Isoquinoline derivatives and methods of use thereof Number:7,393,955 from the United States Patent and Trademark Office (PTO) owispatent The invention provides novel classes of Isoquinoline Derivatives. Pharmaceutical compositions and methods of making and using the compounds, are also described.<H Isoquinoline, derivatives, Isoquinoline, de, 7393955.html, Patent, pto, 7393955

Title: Isoquinoline derivatives and methods of use thereof

Abstract: The invention provides novel classes of Isoquinoline Derivatives. Pharmaceutical compositions and methods of making and using the compounds, are also described.

Patent Number: 7,393,955 Issued on 07/01/2008 to Jagtap, et al.

Inventors: Jagtap; Prakash (Beverly, MA), Roy; Aloka (Acton, MA), Williams; William (Ipswich, MA)
Assignee: Inotek Pharmaceuticals Corporation (Beverly, MA)

Appl. No.: 11/177,161

Filed: July 8, 2005

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
10376746	Feb., 2003	6956035
10233198	Aug., 2002	6828319
09944524	Aug., 2001

Current U.S. Class: 544/125 ; 546/61

Current International Class: C07D 413/12 (20060101); C07D 221/18 (20060101)

Field of Search: 544/125 546/61

References Cited [Referenced By]

U.S. Patent Documents


3710795	January 1973	Higuchi et al.
4113731	September 1978	Winters et al.
4263304	April 1981	Ishizumi et al.
5079246	January 1992	Forbes et al.
5260316	November 1993	Van Duzer et al.
5262564	November 1993	Kun et al.
5597831	January 1997	Michalsky et al.
5710162	January 1998	Okazaki et al.
5733918	March 1998	Okazaki et al.
6028079	February 2000	Okazaki et al.
6346535	February 2002	Cotter et al.
6346536	February 2002	Li et al.
6498194	December 2002	Cotter et al.
6635642	October 2003	Jackson et al.
6828319	December 2004	Jagtap et al.
6956035	October 2005	Jagtap et al.
2002/0099063	July 2002	Cotter et al.
2003/0096833	May 2003	Jagtap et al.
2004/0039009	February 2004	Jagtap et al.

Foreign Patent Documents


2349227	May., 2000	CA
2025932	Jan., 1980	GB
2003267888	Sep., 2003	JP
WO93/05023	Mar., 1993	WO
WO99/08680	Feb., 1999	WO
WO99/11311	Mar., 1999	WO
WO99/11623	Mar., 1999	WO
WO99/11628	Mar., 1999	WO
WO99/11644	Mar., 1999	WO
WO99/11645	Mar., 1999	WO
WO99/11649	Mar., 1999	WO
WO99/59973	Nov., 1999	WO
WO99/59975	Nov., 1999	WO
WO 00/21537	Apr., 2000	WO
WO 00/39070	Jul., 2000	WO
WO 00/39104	Jul., 2000	WO
WO 00/42040	Jul., 2000	WO
WO 01/12199	Feb., 2001	WO
WO-01/90077	Nov., 2001	WO
WO 02/06284	Jan., 2002	WO
WO-04/014862	Feb., 2004	WO
WO-2005/012524	Feb., 2005	WO
WO-2005/053662	Jun., 2005	WO

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Primary Examiner: Aulakh; Charanjit S.
Attorney, Agent or Firm: Wilmer Cutler Pickering Hale and Dorr LLP

Government Interests

This invention was made with government support under grant no. R44 DK54099-03 and grant no. IR43 CA90016-01A1, which were awarded by the National Institutes of Health. The government has certain rights in the invention.

Parent Case Text

This application is a continuation of U.S. application Ser. No. 10/376,746, filed Feb. 28, 2003, which is a continuation-in-part of U.S. application Ser. No. 10/233,198, filed Aug. 30, 2002, now U.S. Pat. No. 6,828,319, which is a continuation-in-part of U.S. application Ser. No. 09/944,524, filed Aug. 31, 2001, abandoned, the entire disclosure of each of the aforementioned applications or patents being incorporated by reference herein in its entirety.

Claims

What is claimed is:

1. A method for making a compound of formula 13a ##STR00032## the method comprising allowing a compound having the formula ##STR00033## to react with the compound having the formula ##STR00034## in the presence of triethylamine, for under conditions that are sufficient to make the compound of formula 13a.

2. A method for making a compound of the formula ##STR00035## the method comprising the steps of: (i) allowing Compound 13a ##STR00036## to react with chlorosulfonic acid under conditions that are sufficient to make Compound 7 ##STR00037## (ii) allowing Compound 7 to react with the compound of the formula ##STR00038## in the presence of triethylamine or sodium carbonate, under conditions that are sufficient to make Compound 8l.

3. A method for making a compound of the formula ##STR00039## comprising allowing Compound 8l ##STR00040## to react with methanesulfonic acid under conditions that are sufficient to make Compound 8l (mesylate salt).

Description

1. FIELD OF THE INVENTION

The invention relates to Isoquinoline Derivatives; compositions comprising an Isoquinoline Derivative; and methods for treating or preventing an inflammatory disease or a reperfusion disease comprising the administration of an effective amount of an Isoquinoline Derivative.

