U.S. patent application number 09/756593 was filed with the patent office on 2001-08-30 for dolastatin 15 derivatives.
This patent application is currently assigned to BASF Aktiengesellschaft. Invention is credited to Amberg, Wilhelm, Barlozzari, Teresa, Haupt, Andreas, Janssen, Bernd, Kling, Andreas, Ritter, Kurt.
Application Number | 20010018422 09/756593 |
Document ID | / |
Family ID | 22342878 |
Filed Date | 2001-08-30 |
United States Patent
Application |
20010018422 |
Kind Code |
A1 |
Ritter, Kurt ; et
al. |
August 30, 2001 |
Dolastatin 15 derivatives
Abstract
Compounds of the present invention include cell growth
inhibitors which are peptides of Formula I A-B-D-E-F-G (I) and acid
salts thereof, wherein A, D, and E are .alpha.-amino acid residues,
B is an .alpha.-amino acid residue or an .alpha.-hydroxy acid
residue, F is an aminobenzoic acid residue or an
aminocycloalkanecarboxyl- ic acid residue, and G is a monovalent
radical, such as, for example, a hydrogen atom, an amino group, an
alkyl group, an alkylene alkyl ether, an alkylene alkyl thioether,
an alkylene aldehyde, an alkylene amide, a .beta.-hydroxylamino
group, a hydrazido group, an alkoxy group, a thioalkoxy group, an
aminoxy group, an oximato group, an alkylene aryl group, an
alkylene ester, an alkylene sultoxide or an alkylene sulfone.
Another aspect of the present invention includes pharmaceutical
compositions comprising a compound of Formula I and a
pharmaceutically acceptable carrier. An additional embodiment of
the present invention is a method for treating cancer in a mammal,
such as a human, comprising administering to the mammal an
effective amount of a compound of Formula I in a pharmaceutically
acceptable composition.
Inventors: |
Ritter, Kurt; (Newton,
MA) ; Janssen, Bernd; (Marlborough, MA) ;
Haupt, Andreas; (Westborough, MA) ; Kling,
Andreas; (Mannheim, DE) ; Barlozzari, Teresa;
(Wellesley, MA) ; Amberg, Wilhelm;
(Friedrichsdorf, DE) |
Correspondence
Address: |
Carolyn S. Elmore
HAMILTON, BROOK, SMITH & REYNOLDS, P.C.
Two Militia Drive
Lexington
MA
02421-4799
US
|
Assignee: |
BASF Aktiengesellschaft
|
Family ID: |
22342878 |
Appl. No.: |
09/756593 |
Filed: |
January 8, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09756593 |
Jan 8, 2001 |
|
|
|
PCT/US99/14099 |
Jun 23, 1999 |
|
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|
Current U.S.
Class: |
514/19.3 ;
530/330 |
Current CPC
Class: |
A61P 35/00 20180101;
C07K 5/101 20130101; A61K 38/00 20130101; C07K 7/02 20130101; C07K
5/1024 20130101 |
Class at
Publication: |
514/17 ;
530/330 |
International
Class: |
A61K 038/04 |
Claims
We claim:
1. A compound of the formula A-B-D-E-F-G, or a salt thereof with a
pharmaceutically acceptable acid, wherein A is a proline derivative
of Formula II.sub.a, 47wherein n.sub.a is 0 to 3; R.sub.a is
hydrogen, or unsubstituted or fluorine-substituted normal, branched
or cyclic C.sub.1-C.sub.3-alkyl; R.sup.1.sub.a is hydrogen,
C.sub.1-C.sub. 3-alkyl, phenyl, or substituted phenyl; or R.sub.a
and R.sup.1.sub.a together form a propylene bridge; and
R.sup.2.sub.a, R.sup.3.sub.a, R.sup.4.sub.a and R.sup.5.sub.a are
each, independently, hydrogen or alkyl; or an .alpha.-amino acid
derivative of Formula III.sub.a, 48wherein R.sub.a is hydrogen or
unsubstituted or fluorine-substituted C.sub.1-C.sub.3-alkyl;
R.sup.1.sub.a is hydrogen or C.sub.1-C.sub.4-alkyl; R.sup.6.sub.a
is alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl;
or R.sup.1.sub.a is an alkyl group and R.sup.6.sub.a is
C.sub.1-C.sub.6-alkyl, cycloalkylmethyl, benzyl or substituted
benzyl; and R.sup.7.sub.a is hydrogen or alkyl; or an .alpha.-amino
acid derivative of Formula IV.sub.a, 49wherein m.sub.a is 1 or 2;
R.sup.7.sub.a is hydrogen or alkyl; R.sub.a is hydrogen, or
unsubstituted or fluorine-substituted alkyl; or an .alpha.-amino
acid derivative of Formula V.sub.a, 50wherein R.sup.7.sub.a is
hydrogen or alkyl and R.sub.a is hydrogen, or unsubstituted or
fluorine-substituted alkyl; or an .alpha.-amino acid of Formula
VI.sub.a, 51wherein R.sub.a is hydrogen, or unsubstituted or
fluorine-substituted alkyl; R.sup.1.sub.a is hydrogen, alkyl,
phenyl, or substituted phenyl; or R.sub.a and R.sup.1.sub.a
together form a propylene bridge; and X.sub.a is hydroxy, alkoxy or
fluorine; or an .alpha.-amino acid of Formula VII.sub.a, 52wherein
R.sub.a is hydrogen, or unsubstituted or fluorine-substituted
alkyl; R.sup.1.sub.a is hydrogen, alkyl, phenyl, or substituted
phenyl; or R.sub.a and R.sup.1.sub.a together form a propylene
bridge; and R.sup.2.sub.a, R.sup.3.sub.a, R.sup.4.sub.a and
R.sup.5.sub.a are each, independently, hydrogen or alkyl; or an
.alpha.-amino acid residue of Formula VIII.sub.a, 53wherein R.sub.a
is hydrogen, or unsubstituted or fluorine-substituted alkyl; or a
2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula
IX.sub.a, 54wherein the 3-carbonyl moiety is in the endo or exo
position, Z.sub.a is a single bond or a double bond, and R.sub.a is
hydrogen or unsubstituted or fluorine-substituted alkyl; or an
.alpha.-amino acid residue of Formula X.sub.a, 55wherein n.sub.a is
1, 2 or 3, and R.sup.7.sub.a is hydrogen or alkyl and R.sub.a is
hydrogen , unsubstituted alkyl or fluorine-substituted alkyl; B is
a valyl, isoleucyl, allo-isoleucyl, norvalyl, 2-tert-butylglycyl or
2-ethylglycyl residue; or an .alpha.-amino acid residue of Formula
II.sub.b, 56wherein R.sup.1.sub.b is hydrogen, and R.sup.2.sub.b is
alkyl or alkenyl; or R.sup.1.sub.b and R.sup.2.sub.b together form
an isopropylidene group; D is an N-alkylvalyl,
N-alkyl-2-ethylglycyl, N-alkyl-2-tert-butylglycyl,
N-alkylnorleucyl, N-alkylisoleucyl, N-alkyl-allo-isoleucyl or
N-alkylnorvalyl residue; or an .alpha.-amino acid residue of
Formula II.sub.d, 57wherein R.sub.d is hydrogen, or unsubstituted
or fluorine-substituted alkyl; R.sup.1.sub.d is hydrogen; and
R.sup.2.sub.d is alkyl, substituted alkyl or alkenyl; or
R.sup.1.sub.d and R.sup.2.sub.d together form an isopropylidene
group; or an .alpha.-amino acid residue of Formula III.sub.d,
58wherein n.sub.d is 1 or 2; R.sup.3.sub.d is hydrogen, alkyl or
fluorine-substituted alkyl; and X.sub.d is hydrogen; or n.sub.d is
1 and X.sub.d is fluorine, hydroxy, methoxy, or ethoxy; E is a
prolyl, thiazolidinyl-4-carbonyl, homoprolyl,or hydroxyprolyl
residue; or an .alpha.-amino acid residue of Formula II.sub.e,
59wherein n.sub.e is 0, 1 or 2, R.sup.1.sub.e is hydrogen, or
unsubstituted or fluorine-substituted alkyl; R.sup.2.sub.e and
R.sup.3.sub.e are each, independently, hydrogen or alkyl;
R.sup.4.sub.e is hydrogen, hydroxy or alkoxy; and R.sup.5.sub.e is
hydrogen or fluorine; or n.sub.e is 1 and R.sup.3.sub.e and
R.sup.4.sub.e together form a double bond; or n.sub.e is 1 and
R.sup.4.sub.e and R.sup.5.sub.e together form a double-bonded
oxygen diradical; or n.sub.e is 1 or 2 and R.sup.1.sub.e and
R.sup.2.sub.e together form a double bond; or an
aminocyclopentanecarboxylic acid residue of Formula III.sub.e,
60wherein R.sub.e is alkyl and R.sup.1.sub.e is hydrogen, or
unsubstituted or fluorine-substituted alkyl; F is an aminobenzoyl
derivative of Formula II.sub.f, 61wherein R.sub.f is a hydrogen
atom or an alkyl group; the carbonyl group is ortho, meta, or para
to the nitrogen atom; R.sup.1.sub.f and R.sup.2.sub.f are each,
independently, a hydrogen atom; a halogen atom; a
C.sub.1-C.sub.4-alkyl group; a methoxy, ethoxy, trifluoromethyl,
nitro, cyano, amino or dimethyalmino group; or R.sup.1.sub.f and
R.sup.2.sub.f can together form a dioxymethylene group; or F is an
aminocycloalkanecarboxylic acid residue of Formula III.sub.f,
62wherein R.sub.f is a hydrogen atom or an alkyl group; a.sub.f is
0, 1 or 2; and the carbonyl group is in position 2 or position 3 of
the cycloalkane ring relative to the nitrogen atom; and G is a
substituted or unsubstituted amino, hydrazido, aminoxy, oximato,
arylalkyl, heteroarylalkyl, aryl, heteroaryl, alkoxycarbonylalkyl,
aryloxycarbonylalkyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonylalkyl, aminocarbonyl, alkylcarbonylalkyl,
alkylcarbonyl, arylcarbonylalkyl, arylcarbonyl, alkylsulfinylalkyl,
alkylsulfinyl, arylsulfinylalkyl, arylsulfinyl, alkylsulfonylalkyl,
alkylsulfonyl, arylsulfonylalkyl or arylsulfonyl group.
2. The compound of claim 1 wherein the pharmaceutically acceptable
acid is hydrochloric acid, citric acid, tartaric acid, lactic acid,
phosphoric acid, methanesulfonic acid, acetic acid, formic acid,
maleic acid, fumaric acid, malic acid, succinic acid, malonic acid,
sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid,
mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic
acid or acetylglycine.
3. The compound of claim 1 wherein G is a monovalent radical of
Formula II.sub.g, 63wherein R.sup.1.sub.l is a hydrogen atom, a
normal or branched, saturated or unsaturated
C.sub.1-C.sub.18-alkoxy group, a substituted or unsubstituted
aryloxy group, a substituted or unsubstituted
aryl-C.sub.1-C.sub.6-alkoxy group, a substituted or unsubstituted
aryloxy-C.sub.1-C.sub.6-alkoxy group, wherein the aryl substituents
comprise one or more halogen atoms or one or more
C.sub.1-C.sub.4-alkyl, methoxy, ethoxy, trifluoromethyl, nitro or
dioxymethylene groups; or a heteroaryl-C.sub.1-C.sub.6-alkoxy
group, wherein the heteroaryl group is derived from imidazole,
isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene,
furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole,
benzofuran, benzothiophene, indole, isoindole, indazole, quinoline,
pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole,
oxadiazole, thiadiazole or pyridine; and R.sup.2.sub.l is a
hydrogen atom, a normal or branched C.sub.1-C.sub.18-alkyl group, a
normal C.sub.1-C.sub.18 alkenyl group, a
C.sub.3-C.sub.10-cycloalkyl group, an aryl group, or a substituted
aryl group, wherein the aryl substituents comprise one or more
halogen atoms, or one or more alkyl, alkoxy, dioxymethylene,
trifluoromethyl or nitro groups; or a heteroaryl or substituted
heteroaryl group derived from imidazole, isoxazole, isothiazole,
thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or
1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene,
isoindole, indazole, quinoline, pyridazine, pyrimidine,
benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole
or pyridine and the heteroaryl substituents comprise one or more
C.sub.1-C.sub.6-alkyl, hydroxyl or phenyl groups; or a monovalent
radical of Formula II.sub.l, 64wherein a.sub.l is 0, 1, 2, 3, 4, or
5; R.sup.3.sub.l is a methyl, ethyl, normal propyl or isopropyl
group; R.sup.4.sub.l is a saturated or partially unsaturated
carbocyclic system which contains from 3 to 10 carbon atoms, an
aryl group, or a substituted aryl group, wherein the aryl
substituents comprise one or more halogen atoms or one or more
alkoxy, dioxymethylene, trifluoromethyl, nitro, cyanof
C.sub.1-C.sub.7-alkoxycarbonyl, C.sub.1-C.sub.7-alkylsulfonyl,
amino, or C.sub.1-C.sub.7-dialkylamino groups; or a substituted or
unsubstituted heteroaryl group derived from imidazole, pyrrole,
thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or
1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole,
pyrazine, pyridazine, pyrimidine, pyridine, benzofuran,
benzothiophene, benzimidazole, benzothiazole, benzopyran, indole,
isoindole, indazole or quinoline, and the heteroaryl group
substituents comprise one or more C.sub.1-C.sub.6-alkyl, hydroxyl
or phenyl groups; or a monovalent radical of Formula III.sub.l,
--(CH.sub.2).sub.2-W.sub.l-R.sup.5.sub.l (III.sub.l), wherein
W.sub.l is an NR.sup.6.sub.l group, an oxygen atom or a sulfur
atom, R.sup.5.sub.l and R.sup.6.sub.l are each, independently, a
hydrogen atom or a C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.7-cycloalkyl, aryl, arylmethyl or substituted aryl or
arylmethyl group, wherein the aryl substituents comprise one or
more halogen atoms or one or more alkoxy, dioxymethylene,
trifluoromethyl, nitro, cyano, C.sub.1-C.sub.7-alkoxycarbonyl,
C.sub.1-C.sub.7-alkylsulfon- yl, amino, or
C.sub.1-C.sub.7-dialkylamino groups; or R.sup.6.sub.l is a
C.sub.1-C.sub.18-alkanoyl or benzoyl group; or a monovalent radical
of Formula IV.sub.l, --(CH.sub.2).sub.b.sub..sub.l-Z.sub.l
(IV.sub.l), b.sub.l is 2, 3, or 4 and Z.sub.l is a formyl,
aminocarbonyl, hydrazinocarbonyl, cyclic acetal, cyclic thioacetal,
acyclic acetal or acyclic thioacetal group; or a monovalent radical
of Formula V.sub.l, 65b.sub.l is 2, 3, or 4; R.sup.7.sub.l is a
polyglycol group of the formula
--O--(CH.sub.2--CH.sub.2--O).sub.dl--CH.sub.3; and d.sub.l is
between about 2 and about 4, or between about 40 and about 90; or a
monovalent radical of Formula VI.sub.l, 66wherein R.sup.8.sub.l is
a hydrogen atom, or a C.sub.1-C.sub.4 alkanoyl, C.sub.1-C.sub.4
alkyl, benzoyl, or benzyl group.
4. The compound of claim 1 wherein G is a .beta.-hydroxy amino
group of Formula III.sub.g, 67R.sup.9.sub.l is a hydrogen atom, or
a C.sub.1-C.sub.6-alkyl, aryl or substituted aryl group wherein the
aryl substituents comprise one or more halogen atoms or one or more
alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano,
C.sub.1-C.sub.7-alkoxycarb- onyl, C.sub.1-C.sub.7-alkylsulfonyl,
amino, or C.sub.1-C.sub.7-dialkylamin- o groups; and R.sup.10.sub.l
is a hydrogen atom, a methyl group or a phenyl group.
5. The compound of claim 1 wherein G is a hydrazido group of
Formula IV.sub.g, 68wherein R.sup.11.sub.l is a hydrogen atom and
R.sup.12.sub.l is a hydrogen atom, a normal or branched
C.sub.1-C.sub.8-alkyl group, a C.sub.3-C.sub.8-cycloalkyl group, a
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.- sub.4-alkyl group, an
aryl-C.sub.1-C.sub.4-alkyl group, an aryl group, a substituted aryl
group, wherein the aryl substituents comprise one or more halogen
atoms or one or more alkoxy, trifluoromethyl, dioxymethylene,
nitro, cyano, C.sub.1-C.sub.7-alkoxycarbonyl,
C.sub.1-C.sub.7-alkylsulfonyl, amino, or
C.sub.1-C.sub.7-dialkylamino groups; or a heteroaryl group, a
heteroaryl-C.sub.1-C.sub.4-alkyl group or a substituted heteroaryl
group derived from imidazole, pyrrole, thiophene, furan, thiazole,
oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole,
thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine,
pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole,
benzothiazole, benzopyran, indole, isoindole, indazole or quinoline
and the heteroaryl substituents comprise one or more
C.sub.1-C.sub.6-alkyl, hydroxyl or phenyl groups.
6. The compound of claim 1 wherein G is a monovalent radical of the
formula --O--R.sup.13.sub.l or of the formula --S--R.sup.13.sub.l,
and R.sup.13.sub.l is a C.sub.3-C.sub.10-cycloalkyl, straight-chain
or branched C.sub.2-C.sub.16-alkenylmethyl, C.sub.1-C.sub.16-alkyl
or halogen-substituted C.sub.1-C.sub.16-alkyl group; R.sup.13.sub.l
is a monovalent radical of the formula
--(CH.sub.2).sub.el--R.sup.14.sub.l, e.sub.l is 1, 2, or 3, and
R.sup.14.sub.l is a saturated or partially unsaturated
C.sub.3-C.sub.10 carbocyclic group; R.sup.13.sub.l is a monovalent
radical of the formula --[CH.sub.2--CH.dbd.C(CH.sub.3)--
CH.sub.2].sub.fl--H, and f.sub.l is 1, 2, 3, or 4; R.sup.13.sub.l
is a monovalent radical of the formula
--[CH.sub.2--CH.sub.2--O].sub.gl--CH.su- b.3, and g.sub.l is
between about 2 and about 4, or between about 40 and about 90;
R.sup.13.sub.l is a monovalent radical of the formula
--(CH.sub.2).sub.hl--X, h.sub.l is 0, 1, 2, or 3; and X is an aryl
or substituted aryl group wherein the aryl substituents comprise
one or more halogen atoms or one or more alkoxy, trifluoromethyl,
dioxymethylene, nitro, cyano, C.sub.1-C.sub.7-alkoxycarbonyl,
C.sub.1-C.sub.7-alkylsulfon- yl, amino, or
C.sub.1-C.sub.7-dialkylamino groups; or a heteroaryl or substituted
heteroaryl group derived from imidazole, pyrrole, thiophene, furan,
thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole,
thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine,
pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole,
benzothiazole, benzopyran, indole, isoindole, indazole or quinoline
and the heteroaryl substituents comprise one or more
C.sub.1-C.sub.6-alkyl, hydroxyl or phenyl groups; R.sup.13.sub.l is
a monovalent radical of the formula
--(CH.sub.2).sub.bl-W.sub.l-R.sup.5.sub.l, b.sub.l is 2, 3, or 4,
W.sub.l is an oxygen atom, a sulfur atom or an NR.sup.6.sub.l
group; R.sup.5.sub.l is a saturated carbocyclic system which
contains from about 3 to about 10 carbon atoms, a partially
unsaturated carbocyclic system containing from about 3 to about 10
carbon atoms, an aryl or substituted aryl group wherein the aryl
substituents comprise one or more halogen atoms or one or more
alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano,
C.sub.1-C.sub.7-alkoxycarbonyl, C.sub.1-C.sub.7-alkylsulfonyl,
amino, or C.sub.1-C.sub.7-dialkylamino groups; a heteroaryl or
substituted heteroaryl group derived from imidazole, pyrrole,
thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or
1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole,
pyrazine, pyridazine, pyrimidine, pyridine, benzofuran,
benzothiophene, benzimidazole, benzothiazole, benzopyran, indole,
isoindole, indazole or quinoline and the heteroaryl substituents
comprise one or more C.sub.1-C.sub.6-alkyl, hydroxyl or phenyl
groups; and R.sup.6.sub.l is a hydrogen atom, or a C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.18-alkanoyl,
benzoyl, arylmethyl, aryl or substituted aryl or arylmethyl group,
wherein the aryl substituents comprise one or more halogen atoms or
one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano,
C.sub.1-C.sub.7-alkoxycarbonyl, C.sub.1-C.sub.7-alkylsulfonyl,
amino, or C.sub.1-C.sub.7-dialkylamino groups.
7. The compound of claim 1 wherein G is an aminoxy group of the
formula --O--N(R.sup.16.sub.l)(R.sup.15.sub.l), wherein
R.sup.15.sub.l and R.sup.16.sub.l are each, independently, a
hydrogen atom, a normal or branched C.sub.1-C.sub.8 alkyl group, a
halogen-substituted normal or branched C.sub.1-C.sub.8-alkyl group,
a C.sub.3-C.sub.8-cycloalkyl group, a
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4 alkyl group, an
aryl-C.sub.1-C.sub.4-alkyl group, an aryl group or a substituted
aryl-C.sub.1-C.sub.4-alkyl or aryl group, wherein the aryl
substituents comprise one or more halogen atoms or one or more
alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano,
C.sub.1-C.sub.7-alkoxycarb- onyl, C.sub.1-C.sub.7-alkylsulfonyl,
amino, or C.sub.1-C.sub.7-dialkylamin- o groups; a heteroaryl or
substituted heteroaryl group derived from imidazole, pyrrole,
thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or
1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole,
pyrazine, pyridazine, pyrimidine, pyridine, benzofuran,
benzothiophene, benzimidazole, benzothiazole, benzopyran, indole,
isoindole, indazole or quinoline and the heteroaryl substituents
comprise one or more C.sub.1-C.sub.6-alkyl, hydroxyl or phenyl
groups; or R.sup.15.sub.l and R.sup.16.sub.l together with the
nitrogen atom form a heterocyclic ring structure comprising 5, 6,
or 7 atoms.
8. The compound of claim 1 wherein G is a oximato group of the
formula --O--N.dbd.C(R.sup.15.sub.l)(R.sup.16.sub.l), wherein
R.sup.15.sub.l and R.sup.16.sub.l are each, independently, a
hydrogen atom, a normal or branched C.sub.1-C.sub.8 alkyl group, a
halogen-substituted normal or branched C.sub.1-C.sub.8-alkyl group,
a C.sub.3-C.sub.8-cycloalkyl group, a
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4 alkyl group, an
aryl-C.sub.1-C.sub.4-alkyl group, an aryl group or a substituted
aryl-C.sub.1-C.sub.4-alkyl or aryl group, wherein the aryl
substituents comprise one or more halogen atoms or one or more
alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano,
C.sub.1-C.sub.7-alkoxycarb- onyl, C.sub.1-C.sub.7-alkylsulfonyl,
amino, or C.sub.1-C.sub.7-dialkylamin- o groups; a heteroaryl or
substituted heteroaryl group derived from imidazole, pyrrole,
thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or
1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole,
pyrazine, pyridazine, pyrimidine, pyridine, benzofuran,
benzothiophene, benzimidazole, benzothiazole, benzopyran, indole,
isoindole, indazole or quinoline and the heteroaryl substituents
comprise one or more C.sub.1-C.sub.6-alkyl, hydroxyl or phenyl
groups; or R.sup.15.sub.l and R.sup.16.sub.l, together with the
carbon atom, form a cyclic system, a cyclic system fused to an
aromatic ring system or a cyclic system selected from the group
consisting of: 69
9. The compound of claim 1 wherein G is a hydrogen atom, a normal
or branched C.sub.1-C.sub.8-alkyl group, a halogen-substituted
normal or branched C.sub.1-C.sub.8-alkyl group, a C.sub.3-C.sub.8
cycloalkyl group, or a
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl group.
10. The compound of claim 1 wherein G is a monovalent radical of
Formula V.sub.g, --(CH.sub.2).sub.a.sub..sub.g--R.sup.17.sub.l
(V.sub.g) a.sub.g is 0, 1, or 2, and R.sup.17.sub.l is an aryl
group or a substituted aryl group wherein the aryl substituents
comprise one or more halogen atoms or one or more alkoxy,
trifluoromethyl, dioxymethylene, nitro, cyano,
C.sub.1-C.sub.7-alkoxycarbonyl, C.sub.1-C.sub.7-alkylsulfonyl,
amino, or C.sub.1-C.sub.7-dialkylamino groups; or a heteroaryl or
substituted heteroaryl group derived from imidazole, pyrrole,
thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or
1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole,
pyrazine, pyridazine, pyrimidine, pyridine, benzofuran,
benzothiophene, benzimidazole, benzothiazole, benzopyran, indole,
isoindole, indazole or quinoline and the heteroaryl substituents
comprise one or more C.sub.1-C.sub.6-alkyl, hydroxyl or phenyl
groups
11. The compound of claim 1 wherein G is a monovalent radical of
Formula VI.sub.g, 70b.sub.g is 0, 1, 2, or 3; e.sub.g is 0 or 1;
R.sup.18.sub.l is a hydrogen atom, a normal or branched
C.sub.1-C.sub.8-alkyl group, a halogen substituted normal or
branched C.sub.1-C.sub. 8-alkyl group, a C.sub.3-C.sub.8-cycloalkyl
group, a C.sub.3-C.sub.8-cycloalkyl-C.sub. 1-C.sub.4-alkyl group,
an aryl group or a substituted aryl group wherein the aryl
substituents comprise one or more halogen atoms or one or more
alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano,
C.sub.1-C.sub.7-alkoxycarbonyl, C.sub.1-C.sub.7-alkylsulfonyl,
amino, or C.sub.1-C.sub.7-dialkylamino groups.
12. The compound of claim 1 wherein G is a monovalent radical of
Formula VII.sub.g, 71d.sub.g is 0, 1, 2, or 3; eg is 0 or 1;
R.sup.19.sub.l and R.sup.20.sub.l are, independently, a hydrogen
atom, a normal or branched C.sub.1-C.sub.8-alkyl group, a
halogen-substituted C.sub.1-C.sub.8-alkyl group, a
C.sub.3-C.sub.8-cycloalkyl group, a C.sub.3-C.sub.
8-cycloalkyl-C.sub.1-C.sub.4-alkyl group, an aryl group or a
substituted aryl group wherein the aryl substituents comprise one
or more halogen atoms or one or more alkoxy, trifluoromethyl,
dioxymethylene, nitro, cyano, C.sub.1-C.sub.7-alkoxycarbonyl,
C.sub.1-C.sub.7-alkylsulfonyl, amino, or
C.sub.1-C.sub.7-dialkylamino groups; a heteroaryl or substituted
heteroaryl group derived from imidazole, pyrrole, thiophene, furan,
thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole,
thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine,
pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole,
benzothiazole, benzopyran, indole, isoindole, indazole or quinoline
and the heteroaryl substituents comprise one or more
C.sub.1-C.sub.6-alkyl, hydroxyl or phenyl groups; or
R.sup.19.sub.l, R.sup.20.sub.l and the nitrogen atom form a ring
system comprising 6 or fewer carbon atoms.
13. The compound of claim 1 wherein G is an alkylene sulfoxide or
an alkylene sulfone of Formula VIII.sub.g, 72g.sub.g is 1 or 2,
h.sub.g is 1 or 2, and R.sup.21.sub.l is a methyl, trifluoromethyl,
ethyl or phenyl group.
14. A compound of the formula A-B-D-E-F-G wherein A is
N,N-dimethylvalyl, B is tertiary-leucyl, D is N-methylvalyl, E is
prolyl, F is an aminobenzoic acid residue or an
aminocycloalkanecarboxylic acid residue and C is a monovalent
radical.
15. A compound of the formula A-B-D-E-F-G wherein A is
N,N-dimethylvalyl, B is valyl, D is N-methyl-tertiaryleucyl, E is
prolyl, F is an aminobenzoic acid residue or an
aminocycloalkanecarboxylic acid residue and G is a monovalent
radical.
16. A compound of the formula A-B-D-E-F-G wherein A is
N-methyl-d-prolyl, B is valyl, D is N-methylvalyl, E is prolyl, F
is an aminobenzoic acid residue or an aminocycloalkanecarboxylic
acid residue and G is a monovalent radical.
