Somatostatin agonist compounds of formula I are disclosed: ##STR1## including pharmaceutically acceptable salts and hydrates thereof These compounds are useful in the treatment of diabetes, cancer, acromegaly, restenosis, depression, irritable bowel syndrome and pain. The compounds are potent with high selectivity toward the receptor subtype 2. Pharmaceutical compositions and methods of treatment are also included.

BACKGROUND OF THE INVENTION 
Somatostatin (SST) is a widely distributed peptide occurring in two forms 
SST-14 (with 14 amino acids) and SST-28 (with 28 amino acids). SST has 
multiple functions including modulation of secretion of growth hormone, 
insulin, glucagon, pancreatic enzymes and gastric acid, in addition to 
having potent anti-proliferative effects. 
The mechanism of action of somatostatin is mediated via high affinity 
membrane associated receptors. Five somatostatin receptors (SSTR1-5) are 
known (Reisine, T.; Bell, G.I. Endocrine Reviews 1995, 16, 427-442). All 
five receptors are heterogeneously distributed and pharmacologically 
distinct. Structure-function studies with a large number of peptidal 
analogs have shown that the Trp-Lys dipeptide of somatostatin is important 
for high-affinity binding. The availability of these receptors now makes 
it possible to design selectively active ligands for the subtypes to 
determine their physiological functions and to guide potential clinical 
applications. For example, studies utilizing subtype selective peptides 
have provided evidence that somatostatin subtype 2 receptors (SSTR2) 
mediates the inhibition of growth hormone release from the anterior 
pituitary and glucagon release from the pancreas, whereas SSTR5 selective 
agonists inhibit insulin release. These results imply the usefulness of 
SSTR2 selective analogs in the treatment of diabetes and many of the 
compounds of this invention have that selectivity. 
In addition, the novel compounds described herein are useful in the therapy 
of a variety of conditions which include acromegaly, retinal 
neovascularization, neuropathic and visceral pain, irritable bowel 
syndrome, chronic atrophic gastritis, Crohn's disease, rheumatoid 
arthritis and sarcoidosis. The instant compounds inhibit cell 
proliferation and cause the regression of certain tumors including breast 
and pancreatic cancer. They are useful in preventing restenosis after 
angioplasty, they prevent non-steroid antiinflammatory drug (NSAID) 
induced ulcers, they are useful in treating colitis and to inhibit cystoid 
macular edema. Their central activities include promotion of REM sleep and 
an increase in cognitive function. They also have analgesic activities and 
can be used, for example, to treat cancer pain, cluster headache and post 
operative pain and they are useful in the prevention and treatment of 
migraine attacks and depression. The compounds described herein may be 
used in combination with other therapies, for example, with rapamycin to 
treat cancers, restenosis and atherosclerosis and with angiotensin 
converting enzyme inhibitors and insulin in the treatment of diabetes. The 
compounds of this invention are also remarkably reduced in size in 
comparison with the natural hormone and its peptide analogs such as 
octreotide and seglitide, which allows ease of formulation. Many of the 
instant compounds show activity following oral administration. 
This invention relates to compounds which are agonists of somatostatin and 
selective toward somatostatin receptor subtype SSTR2. The compounds have a 
number of clinical uses including in the treatment and prevention of 
diabetes, cancer, acromegaly, depression, chronic atrophic gastritis, 
Crohn's disease, ulcerative colitis, retinopathy, arthritis, pain both 
viseral and neuropathic and to prevent restenosis. 
SUMMARY OF THE INVENTION 
The present invention relates to compounds represented by formula I: 
##STR2## 
as well as pharmaceutically acceptable salts and hydrates thereof, 
wherein: 
R.sup.1 is selected from the group consisting of: C.sub.1-10 alkyl, aryl, 
aryl(C.sub.1-6 alkyl)--, C.sub.3-7 cycloalkyl(C.sub.1-6 alkyl)--, 
C.sub.1-5 alkyl-K-(C.sub.1 -C.sub.5 alkyl)--, aryl(C.sub.0-5 
alkyl)-K-(C.sub.1-5 alkyl)--, and C.sub.3-7 cycloalkyl(C.sub.0-5 
alkyl)-K-(C.sub.1-5 alkyl)--, 
wherein K is --O--, --S(O).sub.m --, --N(R.sup.2)C(O)--, 
--C(O)N(R.sup.2)--, --CR.sup.2 .dbd.CR.sup.2 -- or --C.tbd.C--, 
the alkyl portions of which being optionally substituted with by 1 to 5 
halogen groups, S(O).sub.m R.sup.2a, 1 to 3 of OR.sup.2a groups or 
C(O)OR.sup.2a, 
and wherein aryl is selected from the group consisting of: phenyl, 
naphthyl, biphenyl, quinolinyl, isoquinolinyl, indolyl, azaindolyl, 
pyridyl, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, 
said aryl groups being unsubstituted or substituted with 1 to 3 C.sub.1-6 
alkyl or halo groups, 1 to 2 --OR.sup.2 groups, methylenedioxy, 
--S(O).sub.m R.sup.2, 1 to 2 --CF.sub.3 groups, --OCF.sub.3, --NO.sub.2, 
--N(R.sup.2)C(O)(R.sup.2), --C(O)OR.sup.2, --C(O)N(R.sup.2).sub.2, 
1H-tetrazol-5-yl, --SO.sub.2 N(R.sup.2)(R.sup.2), --N(R.sup.2)SO.sub.2 
phenyl, or --N(R.sup.2)SO.sub.2 R.sup.2 ; 
R.sup.2 is selected from the group consisting of: H, C.sub.1-8 alkyl, 
--(CH.sub.2).sub.t -aryl and C.sub.3-7 cycloalkyl, and where two R.sup.2 
groups are present, they optionally are joined to form a C.sub.3 -C.sub.8 
ring, optionally interrupted by O, S or NR.sup.3a, in which R.sup.3a is H 
or C.sub.1-6 alky optionally substituted by OH; 
t is an integer from 0 to 3; 
and when R.sup.2 is other than H, R.sup.2 is optionally substituted with 1 
to 5 halogen groups, S(O).sub.m R.sup.2a, 1 to 3 of OR.sup.2a groups or 
C(O)OR.sup.2a, 
R.sup.2a is H or C.sub.1-3 alkyl optionally substituted by OH; 
m is 0, 1 or 2; 
R.sup.1a is H or C.sub.1-3 alkyl; 
Z.sup.1 is selected from the group consisting of --O--, --CH.sub.2 -- and 
NR.sup.2a ; 
E is selected from the group consisting of --SO.sub.2 --, --C(O)--, 
--CO(C(R.sup.2).sub.2).sub.n --, --C(.dbd.N--CN)--, 
--C(.dbd.N--NO.sub.2)-- and --C(.dbd.N--SO.sub.2 N(R.sup.2).sub.2)--; 
n is an integer from 0 to 3; 
B is selected from the group consisting of: 
##STR3## 
where attachment points are indicated by lines 
##STR4## 
and q is 0, 1, 2 or 3, said group being optionally substituted by 
C.sub.1-6 alkyl, and the R.sup.2 and (CH.sub.2).sub.q groups are 
optionally substituted as described above; 
##STR5## 
represents an aromatic or non-aromatic 5-6 membered ring structure 
wherein: 
G is N, CH or C; 
Y is --C(O)--, --SO.sub.2 --, --C(OR.sup.11).dbd., --C(SR.sup.11).dbd., 
--C(NR.sup.11).dbd., .dbd.N--, --NR.sup.11)--, .dbd.NC(O)-- or 
--C(R.sup.11).sub.2 --; and 
X is --N(R.sup.11)--, .dbd.N--, .dbd.N--C(R.sup.11).sub.2 --, 
--N(R.sup.11)C(R.sup.11).sub.2 --, --O--, --O--C(R.sup.11).sub.2 --, 
--S--, --S--C(R.sup.11).sub.2 -- or C(R.sup.11).sub.2 ; 
R.sup.11 is H, C.sub.1-8 alkyl, CF.sub.3, CH.sub.2 CF.sub.3, 
--(CH.sub.2).sub.p OR.sup.2, --(CH.sub.2).sub.p N(R.sup.2).sub.2, 
--(CH.sub.2).sub.p N(R.sup.2)C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.p 
N(R.sup.2)C(O)R.sup.2, --(CH.sub.2).sub.2 -heteroaryl, --(CH.sub.2).sub.p 
N(R.sup.2)SO.sub.2 C.sub.1-4 alky, --(CH.sub.2).sub.p C(O)N(R.sup.2).sub.2 
or --(CH.sub.2).sub.p C(O)OR.sup.2, wherein heteroaryl is selected from 
tetrazolyl, oxadiazolyl, imidazolyl and triazolyl, said heteroaryl being 
optionally substituted with R.sup.2, OR.sup.2, CF.sub.3 or 
N(R.sup.2).sub.2 and where p is 0-3; 
##STR6## 
is a 5-10 membered fused aryl or heteroaryl group having 1-4 heteroatoms 
selected from O, S and N, or a 5-10 membered cycloall or heterocycloalkyl 
group having 1-3 heteroatoms selected from O, S and N, said aryl, 
heteroaryl, cycloalyl or heterocycloalkyl group being optionally 
substituted with 1-3 C.sub.1-6 alkyl or halo groups, --OR.sup.2, 
N(R.sup.2).sub.2, methylenedioxy, --S(O).sub.m R.sup.2, --CF.sub.3, 
--OCF.sub.3, --NO.sub.2, --N(R.sup.2)C(O)(R.sup.2), --C(O)OR.sup.2, 
--C(O)N(R.sup.2).sub.2, 1H-tetrazol-5-yl, --SO.sub.2 N(R.sup.2).sub.2, 
--N(R.sup.2)SO.sub.2 phenyl, --N(R.sup.2)C(O)N(R.sup.2).sub.2 or 
--N(R.sup.2)SO.sub.2 R.sup.2 ; 
Z.sup.2 is selected from the group consisting of --O--, --CH.sub.2 
--,--CHR.sup.2b -- and --NR.sup.2b --, 
wherein R.sup.2b is selected from the group consisting of: H, C.sub.1-8 
alkyl, --(CH.sub.2).sub.t -aryl, --(CH.sub.2).sub.n CO.sub.2 R.sup.2, 
--(CH.sub.2).sub.n CON(R.sup.2).sub.2 and --(CH.sub.2).sub.n OR.sup.2, and 
when Z.sup.2 is NR.sup.2b it can optionally be linked to R.sup.1c, Q or W 
to form a C5-8 ring, which is optionally interrupted by O, S(O).sub.m or 
NR.sup.2a ; 
R.sup.1c is selected from the group consisting of: H, --(CH.sub.2).sub.q 
SR.sup.2, --(CH.sub.2).sub.q OR.sup.2 and C.sub.1-8 alkyl; 
W is selected from the group consisting of: H, C.sub.1-8 alkyl, 
(CH.sub.2).sub.t -aryl, --(CH.sub.2).sub.q C(O)OR.sup.2, 
--(CH.sub.2).sub.q OR.sup.2,--(CH.sub.2).sub.q OC(O)R.sup.2, 
--(CH.sub.2).sub.q C(O)R.sup.2, --(CH.sub.2).sub.q C(O)(CH.sub.2).sub.t 
aryl, --(CH.sub.2).sub.q C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
N(R.sup.2)C(O)R.sup.2, --(CH.sub.2).sub.q N(R.sup.2)SO.sub.2 R.sup.2, 
--(CH.sub.2).sub.q N(R.sup.2)C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
OC(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q N(R.sup.2)C(O)OR.sup.2, 
--(CH.sub.2).sub.q N(R.sup.2)SO.sub.2 N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
S(O).sub.m R.sup.2 and --(CH.sub.2).sub.t -heteroaryl, the heteroaryl 
portion of which is selected from: tetrazolyl, oxadiazolyl, thiadiazolyl, 
triazolyl and pyrazinyl, optionally substituted with R.sup.2, 
N(R.sup.2).sub.2 or OR.sup.2, 
and when R.sup.2 is other than H, said R.sup.2, (CH.sub.2).sub.q and the 
(CH.sub.2).sub.t portions of W are optionally substituted with 1 to 2 
C.sub.1-4 all4rl, OR.sup.2a, C(O)OR.sup.2a or 1-3 halo groups, and 
the aryl and heteroaryl portions of W are optionally substituted with 1 to 
3 halo groups, --OR.sup.2, --CON(R.sup.2).sub.2, --C(O)OR.sup.2, C.sub.1-4 
alkyl, --S(O).sub.m R.sup.2 N(R.sup.2).sub.2, CF.sub.3 or 
1H-tetrazol-5-yl; 
k is 0 or 1, such that when k is 0, Q is attached directly to Z.sup.2 ; 
Q represents a member selected from the group consisting of: 
##STR7## 
wherein x and y are independently 0, 1, 2, 3, 4, 5 or 6; 
V is a C.sub.3 -10 saturated, partially saturated or aromatic mono- or 
bicyclic ring system, containing 1-4 N atoms and 0-2 O or S atoms, said 
ring system being optionally substituted with 1 to 3 halo groups, 
--OR.sup.2, --CON(R.sup.2).sub.2, --C(O)OR.sup.2, C.sub.1-4 alkyl, 
--S(O).sub.m R.sup.2, (CH.sub.2).sub.t N(R.sup.2).sub.2, CF.sub.3 or 
1H-tetrazol-5-yl; 
R.sup.7 and R.sup.7a are independently CF.sub.3 or R.sup.2 ; 
R.sup.8 is selected from the group consisting of H, 
EQU --NR.sup.4 R.sup.5, --C(.dbd.NR.sup.9)N(R.sup.10).sub.2 and --N.sup.+ 
R.sup.4).sub.3 ; 
R.sup.4 and R.sup.5 are independently selected from the group consisting 
of: R.sup.2, --C(.dbd.NR.sup.2)N(R.sup.2).sub.2, 
--C(.dbd.NCN)N(R.sup.2).sub.2, --C(.dbd.NC(O)R.sup.2)N(R.sup.2).sub.2, 
C(.dbd.NSO.sub.2 R.sup.2)N(R.sup.2).sub.2, C(.dbd.NNO.sub.2)NR.sup.2, 
heteroaxyl, --C(O)N(R.sup.2).sub.2, --C(.dbd.S)N(R.sup.2).sub.2, 
--C(O)R.sup.2, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 
--(CH.sub.2).sub.t -cyclopropyl, or 
R.sup.4 and R.sup.5 are taken together and represent 
EQU --(CH.sub.2).sub.d --L.sub.a (CH.sub.2).sub.e -- 
wherein L.sub.a is --C(R.sup.2).sub.2 --, --O--, --S(O).sub.m -- or 
--N(R.sup.2)--, and d and e are independently 0 to 3 such that d plus e 
equals 2-6, 
and said heteroaryl and R.sup.2 other than H being optionally substituted 
with 1-3 C.sub.1-6 alkyl groups, 1-7 halo groups, N(R.sup.2).sub.2, 
OR.sup.2, N(R.sup.2)C(O)R.sup.2, C(O)N(R.sup.2), OC(O)R.sup.2, S(O).sub.m 
R.sup.2, CF.sub.3, OCF.sub.3, NO.sub.2, N(R.sup.2)C(O)(R.sup.2), 
N(R.sup.2)C(O)N(R.sup.2).sub.2, C(O)OR.sup.2, C(O)N(R.sup.2).sub.2, 
SO.sub.2 N(R.sup.2).sub.2, N(R.sup.2)SO.sub.2 R.sup.2 or methylenedioxy; 
and R.sup.9 and R.sup.10 are independently H or C.sub.1-8 alkyl or may be 
taken together and represent a C.sub.5-8 ring, optionally substituted by 
1-5 halo groups, OR.sup.2 or S(O).sub.m R.sup.2. 
Pharmaceutical compositions and methods of treatment are also included. 
DETAIL DESCRIPTION OF THE INVENTION 
One aspect of the invention that is of particular interest, relates to 
compounds of formula I wherein: Q is 
##STR8## 
and x and y are independently 0, 1, 2 or 3. Within this subset, all other 
variables are as originally defined with respect to formula I. 
Another aspect of the invention that is of particular interest relates to 
compounds of formula I wherein: 
B is selected from the group consisting of a noncyclic or heterocyclic 
selected from the group consisting of 
##STR9## 
where attachment points are indicated by lines 
##STR10## 
external to the rings and to the open ring which are optionally 
substituted by C.sub.1 -C.sub.6 alkyl and where R.sup.2 and 
(CH.sub.2).sub.q are as originally described. Within this subset, all 
other variables are as originally defined with respect to formula I. 
More particularly, another aspect of the invention that is of particular 
interest relates to compounds of formula I wherein: 
##STR11## 
Even more particularly, another aspect of the invention that is of 
particular interest relates to compounds of formula I wherein B is 
##STR12## 
Within this subset, all other variables are as originally defined with 
respect to formula I. 
Another aspect of the invention that is of particular interest relates to 
compounds of formula I wherein: V represents a member selected from the 
group consisting of: 
##STR13## 
which can be optionally substituted with 1 to 3 halogen, --OR.sup.2, 
--CON(R.sup.2).sub.2, --C(O)OR.sup.2, C.sub.1 -C.sub.4 alkyl, --S(O).sub.m 
R.sup.2, N(R.sup.2).sub.2, CF.sub.3 or 1H-tetrazol-5-yl, and in the case 
where diastereo- or regioisomers are present, all are included. Within 
this subset, all other variables are as originally defined with respect to 
formula I. 