2. BACKGROUND OF THE INVENTION

Inflammatory diseases, such as arthritis, colitis, and autoimmune diabetes, typically manifest themselves as disorders distinct from those associated with reperfusion diseases, e.g., stroke and heart attack, and can clinically manifest themselves as different entities. However, there can be common underlying mechanisms between these two types of disorders. In particular, inflammatory disease and reperfusion disease can induce proinflammatory cytokine and chemokine synthesis which can, in turn, result in production of cytotoxic free radicals such as nitric oxide and superoxide. NO and superoxide can react to form peroxynitrite (ONOO.sup.-) (Szabo et al., Shock 6:79 88, 1996).

The ONOO.sup.--induced cell necrosis observed in inflammatory disease and in reperfusion disease involves the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Activation of PARS is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion disease (Szabo et al., Trends Pharmacol. Sci. 19: 287 98, 1998).

A number of PARS inhibitors have been described in the art. See, e.g., Banasik et al., J. Biol. Chem., 267:1569 75, 1992, and Banasik et al., Mol. Cell. Biochem., 138:185 97, 1994; WO 00/39104; WO 00/39070; WO 99/59975; WO 99/59973; WO 99/11649; WO 99/11645; WO 99/11644; WO 99/11628; WO 99/11623; WO 99/11311; WO 00/42040; Zhang et al., Biochem. Biophys. Res. Commun., 278:590 98, 2000; White et al., J. Med. Chem., 43:4084 4097, 2000; Griffin et al., J. Med. Chem., 41:5247 5256, 1998; Shinkwin et al., Bioorg. Med. Chem., 7:297 308, 1999; and Soriano et al., Nature Medicine, 7:108 113, 2001. Adverse effects associated with administration of PARS inhibitors have been discussed in Milan et al, Science, 223:589 591, 1984.

Isoquinoline compounds have been previously discussed in the art. For example, cytotoxic non-camptothecin topoisomerase I inhibitors are reported in Cushman et al., J. Med. Chem., 43:3688 3698, 2300 and Cushman et al., J. Med. Chem. 42:446 57, 1999; indeno[1,2-c]isoquinolines are reported as antineoplastic agents in Cushman et al., WO 00/21537; and as neoplasm inhibitors in Hrbata et al., WO 93/05023.

Syntheses of isoquinoline compounds have been reported. For example, see Wawzonek et al., Org. Prep. Proc. Int. 14:163 8, 1982; Wawzonek et al., Can. J. Chem. 59:2833, 1981; Andoi et al., Bull. Chem. Soc. Japan, 47:1014 17, 1974; Dusemund et al., Arch. Pharm (Weinheim, Ger.), 3 17:381 2, 1984; and Lal et al., Indian J. Chem., Sect. B, 38B:33 39, 1999.

There remains, however, a need in the art for compounds useful for treating or preventing inflammatory diseases or reperfusion diseases.

Citation of any reference in Section 2 of this application is not an admission that the reference is prior art.

3. SUMMARY OF THE INVENTION

The invention is based in part on the discovery of novel substituted tetracyclic benzamide derivatives and their demonstrated effects in the treatment of inflammation, cell death and in treating shock and reperfusion diseases.

Accordingly, in one aspect the invention includes a compound of Formula I, Formula Ia, Formula Ib, Formula II, Formula III, Formula 13, Formula 22, Formula 37 or Formula 40, or a pharmaceutically acceptable salt or hydrate thereof (an "Isoquinoline Derivative") as set forth below in the Detailed Description of the Invention.

Also provided by the invention is a method for treating or preventing an inflammatory disease or a reperfusion disease in a subject, comprising administering to a subject in need of such treatment or prevention an effective amount of an Isoquinoline Derivative.

In a further aspect, the invention also includes methods for making an Isoquinoline Derivative of Formula Ia, Formula Ib, Formula II, Formula III, Formula 13, Formula 22, Formula 37 or Formula 40.

##STR00001## ##STR00002##

The Isoquinoline Derivatives can be used to treat or prevent a variety of conditions and diseases, including, but not limited to, an inflammatory disease or a reperfusion disease.

The invention also includes pharmaceutical compositions that comprise an effective amount of an Isoquinoline Derivative and a pharmaceutically acceptable carrier. The compositions are useful for treating or preventing an inflammatory disease or a reperfusion disease. The invention includes an Isoquinoline Derivative when provided as a pharmaceutically acceptable prodrug, a hydrated salt, such as a pharmaceutically acceptable salt, or mixtures thereof.

The details of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated by reference.

4. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides Isoquinoline Derivatives according to Formula I, Formula Ia, Formula Ib, Formula II, Formula III, Formula 13, Formula 37 and Formula 40 as set forth below:

##STR00003## and pharmaceutically acceptable salts and hydrates thereof, wherein:

R.sub.5 is NH or S;

R.sub.6 is --H or C.sub.1 C.sub.4 alkyl;

X is --C(O)--, --CH.sub.2--, --CH(halo)-, --CH(OH)--(CH.sub.2).sub.n--, --CH(OH)-arylene-, --O--, --NH--, --S--, --CH(NR.sub.11R.sub.12)-- or --N(SO.sub.2Y)--, wherein Y is --OH, --NH.sub.2 or -alkylheterocycle and n is an integer ranging from 0 5;

R.sub.11 and R.sub.12 are independently -hydrogen or --C.sub.1 C.sub.9 alkyl, or N, R.sub.11 and R.sub.12 are taken together to form a heterocyclic amine;

R.sub.1 is -hydrogen, -halo, --C.sub.1 C.sub.10 alkyl, -alkylhalo, --C.sub.2 C.sub.10 alkenyl, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, --C(O)OH, --C(O)O(C.sub.1 C.sub.5 alkyl), NO.sub.2 or -A-B;