17. A compound of the formula A-B-D-E-F-G wherein A is
N-methylhomoprolyl, B is valyl, D is N-methylvalyl, E is prolyl, F
is an aminobenzoic acid residue or an aminocycloalkanecarboxylic
acid residue and G is a monovalent radical.
18. A compound of the formula Me.sub.2Val-Val-MeVal-Pro-F-G,
wherein F is of Formula II.sub.f and R.sub.f is a hydrogen atom or
a methyl group, R.sup.1.sub.f and R.sup.2.sub.f are each a hydrogen
atom, an alkyl group or an alkoxy group, and G is an amino group,
an N-substituted amino group, a hydrazido, an alkyl, cycloalkyl,
aryl, or alkylaryl, an alkylene ester, an alkylene amide, an
alkylene sulfoxide or an alkylene sulfone group or a monovalent
radical of the formula --O--R.sup.13.sub.l or --S--R.sup.13.sub.l,
and R.sup.13.sub.l is an alkyl, aryl or alkylaryl group.
19. A compound of the formula Me.sub.2Val-Val-MeVal-Pro-F-G,
wherein F is of Formula III.sub.f, R.sub.f is a hydrogen atom or a
methyl group, a.sub.f is 1 or 2, and G is an amino group, an
N-substituted amino group, a hydrazido, an alkyl, cycloalkyl, aryl,
or alkylaryl, an alkylene ester, an alkylene amide, an alkylene
sulfoxide or an alkylene sulfone group or a monovalent radical of
the formula --O--R.sup.13.sub.l or --S--R.sup.13.sub.l, and
R.sup.13.sub.l is an alkyl, aryl or alkylaryl group.
20. A method for treating cancer in a mammal, comprising
administering to the mammal a therapeutically effective amount of a
compound of claim 1.
21. The method of claim 45 wherein the mammal is a human.
Description
RELATED APPLICATION(S)
[0001] This application is a continuation of International
Application No. PCT/US99/14099, which designated the United States
and was filed on Jun. 23, 1999, published in English, which is a
continuation of, and claims priority to, Ser. No. 09/112,249, filed
Jul. 8, 1998, the teachings of which are incorporated herein by
reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] A number of short peptides with significant activity as
inhibitors of cell growth have been isolated from the Indian Ocean
sea hare Dolabella auricularia (Bai, et al., Biochem. Pharmacology
40: 1859-1864 (1990); Beckwith et al., J. Natl. Cancer Inst. 85:
483-488 (1993) and references cited therein). These include
Dolastatins 1-10 (U.S. Pat. No. 4,816,444, issued to Pettit et al.)
and Dolastatin-15 (European Patent Application No. 398558).
Dolastatin 15, for example, markedly inhibits the growth of the
National Cancer Institute's P388 lymphocytic leukemia (PS system)
cell line, a strong predictor of efficacy against various types of
human malignancies.
[0003] The exceedingly small amounts of the various Dolastatin
peptides present in Dolabella auricularia (about 1 mg each per 100
kg sea hare) and the consequent difficulties in purifying amounts
sufficient for evaluation and use, have motivated efforts toward
the synthesis of these compounds (Roux et al., Tetrahedron 50:
5345-5360 (1994); Shioiri et al., Tetrahedron 49: 1913-24 (1993);
Patino et al., Tetrahedron 48: 4115-4122 (1992) and references
cited therein). Synthetic Dolastatin 15, however, suffers from
drawbacks which include poor solubility in aqueous systems and the
need for expensive starting materials for its synthesis. These, in
turn, have led to the synthesis and evaluation of structurally
modified Dolastatin 15 derivatives (see, for example, Bioorg. Med.
Chem. Lett. 4: 1947-50 (1994); WO 93 03054; JP-A-06234790).
[0004] However, there is a need for synthetic compounds with the
biological activity of Dolastatin 15 which have useful aqueous
solubility and can be produced efficiently and economically.
SUMMARY OF THE INVENTION
[0005] Compounds of the present invention include cell growth
inhibitors which are peptides of Formula I
A-B-D-E-F-G (I)
[0006] and acid salts thereof, wherein A, D, and E are
.alpha.-amino acid residues, B is an .alpha.-amino acid residue, F
is an aminobenzoic acid residue or an aminocycloalkanecarboxylic
acid residue, and G is a monovalent radical, such as, for example,
a hydrogen atom, an amino group, an alkyl group, an alkylene alkyl
ether, an alkylene alkyl thioether, an alkylene aldehyde, an
alkylene amide, a .beta.-hydroxylamino group, a hydrazido group, an
alkoxy group, a thioalkoxy group, an aminoxy group, an oximato
group, an alkylene aryl group, an alkylene ester, an alkylene
sulfoxide or an alkylene sulfone.
[0007] Another aspect of the present invention includes
pharmaceutical compositions comprising a compound of Formula I and
a pharmaceutically acceptable carrier.
[0008] An additional embodiment of the present invention is a
method for treating cancer in a mammal, such as a human, comprising
administering to the mammal an effective amount of a compound of
Formula I in a pharmaceutically acceptable composition.
[0009] The present invention provides compounds with antineoplastic
activity as well as increased metabolic stability relative to
Dolastatin 15.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The present invention relates to peptides having
antineoplastic activity. It also includes pharmaceutical
compositions comprising these compounds and methods for treating
cancer in a mammal, including a human, by administration of these
compositions to the mammal.
[0011] The invention is based on the discovery that Dolastatin 15,
a peptide isolated from the sea hare Dolabella auricularia, is a
potent inhibitor of cell growth. This compound, however, is present
in trace quantities in the sea hare, and is, thus, difficult to
isolate and expensive to synthesize and suffers from poor aqueous
solubility. As shown herein, however, Dolastatin 15 can serve as a
starting point for the development of compounds which overcome
these disadvantages while retaining antineoplastic activity or
exhibiting greater antineoplastic activity than the natural
product. Applicants have discovered that certain structural
modifications of Dolastatin 15 provide compounds with a
surprisingly improved therapeutic potential for the treatment of
neoplastic diseases as compared to Dolastatins-10 and -15. The
Dolastatin-15 derivatives exhibit activity even in multiple
drug-resistant tumor systems and an unpredicted high solubility in
aqueous solvents. Furthermore, the compounds of the present
invention can be conveniently synthesized, as described below in
detail.
[0012] For the purposes of the present invention, the term
"monovalent radical" is intended to mean an electrically neutral
molecular fragment capable of forming one covalent bond with a
second neutral molecular fragment. Monovalent radicals include the
hydrogen atom, alkyl groups, such as methyl, ethyl and propyl
groups, halogen atoms, such as fluorine, chlorine and bromine
atoms, aryl groups, such as phenyl and naphthyl groups, and alkoxy
groups, such as methoxy and ethoxy groups. Two monovalent radicals
on adjacent sigma-bonded atoms can also together form a pi bond
between the adjacent atoms. Two monovalent radicals may also be
linked together, for example, by a polymethylene unit, to form a
cyclic structure. For example, in the unit --N(R)R', R and R' are
each a monovalent radical, and can, together with the nitrogen
atom, form a heterocyclic ring. In addition, two monovalent
radicals bonded to the same atom can also together form a divalent
radical, such as an alkylidene group, for example, a propylidene
group, or an oxygen atom.
[0013] For the purposes of the present invention, the term
"residue" refers to the molecular fragment remaining after the
removal of the elements of a water molecule (one oxygen atom, two
hydrogen atoms) from a molecule, such as an amino acid or a hydroxy
acid.
[0014] For the purposes of the present invention the term "normal
alkyl" refers to an unbranched, or straight chain, alkyl group, for
example, normal propyl (n-propyl, --CH.sub.2CH.sub.2CH.sub.3).
[0015] The compounds of the present invention can be represented by
Formula I,
A-B-D-E-F-G (I),
[0016] wherein A, D and E are .alpha.-amino acid residues; B is an
.alpha. -amino acid residue or an .alpha.-hydroxy acid residue; F
is an aminobenzoic acid residue, or an aminocycloalkanecarboxylic
acid residue, such as an aminocyclobutanecarboxylic acid residue,
an aminocylopentanecarboxylic acid residue, or an
aminocyclohexanecarboxylic acid residue; and G is a monovalent
radical.
[0017] The peptides of Formula I are generally composed of L-amino
acids but they can contain one or more D-amino acids. They can also
be present as salts with physiologically-compatible acids,
including hydrochloric acid, citric acid, tartaric acid, lactic
acid, phosphoric acid, methanesulfonic acid, acetic acid, formic
acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic
acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic
acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid,
ascorbic acid and acetylglycine.
[0018] The following is a description of the present invention,
including a detailed description of individual components and of
methods of using the claimed compounds.
Compounds of the Present Invention
[0019] Identity of A
[0020] In one embodiment, A is an amino acid derivative of Formula
II.sub.a, 1
[0021] where n.sub.a is an integer, preferably 0, 1, 2, or 3.
R.sub.a is a monovalent radical, such as a hydrogen atom or a
C.sub.1-C.sub.3-alkyl group which can be normal, branched or cyclic
and can be substituted by one or more, preferably 1 to about 3,
fluorine atoms; suitable examples include methyl, ethyl, isopropyl,
2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl,
1-fluoromethyl-2-fluoroethyl or cyclopropyl; methyl, ethyl or
isopropyl are preferred;
[0022] In this embodiment, R.sup.1.sub.a is a monovalent radical,
such as a hydrogen atom or a methyl, ethyl, propyl or phenyl group.
The phenyl group can be substituted; suitable substituents include
one or more halogen atoms, with fluorine, chlorine and bromine
being preferred, C.sub.1-C.sub.4-alkyl groups, methoxy, ethoxy,
trifluoromethyl or nitro groups.
[0023] R.sup.2.sub.a, R.sup.3.sub.a, R.sup.4.sub.a and
R.sup.5.sub.a are each, independently, a monovalent radical, such
as a hydrogen atom or a methyl group. R.sub.a and R.sup.1.sub.a
together can also form a propylene bridge.
[0024] In another embodiment, A is an amino acid derivative of
Formula III.sub.a, 2
[0025] where R.sub.a has the meaning stated for Formula II.sub.a,
R.sup.1.sub.a is a monovalent radical, for example, a hydrogen atom
or a lower alkyl group, preferably a methyl, ethyl or propyl
group.
[0026] In this embodiment, R.sup.6.sub.a is a monovalent radical,
such as a hydrogen atom, a normal or branched C.sub.1-C.sub.8-alkyl
group, which can he substituted by one or more halogen, preferably
fluorine, atoms, or a C.sub.3-C.sub.8-cycloalkyl or
C.sub.3-C.sub.8-cycloalkyl-C.sub. 1-C.sub.4-alkyl group, a
C.sub.1-C.sub.4-oxoalkyl group such as a methoxymethyl,
1-methoxyethyl or 1,1-dimethylhydroxymethyl group, a
C.sub.2-C.sub.5 alkenyl group, such as a vinyl or 1-methylvinyl
group, or a substituted or unsubstituted phenyl group. Suitable
phenyl substituents include one or more halogen atoms, preferably
fluorine, chlorine or bromine atoms, and alkyl, methoxy, ethoxy,
trifluoromethyl, or nitro groups. R.sup.7.sub.a is a monovalent
radical, preferably a methyl group or an ethyl group.
[0027] In another embodiment, A is an amino acid residue of Formula
IV.sub.a, 3
[0028] where m.sub.a is an integer, preferably 1 or 2. R.sub.a and
R.sup.7.sub.a have the meanings stated for R.sub.a and
R.sup.7.sup.a in Formula III.sub.a.
[0029] In another embodiment, A is an amino acid residue of Formula
V.sub.a, 4
[0030] where R.sub.a and R.sup.7.sub.a have the meanings stated for
R.sub.a and R.sup.7.sup.a in Formula III.sub.a.
[0031] In a further embodiment, A is a substituted proline
derivative of Formula VI.sub.a, 5
[0032] where R.sub.a and R.sup.1.sub.a have the meanings stated for
R.sub.a and R.sup.1.sub.a in Formula II.sub.a, and X.sub.a is a
monovalent radical, preferably a hydroxyl, methoxy or ethoxy group
or a fluorine atom.
[0033] In another embodiment, A is a thiaprolyl derivative of
Formula VII.sub.a, 6
[0034] where R.sub.a, R.sup.1.sub.a, R.sup.2.sub.a, R.sup.3.sub.a,
R.sup.4.sub.a and R.sup.5.sub.a have the meanings stated for these
variables in Formula II.sub.a.
[0035] In another embodiment, A is a 1,3-dihydroisoindole
derivative of Formula VIII.sub.a, 7
[0036] where R.sub.a has the meaning stated for R.sub.a in Formula
II.sub.a.
[0037] In another embodiment, A is a
2-azabicyclo[2.2.1]heptane-3-carboxyl- ic acid derivative of
Formula IX.sub.a, 8
[0038] where Z.sub.a is a single or double bond and R.sub.a has the
meaning stated for this variable in Formula II.sub.a. The
3-carbonyl substituent can have either the exo or endo
orientation.
[0039] Identity of B
[0040] B is a valyl, isoleucyl, allo-isoleucyl, norvalyl,
2-tert-butylglycyl or 2-ethylglycyl residue. B can also be a
carboxylic acid derivative of Formula IIb, 9
[0041] wherein R.sup.1.sub.b and R.sup.2.sub.b are each a
monovalent radical. R.sup.1.sub.b is, preferably, a hydrogen atom
and R.sup.2.sub.b is, for example, a cyclopropyl group, a normal or
branched butyl, preferably tertiary-butyl, group, a methoxymethyl
group, a 1-methoxyethyl group or a 1-methylvinyl group.
Additionally, R.sup.1.sub.b and R.sup.2.sub.b together can be an
isopropylidene group.
[0042] Identity of D
[0043] D is an N-alkylvalyl, N-alkyl-2-ethylglycyl,
N-alkyl-2-tert-butylglycyl, N-alkyl-norleucyl, N-alkyl-isoleucyl,
N-alkyl-allo-isoleucyl or N-alkyl-norvalyl residue, where the alkyl
group is preferably methyl or ethyl.
[0044] In another embodiment, D is an .alpha.-amino carboxylic acid
derivative of Formula II.sub.d, 10
[0045] where R.sub.d has the meaning stated for R.sub.a in Formula
III.sub.a, R.sup.1.sub.d is a monovalent radical, preferably a
hydrogen atom, and R.sup.2 is a monovalent radical such as a
cyclopropyl group, a methoxymethyl group, a 1-methoxyethyl group or
a 1-methylvinyl group. Additionally, R.sup.1.sub.d and
R.sup.2.sub.d together can form an isopropylidene group.
[0046] Alternatively, D can be a proline derivative of Formula
III.sub.d, 11
[0047] where n.sub.d is an integer, for example, 1 or 2. and
R.sup.3.sub.d has the meaning stated for R.sup.1.sub.a in Formula
III.sub.a. X.sub.d is a monovalent radical, preferably a hydrogen
atom, and, in the case where n.sub.d equals 1, can also be a
hydroxyl, methoxy or ethoxy group or a fluorine atom.
[0048] Identity of E
[0049] E is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or
hydroxyprolyl residue, or a cyclic .alpha.-amino carboxylic acid
residue of Formula II.sub.e, 12
[0050] where n.sub.e is an integer, preferably 0, 1 or 2.
R.sup.1.sub.e has the meaning stated for R.sup.1.sub.a in Formula
III.sub.a. R.sup.2.sub.e and R.sup.3.sub.e are each a monovalent
radical, and can be, independently, a hydrogen atom or a methyl
group. R.sup.4.sub.e is a monovalent radical, preferably a hydrogen
atom, a hydroxyl, methoxy or ethoxy group or a fluorine atom.
R.sup.5.sub.e is a monovalent radical, preferably a hydrogen atom.
In the case where n.sub.e has the value 1, R.sup.3.sub.e and
R.sup.4.sub.e together can form a double bond or R.sup.4.sub.e and
R.sup.5.sub.e can together be a double-bonded oxygen radical. In
the case where n.sub.e has the value 1 or 2, R.sup.1.sub.e and
R.sup.2.sub.e can together form a double bond.
[0051] In another embodiment, E is a 2- or
3-amino-cyclopentanecarboxylic acid residue of Formula III.sub.e,
13
[0052] where R.sub.e is a monovalent radical, such as a methyl or
ethyl group and R.sup.1.sub.e has the meaning stated for
R.sup.1.sub.a in Formula III.sub.a.
[0053] Identity of F
[0054] In one embodiment, F is an aminobenzoyl derivative of
Formula II.sub.f, 14
[0055] where R.sub.f is a hydrogen atom or an alkyl group,
preferably a methyl, ethyl or propyl group. The carbonyl group can
be in position 1 (ortho), 2 (meta), or 3 (para) of the phenyl ring
relative to the nitrogen atom. R.sup.1.sub.f and R.sup.2.sub.f are
each, independently, a hydrogen atom; a halogen atom, for example,
a fluorine, chlorine, bromine, or iodine atom; a
C.sub.1-C.sub.4-alkyl group; a methoxy, ethoxy, trifluoromethyl,
nitro, cyano, amino or dimethyalmino group. Additionally,
R.sup.1.sub.f and R.sup.2.sub.f can together form a dioxymethylene
group.
[0056] In another embodiment, F is an aminocycloalkanecarboxylic
acid residue of Formula III.sub.f, 15
[0057] where R.sub.f is a monovalent radical, such as a hydrogen
atom or a lower alkyl group, preferably a methyl, ethyl or propyl
group. a.sub.f is an integer, for example, 0, 1 or 2. The carbonyl
group is in position 2 or position 3 of the cycloalkane ring
relative to the nitrogen atom at position 1. The stereogenic
centers can be, independently of each other, R or S. For a
five-membered ring (a.sub.f=1) , the combinations R1,S2 and S1,R2
would be referred to as cis-pentacin derivatives, while the
combinations R1,R2 and S1,S2 are trans-pentacin derivatives.
[0058] Identity of G
[0059] In one embodiment, G is an amino or substituted amino group
of Formula II.sub.g, 16
[0060] where R.sup.1.sub.l is a monovalent radical, such as a
hydrogen atom, a normal or branched, saturated or unsaturated
C.sub.1-C.sub.18-alkoxy group, a substituted or unsubstituted
aryloxy group, a substituted or unsubstituted
aryl-C.sub.1-C.sub.6-alkoxy group, or a substituted or
unsubstituted aryloxy-C.sub.1-C.sub.6-alkoxy or
heteroaryl-C.sub.1-C.sub.6-alkoxy group. The aryl group is
preferably a phenyl or naphthyl group. The heteroaryl group is a 5-
or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing,
ring system, such as, for example, imidazolyl, isoxazolyl,
isothiazolyl, thiazolyl, oxazolyl, pyrazolyl, thiophenyl, furanyl,
pyrrolyl, 1,2,4- or 1,2,3-triazolyl, pyrazinyl, indolyl,
benzofuranyl, benzothiophenyl, isoindolyl, indazolyl, quinolinyl,
pyridazinyl, pyrimidinyl, benzimidazolyl, benzopyranyl,
benzothiazolyl, oxadiazolyl, thiadiazolyl or pyridinyl group.
Suitable aryl or heteroaryl substituents include one or more
halogen atoms, preferably fluorine, bromine or chlorine;
C.sub.1-C.sub.4-alkyl groups; methoxy, ethoxy or trifluoromethyl
groups, a dioxymethylene group or a nitro group.
[0061] R.sup.2.sub.l is a monovalent radical, such as a hydrogen
atom, a normal or branched, saturated or unsaturated
C.sub.1-C.sub.18-alkyl group, a C.sub.3-C.sub.10-cycloalkyl group,
a substituted or unsubstituted aryl group, where aryl is preferably
phenyl or naphthyl. Suitable aryl substituents include one or more
halogen, preferably fluorine, chlorine or bromine, atoms,
C.sub.1-C.sub.4-alkyl groups, methoxy, ethoxy or trifluoromethyl
groups, a dioxymethylene group, nitro or cyano groups, a
C.sub.1-C.sub.7-alkoxycarbonyl group, a
C.sub.1-C.sub.7-alkylsulfonyl group, an amino or
C.sub.1-C.sub.7-dialkyla- mino group, where the alkyl groups can,
together with the nitrogen atom, also form a 5- or 6-membered
heterocycle, or an unsubstituted or substituted heteroaryl group.
The heteroaryl group can be a 5- or 6-membered, preferably
nitrogen-, oxygen- or sulfur-containing, ring system which can be
fused to a benzene ring, such as, for example, imidazolyl,
pyrrolyl, thiophenyl, furanyl, thiazolyl, oxazolyl, pyrazolyl,
1,2,4- or 1,2,3-triazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl,
isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl,
benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl,
benzopyranyl, indolyl, isoindolyl, indazolyl or quinolinyl group,
with preferred substituents being C.sub.1-C.sub.6-alkyl groups, or
hydroxyl or phenyl groups.
[0062] R.sup.2.sub.l can additionally be of Formula II.sub.l,
17
[0063] wherein a.sub.l is an integer, preferably 0, 1, 2, 3, 4, or
5. R.sup.3.sub.l is a monovalent radical, such as a lower alkyl
group, for example, a methyl, ethyl, propyl or isopropyl group.
R.sup.4.sub.l is a saturated or partially unsaturated carbocyclic
group containing from 3 to about 10 carbon atoms, or a substituted
or unsubstituted aryl or heteroaryl group, where the preferred aryl
and heteroaryl groups and suitable substituents are as stated for
R.sup.2.sub.l in Formula II.sub.g.
[0064] R.sup.2.sub.l can also be a monovalent radical of Formula
III.sub.l, 18
[0065] wherein W.sub.l is an oxygen or sulfur atom or an
N--R.sup.6.sub.l group. R.sup.5.sub.l is a monovalent radical, such
as a hydrogen atom, a C.sub.1-C.sub.4-alkyl or
C.sub.3-C.sub.7-cycloalkyl group or a substituted or unsubstituted
aryl or arylmethyl group, with aryl and its preferred substituents
having the meaning stated for R.sup.2.sub.l from Formula II.sub.g.
R.sup.6.sub.l is a monovalent radical, preferably a hydrogen atom,
a C.sub.1-C.sub.4-alkyl group or a C.sub.3-C.sub.7-cycloal- kyl
group, a C.sub.1-C.sub.18-alkanoyl group, a benzoyl group or a
substituted or unsubstituted aryl or arylmethyl group, with aryl
and its preferred substituents having the meaning stated for
R.sup.2.sub.l in Formula II.sub.g,
[0066] R.sup.2.sub.l can alternately be a substituent of Formula
IV.sub.l, 19
[0067] where b.sub.l is an integer, preferably 2, 3 or 4. Z.sub.l
is a monovalent radical, such as a formyl, aminocarbonyl or
hydrazinocarbonyl group, or a cyclic or acyclic acetal or
thioacetal group.
[0068] R.sup.2.sub.l can also be a substituent of Formula V.sub.l,
20
[0069] in which b.sub.l is an integer, preferably 2, 3 or 4.
R.sup.7.sub.l is a monovalent radical, such as a glycol oligomer of
the formula
--O(CH.sub.2CH.sub.2O).sub.dl--CH.sub.3,
[0070] where d.sub.l is an integer, preferably in the range from
about 2 to about 4 or from about 40 to about 90.
[0071] R.sup.2.sub.l can further be a carbohydrate of Formula
VI.sub.l, 21
[0072] where R.sup.8.sub.l is a monovalent radical, such as a
hydrogen atom, a C.sub.1-C.sub.4-alkanoyl or alkyl group, a benzoyl
group or a benzyl group.
[0073] In another embodiment, G is an .beta.-hydroxy amine of
Formula III.sub.g, 22
[0074] where R.sup.9.sub.l is a monovalent radical such as a
hydrogen atom, a C.sub.1-C.sub.6-alkyl group or a substituted or
unsubstituted aryl group, with aryl and its preferred substituents
having the meaning stated for R.sup.2.sub.l in Formula II.sub.g.
R.sup.10.sub.l is a monovalent radical, preferably a hydrogen atom,
alkyl, for example, methyl, or a phenyl group.
[0075] Another subclass of compounds of this invention includes
peptides of Formula I wherein G is a hydrazido group of Formula
IV.sub.g, 23
[0076] where R.sup.11.sub.l and R.sup.12.sub.l are each,
independently, a monovalent radical such as a hydrogen atom, a
normal or branched C.sub.1-C.sub.8-alkyl group, a C.sub.3-C.sub.8-
cycloalkyl group, a
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl group or a
substituted or unsubstituted aryl, heteroaryl,
aryl-C.sub.1-C.sub.4-alkyl or heteroaryl-C.sub.1-C.sub.4-alkyl
group, where aryl, heteroaryl and their preferred substituents can
be selected from among the options listed for R.sup.2.sub.1 in
Formula II.sub.g. R.sup.11.sub.l and R.sup.12.sub.l can also
together form a propylene or butylene bridge.
[0077] Another subclass of compounds of this invention includes
peptides of Formula I wherein G is a monovalent radical of the
formula --O--R.sup.13.sub.l or --S--R.sup.13.sub.l, where
R.sup.13.sub.l is a monovalent radical, such as a
C.sub.3-C.sub.10-cycloalkyl group, a normal or branched
C.sub.2-C.sub.16-alkenylmethyl group or a C.sub.1-C.sub.16-alkyl
group which can be substituted by from 1 to about 5 halogen,
preferably fluorine, atoms.
[0078] R.sup.13.sub.l can also be the radical
--(CH.sub.2).sub.el--R.sup.1- 4.sub.l where e.sub.l is an integer,
preferably 1, 2 or 3. R.sup.14.sub.l is a monovalent radical,
preferably a saturated or partially unsaturated
C.sub.3-C.sub.10-carbocycle.
[0079] R.sup.13.sub.l can further be the radical
--[CH.sub.2--CH.dbd.C(CH.sub.3)--CH.sub.2].sub.fl--H,
[0080] where f.sub.l is an integer, preferably 1, 2, 3 or 4.
[0081] R.sup.13.sub.l can also be the radical
--[CH.sub.2--CH.sub.2--O].sub.gl--CH.sub.3,
[0082] where g.sub.l is an integer, preferably from about 2 to
about 4, or from about 40 to about 90.
[0083] R.sup.13.sub.l can also be the radical
--(CH.sub.2).sub.hl-aryl or --(CH.sub.2).sub.hl-heteroaryl,
[0084] where aryl and heteroaryl can also be substituted and, along
with their preferred substituents, can be selected from the group
listed for R.sup.2.sub.l in Formula II.sub.g. h.sub.l is an
integer, preferably 0, 1, 2 or 3.
[0085] R.sup.13.sub.l can further be the radical
--(CH.sub.2).sub.bl-W.sub.l-R.sup.5.sub.l,
[0086] where b.sub.l, W.sub.l and R.sup.5.sub.l are each selected
from among the options described for Formula III.sub.l.
[0087] Another subclass of compounds of this invention includes
peptides of Formula I in which G is an aminoxy group of the
formula
--O--N(R.sup.15.sub.l)(R.sup.16.sub.l),
[0088] where R.sup.15.sub.l and R.sup.16.sub.l are each a
monovalent radical, and can independently be a hydrogen atom, a
normal or branched C.sub.1-C.sub.8-alkyl group, which can be
substituted by halogen, preferably fluorine, atoms, a
C.sub.3-C.sub.8-cycloalkyl group, a
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl group, a
substituted or unsubstituted aryl or heteroaryl group or a
substituted or unsubstituted aryl-C.sub.1-C.sub.4-alkyl group. Aryl
and heteroaryl groups and the preferred substituents thereof can be
selected from the options listed for R.sup.2.sub.l in Formula
II.sub.g. Additionally, R.sup.15.sub.l and R.sup.16.sub.l can
together form a 5-, 6- or 7-membered heterocycle.
[0089] Another subclass of compounds of this invention includes
peptides of Formula I wherein G is an oximato group of the
formula
--O--N.dbd.C(R.sup.15.sub.l)(R.sup.16.sub.l),
[0090] where R.sup.15.sub.l and R.sup.16.sub.l are selected from
among the options listed above and, additionally, can together form
a cyclic system comprising, preferably, from about 3 to about 7
ring atoms. This cyclic system can additionally be fused to one or
more aromatic rings. Particularly preferred cyclic systems are
shown below. 24
[0091] A further subclass of compounds of this invention includes
peptides of Formula I wherein G is a hydrogen atom, a normal or
branched C.sub.1-C.sub.8-alkyl group, which can be substituted by
up to six halogen, preferably fluorine, atoms, a
C.sub.3-C.sub.8-cycloalkyl group or a
C.sub.3-C.sub.8-cycloalkyl-C.sub. 1-C.sub.4-alkyl group.