Another aspect of the invention that is of particular interest relates to 
compounds of formula I wherein: R.sup.8 represents H or --NR.sup.4 
R.sup.5. Within this subset, all other variables are as originally defined 
with respect to formula I. 
More particularly, an aspect of the invention that is of interest relates 
to compounds of formula I wherein R.sup.8 represents H or --NR.sup.4 
R.sup.5, and 
R.sup.4 and R.sup.5 are independently selected from the group consisting of 
R.sup.2, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and (CH.sub.2).sub.t 
-cyclopropyl wherein t=0 or 1. Within this subset, all other variables are 
as originally defined with respect to formula I. 
Another aspect of the invention that is of interest relates to compounds of 
formula I wherein: 
R.sup.1 is selected from the group consisting of: 
##STR14## 
where the aryl portion is unsubstituted or substituted with: 1 to 3 of 
C.sub.1 -C.sub.6 alkyl, 1 to 3 of halogen, 1 to 2 of --OR.sup.2, 
methylenedioxy, --S(O).sub.m R.sup.2, 1 to 2 of --CF.sub.3, --OCF.sub.3, 
nitro, --N(R.sup.2)C(O)(R.sup.2), --C(O)OR.sup.2, 
--C(O)N(R.sup.2)(R.sup.2), --1H-tetrazol-5-yl, --SO.sub.2 
N(R.sup.2)(R.sup.2), --N(R.sup.2)SO.sub.2 phenyl, or --N(R.sup.2)SO.sub.2 
R.sup.2. Within this subset, all other variables are as originally defined 
with respect to formula I. 
Another aspect of the invention that is of particular interest relates to 
compounds of formula I wherein: 
R.sup.2 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl and t-butyl. Within this subset, all other variables are 
as originally defined with respect to formula I. 
Another aspect of the invention that is of particular interest relates to 
compounds of formula I wherein: 
##STR15## 
represents 
##STR16## 
and is selected from the group consisting of: 
##STR17## 
and the aromatic rings can be optionally substituted with 1 to 2 R2, 1 to 3 
halogen, --OR.sup.2, --CON(R.sup.2).sub.2, --C(O)OR.sup.2, C.sub.1 
-C.sub.4 alkyl, --S(O).sub.m R.sup.2, N(R.sup.2).sub.2, CF.sub.3 ; and in 
the case where diastereo- or regioisomers are present, all are included; 
and x is an integer from 0 to 3. Within this subset, all other variables 
are as originally defined with respect to formula I. 
Another aspect of the invention that is of particular interest relates to 
compounds of formula I wherein: 
W is selected from the group consisting of: hydrogen, C.sub.1 -C.sub.4 
allyl, (CH.sub.2).sub.q C(O)OR.sup.2. Within this subset, all other 
variables are as originally defined with respect to formula I. 
Another aspect of the invention that is of particular interest relates to 
compounds of formula I wherein: 
E is selected from the group consisting of --CO--, --C(.dbd.N--CN)--, and 
--SO.sub.2 --. Within this subset, all other variables are as originally 
defined with respect to formula I. 
Another aspect of the invention that is of particular interest relates to 
compounds of formula I wherein: 
##STR18## 
is selected from the group consisting of: 
##STR19## 
where the aromatic rings are optionally substituted with 1-3 groups of 
C.sub.1 -C.sub.6 alkyl, halogen, --OR.sup.2.sub.3 N(R.sup.2).sub.2, 
methylenedioxy, --S(O).sub.m R.sup.2, --CF.sub.3, --OCF.sub.3, nitro, 
--N(R.sup.2)C(O)(R.sup.2), --C(O)OR.sup.2, --C(O)N(R.sup.2).sub.2, 
--1H-tetrazol-5-yl, --SO.sub.2 N(R.sub.2).sub.2, --N(R.sup.2)SO.sub.2 
phenyl, N(R.sup.2)C(O)N(R.sup.2) or --N(R.sup.2)SO.sub.2 R.sup.2. Within 
this subset, all other variables are as originally defined with respect to 
formula I. 
In one aspect of the invention the compounds and their pharmaceutically 
acceptable salts and hydrates thereof are of the formula: 
##STR20## 
wherein: 
R.sup.1 is selected from the group consisting of: C.sub.1 -C.sub.10 alkyl, 
aryl, aryl (C.sub.1 -C.sub.6 alkyl), (C.sub.3 -C.sub.7 cycloalkyl)(C.sub.1 
-C.sub.6 alkyl)--, (C.sub.1 -C.sub.5 alkyl)--K--(C.sub.1 -C.sub.5 
alkyl)--, aryl(C.sub.0 -C.sub.5 alkyl)--K--(C.sub.1 -C.sub.5 alkyl)--, and 
(C.sub.3 -C.sub.7 cycloalkyl)(C.sub.0 -C.sub.5 alkyl)--K--(C.sub.1 
-C.sub.5 alkyl)--, where K is --O--, --S(O).sub.m --, --N(R.sup.2)C(O)--, 
--C(O)N(R.sup.2)--, --CR.sup.2 .dbd.CR.sup.2 --, or --C.intg.C--, where 
R.sup.2 and alkyl may be further substituted by 1 to 5 halogen, S(O).sub.m 
R.sup.2a, 1 to 3 of OR.sup.2a or C(O)OR.sup.2a, and aryl is selected from: 
phenyl, naphthyl, biphenyl, quinolinyl, isoquinolinyl, indolyl, azaindole, 
pyridyl, benzothienyl, benzofaranyl, thiazolyl, and benzimidazolyl, and 
where the aryl is unsubstituted or substituted with a substitutent 
selected from: 1 to 3 of C.sub.1 -C.sub.6 alkyl, 1 to 3 of halogen, 1 to 2 
of --OR.sup.2, methylenedioxy, --S(O).sub.m R.sup.2, 1 to 2 of --CF.sub.3, 
--OCF.sub.3, nitro, --N(R.sup.2)C(O)(R.sup.2), --C(O)OR.sup.2, 
--C(O)N(R.sup.2)(R.sup.2), --1H-tetrazol-5-yl, --SO.sub.2 
N(R.sup.2)(R.sup.2), --N(R.sup.2)SO.sub.2 phenyl, or --N(R.sup.2)SO.sub.2 
R.sup.2 ; 
R.sup.2 is selected from: hydrogen, C.sub.1 -C.sub.8 alkyl, 
(CH.sub.2).sub.t aryl, and C.sub.3 -C.sub.7 cycloalkyl, and where two 
C.sub.1 -C.sub.6 alkyl groups are present on one atom, they optionally are 
joined to form a C.sub.3 -C.sub.8 cyclic ring, optionally including 
oxygen, sulfiz or NR.sup.3a, where R.sup.3a is hydrogen, or C.sub.1 
-C.sub.6 alkyl, optionally substituted by hydroxyl; Aryl is defined in the 
body of the case. 
R.sup.1a is selected from the group consisting of hydrogen, and C.sub.1 
-C.sub.3 alkyl; 
R.sup.2a is selected from the group consisting of hydrogen and C.sub.1 
-C.sub.3 alkyl, said alkyl optionally substituted by hydroxyl; R.sup.2b is 
selected from hydrogen, C.sub.1 -C.sub.8 alkyl, (CH.sub.2).sub.t aryl, 
--(CH.sub.2).sub.n CO.sub.2 R.sup.2, --(CH.sub.2).sub.n 
CON(R.sup.2).sub.2, --(CH.sub.2).sub.n OH or --(CH.sub.2).sub.n OR.sup.2 ; 
R.sup.1c is selected from the group consisting of hydrogen, 
--(CH.sub.2).sub.q SR.sup.2, --(CH.sub.2).sub.q OR.sup.2 and C.sub.1 
-C.sub.8 alkyl; 
Z.sup.1 is selected from the group consisting of --O--, --CH2-- and 
--NR.sup.2a ; 
Z.sup.2 is selected from the group consisting of --O--, 
--CH2--,--CHR.sup.2b -- and --NR.sup.2b, when Z.sup.2 is NR.sup.2b it can 
optionally be linked to R.sup.1c, Q and/or W to form a C5-8 cyclic ring, 
which can optionally be interrupted by oxygen, S(O).sub.m or NR.sup.2a ; 
W is selected from the group consisting of: hydrogen, C.sub.1 -C.sub.8 
alkyl, (CH2).sub.t aryl, --(CH.sub.2).sub.q C(O)OR.sup.2, 
--(CH.sub.2).sub.q OR.sup.2, --(CH.sub.2).sub.q OC(O)R.sup.2, 
--(CH.sub.2).sub.q C(O)R.sup.2, --(CH.sub.2).sub.q C(O)(CH.sub.2).sub.t 
aryl, --(CH.sub.2).sub.q C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
N(R.sup.2)C(O)R.sup.2, --(CH.sub.2).sub.q N(R.sup.2)SO.sub.2 R.sup.2, 
--(CH.sub.2).sub.q N(R.sup.2)C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
OC(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q N(R.sup.2)C(O)OR.sup.2, 
--(CH.sub.2).sub.q N(R.sup.2)SO.sub.2 N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
S(O).sub.m R.sup.2, and (CH.sub.2).sub.t heteroaryl where the heteroaryl 
is preferably tetrazole, oxadiazole, thiadiazole, triazole or pyrazine, 
which is optionally substituted with R.sup.2, N(R.sup.2).sub.2 and 
OR.sup.2, where R.sup.2, (CH.sub.2).sub.q and (CH.sub.2).sub.t are 
optionally substituted with 1 to 2 C.sub.1 -C.sub.4 allyl, OR.sup.2, 
C(O)OR.sup.2, 1-3 halo and said aryl is optionally substituted with 1 to 3 
halogen, --OR.sup.2, --CON(R.sup.2).sub.2, --C(O)OR.sup.2, C.sub.1 
-C.sub.4 alkyl, --S(O).sub.m R.sup.2, N(R.sup.2).sub.2, CF.sub.3 or 
1H-tetrazol-5-yl; 
Q is selected from the group consisting of: 
##STR21## 
where x and y are independently 0, 1, 2, 3, 4, 5, 6; 
V is a C.sub.3-10 heterocyclic ring which may be a saturated, partially 
saturated or aromatic cyclic or bicyclic ring, including all regio- and 
diastereo- isomers, containing 1-4 of N or 1-2 of O or S and including the 
group consisting of furan, thiophene, imidazole, oxazole, thiazole, 
pyridine, pyrimidine, purine, indole, quinoline, isoquinoline, thiolane, 
tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, 
imidazoline, morpholine, piperazine, pyrazine, tetrahydrothiopyran, 
1,3-dioxolane, 1,3-dioxane, said the heterocyclic ring can be optionally 
substituted with 1 to 3 halogen, --OR.sup.2, --CON(R.sup.2).sub.2, 
--C(O)OR.sup.2, C.sub.1 -C.sub.4 alkyl, --S(O).sub.m R.sup.2, 
(CH.sub.2).sub.t N(R.sup.2).sub.2, CF.sub.3 or 1H-tetrazole-5-yl; and in 
the case where diastereo- or regio- isomers are present, all are included; 
R.sup.7 and R.sup.7a are independently txifluoromethyl or R.sup.2 ; 
R8 is selected from the group consisting of hydrogen, 
##STR22## 
R.sup.4 and R.sup.5 are independently selected from the group consisting of 
R.sup.2, --C(.dbd.NR.sup.2)N(R.sup.2).sub.2, 
--C(.dbd.NCN)N(R.sup.2).sub.2, --C(.dbd.NC(O)R.sup.2)N(R.sup.2).sub.2, 
C(.dbd.NSO.sub.2 R.sup.2)N(R.sup.2).sub.2, --C(.dbd.NNO.sub.2)NR.sup.2, 
heteroaryl, --C(.dbd.O)N(R.sup.2).sub.2, --C(.dbd.S)N(R.sup.2).sub.2, 
C(.dbd.O)R.sup.2, 2,2,2-tufluoroethyl, 3,3,3-trifluoropropyl, 
(CH.sub.2).sub.t cyclopropyl, or R.sup.4 and R.sup.5 may be taken together 
to form --(CH.sub.2).sub.d -L.sub.a (CH.sub.2).sub.e -- where L.sub.a is 
--C(R.sup.2).sub.2 --, --O--, --S(O).sub.m -- or --N(R.sup.2)--, d and e 
are independently 1 to 3, said heteroaryl and R.sup.2 optionally 
substituted with 1-3 groups of C.sub.1-6 alkyl, 1-7 halo, 
N(R.sup.2).sub.2, OR.sup.2, N(R.sup.2)C(O)R.sup.2, C(O)N(R.sup.2), 
OC(O)R.sup.2, S(O).sub.m R.sup.2, CF.sub.3, OCF.sub.3, NO.sub.2, 
N(R.sup.2)C(O)(R.sup.2), N(R.sup.2)C(O)N(.sup.2).sub.2, C(O)OR.sup.2, 
C(O)N(R.sup.2).sub.2, SO.sub.2 N(R.sup.2).sub.2, N(R.sup.2)SO.sub.2 
R.sup.2, or methylenedioxy; and the heteroaryl is pyridyl, imidazolyl, 
pyrimidinyl, hiazolyl or pyrazinyl; 
E is selected from the group consisting of --SO.sub.2 --, 
--CO(C(R.sup.2).sub.2).sub.n --, --C(.dbd.N--CN)--, 
--C(.dbd.N--NO.sub.2)-- and --C(.dbd.N--SO.sub.2 N(R.sup.2).sub.2)--; 
R.sup.9 and R.sup.10 are independently H, C.sub.1-8 alkyl or may be taken 
together to form a C5-8 cyclic ring, which can optionally be substituted 
by 1-5 halogen, OR.sup.2 or S(O).sub.m R.sup.2 ; B is selected from the 
group consisting of a noncyclic, heterocyclic or heterobicyclic ring 
selected from the group consisting of 
##STR23## 
where attachment points are indicated by lines 
##STR24## 
external to the rings and to the open ring which are optionally 
substituted by C.sub.1 -C.sub.6 alkyl and where R.sup.2 and 
(CH.sub.2).sub.q are described above; 
G is N, CH or C.dbd.; 
Y is --C(O)--, --SO.sub.2 --, --C(OR.sup.11).dbd., --C(SR.sup.11).dbd., 
--C(NR.sup.11).dbd., .dbd.N--, --N(R.sup.11)--, .dbd.NC(O)--, or 
C(R.sup.11).sub.2 --; 
X is --N(R.sup.11)--, .dbd.N--, .dbd.N--C(R.sup.11).sub.2 --, 
--N(R.sup.11)C(R.sup.11).sub.2 --, --O--, --O--C(R.sup.11).sub.2 --, 
--S--, --S--C(R.sup.11).sub.2 -- or C(R.sup.11).sub.2 ; 
R.sup.11 is H, C.sub.1 -C.sub.8 alkyl, CF.sub.3, CH.sub.2 CF.sub.3, 
--(CH.sub.2).sub.p OR.sup.2, --(CH.sub.2).sub.p N(R.sup.2).sub.2, 
(CH.sub.2).sub.p N(R.sup.2)C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.p 
N(R.sup.2)C(O)R.sup.2, (CH.sub.2).sub.2 heteroaryl, (CH.sub.2).sub.p 
N(R.sup.2)SO.sub.2 C.sub.1 -C.sub.4 alkyl, --(CH.sub.2).sub.p 
C(O)N(R.sup.2).sub.2, or --(CH.sub.2).sub.p C(O)OR.sup.2 where heteroaryl 
is tetrazole, oxadiazole, imidazole or triazole which are optionally 
substituted with R.sup.2, OR.sup.2, CF.sub.3 or N(R.sub.2).sub.2 and where 
p is 0-3; 
A is a fused aryl or heteroaryl group 1-4 atoms of which are heteroatoms of 
N, O and/or S; cycloalkyl; or heterocycloalkyl group, 1-3 atoms of which 
are heteroatoms N, O and/or S, said aryl, heteroaryl, cycloail or 
heterocycloalkyl group containing from 5 to 10 atoms and being optionally 
substituted with 1-3 groups of C.sub.1 -C.sub.6 alkl, halogen, --OR.sup.2, 
N(R.sup.2).sub.2, methylenedioxy, --S(O).sub.m R.sup.2, --CF.sub.3, 
--OCF.sub.3, nitro, --N(R.sup.2)C(O)(R.sup.2), --C(O)OR.sup.2, 
--C(O)N(R.sup.2).sub.2, --1H-tetrazol-5-yl, --SO.sub.2 N(R.sup.2).sub.2, 
--N(R.sup.2)SO.sub.2 phenyl, N(R.sub.2)C(O)N(R.sub.2) or 
--N(R.sup.2)SO.sub.2 R.sup.2, and in the case where regioisomers are 
present, all are included; 
k is an integer from 0 to 1, such that when k is 0, Q is attached directly 
to Z.sup.2 ; 
m is an integer from 0 to 2; 
n is an integer from 0 to 3; 
q is an integer from 0 to 3; and 
t is an integer from 0 to 3. 
