CA2282720C - Dolastatin-15 derivatives in combination with taxanes - Google Patents

Abstract

The present invention provides compositions and methods for the treatment of cancer in a subject wherein compounds of Formula (I) as defined herein in combination with paclitaxel, taxotere or modified taxane or taxoid analogs provide enhanced anticancer effects over the effects achieved with the individual compounds.

Description

BACKGROUND OF THE INVENTION
Cancer is a disease for which many potentially effective treatments are available. However, due to the prevalence of cancers of various types and the serious effects it can have, more effective treatments, especially those with fewer adverse side effects than currently available forms of treatment, are needed.

SUMMARY OF THE INVENTION
This invention relates to pharmaceutical compositions useful in treating cancer in a mammal. The pharmaceutical compositions of the present invention comprise two compounds: a first compound which is paclitaxel, taxotere or a modified taxane or taxoid analog and a second compound, which is a compound of Formula I:

R' RZ N-CHX-CO-A-B-D- (E) S- (F) t- (G) õ-K (I) Formula I is discussed in detail below. Some examples of compounds of Formula I are specifically presented herein.
For example, compounds of Formula I can be those in which R' and RZ are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or 2-tert-butylglycyl; D is thiazolidinyl-carbonyl, 3,4-dehydroprolyl or prolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, hydroxyprolyl or 3,4-dehydroprolyl; and K is a substituted amino moiety having the formula R5-N-R6, wherein R5 is hydrogen or C1-Cg-alkoxy and R6 is a monovalent radical such as (1)- or (2)-adamantyl; (CH2)v-phenyl with v=1; cx,cx-dimethylbenzyl; a C1-C12 linear or branched hydroxyalkyl group, such as -C(CH3)Z-CH2-CH2-OH, also referred to as 3-hydroxy-1,1-dimethylpropyl; a C3-Clo cycloalkyl group, such as bicyclo[3.3.0]octa-l-yl, 1-methylcyclopentyl or 1-methylcyclohexyl; or a C1-C12 linear or branched alkyl group, such as -C(CH3)3, also referred to as tert-butyl;
-C-CH2-CH3, also referred to as 1,1-dimethylpropyl;
( CH3 ) 2 -C(CH2-CH3)2, also referred to as 1-methyl-l-ethylpropyl;

-CH-C(CH3)3, also referred to as (S)- or (R)-i-methyl-2,2-CH3 dimethyl-propyl;
-CH-CH (CH3) 2, also referred to as (S) - or (R) -1-ethyl-2-C2H5 methylpropyl;

-CH-CH (CH3) 2, also referred to as 1-isopropyl-2-methyl-CH ( CH3 ) 2 propyl ; or -C (CH3) 2-CH (CH3) 2, also referred to as 1,1-dimethyl-2-methylpropyl;
-CH(CH3)2 , also referred to as isopropyl;

-CH (CH3) CH2CH3, sec-butyl [(S) or (R) ] ; or -CH(CH3)CH(CH3)2, also referred to as 1,2-dimethylpropyl.
Each compound is present in the pharmaceutical composition in an effective amount. The pharmaceutical composition can include one or more of each type of compound (e.g., one or more of the first type of compound, such as paclitaxel or paclitaxel and taxotere and one or more compounds of Formula I).
This invention also relates to methods of treating cancer in a mammal in which the pharmaceutical compounds described herein are used. In the method of the present invention, the two compounds are administered in the pharmaceutical composition or as individual/separate compounds which are given sufficiently close in time to have the desired effect.
It has been discovered that, surprisingly the combination of paclitaxel, taxotere or a modified taxane or taxoid analog as described herein and a compound having Formula I as described herein provides enhanced or therapeutically synergistic anticancer effects in vivo.
For purposes of this invention, two drugs are considered therapeutically synergistic if a combination regimen produces a_significantly better tumor cell kill than the best constituent when it is administered alone at optimal or maximum tolerated doses. Differences in tumor cell kill less than half a decade are not considered signficant.

BRIEF DESCRIPTION OF THE DRAWINGS
The Figure depicts compounds i-xvii, as examples of compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to pharmaceutical compositions useful in treating cancer in a mammal. The pharmaceutical composition of the present invention comprises two compounds: a first compound which is paclitaxel, taxotere or a modified taxane or taxoid analog and a second compound of Formula I as further described below. Each compound is present in the pharmacuetical composition in an effective amount. One or more of each type of compound can be present in the pharmaceutical composition or administered in the present method. As used herein the term "an effective amount" refers to an amount sufficient to elicit the desired biological response. In the instant invention, the desired biological response is inhibition (partial or total) of formation of a tumor or a hematological malignancy, reversal of the development of a solid tumor or other malignancy or prevention or reduction of its further progression.

PACLITAXEL, TAXOTERE OR A MODIFIED TAXANE OR TAXOID ANALOG
Paclitaxel (Taxol ), which is one example of a first compound of the pharmaceutical composition, is a diterpene isolated from the bark of the Western (Pacific) yew, Taxus brevifolia and is representative of a class of therapeutic agent having a taxane ring system. For purposes of this invention any therapeutic agent which has a taxane ring system is defined as a"taxane". The formula for paclitaxel is:

i i OH

O

Paclitaxel and its analogs have been produced by partial synthesis from 10-deacetylbaccatin III, a precursor obtained from yew needles and twigs, and by total synthesis. See Holton, et al., J. Am. Chem. Soc. 116:1597-1601 (1994) and Nicolaou, et al., Nature 367:630 (1994).
Paclitaxel has been demonstrated to possess antineoplastic activity. More recently, it was shown that the antitumor activity of paclitaxel is due to a promotion of microtubule polymerization. See Kumar, N., J. Bio1. Chem. 256:10435-10441 (1981); Rowinsky, et al., J. Natl. Cancer Inst.
82:1247-1259 (1990); and Schiff, et al., Nature 277:655-667 (1979). Paclitaxel has now demonstrated efficacy in several human tumors in clinical trials. See McGuire, et al., Ann. Int. Med. 211:237-279 (1989) ;Holmes, et al. , J.
Natl. Cancer Inst. 83:1797-1805 (1991); Kohn et al., J.
Natl. Cancer Inst. 86:18-24 (1994); and Kohn, et al., American Society for Clinical Oncology 12 (1993).
Paclitaxel is available from Bristol-Myers Squibb Company, New York, NY by the registered tr&dename Taxol .
The first compound in the pharmaceutical composition is typically paclitaxel (Taxol 0), taxotere or a modified taxane or taxoid analog. The modified taxane or taxoid analogs are those compounds having a taxane ring bearing modified side chains. A number of these analogs have improved properties, such as greater water solubility and stability than that of naturally occurring paclitaxel. For example, RPR109881 is a new oral-and iv active taxoid analog under development by Rhone-Poulenc Rhorer and currently in Phase I Clinical Trials. These analogs are known to those of skill in the art and are disclosed, for example, in U.S. Patent Nos. 5,278,324; 5,272,171;
5,254,580; 5,250,683; 5,248,796; and 5,227,400.
Taxotere can be prepared by the method in WO 93/18210.
In particular embodiments, the first compound in the pharmaceutical composition is paclitaxel or taxotere.
COMPOUNDS OF FORMULA I
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. Nat1. Cancer Inst., 85: 483-488 (1993) and references cited therein). These include Dolastatins 1-10 (U.S. Patent 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 cell line, a strong predictor of efficacy against various types of human malignancies. This compound, however, is present only in trace quantities in the sea hare and is difficult to isolate, expensive to synthesize and suffers from poor aqueous solubility.
The compounds of Formula I are derivatives of Dolastatin-15, which overcome the above-mentioned disadvantages of Dolastatin-15 while retaining .10 antineoplastic activity or exhibiting greater -antineoplastic activity than the natural product.
The Dolastatin-15 derivatives of Formula I, which are employed in combination with paclitaxel, taxotere or a modified taxane or taxoid analog in the present invention, can be synthesized, as described herein and in related copending application U.S.S.N. 08/472,453, filed June 7, 1995, now U.S. Patent No. 5,831,002.