[0092] G can also be an arylalkyl, heteroarylalkyl, aryl or
heteroaryl group of Formula V.sub.g,
--(CH.sub.2).sub.ag--R.sup.17.sub.l (V.sub.g)
[0093] where a.sub.g is an integer, such as 0, 1 or 2.
R.sup.17.sub.l is a substituted or unsubstituted aryl or heteroaryl
group. Preferred aryl groups include phenyl and naphthyl groups.
Suitable aryl substituents include halogen, preferably fluorine,
bromine or chlorine, atoms, C.sub.1-C.sub.4-alkyl groups, methoxy,
ethoxy or trifluoromethyl groups, a dioxymethylene group, a nitro
or cyano group, a C.sub.1-C.sub.7-alkoxyc- arbonyl group, a
C.sub.1-C.sub.7- alkylsulfonyl group, an amino group or a
C.sub.1-C.sub.6-dialkylamino group, where the alkyl groups can,
together with the nitrogen atom, also form a 5- or 6-membered
heterocycle. R.sup.17.sub.l can also be a 5- or 6-membered,
preferably nitrogen-, oxygen- or sulfur-containing, ring system
which can be fused to a benzene ring. Suitable heteroaryl groups
include imidazolyl, pyrrolyl, thiophenyl, furanyl, thiazolyl,
oxazolyl, pyrazolyl, 1,2,4- or 1,2,3-triazolyl, oxadiazolyl,
thiadiazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl,
pyrimidinyl, pyridinyl, benzofuranyl, benzothiophenyl,
benzimidazolyl, benzothiazolyl, benzopyranyl, indolyl, isoindolyl,
indazolyl and quinolinyl groups. Preferred heteroaryl substituents
are C.sub.1-C.sub.6-alkyl groups, a hydroxyl group or a phenyl
group.
[0094] Another subclass of compounds of this invention includes
compounds of Formula I wherein G is a monovalent radical of Formula
VI.sub.g,
--(CH.sub.2).sub.bg--(C.dbd.O).sub.cg--OR.sup.18.sub.l
(VI.sub.g),
[0095] where b.sub.g is an integer, preferably 0, 1, 2 or 3, and
c.sub.g is an integer, preferably 0 or 1. b.sub.g and c.sub.g are
not both simultaneously 0. R.sup.18.sub.l is a monovalent radical,
such as a hydrogen atom, a straight-chain or branched
C.sub.1-C.sub.8-alkyl group which can be substituted by halogen,
preferably fluorine, atoms, especially a CF.sub.2-moiety, a
C.sub.3-C.sub.8-cycloalkyl group, a
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl group, a
substituted or unsubstituted aryl, preferably phenyl or naphthyl,
group. Suitable aryl substituents are halogen, preferably fluorine,
bromine or chlorine, atoms, C.sub.1-C.sub.4-alkoxy,
trifluoromethyl, nitro or cyano groups, a dioxymethylene moiety, a
C.sub.1-C.sub.7-alkoxycarbonyl moiety, a
C.sub.1-C.sub.7-alkylsulfonyl moiety, an amino group or a
C.sub.1-C.sub.6-dialkylamino group, where the alkyl groups can,
together with the nitrogen atom, also form a 5- or 6-membered
heterocycle.
[0096] G can also be a monovalent radical of Formula VII.sub.g
25
[0097] where d.sub.g is an integer, preferably 0, 1, 2 or 3, and
e.sub.g is an integer such as 0 or 1. d.sub.g and e.sub.g cannot
both simultaneously take the value 0. R.sup.19.sub.l and
R.sup.20.sub.l are each, independently, a monovalent radical, such
as a hydrogen atom, a straight-chain or branched
C.sub.1-C.sub.8-alkyl group, which can further be substituted by
halogen, preferably fluorine, atoms, especially a CF.sub.2-moiety,
a C.sub.3-C.sub.8-cycloalkyl group, a
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl group, a
substituted or unsubstituted aryl, preferably phenyl or naphthyl
group. Suitable aryl substituents include one or more halogen,
referably fluorine, bromine or chlorine, atoms,
C.sub.1-C.sub.4-alkoxy, trifluoromethyl, nitro or cyano groups, a
dioxymethylene moiety, a C.sub.1-C.sub.7-alkoxycarbonyl moiety, a
C.sub.1-C.sub. 7-alkylsulfonyl group, an amino group or a
C.sub.1-C.sub.6-dialkylamino group, where the alkyl groups can,
together with the nitrogen atom, also form a 5- or 6-membered
heterocycle. N(R.sup.19.sub.l)R.sup.20.sub.l can additionally form
a ring system of the formula N(CH.sub.2).sub.fg, where f.sub.g is
an integer selected from among 4, 5 or 6.
[0098] Another subclass of compounds of this invention includes
peptides of Formula I, wherein G is a monovalent radical of Formula
VIII.sub.g,
--(CH.sub.2).sub.gg--S(O).sub.hg--R.sup.21.sub.l (VIII.sub.g),
[0099] where g.sub.g is an integer, for example, 1 or 2, and
h.sub.g is 1 or 2. R.sup.21.sub.l is a monovalent radical,
preferably a methyl group, a trifluoromethyl group, an ethyl group
or a phenyl group.
[0100] G can also be an alkyl- or arylcarbonylalkyl group of
Formula IX.sub.g,
--(CH.sub.2).sub.ig--(C.dbd.O)--R.sup.22.sub.l (IX.sub.g),
[0101] where R.sup.22.sub.l is a monovalent radical, such as a
hydrogen atom, a straight-chain or branched C.sub.1-C.sub.8-alkyl
group which can be substituted by up to six halogen, preferably
fluorine, atoms, especially a CF.sub.2-moiety, a
C.sub.3-C.sub.8-cycloalkyl group, a
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl group, a
substituted or unsubstituted aryl, preferably phenyl or naphthyl,
group. Suitable aryl substituents are halogen, preferably fluorine,
bromine or chlorine, atoms, C.sub.1-C.sub.4-alkoxy,
trifluoromethyl, nitro or cyano groups, a dioxymethylene moiety, a
C.sub.1-C.sub.7-alkoxycarbonyl moiety, a
C.sub.1-C.sub.7-alkylsulfonyl moiety, an amino group or a
C.sub.1-C.sub.6-dialkylamino group, where the alkyl groups can,
together with the nitrogen atom, also form a 5- or 6-membered
heterocycle.
[0102] Synthetic Methods
[0103] The compounds of the present invention can be prepared by
known methods of peptide synthesis. Thus, the peptides can be
assembled sequentially from individual amino acids or by linking
suitable small peptide fragments. In sequential assemblage, the
peptide chain is extended stepwise, starting at the C-terminus, by
one amino acid per step. In fragment coupling, fragments of
different lengths can be linked together, and the fragments in turn
can be obtained by sequential assembly from amino acids or by
fragment coupling of still shorter peptides.
[0104] In both sequential assemblage and fragment coupling it is
necessary to link the units by forming an amide linkage, which can
be accomplished via a variety of enzymatic and chemical methods.
Chemical methods for forming the amide linkage are described in
detail in standard references on peptide chemistry, including
Muller, Methoden der organischen Chemie Vol. XV/2, pages 1-364,
Thieme Verlag, Stuttgart, Germany (1974); Stewart and Young, Solid
Phase Peptide Synthesis, pages 31-34 and 71-82, Pierce Chemical
Company, Rockford, Ill. (1984); Bodanszky et al., Peptide
Synthesis, pages 85-128, John Wiley & Sons, New York, (1976).
Preferred methods include the azide method, the symmetric and mixed
anhydride method, the use of in situ generated or preformed active
esters, the use of urethane protected N-carboxy anhydrides of amino
acids and the formation of the amide linkage using coupling
reagents, such as carboxylic acid activators, especially
dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),
1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquino- line (EEDQ), pivaloyl
chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiim- ide
hydrochloride (EDCI), n-propane-phosphonic anhydride (PPA),
N,N-bis(2-oxo-oxazolidinyl)imido-phosphoryl chloride (BOP-Cl),
bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop),
diphenyl-phosphoryl azide (DPPA), Castro's reagent (BOP, PyBop),
O-benzotriazolyl-N,N,N', N'-tetramethyluronium salts (HBTU),
diethylphosphoryl cyanide (DEPCN),
2,5-diphenyl-2,3-dihydro-3-oxo-4-hydro- xy-thiophene dioxide
(Steglich's reagent; HOTDO), and 1,1'-carbonyl-diimidazole (CDI).
The coupling reagents can be employed alone or in combination with
additives such as N,N-dimethyl-4-aminopyridi- ne (DMAP),
N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt),
N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.
[0105] Although the use of protecting groups is generally not
necessary in enzymatic peptide synthesis, reversible protection of
reactive groups not involved in formation of the amide linkage is
necessary for both reactants in chemical synthesis. Three
conventional protective group techniques are preferred for chemical
peptide synthesis: the benzyloxycarbonyl (Z), the t-butoxycarbonyl
(Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) techniques.
Identified in each case is the protective group on the
.alpha.-amino group of the chain-extending unit. A detailed review
of amino-acid protective groups is given by Muller, Methoden der
organischen Chemie Vol. XV/1, pp 20-906, Thieme Verlag, Stuttgart
(1974). The units employed for assembling the peptide chain can be
reacted in solution, in suspension or by a method similar to that
described by Merrifield (J. Am. Chem. Soc. 85: 2149 (1963)).
Particularly preferred methods are those in which peptides are
assembled sequentially or by fragment coupling using the Z, Boc or
Fmoc protective group technique, with one of the reactants in the
said Merrifield technique being bonded to an insoluble polymeric
support (also called resin hereinafter). This typically entails
assembling the peptide sequentially on the polymeric support using
the Boc or Fmoc protective group technique, with the growing
peptide chain covalently bonded at the C terminus to the insoluble
resin particles. This procedure allows the removal of reagents and
byproducts by filtration, eliminating the need to recrystallize
intermediates.
[0106] The protected amino acids can be linked to any suitable
polymer, which must be insoluble in the solvents used and have a
stable physical form which permits filtration. The polymer must
contain a functional group to which the first protected amino acid
can be covalently attached. A wide variety of polymers are suitable
for this purpose, including cellulose, polyvinyl alcohol,
polymethacrylate, sulfonated polystyrene, chloromethylated
styrene/divinylbenzene copolymer (Merrifield resin),
4-methylbenzhydrylamine resin (MBHA-resin), phenylacetamidomethyl
resin (Pam-resin), p-benzyloxy-benzyl-alcohol-resin,
benzhydryl-amine-resin (BHA-resin),
4-(hydroxymethyl)-benzoyl-oxymethyl-resin, the resin of Breipohl et
al. (Tetrahedron Letters 28 (1987) 565; supplied by BACHEM),
4-(2,4-dimethoxyphenylaminomethyl) phenoxy resin (supplied by
Novabiochem) or o-chlorotrityl-resin (supplied by Biohellas).
[0107] Solvents suitable for peptide synthesis include any solvent
which is inert under the reaction conditions, especially water,
N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
acetonitrile, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran
(THF), N-methyl-2-pyrrolidone (NMP) and mixtures of these
solvents.
[0108] Peptide synthesis on the polymeric support can be carried
out in a suitable inert organic solvent in which the amino acid
derivatives starting materials are soluble. However, preferred
solvents additionally have resin-swelling properties and include
DMF, DCM, NMP, acetonitrile, DMSO, and mixtures of these solvents.
Following synthesis, the peptide is removed from the polymeric
support. The conditions under which this cleavage is accomplished
for various resin types are disclosed in the literature. The
cleavage reactions most commonly used are acid- or
palladium-catalyzed, the former being conducted in, for example,
liquid anhydrous hydrogen fluoride, anhydrous
trifluoromethanesulfonic acid, dilute or concentrated
trifluoroacetic acid, and acetic
acid/dichloromethane/trifluoroethanol mixtures. The latter can be
carried out in THF or THF-DCM-mixtures in the presence of a weak
base such as morpholine. Certain protecting groups are also cleaved
off under these conditions.
[0109] Partial deprotection of the peptide may also be necessary
prior to certain derivatization reactions. For example, peptides
dialkylated at the N-terminus can be prepared either by coupling
the appropriate N,N-di-alkylamino acid to the peptide in solution
or on the polymeric support or by reductive alkylation of the
resin-bound peptide in DMF/1% acetic acid with NaCNBH.sub.3 and the
appropriate aldehyde.
[0110] The two schemes which follow present a more detailed
description of the synthesis of the compounds of the present
invention. 26
[0111] The tetrapeptide A-B-D-E-OH is coupled with an
amino-derivative F-G to give the final compound A-B-D-E-F-G using
the methods for peptide coupling as described above. 27
[0112] Here, the N-terminal protected tetrapeptide A'-B-D-E-OH is
coupled with an amino-derivative F-G to give an intermediate
compound A'-B-D-E-F-G using the methods for peptide coupling as
described above. Then, the N-protecting group is removed by
conventional methods as described above. The groups R.sub.A and
R.sup.7.sub.A can then be attached to the amino terminus via
reductive alkylation as described above.
[0113] Building blocks of use in the synthesis of the claimed
compounds (described in scheme I and II as F-G) can be prepared by
the following general methods:
[0114] a) Synthesis of Amino-phenyl-ketones
[0115] The following schemes describe synthetic routes to
aminophenyl-ketones which are not commercially available. 28
[0116] In scheme III.1, the synthesis starts with a
nitrobenzaldehyde. Addition of organometallic compounds such as
lithium or Grignard reagents led to the corresponding alcohols
(Furstner et al. Tetrahedron 52: 7329-7344 (1996); Furstner et al.,
Tetrahedron 51, 773-786 (1995)). These alcohols can be oxidised to
the ketones with known oxidation agents, such as chromium(VI)
compounds (for example, pyridinium dichromate in dichloromethane,
as described by Furstner et al., supra) or the Dess Martin reagent.
The nitrophenyl ketones are then reduced to the corresponding
amino-phenyl-ketones either by hydrogenation in presence of a
palladium catalyst, such as palladium on carbon, or by metal salts
in presence of acids such as the combination of tin(II)chloride and
hydrochloric acid (Nunn et al., J. Chem. Soc. 1952: 583-588).
29
[0117] A more direct route (see scheme III.2) is the reaction of
nitrobenzoyl chlorides with an organometallic reagent such as a
lithium or Grignard reagent (Furstner et al., Tetrahedron 51,
773-786 (1995)). 30
[0118] 2-Amino-phenyl ketones can be obtained by reaction of the
corresponding 2-fluorophenyl-ketone with sodium azide in a polar
solvent, such as N,N-dimethylformamide, and subsequent reduction of
the intermediate benzisoxazole (see scheme III.3). For example, the
synthesis of 2-aminophenyl-(4-pyridazinyl)-ketone has been
described by N. Haider et al. (Arch. Pharm. 325: 119-122
(1992)).
[0119] b) Synthesis of Amino-benzamides
[0120] The following schemes describe synthetic routes to
aminobenzamides which are not commercially available. 31
[0121] In scheme IV.1, the steps are described starting from
nitrobenzoic acids or substituted nitrobenzoic acids. These acids
are coupled with primary or secondary amines (HNR.sup.1R.sup.2) by
using coupling reagents. Preferred method is the use of coupling
reagents such as carboxylic acid activators, especially
dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),
1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquino- line (EEDQ),
pivaloylchloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimi- de
hydrochloride (EDCI), n-propane-phosphonic anhydride (PPA),
N,N-bis(2-oxo-3oxazolidinyl)-imidophosphoryl chloride (BOP-Cl),
bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop),
diphenylphosphoryl azide (DPPA), Castro's reagent (BOP, PyBop),
O-benzotriazolyl-N,N,N',N'-tetramethyluronium salts (HBTU),
diethylphosphoryl cyanide (DEPCN), 2,5-diphenyl
2,3-dihydro-3-oxo-4-hydro- xythiophene dioxide (Steglich's reagent;
HOTDO) and 1,1'-carbonyldiimidazole (CDI). The coupling reagents
can be employed alone or in combination with additives such as
N,N-dimethyl-4-aminopyridi- ne (DMAP), N-hydroxy-benzotriazole
(HOBt), N-hydroxybenzotriazine (HOOBt), azabenzotriazole,
N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.
[0122] In place of the acids, the corresponding nitro-benzoyl
chloride can be used. These are either commercially available or
could be synthesized from the corresponding acids with thionyl
chloride. The amines react with the nitrobenzoylchlorides in the
presence of a base such as pyridine, which can also be used as the
solvent (N. S. Cho et al., J. Heterocycl. Chem. 33, 1201-1206
(1996)). The nitro-benzamides are then reduced to the corresponding
amino-benzamides by reducing agents such as metal salts in presence
of hydrochloride acids or by metal-catalysed hydrogenation using
palladium on a solid such as palladium on charcoal as catalyst.
This route is described in Example 1.
[0123] Another method involves transforming the amine to the
trifluoroacetamide by treatment with trifluoroacetic anhydride. The
amide is deprotonated with a base such as sodium hydride or
potassium t-butanolate and then treated with the corresponding
alkyl halide such as methyl iodide, ethyl iodide or isopropyl
iodide. The trifluoroacetamide is easily cleaved in basic alcoholic
solution such as potassium carbonate in methanol. 32
[0124] In scheme IV.2. the starting materials for the synthesis of
amino-benzamides are the N-protected aminobenzoic acids. Different
protecting groups for the nitrogen are compatible such as the above
mentioned Z-, Boc- or Fmoc-protecting groups. The N-protected
amino-benzoic acids are coupled with amines as described above for
the nitro-benzoic acids using the above mentioned coupling
conditions. This route is exemplified in Example 2. 33
[0125] A route for the preparation of 2-aminobenzamides is
described in scheme IV.3. Opening of isatoic anhydride (substituted
or unsubstituted at the nitrogen) by amines with evolution of
carbon dioxide led to the corresponding 2-amino-benzamides, as
described by Clark et al., J. Org. Chem. 9: 55-64 (1944).
[0126] c) Amino-cyclopentane- or Aminocyclohexane-carboxamides
[0127] Different routes have been described to the synthesis of
cis-2-amino-cyclopentylcarboxylic acid (cispentacin) in racemic
form or as pure enantiomer. Using an intramolecular nitrone-olefin
cycloaddition
cis-2-(t-butoxycarbonylamino)cyclopentane-1-carboxylic acid could
be prepared in a few synthetic steps (Konosu et al., Chem. Pharm.
Bull. 41: 1012 (1993)). Another route to enantiomerically pure
cis-(1R, 2S)-2-amino-cyclopentylcarboxylic acid is the addition of
chiral lithium (S)-(-methylbenzyl)benzylamide to
t-butyl-1-cyclopentene-1-carboxylate with subsequent removal of the
benzyl groups by hydogenation and removal of the t-butyl group by
acid treatment (Davies et al., Synlett 1993, p. 461). The
corresponding trans-epimer could be obtained by isomerisation with
a base such as potassium t-butoxide. By using the lithium
(R)-(-methylbenzyl)benzylamide in the Michael addition (1S,
2R)-2-amino-cyclopentylcarboxylic acid and (1S,
2S)-2-amino-cyclopentylca- rboxylic acid can be obtained. This
method is also applicable to the synthesis of cis-and
trans-aminocyclohexane-1-carboxylic acid.
[0128] Resolution of racemic Boc-protected cis-2-aminocyclopentane
carboxylic acid (Bernath et al., Acta Chim. 74: 479 (1972); Nativ
et al., Isr. J. Chem. 10: 55 (1972)) can be achieved with (+)- and
(-)-ephedrine in high enantiomeric excess (Noteberg et al.,
Tetrahedron 53: 7975 (1997)). In this paper also the synthesis of
the trans-enantiomers of Boc-protected trans-2-aminocyclopentane
carboxylic methyl ester was described, starting with either
trans-(3R, 4R)-bis(methoxycarbonyl)cyclop- entanone or
trans(3S,4S)-bis(methoxycarbonyl)-cyclopentanone.
[0129] Amides of Boc-protected 2-aminocyclopentylcarboxylic acid
can be obtained by coupling the acid with the corresponding amine
using the standard procedures as described above for the coupling
of nitrobenzoic acid with amines or as described in D. Noteberg et
al., Tetrahedron 53: 7975 (1997). Deprotection of the amine
function can be achieved by using Lewis acids, for example, a
mineral acid such as hydrochloric acid in ether or dioxane or an
organic acid, such as trifluoroacetic acid in methylene
chloride.
[0130] Methods of Use of the Claimed Compounds
[0131] In another embodiment, the present invention comprises a
method for partially or totally inhibiting formation of, or
otherwise treating (e.g., reversing or inhibiting the further
development of) solid tumors (e.g., tumors of the lung, breast,
colon, prostate, bladder, rectum, or endometrial tumors) or
hematological malignancies (e.g., leukemias, lymphomas) in a
mammal, for example, a human, by administering to the mammal a
therapeutically effective amount of a compound or a combination of
compounds of Formula I. The agent may be administered alone or in a
pharmaceutical composition comprising the agent and an acceptable
carrier or diluent. Administration may be by any of the means which
are conventional for pharmaceutical, preferably oncological,
agents, including oral and parenteral means such as subcutaneously,
intravenously, intramuscularly and intraperitoneally, nasally or
rectally. The compounds may be administered alone or in the form of
pharmaceutical compositions containing a compound of Formula I
together with a pharmaceutically accepted carrier appropriate for
the desired route of administration. Such pharmaceutical
compositions may be combination products, i.e., they may also
contain other therapeutically active ingredients.
[0132] The dosage to be administered to the mammal, such as a
human, will contain a therapeutically effective amount of a
compound described herein. As used herein, "therapeutically
effective amount" is an amount sufficient to inhibit (partially or
totally) formation of a tumor or a hematological malignancy or to
reverse development of a solid tumor or other malignancy or prevent
or reduce its further progression. For a particular condition or
method of treatment, the dosage is determined empirically, using
known methods, and will depend upon factors such as the biological
activity of the particular compound employed; the means of
administration; the age, health and body weight of the recipient;
the nature and extent of the symptoms; the frequency of treatment;
the administration of other therapies; and the effect desired. A
typical daily dose will be from about 5 to about 250 milligrams per
kilogram of body weight by oral administration and from about 1 to
about 100 milligrams per kilogram of body weight by parenteral
administration.
[0133] The compounds of the present invention can be administered
in conventional solid or liquid pharmaceutical administration
forms, for example, uncoated or (film-)coated tablets, capsules,
powders, granules, suppositories or solutions. These are produced
in a conventional manner. The active substances can for this
purpose be processed with conventional pharmaceutical aids such as
tablet binders, fillers, preservatives, tablet disintegrants, flow
regulators, plasticizers, wetting agents, dispersants, emulsifiers,
solvents, sustained release compositions, antioxidants and/or
propellant gases (cf. H. Sucker et al.: Pharmazeutische
Technologie, Thieme-Verlag, Stuttgart, 1978). The administration
forms obtained in this way typically contain from about 1 to about
90% by weight of the active substance.
[0134] The following examples are intended to illustrate the
invention but are not to be considered limitations of the
invention.
EXAMPLES
[0135] The proteinogenous amino acids are abbreviated in the
examples using the known three-letter code. Other abbreviations
employed are: TFA=trifluoroacetic acid, Ac= acetic acid,
DCM=dichloromethane, DMSO= dimethylsulfoxide, Bu=butyl, Et=ethyl,
Me=methyl, Bn= benzyl. In the compounds listed, all proteinogenous
amino acids are L-amino acids unless otherwise noted.
[0136] General Materials and Methods
[0137] The compounds of the present invention are synthesized by
classical solution synthesis using standard Z- and Boc-methodology
as discussed above or by standard methods of solid-phase synthesis
on a model 431A synthesizer supplied by APPLIED BIOSYSTEMS. This
apparatus uses different synthetic cycles for the Boc and Fmoc
protective group techniques, as described below.
1 Synthetic cycle for the Boc protecting group technique 1. 30%
trifluoroacetic acid in DCM 1 .times. 3 min 2. 50% trifluoroacetic
acid in DCM 1 .times. 1 min 3. DCM washing 5 .times. 1 min 4. 5%
diisopropylethylamine in DCM 1 .times. 1 min 5. 5%
diisopropylethylamine in NMP 1 .times. 1 min 6. NMP washing 5
.times. 1 min 7. Addition of preactivated 1 .times. 30 min
protected amino acid (activation with 1 equivalent of DCC and 1
equivalent of HOBt in NMP/DCM); Peptide coupling (1st part) 8.
Addition of DMSO to the reaction mixture until it contains 20% DMSO
by volume 9. Peptide coupling (2nd part) 1 .times. 16 min 10.
Addition of 3.8 equivalents of diisopropylethylamine to the
reaction mixture 11. Peptide coupling (3rd part) 1 .times. 7 min
12. DCM washing 3 .times. 1 min 13. if conversion is incomplete,
repetition of coupling (back to step 5) 14. 10% acetic anhydride,
5% diisopropylethylamine in DCM 1 .times. 2 min 15. 10% acetic
anhydride in DCM 1 .times. 4 min 16. DCM washing 4 .times. 1 min
17. back to step 1.
[0138] BOP-Cl and PyBrop were used as reagents for coupling an
amino acid to an N-methylamino acid. The reaction times were
correspondingly increased. In solution synthesis, the use of either
Boc-protected amino acid NCAs (N-tert-butyloxycarbonyl-amino
acid-N-carboxy-anhydrides) or Z-protected amino acid NCAs
(N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides) respectively
is most preferable for this type of coupling.
2 Synthetic cycle for the Fmoc protective group technique 1. DMF
washing 1 .times. 1 min 2. 20% piperidine in DMF 1 .times. 4 min 3.
20% piperidine in DMF 1 .times. 16 min 4. DMF washing 5 .times. 1
min 5. Addition of the preactivated 1 .times. 61 min protected
amino acid (activation by 1 equivalent of TBTU and 1.5 equivalent
of DIPEA in DMF); Peptide coupling 6. DMF washing 3 .times. 1 min
7. If conversion is incomplete, repetition of coupling (back to 5.)
8. 10% acetic anhydride in DMF 1 .times. 8 min 9. DMF washing 3
.times. 1 min 10. back to 2.
[0139] BOP-Cl and PyBrop were used as reagents for coupling an
amino acid to an N-methylamino acid. The reaction times were
correspondingly increased.
[0140] Reductive Alkylation of the N Terminus
[0141] The peptide-resin prepared as described above was
deprotected at the N terminus and then reacted with a 3-fold molar
excess of aldehyde or ketone in DMF/1% acetic acid with addition of
3 equivalents of NaCNBH.sub.3. After reaction was complete
(negative Kaiser test), the resin was washed several times with
water, isopropanol, DMF and dichloromethane.
[0142] Workup of the Peptide-Resins
[0143] The peptide-resin obtained via the Boc protecting group
technique was dried under reduced pressure and transferred into a
reaction vessel of a TEFLON HF apparatus (supplied by PENINSULA). A
scavenger, usually anisole (1 mL/g of resin), was then added and
additionally, in the case of tryptophan-containing peptides, a
thiol (0.5 mL/g of resin), preferably ethanedithiol, to remove the
indolic formyl group. This was followed by condensing in hydrogen
fluoride (10 mL/g of resin) in a bath of liquid N.sub.2. The
mixture was allowed to warm to 0.degree. C. and stirred at this
temperature for 45 min. The hydrogen fluoride was then stripped off
under reduced pressure, and the residue was washed with ethyl
acetate to remove any remaining scavenger. The peptide was
extracted with 30% acetic acid and filtered, and the filtrate was
lyophilized.
[0144] The peptide-resin formed by the Fmoc protecting group method
was dried under reduced pressure and then subjected to one of the
following cleavage procedures, depending upon the amino-acid
composition (Wade, Tregear, Howard Florey Fmoc Workshop Manual,
Melbourne 1985). The suspension of the peptide-resin in the
suitable TFA mixture was stirred at room temperature for the stated
time and then the resin was filtered off and washed with TFA and
DCM. The filtrate and the washings were concentrated, and the
peptide was precipitated by addition of diethyl ether. After
cooling in an ice bath, the precipitate was filtered off, taken up
in 30% acetic acid and lyophilized.
[0145] When an o-chlorotrityl-resin (supplied by Biohellas) was
used, the suspension of the peptide-resin in an acetic
acid/trifluoroethanol/dichlo- romethane mixture (1:1:3) was stirred
at room temperature for 1 h. The suspension was then filtered with
suction and the peptide-resin was thoroughly washed with the
cleavage solution. The combined filtrates were concentrated in
vacuo and treated with water. The precipitated solid was removed by
filtration or centrifugation, washed with diethyl ether and dried
under reduced pressure.