Preferred compounds of the instant invention include those of Formula Ib: 
##STR25## 
as well as pharmaceutically acceptable salts and hydrates thereof, 
wherein: 
R.sup.1 is selected from the group consisting of: C.sub.1 -C.sub.10 alkyl, 
aryl, aryl (C.sub.1 -C.sub.6 alkyl), (C.sub.3 -C.sub.7 cycloalkyl)(C.sub.1 
-C.sub.6 alkyl)--, (C.sub.1 -C.sub.5 alkyl)--K--(C.sub.1 -C.sub.6 
alkyl)--, aryl(C.sub.0 -C.sub.5 alkyl)--K--(C.sub.1 -C.sub.5 alkyl)--, and 
(C.sub.3 -C.sub.7 cycloalkyl)(C.sub.0 -C.sub.5 alkyl)--K--(C.sub.1 
-C.sub.5 alkyl)--, where K is --O--, --S(O).sub.m --, --N(R.sup.2)C(O)--, 
--C(O)N(R.sup.2)--, --CR.sup.2 .dbd.CR.sup.2 --, or --C.tbd.C--, where 
R.sup.2 and alkyl may be fuirther substituted by 1 to 5 halogen, 
S(O).sub.m R.sup.2a, 1 to 3 of OR.sup.2a or C(O)OR.sup.2a, and aryl is 
selected from: phenyl, naphthyl, biphenyl, quinolinyl, isoquinolinyl, 
indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and 
benzimidazolyl, and where the aryl is unsubstituted or substituted with a 
substitutent selected from: 1 to 3 of C.sub.1 -C.sub.6 alkyl, 1 to 3 of 
halogen, 1 to 2 of --OR.sup.2, methylenedioxy, --S(O).sub.m R.sup.2, 1 to 
2 of --CF.sub.3, --OCF.sub.3, nitro, --N(R.sup.2)C(O)(R.sup.2), 
--C(O)OR.sup.2, --C(O)N(R.sup.2)(R.sup.2), --1H-tetrazol-5-yl, --SO.sub.2 
N(R.sup.2)(R.sup.2), --N(R.sup.2)SO.sub.2 phenyl, or --N(R.sup.2)SO.sub.2 
R.sup.2 ; 
R.sup.2 is selected from: hydrogen, C.sub.1 -C.sub.8 alkyl, 
(CH.sub.2).sub.t aryl, and C.sub.3 -C.sub.7 cycloalkyl, and where two 
C.sub.1 -C.sub.6 alkyl groups are present on one atom, they optionally are 
joined to form a C.sub.3 -C.sub.8 cyclic ring, optionally including 
oxygen, sulfir or NR.sub.3a, where R.sub.3a is hydrogen, or C.sub.1 
-C.sub.6 alkyl, optionally substituted by hydroxyl; 
R.sup.2a is selected from the group consisting of hydrogen and C.sub.1 
-C.sub.3 alkyl, said alkyl optionally substituted by hydroxyl; 
R.sup.2b is selected from hydrogen, C.sub.1 -C.sub.8 alkyl, 
(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.n CO.sub.2 R.sup.2, 
--(CH.sub.2).sub.n CON(R.sup.2).sub.2, --(CH.sub.2).sub.n OH or 
--(CH.sub.2).sub.n OR.sup.2 ; 
R.sup.1c is selected from the group consisting of hydrogen, and C.sub.1 
-C.sub.8 alkyl; 
Z.sup.2 is selected from the group consisting of --O--, --CH.sub.2 
--,--CHR.sup.2b -- and --NR.sup.2b, when Z.sup.2 is NR.sup.2b it can 
optionally be linked to R.sup.1c, Q and/or W to form a C.sub.5-8 cyclic 
ring, which can optionally be interrupted by oxygen, S(O).sub.m or 
NR.sup.2a ; 
W is selected from the group consisting of: hydrogen, C.sub.1 -C.sub.8 
alkyl, (CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q C(O)OR.sup.2, 
--(CH.sub.2).sub.q OR.sup.2, --(CH.sub.2).sub.q OC(O)R.sup.2, 
--(CH.sub.2).sub.q C(O)R.sup.2, --(CH.sub.2).sub.q C(O)(CH.sub.2).sub.t 
aryl, --(CH.sub.2).sub.q C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
N(R.sup.2)C(O)R.sup.2, --(CH.sub.2).sub.q N(R.sup.2)SO.sub.2 R.sup.2, 
--(CH.sub.2).sub.q N(R.sup.2)C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
OC(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q N(R.sup.2)C(O)OR.sup.2, 
--(CH.sub.2).sub.q N(R.sup.2)SO.sub.2 N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
S(O).sub.m R.sup.2, and (CH.sub.2).sub.t heteroaryl where the heteroaryl 
is preferably tetrazole, oxadiazole, thiadiazole, triazole or pyrazine, 
which is optionally substituted with R.sup.2, N(R.sup.2).sub.2 and 
OR.sup.2, where R.sup.2, (CH.sub.2).sub.q and (CH.sub.2).sub.t are 
optionally substituted with 1 to 2 C.sub.1 -C.sub.4 alky, OR.sup.2, 
C(O)OR.sup.2, 1-3 halo and said aryl is optionally substituted with 1 to 3 
halogen, --OR.sup.2, --CON(R.sup.2).sub.2, --C(O)OR.sup.2, C.sub.1 
-C.sub.4 alkyl, --S(O).sub.m R.sup.2, N(R.sup.2).sub.2, CF.sub.3 or 
1H-tetrazol-5-yl; 
Q is 
##STR26## 
where x and y are independently 0, 1, 2, 3, 4; 
V is a C.sub.3-10 heterocyclic ring which may be a saturated, partially 
saturated or aromatic cyclic or bicyclic ring, including all regio- and 
diastereo- isomers, containing 1-4 of N or 1-2 of O or S and including the 
group consisting of furan, thiophene, imidazole, oxazole, thiazole, 
pyridine, pyrimidine, purine, indole, quinoline, isoquinoline, thiolane, 
tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, 
imidazoline, morpholine, piperazine, pyrazine, tetrahydrothiopyran, 
1,3-dioxolane, 1,3-dioxane, said the heterocyclic ring can be optionally 
substituted with 1 to 3 halogen, --OR.sup.2, --CON(R.sup.2).sub.2, 
--C(O)OR.sup.2, C.sub.1 -C.sub.4 alkyl, --S(O).sub.m R.sup.2, 
(CH.sub.2).sub.t N(R.sup.2).sub.2, CF.sub.3 or 1H-tetrazol-5-yl; and in 
the case where diastereo- or regio- isomers are present, all are included; 
R.sup.7 and R.sup.7a are independently trifluoromethyl or R.sup.2 ; 
R.sup.8 is selected from the group consisting of hydrogen, 
##STR27## 
R.sup.4 and R.sup.5 are independently selected from the group consisting of 
R.sup.2, --C(.dbd.NR.sup.2)N(R.sup.2).sub.2, 
--C(.dbd.NCN)N(R.sup.2).sub.2, --C(.dbd.NC(O)R.sup.2)N(R.sup.2).sub.2, 
C(.dbd.NSO.sub.2 R.sup.2)N(R.sup.2).sub.2, --C(.dbd.S)N(R.sup.2).sub.2, 
--C(NNO.sub.2)NR.sup.2, heteroaryl, --C(.dbd.O)N(R.sup.2).sub.2, 
--C(.dbd.O)R.sup.2, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 
(CH.sub.2).sub.t cyclopropyl, or R.sup.4 and R.sup.5 may be taken together 
to form --(CH.sub.2).sub.d -L.sub.a (CH.sub.2).sub.e -- where L.sub.a is 
--C(R.sup.2).sub.2 --, --O--, --S(O).sub.m -- or --N(R.sup.2)--, d and e 
are independently 1 to 3, said heteroaryl and R.sup.2 optionally 
substituted with 1-3 groups of C.sub.1-6 alkyl, 1-7 halo, 
N(R.sup.2).sub.2, OR.sup.2, N(R.sup.2)C(O)R.sup.2, C(O)N(R.sup.2), 
OC(O)R.sup.2, S(O).sub.m R.sup.2, CF.sub.3, OCF.sub.3, NO.sub.2, 
N(R.sup.2)C(O)(R.sup.2), N(R.sup.2)C(O)N(.sup.2).sub.2, C(O)OR.sup.2, 
C(O)N(R.sup.2).sub.2, SO.sub.2 N(R.sup.2).sub.2, N(R.sup.2)SO.sub.2 
R.sup.2, or methylenedioxy; and the heteroaryl is pyridyl, imidazolyl, 
pyrimidinyl, thiazolyl or pyrazinyl; 
E is selected from the group consisting of --SO.sub.2 --, 
--CO(C(R.sup.2).sub.2).sub.n --, --C(.dbd.N--CN)--, 
--C(.dbd.N--NO.sub.2)-- and --C(.dbd.N-SO.sub.2 N(R.sup.2).sub.2)--; 
R.sup.9 and R.sup.10 are independently H, C.sub.1-8 alkyl or may be taken 
together to form a C.sub.5-8 cyclic ring, which can optionally be 
substituted by 1-5 halogen, OR.sup.2 or S(O).sub.m R.sup.2 ; 
B is selected from the group consisting of a noncyclic or heterocyclic 
selected from the group consisting of 
##STR28## 
where attachment points are indicated by lines 
##STR29## 
external to the rings and to the open ring which are optionally 
substituted by C.sub.1 -C.sub.6 alkyl and where R.sup.2 and 
(CH.sub.2).sub.q are described above; 
G is N, CH or C.dbd.; 
Y is --C(O)--, --SO.sub.2 --, --C(OR.sup.11).dbd., --C(SR.sup.11).dbd., 
--C(NR.sup.11).dbd., .dbd.N--, --N(R.sup.11)--, .dbd.NC(O)--, or 
--C(R.sup.11).sub.2 --; 
X is --N(R.sup.11)--, .dbd.N--, .dbd.N--C(R.sup.11).sub.2 --, 
--N(R.sup.11)C(R.sup.11).sub.2 --, --O--, --O--C(R.sup.11).sub.2 --, 
--S--, --S--C(R.sup.11).sub.2 -- or C(R.sup.11).sub.2 ; 
R.sup.11 is H, C.sub.1 -C.sub.8 alkyl, CF.sub.3, CH.sub.2 CF.sub.3, 
--(CH.sub.2).sub.p OR.sup.2, --(CH.sub.2).sub.p N(R.sup.2).sub.2, 
(CH.sub.2).sub.p N(R.sup.2)C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.p 
N(R.sup.2)C(O)R.sup.2, (CH.sub.2).sub.2 heteroaryl, (CH.sub.2).sub.p 
N(R.sup.2)SO.sub.2 C.sub.1 -C.sub.4 alkyl, --(CH.sub.2).sub.p 
C(O)N(R.sup.2).sub.2, or --(CH.sub.2).sub.p C(O)OR.sup.2 where heteroaryl 
is tetrazole, oxadiazole, imidazole or triazole which are optionally 
substituted with R.sup.2, OR.sup.2, CF.sub.3 or N(R.sup.2).sub.2 and where 
p is 0-3; 
A is a fused aryl or heteroaryl group 1-4 atoms of which are heteroatoms of 
N, O and/or S; cycloalkyl; or heterocycloalkyl group, 1-3 atoms of which 
are heteroatoms N, O and/or S, said aryl, heteroaryl, cycloalkyl or 
heterocycloalkl group containing from 5 to 10 atoms and being optionally 
substituted with 1-3 groups of C.sub.1 -C.sub.6 alky, halogen, --OR.sup.2, 
N(R.sup.2).sub.2, methylenedioxy, --S(O).sub.m R.sup.2, --CF.sub.3, 
--OCF.sub.3, nitro, --N(R.sup.2)C(O)(R.sup.2), --C(O)OR.sup.2, 
--C(O)N(R.sup.2).sub.2, --1H-tetrazol-5-yl, --SO.sub.2 N(R.sup.2).sub.2, 
--N(R.sup.2)SO.sub.2 phenyl, N(R.sub.2)C(O)N(R.sup.2) or 
--N(R.sup.2)SO.sub.2 R.sup.2, and in the case where regioisomers are 
present, all are included; 
k is an integer from 0 to 1, such that when k is 0, Q is attached directly 
to Z.sup.2 ; 
m is an integer from 0 to 2; 
n is an integer from 0 to 3; 
q is an integer from 0 to 3, and 
t is an integer from 0 to 3. 
Even more preferred compounds of the instant invention include those of 
Formula Ic: 
##STR30## 
as well as pharmaceutically acceptable salts and hydrates thereof, 
wherein: 
R.sup.1 is selected from the group consisting of: C.sub.1 -C.sub.10 alkyl, 
aryl, aryl (C.sub.1 -C.sub.6 alkyl), (C.sub.3 -C.sub.7 cycloalkyl)(C.sub.1 
-C.sub.6 alkyl)--, (C.sub.1 -C.sub.5 alkyl)--O--(C.sub.1 -C.sub.5 
alkyl)--, and aryl(C.sub.0 -C.sub.5 alkyl)--O--(C.sub.1 -C.sub.5 alkyl)--, 
where R.sup.2 and alkyl may be further substituted by 1 to 5 halogen, 
S(O).sub.m R.sup.2a, 1 to 3 of OR.sup.2a or C(O)OR.sup.2a, and aryl is 
selected from: phenyl, naphthyl, biphenyl, quinolinyl, isoquinolinyl, 
indolyl, azaindole, pyridyl, benzothienyl, benzofliranyl, thiazolyl, and 
benzimidazolyl, and where the aryl is unsubstituted or substituted with a 
substitutent selected from: 1 to 3 of C.sub.1 -C.sub.6 alkyl, 1 to 3 of 
halogen, 1 to 2 of --OR.sup.2, methylenedioxy, --S(O).sub.m R.sup.2, 1 to 
2 of --CF.sub.3, --OCF.sub.3, nitro, --N(R.sup.2)C(O)(R.sup.2), 
--C(O)OR.sup.2, --C(O)N(R.sup.2)(R.sup.2), --1H-tetrazol-5-yl, --SO.sub.2 
N(R.sup.2)(R.sup.2), --N(R.sup.2)SO.sub.2 phenyl, or --N(R.sup.2)SO.sub.2 
R.sup.2 ; 
R.sup.2 is selected from: hydrogen, C.sub.1 -C.sub.8 alkyl, 
(CH.sub.2).sub.t aryl, and C.sub.3 -C.sub.7 cycloalkyl, and where two 
C.sub.1 -C.sub.6 alkyl groups are present on one atom, they optionally are 
joined to form a C.sub.3 -C.sub.8 cyclic ring, optionally including 
oxygen, sulfuir or NR.sup.3a, where R.sup.3a is hydrogen, or C.sub.1 
-C.sub.6 alkyl, optionally substituted by hydroxyl; 
R.sup.2a is selected from the group consisting of hydrogen and C.sub.1 
-C.sub.3 alkyl, said alkyl optionally substituted by hydroxyl; 
Z.sup.2 is selected from the group consisting of --O--, 
--CH2--,--CHR.sup.2b -- and --NR.sup.2b, when Z.sup.2 is NR.sup.2b it can 
optionally be linked to R.sup.1c, Q and/or W to form a C5-8 cyclic ring; 
R.sup.2b is selected from hydrogen, C1-C8 alkyl, (CH.sub.2).sub.t aryl, 
--(CH.sub.2).sub.n CO.sub.2 R.sup.2, --(CH.sub.2).sub.n 
CON(R.sup.2).sub.2, --(CH.sub.2).sub.n OH or --(CH.sub.2).sub.n OR.sup.2 ; 
R.sup.1c is selected from the group consisting of hydrogen and C.sub.1 
-C.sub.8 alkyl; 
W is selected from the group consisting of: hydrogen, C.sub.1 -C.sub.8 
alkyl, (CH2).sub.t aryl, --(CH.sub.2).sub.q C(O)OR.sup.2, 
--(CH.sub.2).sub.q OR.sup.2, --(CH.sub.2).sub.q OC(O)R.sup.2, 
--(CH.sub.2).sub.q C(O)R.sup.2, --(CH.sub.2).sub.q C(O)(CH.sub.2).sub.t 
aryl, --(CH.sub.2).sub.q C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
N(R.sup.2)C(O)R.sup.2, --(CH.sub.2).sub.q N(R.sup.2)SO.sub.2 R.sup.2, 
--(CH.sub.2).sub.q N(R.sup.2)C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
OC(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.q N(R.sup.2)C(O)OR.sup.2, 
--(CH.sub.2).sub.q N(R.sup.2)SO.sub.2 N(R.sup.2).sub.2, --(CH.sub.2).sub.q 
S(O).sub.m R.sup.2, and (CH.sub.2).sub.t heteroaryl where the heteroauyl 
is preferably tetrazole, oxadiazole, thiadiazole, triazole or pyrazine, 
which is optionally substituted with R.sup.2, N(R.sup.2).sub.2 and 
OR.sup.2, where R.sup.2, (CH.sub.2).sub.q and (CH.sub.2).sub.t are 
ptionally substituted with 1 to 2 C.sub.1 -C.sub.4 alkyl, OR.sup.2, 
C(O)OR.sup.2, 1-3 halo and said aryl is optionally substituted with 1 to 3 
halogen, --OR.sup.2, 13 CON(R.sup.2).sub.2, --C(O)OR.sup.2, C.sub.1 
-C.sub.4 alkyl, --S(O).sub.m R.sup.2, N(R.sup.2).sub.2, CF.sub.3 or 
1H-tetrazol-5-yl; 
Q is 
##STR31## 
where x and y are independently 0, 1, 2, 3; V is 
##STR32## 
said the heterocyclic ring can be optionally substituted with 1 to 3 
halogen, --OR.sup.2, --CON(R.sup.2).sub.2, --C(O)OR.sup.2, C.sub.1 
-C.sub.4 alkyl, --S(O).sub.m R.sup.2, N(R.sup.2).sub.2, CF.sub.3 or 
1H-tetrazol-5-yl, and in the case where diastereo- or regio- isomers are 
present, all are included; 
R.sup.7 and R.sup.7a are independently trifluoromethyl or R.sup.2 ; 
R.sup.8 is selected from the group consistng of: 
EQU --NR.sup.4 R.sup.5, --C(.dbd.NR.sup.9)N(R.sup.10).sub.2 and --N.sup.+ 
(R.sup.4).sub.3 ; 
R.sup.4 and R.sup.5 are independently selected from the group consisting 
of: R.sup.2, --C(.dbd.NR.sup.2)N(R.sup.2).sub.2, 
--C(.dbd.NCN)N(R.sup.2).sub.2, --C(.dbd.NC(O)R.sup.2)N(R.sup.2).sub.2, 
C(.dbd.NSO.sub.2 R.sup.2)N(R.sup.2).sub.2, --C(.dbd.NNO.sub.2)NR.sup.2, 
heteroaryl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl or 
R.sup.4 and R.sup.5 are taken together and represent 
EQU --(CH.sub.2).sub.d --L.sub.a (CH.sub.2).sub.e -- 
wherein L.sub.a is --C(R.sub.2).sub.2 --, --O--, --S(O).sub.m -- or 
--N(R.sup.2)--, and d and e are independently 1 to 3, and the heteroaryl 
is pyridyl or imidazolyl; 
E is selected from the group consisting of --SO.sub.2 --, --CO--, 
--C(.dbd.N--CN)--, --C(.dbd.N--NO.sub.2)-- and --C(.dbd.N--SO.sub.2 
NH.sub.2)--; 
R.sup.9 and R.sup.10 are independently H or C.sub.1-8 alkyl; 
G is N, CH or C.dbd.; 
Y is --C(O)--, --SO.sub.2 --, --C(OR.sup.11).dbd., --C(SR.sup.11).dbd., 
--C(NR.sup.11).dbd., .dbd.N--, --N(R.sup.11)--, .dbd.NC(O)--, or 
--C(R.sup.11).sub.2 --; 
X is --N(R.sup.11)--, .dbd.N--, .dbd.N--C(R.sup.11).sub.2 --, 
--N(R.sup.11)C(R.sup.11).sub.2 --, --O--, --O--C(R.sup.11).sub.2 --, 
--S--, --S--C(R.sup.11).sub.2 -- or C(R.sup.11).sub.2 ; 
R.sup.11 is H, C.sub.1 -C.sub.8 alkyl, CF.sub.3, CH.sub.2 CF.sub.3, 
--(CH.sub.2).sub.p OR.sup.2, --(CH.sub.2).sub.p N(R.sup.2).sub.2, 
(CH2).sub.p N(R.sup.2)C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.p 
N(R.sup.2)C(O)R.sup.2, (CH.sub.2).sub.2 heteroaryl, (CH.sub.2).sub.p 
N(R.sup.2)SO.sub.2 C.sub.1 -C.sub.4 alkyl, --(CH.sub.2).sub.p 
C(O)N(R.sup.2).sub.2, or --(CH.sub.2).sub.p C(O)OR.sup.2 where heteroaryl 
is tetrazole, oxadiazole, imidazole or triazole which are optionally 
substituted with R.sup.2, OR.sup.2, CF.sub.3 or N(R.sup.2).sub.2 and where 
p is 0-3; 
A is a fused aryl or heteroaryl group 1-4 atoms of which are heteroatoms of 
N, O and/or S; cycloalkyl; or heterocycloalkyl group, 1-3 atoms of which 
are heteroatoms N, O and/or S, said aryl, heteroaryl, cycloalkyl or 
heterocycloalkyl group containing from 5 to 10 atoms and being optionally 
substituted with 1-3 groups of C.sub.1 -C.sub.6 alkyl, halogen, 
--OR.sup.2, N(R.sup.2).sub.2, methylenedioxy, --S(O).sub.m R.sup.2, 
--CF.sub.3, --OCF.sub.3, nitro, --N(R.sup.2)C(O)(R.sup.2), --C(O)OR.sup.2, 
--C(O)N(R.sup.2).sub.2, --1H-tetrazol-5-yl, --SO.sub.2 N(R.sup.2).sub.2, 
--N(R.sup.2)SO.sub.2 phenyl, N(R.sup.2)C(O)N(R.sup.2) or 
--N(R.sup.2)SO.sub.2 R.sup.2, and in the case where regioisomers are 
present, all are included; 
k is an integer from 0 to 1, such that when k is 0, Q is attached directly 
to Z.sup.2 ; 
m is an integer from 0 to 2; 
n is an integer from 0 to 3; 
q is an integer from 0 to 3; and 
t is an integer from 0 to 3. 