The Dolastatin-15 derivatives of Formula I generally comprise L-amino acids, but they can also contain one or more D-amino'acids, as described in related copending application U.S.S.N. 08/472,453 filed on June 7, 1995, now U.S. Patent No. 5,831,002. The compounds of Formula I can also be present as salts with physiologically-compatible acids, such as, but not limited to, 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.

For purposes of the present invention, the term I'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 (e.g.
methyl, ethyl, propyl and tert-butyl groups), cycloalkyl groups, hydroxy alkyl groups, adamantyl groups, halogen atoms (e.g. fluorine, chlorine and bromine atoms), aryl grosps (e.g. phenyl, benzyl and naphthyl groups) and alkoxy groups (e.g. methoxy and ethoxy groups). Two monovalent radicals on adjacent sigma-bonded atoms can also 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, the unit -N(R)R', wherein R and R' are monovalent radicals, can, together with the nitrogen atom, form a heterocyclic ring. In addition, two monovalent radicals bonded to the same atom can also form a divalent radical, such as an alkylidene group, for example, a propylidene group, or an oxygen atom.
More specifically, for the compounds of Formula I:
R1 is alkyl, such as C1-C3; cycloalkyl, such as cyclopropyl; alkylsulfonyl, such as C1-C3;
fluoroalkyl, such as fluoroethyl, difluoroethyl, fluoroisopropyl; aminosulfonyl which may be substituted by alkyl, such as methyl;

R2 is hydrogen; alkyl, such as C1-C3; fluoroalkyl, such as fluoroethyl, difluoroethyl, fluoroisopropyl; cycloalkyl, such as cyclopropyl;
R'-N-R 2 together may be a pyrrolidino or piperidino residue;

A is a valyl, isoleucyl, leucyl, allo-isoleucyl, 2,2-dimethylglycyl, 2-cyclopropylglycyl, 2-cyclopentylglycyl, 3-tert-butylalanyl, 2-tert-butylglycyl, 3-cyclohexylalanyl, 2-ethylglycyl, 2-cyclohexylglycyl, norleucyl or norvalyl residue;

B is a N-alkyl-valyl, -norvalyl, -leucyl, -isoleucyl, -2-tert-butylglycyl, -3-tert-butylalanyl, -2-ethylglycyl, -2-cyclopropylglycyl, -2-cyclopentylglycyl, norleucyl or -2-cyclohexylglycyl residue where N-alkyl is preferably N-methyl or N-ethyl;

D is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue;

E is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue;

F and G are independently selected from the group consisting of prolyl, homoprolyl, hydroxyprolyl, thiazolidinyl-4-carbonyl, 1-aminopentyl-l-carbonyl, valyl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl, N-methylphenylalanyl, tetrahydrosioquinolyl-2-histidyl, 1-aminoindyl-i-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl, norleucyl, norvalyl, neopentylglycyl, trytophanyl, glycyl, 2,2-dimethylglycyl alanyl, 9-alanyl and 3-naphthylalanyl residues;

X is hydrogen, alkyl (such as C1-CS), cycloalkyl (such as C3-C.), -CH2-cyclohexyl or arylalkyl (such as benzyl or phenethyl);

s, t and u are independently 0 or 1; and K is hydroxy, alkoxy (such as C1-C4), phenoxy, benzyloxy or a substituted or unsubstituted amino moiety.

In addition, the compounds of Formula I can be present as a salt thereof with physiologically tolerated acids.
One subclass of compounds of this invention includes compounds of Formula I wherein R1-N-R2 is a pyrrolidinyl or piperidinyl residue.
Another subclass of compounds of this invention includes compounds of Formula I wherein K is an amino moiety of the formula R5-N-R6, wherein:

R5 is hydrogen, or hydroxy, or C1-7 alkoxy, or benzyloxy, or phenyloxy or C1_12 linear or branched hydroxyalkyl, such as 3-hydroxy-1,l-dimethylpropyl, or C1-7 linear or branched alkyl (which may be substituted by one or more fluoro atoms), or C3_10-cycloalkyl, such as, bicyclo[3.3.0locta-lyl, 1-methylcyclopentyl or 1-methylcylcohexyl; or benzyl (which may be substituted by up to three substituents which may independently be CF3, nitro, C1_7 alkylsulfonyl, C1-4 alkoxy, phenoxy, benzoxy, halogen, C1-4-alkyl, cyano, hydroxy, N(CH3)2, COOMe, COOEt, COOiPr, or COONH2);

R6 is hydrogen, or C1-l2 linear or branched alkyl (which may be substituted by one or more fluoro atoms), or C1-12 linear or branched hydroxyalkyl, such as 3-hydroxy-1,1-dimethylpropyl, or C3-10-cycloalkyl, such as bicyclo[3.3.0]octa-l-yl, or 1-methylcyclopentyl or 1-methylcyclohexyl; or - (CH2) ,-C3_7- cycloalkyl (v=0,1,2, or 3), or norephedryl, or norpseudoephedryl, or quinolyl, or pyrazyl, or -CH2-benzimidazolyl, or (1)-adamantyl, or (2)-adamantyl- -CH2-adamantyl, or alpha-methyl-benzyl, or alpha-dimethylbenzyl, or -(CHZ)v-phenyl (v=0,1,2, or 3; which may be substituted by up to two substituents which may independently be CF3, nitro, C1-7 alkylsulfonyl, C1-4 alkoxy, phenoxy, benzoxy, halogen, C1_4-alkyl which may form a cyclic system, cyano, hydroxy, N(CH3)2, COOMe, COOEt, COOiPr, or COONH2), or -( CHz ) n,-naphthyl (m=0 or 1) ; or -( CH2 ) W-benzhydryl (w=0,1, or 2); or biphenyl or picolyl or benzothiazolyl or benzoisothiazolyl or benzopyrazolyl or benzoxazolyl or - (CH2 ) n,- f luorenyl (m=0 or 1) ; or pyrimidyl or -(CH2)m-indanyl (m=0 or 1); or -(CH2CH2O)y-CH3 (y=0,1,2,3,4, or 5), or -(CH2CH20)y-CH2CH3 (y=0,1,2,3,4, or 5), or NH-C6H5 (which may be substituted by up to two substituents which may independently be CF3, nitro, C1-7 alkylsulfonyl, C1_9 alkoxy, halogen, C1_4 alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH2), or -NCH3-C6H5 or -NH-CH2-C6H5 or -NCH3-CH2-C6H5 or 5-membered heteroaryl which may be substituted by up to two substituents which may independently be CF3, nitro, thiomethyl, thioethyl, C3-6-cycloalkyl, -CH2-COOEt, C3-Q-alkylene group forming a bicyclic system with the heterocycle, phenyl; or -CHR7 -5-membered heteroaryl (which may be substituted by up to two substituents which may independently be CF3, nitro, cyano, halogen, COOMe, COOEt, COOiPr, CONH2, C1-4-alkyl, C1-4-alkoxy, phenyl, benzyl, naphthyl, or C1-7-alkylsulfonyl [R7 = hydrogen, linear or branched C1_5 alkyl, benzyl; or R' and R5 together form a group - (CH2 ) 3- or - (CH2 ) 4-).