A is --SO.sub.2--, --SO.sub.2NH--, --NHCO--, --NHCONH--, --CO--, --C(O)O--, --CONH--, --CON(C.sub.1 C.sub.4 alkyl)-, --NH--, --CH.sub.2--, --S-- or --C(S)--;

B is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NZ.sub.1Z.sub.2, --(C.sub.1 C.sub.5 alkylene)-NZ.sub.1Z.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl), --C(O)O-phenyl or --C(NH)NH.sub.2 any of which are unsubstituted or substituted with one or more of --O--(C.sub.1 C.sub.5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, --NO.sub.2, --NH.sub.2, --CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, --C.sub.2 C.sub.10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, --C(O)OH, --C.sub.1 C.sub.5 alkylene-C(O)O--(C.sub.1 C.sub.5 alkyl) or --C.sub.1 C.sub.5 alkylene-OC(O)--(C.sub.1 C.sub.5 alkyl);

R.sub.2, R.sub.3. R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are independently -hydrogen, -halo, -hydroxy, --O--(C.sub.1 C.sub.5 alkyl), --C.sub.1 C.sub.10 alkyl, -alkylhalo, --C.sub.2 C.sub.10 alkenyl, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, --C(O)OH, --C(O)O(C.sub.1 C.sub.5 alkyl), --OC(O)(C.sub.1 C.sub.5 alkyl), NO.sub.2 or -A-B; and at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 or R.sub.10 is other than hydrogen;

A is --SO.sub.2--, --SO.sub.2NH--, --NHCO--, --NHCONH--, --O--, --CO--, --OC(O)--, --C(O)O--, --CONH--, --CON(C.sub.1 C.sub.4 alkyl)-, --NH--, --CH.sub.2--, --S-- or --C(S)--;

B is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NZ.sub.1Z.sub.2, --(C.sub.1 C.sub.5 alkylene)-NZ.sub.1Z.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl), --C(O)O-phenyl or --C(NH)NH.sub.2 any of which are unsubstituted or substituted with one or more of --O--(C.sub.1 C.sub.5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, --NO.sub.2, --NH.sub.2, --CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, --C.sub.2 C.sub.10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, --C(O)OH, --C.sub.1 C.sub.5 alkylene-C(O)O--(C.sub.1 C.sub.5 alkyl) or --C.sub.1 C.sub.5 alkylene-OC(O)--(C.sub.1 C.sub.5 alkyl); and

Z.sub.1 and Z.sub.2 are independently --H or --C.sub.1 C.sub.10 alkyl, which is unsubstituted or substituted with one or more of -halo, --OH or --N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently, --H or --C.sub.1 C.sub.5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or --NH.sub.2; or N, Z.sub.3 and Z.sub.4 are taken together to form an unsubstituted or substituted heterocyclic amine; or N, Z.sub.1 and Z.sub.2 are taken together to form a heterocyclic amine.

In one embodiment, X is --C(O)--, --CH.sub.2--, --CH(halo)-, --CH(OH)--(CH.sub.2).sub.n--, --CH(OH)-arylene-, --O--, --NH--, --S-- or --CH(NR.sub.11R.sub.12)--, wherein n is an integer ranging from 0 5.

In another embodiment B is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NZ.sub.1Z.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl) or --C(O)O-phenyl, any of which are unsubstituted or substituted with one or more of --O--(C.sub.1 C.sub.5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, --NO.sub.2, --NH.sub.2, -aminoalkyl, -aminodialkyl, -heterocyclic amine, --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, --C.sub.2 C.sub.10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, --C.sub.1 C.sub.5 alkylene-C(O)O--C.sub.1 C.sub.5 alkyl or --C.sub.1 C.sub.5 alkylene-OC(O)--C.sub.1 C.sub.5 alkyl.

In another embodiment, R.sub.1 R.sub.4 are hydrogen.

In a further embodiment at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 is other than hydrogen.

The invention also relates to a compounds of formula (Ia):

##STR00004## and pharmaceutically acceptable salts and hydrates thereof, wherein:

R.sub.5 is NH or S;

R.sub.6 is --H or C.sub.1 C.sub.4 alkyl;

X is --C(O)--, --CH.sub.2--, --CH(halo)-, --CH(OH)--(CH.sub.2).sub.n--, --CH(OH)-arylene-, --O--, --NH--, --S--, --CH(NR.sub.11R.sub.12)-- or --N(SO.sub.2Y)--, wherein Y is --OH, --NH.sub.2 or -alkylheterocycle and n is an integer ranging from 0 5;

R.sub.11 and R.sub.12 are independently -hydrogen or --C.sub.1 C.sub.9 alkyl, or N, R.sub.11 and R.sub.12 are taken together to form a heterocyclic amine;

R.sub.1 is -hydrogen, -halo, --C.sub.1 C.sub.10 alkyl, -alkylhalo, --C.sub.2 C.sub.10 alkenyl, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, --C(O)OH, --C(O)O(C.sub.1 C.sub.5 alkyl), NO.sub.2 or -A'-B';

A'is --SO.sub.2--, --SO.sub.2NH--, --NHCO--, --NHCONH--, --CO--, --C(O)O--, --CONH--, --CON(C.sub.1 C.sub.4 alkyl)-, --NH--, --CH.sub.2--, --S-- or --C(S)--;