More preferred compounds of the instant invention include those of Formula 
Id: 
##STR33## 
as well as pharmaceutically acceptable salts and hydrates thereof, wherein 
R.sup.1 is selected from the group consisting of: 
##STR34## 
where the aryl is unsubstituted or substituted with a substitutent 
selected from: 1 to 3 of C.sub.1 -C.sub.6 alkyl, 1 to 3 of halogen, 1 to 2 
of --OR.sup.2, methylenedioxy, --S(O).sub.m R.sup.2, 1 to 2 of --CF.sub.3, 
--OCF.sub.3, nitro, --N(R.sup.2)C(O)(R.sup.2), --C(O)OR.sup.2, 
--C(O)N(R.sup.2)(R.sup.2), --1H-tetrazol-5-yl, --SO.sub.2 
N(R.sup.2)(R.sup.2), --N(R.sup.2)SO.sub.2 phenyl, or --N(R.sup.2)SO.sub.2 
R.sup.2 ; 
R.sup.2 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl and t-butyl; 
##STR35## 
is: 
##STR36## 
and the heterocyclic rings can be optionally substituted with 1 to 2 R2, 1 
to 3 halogen, --OR.sup.2, --CON(R.sup.2).sub.2, --C(O)OR.sup.2, C.sub.1 
-C.sub.4 alkyl, --S(O).sub.m R.sup.2, N(R.sup.2).sub.2, CF.sub.3 ; and in 
the case where diastereo- or regio- isomers are present, all are included; 
and x is an integer from 0 to 3; 
W is selected from the group consisting of: hydrogen, C.sub.1 -C.sub.4 
alkyl, (CH.sub.2).sub.q C(O)OR.sup.2 ; 
R.sup.7 and R.sup.7a are independently trifluoromethyl or R.sup.2 ; 
R.sup.2b is selected from hydrogen and C.sub.1 -C.sub.4 alkyl; 
E is selected from the group consisting of --CO--, --C(.dbd.N--CN)--, and 
--SO.sub.2 --; 
##STR37## 
is: 
##STR38## 
where the aromatic moiety can be optionally substituted with 1-3 groups of 
C.sub.1 -C.sub.6 alkyl, halogen, --OR.sup.2, N(R.sup.2).sub.2, 
methylenedioxy, --S(O).sub.m R.sup.2, --CF.sub.3, --OCF.sub.3, nitro, 
--N(R.sup.2)C(O)(R.sup.2), --C(O)OR.sup.2, --C(O)N(R.sup.2).sub.2, 
--1H-tetrazol-5-yl, --SO.sub.2 N(R.sup.2).sub.2, --N(R.sup.2)SO.sub.2 
phenyl, N(R.sup.2)C(O)N(R.sup.2) or --N(R.sup.2)SO.sub.2 R.sup.2 ; 
R.sup.11 is H, C.sub.1 -C.sub.8 alkyl, CF.sub.3, CH.sub.2 CF.sub.3, 
--(CH.sub.2).sub.p OR.sup.2, --(CH.sub.2).sub.p N(R.sup.2).sub.2, 
(CH2).sub.p N(R.sup.2)C(O)N(R.sup.2).sub.2, --(CH.sub.2).sub.p 
N(R.sup.2)C(O)R.sup.2, (CH.sub.2).sub.p heteroaryl, (CH.sub.2).sub.p 
N(R.sup.2)SO.sub.2 C.sub.1 -C.sub.4 alkyl, --(CH.sub.2).sub.p 
C(O)N(R.sup.2).sub.2, or --(CH.sub.2).sub.p C(O)OR.sup.2 where heteroaryl 
is tetrazole, oxadiazole, imidazole or triazole which are optionally 
substituted with R.sup.2, OR.sup.2, CF3 or N(R.sup.2).sub.2 and where p is 
0-3; 
k is an integer 0 or 1, such that when k is 0, Q is directly attached to 
NR.sup.2b ; 
m is an integer from 0 to 2; 
n is an integer from 0 to 3, and 
q is an integer from 0 to 3. 
Also included in the invention is a pharmaceutical composition which is 
comprised of a compound of formula I in combination with a 
pharmaceutically acceptable carrier. 
The invention also includes a method of treating diabetes, cancer, 
acromegaly chronic atrophic gastritis, Crohn's disease, ulcerative 
colitis, retinopathy, arthritis, viseral and neuropathic pain and to 
prevent restenosis, which comprises administering to a person or animal a 
compound of formula I in an amount which is effective for treating said 
disease or condition. 
The invention is described herein in detail using the terms defined below 
unless otherwise specified. 
The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived 
radical containing from 1 to 15 carbon atoms unless otherwise defined and 
if two carbon atoms or more they may include a double or a triple bond. It 
may be straight, branched or cyclic. Preferred straight or branched alkyl 
groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. 
Preferred cycloalkyl groups include cyclopentyl and cyclohexyl. 
Alkyl also includes a straight or branched alkyl group which contains or is 
interrupted by a cycloalkylene portion. Examples include the following: 
##STR39## 
wherein: x plus y=from 0-10 and w plus z=from 0-9. 
The alkylene and monovalent alkyl portion(s) of the alkyl group can be 
attached at any available point of attachment to the cycloalkylene 
portion. 
When substituted alkyl is present, this refers to a straight, branched or 
cyclic alkyl group as defined above, substituted with 1-3 groups as 
defined with respect to each variable. 
The term "alkenyl" refers to a hydrocarbon radical straight, branched or 
cyclic containing from 2 to 15 carbon atoms and at least one carbon to 
carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, 
butenyl and cyclohexenyl. As described above with respect to alkyl, the 
straight, branched or cyclic portion of the alkenyl group may contain 
double bonds and may be substituted when a substituted alkenyl group is 
provided. 
The term "alkynyl" refers to a hydrocarbon radical straight, branched or 
cyclic, containing from 2 to 15 carbon atoms and at least one carbon to 
carbon triple bond. Up to three carbon-carbon triple bonds may be present. 
Preferred alkynyl groups include ethynyl, propynyl and butynyl. As 
described above with respect to allyl, the straight, branched or cyclic 
portion of the alynyl group may contain triple bonds and may be 
substituted when a substituted alkynyl group is provided. 
The term "alkoxy" refers to those groups of the designated length in either 
a straight or branched configuration and if two or more carbon atoms in 
length, they may include a double or a triple bond. Exemplary of such 
alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 
tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, 
propargyloxy, and the like. 
The term "halogen" is intended to include the halogen atom fluorine, 
chlorine, bromine and iodine. 
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like 
groups as well as rings which are fuised, e.g., naphthyl, indaryl, 
biphenyl and the like. Aryl thus contains at least one ring having at 
least 6 atoms, with up to two such rings being present, containing up to 
10 atoms therein, with alternating (resonating) double bonds between 
adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl. 
Aryl groups may likewise be substituted with from 1 to 3 groups of C.sub.1 
-C.sub.15 alkyl, halogen, --OR.sup.2, methylenedioxy, --S(O).sub.m 
R.sup.2, --CF.sub.3, --OCF.sub.3, nitro, --N(R.sup.2)C(O)(R.sup.2), 
--C(O)OR.sup.2, --C(O)N(R.sup.2).sub.2, --1H-tetrazol-5-yl, --SO.sub.2 
N(R.sup.2).sub.2, --N(R.sup.2)SO.sub.2 phenyl or --N(R.sup.2)SO.sub.2 
R.sup.2. Preferred substituted aryls include phenyl and naphthyl 
substituted with one or two groups. 
The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group 
having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 
atoms, containing at least one heteroatom, O, S or N, in which a carbon or 
nitrogen atom is the point of attachment, and in which one additional 
carbon atom is optionally replaced by a heteroatom selected from O or S, 
and in which from 1 to 3 additional carbon atoms are optionally replaced 
by nitrogen heteroatoms. The heteroaryl group is optionally substituted 
with up to three groups selected from 1 to 3 of C.sub.1 -C.sub.8 alkyl, 
halogen, --OR.sup.2, methylenedioxy, --S(O).sub.m R.sup.2, --CF.sub.3, 
--OCF.sub.3, N(R.sup.2).sub.2, nitro, --N(R.sup.2)C(O)(R.sup.2), 
--C(O)OR.sup.2, --C(O)N(R.sup.2).sub.2, --1H-tetrazol-5-yl, --SO.sub.2 
N(R.sub.2).sub.2, --N(R.sup.2)SO.sub.2 phenyl or --N(R.sup.2)SO.sub.2 
R.sup.2. 
Heteroaryl thus includes aromatic and partially aromatic groups which 
contain one or more heteroatoms. Examples of this type are thiophene, 
oxadiazole, imidazopyridine, pyridine, oxazole, thiazole, pyrazole, 
tetrazole, imidazole, pyrimidine, pyrazine, benzothienyl, benzofuranyl, 
indolyl, azaindole, benzimidazolyl, quinolinyl, isoquinolinyl and 
triazine. 
The terms "heterocycloalkyl" and "heterocyclyl" refer to a cycloalkyl group 
(nonaromatic) in which one of the carbon atoms in the ring is replaced by 
a heteroatom selected from O, S, SO, SO.sub.2 or N, and in which up to 
three additional carbon atoms may be optionally replaced by heteroatoms. 
Heterocyclyl is carbon or nitrogen linked; if carbon linked and contains a 
nitrogen, then the nitrogen may be substituted by R.sup.20. Examples of 
heterocyclyls are piperidinyl, morpholinyl, pyrrolidinyl, 
tetrahydrofuranyl, tetrahydroimidazo[4,5-c]pyridinyl, imidazolinyl, 
piperazinyl, pyrolidin-2-onyl, piperidin-2-onyl and the like 
Certain of the above defined terms may occur more than once in the above 
formula and upon such occurrence each term shall be defined independently 
of the other. 
Salts encompassed within the term "pharmaceutically acceptable salts" refer 
to non-toxic salts of the compounds of this invention which are generally 
prepared by reacting the free base with a suitable organic or inorganic 
acid. Representative salts include the following: 
Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, 
Borate, Camsylate, Carbonate, Citrate, Dihydrochloride, Edetate, 
Edisylate, Estolate, Esylate, Fumarate, Gluconate, Glutamate, 
Hydrobromide, Hydrochloride, Hydroxynaphthoate, Lactate, Lactobionate, 
Laurate, Malate, Maleate, Mandelate, Mesylate, Mucate, Napsylate, Nitrate, 
N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate), 
Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, 
Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, 
Tosylate, and Valerate. 
The compounds of the present invention may contain one or more asymmetric 
carbon atoms and may exist in racemic and optically active forms. All of 
these compounds are contemplated to be within the scope of the present 
invention. Therefore, where a compound is chiral, the separate 
enantiomers, substantially free of the other, are included within the 
scope of the invention; further included are all mixtures of the two 
enantiomers. Also included within the scope of the invention are 
polymorphs and hydrates of the compounds of the instant invention. 
Asymmetric centers may be present in the compounds of the instant invention 
depending upon the nature of the various substituents on the molecule. 
Each such asymmetric center will independently produce two optical isomers 
and it is intended that all of the possible optical isomers and 
diastereomers in mixture and as pure or partially purified compounds are 
included within the ambit of this invention. In the case of the asymmetric 
carbon atom represented by an asterisk in Formula I, it has been found 
that compounds are more active as somatostatin agonists and, therefore 
preferred, in which the nitrogen substituent is above and the R.sup.1a is 
below the plane of the structure as represented in Formula II. An 
equivalent representation places R.sup.1 and the N-substitutent in the 
plane of the structure with the C.dbd.O group above. This configuration 
corresponds to that present in a D-amino acid. In most cases, this is also 
designated an R-configuration, although this will vary according to the 
value of R.sup.1 used in making R- or S-stereochemical assignments. In 
addition, configurations of some of the most preferred compounds of this 
invention are indicated. When the carbon atom in Formula I bearing an 
asterisk is of a defined and usually a D- configuration, up to two times 
more diastereomers result with each additional stereo centers are present. 
These diastereomers are arbitrarily referred to as diastereomer 1 
(d.sub.1) and diastereomer 2 (d.sub.2) and so on as so forth in this 
invention and, if desired, their independent syntheses or chromatographic 
separations may be achieved as described herein. Their absolute 
stereochemistry may be determined by the x-ray crystallography of 
crystalline products or crystalline intermediates which are derivatized, 
if necessary, with a reagent containing an asymmetric center of known 
absolute configuration. 
##STR40## 
The term "pharmacologically effective amount" shall mean hat amount of a 
drug or pharmaceutical agent that will elicit the iological or medical 
response of a tissue, system, animal or human that is being sought by a 
researcher or clinician. 