This subclass includes compounds of Formula I
wherein s, t and u are independently 0 or 1; R1, R2 and X are lower alkyl, A is a lower alkyl amino acid, B is a N-loweralkylated lower alkyl amino acid;
D,E,F,G and K are as previously defined. With the foregoing in mind, three sets of such compounds can thus be depicted by the following formulas II, III, and IV:

R1R2N-CXH-CO-A-B-Pro-Pro-F-G-K II
R1R2N-CXH-CO-A-B-Pro-Pro-F-K III
R1R2N-CXH-CO-A-B-Pro-Pro-K IV
-CHR'-S-membered heteroaryl may, for example, be represented by one of the following residues:

~
S S~N S -`N S S11~N
COOEt COOMe COOBz1 CONHBz1 CONH2 CH2 ~~2 CH2 ~CH2 ~

S-Ie~N S `N S " `N
~
CON(CH3) 2 CH3 COOEt CH3 RN , ~
~

COOEt N COOMe N
~' / CON ( CH 3) 2 ._l/ S S _:/

~l ~

CONH2 COOEt i' -- CH3 CH(CH3)2 CH(CH3)~
~3 COOEt COOMe S
S_.J
CH(c7j3)Z CH(CH3)2 N N
CE3 ~ CONH2 CH (CH3 ) 2 ON CH
( 3) :~r C
CH ( 11,312 CH(CH3)Z
CH ~2 COOEt S
CH3 CH3 ..""

~ CH3 ~2 ~
~ 0 -NR5CHR7 -5-membered heteroaryl may, for example, be represented by the following residues:

N ~
N
j COOEt ! S
C

CON (CH3) S ~
2 ~
N SJr ~

N I S
s Jr CH3 COQEt iz-4N S } S

N COOEt N /1 N S
S
N
N
S
5-membered heteroaryl may, for example, be represented by the following residues:

0 COOCH3 S S COOEt ~I ~I ~I S

COOEt CH3 COOEt CH3 \ ~

` / C S ci 0 S (TH3 i N / ~ ~
CH3 ~
C1 s02 S'l N

S N02' S
S
Br N C(CH3), S N r S/

N CH~ C1 ~i Y N N
S
CH; S S
N

~/ 1 \ N
~
N S /
/COOEt S
..~
S

/

CH3 CH3 (CH3 N N
N N
N N
N

N CH_ N

/ N ~ ` /N Nr CH

c3 Qt\N
.~ N SEt CH3 rO N S
N S-N
>-~
S / S-N N cH3 ~. ~
~ fj - SCH3 N ~ ~ N- N S CF3 \ /1 )Ir S -N 1 ~ N -N
S -N

)3 1:rSEt "/r N-N N-N N-N
CH(CH3)2 ~ ~ s S S
~ ~ N
~ //N CH(CFi3)2 N -N
N-N N-N

I I

N0` CH3 S CH3 S s CH3 rj;::r ' / CH3 N - N
N -N N N

N Cl In another subclass of compounds of this invention RS-N-R6 together may form structures selected from the group consisting of:

-N -N S -N 0 -N S=0 ~/ ~_/ ~/
O
-N~S,,O r N N -N -N
-Nc> -N -N -N -N

Still another subclass of compounds of this invention includes, for example, compounds of Formula I wherein s, t and u are 1 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.
Yet another subclass of compounds of this invention includes, for example, compounds of Formula I wherein s and t are 1, u is 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.
Another subclass of compounds of this invention includes, for example, compounds of Formula I wherein s is 1, t and u are 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.
In particular embodiments, the second compound in the pharmaceutical composition of the invention is a compound of Formula I in which R1 and R2 are each methyl or ethyl; X
is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or -2-tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl or 3,4 dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted or unsubstituted amino moiety having the formula R5-N-R6.
In a further embodiment, the second compound in the pharmaceutical composition is a compound of Formula I in which Rl and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or 2-tertbutylglycyl; D is prolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched alkyl group or a C1-C12 linear or branched hydroxyalkyl group represented, for example, by the following monovalent radicals:

-C(CH3)2-CH2-CH2-OH, also referred to as 3-hydroxy-i,1-dimethylpropyl;
-C(CH3)3, also referred to as tert-butyl;

-C-CH2-CH3, also referred to as 1,1-dimethyl propyl;
(CH3) 2 -C(CH2-CH3)2, also referred to as 1-methyl-1 -ethyl propyl;

-CH-C(CH3)3, also referred to as (S)- or (R)-1-methyl-2,2-CH3 dimethyl propyl;