[0146] Purification and Characterization of the Peptides
[0147] Purification was carried out by gel chromatography (SEPHADEX
G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH) with or without subsequent
medium pressure chromatography (stationary phase: HD-SIL C-18,
20-45 m, 100 .ANG.; mobile phase: gradient with A=0.1% TFA/MeOH,
B=0.1% TFA/H2O). The purity of the resulting products was
determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC
C-18, 5 l, 300 .ANG.; mobile phase: CH.sub.3CN/H.sub.2O gradient,
buffered with 0.1% TFA, 40%C).
[0148] The polypeptides were characterized by amino-acid analysis
and fast atom bombardment mass spectroscopy.
EXAMPLE 1
Synthesis of
(2)-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--CON(CH.su-
b.3).sub.2 (Compound I-78)
[0149] Me.sub.2Val-Val-MeVal-Pro-OH and Z-Val-Val-MeVal-Pro-OH were
prepared by the method disclosed in patent applications DE 4415998
and DE 19527575, the contents of which are incorporated herein by
reference.
[0150] a) Synthesis of N,N-dimethyl-2-nitrobenzamide 34
[0151] To a solution of 2.0 g 2-nitrobenzoic acid and 0.98 g
dimethylammonium chloride in dichloromethane at 0.degree. C. were
added 2.29 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride, 1.62 g N-hydroxy-benzotriazol and 6.05 g
N-methyl-morpholine. The resulting mixture was stirred at room
temperature overnight. The reaction mixture was then washed
sequentially with saturated sodium hydrogen carbonate, a 5% aqueous
solution of citric acid and brine. The organic phase was dried over
sodium sulfate. After filteration the solvent was removed in vacuo
yielding N,N-dimethyl-2-nitrobenzamide (2.13 g).
[0152] .sup.1H-NMR (DMSO, 270 MHz) d=2.7 (s, 3H), 3.0 (s, 3H), 7.5
(d, 1H), 7.7 (dd, 1H), 7.85 (dd, 1H), 8.15 (d, 1H) ppm
[0153] b) Synthesis of N,N-dimethyl-2-aminobenzamide 35
[0154] Palladium on charcoal (0.54 g, 10% Pd by weight) was added
to a solution of 2.1 g N,N-dimethyl-2-nitrobenzamide in 150 mL
methanol. The resulting suspension was hydrogenated at room
temperature at atmospheric pressure for three hours. After
filtration of the catalyst, the solvent was removed in vacuo
affording N,N-dimethyl-2-aminobenzamide (1.8 g).
[0155] .sup.1H-NMR (DMSO, 270 MHz) d=2.9 (s, 6H), 5.1 (s, 2H), 6.5
(dd, 1H), 6.65 (d, 1H), 7.95 (d, 1H), 7.0 (dd, 1H) ppm
[0156] c) Synthesis of
(2)-(Z-Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--CON(C- H.sub.3).sub.2
36
[0157] To a solution of 2.0 g Z-Val-Val-MeVal-Pro-OH and 0.53 g
N,N-dimethyl-2-amino-benzamide in dichloromethane was added 1.66 g
bromo-tris-pyrrolidinophosphonium hexafluoro-phosphate (PyBrop) and
0.77 g N-ethyldiisopropylamine at 0.degree. C. The mixture was
stirred at room temperature overnight, and then washed sequentially
with saturated sodium hydrogen carbonate, a 5% aqueous solution of
citric acid, and brine. The organic phase was dried over sodium
sulfate. After filtration, the solvent was removed in vacuo. The
residue was purified by silica gel chromatography (1:3
dichloromethane:ethyl acetate) to provide
(2)-(Z-Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--CON(CH.sub.3).sub.2
(1.8 g).
[0158] FAB-MS 707.0 (M+H+d)
[0159] d) Synthesis of
2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--C-
ON(CH.sub.3).sub.2 37
[0160] Palladium on charcoal (58 mg, 10% Pd by weight) was added to
a solution of 1.8 g 2-(Z-Val-Val-MeVal-Pro-NH)--C.sub.
6H.sub.4--CON(CH.sub.3).sub.2 in 150 mL methanol. The resulting
suspension was hydrogenated at room temperature at atmospheric
pressure for three hours, then 1.5 mL of an aqueous formaldehyde
solution (37% formaldehyde by weight) and 341 mg of palladium on
charcoal were added. The mixture was hydrogenated at room
temperature at atmospheric pressure overnight. After filtration
over celite the solvent was removed in vacuo to give 1.30 g
2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.
6H.sub.4--CON(CH.sub.3).sub.2.
[0161] FAB-MS: 601.0 (M+H.sup.+)
[0162] .sup.1H-NMR (DMSO, 270 MHz) d=0.7 (s, 6H), 0.8-1.0 (m, 12H),
1.75 (m, 1H), 1.8- 2.2 (m, 6H), 2.2 (s, 6H), 2.6 (d, 1H), 2.8 (s,
3H), 2.9 (s, 3H), 3.05 (s, 3H), 3.55, 3.7 (m, 2H), 4.4 (m, 1H), 4.5
(m, 1H), 5.0 (d, 1H), 7.2 (dd, 1H), 7.25 (d, 1H), 7.4, dd, 1H), 7.6
(dd, 1H), 8.0 (d, 1H), 9.6 (s, 1H)
EXAMPLE 2
Synthesis of
(2)-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--CON(CH.su-
b.3)(OCH.sub.3) (Compound I-60)
[0163] a) Synthesis of
N,O-dimethyl-(2-N-tert.butoxycarbonyl-amino)benzohy- droxylamide
38
[0164] To a solution of 1.5 g 2-N-t-butoxy-carbonyl anthranilic
acid and 0.68 g N,O-dimethylhydroxylamine hydrochloride in
dichloromethane at 0.degree. C., 1.33 g
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 0.94 g
N-hydroxybenzotriazol and 3.20 g N-methylmorpholine were added. The
mixture was stirred at room temperature overnight. The reaction
mixture was washed sequentially with saturated aqueous sodium
hydrogen carbonate, a 5% aqueous solution of citric acid and brine.
The organic phase was dried over sodium sulfate. After filtration
the solvent was removed in vacuo. Flash chromatography (silica gel,
heptane:ethyl acetate 10:1) afforded
N,O-dimethyl-(2-N-tert.Butoxycarbonyl-amino)benzoh- ydroxylamide
(1.18 g).
[0165] .sup.1H-NMR (CDCl.sub.3, 270 MHz) d=1.5 (s, 9H), 3.4 (s,
3H), 3.6 (s, 3H), 7.0 (dd, 1H), 7.2-7.4 (m, 2H), 8.1 (d, 1H), 8.4
(s, 1H)
[0166] b) Synthesis of N,O-dimethyl-(2-amino)benzohydroxylamide
hydrochloride. 39
[0167] To a solution of 0.5 g
N,O-dimethyl-(2-N-tert.butoxycarbonyl-amino)- benzohydroxylamide in
15 mL dichloromethane at 0.degree. C. was added 17 mL of a hydrogen
chloride solution in ether and the resulting solution was stirred
for 2 hours. The solvent was evaporated to give 0.41 g
N,O-dimethyl-(2-amino)benzohydroxylamide hydrochloride.
[0168] .sup.1H-NMR (CDCl.sub.3, 270 MHz) d=3.4 (s, 3H), 3.6 (s,
3H), 7.3 (dd, 1H) , 7.5 (dd, 2H) , 7.6 (d, 1H), 7.9 (d, 1H)
[0169] c) Synthesis of
(2)-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--
-CON(CH.sub.3)(OCH.sub.3) 40
[0170] To a solution of 0.892 g Me.sub.2Val-Val-MeVal-Pro-OH and
0.234 g triethylamine in 10 mL dichloromethane at 0.degree. C. was
added 0.218 g formate. After stirring the resulting mixture for two
hours, 0.41 g N,O-dimethyl-(2-amino)benzohydroxylamide
hydrochloride and 0.234 g triethylamine were added and the mixture
was stirred overnight at room temperature. The reaction mixture was
washed sequentially with saturated sodium hydrogen carbonate
solution and brine. The organic phase was dried over sodium
sulfate. After filtration the solvent was removed in vacuo. The
residue was purified by chromatography (silica gel treated with 1%
triethylamine, solvent: dichloromethane/3% isopropanol) to provide
0.28 g
(2)-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--CON(CH.sub.3)(OCH.sub-
.3).
[0171] FAB-MS: 617.5 (M+H.sup.+)
[0172] .sup.1H-NMR (DMSO, 270 MHz) d=0.7 (s, 6H), 0.8-1.0 (m, 12H),
1.7 (m, 1H), 1.8-2.2 (m, 6H), 2.2 (s, 6H), 2.6 (d, 1H), 3.0 (s,
3H), 3.2 (s, 3H), 3.5 (s, 3H), 3.5, 3.7 (m, 2H), 4.4 (m, 1H), 4.5
(m, 1H) , 5.0 (d, 1H), 7.2 (dd, 1H), 7.3-7.5 (m, 2H), 7.6 (dd, 1H),
8.0 (d, 1H), 9.65 (s, 1H)
EXAMPLE 3
Synthesis of
Me.sub.2-Val-Val-MeVal-Pro-[cis-2-aminocyclopentanecarboxylic
acid]-NHBn (Compound VII-2)
[0173] d) Synthesis of Racemic Cyclopentane-cis-1,2-dicarboxylic
Acid Anhydride 41
[0174] 8.4 g (44.3 mmol) of commercially available
cyclopentane-trans-1,2-- dicarboxylic acid was refluxed for 20 h in
75 ml of acetic acid anhydride, then evaporated and the obtained
residue distilled in a "Kugelrohr-apparatus" at 1.0 mbar. The
fraction boiling at 165.degree. was collected, yielding 5.8 g of
the product as an oil.
[0175] .sup.13C-NMR (400 MHz; DMSO-d.sub.6) d (ppm): 25.3 (C-4),
30.6 (C-3,5), 45.7 (C-1,2), 175.6 (C-6,7).
[0176] b) Synthesis of Racemic
Cis-2-carbamoylcyclopentanecarboxylic Acid 42
[0177] 1.1 g (7.85 mmol) of cyclopentane-cis-1,2-dicarboxylic acid
anhydride were added to 8 ml of an aqueous NH.sub.3-solution and
stirred until dissolution of the educt. The excess of ammonia was
then evaporated, the remaining solution cooled to 0.degree. C. and
acidified with conc. HCl. The resulting precipitate was filtered
off, washed with cold water and dried, yielding 0.7 g of
cis-2-carbamoylcyclopentanecarbox- ylic acid with a melting point
of 132-133.degree. C. (lit.: 126-128.degree. C.).
[0178] c) Synthesis of Racemic Cis-2-aminocyclopentanecarboxylic
Acid 43
[0179] Under stirring at 0.degree. C. 0.41 g (2.6 mmol) of Br.sub.2
were added to an aqueous solution (1.8 mL) of 0.48 g (12 mmol)
NaOH. The mixture was cooled again and then 0.34 g (2.16 mmol) of
cis-2-carbamoylcyclopentanecarboxylic acid added. After stirring
for about 10 minutes again 0.35 g (8.65 mmol) NaOH--dissolved in
1.35 ml of water--were added, and then the whole mixture warmed to
75.degree. C. for about 5 minutes. The mixture then was cooled
again, neutralized by addition of conc. HCl, acidified with acetic
acid and evaporated to dryness. The residue obtained was extracted
five times with refluxing ethanol, and the combined
ethanol-fractions evaporated again yielding 1.1 g of a white
solid.
[0180] Purification was achieved by filtration of this residue over
a column with Dowex 50 ion exchange resin. Therefore the column was
washed with a solution of the solid in water, and then the product
eluted by treatment with solid was dissolved in water and the
column, absorbed on by washing the column with aqueous diluted
NH.sub.3. After evaporation of the water the remaining crude
product was recristallized from acetone yielding 0.14 g of pure
cis-2-aminocyclopentanecarboxylic acid with a melting point of
200-202.degree. C.
[0181] d) Synthesis of Racemic
Cis-2-t-butyloxycarbonylaminocyclopentaneca- rboxylic Acid
Benzylamide 44
[0182] To a solution of 1.5 g (11.6 mmol) of
cis-2-aminocyclopentanecarbox- ylic acid in a mixture of
acetonitrile/water 3:1 were added 3.3 g (15.1 mmol) of
di.sup.tbutyldicarbonate, 0.5 g (12.2 mmol) of NaOH dissolved in 12
ml of H.sub.2O and 0.1 g (0.82 mmol) of DMAP. The mixture was
stirred at ambient temperature for about 3 days, then diluted with
water, extracted with ethylacetate. The combined organic phases
were washed with a saturated aqueous NaCl-solution, dried over
MgSO.sub.4 and evaporated to dryness leaving 1.3 g of the
Boc-protected compound as an oil. A solution of the crude product
and 0.65 g (6.1 mmol) benzylamine in a mixture of THF/DMF 10:1 was
cooled to -10.degree. C., then were added subsequently 0.9 g (5.86
mmol) of HOBT, 1.12 g (5.86 mmol) of EDC.times.HCl and 3 ml of NMM.
The mixture was stirred for 2 h at -10.degree. C., for 3 h at
0.degree. C. and was then allowed to warm up to room temperature.
After evaporation to dryness the remaining residue was dissolved in
ethylacetate, washed with aqueous solutions of 5% citric acid,
NaHCO.sub.3 and NaCl and dried over MgSO.sub.4. Evaporation yielded
1.3 g of cis-2-t-butyloxycarbonylaminocyclo-pentanecarboxylic acid
benzylamide as an oil.
[0183] HPLC (gradient 2): R.sub.t 10.5 min.
[0184] (Column: Machery & Nagel Nucleosil C18 PPN,
100.times.2.1, 5 m/100 A, acetonitrile/H.sub.2O+0.1% TFA; flow: 0.2
ml/min; temp. 40.degree. C.).
[0185] .sup.1H-NMR (270 MHz; DMSO-d.sub.6) d (ppm): 1.35 (s, 9H),
1.35-1.95 (m, 6H), 2.82 (m, 1H), 4.03 (m, 1H), 4.25 (m, 2H), 6.35
(d, NH), 7.1-7.35 (m, 5H), 8.3 (m, 1H).
[0186] e) Synthesis of Racemic Cis-2-aminocyclopentanecarboxylic
Acid Benzylamide Hydrochloride 45
[0187] To a solution of 0.7 g (2.2 mmol) of of
cis-2-tert.butyloxycarbonyl- aminocyclo-pentanecarboxylic acid
benzylamide in 30 ml CH.sub.2Cl.sub.2 were added 25 ml of saturated
HCl in diethylether; the mixture was then stirred for 2 h at
ambient temperature. Evaporation to dryness and coevaporation with
toluene yielded 0.6 g of the deprotected amine as hydrochloride
salt.
[0188] f) Synthesis of
Me.sub.2-Val-Val-MeVal-Pro-[cis-2-aminocyclopentane- carboxylic
Acid]-NHBn (Compound VII-2) 46
[0189] To a solution of 0.86 g (1.9 mmol) of the tetrapeptide
Me.sub.2Val-Val-MeVal-Pro-OH and 0.56 g (2.2 mmol)
aminocyclo-pentanecarboxylic acid benzylamide hydrochloride in 30
ml of THF/DMF 5:1 were added subsequently at -10.degree. C. 0.29 g
(1.9 mmol) of HOBT; 0.37 g (1.9 mmol) of EDC.times.HCl and 1.2 ml
of NMM. The mixture was stirred for another at -10.degree. C., then
for 1-2 h at 0.degree. C. and then allowed to warm up to ambient
temperature. After evaporation the remaining residue was diluted
with ethyl acetate, washed with an aqueous solution of NaCl, dried
over MgSO.sub.4 and evaporated again. The remaining crude product
(1.2 g) was purified by flash cromatography on silica gel
(CH.sub.2Cl.sub.2/CH.sub.3OH) yielding 0.37 g of
Me.sub.2Val-Val-MeVal-Pro-[cis-2-aminocyclopentanecarboxylic
acid]-NHBn.
[0190] FAB-MS: 655 (M+H.sup.+).
[0191] The following compounds can be prepared as outlined in
Schemes I-III and according to the above examples.
[0192] Table 1:
[0193] A is Me.sub.2Val, B is Val, D is MeVal, E is Pro, F is of
Formula II.sub.F and the group --C(.dbd.O)-G is in position 2
relative to the nitrogen atom. G is of Formula II.sub.g or,
III.sub.g or IV.sub.g.
3 No. R.sub.F R.sup.1.sub.F R.sup.2.sub.F --C(.dbd.O)--G I-1 H H H
--NH--CH.sub.3 I-2 H H H --NH--CH.sub.2--C.sub.6H.sub.5 I-3 H H H
--NH-isoC.sub.3H.sub.5 I-4 H H H --NH--C.sub.6H.sub.5 I-5 H H H
1,3-Thiazol-2-yl-amide I-6 H 4-OCH.sub.3 5-OCH.sub.3 --NH--CH.sub.3
I-7 H 3-cycloC.sub.5H.sub.9 H --NH--CH.sub.3 I-8 H H H
--NH--C.sub.2H.sub.5 I-9 H H H --NH-nC.sub.3H.sub.7 I-10 H H H
--NH-nC.sub.4H.sub.9 I-11 H H H --NH-tertC.sub.4H.sub.9 I-12 H H H
--NH-cycloC.sub.3H.sub.5 I-13 H H H --NH-cycloC.sub.4H.sub.7 I-14 H
H H --NH-cycloC.sub.5H.sub.9 I-15 H H H --NH-cycloC.sub.6H.sub.11
I-16 H H H --NH-cycloC.sub.7H.sub.12 I-17 H H H
--NH--CH.sub.3--O--CH.sub.3 I-18 H H H --NH--CH.sub.2--CH.sub.2--O-
--CH.sub.3 I-19 H H H --NH-1-adamantyl I-20 H H H
--NH-(4-HO-C.sub.6H.sub.5) I-21 H H H --NH-(2-CF.sub.3--C.sub.6H.s-
ub.4) I-22 H H H --NH-(3-CF.sub.3--C.sub.6H.sub.4) I-23 H H H
--NH-(4-CF.sub.3--C.sub.6H.sub.4) I-24 H H H
--NH-(2-OCH.sub.3--C.sub.6H.sub.4) I-25 H H H
--NH-(3-OCH.sub.3--C.sub.6H.sub.4) I-26 H H H
--NH-(4-OCH.sub.3--C.sub.6H.sub.4) I-27 H H H
--NH-(2-SCH.sub.3--C.sub.6H.sub.4) I-28 H H H
--NH-(3-SCH.sub.3--C.sub.6H.sub.4) I-29 H H H
--NH-(4-SCH.sub.3--C.sub.6H.sub.4) I-30 H H H
--NH-(2-N(CH.sub.3).sub.2--C.sub.6H.sub.4) I-31 H H H
--NH-(3-N(CH.sub.3).sub.2--C.sub.6H.sub.4) I-32 H H H
--NH-(4-N(CH.sub.3).sub.2--C.sub.6H.sub.4) I-33 H H H
--NH-(4-CN-C.sub.6H.sub.4) I-34 H H H --NH-(4-Cl-C.sub.6H.sub.4)
I-35 H H H --NH-(4-Br-C.sub.6H.sub.4] I-36 H H H
--NH-(4-F-C.sub.6H.sub.4] I-37 H H H --NH-(4-CH.sub.3--C.sub.6H.su-
b.4) I-33 H H H --NH-(2-NO.sub.2--C.sub.6H.sub.4) I-39 H H H
--NH-(3-NO.sub.2--C.sub.6H.sub.4) I-40 H H H
--NH-(4-NO.sub.2--C.sub.6H.sub.4) I-41 H H H
--NH-(2,4-OCH.sub.3--C.sub.6H.sub.3) I-42 H H H
--NH-(3,4-OCH.sub.3--C.sub.6H.sub.3) I-43 H H H
--NH-(3,4,5-OCH.sub.3--C.sub.6H.sub.2) I-44 H H H
--NH-(3,4-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) I-45 H H H
--NH-(2,3-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) I-46 H H H
--NH-2-pyridinyl I-47 H H H --NH-2-furanyl I-48 H H H
--NH-2-thienyl I-49 H H H --NH-3-pyridinyl I-50 H H H
--NH-3-furanyl I-51 H H H --NH-3-thienyl I-52 H H H
--NH-4-pyridinyl I-53 H H H --NH-2-oxazolyl I-54 H H H
--NH-3-isoxazolyl I-55 H H H --NH-4-isoxazolyl I-56 H H H
--NH-5-isoxazloyl I-57 H H H --NH-2R-(but-2-yl) I-58 H H H
--NH-2S-(but-2-yl) I-59 H H H --NH--O--CH.sub.3 I-60 H H H
--N(CH.sub.3) (OCH.sub.3) I-61 H H H --N(--(CH.sub.2)3--O--) I-62 H
H H --NH--O--CH.sub.2--C.sub.6H.sub.5 I-63 H H H
--N(CH.sub.3)(O--CH.sub.2--C.sub.6H.sub.5) I-64 H H H
--N(--(CH.sub.2).sub.2--CH(C.sub.6H.sub.5)--O--) I-65 H H H
--NH--O--C.sub.2H.sub.5 I-66 H H H --N(C.sub.2H.sub.5)(OC.sub.2H.s-
ub.5) I-67 H H H --N(CH.sub.2)(OC.sub.2H.sub.5) I-58 H H H
--NH--O-isoC.sub.3H.sub.7 I-69 H H H --N(CH.sub.3)(O-isoC.sub.3H.s-
ub.7) I-70 H H H --NH--O--nC.sub.3H.sub.7 I-71 H H H
--N(CH.sub.3)(O--nC.sub.3H.sub.7) I-72 H H H
--NH--O--nC.sub.4H.sub.9 I-73 H H H --N(CH.sub.2)(O--nC.sub.4H.sub-
.9) I-74 H H H --NH-O-tertC.sub.4H.sub.9 I-75 H H H
--N(CH.sub.3)(O-tertC.sub.4H.sub.9) I-76 H H H
--NH--O--C.sub.6H.sub.5 I-77 H H H --N(CH.sub.3)(O--C.sub.6H.sub.5-
) I-78 H H H --N(CH.sub.3).sub.2 I-79 H H H
--N(CH.sub.2--C.sub.6H.sub.5).sub.2 I-80 H H H
--N(C.sub.2H.sub.5).sub.2 I-81 H H H --N(isoC.sub.3H.sub.7).sub.2
I-82 H H H --N(nC.sub.3H.sub.7).sub.2 I-83 H H H
--N(nC.sub.4H.sub.9).sub.2 I-84 H H H --N(C.sub.6H.sub.5).sub.2
I-85 H H H --NH--CH.sub.2--CH.sub.2--OH I-86 H H H
--NH--(CH.sub.2).sub.3--OH I-87 H H H --NH(--(CH.sub.2).sub.2CH(C.-
sub.6H.sub.5)OH) I-88 H H H --NH--(CH.sub.2).sub.4--OH I-89 H H H
--NH(--CH(CH.sub.3)--CH.sub.2--OH) I-90 H H H
--NH(--CH.sub.2--CH(CH.sub.3)--OH) I-91 H H H
--NH(CH(CH.sub.3)(CH.sub.2).sub.2OH) I-92 H H H
--NH(--(CH.sub.2).sub.2CH(CH.sub.3)OH) I-93 H 4-CH.sub.3 H
--NH--CH.sub.3 I-94 H 4-CH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5
I-95 H 4-CH.sub.3 H --NH--isoC.sub.3H.sub.7 I-96 H 4-CH.sub.3 H
--NH--C.sub.6H.sub.5 I-97 H 4-CH.sub.3 H --NH--C.sub.2H.sub.5 I-98
H 4-CH.sub.3 H --NH-nC.sub.3H.sub.7 I-99 H 4-CH.sub.3 H
--NH--nC.sub.4H.sub.9 I-100 H 4-CH.sub.3 H --NH-tertC.sub.4H.sub.9
I-101 H 4-CH.sub.3 H --NH-cycloC.sub.3H.sub.5 I-102 H 4-CH.sub.3 H
--NH- cycloC.sub.4H.sub.7 I-103 H 4-CH.sub.3 H
--NH-cycloC.sub.5H.sub.9 I-104 H 4-CH.sub.3 H
--NH-cycloC.sub.6H.sub.11 I-105 H 4-CH.sub.3 H --NH-1-adamantyl
I-106 H 4-CH.sub.3 H --NH-2R-(but-2-yl) I-107 H 4-CH.sub.3 H
--NH-2S-(but-2-yl) I-108 H 4-CH.sub.3 H --NH--O--CH.sub.3 I-109 H
4-CH.sub.3 H --N(CH.sub.3)(OCH.sub.3) I-110 H 4-CH.sub.3 H
--N(--(CH.sub.3--O--) I-111 H 4-CH.sub.3 H --N(CH.sub.3).sub.2
I-112 H 4-CH.sub.3 H --N(CH.sub.2--C.sub.6H.sub.5).sub.2 I-113 H
4-CH.sub.3 H --N(C.sub.2H.sub.5).sub.2 I-114 H 4-CH.sub.3 H
--N(isoC.sub.3H.sub.7).sub.2 I-115 H 4-CH.sub.3 H
--N(nC.sub.3H.sub.7).sub.2 I-116 H 4-CH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 I-117 H 4-CH.sub.3 H
--N(C.sub.6H.sub.5).sub.2 I-118 H 5-CH.sub.3 H --NH--CH.sub.3 I-119
H 5-CH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5 I-120 H 5-CH.sub.3 H
--NH-isoC.sub.3H.sub.7 I-121 H 5-CH.sub.3 H --NH-C.sub.6H.sub.5
I-122 H 5-CH.sub.3 H --NH-C.sub.2H.sub.5 I-123 H 5-CH.sub.3 H
--NH-nC.sub.3H.sub.7 I-124 H 5-CH.sub.3 H --NH-nC.sub.4H.sub.9
I-125 H 5-CH.sub.3 H --NH-tertC.sub.4H.sub.9 I-126 H 5-CH.sub.3 H
--NH-cycloC.sub.3H.sub.5 I-127 H 5-CH.sub.3 H
--NH-cycloC.sub.4H.sub.7 I-128 H 5-CH.sub.3 H
--NH-cycloC.sub.5H.sub.9 I-129 H 5-CH.sub.3 H
--NH-cycloC.sub.6H.sub.11 I-130 H 5-CH.sub.3 H --NH-1-adamantyl
I-131 H 5-CH.sub.3 H --NH-2R-(but-2-yl) I-132 H 5-CH.sub.3 H
--NH-2S-(but-2-yl) I-133 H 5-CH.sub.3 H --NH--O--CH.sub.3 I-134 H
5-CH.sub.3 H --N(CH.sub.3)(OCH.sub.3) I-135 H 5-CH.sub.3 H
--N(--(CH.sub.3).sub.3--O--) I-136 H 5-CH.sub.3 H
--N(CH.sub.3).sub.2 I-137 H 5-CH.sub.3 H --N(CH.sub.2--C.sub.6H.su-
b.5).sub.2 I-138 H 5-CH.sub.3 H --N(C.sub.2H.sub.5).sub.2 I-139 H
5-CH.sub.3 H --N(isoC.sub.3H.sub.7).sub.2 I-140 H 5-CH.sub.3 H
--N(nC.sub.3H.sub.7).sub.2 I-141 H 5-CH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 I-142 H 5-CH.sub.3 H
--N(C.sub.6H.sub.5).sub.2 I-143 CH.sub.3 H H --NH--CH.sub.3 I-144
CH.sub.3 H H --NH--CH.sub.2--C.sub.6H.sub.5 I-145 CH.sub.3 H H
--NH--isoC.sub.3H.sub.7 I-146 CH.sub.3 H H --NH-C.sub.6H.sub.5
I-147 CH.sub.3 H H --NH-C.sub.2H.sub.5 I-148 CH.sub.3 H H
--NH-nC.sub.3H.sub.7 I-149 CH.sub.3 H H --NH-nC.sub.4H.sub.9 I-150
CH.sub.3 H H --NH-tertC.sub.4H.sub.9 I-151 CH.sub.3 H H
--NH-cycloC.sub.3H.sub.5 I-152 CH.sub.3 H H
--NH-cycloC.sub.4H.sub.7 I-153 CH.sub.3 H H
--NH-cycloC.sub.5H.sub.9 I-154 CH.sub.3 H H
--NH-cycloC.sub.6H.sub.11 I-155 CH.sub.3 H H --NH-1-adamantyl I-156
CH.sub.3 H H --NH-2R-(but-2-yl) I-157 CH.sub.3 H H
--NH-2S-(but-2-yl) I-158 CH.sub.3 H H --NH--O--CH.sub.3 I-159
CH.sub.3 H H --N(CH.sub.3)(OCH.sub.3) I-160 CH.sub.3 H H
--N(--(CH.sub.2).sub.3--O--) I-161 CH.sub.3 H H --N(CH.sub.3).sub.2
I-162 CH.sub.3 H H --N(CH.sub.2--C.sub.6H.sub.- 5).sub.3 I-163
CH.sub.3 H H --N(C.sub.2H.sub.5).sub.2 I-164 CH.sub.3 H H
--N(isoC.sub.3H.sub.7).sub.2 I-165 CH.sub.3 H H
--N(nC.sub.3H.sub.7).sub.2 I-155 CH.sub.3 H H
--N(nC.sub.4H.sub.9).sub.2 I-167 CH.sub.3 H H
--N(C.sub.6H.sub.5).sub.2 I-168 H 4-OCH.sub.3 H --NH--CH.sub.3
I-159 H 4-OCH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5 I-170 H
4-OCH.sub.3 H --NH-isoC.sub.3H.sub.7 I-171 H 4-OCH.sub.3 H
--NH-C.sub.6H.sub.5 I-172 H 4-OCH.sub.3 H --NH-C.sub.2H.sub.5 I-173
H 4-OCH.sub.3 H --NH-nC.sub.4H.sub.7 I-174 H 4-OCH.sub.3 H
--NH-nC.sub.5H.sub.9 I-175 H 4-OCH.sub.3 H --NH-tertC.sub.4H.sub.9
I-176 H 4-OCH.sub.3 H --NH-cycloC.sub.3H.sub.5 I-177 H 4-OCH.sub.3
H --NH-cycloC.sub.4H.sub.7 I-178 H 4-OCH.sub.3 H
--NH-cycloC.sub.5H.sub.9 I-179 H 4-OCH.sub.3 H
--NH-cycloC.sub.6H.sub.11 I-180 H 4-OCH.sub.3 H --NH-1-adamantyl
I-181 H 4-OCH.sub.3 H --NH-2R-(but-2-yl) I-182 H 4-OCH.sub.3 H
--NH-2S-(but-2-yl) I-183 H 4-OCH.sub.3 H --NH--O--CH.sub.3 I-184 H
4-OCH.sub.3 H --N(CH.sub.3)(OCH.sub.3) I-185 H 4-OCH.sub.3 H
--N(--(CH.sub.2).sub.3--O--) I-186 H 4-OCH.sub.3 H
--N(CH.sub.3).sub.2 I-187 H 4-OCH.sub.3 H --N(CH.sub.2--C.sub.6H.s-
ub.5).sub.2 I-188 H 4-OCH.sub.3 H --N(C.sub.2H.sub.5).sub.2 I-189 H
4-OCH.sub.3 H --N(isoC.sub.3H.sub.7).sub.2 I-190 H 4-OCH.sub.3 H
--N(nC.sub.3H.sub.7).sub.2 I-191 H 4-OCH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 I-192 H 4-CH.sub.3 H
--N(C.sub.6H.sub.5).sub.2 I-193 H 5-OCH.sub.3 H --NH--CH.sub.3
I-194 H 5-OCH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5 I-195 H
5-OCH.sub.3 H --NH-isoC.sub.3H.sub.7 I-196 H 5-OCH.sub.3 H
--NH--C.sub.6H.sub.5 I-197 H 5-OCH.sub.3 H --NH--C.sub.2H.sub.5
I-198 H 5-OCH.sub.3 H --NH-nC.sub.3H.sub.7 I-199 H 5-OCH.sub.3 H
--NH-nC.sub.4H.sub.9 I-200 H 5-OCH.sub.3 H --NH-tertC.sub.4H.sub.9
I-201 H 5-OCH.sub.3 H --NH-cycloC.sub.3H.sub.5 I-202 H 5-OCH.sub.3
H --NH-cycloC.sub.4H.sub.7 I-203 H 5-OCH.sub.3 H
--NH-cycloC.sub.5H.sub.9 I-204 H 5-OCH.sub.3 H
--NH-cycloC.sub.6H.sub.11 I-205 H 5-OCH.sub.3 H --NH-1-adamantyl
I-206 H 5-OCH.sub.3 H --NH-2R-(but-2-y1) I-207 H 5-OCH.sub.3 H
--NH-2S-(but-2-yl) I-208 H 5-OCH.sub.3 H --NH--O--CH.sub.3 I-209 H
5-OCH.sub.3 H --N(CH.sub.3)(OCH.sub.3) I-210 H 5-OCH.sub.3 H
--N(--(CH.sub.2).sub.3--O--) I-211 H 5-OCH.sub.3 H
--N(CH.sub.3).sub.2 I-212 H 5-OCH.sub.3 H --N(CH.sub.2--C.sub.6H.s-
ub.5).sub.2 I-213 H 5-OCH.sub.3 H --N(C.sub.2H.sub.5).sub.2 I-214 H
5-OCH.sub.3 H --N(isoC.sub.3H.sub.7).sub.2 I-215 H 5-OCH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 I-216 H 5-OCH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 I-217 H 5-OCH.sub.3 H
--N(C.sub.6H.sub.5).sub.2
[0194] Table 2:
[0195] A is Me.sub.2Val, B is Val, D is MeVal, E is Pro and F is of
Formula II.sub.f, the group --C(O)-G is in position 3 relative to
the nitrogen atom and G is of Formula II.sub.g, III.sub.g or
IV.sub.g.