The term "substituted" shall be deemed to include multiple degrees of 
substitution by a named substitutent. 
Where multiple substituent moieties are disclosed or claimed, the 
substituted compound can be independently substituted by one or more of 
the disclosed or claimed substituent moieties, singlely or plurally. 
The ability of the compounds of the present invention to act as 
somatostatin agonists makes them useful as pharmacologic agents for 
mammals, especially for humans, for the treatment and prevention of 
disorders wherein somatostatin itself or the hormones it regulates may be 
involved. Examples of such disorders include diabetes, acromegaly 
restenosis, arthritis and cancer. The instant compounds can also be used 
in combination with other therapeutic agents. Illustrated for diabetes, 
examples of these compounds include metformin or other biguanides, 
acarbose, sulfonylureas theazolidinediones or other insulin sensitizers 
including, but not limited to, compounds which function as agonists on 
peroxisome proliferator-activated receptor gamma (P-gamma), insulin, 
insulin-like-growth factor I, glucagon-like peptide I-glp-I and available 
satiety-promoting agents such as dexfenfluramine or leptin. 
The compounds of the present invention can be administered in such oral 
dosage forms as tablets, capsules (each including timed release and 
sustained release formulations), pills, powders, granules, elixers, 
tinctures, suspensions, syrups and emulsions. Likewise, they may also be 
administered in intravenous (both bolus and infusion), intraperitoneal, 
subcutaneous or intramuscular form, all using forms well known to those of 
ordinary skill in the pharmaceutical arts. 
The dosage regimen utilizing the compounds of the present invention is 
selected in accordance with a variety of factors including type, species, 
age, weight, sex and medical condition of the patient; the severity of the 
condition to be treated; the route of administration; the renal and 
hepatic function of the patient; and the particular compound or salt 
thereof employed. An ordinarily skilled physician or veterinarian can 
readily determine and prescribe the effective amount of the drug required 
to prevent, counter or arrest the progress of the condition. 
Intravenous dosages or oral dosages of the compounds of the present 
invention, when used for the indicated effects, will range between about 
0.001 to 5 mg/kg and 0.1 to 50 mg/kg, respectively. Advantageously, 
compounds of the present invention may be administered in a single daily 
dose, or the total daily dosage may be administered in divided doses of 
two, three or four times daily. Furthermore, preferred compounds for the 
present invention can be administered in intranasal form via topical use 
of suitable intanasal vehicles, or via transdermal routes, using those 
forms of transdermal skin patches well known to those of ordinary skill in 
that art. To be administered in the form of a transdermal delivery system, 
the dosage administration will, of course, be continuous rather than 
intermittent throughout the dosage regimen. 
In the methods of the present invention, the compounds herein described in 
detail can form the active ingredient, and are typically administered in 
admixture with suitable pharmaceutical diluents, excipients or carriers 
(collectively referred to herein as "carrier" materials) suitably selected 
with respect to the intended form of administration, that is, oral 
tablets, capsules, elisirs, syrups and the like, and consistent with 
conventional pharmaceutical practices. 
For instance, for oral administration in the form of a tablet or capsule, 
the active drug component can be combined with an oral, non-toxic 
pharmaceutically acceptable inert carrier such as ethanol, glycerol, water 
and the like. Moreover, when desired or necessary, suitable binders, 
lubricants, disintegrating agents and coloring agents can also be 
incorporated into the mixture. Suitable binders include starch, gelatin, 
natural sugars such as glucose or beta-lactose, corn sweeteners, natural 
and synthetic gums such as acacia, tragacanth or sodium alginate, 
carboxymethylcellulose, polyethylene glycol, waxes and the like. 
Lubricants used in these dosage forms include sodium oleate, sodium 
stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium 
chloride and the lke. Disintegrators include, without limitation, starch, 
methyl cellulose, agar, bentonite, zanthan gum and the like. 
The compounds of the present invention can also be administered in the form 
of liposome delivery systems, such as small unilamellar vesicles, large 
unilamellar vesicles and multilamellar vesicles. Liposomes can be formed 
from a variety of phospholipids, such as cholesterol, steaiylamine or 
phosphatidylcholines. 
Throughout the instant application, the following abbreviations are used 
with the following meanings: 
______________________________________ 
Bu butyl 
Bn benzyl 
BOC, Boc t-butyloxycarbonyl 
BOP Benzotriazol-1-yloxy tris/dimethylamino)- 
phosphonium hexafluorophosphate 
calc. calculated 
CBZ, Cbz Benzyloxycarbonyl 
CDI N,N'-carbonyl diimidazole 
DCC Dicyclohexylcarbodiimide 
DCM dichloromethane 
DIEA diisopropylethylamine 
DMF N,N-dimethylformamide 
DMAP 4-Dimethylaminopyridine 
DSC N,N'-disuccinimidyl carbonate 
EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide 
hydrochloride 
EI-MS Electron ion-mass spectroscopy 
Et ethyl 
EtOAc ethyl acetate 
EtOH ethanol 
eq. equivalent(s) 
FAB-MS Fast atom bombardment-mass spectroscopy 
HOAc acetic acid 
HOBT, HOBt Hydroxybenztriazole 
HPLC High pressure liquid chromatography 
KHMDS Potassium bis(trimethylsilyl)amide 
LAH Lithium aluminum hydride 
LHMDS Lithium bis(trimethylsilyl)amide 
Me methyl 
MeOH methanol 
MF Molecular formula 
MHz Megahertz 
MPLC Medium pressure liquid chromatography 
NMM N-Methylmorpholine 
NMR Nuclear Magnetic Resonance 
Ph phenyl 
Pr propyl 
prep. prepared 
TFA Trifluoroacetic acid 
THF Tetrahydrofuran 
TLC Thin layer chromatography 
TMS Trimethylsilane 
______________________________________ 
The instant compounds can be effective to inhibit the secretion of various 
hormones and trophic factors in mammals. They may be used to suppress 
certain endocrine secretions, such as GH, insulin, glucagon and prolactin, 
in the treatment of disorders such as acromegaly; endocrine tumors such as 
carcinoids, vipomas, insulinomas and glucagonomas; or diabetes and 
diabetes-related pathologies, including retinopathy, neuropathy and 
nephropathy. The compounds may also be used to suppress exocrine 
secretions in the pancreas, stomach and intestines, for treatment of 
disorders such as pancreatitis, fistulas, bleeding ulcers and diarrhea 
associated with such diseases as AIDS or cholera. Disorders involving 
autocrine or paracrine secretions of trophic factors such as IGF-1 (as 
well as some endocrine factors) which may be treated by administration of 
the instant compounds include cancers of the breast, prostate, and lung 
(both small cell and non-small cell epidermoids), as well as hepatomas, 
neuroblastomas, colon and pancreatic adenocarcinomas (ductal type), 
chondrosarcomas, and melanomas, and also atherosclerosis associated with 
vascular grafts and restenosis following angioplasty. 
The compounds of the instant invention are futher useful to suppress the 
mediators of neurogenic inflammation (e.g. substance P or the tachyiins), 
and may be used in the treatment of rheumatoid arthritis; psoriasis; 
topical inflammation such as is associated with sunburn, eczema, or other 
sources of itching; and allergies, including asthma. The compounds can 
also fumction as neuromodulators in the central nervous system, with 
useful applications in the treatment of Alzheimer's disease and other 
forms of dementia, pain (as a spinal analgesic), and headaches. 
Furthermore, in disorders involving the splanchnic blood flow, including 
cirrhosis and oesophagal varices, the compounds of the invention can 
provide cytoprotection. 
The preparation of compounds of Formula I of the present invention may be 
carried out in sequential or convergent synthetic routes. In the interest 
of clarity, the special case of Formula I, where B is 4-piperidinyl and A 
is a fused benzo ring as being unsubstituted (formula IIA), is depicted. 
Compounds fused with different aromatic or non aromatic rings and/or 
bearing additional substituents on these rings are readily prepared by 
minor modification of the methods herein with procedures known in the art. 
Syntheses detailing the preparation of the compounds of Formula I are 
presented in the following reaction schemes. 
##STR41## 
The phrase "standard peptide coupling reaction conditions" is used 
repeatedly here, and it means coupling a carboxylic acid with an amine 
using an acid activating agent such as EDC, DCC, and BOP in a inert 
solvent such as dicbloromethane in the presence of a catalyst such as 
HOBT. The phrase "mixed urea formation" refers to conversion of two 
different amines to form their mixed urea by using phosgene or equivalents 
such as CDI, DSC, or p-nitrophenyl chloroformate. The reaction involves 
reacting one amine first with the phosgene or equivalents in the presence 
of a base such as NMM, TEA or DIEA in a inert solvent such as 
dichloromethane, THF and DMF or mixtures thereof, followed by addition of 
the second amine and a base such as NMM, TEA or DIEA. The uses of 
protective groups for amines and carboxylic acids to facilitate the 
desired reaction and minimize undesired reactions are well documented. 
Conditions required to remove protecting groups which may be present can 
be found in Greene, T, and Wuts, P. G. M., Protective Groups in Organic 
Synthesis, John Wiley & Sons, Inc., New York, N.Y. 1991. CBZ and BOC were 
used extensively and their removal conditions are known to those skilled 
in the art. For example, removal of CBZ groups can be achieved by a number 
of methods such as catalytic hydrogenation in the presence of a noble 
metal or its oxide such as palladium on activated carbon in a protic 
solvent such as ethanol. In cases where catalytic hydrogenation is 
contraindicated by the presence of other potentially reactive 
finctionality, removal of CBZ groups can also be achieved by treatment 
with a solution of hydrogen bromide in acetic acid, or by treatment with a 
mixture of TFA and dimethyl sulfide. Removal of BOC protecting groups is 
carried out in a solvent such as methylene chloride, methanol or ethyl 
acetate, with a strong acid, such as trifluoroacetic acid, hydrochloric 
acid or hydrogen chloride gas. 
The protected amino acid derivatives required in the synthesis of compounds 
of Formula 1 are, in many cases, commercially available, where the 
protecting group (P.sup.1) is, for example, methyl, allyl or benzyl 
groups. Other protected amino acid can be prepared by literature methods 
(Williams, R. M. Synthesis of Optically Active .alpha.-Amino Acids, 
Pergamon Press: Oxford, 1989). Many of the piperidines of Formula 2 are 
either commercially available or known in the literature and others can be 
prepared following literature methods described for analogous compounds. 
Some of these methods are illustrated in the subsequent schemes. 
Purification procedures include crystallization, normal phase or reverse 
phase chromatography. 
The compounds of the present invention can be prepared readily according to 
the following Schemes or modifications thereof using readily available 
starting materials, reagents and conventional synthesis procedures. In 
these reactions, it is also possible to make use of variants which are 
themselves known to those of ordinary skill in this art, but are not 
mentioned in greater detail. The definition for R.sup.1, R.sup.1a, 
R.sup.2, R.sup.4, R.sup.5, G, Y, X, Z.sup.1, Z.sup.2, W, Q, E, B, etc., is 
described above unless otherwise stated. 
##STR42## 
Intermediates of Formula 4A can be synthesized as described in Scheme 1. 
Mixed urea formation between the protected amino acid 1 and the piperidine 
of Formula 2, is convenienty carried out under usual urea formation 
reactions use phosgene or equivalents such as CDI, DSC, or p-nitrophenyi 
chloroformate. Removal of the P.sup.1 protecting group can be achieved by 
saponifacation for most esters, or by catalytic hydrogenolysis when 
P.sup.1 is benzyl, or by palladium (0) based homogeneous catalysis when 
P.sup.1 is allyl. Intermediate 4A can be used as a common intermediate for 
the synthesis of somatostatin agonists with variation of the rest of the 
molecule of Formula I as shown in Scheme 2. 
##STR43## 
The preparation of amide intermediates of formula 4B can be achieved as 
shown in Scheme 1A. Standard peptide coupling reactions of protected amino 
acid 1 with 2-halo acids such as 2-bromoacetic acid gives intermediate 1A, 
which when reacted with aminne of formula 2 gives the compound as 3A in 
the presence of a non-nucleophilic base such as DIEA. The P1 protecting 
group can be removed as described above. 
##STR44## 
Intermediates of Formula 4 can be coupled to intermediates of formula 5 (or 
formula 6 wherein R.sup.4 is P.sup.2) wherein Z.sup.2 is oxygen or 
substituted nitrogen to afford compounds of Formula I-A under standard 
ester or peptide coupling reaction conditions. P.sup.2 is an amine 
protecting group such as BOC, Cbz, etc. Many of the selectively protected 
diamines or amino alcohol's of Formula 5 are either commercially available 
or known in the literature and others can be prepared following literature 
methods described for analogous compounds. Some of these methods are 
illustrated in subsequent schemes. Also if R.sup.4 or R.sup.5 is a 
hydrogen then the protected amino acids 6 are employed in the coupling 
reaction, wherein P.sup.2 is a protecting group as defined above. The 
removal of P.sup.2 in I-A to afford I-B, can be carried out as noted 
above. R.sup.4 as defined above can then be optionally introduced to yield 
compound of general formula I-C according to procedures known in the art. 
For example, if R4 is a substituted a group, it can be introduced by 
reductive amination or opening of epoxide, or by alkylation by an alkyl 
halide; if R4 is an amidino group, it can be introduced by the reagents 
such as 1-amidino-3,5-dimethylpyrazole nitrate (Methods Enzymol., 25b, 
558,1972). 
##STR45## 
Alternatively, compounds of Formula I can be prepared starting from 
compound 5. The protected amino acid derivatives 8 are in many cases 
commercially available, where P3 is, for exple, BOC, Cbz, Fmoc, and the 
like. N-Protected amino acid 8 can be coupled to intermediates of formula 
5, wherein Z.sup.2 is oxygen or substituted nitrogen to afford compounds 
of Formula 9 under standard ester or peptide coupling reaction conditions. 
The protecting group in compound 8 is selected with the criteria that its 
removal can be achieved without removing P.sup.2. When the P2 protecting 
group is removed to afford compound 10, this compound can be further 
converted to compounds of formula I-A according to the procedures 
described in Scheme 1 and Scheme 1A. Further elaboration of compound I-A 
to I-B and I-C are illustrated in Scheme 2. 
##STR46## 
The preparation of compounds of formula II within the scope of this 
invention may be achieved by methods known in the art. Such methods are 
illustrated in the following schemes for piperidines with A shown as an 
unsubstituted fused benzo ring. Analogous methods may be used for the 
preparation of the other ring compounds or with different substitutions on 
the ring or both as defined herein. In the interest of clarity, the benzo 
rings in the following schemes are depicted as being unsubstituted. 
Compounds bearing additional substituents on the benzo rings are readily 
prepared by minor modification of the methods herein with procedures known 
in the art. 
##STR47## 
The piperidinylbenzimidazoliione 16 without substitution is commercially 
available; derivatives with substituents on the benzene ring are prepared 
by the methods shown in Scheme 4 as described in J. Med. Chem., 30, 
814-819 (1987) and U.S. Pat. No. 3,910,930, hereby incorporated by 
reference. P.sup.4 is a protecting group such as benzyl, methyl, BOC, Cbz, 
ethyloxycarbonyl and the like. Thus, condensation of the commercially 
available 4-aminopiperidine 11, where P.sup.4 is C(O)OEt, with a 
substituted o-halo nitrobenzene 12 gives the nitro compound 13. Reduction 
of the nitro group to an amine can be accomplished by catalytic 
hydrogenation with a catalyst such as Raney Ni, palladium on carbon or 
platinum on carbon in a protic solvent such as ethanol. Ring closure can 
be effected by phosgene or its equivalent such as DSC, CDI in the presence 
of a base. The protecting group P.sup.4 can be removed by alkaline 
hydrolysis in the case of C(O)OEt or can be removed by the standard 
deprotection conditions as described in Greene, T, and Wuts, P. G. M., 
Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, 
N.Y. 1991. 
##STR48## 
Similarly, other groups as defined by Y in compounds of Formula I can be 
prepared according to the reactions shown in Scheme 5. Thus, cyclic 
sulfamide 15 A can be prepared by reacting the diamine 14 and sulfamide; 
reaction of diamine 14 with thiophosgene or equivalents in the presence of 
a base gives the thiourea 15B; and reaction with cyanogen bromide yields 
compound 15C. The protecting group P.sup.4 can be removed as described 
above. 
##STR49## 
Benzimidazolones can be modified to introduce substituent R.sup.11 through 
alkylation, acylation etc. with appropriate protecting group P.sup.4 on 
the piperidine nitrogen. Similarly, compounds 15 A-C and 14D can be 
modified as defined by X and Y in formula I. The protecting group P.sup.4 
is selected in a way that its removal will not cause removal or alteration 
of R.sup.11. 
##STR50## 
In cases where R.sup.11 is attached directly to the ring, such compounds 
can be prepared according to Scheme 7. Coupling compound 14 with a 
carboxylic acid or equivalents followed by ring closure under dehydration 
conditions gives compound 17. Removal of the P.sup.4 protecting group 
yields the compound 18. 
##STR51## 
Alternatively, the ortho substituted anine compound 19, where X is --OH, 
--NH2, --NR.sup.11 H, --SH, --CH.sub.2 OH, --CH.sub.2 NH2, --CH.sub.2 
NR.sup.11 H, --CH.sub.2 SH etc. can be reductively aminated with a 
protected 4-piperidinone 11 to afford compound 20. Ring closure can be 
effected through the chemistry discussed above. 