-CH-CH(CH3)2, also referred to as (S)- or (R)-1-ethyl-2-C2H5 methyl propyl;
-CH-CH(CH3)2, also referred to as 1-isopropyl-2-methyl CH ( CH3 ) 2 butyl; or -C(CH3)2-CH(CH3)2, also referred to as 1,l-dimethyl-2-methyl propyl -CH(CH3)2, also referred to as isopropyl -CH (CH3) CHzCH3, also referred to as sec-butyl, (S) - or (R) --CH(CH3)CH(CH3)2, also referred to as 1,2-dimethylpropyl.
In another embodiment, the second compound in the pharmaceutical composition of the invention is a compound of Formula I in which R1 and R 2 are each methyl or ethyl; X
is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, i-isoleucyl or 2-tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl, 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a monovalent radical such as a C3-Clo cycloalkyl group (e.g. cyclobutyl, cyclopentyl, cyclohexyl, or 1-methylcyclopentyl, or 1-methylcyclohexyl or bicyclo[3.3.0]octa-1-yl); a (1)- or (2) -adamantyl group; (CH2) v-phenyl with v=1 or a,ca-dimethylbenzyl.
In a further embodiment, the second compound in the pharmaceutical composition of the invention is a compound of Formula I in which R' and R2 are each methyl; X is isopropyl; s is 1; t and u are each 0; A is valyl; B is N-methylvalyl; D is prolyl; E is prolyl; and K is a substituted amino moiety having the formula RS-N-R6 wherein RS is benzyl and R6 is hydrogen. This compound corresponds to compound (xvii) depicted in the Figure. The results of the use of compound (xvii) of Formula I, in combination with paclitaxel are presented in Tables 1-4.
The pharmaceutical compositions of the present invention may optionally contain a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known to those who are skilled in the art. The choice of a carrier will be determined in part by the particular compounds in the combination, as well as by the particular method used to administer the pharmaceutical composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical compositions of the present invention. For example, paclitaxel (Taxol ) is available as a sterile nonpyrogenic solution which includes polyoxyethylated castor oil (Cremophor EL) and dehydrated alcohol, USP.
In another aspect, 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 endometrium) or hematological malignancies (e.g., leukemias, lymphomas) in a mammal, for example, a human, by administering to the mammal an effective amount of a first compound which is paclitaxel, taxotere or a modified taxane or taxoid analog and administering an effective amount of a second compound, which is a compound of Formula I.
The two compounds are administered in combination according to the invention. The term in combination in this context means that the drugs are given either simultaneously or sequentially. If given sequentially, one of the two compounds is usually detectable in the serum of the subject at the onset of administration of the other compound. In one embodiment, a compound of Formula I is administered first, followed by administration of the above described first compound, such as paclitaxel. In a specific embodiment, paclitaxel is administered about one hour after administration of a compound of Formula I.
Alternatively, the first compound and the second compound can be administered simultaneously, or the first compound could be administered first, followed by administration of a second compound, which is a compound of Formula I.
The first and the second compounds may be administered alone or with a pharmaceutically accepted carrier or diluent appropriate for the desired route of administration. Administration can be by any of the means which are conventional for pharmaceutical, preferably oncological, agents, including oral and parenteral means such as subcutaneously, intravenously, intramuscularly, intraperitoneally, nasally or rectally. Such pharmaceutical compositions may also contain other therapeutically active ingredients.
The dosage administered to the mammal, such as a human, includes a combination of an effective amount of a compound of Formula I and an effective amount of paclitaxel, taxotere or modified taxane or taxoid analog, as described herein. For a particular condition or method of treatment, the dosage can be determined empirically, using known methods, and will depend upon factors such as the biological activity, mechanism of action, cross resistance, overlapping toxicity and toxicity profile of the particular compounds 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 of the compounds of Formula I
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. A typical daily dose of paclitaxel, taxotere or a modified taxane or taxoid analog will generally be from 5 to about 250 milligrams per kilogram.
The first and the second 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.
The compounds of Formula I are described in detail above. In a particular embodiment, the method of the invention uses a compound of Formula I in which R1 and R 2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or 2-tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl or 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted or unsubstituted amino moiety having the formula R5-N-R6.
In a further embodiment, the method of the invention uses a compound of Formula I in which R1 and R2 are each methyl or ethyl ; X is isopropyl, sec-butyl or tert-butyl;
s is 1; t and u are each 0; A is valyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or 2-tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl or 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched alkyl group or C1-C12 linear or branched hydroxyalkyl group represented, for example, by the following monovalent radicals:

-C(CH3)2-CH2-CH2-OH, also referred to as 3-hydroxy-l,1-dimethylpropyl;
-C(CH3)3, also referred to as tert-butyl;

-C-CH2-CH3, also referred to as 1,1-dimethyl propyl;
( CH3 ) 2 -C(CH2-CH3)2, also referred to as 1-methyl-l-ethyl propyl;

-CH-C(CH3)31 also referred to as (S)- or (R)-1-methyl-2,2-CH3 dimethyl propyl;

-CH-CH (CH3) z, also referred to as (S) - or (R) -i-ethyl-2-CH2H5 methyl propyl;

-CH-CH(CH3)2, also referred to as 1-isopropyl-2-methyl CH ( CH3 ) 2 butyl ; or -C(CH3)2-CH(CH3)2, also referred to as 1,1-dimethyl-2-methyl propyl -CH(CH3)2, also referred to as isopropyl -CH (CH3) CH2CH3, also referred to as sec-butyl, (S) - or (R) --CH (CH3) CH (CH3) 2, also referred to as 1, 2-dimethylpropyl .
In another embodiment, the method of the invention uses a compound of Formula I in which R1 and R 2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or 2-tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl, 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein RS is hydrogen or CI-C4 alkoxy and R6 is a monovalent radical such as a C3-Clo cycloalkyl group (e.g. cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1-methylcyclohexyl or bicyclo[3.3.0]octa-l-yl); a (1)- or (2)-adamantyl group; (CH2)v-phenyl with v=1 or a,a-dimethylbenzyl.
In a further embodiment, the method of the invention uses a compound of Formula I in which R' and R2 are each methyl; X is isopropyl; s is 1; t and u are each 0; A is valyl; B is N-methylvalyl; D is prolyl; E is prolyl; and K
is a substituted amino moiety having the formula R5-N-R6 wherein R5 is benzyl and R6 is hydrogen. This compound corresponds to compound (xvii) depicted in the Figure. Tht results of the use of compound (xvii) of Formula I, in combination with paclitaxel are presented in Tables 1-4.
SYNTHETIC METHODS
The compounds of Formula I can be prepared by known methods of peptide synthesis such as those described herein and, in U.S. Patent No. 5,762,127. The peptides can be assembled sequentially from individual amino acids or by linking 1 !

suitable small peptide fragments. In sequential assembly, 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 can also be obtained by sequential assembly from amino acids or by fragment coupling of still shorter peptides.
In both sequential assembly 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. The methods described herein for formation of peptidic amide linkages, are also suitable for the formation of non-peptidic amide linkages.
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, 1-364, Thieme Verlag, Stuttgart, (1974);
Stewart and Young, Solid Phase Peptide Synthesis., 31-34 and 71-82, Pierce Chemical Company, Rockford, IL (1984);
Bodanszky et al., Peptide Synthesis, 85-128, John Wiley &
Sons, New York, (1976); Practice of Peptide Synthesis, M. Bodansky, A. Bodansky, Springer-Verlag, 1994 and other standard works in peptide chemistry. 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 dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloyl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propane-phosphonic anhydride (PPA), N,N-bis (2-oxo-3-oxazolidinyl)amido phosphoryl 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), O-azabenzotriazolyl-N,N,N',N'-tetramethyluronuim salts (TATU), diethylphosphoryl cyanide (DEPCN), 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene 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-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.
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 typically used for chemical peptide synthesis are: the benzyloxycarbonyl (Z), the t-butoxycarbonyl (Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) techniques.
Identified in each case is the protective group on the cx-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 in J. Amer. Chem.
Soc. 85 (1963) 2149. In one method, peptides are assembled sequentially or by fragment coupling using the Z, Boc or Fmoc protective group technique, with one of the reactants in the 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 by-products by filtration, eliminating the need to recrystallize intermediates.
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, for example, 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).
Solvents suitable for peptide synthesis include any solvent which is inert under the reaction conditions, for example, 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.
Peptide synthesis on the polymeric support can be carried out in a suitable inert organic solvent in which the amino acid derivatives and starting materials employed are soluble. Particularly useful solvents are, for example, DMF, DCM, NMP, acetonitrile, DMSO and mixtures thereof, due to their resin swelling properties.
Following synthesis, the peptide is removed (commonly referred to as cleaved) from the polymeric support. The conditions under which this cleavage is accomplished are well known in the art of peptide synthesis and depend in part on the type of resin employed. The cleavage reactions most commonly used are acid- or palladium-catalyzed, the acid catalyzed cleavage being conducted in, for example, liquid anhydrous hydrogen fluoride, anhydrous trifluoromethanesulfonic acid, dilute or concentrated trifluoroacetic acid, and acetic acid/dichloromethane/
trifluoroethanol mixtures. The palladium-catalyzed cleavage 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.
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/lo acetic acid with NaCNBH3 and the appropriate aldehyde or by hydrogenation of the peptide in solution in the presence of aldehyde or ketone and Pd/C.
The various non-naturally occurring amino acids as well as the various non-amino acid moieties disclosed herein may be obtained from commercial sources or synthesized from commercially-available materials using methods known in the art. For example, amino acid building blocks with R' and R2 moieties can be prepared according to E. Wuensch, Huben Weyl, Methoden der organischen Chemie Vol. XV/1, p. 306, Thieme Verlag, Stuttgart (1974) and literature cited therein. Peptides with gamma-or delta-lactam bridges can be prepared by incorporating the appropriate lactam-bridged dipeptide units (R. Freidinger, J. Org. Chem. (1982) 104-109) into the peptide chain.
Peptides with thiazole-, oxazol-, thiazolin- or oxazolin-containing dipeptide building blocks can be prepared by incorporating the appropriate dipeptidic units (P. Jouin et al., Tetrahedron Letters (1992), pp. 2087-2810; P. Wipf et al., Tetrahedon Letters (1992), pp. 907-910; W.R. Tully, J.
Med. Chem. (1991), p 2065; Synthesis (1987), p 235) into the peptide chain.
The following procedures are intended to illustrate methods useful for preparation of compounds of Forumla I.
When applicable, amino acids are abbreviated using the known three letter codes. Other meanings used are:
Me2Va1=N,N-dimethylvaline, MeVal=N-methylvaline, TFA =
trifluoroacetic acid, Ac = acetic acid, Bu = butyl, Et =
ethyl, Me = methyl, Bzl = benzyl, Nal = 3-naphthylalanine, Cha = 3-cyclohexylalanine, Npg = neopentyl glycine, Abu =
2-amino butyryl, Dab = 2,4-diaminobutyryl, iPr = isopropyl GENERAL SYNTHETIC PROCEDURES
I. Compounds of Formula I of the present invention are either synthesized by classical solution synthesis using standard Z- and Boc-methodology as described above or by standard methods of solid-phase synthesis on a completely automatic model 431A synthesizer supplied by APPLIED BIOSYSTEMS. The apparatus uses different synthetic cycles for the Boc and Fmoc protective group techniques.