4 No. R.sub.F R.sup.1.sub.F R.sup.2.sub.F --G II-1 H H H
--NH--CH.sub.3 II-2 H H H --NH--CH.sub.2--C.sub.6H.sub- .5 II-3 H H
H --NH-isoC.sub.3H.sub.5 II-4 H H H --NH--C.sub.6H.sub.5 II-5 H H H
1,3-Thiazol-2-yl-amide II-6 H 4-OCH.sub.3 5-OCH.sub.3
--NH--CH.sub.3 II-7 H 3-cycloC.sub.5H.sub.9 H --NH--CH.sub.3 II-8 H
H H --NH--C.sub.2H.sub.5 II-9 H H H --NH-nC.sub.3H.sub.7 II-10 H H
H --NH-nC.sub.4H.sub.9 II-11 H H H --NH-tertC.sub.4H.sub.9 II-12 H
H H --NH-cycloC.sub.3H.sub.5 II-13 H H H --NH-cycloC.sub.4H.sub.7
II-14 H H H --NH-cycloC.sub.5H.sub.9 II-15 H H H
--NH-cycloC.sub.6H.sub.11 II-16 H H H --NH-cycloC.sub.7H.sub.12
II-17 H H H --NH--CH.sub.3--O--CH.sub.3 II-18 H H H
--NH--CH.sub.2--CH.sub.2--O--CH.sub.3 II-19 H H H --NH-1-adamantyl
II-20 H H H --NH-(4-HO-C.sub.6H.sub.5) II-21 H H H
--NH-(2-CF.sub.3--C.sub.6H.sub.4) II-22 H H H
--NH-(3-CF.sub.3--C.sub.6H.sub.4) II-23 H H H
--NH-(4-CF.sub.3--C.sub.6H.sub.4) II-24 H H H
--NH-(2-OCH.sub.3--C.sub.6H.sub.4) II-25 H H H
--NH-(3-OCH.sub.3--C.sub.6H.sub.4) II-26 H H H
--NH-(4-OCH.sub.3--C.sub.6H.sub.4) II-27 H H H
--NH-(2-SCH.sub.3--C.sub.6H.sub.4) II-28 H H H
--NH-(3-SCH.sub.3--C.sub.6H.sub.4) II-29 H H H
--NH-(4-SCH.sub.3--C.sub.6H.sub.4) II-30 H H H
--NH-(2-N(CH.sub.3).sub.2--C.sub.6H.sub.4) II-31 H H H
--NH-(3-N(CH.sub.3).sub.2--C.sub.6H.sub.4) II-32 H H H
--NH-(4-N(CH.sub.3).sub.2--C.sub.6H.sub.4) II-33 H H H
--NH-(4-CN-C.sub.6H.sub.4) II-34 H H H --NH-(4-Cl-C.sub.6H.sub.4)
II-35 H H H --NH-(4-Br-C.sub.6H.sub.4] II-36 H H H
--NH-(4-F-C.sub.6H.sub.4] II-37 H H H --NH-(4-CH.sub.3--C.sub.6H.s-
ub.4) II-33 H H H --NH-(2-NO.sub.2--C.sub.6H.sub.4) II-39 H H H
--NH-(3-NO.sub.2--C.sub.6H.sub.4) II-40 H H H
--NH-(4-NO.sub.2--C.sub.6H.sub.4) II-41 H H H
--NH-(2,4-OCH.sub.3--C.sub.6H.sub.3) II-42 H H H
--NH-(3,4-OCH.sub.3--C.sub.6H.sub.3) II-43 H H H
--NH-(3,4,5-OCH.sub.3--C.sub.6H.sub.2) II-44 H H H
--NH-(3,4-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) II-45 H H H
--NH-(2,3-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) II-46 H H H
--NH-2-pyridinyl II-47 H H H --NH-2-furanyl II-48 H H H
--NH-2-thienyl II-49 H H H --NH-3-pyridinyl II-50 H H H
--NH-3-furanyl II-51 H H H --NH-3-thienyl II-52 H H H
--NH-4-pyridinyl II-53 H H H --NH-2-oxazolyl II-54 H H H
--NH-3-isoxazolyl II-55 H H H --NH-4-isoxazolyl II-56 H H H
--NH-5-isoxazloyl II-57 H H H --NH-2R-(but-2-yl) II-58 H H H
--NH-2S-(but-2-yl) II-59 H H H --NH--O--CH.sub.3 II-60 H H H
--N(CH.sub.3) (OCH.sub.3) II-61 H H H --N(--(CH.sub.2)3--O--) II-62
H H H --NH--O--CH.sub.2--C.sub.6H.sub.5 II-63 H H H
--N(CH.sub.3)(O--CH.sub.2--C.sub.6H.sub.5) II-64 H H H
--N(--(CH.sub.2).sub.2--CH(C.sub.6H.sub.5)--O--) II-65 H H H
--NH--O--C.sub.2H.sub.5 II-66 H H H --N(C.sub.2H.sub.5)(OC.sub.2H.-
sub.5) II-67 H H H --N(CH.sub.2)(OC.sub.2H.sub.5) II-68 H H H
--NH--O-isoC.sub.3H.sub.7 II-69 H H H --N(CH.sub.3)(O-isoC.sub.3-
H.sub.7) II-70 H H H --NH--O--nC.sub.3H.sub.7 II-71 H H H
--N(CH.sub.3)(O--nC.sub.3H.sub.7) II-72 H H H
--NH--O--nC.sub.4H.sub.9 II-73 H H H --N(CH.sub.2)(O--nC.sub.4H.su-
b.9) II-74 H H H --NH-O-tertC.sub.4H.sub.9 II-75 H H H
--N(CH.sub.3)(O-tertC.sub.4H.sub.9) II-76 H H H
--NH--O--C.sub.6H.sub.5 II-77 H H H --N(CH.sub.3)(O--C.sub.6H.sub.-
5) II-78 H H H --N(CH.sub.3).sub.2 II-79 H H H
--N(CH.sub.2--C.sub.6H.sub.5).sub.2 II-80 H H H
--N(C.sub.2H.sub.5).sub.2 II-81 H H H --N(isoC.sub.3H.sub.7).sub.2
II-82 H H H --N(nC.sub.3H.sub.7).sub.2 II-83 H H H
--N(nC.sub.4H.sub.9).sub.2 II-84 H H H --N(C.sub.6H.sub.5).sub.2
II-85 H H H --NH--CH.sub.2--CH.sub.2--OH II-86 H H H
--NH--(CH.sub.2).sub.3--OH II-87 H H H --NH(--(CH.sub.2).sub.2CH(C-
.sub.6H.sub.5)OH) II-88 H H H --NH--(CH.sub.2).sub.4--OH II-89 H H
H --NH(--CH(CH.sub.3)--CH.sub.2--OH) II-90 H H H
--NH(--CH.sub.2--CH(CH.sub.3)--OH) II-91 H H H
--NH(CH(CH.sub.3)(CH.sub.2).sub.2OH) II-92 H H H
--NH(--(CH.sub.2).sub.2CH(CH.sub.3)OH) II-93 H 4-CH.sub.3 H
--NH--CH.sub.3 II-94 H 4-CH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5
II-95 H 4-CH.sub.3 H --NH--isoC.sub.3H.sub.7 II-96 H 4-CH.sub.3 H
--NH--C.sub.6H.sub.5 II-97 H 4-CH.sub.3 H --NH--C.sub.2H.sub.5
II-98 H 4-CH.sub.3 H --NH-nC.sub.3H.sub.7 II-99 H 4-CH.sub.3 H
--NH--nC.sub.4H.sub.9 II-100 H 4-CH.sub.3 H --NH-tertC.sub.4H.sub.9
II-101 H 4-CH.sub.3 H --NH-cycloC.sub.3H.sub.5 II-102 H 4-CH.sub.3
H --NH- cycloC.sub.4H.sub.7 II-103 H 4-CH.sub.3 H
--NH-cycloC.sub.5H.sub.9 II-104 H 4-CH.sub.3 H
--NH-cycloC.sub.6H.sub.11 II-105 H 4-CH.sub.3 H --NH-1-adamantyl
II-106 H 4-CH.sub.3 H --NH-2R-(but-2-yl) II-107 H 4-CH.sub.3 H
--NH-2S-(but-2-yl) II-108 H 4-CH.sub.3 H --NH--O--CH.sub.3 II-109 H
4-CH.sub.3 H --N(CH.sub.3)(OCH.sub.3) II-110 H 4-CH.sub.3 H
--N(--(CH.sub.3--O--) II-111 H 4-CH.sub.3 H --N(CH.sub.3).sub.2
II-112 H 4-CH.sub.3 H --N(CH.sub.2--C.sub.6H.sub.5).sub.2 II-113 H
4-CH.sub.3 H --N(C.sub.2H.sub.5).sub.2 II-114 H 4-CH.sub.3 H
--N(isoC.sub.3H.sub.7).sub.2 II-115 H 4-CH.sub.3 H
--N(nC.sub.3H.sub.7).sub.2 II-116 H 4-CH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 II-117 H 4-CH.sub.3 H
--N(C.sub.6H.sub.5).sub.2 II-118 H 5-CH.sub.3 H --NH--CH.sub.3
II-119 H 5-CH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5 II-120 H
5-CH.sub.3 H --NH-isoC.sub.3H.sub.7 II-121 H 5-CH.sub.3 H
--NH-C.sub.6H.sub.5 II-122 H 5-CH.sub.3 H --NH-C.sub.2H.sub.5
II-123 H 5-CH.sub.3 H --NH-nC.sub.3H.sub.7 II-124 H 5-CH.sub.3 H
--NH-nC.sub.4H.sub.9 II-125 H 5-CH.sub.3 H --NH-tertC.sub.4H.sub.9
II-126 H 5-CH.sub.3 H --NH-cycloC.sub.3H.sub.5 II-127 H 5-CH.sub.3
H --NH-cycloC.sub.4H.sub.7 II-128 H 5-CH.sub.3 H
--NH-cycloC.sub.5H.sub.9 II-129 H 5-CH.sub.3 H
--NH-cycloC.sub.6H.sub.11 II-130 H 5-CH.sub.3 H --NH-1-adamantyl
II-131 H 5-CH.sub.3 H --NH-2R-(but-2-yl) II-132 H 5-CH.sub.3 H
--NH-2S-(but-2-yl) II-133 H 5-CH.sub.3 H --NH--O--CH.sub.3 II-134 H
5-CH.sub.3 H --N(CH.sub.3)(OCH.sub.3) II-135 H 5-CH.sub.3 H
--N(--(CH.sub.3).sub.3--O--) II-136 H 5-CH.sub.3 H
--N(CH.sub.3).sub.2 II-137 H 5-CH.sub.3 H --N(CH.sub.2--C.sub.6H.s-
ub.5).sub.2 II-138 H 5-CH.sub.3 H --N(C.sub.2H.sub.5).sub.2 II-139
H 5-CH.sub.3 H --N(isoC.sub.3H.sub.7).sub.2 II-140 H 5-CH.sub.3 H
--N(nC.sub.3H.sub.7).sub.2 II-141 H 5-CH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 II-142 H 5-CH.sub.3 H
--N(C.sub.6H.sub.5).sub.2 II-143 CH.sub.3 H H --NH--CH.sub.3 II-144
CH.sub.3 H H --NH--CH.sub.2--C.sub.6H.sub.5 II-145 CH.sub.3 H H
--NH--isoC.sub.3H.sub.7 II-146 CH.sub.3 H H --NH-C.sub.6H.sub.5
II-147 CH.sub.3 H H --NH-C.sub.2H.sub.5 II-148 CH.sub.3 H H
--NH-nC.sub.3H.sub.7 II-149 CH.sub.3 H H --NH-nC.sub.4H.sub.9
II-150 CH.sub.3 H H --NH-tertC.sub.4H.sub.9 II-151 CH.sub.3 H H
--NH-cycloC.sub.3H.sub.5 II-152 CH.sub.3 H H
--NH-cycloC.sub.4H.sub.7 II-153 CH.sub.3 H H
--NH-cycloC.sub.5H.sub.9 II-154 CH.sub.3 H H
--NH-cycloC.sub.6H.sub.11 II-155 CH.sub.3 H H --NH-1-adamantyl
II-156 CH.sub.3 H H --NH-2R-(but-2-yl) II-157 CH.sub.3 H H
--NH-2S-(but-2-yl) II-158 CH.sub.3 H H --NH--O--CH.sub.3 II-159
CH.sub.3 H H --N(CH.sub.3)(OCH.sub.3) II-160 CH.sub.3 H H
--N(--(CH.sub.2).sub.3--O--) II-161 CH.sub.3 H H
--N(CH.sub.3).sub.2 II-162 CH.sub.3 H H --N(CH.sub.2--C.sub.6H.sub-
.5).sub.3 II-163 CH.sub.3 H H --N(C.sub.2H.sub.5).sub.2 II-164
CH.sub.3 H H --N(isoC.sub.3H.sub.7).sub.2 II-165 CH.sub.3 H H
--N(nC.sub.3H.sub.7).sub.2 II-155 CH.sub.3 H H
--N(nC.sub.4H.sub.9).sub.2 II-167 CH.sub.3 H H
--N(C.sub.6H.sub.5).sub.2 II-168 H 4-OCH.sub.3 H --NH--CH.sub.3
II-159 H 4-OCH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5 II-170 H
4-OCH.sub.3 H --NH-isoC.sub.3H.sub.7 II-171 H 4-OCH.sub.3 H
--NH-C.sub.6H.sub.5 II-172 H 4-OCH.sub.3 H --NH-C.sub.2H.sub.5
II-173 H 4-OCH.sub.3 H --NH-nC.sub.4H.sub.7 II-174 H 4-OCH.sub.3 H
--NH-nC.sub.5H.sub.9 II-175 H 4-OCH.sub.3 H --NH-tertC.sub.4H.sub.9
II-176 H 4-OCH.sub.3 H --NH-cycloC.sub.3H.sub.5 II-177 H
4-OCH.sub.3 H --NH-cycloC.sub.4H.sub.7 II-178 H 4-OCH.sub.3 H
--NH-cycloC.sub.5H.sub.9 II-179 H 4-OCH.sub.3 H
--NH-cycloC.sub.6H.sub.11 II-180 H 4-OCH.sub.3 H --NH-1-adamantyl
II-181 H 4-OCH.sub.3 H --NH-2R-(but-2-yl) II-182 H 4-OCH.sub.3 H
--NH-2S-(but-2-yl) II-183 H 4-OCH.sub.3 H --NH--O--CH.sub.3 II-184
H 4-OCH.sub.3 H --N(CH.sub.3)(OCH.sub.3) II-185 H 4-OCH.sub.3 H
--N(--(CH.sub.2).sub.3--O--) II-186 H 4-OCH.sub.3 H
--N(CH.sub.3).sub.2 II-187 H 4-OCH.sub.3 H
--N(CH.sub.2--C.sub.6H.sub.5).sub.2 II-188 H 4-OCH.sub.3 H
--N(C.sub.2H.sub.5).sub.2 II-189 H 4-OCH.sub.3 H
--N(isoC.sub.3H.sub.7).sub.2 II-190 H 4-OCH.sub.3 H
--N(nC.sub.3H.sub.7).sub.2 II-191 H 4-OCH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 II-192 H 4-OCH.sub.3 H
--N(C.sub.6H.sub.5).sub.2 II-193 H 5-OCH.sub.3 H --NH--CH.sub.3
II-194 H 5-OCH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5 II-195 H
5-OCH.sub.3 H --NH-isoC.sub.3H.sub.7 II-196 H 5-OCH.sub.3 H
--NH--C.sub.6H.sub.5 II-197 H 5-OCH.sub.3 H --NH--C.sub.2H.sub.5
II-198 H 5-OCH.sub.3 H --NH-nC.sub.3H.sub.7 II-199 H 5-OCH.sub.3 H
--NH-nC.sub.4H.sub.9 II-200 H 5-OCH.sub.3 H --NH-tertC.sub.4H.sub.9
II-201 H 5-OCH.sub.3 H --NH-cycloC.sub.3H.sub.5 II-202 H
5-OCH.sub.3 H --NH-cycloC.sub.4H.sub.7 II-203 H 5-OCH.sub.3 H
--NH-cycloC.sub.5H.sub.9 II-204 H 5-OCH.sub.3 H
--NH-cycloC.sub.6H.sub.11 II-205 H 5-OCH.sub.3 H --NH-1-adamantyl
II-206 H 5-OCH.sub.3 H --NH-2R-(but-2-y1) II-207 H 5-OCH.sub.3 H
--NH-2S-(but-2-yl) II-208 H 5-OCH.sub.3 H --NH--O--CH.sub.3 II-209
H 5-OCH.sub.3 H --N(CH.sub.3)(OCH.sub.3) II-210 H 5-OCH.sub.3 H
--N(--(CH.sub.2).sub.3--O--) II-211 H 5-OCH.sub.3 H
--N(CH.sub.3).sub.2 II-212 H 5-OCH.sub.3 H
--N(CH.sub.2--C.sub.6H.sub.5).sub.2 II-213 H 5-OCH.sub.3 H
--N(C.sub.2H.sub.5).sub.2 II-214 H 5-OCH.sub.3 H
--N(isoC.sub.3H.sub.7).sub.2 II-215 H 5-OCH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 II-216 H 5-OCH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 II-217 H 5-OCH.sub.3 H
--N(C.sub.6H.sub.5).sub.2
[0196] Table 3:
[0197] A is Me.sub.2Val, B is Val, D is MeVal, E is Pro, F is of
Formula II.sub.f, the substituent --(C.dbd.O)-G is in position 4
relative to the nitrogen. G is of Formula II.sub.g, III.sub.g or
IV.sub.g.