##STR52## 
An alternative preparation involves an acid catalyzed coupling reaction of 
a protected 4-piperidinone 11 with an electron rich aromatic compound such 
as 19a, where X is O, S, NH or N-alkyl, and Y is CH, COH, COR.sup.11, CH 
or N. The resulting 4-substituted tetrahydropyridines 22 obtained by this 
method can be elaborated to the instant compounds by utilizing chemistry 
detailed in Schemes 1-8. The 4-substituted tetrahydropyridines 22 can be 
hydrogenated by use of platinum or palladium catalysts in a protic solvent 
like methanol to give piperidines of formula 23 which can also be 
elaborated to the instant compounds of Formula I. 
##STR53## 
A specific indole embodiment of compound 23, where X.dbd.NH and 
Y.dbd.CR.sup.11 and R.sup.11 is H or alkyl, can be prepared using a Fisher 
indole synthesis protocol (see J. Chem. Soc. Chem. Commun., 563 (1981); J. 
Chem. Soc., 3175 (1957)) starting from a ketone or aldehyde and an 
aromatic hydrazine. Specifically, piperidines of formula 23A may be 
prepared from the protected piperidine acetic acid compound 24 as shown in 
Scheme 10. Conversion of the known carboxylic acid 24 to the corresponding 
aldehyde or ketones can be effected by a variety of conditions known in 
the art. For example, treatment of 24 with either oxalyl chloride or 
thionyl chloride in an inert solvent like benzene or carbon tetrachloride 
gives the corresponding acid chloride that is converted to the aldehyde 25 
(R.sup.11 .dbd.H) by a Rosemund reduction. The conversion can also be 
effected by the Weinreb protocol in which an N,O-dimethyl hydroxylamine 
amide is reacted with a Grignard reagent to give the ketone or is reacted 
with LAH to give the aldehyde. Most hydrazines are commercially available 
or known in the literature and can be prepared accordingly. The 
condensation of the ketone 25 and hydrazine under the Fisher indole 
synthesis conditions yields the indole compound 23A. The protecting group 
P.sup.4 can be removed by standard protocols and elaborated to the instant 
compounds by using chemistry presented in Schemes 1-8. 
##STR54## 
An analogous synthesis of benzofurans of formula 23B from o-aryloximes is 
exemplified by the transformation of 25 to 26 (see Tetrahedron Lett., 2867 
(1967)) as depicted in Scheme 12. 
##STR55## 
In many cases, compounds of Formula III or its mono protected form within 
the scopes of this invention are either commercially available or known in 
the art. In the simplest case where Z.sup.2 is NH or O, R.sup.1a, W, 
R.sup.4 and R.sup.5 are H's, Q is --(CH.sub.2).sub.x --V--(CH.sub.2).sub.y 
--; where x and y are 1-7, the formula represents diamines some of which 
are commercially available. Mono Boc protected amine can be prepared by 
reacting excess diamine with Boc.sub.2 O in methanol, where Boc protected 
amino alcohols can be preprared by reacting the amino alcohol with Boc2O. 
##STR56## 
The above procedure is also applicable to compounds of formula III where 
R.sup.1a and W are groups as define defined before. 
The following synthetic routes can be used to prepare compounds of Formula 
III. Using method I (as exemplified by Intermediate 1), 
4-aminomethylpyridine is converted to the Boc protected derivative using 
standard procedures. Introduction of nitrile group at 2-position of the 
pyridine can be accomplished by the procedure of Shuman et al (J. Org. 
Chem. 55, 738-741, 1990). The nitrite reduction to amine can be done in 
many ways, illustrated is Raney Ni reduction at high temperature and 
pressure to give 
2-a-minomethfyl-4(t-butyloxycarbonylaminomethyl)-pyridine. The protection 
pattern can be reversed by protecting the free amine with Cbz followed by 
removal of Boc. All compounds with a 2-aminomethylpyridine substructure 
can be prepared this way. 
##STR57## 
Using Method II (as exemplified by Intermediate 2), a series of pyridines 
can be prepared that are not easily accessible by Method I. A 
bromopyridine can be converted to cyano pyridine using CuCN in DMF at 
reflux. Any amino group can be protected as Boc derivative at this point. 
Reduction of the cyano group give the desired aminomethyl pyridine. The 
intermediate cyanide can be modified to afford different substituents. 
##STR58## 
Piperazine incorporated compounds such as 
1-(2-aminoethyl)-4t-butyloxycarbonyl-piperazine can be prepared via a 
nitrile as exemplified by Intermediate 7B. The protection pattern can be 
reversed through Cbz protection of the primary amine. 
##STR59## 
Compounds of Formula IV represent amino acids, which in some cases are 
commercially available. Amino acids can be modified to give compounds as 
defilned by the scope of the instant application. For example, with the 
two amino groups properly protected, the carboxylic acid can be converted 
into its next higher homologue, or to a derivative of the homologous acid, 
such as amide or ester by an Arndt-Eistert reaction. The acid can also be 
converted amides with a variety of amines as defined. The acid can be 
reduced to alhohol, which can be converted to ether by alkylation or 
reduced with methods know to those skilled in the art. 
The preferred compounds of the invention are any or all of those 
specifically set forth in the Examples below. These compounds are not, 
however, to be construed as forming the only genus that is considered as 
the invention, and any combination of the compounds or their moieties may 
itself form a genus. The following examples further illustrate details for 
the preparation of the compounds of the present invention. Those skilled 
in the art will readily understand that known variations of the conditions 
and processes of the following preparative procedures can be used to 
prepare these compounds. All temperatures are degrees Celsius unless noted 
otherwise. 
INTERMEDIATE 1 
##STR60## 
Step A: 4-(t-butyloxycarbonylaminomethyl)-pyridine N-oxide: 
To a stirred solution of 4-aminomethylpyridine (12.48 g, 0.115 mol) in 
dichloromethane (200 mL) at ambient temperature, was slowly added a 
solution of Boc2O (26.6 g, 1.05 equiv.) in dichloromethane (100 mL). The 
resulting mixture was stirred at room temperature for 4 hours, and then 
evaporated to remove solvents to afford 
4-(t-butyloxycarbonylaminomethyl)-pyridine in quantitative yield. The 
residue was dissolved in acetic acid (30 mL) and hydrogen peroxide (30%, 
13 mL) and the resulting solution was stirred at room temperature for one 
week. The reaction mixte was then evaporated and partition between 3N HCl 
and dichloromethane. The inorganic layer was extracted with 
dichloromethane five times and the extracts was combined and washed with 
small volume of sodium bicarbonate solution. The organic solution was 
dried and evaporated and purified by 5-10% methanol in dichloromethane to 
give the N-oxide (4.33 g). 
.sup.1 H NMR (CDCl.sub.3, 300 MHz) 8.23 (d, J=7 Hz, 2H), 7.26 (d, J=7 Hz, 
2H), 4.30 (d, J=5.6 Hz, 2 H); 1.44 (s, 9H). CI-MS calc. for C.sub.11 
H.sub.16 N.sub.2 O.sub.3 : 224; Found 225 (M+H), 
Step B:4-(t-butyloxycarbonylaminomethyl)-2-cyano-pyridine 
To a stirred solution of the intermediate from the previous step (4.33 g, 
19.3 mmol) and trimethylsilyl cyanide (3.35 mL, 1.3 equiv.) in 
dichloromethane (30 mL), was added dimethyl carbamyl chloride (2.3 mL, 1.3 
equiv.) in 10 mL of dichloromethane at ambient temperature. After the 
reaction mixture had been stirred for one day, 20 mL of 10% potassium 
carbonate solution was added very slowly. The organic layer was separated 
and the aqueous layer was washed with dichloromethane twice. The combined 
organic extracts were dried and purified by silica gel chromatography 
eluting with 60% ethyl acetate in hexane to give the desired product (2.37 
g). .sup.1 H NMR (CDCl.sub.3, 300 MHz) 8.65 (d, J=5 Hz, 1H), 7.61 (d, J=1 
Hz, 1H), 7.42 (dd, J=1, 5 Hz, 1H), 5.10 (br.s, 1 H); 4.37 (d. J=6 Hz, 2H), 
1.47 (s, 9H). CI-MS calc. for C.sub.12 H.sub.15 N.sub.3 O.sub.2 : 233; 
Found 234 (M+H), 
Step C: 2-aminomethyl-4(t-butyloxycarbonylaminomethyl)-pyridine: 
A solution of the intermediate from the previous step (1.37 g) and Raney Ni 
(1 g) in 20 mL of ethanol saturated with ammonia under 1000 psi of 
hydrogen, was stirred at 80.degree. C. for 8 hours. The catalyst was 
removed by filtration and the solution was evaporated to give the desired 
compound (1.35 g) as a very thick oil. .sup.1 H NMR (CDCl.sub.3, 300 MHz) 
8.40 (d, 3 Hz, 1H), 7.33 (s, 1H), 7.20 (d, J=3 Hz, 1 H), 4.27 (s, 2H), 
3.88 (s, 2H), 1.45 (s, 9H). 
INTERMEDIATE 1A 
##STR61## 
Prepared similarly from 2-aminomethylpyridine: 
.sup.1 H NMR (CD.sub.3 OD, 400 MHz) 7.74 (dd, J=7.80, 7.70 Hz, 1H), 7.26 
(d, J=7.88 Hz, 1H), 7.22 (d, J=3 Hz, 1 H), 4.33 (s, 2H), 3.91 (s, 2H), 
1.46-1.40 (m, 9H). 
INTERMEDIATE 1B 
##STR62## 
Step A: 
4-(t-butyloxycarbonylaminomethyl)-2-(benzyloxycarbonylaminomethyl)-pyridin 
e: 
A mixture of 4-(t-butyloxycarbonylaminomethyl)-2-aminomethyl-pyridine(600 
mg, 2.63 mmol), NMM (341 ml, 3.03 mmol), 4-DMAP (920 mg, 0.16 mmol) and 
benzyl chloroformate (433 ml, 3.30 mmol) in methylene chloride (15 ml) was 
stirred at room temperature overnight. The mixture was diluted with 
methylene chloride (50 ml) and then washed with water and saturated sodium 
bicarbonate. The organic layer was dried over sodium sulfate, filtered and 
evaporated in vacuo to give an oil. The crude product was purified by MPLC 
using 70% ethyl acetate in hexane as eluting solvent to give the title 
compound 844 mg (100%). 
1H NMR (CDCl3) d=1.45 (s, 3H), 4.25(br, 2H), 4.43 (d, J=5.7 Hz, 2H), 5.10 
(s, 2H), 5.28 (br, 1H), 6.10 (br, 1H), 7.05 (d, J=5.1 HZ, 1 H), 7.11 (s, 1 
H), 7.32 (m, 5H), 8.40 (d, J=5.1 Hz, 1H) 
Step B: 4-aminomethyl-2-(benzyloxycarbonylaminomethyl)-pyridine 
The 4-(t-butyloxycarbonylaminomethyl)-2-aminomethyl-pyridine (160 mg, 0.43 
mmol) was dissolved in TFA (10 ml) and stirred at room temperature for two 
hours. The solvent was removed in vacuo. 163 mg of the crude product was 
collected and brought to next step reaction without further purification. 
INTERMEDIATE 2 
##STR63## 
Step A: 2-Amino-5-cyano-6-methyl pyridine: 
A mixture of 6-amino-3-bromo-2-methyl-pyridine (20 g, 0.107 mol) and copper 
(I) cyanide (11.0 g, 0.123 mol) in DMF (25 mL) was heated to reflux for 4 
h. The DMF was evaporated in vacuo and the residue was partitioned between 
ethyl acetate and 10% sodium cyanide solution. The organic layer was 
washed with 10% sodium cyanide solution and brine, dried (Na2SO4) and 
evaporate in vacuo to a brown solid. This was dissolved in a minimum 
amount of ethyl acetate and the product was precipitated by adding hexane. 
The mixture was filtered to give the title compound (12 g, 85%) as a brown 
powder: 
.sup.1 H NMR (CDCl.sub.3, 400 MHz) 7.54 (d, J=8.6 Hz, 1H), 6.33 (d, J=8.6 
Hz, 1 H), 4.97 (br. s, 2 H), 2.56 (s, 3 H). 
Step B: 2-t-Butoxycarbonylamino-5-cyano-6-methyl-pyridine: 
A mixture of 2-amino-5-cyano-6-methyl-pyridine (8.0 g, 60 mmol), (Boc)20 
(19.64 g, 90 mmol), 4-methylmorpholine (6.60 mL, 60 mmol), and DMAP (1.10 
g, 9.0 mmol) in 150 mL of methylene chloride and TBIF (75 mL each) was 
stirred overnight. The solvent was removed in vacuo and the residue was 
taken into ethyl acetate (200 mL). The mixture was washed with 1.5 N HCl 
and brine, saturated NaHCO.sub.3, and then with brine. The organic layer 
was dried over magnesium sulfate, filtered, and evaporated in vacuo to 
give an oil. The crude product was purified by flash column chromatography 
(gradient 0-15% ethyl acetate/hexane) to give the title compound (13.52 g, 
97%) as a white solid: 
1H NMR (CDCl.sub.3) d 1.52 (s, 9H) 2.62 (s, 3H) 7.46 (br. s, 1 H), 7.80 (d, 
J=8.8 Hz, 1 H) 7.88 (d, J=8.8 Hz, 1 H). FAB-MS C12H15N3O2 Calc: 233 Found: 
234 
Step C: 2-t-Butoxycarbonylamino-5-methylamino-6-methyl-pyridine: 
A mixture of 2-t-butoxycarbonylamino-5-cyano-6-methyl-pyridine (7.88 g, 
33.80 mmol) and Raney--Nickel (6.30 g) in ammonia saturated ethanol (100 
mL) was heated to 80.degree. C. at 1000 psi for 10 hours. The reaction 
mixture was cooled to room temperature and filtered through celite. The 
filtrate was evaporated in vacuo and the residue was purified using flash 
column chromatography (1-2% NH4OH/10-20% methanol/90-80% methylene 
chloride) to give the title compound (6.92 g, 86% yield). 
1H NMR (CDCl.sub.3) d 1.50 (s, 9H) 2.43 (s, 3H) 3.81 (s, 3H), 7.23 (br. s, 
1 H), 7.57 (d, J=8.3 Hz, 1 H) 7.70 (d, J=8.3 Hz, 1 H). 
INTERMEDIATE 2A 
##STR64## 
Prepared similarly from 2-amino-5-bromopyridine. 
INTERMEDIATE 2B 
##STR65## 
A mixture of 6-aminonicotinamide (15 g) and LAH (1M in THF, 200 ml, 0.2 
mol) in anhydrous THF (300) was refluxed for one week. The reaction 
mixture was cooled to 0.degree. C. and quenched by adding cold water 
dropwise until the bubbling ceased. The solvent was removed in vacuo and 
the residue was taken to ethyl acetate. The mixture was washed with brine 
and saturated sodiu,m bicarbonate. The organic layer was dried over sodium 
sulfate, filtered and evaporated in vacuo. The crude product was purified 
by flash column chromatography using 80% CH2Cl2-18% MeOH-2% NH4OH as 
eluent to give the title compound as yellow solid (5.53 g, 41%). 
1H (CD3OD) d 3.64 (s, 2H), 6.57 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4 Hz, 
J=2.7 Hz, 1H), 7.83 (d=2.4 Hz, 1H). 
##STR66## 
Step A: 
##STR67## 
b-Methyl-D-Tryptophan methyl ester (6.00 g, 25.9 mmol) was combined with 
disuccinimidyl carbonate (6.95 g, 27.1 mmol) and DIEA (11.3 mL, 64.6 mmol) 
in dichloromethane. After stirring the reaction mixture for 0.5 h, 
4-(2-keto-1-benzinuidazolinyl)-piperidine (5.90 g, 27.1 mmol) was added 
and the mixture was permitted to stir over night. The reaction mixture was 
diluted with dichloromethane, and washed in succession with 1N HCl (100 
mL), saturated NaHCO.sub.3 solution (100 mL) and brine (100 mL), dried 
over MgSO.sub.4, filtered and concentrated. The resulting crude product 
was purified by MPLC (silica, 5% methanol/ethyl acetate) to give 7.55 g of 
a white solid. 
Step B: 
##STR68## 
The coupled product from the previous step (7.55 g, 15.9 mmol) was 
dissolved in THF (30 mL), treated with LiOH (2.67 g, 63.6 mmol) in 1:1 
EtOH/water (60 mL) and stirred for 4 h at room temperature. The pH was 
adjusted to .about.2-3 by addition of 3N HCl and the resulting solution 
was extracted with ethyl acetate 3 times. The combined organic layers were 
washed with brine, dried over MgSO.sub.4, filtered and concentrated to 
give 6.50 g of a white solid. 
INTERMEDIATE 4 
##STR69## 
Step A: 
##STR70## 
To a mixture, cooled to 0.degree. C. by ice/water bath, of 
N-Cbz-b-methyl-tryptophan (500 mg, 1.42 mmol), HOBt (190 mg, 1.42 mmol) 
and Intermediate 2 (337 mg, 1.42 mmol) in methylene chloride and DMF (10/2 
mL) was added EDC (544 mg, 2.84 mmol) and stirred overnight. The reaction 
mixture was evaporated in vacuo and the residue was dissolved in ethyl 
acetate. The solution was washed with 1.5N HCl and brine, and saturated 
NaHCO.sub.3. The organic layer was dried over magnesium sulfate, filtered, 
and evaporated in vacuo to give the product as a yellow oil. The crude 
product was purified by MPLC (80% ethyl acetate/hexane) to give the title 
compound (583 mg, 72%) as a white powder. 