In the case of solid phase synthesis, the N,N-dialkyl-penta- or hexapeptide acids are liberated from the solid support and further coupled with the corresponding C-terminal amines in solution. BOP-C1 and PyBrop were used as reagents for coupling of the amino acid following the N-methylamino acids. The reaction times were correspondingly increased. For reductive alkylation of the N-terminus, the peptide-resin was deprotected at the N terminus and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/lo acetic acid with addition of 3 equivalents of NaCNBH3. After the reaction was complete (negative Kaiser test) the resin was washed several times with water, isopropanol, DMF and dichloromethane.

In solution synthesis, the use of either Boc-protected amino acid NCAs (N-tert-butyloxycarbonyl-amino acid-N-carboxy-anhydrides), Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides), or the use of pivaloylchloride as condensing agent respectively is most advantageous for coupling of the amino acid following the N-methylamino acids.
Reductive alkylation of the N terminus can, for example, be achieved by reaction of the N-terminally deprotected peptides or amino acids with the corresponding aldehydes or ketones using NaCNBH3 or hydrogen, Pd/C.
a) Synthetic cycle for the Boc protective group technique:
1. 30% trifluoroacetic acid in DCM 1 x 3 min 2. 50o trifluoroacetic acid in DCM 1 x 1 min 3. DCM washing 4. 5% diisopropylethylamine in DCM 5 x 1 min 5. 5% diisopropylethylamine in NMP 1 x 1 min 6. NMP washing 5 x 1 min 7. Addition of preactivated protected amino acid (DCC and 1 equivalent of HOBt in NMP/DCM);
Peptide coupling (1st part) 1 x 30 min 8. Addition of DMSO to the reaction mixture until it contains 20% DMSO
by volume;
Peptide coupling (2nd part) 1 x 16 min 9. Addition of 3.8 equivalents of diisopropylethylamine to the reaction mixture;
Peptide coupling (3rd part) 1 x 7 min 10. DCM washing 3 x 1 min 11. If conversion is incomplete, repetition of coupling (back to 6) 12. 10o acetic anydride, 59,5 diisopropylethylamine in DCM 1 x 2 min 13. 10% acetic anhydride in DCM 1 x 4 min 14. DCM washing 4 x 1 min 15. Back to 1.

BOP-Cl and PyBrop were used as reagents for coupling of the amino acid following N-methylamino acids. 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 acids NCAs respectively is most advantageous for this type of coupling.

b) Synthetic cycle for the Fmoc protective group technique:
1. DMF washing 1 x 1 min 2. 20o piperidine in DMF 1 x 4 min 3. 20% piperidine in DMF 1 x 16 min 4. DMF washing 5 x 1 min 5. Addition of the preactivated protected amino acid (activation by 1 equivalent of TBTU and 5 equivalents of DIPEA in DMF ) ;
Peptide coupling 1 x 61 min 6. DMF washing 3 x 1 min 7. If conversion is incomplete, repetition of coupling (back to 5) 8. 10o acetic anhydride in DMF 1 x 8 min 9. DMF washing 3 x 1 min 10. Back to 2.

BOP-Cl and PyBrop were used as reagents for coupling on the amino acid following the N-methylamino acids. The reaction times were correspondingly increased.

Ii. Reductive Alkylation of the N-terminus The peptide-resin prepared in Ia or Ib above was deprotected at the N-terminus (steps 2-4 in Ib or 1-6 in la) and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/1o acetic acid with addition of 3 equivalents of NaCNBH3. After reaction was complete (negative Kaiser test) the resin was washed several times with water, isopropanol, DMF and dichloromethane.

III. Workup of the peptide-resins obtained as in Ia and II
The peptide-resin was dried under reduced pressure and transferred into a reaction vessel of a TEFLON HF apparatus (supplied by PENINSULA). Addition of a scavenger, for example, anisole (lml/g of resin), and in the case of tryptophan-containing peptides of a thiol to remove the indolic formyl group, for example, ethanedithiol (0.5 ml/g of resin), was followed by condensing in hydrogen fluoride (10 ml/g of resin) while cooling with liquid N2. The mixture was allowed to warm to 0 C and stirred at this temperature for 45 minutes. The hydrogen fluoride was then stripped off under reduced pressure, and the residue was washed with ethyl acetate in order to remove remaining scavenger. The peptide was extracted with 30% acetic acid and filtered, and the filtrate was lyophilized.

IV. Work-up of the peptide-resins obtained as in lb and II
The peptide-resin was dried under reduced pressure and then subjected to one of the following cleavage procedures, depending on the amino acid composition (Fmoc Workshop Manual, by authors Wade and Tregear, as published in 1985 by the Howard Florey Institute of Experimental Physiology and Medicine in Melbourne, Australia).

Cleavage conditions:
TFA Scavenger Reaction time 1. 950 5% water 1.5 h 2. 95% 5o ethanethiol/
anisole (1:3) 1.5 h 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 the diethyl ether. After cooling in an ice bath, the precipitate was filtered off, taken up in 30% acetic acid and lyophilized.