5 No. R.sub.F R.sup.1.sub.F R.sup.2.sub.F --G III-1 H H H
--NH--CH.sub.3 III-2 H H H --NH--CH.sub.2--C.sub.6H.s- ub.5 III-3 H
H H --NH-isoC.sub.3H.sub.5 III-4 H H H --NH--C.sub.6H.sub.5 III-5 H
H H 1,3-Thiazol-2-yl-amide III-6 H 4-OCH.sub.3 5-OCH.sub.3
--NH--CH.sub.3 III-7 H 3-cycloC.sub.5H.sub.9 H --NH--CH.sub.3 III-8
H H H --NH--C.sub.2H.sub.5 III-9 H H H --NH-nC.sub.3H.sub.7 III-10
H H H --NH-nC.sub.4H.sub.9 III-11 H H H --NH-tertC.sub.4H.sub.9
III-12 H H H --NH-cycloC.sub.3H.sub.5 III-13 H H H
--NH-cycloC.sub.4H.sub.7 III-14 H H H --NH-cycloC.sub.5H.sub.9
III-15 H H H --NH-cycloC.sub.6H.sub.11 III-16 H H H
--NH-cycloC.sub.7H.sub.12 III-17 H H H --NH--CH.sub.3--O--CH.sub.3
III-18 H H H --NH--CH.sub.2--CH.sub.2-- -O--CH.sub.3 III-19 H H H
--NH-1-adamantyl III-20 H H H --NH-(4-HO-C.sub.6H.sub.5) III-21 H H
H --NH-(2-CF.sub.3--C.sub.6H- .sub.4) III-22 H H H
--NH-(3-CF.sub.3--C.sub.6H.sub.4) III-23 H H H
--NH-(4-CF.sub.3--C.sub.6H.sub.4) III-24 H H H
--NH-(2-OCH.sub.3--C.sub.6H.sub.4) III-25 H H H
--NH-(3-OCH.sub.3--C.sub.6H.sub.4) III-26 H H H
--NH-(4-OCH.sub.3--C.sub.6H.sub.4) III-27 H H H
--NH-(2-SCH.sub.3--C.sub.6H.sub.4) III-28 H H H
--NH-(3-SCH.sub.3--C.sub.6H.sub.4) III-29 H H H
--NH-(4-SCH.sub.3--C.sub.6H.sub.4) III-30 H H H
--NH-(2-N(CH.sub.3).sub.2--C.sub.6H.sub.4) III-31 H H H
--NH-(3-N(CH.sub.3).sub.2--C.sub.6H.sub.4) III-32 H H H
--NH-(4-N(CH.sub.3).sub.2--C.sub.6H.sub.4) III-33 H H H
--NH-(4-CN-C.sub.6H.sub.4) III-34 H H H --NH-(4-Cl-C.sub.6H.sub.4)
III-35 H H H --NH-(4-Br-C.sub.6H.sub.4] III-36 H H H
--NH-(4-F-C.sub.6H.sub.4] III-37 H H H --NH-(4-CH.sub.3--C.sub.6H.-
sub.4) III-33 H H H --NH-(2-NO.sub.2--C.sub.6H.sub.4) III-39 H H H
--NH-(3-NO.sub.2--C.sub.6H.sub.4) III-40 H H H
--NH-(4-NO.sub.2--C.sub.6H.sub.4) III-41 H H H
--NH-(2,4-OCH.sub.3--C.sub.6H.sub.3) III-42 H H H
--NH-(3,4-OCH.sub.3--C.sub.6H.sub.3) III-43 H H H
--NH-(3,4,5-OCH.sub.3--C.sub.6H.sub.2) III-44 H H H
--NH-(3,4-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) III-45 H H H
--NH-(2,3-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) III-46 H H H
--NH-2-pyridinyl III-47 H H H --NH-2-furanyl III-48 H H H
--NH-2-thienyl III-49 H H H --NH-3-pyridinyl III-50 H H H
--NH-3-furanyl III-51 H H H --NH-3-thienyl III-52 H H H
--NH-4-pyridinyl III-53 H H H --NH-2-oxazolyl III-54 H H H
--NH-3-isoxazolyl III-55 H H H --NH-4-isoxazolyl III-56 H H H
--NH-5-isoxazloyl III-57 H H H --NH-2R-(but-2-yl) III-58 H H H
--NH-2S-(but-2-yl) III-59 H H H --NH--O--CH.sub.3 III-60 H H H
--N(CH.sub.3) (OCH.sub.3) III-61 H H H --N(--(CH.sub.2)3--O--)
III-62 H H H --NH--O--CH.sub.2--C.sub.6H.s- ub.5 III-63 H H H
--N(CH.sub.3)(O--CH.sub.2--C.sub.6H.sub.5) III-64 H H H
--N(--(CH.sub.2).sub.2--CH(C.sub.6H.sub.5)--O--) III-65 H H H
--NH--O--C.sub.2H.sub.5 III-66 H H H
--N(C.sub.2H.sub.5)(OC.sub.2H.sub.5) III-67 H H H
--N(CH.sub.2)(OC.sub.2H.sub.5) III-58 H H H
--NH--O-isoC.sub.3H.sub.7 III-69 H H H --N(CH.sub.3)(O-isoC.sub.3H-
.sub.7) III-70 H H H --NH--O--nC.sub.3H.sub.7 III-71 H H H
--N(CH.sub.3)(O--nC.sub.3H.sub.7) III-72 H H H
--NH--O--nC.sub.4H.sub.9 III-73 H H H --N(CH.sub.2)(O--nC.sub.4H.s-
ub.9) III-74 H H H --NH-O-tertC.sub.4H.sub.9 III-75 H H H
--N(CH.sub.3)(O-tertC.sub.4H.sub.9) III-76 H H H
--NH--O--C.sub.6H.sub.5 III-77 H H H --N(CH.sub.3)(O--C.sub.6H.sub-
.5) III-78 H H H --N(CH.sub.3).sub.2 III-79 H H H
--N(CH.sub.2--C.sub.6H.sub.5).sub.2 III-80 H H H
--N(C.sub.2H.sub.5).sub.2 III-81 H H H --N(isoC.sub.3H.sub.7).sub.-
2 III-82 H H H --N(nC.sub.3H.sub.7).sub.2 III-83 H H H
--N(nC.sub.4H.sub.9).sub.2 III-84 H H H --N(C.sub.6H.sub.5).sub.2
III-85 H H H --NH--CH.sub.2--CH.sub.2--OH III-86 H H H
--NH--(CH.sub.2).sub.3--OH III-87 H H H --NH(--(CH.sub.2).sub.2CH(-
C.sub.6H.sub.5)OH) III-88 H H H --NH--(CH.sub.2).sub.4--OH III-89 H
H H --NH(--CH(CH.sub.3)--CH.sub.2--OH) III-90 H H H
--NH(--CH.sub.2--CH(CH.sub.3)--OH) III-91 H H H
--NH(CH(CH.sub.3)(CH.sub.2).sub.2OH) III-92 H H H
--NH(--(CH.sub.2).sub.2CH(CH.sub.3)OH) III-93 H 2-CH.sub.3 H
--NH--CH.sub.3 III-94 H 2-CH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.-
5 III-95 H 2-CH.sub.3 H --NH--isoC.sub.3H.sub.7 III-96 H 2-CH.sub.3
H --NH--C.sub.6H.sub.5 III-97 H 2-CH.sub.3 H --NH--C.sub.2H.sub.5
III-98 H 2-CH.sub.3 H --NH-nC.sub.3H.sub.7 III-99 H 2-CH.sub.3 H
--NH--nC.sub.4H.sub.9 III-100 H 2-CH.sub.3 H
--NH-tertC.sub.4H.sub.9 III-101 H 2-CH.sub.3 H
--NH-cycloC.sub.3H.sub.5 III-102 H 2-CH.sub.3 H --NH-
cycloC.sub.4H.sub.7 III-103 H 2-CH.sub.3 H --NH-cycloC.sub.5H.sub.-
9 III-104 H 2-CH.sub.3 H --NH-cycloC.sub.6H.sub.11 III-105 H
2-CH.sub.3 H --NH-1-adamantyl III-106 H 2-CH.sub.3 H
--NH-2R-(but-2-yl) III-107 H 2-CH.sub.3 H --NH-2S-(but-2-yl)
III-108 H 2-CH.sub.3 H --NH--O--CH.sub.3 III-109 H 2-CH.sub.3 H
--N(CH.sub.3)(OCH.sub.3) III-110 H 2-CH.sub.3 H
--N(--(CH.sub.3--O--) III-111 H 2-CH.sub.3 H --N(CH.sub.3).sub.2
III-112 H 2-CH.sub.3 H --N(CH.sub.2--C.sub.6H.sub.5).sub.2 III-113
H 2-CH.sub.3 H --N(C.sub.2H.sub.5).sub.2 III-114 H 2-CH.sub.3 H
--N(isoC.sub.3H.sub.7).sub.2 III-115 H 2-CH.sub.3 H
--N(nC.sub.3H.sub.7).sub.2 III-116 H 2-CH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 III-117 H 2-CH.sub.3 H
--N(C.sub.6H.sub.5).sub.2 III-118 H 3-CH.sub.3 H --NH--CH.sub.3
III-119 H 3-CH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5 III-120 H
3-CH.sub.3 H --NH-isoC.sub.3H.sub.7 III-121 H 3-CH.sub.3 H
--NH-C.sub.6H.sub.5 III-122 H 3-CH.sub.3 H --NH-C.sub.2H.sub.5
III-123 H 3-CH.sub.3 H --NH-nC.sub.3H.sub.7 III-124 H 3-CH.sub.3 H
--NH-nC.sub.4H.sub.9 III-125 H 3-CH.sub.3 H --NH-tertC.sub.4H.sub.9
III-126 H 3-CH.sub.3 H --NH-cycloC.sub.3H.sub.5 III-127 H
3-CH.sub.3 H --NH-cycloC.sub.4H.sub.7 III-128 H 3-CH.sub.3 H
--NH-cycloC.sub.5H.sub.9 III-129 H 3-CH.sub.3 H
--NH-cycloC.sub.6H.sub.11 III-130 H 3-CH.sub.3 H --NH-1-adamantyl
III-131 H 3-CH.sub.3 H --NH-2R-(but-2-yl) III-132 H 3-CH.sub.3 H
--NH-2S-(but-2-yl) III-133 H 3-CH.sub.3 H --NH--O--CH.sub.3 III-134
H 3-CH.sub.3 H --N(CH.sub.3)(OCH.sub.3) III-135 H 3-CH.sub.3 H
--N(--(CH.sub.3).sub.3--O--) III-136 H 3-CH.sub.3 H
--N(CH.sub.3).sub.2 III-137 H 3-CH.sub.3 H
--N(CH.sub.2--C.sub.6H.sub.5).sub.2 III-138 H 3-CH.sub.3 H
--N(C.sub.2H.sub.5).sub.2 III-139 H 3-CH.sub.3 H
--N(isoC.sub.3H.sub.7).sub.2 III-140 H 3-CH.sub.3 H
--N(nC.sub.3H.sub.7).sub.2 III-141 H 3-CH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 III-142 H 3-CH.sub.3 H
--N(C.sub.6H.sub.5).sub.2 III-143 CH.sub.3 H H --NH--CH.sub.3
III-144 CH.sub.3 H H --NH--CH.sub.2--C.sub.6H.sub.5 III-145
CH.sub.3 H H --NH--isoC.sub.3H.sub.7 III-146 CH.sub.3 H H
--NH-C.sub.6H.sub.5 III-147 CH.sub.3 H H --NH-C.sub.2H.sub.5
III-148 CH.sub.3 H H --NH-nC.sub.3H.sub.7 III-149 CH.sub.3 H H
--NH-nC.sub.4H.sub.9 III-150 CH.sub.3 H H --NH-tertC.sub.4H.sub.9
III-151 CH.sub.3 H H --NH-cycloC.sub.3H.sub.5 III-152 CH.sub.3 H H
--NH-cycloC.sub.4H.sub.7 III-153 CH.sub.3 H H
--NH-cycloC.sub.5H.sub.9 III-154 CH.sub.3 H H
--NH-cycloC.sub.6H.sub.11 III-155 CH.sub.3 H H --NH-1-adamantyl
III-156 CH.sub.3 H H --NH-2R-(but-2-yl) III-157 CH.sub.3 H H
--NH-2S-(but-2-yl) III-158 CH.sub.3 H H --NH--O--CH.sub.3 III-159
CH.sub.3 H H --N(CH.sub.3)(OCH.sub.3) III-160 CH.sub.3 H H
--N(--(CH.sub.2).sub.3--O--) III-161 CH.sub.3 H H
--N(CH.sub.3).sub.2 III-162 CH.sub.3 H H --N(CH.sub.2--C.sub.6H.su-
b.5).sub.3 III-163 CH.sub.3 H H --N(C.sub.2H.sub.5).sub.2 III-164
CH.sub.3 H H --N(isoC.sub.3H.sub.7).sub.2 III-165 CH.sub.3 H H
--N(nC.sub.3H.sub.7).sub.2 III-166 CH.sub.3 H H
--N(nC.sub.4H.sub.9).sub.2 III-167 CH.sub.3 H H
--N(C.sub.6H.sub.5).sub.2 III-168 H 2-OCH.sub.3 H --NH--CH.sub.3
III-169 H 2-OCH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5 III-170 H
2-OCH.sub.3 H --NH-isoC.sub.3H.sub.7 III-171 H 2-OCH.sub.3 H
--NH-C.sub.6H.sub.5 III-172 H 2-OCH.sub.3 H --NH-C.sub.2H.sub.5
III-173 H 2-OCH.sub.3 H --NH-nC.sub.4H.sub.7 III-174 H 2-OCH.sub.3
H --NH-nC.sub.5H.sub.9 III-175 H 2-OCH.sub.3 H
--NH-tertC.sub.4H.sub.9 III-176 H 2-OCH.sub.3 H
--NH-cycloC.sub.3H.sub.5 III-177 H 2-OCH.sub.3 H
--NH-cycloC.sub.4H.sub.7 III-178 H 2-OCH.sub.3 H
--NH-cycloC.sub.5H.sub.9 III-179 H 2-OCH.sub.3 H
--NH-cycloC.sub.6H.sub.11 III-180 H 2-OCH.sub.3 H --NH-1-adamantyl
III-181 H 2-OCH.sub.3 H --NH-2R-(but-2-yl) III-182 H 2-OCH.sub.3 H
--NH-2S-(but-2-yl) III-183 H 2-OCH.sub.3 H --NH--O--CH.sub.3
III-184 H 2-OCH.sub.3 H --N(CH.sub.3)(OCH.sub.3) III-185 H
2-OCH.sub.3 H --N(--(CH.sub.2).sub.3--O--) III-186 H 2-OCH.sub.3 H
--N(CH.sub.3).sub.2 III-187 H 2-OCH.sub.3 H
--N(CH.sub.2--C.sub.6H.sub.5).sub.2 III-188 H 2-OCH.sub.3 H
--N(C.sub.2H.sub.5).sub.2 III-189 H 2-OCH.sub.3 H
--N(isoC.sub.3H.sub.7).sub.2 III-190 H 2-OCH.sub.3 H
--N(nC.sub.3H.sub.7).sub.2 III-191 H 2-OCH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 III-192 H 2-OCH.sub.3 H
--N(C.sub.6H.sub.5).sub.2 III-193 H 3-OCH.sub.3 H --NH--CH.sub.3
III-194 H 3-OCH.sub.3 H --NH--CH.sub.2--C.sub.6H.sub.5 III-195 H
3-OCH.sub.3 H --NH-isoC.sub.3H.sub.7 III-196 H 3-OCH.sub.3 H
--NH--C.sub.6H.sub.5 III-197 H 3-OCH.sub.3 H --NH--C.sub.2H.sub.5
III-198 H 3-OCH.sub.3 H --NH-nC.sub.3H.sub.7 III-199 H 3-OCH.sub.3
H --NH-nC.sub.4H.sub.9 III-200 H 3-OCH.sub.3 H
--NH-tertC.sub.4H.sub.9 III-201 H 3-OCH.sub.3 H
--NH-cycloC.sub.3H.sub.5 III-202 H 3-OCH.sub.3 H
--NH-cycloC.sub.4H.sub.7 III-203 H 3-OCH.sub.3 H
--NH-cycloC.sub.5H.sub.9 III-204 H 3-OCH.sub.3 H
--NH-cycloC.sub.6H.sub.11 III-205 H 3-OCH.sub.3 H --NH-1-adamantyl
III-206 H 3-OCH.sub.3 H --NH-2R-(but-2-y1) III-207 H 3-OCH.sub.3 H
--NH-2S-(but-2-yl) III-208 H 3-OCH.sub.3 H --NH--O--CH.sub.3
III-209 H 3-OCH.sub.3 H --N(CH.sub.3)(OCH.sub.3) III-210 H
3-OCH.sub.3 H --N(--(CH.sub.2).sub.3--O--) III-211 H 3-OCH.sub.3 H
--N(CH.sub.3).sub.2 III-212 H 3-OCH.sub.3 H
--N(CH.sub.2--C.sub.6H.sub.5).sub.2 III-213 H 3-OCH.sub.3 H
--N(C.sub.2H.sub.5).sub.2 III-214 H 3-OCH.sub.3 H
--N(isoC.sub.3H.sub.7).sub.2 III-215 H 3-OCH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 III-216 H 3-OCH.sub.3 H
--N(nC.sub.4H.sub.9).sub.2 III-217 H 3-OCH.sub.3 H
--N(C.sub.6H.sub.5).sub.2
[0198] Table 4:
[0199] A is Me.sub.2Val, B is Val, D is MeVal, E is Pro and F is of
Formula II.sub.f, the substituent --(C.dbd.O)-G is in position 2
relative to the nitrogen. G is of Formula V.sub.g, VI.sub.g,
VII.sub.g, VIII.sub.g or IX.sub.g.
6 No. R.sub.F R.sup.1F R.sup.2F -G IV-1 H H H --CH.sub.3 IV-2 H H H
--C.sub.2H.sub.5 IV-3 H H H -nC.sub.3H.sub.7 IV-4 H H H
-isoC.sub.3H.sub.7 IV-5 H H H -nC.sub.4H.sub.9 IV-6 H H H
-tertC.sub.4H.sub.9 IV-7 H H H -cycloC.sub.3H.sub.5 IV-8 H H H
-cycloC.sub.4H.sub.7 IV-9 H H H -cycloC.sub.5H.sub.9 IV-10 H H H
-cycloC.sub.6H.sub.11 IV-11 H H H -cycloC.sub.7H.sub.12 IV-12 H H H
--CH.sub.2--O--CH.sub.3 IV-13 H H H --CH.sub.2--CH.sub.2--O--CH.su-
b.3 IV-14 H H H --CH.sub.2--C.sub.6H.sub.5 IV-15 H H H
--C.sub.6H.sub.5 IV-16 H H H -(4-HO--C.sub.6H.sub.5) IV-17 H H H
-(2-CF.sub.3--C.sub.6H.sub.4) IV-18 H H H
-(3-CF.sub.3--C.sub.6H.sub.4) IV-19 H H H -(4-CF.sub.3--C.sub.6H.s-
ub.4) IV-20 H H H -(2-OCH.sub.3--C.sub.6H.sub.4) IV-21 H H H
-(3-OCH.sub.3--C.sub.6H.sub.4) IV-22 H H H -(4-OCH.sub.3--C.sub.6H-
.sub.4) IV-23 H H H -(2-SCH.sub.3--C.sub.6H.sub.4) IV-24 H H H
-(3-SCH.sub.3--C.sub.6H.sub.4) IV-25 H H H
-(4-SCH.sub.3--C.sub.6H.sub.4) IV-26 H H H -(2-N(CH.sub.3).sub.2---
C.sub.6H.sub.4) IV-27 H H H -(3-N(CH.sub.3).sub.2--C.sub.6H.sub.4)
IV-28 H H H -(4-N(CH.sub.3).sub.2--C.sub.6H.sub.4) IV-29 H H H
-(4-CN--C.sub.6H.sub.4) IV-30 H H H -(4-Cl--C.sub.6H.sub.4) IV-31 H
H H -(4-Br--C.sub.6H.sub.4] IV-32 H H H -(4-F--C.sub.6H.sub.4]
IV-33 H H H -(4-CH.sub.3--C.sub.6H.sub.4) IV-34 H H H
-(2-NO.sub.2--C.sub.6H.sub.4) IV-35 H H H
-(3-NO.sub.2--C.sub.6H.sub.4) IV-36 H H H -(4-NO.sub.2--C.sub.6H.s-
ub.4] IV-37 H H H -(2,4-OCH.sub.3--C.sub.6H.sub.3) IV-38 H H H
-(3,4-OCH.sub.3--C.sub.6H.sub.3) IV-39 H H H
-(3,4,5-OCH.sub.3--C.sub.6H.sub.2) IV-40 H H H
-(3,4-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) IV-41 H H H
-(2,3-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) IV-42 H H H -2-pyridinyl
IV-43 H H H -2-furanyl IV-44 H H H -2-thienyl IV-45 H H H
-3-pyridinyl IV-46 H H H -3-furanyl IV-47 H H H -3-thienyl IV-48 H
H H -4-pyridinyl IV-49 H H H -2-thiazolyl IV-50 H H H -2-oxazolyl
IV-51 H H H -3-isoxazolyl IV-52 H H H -4-isoxazolyl IV-53 H H H
-5-isoxazolyl IV-54 H H H --CF.sub.3 IV-55 H H H --C.sub.2F.sub.5
IV-56 H H H --CH.sub.3 IV-57 H H H --C.sub.2H.sub.5 IV-58 H H H
-nC.sub.3H.sub.7 IV-59 H H H -tertC.sub.4H.sub.9 IV-60 H H H
--CH.sub.2--C.sub.6H.sub.5 IV-61 H H H --C.sub.6H.sub.5 IV-62 H H H
--CH.sub.2--COOCH.sub.3 IV-63 H H H --CH.sub.2--COOC.sub.2H.sub.5
IV-64 H H H --CF.sub.2--COOCH.sub.3 IV-65 H H H
--CF.sub.2--COOC.sub.2H.sub.5 IV-66 H H H --CH.sub.2--CONH.sub.2
IV-67 H H H --CH.sub.2--CONHCH.sub.3 IV-68 H H H
--CH.sub.2--CON(CH.sub.3).sub- .2 IV-69 H H H
--CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 IV-70 H H H
--CH.sub.2--CONH--C.sub.6H.sub.5 IV-71 H H H
--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 IV-72 H H H
--CH.sub.2--CON(--CH.sub.2--CH.sub.2-- CH.sub.2--CH.sub.2--) IV-73
H H H --CH.sub.2--CON(--CH.sub.2--CH.sub.2--
CH.sub.2--CH.sub.2--CH.sub.2) IV-74 H H H --CH.sub.2--CH.sub.2--CO-
OCH.sub.3 IV-75 H H H --CH.sub.2--CH.sub.2--COOC.sub.2H.sub.5 IV-76
H H H --CH.sub.2--CH.sub.2--CONH.sub.2 IV-77 H H H
--CH.sub.2--CH.sub.2--CONHCH.sub.3 IV-78 H H H
--CH.sub.2--CH.sub.2--CON(CH.sub.3).sub.2 IV-79 H H H
--CH.sub.2--CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 IV-80 H H H
--CH.sub.2--CH.sub.2--CONH--C.sub.6H.sub.5 IV-81 H H H
--CH.sub.2--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 IV-82 H
H H --CH.sub.2--CH.sub.2--CON(--CH.sub.2--CH.sub.2--
CH.sub.2--CH.sub.2--) IV-83 H H H --CH.sub.2--CH.sub.2--CON(--CH.s-
ub.2-- (CH.sub.2).sub.3--CH.sub.2) IV-84 H H H
--CH.sub.2--COCH.sub.3 IV-85 H H H --CH.sub.2--CH.sub.2--COCH.sub.-
3 IV-86 H H H --CH.sub.2--COC.sub.2H.sub.5 IV-87 H H H
--CH.sub.2--CH.sub.2--COC.sub.2H.sub.5 IV-88 H H H
--CH.sub.2--CO--C.sub.6H.sub.5 IV-89 H H H --CH.sub.2--CH.sub.2--C-
O--C.sub.6H.sub.5 IV-90 H H H
--CH.sub.2--CO--CH.sub.2--C.sub.6H.su- b.5 IV-91 H H H
--CH.sub.2--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.5 IV-92 H H H
--CH.sub.2--SOC.sub.6H.sub.5 IV-93 H H H --CH.sub.2--SOCH.sub.3
IV-94 H H H --CH.sub.2SO(4-CH.sub.3--C.sub.- 6H.sub.4) IV-95 H H H
--CH.sub.2--SO.sub.2C.sub.6H.sub.5 IV-96 H H H
--CH.sub.2--SO.sub.2CH.sub.3 IV-97 H H H
--CH.sub.2--SO.sub.2(4-CH.sub.3--C.sub.6H.sub.4) IV-98 H H H
--CH.sub.2--CH.sub.2--SOC.sub.6H.sub.5 IV-99 H H H
--CH.sub.2--CH.sub.2--SOCH.sub.3 IV-100 H H H
--CH.sub.2--CH.sub.2--SO(4-CH.sub.3--C.sub.6H.sub.4) IV-101 H H H
--CH.sub.2--CH.sub.2--SO.sub.2C.sub.6H.sub.5 IV-102 H H H
--CH.sub.2--CH.sub.2--SO.sub.2CH.sub.3 IV-103 H H H
--CH.sub.2--CH.sub.2--SO.sub.3(4-CH.sub.3--C.sub.6H.sub.4) IV-104
CH.sub.3 H H --CH.sub.3 IV-105 CH.sub.3 H H --C.sub.2H.sub.5 IV-106
CH.sub.3 H H -nC.sub.3H.sub.7 IV-107 CH.sub.3 H H
-isoC.sub.3H.sub.7 IV-108 CH.sub.3 H H -nC.sub.4H.sub.9 IV-109
CH.sub.3 H H -tertC.sub.4H.sub.9 IV-110 CH.sub.3 H H
-cycloC.sub.3H.sub.5 IV-111 CH.sub.3 H H -cycloC.sub.4H.sub.7
IV-112 CH.sub.3 H H -cycloC.sub.5H.sub.9 IV-113 CH.sub.3 H H
-cycloC.sub.6H.sub.11 IV-114 CH.sub.3 H H -cycloC.sub.7H.sub.12
IV-115 CH.sub.3 H H --CH.sub.2--O--CH.sub.3 IV-116 CH.sub.3 H H
--CH.sub.2--CH.sub.3--O--CH.sub.3 IV-117 CH.sub.3 H H
--CH.sub.2--C.sub.6H.sub.5 IV-118 CH.sub.3 H H --C.sub.6H.sub.5
IV-119 CH.sub.3 H H -(4-HO-C.sub.6H.sub.5) IV-120 CH.sub.3 H H
-(2-CF.sub.3--C.sub.6H.sub.4) IV-121 CH.sub.3 H H
-(3-CF.sub.3--C.sub.6H.sub.4) IV-122 CH.sub.3 H H
-(4-CF.sub.3--C.sub.6H.sub.4) IV-123 CH.sub.3 H H
-(2-OCH.sub.3--C.sub.6H.sub.4) IV-124 CH.sub.3 H H
-(3-OCH.sub.3--C.sub.6H.sub.4) IV-125 CH.sub.3 H H
-(4-OCH.sub.3--C.sub.6H.sub.4) IV-126 CH.sub.3 H H
-(2-SCH.sub.3--C.sub.6H.sub.4) IV-127 CH.sub.3 H H
-(3-SCH.sub.3--C.sub.6H.sub.4) IV-128 CH.sub.3 H H
-(4-SCH.sub.3--C.sub.6H.sub.4) IV-129 CH.sub.3 H H
-(2-N(CH.sub.3).sub.2--C.sub.6H.sub.4) IV-130 CH.sub.3 H H
-(3-N(CH.sub.3).sub.2--C.sub.6H.sub.4) IV-131 CH.sub.3 H H
-(4-N(CH.sub.3).sub.2--C.sub.6H.sub.4) IV-132 CH.sub.3 H H
-(4-CN-C.sub.6H.sub.4) IV-133 CH.sub.3 H H -(4-Cl--C.sub.6H.sub.4)
IV-134 CH.sub.3 H H -(4-Br--C.sub.6H.sub.4] IV-135 CH.sub.3 H H
-(4-F--C.sub.6H.sub.4] IV-136 CH.sub.3 H H
-(4-CH.sub.3--C.sub.6H.sub.4) IV-137 CH.sub.3 H H
-(2-NO.sub.2--C.sub.6H.sub.4) IV-138 CH.sub.3 H H
-(3-NO.sub.2--C.sub.6H.sub.4) IV-139 CH.sub.3 H H
-(4-NO.sub.2--C.sub.6H.sub.4] IV-140 CH.sub.3 H H
-(2,4-OCH.sub.3--C.sub.6H.sub.3) IV-141 CH.sub.3 H H
-(3,4-OCH.sub.3--C.sub.6H.sub.3) IV-142 CH.sub.3 H H
-(3,4,5-OCH.sub.3--C.sub.6H.sub.2) IV-143 CH.sub.3 H H
-(3,4-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) IV-144 CH.sub.3 H H
-(2,3-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) IV-145 CH.sub.3 H H
-2-pyridinyl IV-146 CH.sub.3 H H -2-furanyl IV-147 CH.sub.3 H H
-2-thienyl IV-148 CH.sub.3 H H -3-pyridinyl IV-149 CH.sub.3 H H
-3-furanyl IV-150 CH.sub.3 H H -3-thienyl IV-151 CH.sub.3 H H
-4-pyridinyl IV-152 CH.sub.3 H H -2-thiazolyl IV-153 CH.sub.3 H H
-2-oxazolyl IV-154 CH.sub.3 H H -3-isoxazolyl IV-155 CH.sub.3 H H
-4-isoxazolyl IV-156 CH.sub.3 H H -5-isoxazoyl IV-157 CH.sub.3 H H
--CF.sub.3 IV-158 CH.sub.3 H H --C.sub.2F.sub.5 IV-159 CH.sub.3 H H
--CH.sub.3 IV-160 CH.sub.3 H H --C.sub.2H.sub.5 IV-161 CH.sub.3 H H
-nC.sub.3H.sub.7 IV-162 CH.sub.3 H H -tertC.sub.4H.sub.9 IV-163
CH.sub.3 H H --CH.sub.2--C.sub.6H.sub.5 IV-164 CH.sub.3 H H
--C.sub.6H.sub.5 IV-165 CH.sub.3 H H --CH.sub.2--COOCH.sub.3 IV-166
CH.sub.3 H H --CH.sub.2--COOC.sub.2H.sub.5 IV-167 CH.sub.3 H H
--CF.sub.2--COOCH.sub.3 IV-168 CH.sub.3 H H
--CF.sub.2--COOC.sub.2H.sub.5 IV-169 CH.sub.3 H H
--CH.sub.2--CONH.sub.2 IV-170 CH.sub.3 H H --CH.sub.2--CONHCH.sub.-
3 IV-171 CH.sub.3 H H --CH.sub.2--CON(CH.sub.3).sub.2 IV-172
CH.sub.3 H H --CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 IV-173
CH.sub.3 H H --CH.sub.2--CONH--C.sub.6H.sub.5 IV-174 CH.sub.3 H H
--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 IV-175 CH.sub.3 H
H --CH.sub.2--CON(--CH.sub.2--CH.sub.2-- CH.sub.2--CH.sub.2--)
IV-176 CH.sub.3 H H --CH.sub.2--CON(--CH.sub.2--CH.sub.2--CH.sub.2-
-- CH.sub.2--CH.sub.2) IV-177 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COOCH.sub.3 IV-178 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COOC.sub.2H.sub.5 IV-179 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONH.sub.2 IV-180 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONHCH.sub.3 IV-181 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CON(CH.sub.3).sub.2 IV-182 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 IV-183
CH.sub.3 H H --CH.sub.2--CH.sub.2--CONH--C.sub.6H.sub.5 IV-184
CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 IV-185
CH.sub.3 H H --CH.sub.2--CH.sub.2--CON(--
CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--) IV-186 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CON(--CH.sub.2-- (CH.sub.2).sub.3--CH.su-
b.2) IV-187 CH.sub.3 H H --CH.sub.2--COCH.sub.3 IV-188 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COCH.sub.3 IV-189 CH.sub.3 H H
--CH.sub.2--COC.sub.2H.sub.5 IV-190 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COC.sub.2H.sub.5 IV-191 CH.sub.3 H H
--CH.sub.2--CO--C.sub.6H.sub.5 IV-192 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CO--C.sub.6H.sub.5 IV-193 CH.sub.3 H H
--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.5 IV-194 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.5 IV-195 CH.sub.3
H H --CH.sub.2--SOC.sub.6H.sub.5 IV-196 CH.sub.3 H H
--CH.sub.2--SOCH.sub.3 IV-197 CH.sub.3 H H --CH.sub.2--SO(4-CH.sub-
.3--C.sub.6H.sub.4) IV-198 CH.sub.3 H H
--CH.sub.2--SO.sub.2C.sub.6- H.sub.5 IV-199 CH.sub.3 H H
--CH.sub.2--SO.sub.2CH.sub.3 IV-200 CH.sub.3 H H
--CH.sub.2--SO.sub.2(4-CH.sub.3--C.sub.6H.sub.4) IV-201 CH.sub.3 H
H --CH.sub.2--CH.sub.2--SOC.sub.6H.sub.5 IV-202 CH.sub.3 H H
--CH.sub.2--CH.sub.2--SOCH.sub.3 IV-203 CH.sub.3 H H
--CH.sub.2--CH.sub.2--SO(4-CH.sub.3--C.sub.6H.sub.4) IV-204
CH.sub.3 H H --CH.sub.2--CH.sub.2--SO.sub.2C.sub.6H.sub.5 IV-205
CH.sub.3 H H --CH.sub.2--CH.sub.2--SO.sub.2CH.sub.3 IV-206 CH.sub.3
H H --CH.sub.2--CH.sub.2--SO.sub.2(4-CH.sub.3--C.sub.6H.sub.4)
[0200] Table 5:
[0201] A is Me.sub.2Val, B is Val, D is MeVal, E is Pro and F is of
Formula II.sub.f, the substituent --(C.dbd.O)-G is in position 3
relative to the nitrogen. G is of Formula V.sub.g, VI.sub.g,
VII.sub.g, VIII.sub.g or IX.sub.g.