B' is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NZ.sub.1Z.sub.2, --(C.sub.1 C.sub.5 alkylene)-NZ.sub.1Z.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl), --C(O)O-phenyl or --C(NH)NH.sub.2 any of which are unsubstituted or substituted with one or more of --O--(C.sub.1 C.sub.5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, --NO.sub.2, --NH.sub.2, --CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, --C.sub.2 C.sub.10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, --C(O)OH, --C.sub.1 C.sub.5 alkylene-C(O)O--(C.sub.1 C.sub.5 alkyl) or --C.sub.1 C.sub.5 alkylene-OC(O)--(C.sub.1 C.sub.5 alkyl);

R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are independently -hydrogen, -halo, -hydroxy, --O--(C.sub.1 C.sub.5 alkyl), --C.sub.1 C.sub.10 alkyl, -alkylhalo, --C.sub.2 C.sub.10 alkenyl, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, --C(O)OH, --C(O)O(C.sub.1 C.sub.5 alkyl), --OC(O)(--C.sub.1 C.sub.5 alkyl), NO.sub.2 or -A-B; and at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 or R.sub.10 is other than hydrogen;

A is --SO.sub.2--, --SO.sub.2NH--, --NHCO--, --NHCONH--, --O--, --CO--, --OC(O)--, --C(O)O--, --CONH--, --CON(C.sub.1 C.sub.4 alkyl)-, --NH--, --CH.sub.2--, --S-- or --C(S)--;

B is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NZ.sub.1Z.sub.2, --(C.sub.1 C.sub.5 alkylene)-NZ.sub.1Z.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl), --C(O)O-phenyl or --C(NH)NH.sub.2 any of which are unsubstituted or substituted with one or more of --O--(C.sub.1 C.sub.5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, --NO.sub.2, --NH.sub.2, --CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, --C.sub.2 C.sub.10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, --C(O)OH, --C.sub.1 C.sub.5 alkylene-C(O)O--(C.sub.1 C.sub.5 alkyl) or --C.sub.1 C.sub.5 alkylene-OC(O)--(C.sub.1 C.sub.5 alkyl); and

Z.sub.1 and Z.sub.2 are independently --H or --C.sub.1 C.sub.10 alkyl, which is unsubstituted or substituted with one or more of -halo, --OH or --N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently, --H or --C.sub.1 C.sub.5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or --NH.sub.2; or N, Z.sub.3 and Z.sub.4 are taken together to form an unsubstituted or substituted heterocyclic amine; or N, Z.sub.1 and Z.sub.2 are taken together to form a heterocyclic amine.

In one embodiment, X is --C(O)--, --CH.sub.2--, --CH(halo)-, --CH(OH)--(CH.sub.2).sub.n--, --CH(OH)-arylene-, --O--, --NH--, --S-- or --CH(NR.sub.11R.sub.12)--, wherein n is an integer ranging from 0 5.

In another embodiment B is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NZ.sub.1Z.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl) or --C(O)O-phenyl, any of which are unsubstituted or substituted with one or more of --O--(C.sub.1 C.sub.5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, --NO.sub.2, --NH.sub.2, -aminoalkyl, -aminodialkyl, -heterocyclic amine, --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, --C.sub.2 C.sub.10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, --C.sub.1 C.sub.5 alkylene-C(O)O--C.sub.1 C.sub.5 alkyl or --C.sub.1 C.sub.5 alkylene-OC(O)--C.sub.1 C.sub.5 alkyl.

In another embodiment, R.sub.1 R.sub.4 are hydrogen.

In a further embodiment at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 is other than hydrogen.

In one embodiment, A is --SO.sub.2--.

In other illustrative embodiments R.sup.5 and X in a compound of formula Ia are as set forth below:

TABLE-US-00001 R.sup.5 X NH --C(O)-- NH --CH.sub.2-- NH --CH(halo)- NH --CH(OH)(CH.sub.2).sub.n-- NH --CH(arylene)(OH)-- NH --O-- NH --NH-- NH --S-- NH --CH(NR.sup.11R.sup.12)-- NH --N(SO.sub.2Y)-- S --C(O)-- S --CH.sub.2-- S --CH(halo)- S --CH(OH)(CH.sub.2).sub.n-- S --CH(arylene)(OH)-- S --O-- S --NH-- S --S-- S --CH(NR.sup.11R.sup.12)-- S --N(SO.sub.2Y)--

The invention also relates to compounds of Formula Ib:

##STR00005## and pharmaceutically acceptable salts and hydrates thereof, wherein:

R.sub.5 is NH or S;

R.sub.6 is --H or C.sub.1 C.sub.4 alkyl;

X is --C(O)--, --CH.sub.2--, --CH(halo)-, --CH(OH)--(CH.sub.2).sub.n--, --CH(OH)-arylene-, --O--, --NH--, --S--, --CH(NR.sub.11R.sub.12)-- or --N(SO.sub.2Y)--, wherein Y is --OH, --NH.sub.2 or -alkylheterocycle and n is an integer ranging from 0 5;

R.sub.11 and R.sub.12 are independently -hydrogen or --C.sub.1 C.sub.9 alkyl, or N, R.sub.11 and R.sub.12 are taken together to form a heterocyclic amine;

R.sub.1 is -hydrogen, -halo, --C.sub.1 C.sub.10 alkyl, -alkylhalo, --C.sub.2 C.sub.10 alkenyl, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, --C(O)OH, --C(O)O(C.sub.1 C.sub.5 alkyl), NO.sub.2 or -A'-B';