V. When an o-chlorotrityl-resin (supplied by Biohellas) is used, the suspension of the peptide-resin in an acetic acid/ trifluoroethanol/ dichloromethane mixture (1:1:3) is stirred at room temperature for 1 h. The resin is then filtered off with suction and thoroughly washed with the cleavage solution. The combined filtrates are concentrated in vacuo and treated with water. The precipitated solid is removed by filtration or centrifugation, washed with diethyl ether and dried under reduced pressure.

VI. Purification and characterization of the peptides Purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX
LH2O/MeOH) medium pressure chromatography (stationary phase: HD-SIL C-18, 20-45 micron, 100 Angstrom;
mobile phase: gradient with A=0.1o TFA/MeOH, B=0.1%
TFA/water) or preparative HPLC (stationary phase:
water Delta-Pak C-18, 15 micron, 100 Angstrom; mobile phase: gradient with A= 0.1o TFA/MeOH, B= 0.10 TFA/water).
The purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 51, 300 Angstrom; mobile phase:
acetonitrile-water gradient, buffered with 0.1% TFA, 40 C) .
Characterization was by amino acid analysis and fast atom bombardment mass spectroscopy.

SPECIFIC SYNTHETIC PROCEDURES
EXAMPLE 1A: N,N-dimethyl-Val-Val-N-methyl-Val-Pro-Pro-Val-Phe-NH2 1.98 g of Fmoc-RINK-resin (substitution 0.46 mmol/g), corresponding to a batch size of 0.84 mmol, were reacted as in Ib above with 1.26 mmol each of Fmoc-Phe-OH
Fmoc-Val-OH
Fmoc-Pro-OH
Fmoc-Pro-OH
Fmoc-N-methyl-Val-OH
Fmoc-Val-OH
Fmoc-Val-OH
The amino acid following the N-methyl amino acid was coupled on with PyBrop as coupling reagent. After the iterative synthetic cycles were completed, the peptide-resin underwent N-terminal deprotection (steps 2-4 in Ib), and was further reacted with aqueous formaldehyde solution as in II and then dried under reduced pressure. The resulting resin was subjected to TFA cleavage as in IV.
The crude product (590 mg) was purified by gel filtration (SEPHADEX-LH-20). The yield was 295 mg.
EXAMPLE 1A:
Example 1 can also be prepared via classical solution phase methodology. The synthesis of N,N-dimethyl-Val-Val-N-methyl-Val-Pro-Pro-Val-Phe-NH2 and its associated intermediates is described in the following paragraph.
a) Z-MeVal-Pro-OMe 66.25 g (250 mmol) of Z-MeVal-OH were dissolved in 250 ml of dry dichloromethane. After addition of 36.41 ml (262.5 mmol) of triethylamine, the reaction mixture was cooled to -25 C and 32.37 ml (262.5 mmol) pivaloyl chloride were added. After stirring for 2.5 hours, 41.89g (250 mmol) of H-Pro-OMe-HC1 in 250 ml of dichloromethane, neutralized with 36.41 ml (262.5 mmol) triethylamine at 0 C, were added to the reaction mixture. Stirring was continued for 2h at -25 C and overnight at room temperature. The reaction mixture was diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (3X), water (1X), 5% citric acid (3X) and saturated NaCl solution.
The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue (91.24 g) was stirred with petroleum ether overnight and filtered. 62.3 g of product were obtained.

b) H-MeVal-Pro-OMe 48.9 g (130 mmol) Z-MeVal-Pro-OMe were dissolved in 490 ml of methanol. After addition of 10.9 ml (1.30 mmol) concentrated hydrochloric acid and 2.43 g of 100 palladium/charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 36.43 g of product.

c) Z-Val-MeVal-Pro-OMe 18.1 g (65 mmol) of H-MeVal-Pro-OMe, 21.6 g (78 mmol) Z-Val-N-carboxyanhydride and 22.8 ml (130 mmol) diisopropylethylamine were stirred in 110 ml of DMF at 40 C for 2 days. After evaporation of DMF, dichloromethane was added and the organic phase washed with saturated aqueous NaHCO3 solution (3X), water (1X) 5% citric acid (3X) and saturated NaCl solution.
The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The product (29.3 g) was obtained as a viscous oil.

d) H-Val-MeVal-Pro-OMe 29.3 g (61.6 mmol) of Z-Val-MeVal-Pro-OMe were dissolved in 230 ml of methanol. After addition of 1.15 g of 10% palladium/charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of product.

e) Z-Val-Val-MeVal-Pro-OMe 15.29 g (61 mmol) of Z-Val-OH and 21.96 g (61 mmol) of H-Val-MeVal-Pro-OMe were dissolved in 610 ml of dichloromethane and cooled to 0 C. After addition of 8.16 mol(73.2 mmol) of N-methylmorpholine, 2.77 g (20.3 mmol) of HOEt and 11.74g (61 mmol) of EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (3X), water (1X), 5% citric acid (3X) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 31.96 g of the product.

f) Z-Val-Val-MeVal-Pro-OH

31.96 g (57 mmol) of Z-Val-Val-MeVal-Pro-OMe were dissolved in 250 ml of methanol. 102.6 ml of a iN
LiOH solution was added and the mixture stirred overnight at room temperature. After addition of 500 ml of water, the aqueous phase was washed three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness yielding 30.62 g of the desired product as a white solid.

g) Z-Val-Val-MeVal-Pro-Pro-Val-Phe-NH2 g (43.3 mmol) of Z-Val-Val-MeVal-Pro-OH and 15.59 g (43.3 mmol) of H-Pro-Val-Phe-NH2 were suspended in 430 ml of dry dichloromethane. After cooling to 0 C, 5.81 ml (52 mmol) N-methylmorpholine, 1.97 g (15 mmol) of 25 HOBt and 8.33 g (43.3 mmol) of EDCI were added and the reaction mixture stirred overnight at room temperature. The solvents were evaporated, the residue dissolved in 640 ml of dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (4X), water (1X), 5o citric acid (3X) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 33.04 g of the product. The crude product was chromatographed on a silica gel column with 20% MeOH/hexane. 18.32 g of the desired product were obtained.

h) N,N-dimethyl-Val-Val-MeVal-Pro-Pro-Val-Phe-NHz 18.32 g of Z-Val-Val-MeVal-Pro-Pro-Val-Phe-NHZ were dissolved in 80 ml of methanol. 0.4 g of 10%
palladium/carbon were added under nitrogen atmosphere and the reaction mixture hydrogenated at room temperature for 4 hours. After addition of 6.22 ml (81.24 mmol) of a 37% aqueous formaldehyde solution, hydrogenation was continued for 5 hours. Filtration and evaporation of the solvent gave rise to 15.6 g of crude product. Further purification was achieved by dissolving the peptide in water, adjusting the pH to 2 and extracting the aqueous phase three times with ethyl acetate. The aqueous phase was then adjusted to pH 8-9 and extracted four times with ethyl acetate.
The organic phase was washed with water and dried over sodium sulfate, filtered and evaporated to yield 11.3 g of purified product as a white powder. The compound was characterized by fast atom bombardment mass spectrometry ([M+H)+ = 797).