7 No. R.sub.F R.sup.1F R.sup.2F -G V-1 H H H --CH.sub.3 V-2 H H H
--C.sub.2H.sub.5 V-3 H H H -nC.sub.3H.sub.7 V-4 H H H
-isoC.sub.3H.sub.7 V-5 H H H -nC.sub.4H.sub.9 V-6 H H H
-tertC.sub.4H.sub.9 V-7 H H H -cycloC.sub.3H.sub.5 V-8 H H H
-cycloC.sub.4H.sub.7 V-9 H H H -cycloC.sub.5H.sub.9 V-10 H H H
-cycloC.sub.6H.sub.11 V-11 H H H -cycloC.sub.7H.sub.12 V-12 H H H
--CH.sub.2--O--CH.sub.3 V-13 H H H --CH.sub.2--CH.sub.2--O--CH.sub-
.3 V-14 H H H --CH.sub.2--C.sub.6H.sub.5 V-15 H H H
--C.sub.6H.sub.5 V-16 H H H -(4-HO--C.sub.6H.sub.5) V-17 H H H
-(2-CF.sub.3--C.sub.6H.sub.4) V-18 H H H
-(3-CF.sub.3--C.sub.6H.sub.4) V-19 H H H -(4-CF.sub.3--C.sub.6H.su-
b.4) V-20 H H H -(2-OCH.sub.3--C.sub.6H.sub.4) V-21 H H H
-(3-OCH.sub.3--C.sub.6H.sub.4) V-22 H H H -(4-OCH.sub.3--C.sub.6H.-
sub.4) V-23 H H H -(2-SCH.sub.3--C.sub.6H.sub.4) V-24 H H H
-(3-SCH.sub.3--C.sub.6H.sub.4) V-25 H H H -(4-SCH.sub.3--C.sub.6H.-
sub.4) V-26 H H H -(2-N(CH.sub.3).sub.2--C.sub.6H.sub.4) V-27 H H H
-(3-N(CH.sub.3).sub.2--C.sub.6H.sub.4) V-28 H H H
-(4-N(CH.sub.3).sub.2--C.sub.6H.sub.4) V-29 H H H
-(4-CN--C.sub.6H.sub.4) V-30 H H H -(4-Cl--C.sub.6H.sub.4) V-31 H H
H -(4-Br--C.sub.6H.sub.4] V-32 H H H -(4-F--C.sub.6H.sub.4] V-33 H
H H -(4-CH.sub.3--C.sub.6H.sub.4) V-34 H H H
-(2-NO.sub.2--C.sub.6H.sub.4) V-35 H H H
-(3-NO.sub.2--C.sub.6H.sub.4) V-36 H H H -(4-NO.sub.2--C.sub.6H.su-
b.4] V-37 H H H -(2,4-OCH.sub.3--C.sub.6H.sub.3) V-38 H H H
-(3,4-OCH.sub.3--C.sub.6H.sub.3) V-39 H H H
-(3,4,5-OCH.sub.3--C.sub.6H.sub.2) V-40 H H H
-(3,4-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) V-41 H H H
-(2,3-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) V-42 H H H -2-pyridinyl
V-43 H H H -2-furanyl V-44 H H H -2-thienyl V-45 H H H -3-pyridinyl
V-46 H H H -3-furanyl V-47 H H H -3-thienyl V-48 H H H -4-pyridinyl
V-49 H H H -2-thiazolyl V-50 H H H -2-oxazolyl V-51 H H H
-3-isoxazolyl V-52 H H H -4-isoxazolyl V-53 H H H -5-isoxazolyl
V-54 H H H --CF.sub.3 V-55 H H H --C.sub.2F.sub.5 V-56 H H H
--CH.sub.3 V-57 H H H --C.sub.2H.sub.5 V-58 H H H -nC.sub.3H.sub.7
V-59 H H H -tertC.sub.4H.sub.9 V-60 H H H
--CH.sub.2--C.sub.6H.sub.5 V-61 H H H --C.sub.6H.sub.5 V-62 H H H
--CH.sub.2--COOCH.sub.3 V-63 H H H --CH.sub.2--COOC.sub.2H.s- ub.5
V-64 H H H --CF.sub.2--COOCH.sub.3 V-65 H H H
--CF.sub.2--COOC.sub.2H.sub.5 V-66 H H H --CH.sub.2--CONH.sub.2
V-67 H H H --CH.sub.2--CONHCH.sub.3 V-68 H H H
--CH.sub.2--CON(CH.sub.3).sub.2 V-69 H H H --CH.sub.2--CONH--CH.su-
b.2--C.sub.6H.sub.5 V-70 H H H --CH.sub.2--CONH--C.sub.6H.sub.5
V-71 H H H --CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 V-72 H
H H --CH.sub.2--CON(--CH.sub.2--CH.sub.2-- CH.sub.2--CH.sub.2--)
V-73 H H H --CH.sub.2--CON(--CH.sub.2--CH.su- b.2--
CH.sub.2--CH.sub.2--CH.sub.2) V-74 H H H
--CH.sub.2--CH.sub.2--COOCH.sub.3 V-75 H H H
--CH.sub.2--CH.sub.2--COOC.sub.2H.sub.5 V-76 H H H
--CH.sub.2--CH.sub.2--CONH.sub.2 V-77 H H H
--CH.sub.2--CH.sub.2--CONHCH.sub.3 V-78 H H H
--CH.sub.2--CH.sub.2--CON(CH.sub.3).sub.2 V-79 H H H
--CH.sub.2--CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 V-80 H H H
--CH.sub.2--CH.sub.2--CONH--C.sub.6H.sub.5 V-81 H H H
--CH.sub.2--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 V-82 H H
H --CH.sub.2--CH.sub.2--CON(--CH.sub.2--CH.sub.2--
CH.sub.2--CH.sub.2--) V-83 H H H --CH.sub.2--CH.sub.2--CON(--CH.su-
b.2-- (CH.sub.2).sub.3--CH.sub.2) V-84 H H H --CH.sub.2--COCH.sub.3
V-85 H H H --CH.sub.2--CH.sub.2--COCH.sub.3 V-86 H H H
--CH.sub.2--COC.sub.2H.sub.5 V-87 H H H
--CH.sub.2--CH.sub.2--COC.sub.2H.sub.5 V-88 H H H
--CH.sub.2--CO--C.sub.6H.sub.5 V-89 H H H --CH.sub.2--CH.sub.2--CO-
--C.sub.6H.sub.5 V-90 H H H
--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.- 5 V-91 H H H
--CH.sub.2--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.5 V-92 H H H
--CH.sub.2--SOC.sub.6H.sub.5 V-93 H H H --CH.sub.2--SOCH.sub.3 V-94
H H H --CH.sub.2SO(4-CH.sub.3--C.sub.6- H.sub.4) V-95 H H H
--CH.sub.2--SO.sub.2C.sub.6H.sub.5 V-96 H H H
--CH.sub.2--SO.sub.2CH.sub.3 V-97 H H H
--CH.sub.2--SO.sub.2(4-CH.sub.3--C.sub.6H.sub.4) V-98 H H H
--CH.sub.2--CH.sub.2--SOC.sub.6H.sub.5 V-99 H H H
--CH.sub.2--CH.sub.2--SOCH.sub.3 V-100 H H H
--CH.sub.2--CH.sub.2--SO(4-CH.sub.3--C.sub.6H.sub.4) V-101 H H H
--CH.sub.2--CH.sub.2--SO.sub.2C.sub.6H.sub.5 V-102 H H H
--CH.sub.2--CH.sub.2--SO.sub.2CH.sub.3 V-103 H H H
--CH.sub.2--CH.sub.2--SO.sub.3(4-CH.sub.3--C.sub.6H.sub.4) V-104
CH.sub.3 H H --CH.sub.3 V-105 CH.sub.3 H H --C.sub.2H.sub.5 V-106
CH.sub.3 H H -nC.sub.3H.sub.7 V-107 CH.sub.3 H H -isoC.sub.3H.sub.7
V-108 CH.sub.3 H H -nC.sub.4H.sub.9 V-109 CH.sub.3 H H
-tertC.sub.4H.sub.9 V-110 CH.sub.3 H H -cycloC.sub.3H.sub.5 V-111
CH.sub.3 H H -cycloC.sub.4H.sub.7 V-112 CH.sub.3 H H
-cycloC.sub.5H.sub.9 V-113 CH.sub.3 H H -cycloC.sub.6H.sub.11 V-114
CH.sub.3 H H -cycloC.sub.7H.sub.12 V-115 CH.sub.3 H H
--CH.sub.2--O--CH.sub.3 V-116 CH.sub.3 H H
--CH.sub.2--CH.sub.3--O--CH.sub.3 V-117 CH.sub.3 H H
--CH.sub.2--C.sub.6H.sub.5 V-118 CH.sub.3 H H --C.sub.6H.sub.5
V-119 CH.sub.3 H H -(4-HO-C.sub.6H.sub.5) V-120 CH.sub.3 H H
-(2-CF.sub.3--C.sub.6H.sub.4) V-121 CH.sub.3 H H
-(3-CF.sub.3--C.sub.6H.sub.4) V-122 CH.sub.3 H H
-(4-CF.sub.3--C.sub.6H.sub.4) V-123 CH.sub.3 H H
-(2-OCH.sub.3--C.sub.6H.sub.4) V-124 CH.sub.3 H H
-(3-OCH.sub.3--C.sub.6H.sub.4) V-125 CH.sub.3 H H
-(4-OCH.sub.3--C.sub.6H.sub.4) V-126 CH.sub.3 H H
-(2-SCH.sub.3--C.sub.6H.sub.4) V-127 CH.sub.3 H H
-(3-SCH.sub.3--C.sub.6H.sub.4) V-128 CH.sub.3 H H
-(4-SCH.sub.3--C.sub.6H.sub.4) V-129 CH.sub.3 H H
-(2-N(CH.sub.3).sub.2--C.sub.6H.sub.4) V-130 CH.sub.3 H H
-(3-N(CH.sub.3).sub.2--C.sub.6H.sub.4) V-131 CH.sub.3 H H
-(4-N(CH.sub.3).sub.2--C.sub.6H.sub.4) V-132 CH.sub.3 H H
-(4-CN-C.sub.6H.sub.4) V-133 CH.sub.3 H H -(4-Cl--C.sub.6H.sub.4)
V-134 CH.sub.3 H H -(4-Br--C.sub.6H.sub.4] V-135 CH.sub.3 H H
-(4-F--C.sub.6H.sub.4] V-136 CH.sub.3 H H
-(4-CH.sub.3--C.sub.6H.sub.4) V-137 CH.sub.3 H H
-(2-NO.sub.2--C.sub.6H.sub.4) V-138 CH.sub.3 H H
-(3-NO.sub.2--C.sub.6H.sub.4) V-139 CH.sub.3 H H
-(4-NO.sub.2--C.sub.6H.sub.4] V-140 CH.sub.3 H H
-(2,4-OCH.sub.3--C.sub.6H.sub.3) V-141 CH.sub.3 H H
-(3,4-OCH.sub.3--C.sub.6H.sub.3) V-142 CH.sub.3 H H
-(3,4,5-OCH.sub.3--C.sub.6H.sub.2) V-143 CH.sub.3 H H
-(3,4-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) V-144 CH.sub.3 H H
-(2,3-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) V-145 CH.sub.3 H H
-2-pyridinyl V-146 CH.sub.3 H H -2-furanyl V-147 CH.sub.3 H H
-2-thienyl V-148 CH.sub.3 H H -3-pyridinyl V-149 CH.sub.3 H H
-3-furanyl V-150 CH.sub.3 H H -3-thienyl V-151 CH.sub.3 H H
-4-pyridinyl V-152 CH.sub.3 H H -2-thiazolyl V-153 CH.sub.3 H H
-2-oxazolyl V-154 CH.sub.3 H H -3-isoxazolyl V-155 CH.sub.3 H H
-4-isoxazolyl V-156 CH.sub.3 H H -5-isoxazoyl V-157 CH.sub.3 H H
--CF.sub.3 V-158 CH.sub.3 H H --C.sub.2F.sub.5 V-159 CH.sub.3 H H
--CH.sub.3 V-160 CH.sub.3 H H --C.sub.2H.sub.5 V-161 CH.sub.3 H H
-nC.sub.3H.sub.7 V-162 CH.sub.3 H H -tertC.sub.4H.sub.9 V-163
CH.sub.3 H H --CH.sub.2--C.sub.6H.sub.5 V-164 CH.sub.3 H H
--C.sub.6H.sub.5 V-165 CH.sub.3 H H --CH.sub.2--COOCH.sub.3 V-166
CH.sub.3 H H --CH.sub.2--COOC.sub.2H.sub.5 V-167 CH.sub.3 H H
--CF.sub.2--COOCH.sub.3 V-168 CH.sub.3 H H --CF.sub.2--COOC.sub.2H-
.sub.5 V-169 CH.sub.3 H H --CH.sub.2--CONH.sub.2 V-170 CH.sub.3 H H
--CH.sub.2--CONHCH.sub.3 V-171 CH.sub.3 H H
--CH.sub.2--CON(CH.sub.3).sub.2 V-172 CH.sub.3 H H
--CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 V-173 CH.sub.3 H H
--CH.sub.2--CONH--C.sub.6H.sub.5 V-174 CH.sub.3 H H
--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 V-175 CH.sub.3 H H
--CH.sub.2--CON(--CH.sub.2--CH.sub.2-- CH.sub.2--CH.sub.2--) V-176
CH.sub.3 H H --CH.sub.2--CON(--CH.sub.2--CH.sub.2--CH.sub.2-- -
CH.sub.2--CH.sub.2) V-177 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COOCH.sub.3 V-178 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COOC.sub.2H.sub.5 V-179 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONH.sub.2 V-180 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONHCH.sub.3 V-181 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CON(CH.sub.3).sub.2 V-182 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 V-183 CH.sub.3
H H --CH.sub.2--CH.sub.2--CONH--C.sub.6H.sub.5 V-184 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 V-185
CH.sub.3 H H --CH.sub.2--CH.sub.2--CON(--
CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--) V-186 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CON(--CH.sub.2-- (CH.sub.2).sub.3--CH.su-
b.2) V-187 CH.sub.3 H H --CH.sub.2--COCH.sub.3 V-188 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COCH.sub.3 V-189 CH.sub.3 H H
--CH.sub.2--COC.sub.2H.sub.5 V-190 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COC.sub.2H.sub.5 V-191 CH.sub.3 H H
--CH.sub.2--CO--C.sub.6H.sub.5 V-192 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CO--C.sub.6H.sub.5 V-193 CH.sub.3 H H
--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.5 V-194 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.5 V-195 CH.sub.3 H
H --CH.sub.2--SOC.sub.6H.sub.5 V-196 CH.sub.3 H H
--CH.sub.2--SOCH.sub.3 V-197 CH.sub.3 H H --CH.sub.2--SO(4-CH.sub.-
3--C.sub.6H.sub.4) V-198 CH.sub.3 H H
--CH.sub.2--SO.sub.2C.sub.6H.- sub.5 V-199 CH.sub.3 H H
--CH.sub.2--SO.sub.2CH.sub.3 V-200 CH.sub.3 H H
--CH.sub.2--SO.sub.2(4-CH.sub.3--C.sub.6H.sub.4) V-201 CH.sub.3 H H
--CH.sub.2--CH.sub.2--SOC.sub.6H.sub.5 V-202 CH.sub.3 H H
--CH.sub.2--CH.sub.2--SOCH.sub.3 V-203 CH.sub.3 H H
--CH.sub.2--CH.sub.2--SO(4-CH.sub.3--C.sub.6H.sub.4) V-204 CH.sub.3
H H --CH.sub.2--CH.sub.2--SO.sub.2C.sub.6H.sub.5 V-205 CH.sub.3 H H
--CH.sub.2--CH.sub.2--SO.sub.2CH.sub.3 V-206 CH.sub.3 H H
--CH.sub.2--CH.sub.2--SO.sub.2(4-CH.sub.3--C.sub.6H.sub.4)
[0202] Table 6:
[0203] A is Me.sub.2Val, B is Val, D is MeVal, E is Pro and F is of
Formula II.sub.f, the substituent --(C.dbd.O)-G is in position 4
relative to the nitrogen. G is of Formula V.sub.g, VI.sub.g,
VII.sub.g, VIII.sub.g or IX.sub.g.
8 No. R.sub.F R.sup.1F R.sup.2F -G VI-1 H H H --CH.sub.3 VI-2 H H H
--C.sub.2H.sub.5 VI-3 H H H -nC.sub.3H.sub.7 VI-4 H H H
-isoC.sub.3H.sub.7 VI-5 H H H -nC.sub.4H.sub.9 VI-6 H H H
-tertC.sub.4H.sub.9 VI-7 H H H -cycloC.sub.3H.sub.5 VI-8 H H H
-cycloC.sub.4H.sub.7 VI-9 H H H -cycloC.sub.5H.sub.9 VI-10 H H H
-cycloC.sub.6H.sub.11 VI-11 H H H -cycloC.sub.7H.sub.12 VI-12 H H H
--CH.sub.2--O--CH.sub.3 VI-13 H H H --CH.sub.2--CH.sub.2--O--CH.su-
b.3 VI-14 H H H --CH.sub.2--C.sub.6H.sub.5 VI-15 H H H
--C.sub.6H.sub.5 VI-16 H H H -(4-HO--C.sub.6H.sub.5) VI-17 H H H
-(2-CF.sub.3--C.sub.6H.sub.4) VI-18 H H H
-(3-CF.sub.3--C.sub.6H.sub.4) VI-19 H H H -(4-CF.sub.3--C.sub.6H.s-
ub.4) VI-20 H H H -(2-OCH.sub.3--C.sub.6H.sub.4) VI-21 H H H
-(3-OCH.sub.3--C.sub.6H.sub.4) VI-22 H H H -(4-OCH.sub.3--C.sub.6H-
.sub.4) VI-23 H H H -(2-SCH.sub.3--C.sub.6H.sub.4) VI-24 H H H
-(3-SCH.sub.3--C.sub.6H.sub.4) VI-25 H H H
-(4-SCH.sub.3--C.sub.6H.sub.4) VI-26 H H H -(2-N(CH.sub.3).sub.2---
C.sub.6H.sub.4) VI-27 H H H -(3-N(CH.sub.3).sub.2--C.sub.6H.sub.4)
VI-28 H H H -(4-N(CH.sub.3).sub.2--C.sub.6H.sub.4) VI-29 H H H
-(4-CN--C.sub.6H.sub.4) VI-30 H H H -(4-Cl--C.sub.6H.sub.4) VI-31 H
H H -(4-Br--C.sub.6H.sub.4] VI-32 H H H -(4-F--C.sub.6H.sub.4]
VI-33 H H H -(4-CH.sub.3--C.sub.6H.sub.4) VI-34 H H H
-(2-NO.sub.2--C.sub.6H.sub.4) VI-35 H H H
-(3-NO.sub.2--C.sub.6H.sub.4) VI-36 H H H -(4-NO.sub.2--C.sub.6H.s-
ub.4] VI-37 H H H -(2,4-OCH.sub.3--C.sub.6H.sub.3) VI-38 H H H
-(3,4-OCH.sub.3--C.sub.6H.sub.3) VI-39 H H H
-(3,4,5-OCH.sub.3--C.sub.6H.sub.2) VI-40 H H H
-(3,4-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) VI-41 H H H
-(2,3-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) VI-42 H H H -2-pyridinyl
VI-43 H H H -2-furanyl VI-44 H H H -2-thienyl VI-45 H H H
-3-pyridinyl VI-46 H H H -3-furanyl VI-47 H H H -3-thienyl VI-48 H
H H -4-pyridinyl VI-49 H H H -2-thiazolyl VI-50 H H H -2-oxazolyl
VI-51 H H H -3-isoxazolyl VI-52 H H H -4-isoxazolyl VI-53 H H H
-5-isoxazolyl VI-54 H H H --CF.sub.3 VI-55 H H H --C.sub.2F.sub.5
VI-56 H H H --CH.sub.3 VI-57 H H H --C.sub.2H.sub.5 VI-58 H H H
-nC.sub.3H.sub.7 VI-59 H H H -tertC.sub.4H.sub.9 VI-60 H H H
--CH.sub.2--C.sub.6H.sub.5 VI-61 H H H --C.sub.6H.sub.5 VI-62 H H H
--CH.sub.2--COOCH.sub.3 VI-63 H H H --CH.sub.2--COOC.sub.2H.sub.5
VI-64 H H H --CF.sub.2--COOCH.sub.3 VI-65 H H H
--CF.sub.2--COOC.sub.2H.sub.5 VI-66 H H H --CH.sub.2--CONH.sub.2
VI-67 H H H --CH.sub.2--CONHCH.sub.3 VI-68 H H H
--CH.sub.2--CON(CH.sub.3).sub- .2 VI-69 H H H
--CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 VI-70 H H H
--CH.sub.2--CONH--C.sub.6H.sub.5 VI-71 H H H
--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 VI-72 H H H
--CH.sub.2--CON(--CH.sub.2--CH.sub.2-- CH.sub.2--CH.sub.2--) VI-73
H H H --CH.sub.2--CON(--CH.sub.2--CH.sub.2--
CH.sub.2--CH.sub.2--CH.sub.2) VI-74 H H H --CH.sub.2--CH.sub.2--CO-
OCH.sub.3 VI-75 H H H --CH.sub.2--CH.sub.2--COOC.sub.2H.sub.5 VI-76
H H H --CH.sub.2--CH.sub.2--CONH.sub.2 VI-77 H H H
--CH.sub.2--CH.sub.2--CONHCH.sub.3 VI-78 H H H
--CH.sub.2--CH.sub.2--CON(CH.sub.3).sub.2 VI-79 H H H
--CH.sub.2--CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 VI-80 H H H
--CH.sub.2--CH.sub.2--CONH--C.sub.6H.sub.5 VI-81 H H H
--CH.sub.2--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 VI-82 H
H H --CH.sub.2--CH.sub.2--CON(--CH.sub.2--
CH.sub.2--CH.sub.2--CH.sub.2--) VI-83 H H H
--CH.sub.2--CH.sub.2--CON(--CH.sub.2-- (CH.sub.2).sub.3--CH.su-
b.2) VI-84 H H H --CH.sub.2--COCH.sub.3 VI-85 H H H
--CH.sub.2--CH.sub.2--COCH.sub.3 VI-86 H H H
--CH.sub.2--COC.sub.2H.sub.5 VI-87 H H H --CH.sub.2--CH.sub.2--COC-
.sub.2H.sub.5 VI-88 H H H --CH.sub.2--CO--C.sub.6H.sub.5 VI-89 H H
H --CH.sub.2--CH.sub.2--CO--C.sub.6H.sub.5 VI-90 H H H
--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.5 VI-91 H H H
--CH.sub.2--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.5 VI-92 H H H
--CH.sub.2--SOC.sub.6H.sub.5 VI-93 H H H --CH.sub.2--SOCH.sub.3
VI-94 H H H --CH.sub.2SO(4-CH.sub.3--C.sub.6H.sub.4) VI-95 H H H
--CH.sub.2--SO.sub.2C.sub.6H.sub.5 VI-96 H H H
--CH.sub.2--SO.sub.2CH.sub.3 VI-97 H H H --CH.sub.2--SO.sub.2(4-CH-
.sub.3--C.sub.6H.sub.4) VI-98 H H H
--CH.sub.2--CH.sub.2--SOC.sub.6- H.sub.5 VI-99 H H H
--CH.sub.2--CH.sub.2--SOCH.sub.3 VI-100 H H H
--CH.sub.2--CH.sub.2--SO(4-CH.sub.3--C.sub.6H.sub.4) VI-101 H H H
--CH.sub.2--CH.sub.2--SO.sub.2C.sub.6H.sub.5 VI-102 H H H
--CH.sub.2--CH.sub.2--SO.sub.2CH.sub.3 VI-103 H H H
--CH.sub.2--CH.sub.2--SO.sub.3(4-CH.sub.3--C.sub.6H.sub.4) VI-104
CH.sub.3 H H --CH.sub.3 VI-105 CH.sub.3 H H --C.sub.2H.sub.5 VI-106
CH.sub.3 H H -nC.sub.3H.sub.7 VI-107 CH.sub.3 H H
-isoC.sub.3H.sub.7 VI-108 CH.sub.3 H H -nC.sub.4H.sub.9 VI-109
CH.sub.3 H H -tertC.sub.4H.sub.9 VI-110 CH.sub.3 H H
-cycloC.sub.3H.sub.5 VI-111 CH.sub.3 H H -cycloC.sub.4H.sub.7
VI-112 CH.sub.3 H H -cycloC.sub.5H.sub.9 VI-113 CH.sub.3 H H
-cycloC.sub.6H.sub.11 VI-114 CH.sub.3 H H -cycloC.sub.7H.sub.12
VI-115 CH.sub.3 H H --CH.sub.2--O--CH.sub.3 VI-116 CH.sub.3 H H
--CH.sub.2--CH.sub.3--O--CH.sub.3 VI-117 CH.sub.3 H H
--CH.sub.2--C.sub.6H.sub.5 VI-118 CH.sub.3 H H --C.sub.6H.sub.5
VI-119 CH.sub.3 H H -(4-HO-C.sub.6H.sub.5) VI-120 CH.sub.3 H H
-(2-CF.sub.3--C.sub.6H.sub.4) VI-121 CH.sub.3 H H
-(3-CF.sub.3--C.sub.6H.sub.4) VI-122 CH.sub.3 H H
-(4-CF.sub.3--C.sub.6H.sub.4) VI-123 CH.sub.3 H H
-(2-OCH.sub.3--C.sub.6H.sub.4) VI-124 CH.sub.3 H H
-(3-OCH.sub.3--C.sub.6H.sub.4) VI-125 CH.sub.3 H H
-(4-OCH.sub.3--C.sub.6H.sub.4) VI-126 CH.sub.3 H H
-(2-SCH.sub.3--C.sub.6H.sub.4) VI-127 CH.sub.3 H H
-(3-SCH.sub.3--C.sub.6H.sub.4) VI-128 CH.sub.3 H H
-(4-SCH.sub.3--C.sub.6H.sub.4) VI-129 CH.sub.3 H H
-(2-N(CH.sub.3).sub.2--C.sub.6H.sub.4) VI-130 CH.sub.3 H H
-(3-N(CH.sub.3).sub.2--C.sub.6H.sub.4) VI-131 CH.sub.3 H H
-(4-N(CH.sub.3).sub.2--C.sub.6H.sub.4) VI-132 CH.sub.3 H H
-(4-CN-C.sub.6H.sub.4) VI-133 CH.sub.3 H H -(4-Cl--C.sub.6H.sub.4)
VI-134 CH.sub.3 H H -(4-Br--C.sub.6H.sub.4] VI-135 CH.sub.3 H H
-(4-F--C.sub.6H.sub.4] VI-136 CH.sub.3 H H
-(4-CH.sub.3--C.sub.6H.sub.4) VI-137 CH.sub.3 H H
-(2-NO.sub.2--C.sub.6H.sub.4) VI-138 CH.sub.3 H H
-(3-NO.sub.2--C.sub.6H.sub.4) VI-139 CH.sub.3 H H
-(4-NO.sub.2--C.sub.6H.sub.4] VI-140 CH.sub.3 H H
-(2,4-OCH.sub.3--C.sub.6H.sub.3) VI-141 CH.sub.3 H H
-(3,4-OCH.sub.3--C.sub.6H.sub.3) VI-142 CH.sub.3 H H
-(3,4,5-OCH.sub.3--C.sub.6H.sub.2) VI-143 CH.sub.3 H H
-(3,4-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) VI-144 CH.sub.3 H H
-(2,3-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) VI-145 CH.sub.3 H H
-2-pyridinyl VI-146 CH.sub.3 H H -2-furanyl VI-147 CH.sub.3 H H
-2-thienyl VI-148 CH.sub.3 H H -3-pyridinyl VI-149 CH.sub.3 H H
-3-furanyl VI-150 CH.sub.3 H H -3-thienyl VI-151 CH.sub.3 H H
-4-pyridinyl VI-152 CH.sub.3 H H -2-thiazolyl VI-153 CH.sub.3 H H
-2-oxazolyl VI-154 CH.sub.3 H H -3-isoxazolyl VI-155 CH.sub.3 H H
-4-isoxazolyl VI-156 CH.sub.3 H H -5-isoxazoyl VI-157 CH.sub.3 H H
--CF.sub.3 VI-158 CH.sub.3 H H --C.sub.2F.sub.5 VI-159 CH.sub.3 H H
--CH.sub.3 VI-160 CH.sub.3 H H --C.sub.2H.sub.5 VI-161 CH.sub.3 H H
-nC.sub.3H.sub.7 VI-162 CH.sub.3 H H -tertC.sub.4H.sub.9 VI-163
CH.sub.3 H H --CH.sub.2--C.sub.6H.sub.5 VI-164 CH.sub.3 H H
--C.sub.6H.sub.5 VI-165 CH.sub.3 H H --CH.sub.2--COOCH.sub.3 VI-166
CH.sub.3 H H --CH.sub.2--COOC.sub.2H.sub.5 VI-167 CH.sub.3 H H
--CF.sub.2--COOCH.sub.3 VI-168 CH.sub.3 H H
--CF.sub.2--COOC.sub.2H.sub.5 VI-169 CH.sub.3 H H
--CH.sub.2--CONH.sub.2 VI-170 CH.sub.3 H H --CH.sub.2--CONHCH.sub.-
3 VI-171 CH.sub.3 H H --CH.sub.2--CON(CH.sub.3).sub.2 VI-172
CH.sub.3 H H --CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 VI-173
CH.sub.3 H H --CH.sub.2--CONH--C.sub.6H.sub.5 VI-174 CH.sub.3 H H
--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 VI-175 CH.sub.3 H
H --CH.sub.2--CON(--CH.sub.2--CH.sub.2-- CH.sub.2--CH.sub.2--)
VI-176 CH.sub.3 H H --CH.sub.2--CON(--CH.sub.2--CH.sub.2--CH.sub.2-
-- CH.sub.2--CH.sub.2) VI-177 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COOCH.sub.3 VI-178 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COOC.sub.2H.sub.5 VI-179 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONH.sub.2 VI-180 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONHCH.sub.3 VI-181 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CON(CH.sub.3).sub.2 VI-182 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONH--CH.sub.2--C.sub.6H.sub.5 VI-183
CH.sub.3 H H --CH.sub.2--CH.sub.2--CONH--C.sub.6H.sub.5 VI-184
CH.sub.3 H H
--CH.sub.2--CH.sub.2--CONH(CH.sub.2--C.sub.6H.sub.5).sub.2 VI-185
CH.sub.3 H H --CH.sub.2--CH.sub.2--CON(--
CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--) VI-186 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CON(--CH.sub.2-- (CH.sub.2).sub.3--CH.su-
b.2) VI-187 CH.sub.3 H H --CH.sub.2--COCH.sub.3 VI-188 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COCH.sub.3 VI-189 CH.sub.3 H H
--CH.sub.2--COC.sub.2H.sub.5 VI-190 CH.sub.3 H H
--CH.sub.2--CH.sub.2--COC.sub.2H.sub.5 VI-191 CH.sub.3 H H
--CH.sub.2--CO--C.sub.6H.sub.5 VI-192 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CO--C.sub.6H.sub.5 VI-193 CH.sub.3 H H
--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.5 VI-194 CH.sub.3 H H
--CH.sub.2--CH.sub.2--CO--CH.sub.2--C.sub.6H.sub.5 VI-195 CH.sub.3
H H --CH.sub.2--SOC.sub.6H.sub.5 VI-196 CH.sub.3 H H
--CH.sub.2--SOCH.sub.3 VI-197 CH.sub.3 H H --CH.sub.2--SO(4-CH.sub-
.3--C.sub.6H.sub.4) VI-198 CH.sub.3 H H
--CH.sub.2--SO.sub.2C.sub.6- H.sub.5 VI-199 CH.sub.3 H H
--CH.sub.2--SO.sub.2CH.sub.3 VI-200 CH.sub.3 H H
--CH.sub.2--SO.sub.2(4-CH.sub.3--C.sub.6H.sub.4) VI-201 CH.sub.3 H
H --CH.sub.2--CH.sub.2--SOC.sub.6H.sub.5 VI-202 CH.sub.3 H H
--CH.sub.2--CH.sub.2--SOCH.sub.3 VI-203 CH.sub.3 H H
--CH.sub.2--CH.sub.2--SO(4-CH.sub.3--C.sub.6H.sub.4) VI-204
CH.sub.3 H H --CH.sub.2--CH.sub.2--SO.sub.2C.sub.6H.sub.5 VI-205
CH.sub.3 H H --CH.sub.2--CH.sub.2--SO.sub.2CH.sub.3 VI-206 CH.sub.3
H H --CH.sub.2--CH.sub.2--SO.sub.2(4-CH.sub.3--C.sub.6H.sub.4)
[0204] Table 7:
[0205] A is Me.sub.2Val, B is Val, D is MeVal, E is Pro and F is of
Formula III.sub.f, the substituent --(C.dbd.O)-G is in position 2
relative to the nitrogen and a.sub.f is 1. G is of Formula II.sub.g
or III.sub.g. The compounds are mixtures of diasteromers,
configuration in F is R, S (cis) or S,R (cis).