A' is --SO.sub.2--, --SO.sub.2NH--, --NHCO--, --NHCONH--, --CO--, --C(O)O--, --CONH--, --CON(C.sub.1 C.sub.4 alkyl)-, --NH--, --CH.sub.2--, --S-- or --C(S)--;

B' is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NZ.sub.1Z.sub.2, --(C.sub.1 C.sub.5 alkylene)-NZ.sub.1Z.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl), --C(O)O-phenyl or --C(NH)NH.sub.2 any of which are unsubstituted or substituted with one or more of --O--(C.sub.1 C.sub.5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, --NO.sub.2, --NH.sub.2, --CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, --C.sub.2 C.sub.10 alkynyl, -aryl, -benzyl, -alkylamido , -alkylcarboxy, --C(O)OH, --C.sub.1 C.sub.5 alkylene-C(O)O--(C.sub.1 C.sub.5 alkyl) or --C.sub.1 C.sub.5 alkylene-OC(O)--(C.sub.1 C.sub.5 alkyl);

R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are independently -hydrogen, -halo, -hydroxy, --O--(C.sub.1 C.sub.5 alkyl), --C.sub.1 C.sub.10 alkyl, -alkylhalo, --C.sub.2 C.sub.10 alkenyl, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, --C(O)OH, --C(O)O(C.sub.1 C.sub.5 alkyl), --OC(O)(C.sub.1 C.sub.5 alkyl), NO.sub.2 or -A-B; and at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 or R.sub.10 is other than hydrogen;

A is --SO.sub.2--, --SO.sub.2NH--, --NHCO--, --NHCONH--, --O--, --CO--, --OC(O)--, --C(O)O--, --CONH--, --CON(C.sub.1 C.sub.4 alkyl)-, --NH--, --CH.sub.2--, --S-- or --C(S)--;

B is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NZ.sub.1Z.sub.2, --(C.sub.1 C.sub.5 alkylene)-NZ.sub.1Z.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl), --C(O)O-phenyl or --C(NH)NH.sub.2 any of which are unsubstituted or substituted with one or more of --O--(C.sub.1 C.sub.5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, --NO.sub.2, --NH.sub.2, --CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, --C.sub.2 C.sub.10 alkynyl, -aryl, -benzyl, -alkylamido , -alkylcarboxy, --C(O)OH, --C.sub.1 C.sub.5 alkylene-C(O)O--(C.sub.1 C.sub.5 alkyl) or --C.sub.1 C.sub.5 alkylene-OC(O)--(C.sub.1 C.sub.5 alkyl); and

Z.sub.1 and Z.sub.2 are independently --H or --C.sub.1 C.sub.10 alkyl, which is unsubstituted or substituted with one or more of -halo, --OH or --N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently, --H or --C.sub.1 C.sub.5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or --NH.sub.2; or N, Z.sub.3 and Z.sub.4 are taken together to form an unsubstituted or substituted heterocyclic amine; or N, Z.sub.1 and Z.sub.2 are taken together to form a heterocyclic amine.

In one embodiment, X is --C(O)--, --CH.sub.2--, --CH(halo)-, --CH(OH)--(CH.sub.2).sub.n--, --CH(OH)-arylene-, --O--, --NH--, --S-- or --CH(NR, R.sub.12)--, wherein n is an integer ranging from 0 5.

In another embodiment B is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NZ.sub.1Z.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl) or --C(O)O-phenyl, any of which are unsubstituted or substituted with one or more of --O--(C.sub.1 C.sub.5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, --NO.sub.2, --NH.sub.2, -aminoalkyl, -aminodialkyl, -heterocyclic amine, --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, --C.sub.2 C.sub.10 alkynyl, -aryl, -benzyl, -alkylamido , -alkylcarboxy, --C.sub.1 C.sub.5 alkylene-C(O)O--C.sub.1 C.sub.5 alkyl or --C.sub.1 C.sub.5 alkylene-OC(O)--C.sub.1 C.sub.5 alkyl.

In another embodiment, R.sub.1 R.sub.4 are hydrogen.

In a further embodiment at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 is other than hydrogen.

In one embodiment, A is --SO.sub.2-- or --SO.sub.2NH.sub.2--.

In yet another embodiment, R.sub.5 is O.

In illustrative embodiments R.sup.5 and X in a compound of formula Ib are as set forth below:

TABLE-US-00002 R.sup.5 X O --CH.sub.2-- O --CH(halo)- O --CH(OH)(CH.sub.2).sub.n-- O --CH(arylene)(OH)-- O --O-- O --NH-- O --S-- O --CH(NR.sup.11R.sup.12)-- O --N(SO.sub.2Y)--

Illustrative Compounds of Formula Ib are set forth below:

TABLE-US-00003 ##STR00006## Com- pound R.sub.7 R.sub.8 R.sub.9 R.sub.10 22a --H --H --H --H 22b --H --OMe --H --H 22c --H --H --OMe --H 22d --H --H --H --OMe 22e --H --Me --H --H 22f --H --COOH --H --H 22g --H --H --COOH --H 23a --H --OH --H --H 23b --H --H --OH --H 23c --H --H --H --OH 25a --H --H --(CH.sub.2).sub.4OH --H 25b --H --H --(CH.sub.2).sub.5OH --H 25c --H --H --(CH.sub.2).sub.6OH --H 25d --H --H --(CH.sub.2).sub.4COOH --H 25e --H --H --(CH.sub.2).sub.5COOH --H 26a --H --C(O)NH(CH.sub.2).sub.3--N- --H --H morpholine 26b --H --C(O)NH(CH.sub.2).sub.2--COOH --H --H 26c --H --C(O)NH(CH.sub.2).sub.3--N-(1,3- --H --H imidazole) 26d --H --C(O)NH(CH.sub.2).sub.2--NMe.sub.2 --H --H

and pharmaceutically acceptable salts and hydrates thereof.