EXAMPLE 2A: N,N-dimethyl-Val-Val-NMe-Val-Pro-{1-[thiazol-(2)-yl]-2-phenyl}-ethylamide 4.11 g of Fmoc-Pro-p-alkoxybenzyl-alcohol-resin (substitution 0.73 mmol/g), corresponding to a batch size of 3 mmol, were reacted as in Ib with 4.5 mmol each of Fmoc-N-MeVal-OH
Fmoc-Val-OH
Fmoc-Val-OH

The amino acid following the N-methylamino acid was in this case reacted with double coupling using PyBrop or Bop-C1 with increased reaction times. After the synthesis was complete, the peptide-resin underwent N-terminal deprotection (Steps 2-4 in Ib), and was further reacted with aqueous formaldehyde solution as in II and then dried under reduced pressure. The resin obtained in this way was subjected to TFA cleavage as in IV. The crude product (750 mg) was employed directly for the next coupling: 100 mg of this compound were reacted with 45 mg of (S)-2-j1-amino-2-phenylethyl)thiazole and 230 mg of PyBop with the addition of 192 microliters of DIPEA in DMF at room temperature for 2 days. The reaction mixture was purified by gel TM
chromatography (SEPHADEX LH-20, methanol) and the product fractions were combined. 83 mg of product were obtained.

Me2Va1-Val-MeVal-Pro-Pro-NHCH(CH3)2 a) Z-MeVal;Pro-OMe 66.25 g (250 mmol) Z-MeVal-OH were dissolved in 250 ml dry dichloromethane. After addition of 36.41 ml (262.5 mmol) triethylamine, the reaction mixture was cooled to -25 C and 32.27 ml (262.5 mmol) pivaloyl chloride were added. After stirring for 2.5 h, 41.89 g (250 mmol) H-Pro-OMe x HC1 in 250 ml dichloromethane, neutralized with 36.41 ml (262.5 mmol) triethylamine at 0 C, were added to the reaction mixture. Stirring continued for 2 h at -25 C and overnight at room temperature. The reaction mixture was diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (3x), water (ix), 59k citric acid (3x) and saturated NaCl solution.
The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue (91.24 g) was stirred with petroleum ether overnight and filtered. 62.3 g of product were obtained.

b) H-MeVal-Pro-OMe 48.9 g (130 mmol) Z-MeVal-Pro-OMe were dissolved in 490 ml methanol. After addition of 10.9 ml (130 mmol) concentrated hydrochloric acid and 2.43 g 10 %
palladium/charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 36.43 g of the product.

c) Z-Val-MeVal-Pro-OMe 18.1 g (65 mmol) H-MeVal-Pro-OMe, 21.6 g (78 mmol) Z-Val-N-carboxyanhydride and 22.8 ml (130 mmol) diisopropylethylamine were stirred in 110 ml DMF at 40 C for 2 d. After evaporation of DMF, dichloromethane was added and the organic phase washed with saturated aqueous NaHCO3 solution (3x), water (lx), 5% citric acid (3x) and saturated NaCl solution.
The organic phase was dried over sodium sulfate and evaporated to dryness. The product (29.3 g) was obtained as a viscous oil.

d) H-Val-MeVal-Pro-OMe 29.3 g (61.6 mmol) of Z-Val-MeVal-Pro-OMe were dissolved in 230 ml methanol. After addition of 1.15 g 10% Palladium/charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of the product.

e) Z-Val-Val-MeVal-Pro-OMe 15.29 g (61 mmol) Z-Val-OH and 21.96 g (61 mmol) H-Val-MeVal-Pro-OMe were dissolved in 610 ml dichloromethane and cooled to 0 C. After addition of 8.16 ml (73.2 mmol) N-Methylmoropholine, 2.77 g (20.3 mmol) HOBt and 11.74 g (61 mmol) EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (3x), water (lx), 5% citric acid (3x) and saturated NaCl solution.
The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 31.96 g of the product.

f) Z-Val-Val-MeVal-Pro-OH

31.96 g (57 mmol) Z-Val-Val-MeVal-Pro-OMe were dissolved in 250 ml methanol. 102.6 ml of a 1 N LiOH
solution was added and the mixture stirred overnight at room temperature. After addition of 500 ml water, the aqueous phase was washed three times with ethyl acetate, adjusted to pH 2 at 0 C and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness yielding 30.62 g of the desired product as a white solid.

g) Z-Val-Val-MeVal-Pro-Pro-NHCH(CH3) 2 2 g (3.35 mmol) Z-Val-Val-MeVal-Pro-OH and 0.664 g (3.35 mmol) H-Pro-NHCH(CH3)2 were dissolved in 34 ml of dry dichloromethane. After cooling to 0 C, 1.35 ml (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. 80 ml dichloromethane were added and the organic phase thoroughly washed with saturated aqueous NaHCO3 solution (3x), water (lx), 5% citric acid (3x) and saturated NaCl solution (lx). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 1.96 g of the product which was used in the next reaction without further purification.

h) Me2Val-Val-MeVal-Pro-Pro-NHCH(CH3)2 1.96 g Z-Val-Val-MeVal-Pro-Pro-NHCH(CH3)2 were dissolved in 11 ml methanol. 0.054 g 10o Pd/C were added under nitrogen atmosphere and the reaction mixture hydrogenated at room temperature for 4 h.
After addition of 0.86 ml (11.24 mmol) of a 370 aqueous formaldehyde solution and 0.281 g 10% Pd/C, hydrogenation was continued for 5 h. Filtration and evaporation of the solvent gave rise to 2.77 g of crude product. Further purification was achieved by dissolving the peptide in water, adjusting the pH to 2 and extracting the aqueous phase three times with ethyl acetate. The aqueous phase was then adjusted to pH 8-9 and extracted four times with dichloromethane.
The organic phase was dried over sodium sulfate, 20, filtered and evaporated to yield 1.37 g of purified product as a white foam. The compound was further purified using medium pressure liquid chromatography (10-50% A in 10 min.; 50-90% A in 320 min.).
Fractions containing the product were combined, lyophilized, redissolved in water and the pH adjusted to 9 with 1 N LiOH. After extraction with dichloromethane, the organic phase was dried over sodium sulfate, filtered and evaporated to dryness.
Lyophilization led to 500 mg of pure product, which was characterized by fast atom bombardment mass spectrometry ([M+H]+ = 593).

Me2Va1-Val-MeVal-Pro-Pro-NHC(CH3)3 a) Z-Val-Val-MeVal-Pro-Pro-NHC(CH3)3 2 g (3.35 mmol) Z-Val-Val-MeVal-Pro-OH and 0.692 g (3.35 mmol) H-Pro-NHC(CH3)3 were dissolved in 34 ml of dry dichloromethane. After cooling to 0 C, 1.35 ml (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. 80 ml dichloromethane were added and the organic phase thoroughly washed with saturated aqueous NaHCO3 solution (3x), water (lx), 5o citric acid (3x) and saturated NaCl solution (lx). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 1.8 g of the product which was used in the next reaction without further purification.

b) MezVal-Val-MeVal-Pro-Pro-NHC(CH3)3 1.8 g Z-Val-Val-MeVal-Pro-Pro-NHC(CH3)3 were dissolved in 10 ml methanol. 0.045 g 109.- Pd/C were added under nitrogen atmosphere and the reaction mixture hydrogenated at room temperature for 4 h. After addition of 0.86 ml (11.24 mmol) of a 371 aqueous formaldehyde solution and 0.252 g 10a Pd/C, hydrogenation was continued for 5 h. Filtration and evaporation of the solvent gave rise to 1.82 g of crude product. The compound was further purified using medium pressure liquid chromatography (10-50% A
in 10 min.; 50-90% A in 320 min.). Fractions containing the product were combined, lyophilized, redissolved in water and the pH adjusted to 9 with 1 N
LiOH. After extraction with dichloromethane, the organic phase was dried over sodium sulfate and evaporated to dryness. Lyophilization led to 547 mg of pure product, which was characterized by fast atom bombardment mass spectrometry ([M+H]+ = 607).