Step B: 
##STR71## 
A mixture of the intermediate from the previous step (553 mg, 0.967 mmol) 
and 10% Pd-C (55 mg) in THF (20 mL) was stirred at room temperature under 
a balloon of hydrogen overnight. The reaction was filtered through celite 
and evaporated in vacuo to give the title compound (407 mg, 96%). The 
compound was used without further purification. 
H NMR (CD.sub.3 OD, 400 MHz) 7.65 (d, J=8.08 Hz, 1H), 7.47 (d, J=8.53 Hz, 
1H), 7.34 (d, J=8.21 Hz, 1H), 7.10-7.01 (m, 4H), 4.20 (d, J=15.0 Hz, 1H), 
4.09 (d, J=15.0 Hz, 1H) 3.63 (d, 6.82 Hz, 1H) 3.45 (p, 1H) 2.24 (s, 3H) 
1.52 (s, 9H) 1.36 (d, J=7.15 Hz, 3H). 
FAB-MS C24H31N5O3 Calc: 437 Found: 438 
INTERMEDIATE 5 
##STR72## 
Similarly prepared as Intermediate 4 using 
mono-t-butyloxycarbonyl-1,3-xylenediamine 
INTERMEDIATE 6 
##STR73## 
Similarly prepared as Intermediate 4 using Intermediate I 
Cbz intermediate: 
H NMR (CD.sub.3 OD, 400 MHz) 8.27 (d, J=5.0 Hz, 1H), 7.97 (s), 7.64 (d, 
J=8.0 Hz, 1H), 7.26-7.14 (m, 5H), 7.11-6.97 (m, 4H), 6.78 (s, 1H), 5.07 
(d, 1H) 5.05 (d, 1H) 4.50 (d, J=8.26 Hz, 1H), 4.24 (d, 1H), 4.19 (d, 1H), 
4.09 (d, 1H), 4.05 (d, 1H) 3.60 (p, 1H) 1.44 (s, 9H), 1.40 (d, J=7.14 Hz, 
3H). 
Title compound: 
H NMR (CD.sub.3 OD, 400 MHz) 8.33 (d, J=5.22 Hz, 1H), 7.97 (s), 7.685 (d, 
J=8.0 Hz, 1H), 7.33 (d, 8.0 Hz, 1H) 7.16-7.00 (m, 5H), 4.45 (d, 1H) 4.43 
(d, 1H), 4.17 (s, 2H), 3.76 (d, J=5.55 Hz, 1H), 3.60 (p, 1H) 1.43 (s, 9H), 
1.35 (d, J=7.14 Hz, 3H). 
INTERMEDIATE 7 
##STR74## 
Step A: 
##STR75## 
To a stirred solution of 4-[2-(methylamino)ethylpyridine (10.0 g, 73.4 
mmol) in tetrahydrofuran (200 mL) at 0.degree. C., was slowly added a 
solution of Boc.sub.2 O (16.0 g, 73.4 mmol) in tetrahydrofuran (200 mL). 
The resulting mixture was stirred at room temperature overnight, and then 
evaporated to remove solvent and purified by MPLC eluting with 1% methanol 
in ethyl acetate to give the Boc compound (16.00 g, 92% yield) as an oil. 
Step B: 
##STR76## 
A mixture of the intermediate from the previous step (4.54 g, 19.2 mmol) 
and 450 mg of platinum (IV) oxide in 20 mL acetic acid was stirred at room 
temperature under a balloon of hydrogen overnight. The reaction mixture 
was filtered through celite and evaporated in vacuo to give the residue 
which was partition between saturated NaHCO.sub.3 solution and 
dichloromethane. The aqueous layer was extracted with dichloromethane 
three times and the extracts were combined and dried over magnesium 
sulfate, filtered and concentrated to give the product in quantitative 
yield. .sup.1 H NMR (CDCl.sub.3, 400 MHz) d3.19(s, 2H), 3.03(d, J=12 Hz, 
2H), 2.78(s, 3H) 2.53(t, J1, J2=12 Hz), 2.45 (s, 2H), 1.66 (d, J=12.4 Hz, 
2H), 1.44 (s, 9H), 1.40 (m., 3H), 1.11(m., 2H). ESI-MS calc. for 
C13H26N2O2: 242; Found 243(M+1). 
Step C: 
##STR77## 
To a mixture of above product (0.75 g, 3.1 mmol) and triethyl amine (410 
mL, 3.73 mmol.) in dichloromethane (20 mL) at 0.degree. C., was slowly 
added benzyl chloroformate (488 mL, 3.42 mmol). The resulting mixture was 
stirred at room temperature overnight. The reaction mixture was washed 
with saturated NaHCO.sub.3 solution, 1N HCl and brine, dried over 
magnesium sulfate, filtered, and concentrated to give the crude product in 
quantitative yield. .sup.1 H NMR (CDCl.sub.3, 400 MHz) d 7.36 (m., 
5H),5.10(s, 2H) 4.15(br. s, 2H), 3.22(br. s, 2H), 2.80(s, 3H), 2.70(br. s, 
2H), 1.60 (m, 3H), 1.40(s, 9H), 1.40(m, 2H), 1.10(m, 2H). The crude 
product was dissolved in ethyl acetate at 0.degree. C. and HCl (gas) was 
bubbled through this solution for 2 min. This solution was evaporated to 
give a white solid. .sup.1 H NMR (CDCl.sub.3) d9.43(br. s, 1H), 7.35(m, 
5H), 5.08(br. s, 2H), 4.13(br. s, 2H), 2.94 (m, 2H), 2.72(br. s, 2H), 2.63 
(m, 3H), 2.07(br. s, 1H), 1.75(m, 2H), 1.63(m, 2H), 1.15(m, 2H). ESI-MS 
calc. for C16H24N2O2: 276; Found: 277(m+1).

EXAMPLE 1 
##STR78## 
Step A: 
To a mixture of Intermediate 3 (276 mg, 0.60 mmol), Intermediate 2 (147 mg, 
0.62 mmol), HOBt (81 mg, 0.6 mmol) in methylene chloride was added EDC(173 
mg, 0.9 mmol) in portions at 0.degree. C. The mixture was stirred at room 
temperature overnight and then diluted with methylene chloride, and then 
washed with water and saturated sodium bicarbonate. The organic layer was 
dried over sodium sulfate, filtered and evaporated in vacuo. The crude 
product was purified by flash column chromatography using 5% methanol in 
ethyl acetate as eluent solvent. Evaporation of solvent in vacuo provided 
the Boc intermediate as white foam solid (328 mg, 80%). FAB-MS C37H42N8O5 
Calc: 680 Found 681 
Step B: 
The intermediate from previous step(260 mg, 0.38 mmol) was dissolved in TFA 
(10 ml) and stirred at room temperature for two hours. Evaporation of the 
solvent in vacuo provided the title product as light brown solid (262 mg, 
99%). 
.sup.1 H NMR (CDCl3, 400 MHz) d 8.05 (m, 1H), 7.50 (d, J=8 Hz, 1H), 7.30 
(d, J=8 Hz, 1H), 7.2-7.0 (m, 7H), 6.92 (t, J=7.2 Hz, 1H), 6.45 (d, J=8.8 
Hz), 4.42 (m, 1H), 4.15 (d, J=10.4 Hz, 1H), 4.32-4.20 (m, 2H), 4.05 (dd, 
J=14.0 Hz, 6.4 Hz, 1H), 3.73 (dd, J=14.0 Hz, J=1.6 Hz, 1H), 3.52-3.40 (m, 
1H), 3.48-2.93 (m, 2H), 2.45-2.25 (m, 2H), 2.07 (s, 3H), 1.80 (d, J=12.4 
Hz, 2H), 1.45(d, J=6.9 Hz, 3H) 
FAB-MS C32H36N8O3 Calc: 580 Found 581 
EXAMPLE 2 
##STR79## 
Intermediate 3 (131 mg, 0.283 mmol) was combined with histamine 
dihydrochloride (104 mg, 0.567 mmol), HOBt (77 mg, 0.57 mmol), and DIEA 
(200 mL, 1.13 mmol) in DCM/DMF (1:1, 7 mL), cooled to 0.degree. C. and 
treated with EDC (108 mg, 0.567 mmol). The reaction mixture was allowed to 
warm to room temperature and was stirred overnight. The reaction mixture 
was diluted with DCM (50 mL) and 1N HCl (50 mL). The organic layer was 
separated and washed with saturated NaHCO.sub.3 solution (40 mL) and brine 
(40 ml). The organic layer was dried over MgSO.sub.4, filtered and 
concentrated. During the work up an insoluble viscous oil precipitated 
out. This material was dissolved in methanol and combined with the crude 
product obtained from concentration of the DCM. Purification by 
preparative TLC (silica, 1.8% NH.sub.3 solution-30%, 18.2% methanol, 80% 
DCM) afforded 51.1 mg of pure product. 
.sup.1 H NMR (CD.sub.3 OD, 400 MHz) d 8.70 (s, 1H), 7.63 (d, J=8 Hz, 1H), 
7.30 (d, J=8 Hz, 1H), 7.16 (s, 1H), 7.14-6.98 (m, 7H), 4.45 (m, 1H, 4.37 
(d, J=8.8 Hz, 1H), 4.26-4.15 (m, 2H), 3.60 (m, 1H), 3.16 (dt, J=2.4, 6.8 
Hz, 2H), 3.03-2.91 (m, 2H), 2.50 (m, 2H), 2.45-2.19 (m, 2H), 1.79 (m, 2H), 
1.45 d, J=7.2 Hz, 3H). 
ESI-MS calc for C30H34N8O3: 554; Found: 555 (M+H). 
EXAMPLE 3 
##STR80## 
Step A: 
##STR81## 
To a mixture of Intermediate 3 (100 mg, 0.21 mmol), Intermediate 1 (57 mg, 
0.23 mmol), HOBt (30 mg, 0.21 mmol) in methylene chloride (8 ml) was added 
EDC (60 mg, 0.32 mmol) in portions at 0.degree. C. The mixture was stirred 
at room temperature overnight, and then diluted with methylene chloride 
and washed with water and saturated sodium bicarbonate. The organic layer 
was dried over sodium sulfate, filtered and evaporated in vacuo. The crude 
product was purified by MPLC using 10% methanol in ethyl acetate as 
eluent. Evaporation of solvent in vacuo provided the title product as 
white foam solid (120 mg, 85%). 
FAB-MS C.sub.37 H.sub.42 N.sub.8 O.sub.5 Calc: 680, Found 681 
Step B: 
##STR82## 
The intermediate from previous step (110 mg, 0.16 mmol) was dissolved in 
TFA (8 ml) and stirred at room temperature for two hours. Evaporation of 
the solvent in vacuo provided the title product as light brown solid (109 
mg, 98%). 
.sup.1 H NMR (CD3OD, 300 MHz) d 8.57 (d, J=5.3 Hz, HI), 7.64 (d, J=7.8 Hz, 
1H), 7.55 (d, J=5.7 Hz, 1H), 7.50 (s, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.22 
(s, 1H), 7.15-6.95 (m, 6H), 4.52-4.11 (m, 8H), 3.75-3.60(m, 1H), 3.05-2.90 
(m, 2H), 2.45-2.25 (m, 1H), 2.25-2.10(m, 1H), 1.80-1.70 (m, 2H), 1.51 (d, 
J=7.2 Hz, 3H). 
FAB-MS C.sub.32 H.sub.36 N.sub.8 O.sub.3 Calc: 580, Found 581 
EXAMPLE 4 
##STR83## 
To a mixture of the title compound of Example 3 (200 mg, 0.24 mmol) and 
NaOAc (203 mg, 2.4 mmol) in methanol was added formaldehyde (37% in water, 
136 mg, 1.68 mmol). The mixture was stirred at room temperature for 30 
min., and then to this mixture was added NaBH3CN (30 mg, 0.48 mmol). The 
reaction mixture was stirred at room temperature overnight and then 
evaporated to dryness. The residue was taken to ethyl acetate and washed 
with saturated. NaHCO3. The organic layer was dried over sodium sulfate, 
filtered and evaporated in vacuo. The crude product was purified by Prep. 
TLC using 85% CH2Cl2-14% MeOH-1% NH4OH as eluent to give the title 
compound as white solid (38 mg). 
FAB-MS C.sub.34 H.sub.40 N.sub.8 O.sub.3 Calc: 608, Found 609 
EXAMPLE 5 
##STR84## 
Step A: 1-cyanomethyl-4-butoxycarbonylpiperazine: 
A solution of N-t-butoxycarbonylpiperazine (10 g, 53.8 mmol), 
chloroacetonitrile (4 mL, 1.05 equiv.) and DIEA (10 mL, 1.1 equiv.) in 
dichloromethane (300 mL) was refluxed overnight. The reaction mixture was 
evaporated to give a thick oil, which was tritiated with ether (30 mL) and 
the organic layer was separated and stored in freezer overnight and 
filtered. The ether solution was evaporated to give the product as a white 
solid (12.7 g). 
Step B: 1-(2-aminoethyl)-4butoxycarbonylpiperazine: 
A solution of 1-cyanomethyl-4-butoxycarbonylpiperazine (12 g) in ethanol 
(100 mL) saturated with ammonia, was hydrogenated over Raney Ni (5 g) at 
1000 psi and 80.degree. C. for 8 hours. The resulting mixture was filtered 
and evaporated to give 1-(2-aminoethyl)-4-butoxycarbonylpiperazine as a 
solid (12 g). 
Step C: 
##STR85## 
To a solution of Intermediate 3 (100.0 mg, 0.2169 mmol), 
1-(2-aminoethyl)-4-butoxycarbonylpiperazine (60.0 mg, 0.260 mmol), and 
HOBt(32 mg, 0.228 mmol) in dichloromethane (5 mL) was added EDC(50.0 mg, 
0.260 mmol). The resulting mixture was stirred at room temperature 
overnight. The reaction mixture was washed with saturated NaHCO3 solution, 
1N HCl and brine, dried over magnesium sulfate, filtered and concentrated 
to give the crude product. The crude product was purified by MPLC (20% 
methanol in ethyl acetate) to give 100 mg as white solid. ESI-MS calc. for 
C36H48N8O5: 672; Found: 673(M+1). 
Step D: 
##STR86## 
To a solution of the Boc intermediate from the previous step (100 mg) in 
ethyl acetate (5 mL) at 0.degree. C. was bubbled HCl (gas) for 2 min. 
After 15 minutes, the solution was evaporated to give the title compound 
as a white solid. 
.sup.1 H NMR(CD.sub.3 OD, 400 MHz) 7.63(d, J=8 Hz, 1H), 7.36 (d, J=8.0 Hz, 
1H), 7.24(S, 1H), 7.17(m, 3H), 7.06(m, 3H), 4.43(m, 1H), 4.30 (d, J=8.8 
Hz, 1H), 4.20 (m, 2H), 3.66 (m, 6H), 3.30 (m, 5H), 2.96 (m, 2H), 2.85 (m, 
2H), 2.37 (m, 1H), 2.27 (m, 1H), 1.78 (d, J=11.6 Hz, 2H), 1.50(d, J=6.8 
Hz, 3H) ESI-MS calc. for C31H40N8O3: 572; Found: 573 (M+1). 
EXAMPLE 6 
##STR87## 
To the solution of "top piece" acid (50.0 mg, 0.108 mmol) in 
dichloromethane, was added amine (38.0 mg, 1.19 mmol), HOBt (16 mg, 0.114 
mmol) and EDC(25.0 mg, 0.130 mmol). The resulting mixture was stirred at 
room temperature overnight. The reaction mixture was washed with saturated 
NaHCO3 solution, 1N HCl and brine, dried over magnesium sulfate, filtered 
and concentrated to give the crude product. The crude product was purified 
by MPLC (7% methanol in ethyl acetate) to give 36.0 mg as white solid. 
ESI-MS calc. for C41H49N7O5: 719; Found: 720(M+1). A mixture of the 
intermediate from the previous step (36 mg, 0.050 mmol) and 10% 
Pd(OH)2-C(7.2 mg) in ethyl alcohol was stirred at room temperature under a 
balloon of hydrogen overnight. The reaction solution was filtered through 
celite and 12N HCl (4.2 mL, 0.050 mmol) was added. The resulting solution 
was concentrated to give the white solid. 
.sup.1 H NMR (CD.sub.3 OD, 400 MHz) 7.62(d, J=8.0 Hz, 1H), 7.34(d, J=8.0 
Hz, 1H), 7.21(m, 2H), 7.05 (m, 5H), 4.46 (m, 1H), 4.30 (m, 1H), 3.58(m, 
1H), 3.40(m, 1H), 3.30(m, 1H), 3.20(m, 1H), 3.00(m, 1H), 2.80(m, 2H), 
2.69(m, 1H), 2.70(s, 3H), 2.55(m, 1H), 2.40(m, 1H), 2.00(m, 1H), 1.82(m, 
1H), 1.68(m, 1H), 1.58(m, 1H), 1.55(d, J=7.2 Hz), 1.25(m, 2H), 1.12(m, 
2H), 0.97(m, 1H), 0.85(m, 2H); 
ESI-MS calc. for C33H43N7O3: 585 (free base); Found: 586(M+1). 