Additional Illustrative Compounds of Formula Ib are set forth below:

TABLE-US-00004 ##STR00007## Compound X R.sub.9 31 --NNH-- --H 34 --N(SO.sub.3H)-- --SO.sub.3H 35a --N(SO.sub.2NH.sub.2)-- --SO.sub.2NH.sub.2 35b --N[SO.sub.2NH(CH.sub.2).sub.3(N- --SO.sub.2NH(CH.sub.2).sub.3(N- morpholine)]- morpholine) 40a --S-- --H

and pharmaceutically acceptable salts and hydrates thereof.

The invention also relates to compounds of Formula II:

##STR00008## and pharmaceutically acceptable salts and hydrates thereof, wherein:

R.sub.6 is --H or C.sub.1 C.sub.4 alkyl;

R.sub.1 is -hydrogen, -halo, --C.sub.1 C.sub.10 alkyl, -alkylhalo, --C.sub.2 C.sub.10 alkenyl, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, --C(O)OH, --C(O)O(C.sub.1 C.sub.5 alkyl), NO.sub.2 or -A'-B';

A' is --SO.sub.2--, --SO.sub.2NH--, --NHCO--, --NHCONH--, --CO--, --C(O)O--, --CONH--, --CON(C.sub.1 C.sub.4 alkyl)-, --NH--, --CH.sub.2--, --S-- or --C(S)--;

B' is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl), --C(O)O-phenyl or --NZ.sub.1Z.sub.2;

R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are independently -hydrogen, -halo, -hydroxy, --O--(C.sub.1 C.sub.5 alkyl), --C.sub.1 C.sub.10 alkyl, -alkylhalo, --C.sub.2 C.sub.10 alkenyl, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, --C(O)OH, --C(O)O(C.sub.1 C.sub.5 alkyl), --OC(O)(C.sub.1 C.sub.5 alkyl), NO.sub.2 or -A-B; wherein at least one of R.sup.1, R.sup.4 and R.sup.10 is other than hydrogen;

A is --SO.sub.2--, --SO.sub.2NH--, --NHCO--, --NHCONH--, --O--, --CO--, --OC(O)--, --C(O)O--, --CONH--, --CON(C.sub.1 C.sub.4 alkyl)-, --NH--, --CH.sub.2--, --S-- or --C(S)--;

B is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl), --C(O)O-phenyl or --NZ.sub.1Z.sub.2; and

Z.sub.1 and Z.sub.2 are independently --H or --C.sub.1 C.sub.10 alkyl, which is unsubstituted or substituted with one or more of -halo, --OH or --N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently, --H or --C.sub.1 C.sub.5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or --NH.sub.2; or N, Z.sub.3 and Z.sub.4 are taken together to form an unsubstituted or substituted heterocyclic amine; or N, Z.sub.1 and Z.sub.2 are taken together to form a heterocyclic amine.

In one embodiment, B is a heterocyclic amine.

In another embodiment, B is arylalkyl.

In still another embodiment, R.sub.1 is -hydrogen, -halo, --C.sub.1 C.sub.10 alkyl, -alkylhalo, --C.sub.2 C.sub.10 alkenyl, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, --C(O)OH, --C(O)O(C.sub.1 C.sub.5 alkyl), NO.sub.2 or -A-B;

A is --SO.sub.2--, --SO.sub.2NH--, --NHCO--, --NHCONH--, --CO--, --C(O)O--, --CONH--, --CON(C.sub.1 C.sub.4 alkyl)-, --NH--, --CH.sub.2--, --S-- or --C(S)--;

B is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl), --C(O)O-phenyl or --NZ.sub.1Z.sub.2.

In a further embodiment at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 is not hydrogen.

The invention also relates to compounds of Formula III:

##STR00009## and pharmaceutically acceptable salts and hydrates thereof, wherein:

X is --CH.sub.2-- or --O--;

R.sub.2 and R.sub.3 are independently -hydrogen, -halo, -alkylhalo, -hydroxy, --O--(C.sub.1 C.sub.5 alkyl), --C.sub.1 C.sub.3 alkyl, --NO.sub.2, --NH.sub.2, --CONF.sub.2, --C(O)OH, --OC(O)--C.sub.1 C.sub.5 alkyl or --C(O)O--C.sub.1 C.sub.5 alkyl;

R.sub.8 and R.sub.9 are independently -hydrogen or -A-B;

A is --SO.sub.2--, --SO.sub.2NH-- or --NHCO--; and

B is --C.sub.1 C.sub.3 alkyl, --NZ.sub.1Z.sub.2, -heterocycle or -alkylamino, each unsubstituted or substituted with one or more of -alkanol, -alkylamino, -aminoalkyl, -aminodialkyl or -heterocycle, each unsubstituted or substituted with --C.sub.1 C.sub.10 alkyl or -alkanol; and

Z.sub.1 and Z.sub.2 are independently -hydrogen or --C.sub.1 C.sub.8 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or --NZ.sub.3Z.sub.4, where Z.sub.3 and Z.sub.4 are independently --H or --C.sub.1 C.sub.3 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or --NH.sub.2, or N, Z.sub.3 and Z.sub.4 are taken together to a heterocyclic amine, or N, Z.sub.1 and Z.sub.2 are taken together to form a heterocyclic amine.