9 No. R.sub.f -G VII-1 H --NH--CH.sub.3 VII-2 H
--NH--CH.sub.2--C.sub.6H.sub.5 VII-3 H --NH-isoC.sub.3H.sub.7 VII-4
H --NH--C.sub.6H.sub.5 VII-5 H 1,3-Thiazol-2-yl-amide VII-6 H
--NH--CH.sub.3 VII-7 H --NH--CH.sub.3 VII-8 H --NH--C.sub.2H.sub.5
VII-9 H --NH-nC.sub.3H.sub.7 VII-10 H --NH-nC.sub.4H.sub.9 VII-11 H
--NH-tertC.sub.4H.sub.9 VII-12 H --NH-cycloC.sub.3H.sub.5 VII-13 H
--NH-cycloC.sub.4H.sub.7 VII-14 H --NH-cycloC.sub.5H.sub.9 VII-15 H
--NH-cycloC.sub.6H.sub.11 VII-16 H --NH-cycloC.sub.7H.sub.12 VII-17
H --NH--CH.sub.2--O--CH.sub.3 VII-18 H
--NH--CH.sub.2--CH.sub.2--O-- -CH.sub.3 VII-19 H --NH-1-adamantyl
VII-20 H --NH-(4-HO--C.sub.6H.sub.5) VII-21 H
--NH-(2-CF.sub.3--C.sub.6H.s- ub.4) VII-22 H
--NH-(3-CF.sub.3--C.sub.4H.sub.4) VII-23 H
--NH-(4-CF.sub.3--C.sub.6H.sub.4) VII-24 H
--NH-(2-OCH.sub.3--C.sub.6H.sub.4) VII-25 H
--NH-(3-OCH.sub.3--C.sub.6H.sub.4) VII-26 H
--NH-(4-OCH.sub.3--C.sub.6H.sub.4) VII-27 H
--NH-(2-SCH.sub.3--C.sub.6H.sub.4) VII-28 H
--NH-(3-SCH.sub.3--C.sub.6H.sub.4) VII-29 H
--NH-(4-SCH.sub.3--C.sub.6H.sub.4) VII-30 H
--NH-(2-N(CH.sub.3).sub.2--C.sub.6H.sub.4) VII-31 H
--NH-(3-N(CH.sub.3).sub.2--C.sub.6H.sub.4) VII-32 H
--NH-(4-N(CH.sub.3).sub.2--C.sub.6H.sub.4) VII-33 H
--NH-(4-CN--C.sub.6H.sub.4) VII-34 H --NH-(4-Cl--C.sub.6H.sub.4)
VII-35 H --NH-(4-Br--C.sub.6H.sub.4] VII-36 H
--NH-(4-F--C.sub.6H.sub.4] VII-37 H --NH-(4-CH.sub.3--C.sub.6H.su-
b.4) VII-38 H --NH-(2-NO.sub.2--C.sub.6H.sub.4) VII-39 H
--NH-(3-NO.sub.2--C.sub.6H.sub.4) VII-40 H
--NH-(4-NO.sub.2--C.sub.6H.sub.4] VII-41 H
--NH-(2,4-OCH.sub.3--C.sub.6H.sub.3) VII-42 H
--NH-(3,4-OCH.sub.3--C.sub.6H.sub.3) VII-43 H
--NH-(3,4,5-OCH.sub.3--C.sub.6H.sub.2) VII-44 H
--NH-(3,4-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) VII-45 H
--NH-(2,3-CH.sub.2OCH.sub.2--C.sub.6H.sub.3) VII-46 H
--NH-2-pyridinyl VII-47 H --NH-2-furanyl VII-48 H --NH-2-thienyl
VII-49 H --NH-3-pyridinyl VII-50 H --NH-3-furanyl VII-51 H
--NH-3-thienyl VII-52 H --NH-4-pyridinyl VII-53 H --NH-2-oxazolyl
VII-54 H --NH-3-isoxazolyl VII-55 H --NH-4-isoxazolyl VII-56 H
--NH-5-isoxazoyl VII-57 H --NH-2R-(but-2-yl) VII-58 H
--NH-2S-(but-2-yl) VII-59 H --NH--O--CH.sub.3 VII-60 H
--N(CH.sub.3)(OCH.sub.3) VII-61 H --N(--(CH.sub.2).sub.3--O--)
VII-62 H --NH--O--CH.sub.2--C.sub.6H.sub.5 VII-63 H
--N(CH.sub.3)(O--CH.sub.2--C.sub.6H.sub.5) VII-64 H
--N(--(CH.sub.2).sub.2--CH(C.sub.6H.sub.5)--O--) VII-65 H
--NH--O--C.sub.2H.sub.5 VII-66 H --N(C.sub.2H.sub.5)(OC.sub.2H.su-
b.5) VII-67 H --N(CH.sub.3)(OC.sub.2H.sub.5) VII-68 H
--NH--O-isoC.sub.3H.sub.7 VII-69 H --N(CH.sub.3)(O-isoC.sub.3H.su-
b.7) VII-70 H --NH--O-nC.sub.3H.sub.7 VII-71 H
--N(CH.sub.3)(O-nC.sub.3H.sub.7) VII-72 H --NH--O-nC.sub.4H.sub.9
VII-73 H --N(CH.sub.3)(O-nC.sub.4H.sub.9) VII-74 H
--NH--O-tertC.sub.4H.sub.9 VII-75 H --N(CH.sub.3)(O-tertC.sub.4H.-
sub.9) VII-76 H --NH--O--C.sub.6H.sub.5 VII-77 H
--N(CH.sub.3)(O--C.sub.6H.sub.5) VII-78 H --N(CH.sub.3).sub.2
VII-79 H --N(CH.sub.2--C.sub.6H.sub.5).sub.2 VII-80 H
--N(C.sub.2H.sub.5).sub.2 VII-81 H --N(isoC.sub.3H.sub.7).sub.2
VII-82 H --N(nC.sub.3H.sub.7).sub.2 VII-83 H
--N(nC.sub.4H.sub.9).sub.2 VII-84 H --N(C.sub.6H.sub.5).sub.2
VII-85 H --NH--CH.sub.2--CH.sub.2--OH VII-86 H
--NH--(CH.sub.2).sub.3--OH VII-87 H --NH(--(CH.sub.2).sub.2--CH(C-
.sub.6H.sub.5)--OH) VII-88 H --NH--(CH.sub.2).sub.4--OH VII-89 H
--NH(--CH(CH.sub.3)--CH.sub.2--OH) VII-90 H
--NH(--CH.sub.2--CH(CH.sub.3)--OH) VII-91 H
--NH(--CH(CH.sub.3)--(CH.sub.2).sub.2--OH) VII-92 H
--NH(--(CH.sub.2).sub.2--CH(CH.sub.3)--OH) VII-93 CH.sub.3
--NH--CH.sub.3 VII-94 CH.sub.3 --NH--CH.sub.2--C.sub.6H.sub.5
VII-95 CH.sub.3 --NH-isoC.sub.3H.sub.7 VII-96 CH.sub.3
--NH--C.sub.6H.sub.5 VII-97 CH.sub.3 --NH--C.sub.2H.sub.5 VII-98
CH.sub.3 --NH-nC.sub.3H.sub.7 VII-99 CH.sub.3 --NH-nC.sub.4H.sub.9
VII-100 CH.sub.3 --NH-tertC.sub.4H.sub.9 VII-101 CH.sub.3
--NH-cycloC.sub.3H.sub.5 VII-102 CH.sub.3 --NH-cycloC.sub.4H.sub.7
VII-103 CH.sub.3 --NH-cycloC.sub.5H.sub.- 9 VII-104 CH.sub.3
--NH-cycloC.sub.6H.sub.11 VII-105 CH.sub.3 --NH-1-adamantyl VII-106
CH.sub.3 --NH-2R-(but-2-yl) VII-107 CH.sub.3 --NH-2S-(but-2-yl)
VII-108 CH.sub.3 --NH--O--CH.sub.3 VII-109 CH.sub.3
--N(CH.sub.3)(OCH.sub.3) VII-110 CH.sub.3
--N(--(CH.sub.2).sub.3--O--) VII-111 CH.sub.3 --N(CH.sub.3).sub.2
VII-112 CH.sub.3 --N(CH.sub.2--C.sub.6H.sub.5- ).sub.2 VII-113
CH.sub.3 --N(C.sub.2H.sub.5).sub.2 VII-114 CH.sub.3
--N(isoC.sub.3H.sub.7).sub.2 VII-115 CH.sub.3
--N(nC.sub.3H.sub.7).sub.2 VII-116 CH.sub.3
--N(nC.sub.4H.sub.9).sub.2 VII-117 CH.sub.3
--N(C.sub.6H.sub.5).sub.2
[0206] Table 8:
[0207] A is Me.sub.2Val, B is Val, D is MeVal, E is Pro and F is of
Formula III.sub.f, the substituent --(C.dbd.O)-G is in position 2
relative to the nitrogen and a.sub.f is 1. G is of Formula II.sub.g
or III.sub.g.
[0208] The compounds are mixtures of diasteromers, configuration in
F is either R, R (trans) or S,S (trans).
10 No. R.sub.f -G VIII-1 H --NH--CH.sub.3 VIII-2 H
--NH--CH.sub.2--C.sub.6H.sub.5 VIII-3 H --NH-isoC.sub.3H.sub.7
VIII-4 H --NH--C.sub.6H.sub.5 VIII-5 H 1,3-Thiazol-2-yl-amide
VIII-6 H --NH--CH.sub.3 VIII-7 H --NH--CH.sub.3 VIII-8 H
--NH--C.sub.2H.sub.5 VIII-9 H --NH-nC.sub.3H.sub.7 VIII-10 H
--NH-nC.sub.4H.sub.9 VIII-11 H --NH-tertC.sub.4H.sub.9 VIII-12 H
--NH-cycloC.sub.3H.sub.5 VIII-13 H --NH-cycloC.sub.4H.sub.7 VIII-14
H --NH-cycloC.sub.5H.sub.9 VIII-15 H --NH-cycloC.sub.6H.sub.11
VIII-16 H --NH-cycloC.sub.7H.sub.12 VIII-17 H
--NH--CH.sub.2-O-CH.sub.3 VIII-18 H
--NH--CH.sub.2--CH.sub.2--O-CH.sub.3 VIII-19 H --NH-1-adamantyl
VIII-20 H --NH-(4-HO-C.sub.6H.sub.5) VIII-21 H
--NH-(2-CF.sub.3--C.sub.6H.sub.4) VIII-22 H
--NH-(3-CF.sub.3--C.sub.6H.sub.4) VIII-23 H
--NH-(4-CF.sub.3--C.sub.6H.sub.4) VIII-24 H
--NH-(2-OCH.sub.3--C.sub.6H.sub.4) VIII-25 H
--NH-(3-OCH.sub.3--C.sub.6H.sub.4) VIII-26 H
--NH-(4-OCH.sub.3--C.sub.6H.sub.4) VIII-27 H
--NH-(2-SCH.sub.3--C.sub.6H.sub.4) VIII-28 H
--NH-(3-SCH.sub.3--C.sub.6H.sub.4) VIII-29 H
--NH-(4-SCH.sub.3--C.sub.6H.sub.4) VIII-30 H
--NH-(2-N(CH.sub.3).sub.2--C.sub.6H.sub.4) VIII-31 H
--NH-(3-N(CH.sub.3).sub.2-C.sub.6H.sub.4) VIII-32 H
--NH-(4-N(CH.sub.3).sub.2-C.sub.6H.sub.4) VIII-33 H
--NH-(4-CN-C.sub.6H.sub.4) VIII-34 H --NH-(4-Cl-C.sub.6H.sub.4)
VIII-35 H --NH-(4-Br-C.sub.6H.sub.4] VIII-36 H
--NH-(4-F-C-.sub.6H.sub.4] VIII-37 H --NH-(4-CH.sub.3-C.sub.6H.su-
b.4) VIII-38 H --NH-(2-NO.sub.2-C.sub.4H.sub.4) VIII-39 H
--NH-(3-NO.sub.2-C.sub.6H.sub.4) VIII-40 H
--NH-(4-NO.sub.2-C.sub.6H.sub.4] VIII-41 H
--NH-(2,4-OCH.sub.3-C.sub.6H.sub.3) VIII-42 H
--NH-(3,4-OCH.sub.3-C.sub.6H.sub.3) VIII-43 H
--NH-(3,4,5-OCH.sub.3-C.sub.6H.sub.2) VIII-44 H
--NH-(3,4-CH.sub.2OCH.sub.2-C.sub.6H.sub.3) VIII-45 H
--NH-(2,3-CH.sub.2OCH.sub.2-C.sub.6H.sub.3) VIII-46 H
--NH-2-pyridinyl VIII-47 H --NH-2-furanyl VIII-48 H --NH-2-thienyl
VIII-49 H --NH-3-pyridinyl VIII-50 H --NH-3-furanyl VIII-51 H
--NH-3-thienyl VIII-52 H --NH-4-pyridinyl VIII-53 H --NH-2-oxazolyl
VIII-54 H --NH-3-isoxazolyl VIII-55 H --NH-4-isoxazolyl VIII-56 H
--NH-5-isoxazoyl VIII-57 H --NH-2R-(but-2-yl) VIII-58 H
--NH-2S-(but-2-yl) VIII-59 H --NH--O--CH.sub.3 VIII-60 H
--N(CH.sub.3) (OCH.sub.3) VIII-61 H --N(--(CH.sub.2).sub.3--O--)
VIII-62 H --NH--O--CH.sub.2--C.sub.6H.sub.5 VIII-63 H --N(CH.sub.3)
(O--CH.sub.2--C.sub.6H.sub.5) VIII-64 H
--N(--(CH.sub.2).sub.2--CH(C.sub.6H.sub.5)--O--) VIII-65 H
--NH--O--C.sub.2H.sub.5 VIII-66 H --N(C.sub.2H.sub.5)
(OC.sub.2H.sub.5) VIII-67 H --N(CH.sub.3) (OC.sub.2H.sub.5) VIII-68
H NH--O-isoC.sub.3H.sub.7 VIII-69 H --N(CH.sub.3)
(O-isoC.sub.3H.sub.7) VIII-70 H --NH--O-nC.sub.3H.sub.7 VIII-71 H
--N(CH.sub.3) (O-nC.sub.3H.sub.7) VIII-72 H --NH--O-nC.sub.4H.sub.9
VIII-73 H --N(CH.sub.3) (O-nC.sub.4H.sub.9) VIII-74 H
--NH--O-tertC.sub.4H.sub.9 VIII-75 H --N(CH.sub.3)
(O-tertC.sub.4H.sub.9) VIII-76 H --NH--O--C.sub.6H.sub.5 VIII-77 H
--N(CH.sub.3) (O--C.sub.6H.sub.5) VIII-78 H --N(CH.sub.3).sub.2
VIII-79 H --N(CH.sub.2--C.sub.6H.sub.5).sub.2 VIII-80 H
--N(C.sub.2H.sub.5).sub.2 VIII-81 H --N(isoC.sub.3H.sub.7).sub.2
VIII-82 H --N(nC.sub.3H.sub.7).sub.2 VIII-83 H
--N(nC.sub.4H.sub.9).sub.2 VIII-84 H --N(C.sub.6H.sub.5).sub.2
VIII-85 H --NH--CH.sub.2--CH.sub.2--OH VIII-86 H
--NH--(CH.sub.2).sub.3--OH VIII-87 H --NH(--(CH.sub.2).sub.2--CH(-
C.sub.6H.sub.5) --OH) VIII-88 H --NH--(CH.sub.2).sub.4--OH VIII-89
H --NH(--CH(CH.sub.3)--CH.sub.2--OH) VIII-90 H
--NH(--CH.sub.2CH(CH.sub.3) --OH) VIII-91 H
--NH(--CH(CH.sub.3)--(CH.sub.2).sub.2OH) VIII-92 H
--NH(--(CH.sub.2).sub.2--CH(CH.sub.3)--OH) VIII-93 CH.sub.3
--NH--CH.sub.3 VIII-94 CH.sub.3 --NH--CH.sub.2--C.sub.6H.sub.5
VIII-95 CH.sub.3 --NH-isoC.sub.3H.sub.7 VIII-96 CH.sub.3
--NH--C.sub.6H.sub.5 VIII-97 CH.sub.3 --NH--C.sub.2H.sub.5 VIII-98
CH.sub.3 --NH-nC.sub.3H.sub.7 VIII-99 CH.sub.3 --NH-nC.sub.4H.sub.9
VIII-100 CH.sub.3 --NH-tertC.sub.4H.sub.9 VIII-101 CH.sub.3
--NH-cycloC.sub.3H.sub.5 VIII-102 CH.sub.3 --NH-cycloC.sub.4H.sub.7
VIII-103 CH.sub.3 --NH-cycloC.sub.5H.sub.9 VIII-104 CH.sub.3
--NH-cycloC.sub.6H.sub.11 VIII-105 CH.sub.3 --NH-1-adamantyl
VIII-106 CH.sub.3 --NH-2R-(but-2-yl) VIII-107 CH.sub.3
--NH-2S-(but-2-yl) VIII-108 CH.sub.3 --NH--O--CH.sub.3 VIII-109
CH.sub.3 --N(CH.sub.3) (OCH.sub.3) VIII-110 CH.sub.3
--N(--(CH.sub.2).sub.3--O--) VIII-111 CH.sub.3 --N(CH.sub.3).sub.2
VIII-112 CH.sub.3 --N(CH.sub.2--C.sub.6H.sub.- 5).sub.2 VIII-113
CH.sub.3 --N(C.sub.2H.sub.5).sub.2 VIII-114 CH.sub.3
--N(isoC.sub.3H.sub.7).sub.2 VIII-115 CH.sub.3
--N(nC.sub.3H.sub.7).sub.2 VIII-116 CH.sub.3
--N(nC.sub.4H.sub.9).sub.2 VIII-117 CH.sub.3
--N(C.sub.6H.sub.5).sub.2
[0209] Mass spectrometry data of selected examples:
11 I-1 2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4C(O)-
NHCH.sub.3 FAB-MS: 588 (M + H.sup.+) I-2
2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4C(O)NHCH.sub.2C.sub.6H.su-
b.5 FAB-MS: 664 (M + H.sup.+) I-3 2-(Me.sub.2Val-Val-MeVal--
Pro-NH)--C.sub.6H.sub.4C(O)NHCH(CH.sub.3).sub.2 FAB-MS: 616 (M +
H.sup.+) I-4 2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4C(O)N-
HC.sub.6H.sub.5 FAB-MS: 650 (M + H.sup.+) I-5
2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4C(O)NH(thiazol-2-yl)
FAB-MS: 657 (M + H.sup.+) I-6 2(Me.sub.2Val-Val-MeVal-ProNH)-4,
5-bis(methoxy)C.sub.6H.sub.2C(O)NHCH.sub.3 FAB-MS: 649 (M +
H.sup.+) I-7 2-(Me.sub.2ValVal-MeVal-ProNH)-3-cyclopentanyl-C.sub.-
6H.sub.3C(O)NHCH.sub.3 FAB-MS: 656 (M + H.sup.+) I-64
2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--CO--N(--(CH.sub.2).sub.-
2-- CH(C.sub.6H.sub.5)O--) (mix. of diastereomers) FAB-MS: 706 (M +
H.sup.+) I-79 2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.-
sub.4--CO--N(CH.sub.2C.sub.6H.sub.5).sub.2 FAB-MS: 754 (M +H.sup.+)
I-86 2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--C-
O--NH--(--(CH.sub.2).sub.3 -- OH) FAB-MS: 632 (M + H.sup.+) I-87
2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4C(O)-
NH((CH.sub.2).sub.2CH(C.sub.6H.sub.5) OH) FAB-MS: 708 (M + H.sup.+)
I-143 2-(Me.sub.2Val-Val-MeVal-Pro-N(CH.sub.3))--C.sub.6H-
.sub.4--CONHCH.sub.3 FAB-MS: 601 (M + H.sup.+) II-1
3-(Ne.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--CO--NHCH.sub.3
FAB-MS: 588 (M + H.sup.+) II-2 3-(Me.sub.2Val-Val-MeVal-Pro-NH)--C-
.sub.6H.sub.4--CO--NH CH.sub.2C.sub.6H.sub.5 FAB-MS: 664 (M +
H.sup.+) IV-1 2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--CO-
--CH.sub.3 FAB-MS: 609 (M + H.sup.+) IV-15
2-(Me.sub.2Val-Val-MeVal-Pro-NH)--C.sub.6H.sub.4--CO--C.sub.6H.sub.5
FAB-MS: 635 (M + H+)
Evaluation of Biological Activity
[0210] In Vitro Methodology
[0211] Cytotoxicity was measured using a standard methodology for
adherent cell lines, such as the microculture tetrazolium assay
(MTT). Details of this assay have been published (Alley, M. C. et
al., Cancer Research 48: 589-601, 1988). Exponentially growing
cultures of tumor cells such as the HT-29 colon carcinoma or LX-1
lung tumor were used to make microtiter plate cultures. Cells were
seeded at 5000-20,000 cells per well in 96-well plates (in 150 mL
of media), and grown overnight at 37.degree. C. Test compounds were
added, in 10-fold dilutions varying from 10.sup.-4 M to 10.sup.-10
M. Cells were then incubated for 48 hours. To determine the number
of viable cells in each well, the MTT dye was added (50 mL of a 3
mg/mL solution of
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in
saline). This mixture was incubated at 37.degree. C. for 5 hours,
and then 50 mL of 25% SDS, pH 2, was added to each well. After an
overnight incubation, the absorbance of each well at 550 nm was
read using an ELISA reader. The values for the mean+/-SD of data
from replicated wells were calculated, using the formula % T/C (%
viable cells treated/control). The concentration of test compound
which gives a T/C of 50% growth inhibition was designated as the
IC.sub.50.
12 Compound No. IC.sub.50 (mol/l) I-1 4 .times. 10.sup.-7 I-2
>10.sup.-6 I-3 5 .times. 10.sup.-7 I-4 4 .times. 10.sup.-7 I-5
1.5 .times. 10.sup.-7 I-6 2 .times. 10.sup.-7 I-7 4 .times.
10.sup.-7 I-60 4 .times. 10.sup.-7 I-64 2.5 .times. 10.sup.-7 I-86
6 .times. 10.sup.-7 I-87 2 .times. 10.sup.-7 II-1 >10.sup.-6
II-2 >10.sup.-6 IV-1 >10.sup.-6 IV-15 7 .times. 10.sup.-8
VII-2 >10.sup.-6
[0212] In Vivo Methodology
[0213] Compounds of this invention may be further tested in any of
the various preclinical assays for in vivo activity which are
indicative of clinical utility. Such assays are conducted with nude
mice into which tumor tissue, preferably of human origin, has been
transplanted ("xenografted"), as is well known in this field. Test
compounds are evaluated for their anti-tumor efficacy following
administration to the xenograft-bearing mice.
[0214] More specifically, human tumors which have been grown in
athymic nude mice are transplanted into new recipient animals,
using tumor fragments which are about 50 mg in size. The day of
transplantation is designated as day 0. Six to ten days later, the
mice are treated with the test compounds given as an intravenous or
intraperitoneal injection, in groups of 5-10 mice at each dose.
Compounds are given daily for 5 days, 10 days or 15 days, at doses
from 10-100 mg/kg body weight. Tumor diameters and body weights are
measured twice weekly. Tumor masses are calculated using the
diameters measured with Vernier calipers, and the formula:
(length.times.width.sup.2)/2=mg of tumor weight
[0215] Mean tumor weights are calculated for each treatment group,
and T/C values determined for each group relative to the untreated
control tumors.
[0216] The novel compounds of the present invention show good in
vitro activity in the above-mentioned assay system.
Equivalents
[0217] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
spirit and scope of the invention as defined by the appended
claims. Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
specifically herein. Such equivalents are intended to be
encompassed in the scope of the claims.
* * * * *