EXAMPLE 7 
##STR88## 
Step A: 
##STR89## 
A stirred mixture of N-Cbz-serinol (497 mg, 2.21 mmol), prepared using 
standard procedures from commercially available serinol oxalate and 
Cbz-Cl, phthalimidoacetaldehyde diethyl acetal (Aldrich, 581 mg, 2.21 
mmol) and TsOH (21 mg, 0.11 mmol) in toluene (10 mL) was heated to reflux 
for 6 h. The resulting solution was cooled and evaporated in vacuo. 
Purification by flash chromatography (dry loaded on silica, 30% ethyl 
acetate/hexanes to 40% ethyl acetate/hexanes) afforded a 4:1 trans/cis 
mixture (107 mg) and a 1:4 trans/cis mixture (300 mg). The trans isomer 
was crystallized from absolute ethanol. 
Step B: 
##STR90## 
To a suspension of the product from the above reaction (106 mg, 0.268 mmol) 
in absolute ethanol was added hydrazine (1 M solution in ethanol, 0.268 
mmol) and the mixture was heated at reflux for 1 h. The resulting 
suspension was cooled and evaporated in vacuo. 2 M HCl (5 mL) was added 
and the mixture was warmed to 50.degree. C. for 5 min. to give a 
suspension which was cooled and filtered. The solids were washed with more 
2 M HCl. The resulting solution was washed with DCM (2X) then basified 
with 50% NaOH solution (cooling in an ice bath), and the mixture was 
extracted with ethyl acetate (2X). The combined extracts were dried over 
Na.sub.2 SO.sub.4, filtered and evaporated to give 57 mg of product as a 
waxy solid. 
Step C: 
##STR91## 
To a solution of Intermediate 3 (85.5 mg, 0.185 mmol), aminomethyl dioxane 
from the previous step (54.3 mg, 0.204 mmol), and HOBt (38 mg, 0.28 mmol) 
in DCM (5 mL) at 0.degree. C. was added EDC (53 mg, 0.28 mmol). The 
mixture was allowed to warm to room temperature and stir for 16 h. The 
reaction mixture was diluted with DCM (40 mL) and washed with 1N HCl (30 
mL), saturated NaHCO.sub.3 solution (30 mL) and brine (30 mL). The organic 
layer was dried over MgSO.sub.4, filtered and concentrated. Purification 
by MPLC (silica, 5% ethyl acetate/hexane) afforded the pure product as a 
white solid (101.9 mg). This was then dissolved in 1:1 THF/ethanol (10 
mL), and stirred at room temperature under H.sub.2 (1 atm) with 
Pd(OH).sub.2 /C (20%, 20 mg) for 5 h. The reaction mixture was filtered 
through celite (the filter cake was washed with methanol, 30 mL) and the 
filtrate was treated with concentrated HCl solution (12 mL) and 
concentrated to give the target compound as a yellow/white solid (80 mg). 
.sup.1 H NMR (CD.sub.3 OD, 400 MHz) d 7.64 (d, J=8 Hz, 1H), 7.36 (d, J=8 
Hz, 1H), 7.17 (s, 1H), 7.15-7.00 (m, 6H), 4.49 (d, J=8.8 Hz, 1H), 4.45 (m, 
1H), 4.21 (m, 2H), 4.11 (m, 2H), 3.91 (m, 1H), 3.58 (m, 1H), 3.48-3.22 (m, 
3H?), 3.18 (m, 1H?), 2.99 (m, 3H), 2.42-2.22 (m, 2H), 1.78 (m, 2H), 1.46 
(d, J=7.2 Hz, 3H). 
ESI-MS calc for C30H37N7O5: 575; Found: 576 (M+H). 
EXAMPLE 8 
##STR92## 
Step A: 2-(N-t-Butoxycarbonylaminomethyl)-5-hydroxymethyl tetrahydrofuran 
2-Aminomethyl-5-hydroxymethyl tetrahydrofuran (2.4 g, 18 mmol) was 
dissolved in THF (40 mL) and treated with a solution of Boc2O (3.99 g, 
18.3 mmol) in THF (20 mL) over about 10 min. The reaction mixture was 
stirred for 24 h and then concentrated to afford the BOC amino protected 
compound which was purified by MPLC (silica, 1% methanol/ethyl acetate). 
Step B: 2-(N-t-Butoxycarbonylaminomethyl)5-azidomethyl tetrahydrofuran 
The product from the previous step (2.66 g, 11.5 mmol) was combined with 
triethyl amine (3.2 mL, 23 mmol) and DMAP (ca. 200 mg) in DCM (40 mL). The 
resulting solution was cooled to 0.degree. C. and treated with MsCl (0.980 
mL, 12.7 mmol), dropwise over 2 min. After 5 h the reaction mixture was 
diluted with DCM (75 mL) and washed with 1N HCl (75 mL), saturated 
NaHCO.sub.3 solution (75 mL) and brine (75 mL). The organic layer was 
dried over MgSO.sub.4, filtered and concentrated to afford 2.88 g of 
mesylate. The mesylate (2.87 g, 9.28 mmol) was combined with NaN.sub.3 
(1.21 g, 18.6 mmol) in DMF (30 mL) and heated at 70.degree. C. for 15 h. 
The reaction mixture was diluted with ether (200 mL) and washed with water 
(5.times.100 mL) and brine (100 mL), dried over MgSO.sub.4, filtered and 
concentrated to give 2.18 g of azide. 
Step C: 2-(N-t-Butoxycarbonylaminomethyl)-5-aminomethyl tetrahydrofuran 
##STR93## 
The azide prepared in the previous step (2.0 g, 7.8 mmol) was dissolved in 
methanol (40 mL) and stirred under H.sub.2 (1 atm) with Pd(OH).sub.2 /C 
(200 mg, 20%) for 16 h. The reaction mixture was filtered through celite 
(filter cake was washed with additional methanol) and concentrated to give 
1.77 g of the desired amine. 
ESI-MS calc for C11H22N2O3: 230; Found 231 (M+H). 
Step D: 
##STR94## 
To a solution of Intermediate 3 (169 mg, 0.367 mmol), 
2-(N-t-Butoxycarbonylaminomethyl)-5-aminomethyl tetrahydrofuran (110 mg, 
0.477), and HOBt (84 mg, 0.62 mmol) in DCM (10 mL) at 0.degree. C. was 
added EDC (120 mg, 0.624 mmol). The reaction mixture was permitted to warm 
to room temperature and stir overnight. The mixture was diluted with DCM 
(40 mL) and washed in turn with 1N HCl (30 mL), saturated NaHCO.sub.3 
solution (30 mL) and brine (30 mL). The organic phase was dried over 
MgSO.sub.4, filtered and concentrated. The residue was purified by MPLC 
(silica 9.5% methanol/ethyl acetate) to afford 218.4 mg of pure product. 
ESI-MS calc for C36H47N7O6: 673; Found: 674 (M+H). 
Step E: 
##STR95## 
The BOC protected intermediate so formed from the previous step (199 mg) 
was dissolved in ethyl acetate/DCM (.about.3:1) and HCl (g) was bubbled 
through this solution for 3 min. The reaction mixture was then 
concentrated to afford the target compound (187 mg). ESI-MS calc for 
C31H39N7O4: 573; Found: 574 (M+H). 
EXAMPLE 9 
##STR96## 
Step A 
##STR97## 
To a mixture of Cbz-D-Ala-OH (3.35 g, 15 mmol), PyBrop (8.04 g, 17.25 mmol) 
and diethyl isopropyl amine (5.3 ml, 30 mmol) in CH2Cl2 was added Boc 
piperizine (2.79 g, 15 mmol). The mixture was stirred at room temperature 
overnight, then diluted with CH2Cl2 and washed with 1N HCl aqueous 
solution and saturated NaHCO3. The organic layer was dried over sodium 
sulfate, filtered and evaporated in vacuo. The crude product was purified 
by flash column chromatography using 50% ethyl acetate in hexane to 
provide the title compound as white foam solid (4.69 g, 80%). 
1H NMR (CD3OD, 300 MHz) d 7.34-7.25 (m, 5H), 5.07 (s, 2H), 4.61 (q, J=6.9 
Hz, 1H), 3.7-3.3 (m, 8H), 1.47 (s, 9H), 1.28 (d, J=6.9 Hz, 3H). 
FAB-MS C.sub.20 H.sub.29 N.sub.3 O.sub.5 Calc: 391, Found 392 
Step B: 
##STR98## 
A mixture of the product from the previous step (4.68 g, 11.95 mmol) and 
20% Pd(OH)2-C (468 mg) in methanol (100 ml) was stirred at room 
temperature under a balloon of hydrogen for two hours. The reaction 
mixture was filtered through celite and evaporated in vacuo to give the 
title compound as white solid (2.91 g, 94%). 
FAB-MS C.sub.12 H.sub.23 N.sub.3 O.sub.3 Calc: 257, Found 258 
Step C: 
##STR99## 
To a mixture of the product from the previous step (1.65 g, 6.43 mmol), 
Z-b-me-Trp (2.15 g, 6.10 mmol) and HOBt (0.83 g, 6.12 mmol) in CH2Cl2 (60 
ml) was added EDC (1.76 g, 9.18 mmol) in portions at 0.degree. C. The 
mixture was stirred at room temperature for four hours, and then diluted 
with CH2Cl2 and washed with water and saturated NaHCO3. The organic layer 
was dried over sodium sulfate, filtered and evaporated in vacuo. The crude 
product was purified by flash column chromatography using 80% ethyl 
acetate in hexane to provide the title compound as white foam solid (3.08 
g, 85%). 
FAB-MS C.sub.32 H.sub.41 N.sub.5 O.sub.6 Calc: 591, Found 592. 
Step D: 
##STR100## 
A mixture of the product from the previous step(3.0 g, 5.07 mmol) and 20% 
Pd(OH)2-C (300 mg) in methanol (100 ml) was stirred at room temperature 
under a balloon of hydrogen for two hours. The reaction mixture was 
filtered through celite and evaporated in vacuo to give the title compound 
as white solid (2.19 g, 94%). 
FAB-MS C.sub.24 H.sub.35 N.sub.5 O.sub.4 Calc: 457, Found 458 
Step E: 
##STR101## 
To a mixture of the product from the previous step (200 mg, 0.44 mmol) and 
N,N'-disuccinimidyl carbonate (112 mg, 0.44 mmol) in CH2Cl2 (8 ml) was 
added DIEA (77 ml, 0.44 mmol). The mixture was stirred for 30 min. at room 
temperature, then 4-(2-keto-1-benzimidazolinyl)-piperidine (95 mg, 0.44 
mmol) and DIEA (77 ml, 0.44 mmol) were added. The mixture was stirred at 
room temperature overnight, then diluted with CH2Cl2 and washed with 
saturated NaHCO3. The organic layer was dried over sodium sulfate, 
filtered and evaporated in vacuo. The crude product was purified by MPLC 
5% MeOH in ethyl acetate to provide the title compound as white foam solid 
(257 mg, 83%). 
FAB-MS C.sub.37 H.sub.48 N.sub.8 O.sub.6 Calc: 700, Found 701. 
Step B: 
##STR102## 
To the solution of the product from the previous step (247 mg, 0.35 mmol) 
in ethyl acetate (10 ml) was bubbling HCl gas for 30 seconds (until it was 
saturated) at 0.degree. C., the mixture was stirred at room temperature 
for 5 min. The solvent was removed in vacuo to provided the title compound 
as a solid (244 mg, 100%). 
FAB-MS C.sub.32 H.sub.40 N.sub.8 O.sub.4 Calc: 600, Found 601. 
The examples listed in Table I below were prepared using the same or 
similar protocols as for the examples (1-9) listed above. 
TABLE I 
______________________________________ 
##STR103## 
Example X Y diamine 
______________________________________ 
10 H H 
##STR104## 
11 H H 
##STR105## 
12 ethyl H 
##STR106## 
______________________________________ 
Biological Assays 
The ability of compounds of the present invention to act as somatostatin 
agonist can be determined by the following in vitro assays, which is 
disclosed in Rens-Domiano, et al., Pharmacological Properties of Two 
Cloned Somatostatin Receptors, Mol. Pharm., 42: 28-34 (1992) and 
incorporated herein. 
Receptor Expression Constructs 
Mammalian expression vectors containing full length coding sequences for 
hSSTR1-5 were constructed as follows: Fragments of genomic DNA carrying 
the various human somatostatin receptors were inserted into the multiple 
cloning site of pcDNA3 (Invitrogen). The fragments used were a 1.5-kb 
PstI-XmnI fragment for hSSTR1, 1.7-kb BamHI-HindIII fragment for hSSTR2, 
2.0-kb NcoI-HindIII fragment for hSSTR3, a 1.4-kb NheI-NdeI fragment for 
hSSTR4, and a 3.2-kb XhoI-EcoRI fragment for hSSTR5. 
Transfection 
CHO-K1 cells were obtained from American Type Culture Collection (ATCC) and 
grown in alpha-MEM containing 10% fetal calf serum. Cells were stably 
transfected with DNA for all 5 hSSTRs using lipofectamine. Neomycin 
resistant clones were selected and maintained in medium containing G418 
(400 .mu.g ml). 
Receptor binding assay. 
Cells were harvested 72 hr after transfection to 50 mM Tris-HCl, pH 7.8, 
containing 1 mM EGTA, 5 mM MgCl.sub.2, 10 .mu.ml leupeptin, 10 .mu.g/ml 
pepstatin, 200 .mu.g/ml bacitracin, and 0.5 .mu.g/ml aprotinin (buffer 1) 
and were centrifuged at 24,000.times. g for 7 min at 4.degree.. The pellet 
was homogenized in buffer 1 using a Brinkman Polytron (setting 2.5, 30 
sec). The homogenate was then centrifuged at 48,000 .mu.g for 20 min at 
4.degree. C. The pellet was homogenized in buffer 1 and the membranes were 
used in the radioligand binding assay. Cell membranes (approximately 10 
.mu.g of protein) were incubated with .sup.125 I-Tyr.sup.11 -somatostatin 
(0.2 nM; specific activity, 2000 Ci/mmol; NEN) in the presence or absence 
of competing peptides, in a final volume of 200 .mu.l, for 30 min at 
25.degree.. Nonspecific binding was defined as the radioactivity remaining 
bound in the presence of 100 nM somatastatin. The binding reaction was 
terminated by the addition of ice-cold 50 nM Tris-HCl buffer, pH 7.8, and 
rapid filtration with 12 ml of ice-cold Tris HCl buffer, and the bound 
radioactivity was counted in a gamma scintillation spectrophotometer (80% 
efficiency). Data from radioligand binding studies were used to generate 
inhibition curves. IC.sub.50 values were obtained from curve-fitting 
performed with the mathematical modeling program FITCOMP, available 
through the National Institutes of Health-sponsored PROPHET System. 
Inhibition of forskolin-stimulated cAMP accumulation. 
Cells used for cAMP accumulation studies were subcultured in 12-well 
culture plates. COS-7 cells were transfected 72 hr before the experiments. 
Culture medium was removed from the wells and replaced with 500 .mu.l of 
fresh medium containing 0.5 mM isobutylmethylxanthine. Cells were 
incubated for 20 min at 37.degree.. Medium was then removed and replaced 
with fresh medium containing 0.5 mM isobutylmethylxanthine, with or 
without 10 .mu.M forskolin and various concentrations of test compound. 
Cells were incubated for 30 min at 37.degree.. Medium was then removed, 
and cells were sonicated in the wells in 500 .mu.L of 1N HCl and frozen 
for subsequent determination of cAMP content by radioimmunassay. Samples 
were thawed and diluted in cAMP radioimmunassay buffer before analysis of 
cAMP content using the commercially available assay kit from NEW/DuPont 
(Wilmington, Del.). 
Inhibition of growth hormone release. 
Functional activity of the various compounds was evaluated by quantitating 
release of growth hormone secretion from primary cultures of rat anterior 
pituitary cells. Cells were isolated from rat pituitaries by enzymatic 
digestion with 0.2% collagenase and 0.2% hyaluronidase in Hank's balanced 
salt solution. The cells were suspended in culture medium and adjusted to 
a concentration of 1.5.times.10.sup.5 cells per milliliter, and 1.0 ml of 
this suspension was placed in each well of a 24-well tray. Cells were 
maintained in a humidified 5% CO.sub.2 -95% air atmosphere at 37.degree. 
C. for 3 to 4 days. The culture medium consisted of Dulbecco's modified 
Eagle's medium containing 0.37% NaHCO.sub.3, 10% horse serum, 2.5% fetal 
bovine serum, 1% nonessential amino acids, 1% glutamine, 1% nystatin, and 
0.1% gentamycin. Before testing compounds for their capacity to inhibit GH 
release, cells were washed twice 1.5 hours before and once more 
immediately before the start of the experiment with the above culture 
medium containing 25 mM Hepes (pH 7.4). The compounds of the insant 
invention were tested in quadruplicate by adding them in 1 ml of fresh 
medium to each well and incubating them at 37.degree. C. for 15 min. After 
incubation, the medium was removed and centrifuged at 2000 g for 15 min to 
remove any cellular material. The supernatant fluid was removed and 
assayed for GH by radioimmunoassay. 
The compounds of this invention were found to inhibit the binding of 
somatostatin to its receptor at an IC.sub.50 of about 30 pM to about 3 
.mu.M.