In one embodiment, --X-- is --CH.sub.2--.

In another embodiment, --X-- is --O--.

In one embodiment, R.sup.8 is hydrogen and R.sup.9 is -A-B.

In another embodiment, R.sup.8 is -A-B and R.sup.9 is hydrogen.

In one embodiment, either R.sup.8 is hydrogen and R.sup.9 is -A-B, or R.sup.8 is -A-B and R.sup.9 is hydrogen.

In one embodiment, R.sup.3, R.sup.8 and R.sup.9 are hydrogen and R.sup.2 is -A-B, wherein A is --NHC(O)--.

In another embodiment, R.sup.2, R.sub.9 and R.sup.9 are hydrogen and R.sup.3 is -A-B, wherein A is --NHC(O)--.

In still another embodiment R.sup.2, R.sup.3 and R.sup.8 are hydrogen and R.sup.9 is -A-B, wherein A is --SO.sub.2-- or --SO.sub.2NH--.

In a further embodiment at least one of R.sub.2, R.sub.3, R.sub.8 and R is not hydrogen.

The invention further relates to compounds of Formula 13:

##STR00010##

and pharmaceutically acceptable salts and hydrates thereof

wherein

R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are independently -hydrogen, -halo, -hydroxy, --O--(C.sub.1 C.sub.5 alkyl), --C.sub.1 C.sub.10 alkyl, -alkylhalo, --C.sub.2 C.sub.10 alkenyl, --C.sub.3 C.sub.8 carbocycle, -aryl, --NH.sub.2, -alkylamino, --C(O)OH, --C(O)O(C.sub.1 C.sub.5 alkyl), --OC(O)(C.sub.1 C.sub.5 alkyl), NO.sub.2 or -A-B;

A is --SO.sub.2--, --SO.sub.2NH--, --NHCO--, --NHCONH--, --O--, --CO--, --OC(O)--, --C(O)O--, --CONH--, --CON(C.sub.1 C.sub.4 alkyl)-, --NH--, --CH.sub.2--, --S-- or --C(S)--;

B is --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, -heterocycle, --C.sub.3 C.sub.8 carbocycle, -aryl, --NZ.sub.1Z.sub.2, --(C.sub.1 C.sub.5 alkylene)-NZ.sub.1Z.sub.2, -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, --C(O)OH, --C(O)O--(C.sub.1 C.sub.5 alkyl), --C(O)O-phenyl or --C(NH)NH.sub.2 any of which are unsubstituted or substituted with one or more of --O--(C.sub.1 C.sub.5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, --NO.sub.2, --NH.sub.2, --CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, --C.sub.1 C.sub.10 alkyl, --C.sub.2 C.sub.10 alkenyl, --C.sub.2 C.sub.10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, --C(O)OH, --C.sub.1 C.sub.5 alkylene-C(O)O--(C.sub.1 C.sub.5 alkyl) or --C.sub.1 C.sub.5 alkylene-OC(O)--(C.sub.1 C.sub.5 alkyl); and

Z.sub.1 and Z.sub.2 are independently --H or --C.sub.1 C.sub.10 alkyl, which is unsubstituted or substituted with one or more of -halo, --OH or --N(Z.sub.3)(Z.sub.4), where Z.sub.3 and Z.sub.4 are independently, --H or --C.sub.1 C.sub.5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or --NH.sub.2; or N, Z.sub.3 and Z.sub.4 are taken together to form an unsubstituted or substituted heterocyclic amine; or N, Z and Z.sub.2 are taken together to form a heterocyclic amine.

In one embodiment, R.sub.9 is -A-B, wherein -A- is --SO.sub.2-- or --SO.sub.2NH--.

In another embodiment R.sub.1 R.sub.4 are each hydrogen.

In another embodiment, R.sub.1 R.sub.4 are each hydrogen.

In a further embodiment at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 is other than hydrogen.

The invention further still relates to compounds of Formula 22:

##STR00011##

and pharmaceutically acceptable salts and hydrates thereof

wherein

R.sub.1 R.sub.4 and R.sub.7 R.sub.10 are as defined above for Formula 13.

In one embodiment, R.sub.9 is -A-B, wherein -A- is --SO.sub.2-- or --SO.sub.2NH--.

In another embodiment R.sub.1-R.sub.4 are each hydrogen.

In a further embodiment at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 is other than hydrogen.

The invention further still relates to compounds of Formula 37:

##STR00012##

and pharmaceutically acceptable salts and hydrates thereof

wherein

R.sub.1 R.sub.4 and R.sub.7 R.sub.10 are as defined above for Formula 13.

In one embodiment R.sub.1 R.sub.4 are each hydrogen.

In a further embodiment at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 is other than hydrogen.

The invention also relates to compounds of Formula 40:

##STR00013##

and pharmaceutically acceptable salts and hydrates thereof

wherein

R.sub.1 R.sub.4 and R.sub.7 R.sub.10 are as defined above for Formula 13.

