The combined aqueous layers were neutralized with solid sodium hydroxide pellets, with cooling via ice bath. The resulting mixture was extracted with diethyl ether (3.times.1 L). The combined ether layers were dried over sodium sulfate, filtered and concentrated to a black oil, which was subsequently purified by flash chromatography (1 L silica gel, 20 30% ethyl acetate/hexane) to give the required compound as a brown solid (62 g, 224 mmol, 89.3%).

##STR00017##

tert-Butyllithium (43.4 mL of a 1.7 M solution in pentane, 73.8 mmol) was added to a solution of N-BOC-4-chloroaniline (7.00 g, 30.8 mmol) in THF (154 mL) at -78.degree. C. The reaction mixture was stirred for 15 min then warmed to -20.degree. C. and stirred an additional 2 h. The reaction mixture was cooled to -78.degree. C., treated with 2-pyridinecarboxaldehyde (2.92 mL, 30.8 mmol), stirred for 2 h, treated with saturated aqueous NaHCO.sub.3 (ca. 50 mL), and warmed to room temperature. The mixture was concentrated under reduced pressure and the residue was extracted with EtOAc (1.times.500 mL). The organic phase was washed with saturated aqueous NaHCO.sub.3 (1.times.100 mL), H.sub.2O (1.times.100 mL), saturated aqueous NaCl (1.times.100 mL), dried (Na.sub.2SO.sub.4), and concentrated under reduced pressure. The residue was dissolved in CHCl.sub.3 (150 mL), treated with activated MnO.sub.2 (58% by weight, 30.0 g, 200 mmol), and stirred for 18 h. The reaction mixture was filtered through a pad of Celite using additional CHCl.sub.3 (ca. 100 mL) and the filtrate was concentrated under reduced pressure. Purification by flash chromatography, elution with 9:1 hexane-EtOAc, gave 6.02 g (59%) of the intermediate BOC-protected aminobenzophenone as a foam.

A solution of the BOC-protected aminobenzophenone described above (5.93 g, 17.8 mmol) and HCl (18.0 mL of a 4M solution in 1,4-dioxane, 71.3 mmol) in CH.sub.2Cl.sub.2 was stirred for 4 h at room temperature then concentrated under reduced pressure. The residue was diluted with EtOAc (ca. 200 mL) and treated with saturated aqueous NaHCO.sub.3 until CO.sub.2 evolution ceased. The layers were separated and the organic phase was washed with saturated aqueous NaHCO.sub.3 (1.times.50 mL), H.sub.2O (1.times.50 mL), saturated aqueous NaCl (1.times.50 mL), dried (Na.sub.2SO.sub.4), and concentrated under reduced pressure to give 3.83 g (92%) of the title compound as a yellow amorphous solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.68 (d, J=4.6 Hz, 1H), 8.02 (ddd, J=7.8, 7.8, 1.6 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.59 (m, 1 H), 7.52 (d, J=2.6 Hz, 1H), 7.42 (br s, 2H), 7.31 (dd, J=9.0, 2.6 Hz, 1 H), 6.89 (d, J=9.0 Hz, 1 H); ESIMS 233 (M+H), 107 (base).

##STR00018##

A solution of 2-(2-aminobenzoyl)pyridine (1.29 g, 6.32 mmol, Syn. Comm. 1996, 26, 721 727) and trifluroacetic anhydride (1.10 mL, 7.79 mmol) in CHCl.sub.3 (35 mL) was heated at 42.degree. C. for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (ca. 250 mL), washed with saturated aqueous NaHCO.sub.3 (2.times.50 mL), H.sub.2O (1.times.50 mL), brine (1.times.50 mL), dried (Na.sub.2SO.sub.4) and concentrated under