In one embodiment R.sub.1 R.sub.4 are each hydrogen.

In a further embodiment at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 is other than hydrogen.

4.1 DEFINITIONS

The following definitions are used in connection with the Isoquinoline Derivatives:

"C.sub.1 C.sub.3 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 3 carbon atoms. Examples of a C.sub.1 C.sub.3 alkyl group include, but are not limited to, methyl, ethyl, propyl and isopropyl

"C.sub.1 C.sub.4 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 4 carbon atoms. Examples of a C.sub.1 C.sub.4 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl.

"C.sub.1 C.sub.5 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 4 carbon atoms. Examples of a C.sub.1 C.sub.5 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.

"C.sub.1 C.sub.8 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 8 carbon atoms. Examples of a C.sub.1 C.sub.8 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl and isooctyl.

"C.sub.1 C.sub.9 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 9 carbon atoms. Examples of a C.sub.1 C.sub.9 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl and isononyl.

"C.sub.1 C.sub.10 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 10 carbon atoms. Examples of a C.sub.1 C.sub.10 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, isononyl and isodecyl.

"C.sub.2 C.sub.10 alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 10 carbon atoms and at least one double bond. Examples of a C.sub.2 C.sub.10 alkenyl group include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, 4-octene, 1-nonene, 2-nonene, 3-nonene, 4-nonene, 1-decene, 2-decene, 3-decene, 4-decene and 5-decene.

"C.sub.2 C.sub.10 alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 10 carbon atoms and at least one triple bond. Examples of a C.sub.2 C.sub.10 alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1-pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, isohexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, 4-octyne, 1-nonyne, 2-nonyne, 3-nonyne, 4-nonyne, 1-decyne, 2-decyne, 3-decyne, 4-decyne and 5-decyne.

"C.sub.1 C.sub.4 alkylene" refers to a C.sub.1 C.sub.4 alkyl group in which one of the C.sub.1 C.sub.4 alkyl group's hydrogen atoms has been replaced with a bond. Examples of a C.sub.1 C.sub.4 alkylene include --CH.sub.2--, --CH.sub.2 CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- and --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--.

"C.sub.1 C.sub.5 alkylene" refers to a C.sub.1 C.sub.5 alkyl group in which one of the C.sub.1 C.sub.5 alkyl group's hydrogen atoms has been replaced with a bond. Examples of a C.sub.1 C.sub.4 alkylene include --CH.sub.2--, --CH.sub.2 CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- and -Examples of a C.sub.1 C.sub.4 alkylene include --CH.sub.2--, --CH.sub.2 CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2-- and --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--.

"Alkylhalo" refers to a C.sub.1 C.sub.5 alkyl group, as defined above, wherein one or more of the C.sub.1 C.sub.5 alkyl group's hydrogen atoms has been replaced with --F, --Cl, --Br or --I. Representative examples of an alkylhalo group include, but are not limited to --CH.sub.2F, --CCl.sub.3, --CF.sub.3, --CH.sub.2Cl, --CH.sub.2CH.sub.2Br, --CH.sub.2CH.sub.2I, --CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2CH.sub.2Cl, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2Br, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2I, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2Br, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2I, --CH.sub.2CH(Br)CH.sub.3, --CH.sub.2CH(Cl)CH.sub.2CH.sub.3, --CH(F)CH.sub.2CH.sub.3 and --C(CH.sub.3).sub.2(CH.sub.2Cl).

"Alkylamino" refers to a C.sub.1 C.sub.4 alkyl group, as defined above, wherein one or more of the C.sub.1 C.sub.4alkyl group's hydrogen atoms has been replaced with --NH.sub.2. Representative examples of an alkylamino group include, but are not limited to --CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH(NH.sub.2)CH.sub.3--CH.sub.2CH(NH.sub.2)CH.sub.2CH.sub.3--CH(- NH.sub.2)CH.sub.2CH.sub.3 and --C(CH.sub.3).sub.2(CH.sub.2NH.sub.2).

"Aminoalkyl" refers to an --NH group, the nitrogen atom of said group being attached to a C.sub.1 C.sub.4 alkyl group, as defined above. Representative examples of an aminoalkyl group include, but are not limited to --NHCH.sub.3, --NHCH.sub.2CH.sub.3, --NHCH.sub.2CH.sub.2CH.sub.3, --NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3, --NHCH(CH.sub.3).sub.2, --NHCH.sub.2CH(CH.sub.3).sub.2, --NHCH(CH.sub.3)CH.sub.2CH.sub.3 and --NH--C(CH.sub.3).sub.3.

"Aminodialkyl" refers to a nitrogen atom which has attached to it two C.sub.1 C.sub.4 alkyl groups, as defined above. Representative examples of a aminodialkyl group include, but are not limited to, --N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3)(CH.sub.3), --N(CH.sub.2CH.sub.3).sub.2, --N(CH.sub.2CH.sub.2CH.sub.3).sub.2, --N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.2, --N(CH(CH.sub.3).sub.2).sub.2, --N(CH(CH.sub.3).sub.2)(CH.sub.3), --N(CH.sub.2CH(CH.sub.3).sub.2).sub.2, --NH(CH(CH.sub.3)CH.sub.2CH.sub.3).sub.2, --N(C(CH.sub.3).sub.3).sub.2 and --N(C(CH.sub.3).sub.3)(CH.sub.3).

"Aryl" refers to a phenyl or pyridyl gro