EVALUATION OF BIOLOGICAL ACTIVITY
In vivo Methodology The combination of a compound of Formula I and paclitaxel, taxotere or a modified taxane or taxoid analog was further tested in various preclinical assays for in vivo activity, which are indicative of clinical utility.
The P388 (ascites model), LX-1, CX-1 and PC-3 (human tumor xenograft models for lung, colon and prostate) tumor models are all suitable for use in this invention.
In general, any dosing regimen which appears to provide an acceptable level of antitumor activity for both agents is suitable. Any acceptable method of drug administration can be used in the combination therapy of this invention and can be determined using techniques well known to those of skill in the art. In addition, the drugs can be administered either simultaneously or sequentially, in any order.

The P388 tumor model employs a murine lymphocytic leukemia cell line (See Schabel et al., Pharmac. Ther. A, 1:411-435). The P388 tumor cells used in this invention, were harvested from donor mice by peritoneal lavage at day 7 post transplant. 1x106 P388 tumor cells were then implanted intraperitoneally in a volume of 0.5 ml in mice.
A typical dosing regimen includes initiation of treatment approximately one day post transplant followed by treatment on days 5 and 9 post transplant. Generally the compounds of Formula I are administered intravenously (i.v.) and the paclitaxel, taxotere or modified taxane or taxoid analog is administered intraperitoneally (i.p.).

Therapeutic results of the combinations of the invention against P388 cells, are presented in terms of increase in lifespan reflected by the relative median survival time (MST) of treated (T) versus control (C) group (survival period for untreated mice is generally in the range of 11 to 13 days) and is represented as oT/C values.
According to the National Cancer Institute guidelines a %T/C in the range or 128-190o indicates a drug with moderate to good activity. In addition, the Net log Cell Kill is used to compare efficacy of different schedules and combinations, and is calculated as follows:

Net log Cell Kill =[(T-C) - duration of treatment] x 0.332 Doubling Time Where, Doubling Time = time required for control tumors to double once (0.4 days ) .
T and C = the median survival time (days) for the control (C) and treated (T) mice.
Duration of treatment with drug 0.332 = Derived constant A positive Net log Cell Kill number indicates that fewer tumor cells are present at the end of treatment. A
negative number indicates that the tumor was still growing during treatment.
EXAMPLE 3: Combination Treatment Using Compound (xvii) and Paclitaxel in the P388 Tumor Model 1 x 106 P388 tumor cells were transplanted intraperitoneally in a volume of 0.5 ml in mice. Treatment was initiated approximately 1 day later followed by treatment on both day 5 and day 9, post transplant.
Compound (xvii) was administered IV while paclitaxel was administered IP. Compound (xvii) was administered at either 20, 40 or 60 mg/kg and paclitaxel at either 10, 20 or 30 mg/kg. The dosing was sequential with compouond (xvii) being administered first followed by paclitaxel one hour later.
RESULTS:
The results from Example 3 are shown in Table 1. The data in Table 1 shows that single drug treatment resulted in an optimal oT/C of 1751 for compound (xvii) corresponding to a Net log Cell Killing (NiCK) of 0.66 when administered intravenously at a dose of 60 mg/kg and an optimal oT/C of 183% corresponding to a N1CK of 1.33 for paclitaxel when administered intraperitoneally at a dose of 10 mg/kg. For combination drug treatment the data of Table 1 show that the combination of 60 mg/kg (xvii) and 20 mg/kg of paclitaxel resulted in a significant increase in life span (P Value less than 0.001, as determined by the Mann-Whitney Test) and an optimal %T/C value of 242%
corresponding to a N1CK of 5.98 with 380 of the animals surviving more than 60 days.
HUMAN TUMOR XENOGRAFTS MODEL
Human tumors from lung (LX-1), colon (CX-1) and prostate (PC-3) which had been grown in athymic nude mice were transplanted (xenografted) into new recipient mice, as is well known in the art. The transplanted tumor fragments were approximately 50 mg in size. The day of transplantation was designated as day 0. The combination therapy of the present invention was evaluated for anti-tumor efficacy following administration to the xenograft-bearing mice.
Combination therapy was accomplished by intravenous administration of both drugs. The Q2dx3; 5, 12 and 19 injection schedule was followed with paclitaxel being administered one hour after Compound (xvii). In other words, treatment consisted of 3 cycles, starting on days 5, 12 and 19 post tumor implantation. One cycle of treatment consisted of treatment every other day for a total of three times. The optimal dose for single dose administration of both Compound (xvii) and paclitaxel used in the LX-1 and CX-1 types of human xenograft models tested, can be found in Tables 2-3, with no optimal dose determined with the PC-3 model.
Tumor diameters and body weights were measured twice weekly. Tumor volumes were calculated using the diameters measured with Vernier calipers, and the formula:

(length x width2) / 2 = mg of tumor weight Mean tumor weights (MTW) were calculated for each treatment group, and T/C values determined for each group relative to the untreated control tumors.
Results are also presented as Net log Cell Kill and are calculated as follows:

Net log Cell Kill = [(T-C) - duration of treatmentl x 0.332 Doubling Time T and C = The median days required for the control and treated tumors to reach a specified tumor size, in this instance 2000 mm3.

Doubling Time = Time required for control tumors to double in size.
0.332 = Derived constant EXAMPLE 4: Combination Treatment Using Compound 103793 and Paclitaxel in the LX-1 Human Tumor Xenograft Model The Q2dx3; 5, 12 and 19 dosing regimen described above was used in this example. Paclitaxel was administered IV
one hour after Compound (xvii) was administered IV. The optimal single dose of both paclitaxel and Compound (xvii) can be determined from Table 2.

~
z di w Un H (t E
H .0 =rI lDd'd~ NNN d~~t'd' d' V~d' d'N V~
U C Q M (N N V 4 d~ C N N N N N N C N a m xA kDu H O m N lfl a0 co N tn ;:v =a+
o\o J1 N M H N r-I

E-rnwc~ w I'aw oC) aorn U') inm aowry) H., O, Ol l0 M lD O= O= Ol 01 m lD l0 f~ Q1 Ol M
O~-1 O= I I c1 U1 N fM M r-1 M M f-i =~
>
K
zu co _.CD a) t"M 4J
qa u-+
p W U
aEx-+ E~
x tllM II1cUC0 t- Nd+ NNM [- [- m 0 Q o\o O C- 00 [- t!1 tIl rl -~" O r-1 e-i CO r-1 rl CD
U Nr1i--I t--Is-lr-I NNN NNrI NNr-i N
W

Z E--i q O aao0 (D 00 U) I;zr o r-4 oo cooo U
~
a C\0 N (N
~ n a ~ =~
a~
w X ~--i O .ri 000 0oo 0oo Ooo 00o X
ri M N t-I f'~1 NH ry) N'--I m N r1 1~ a ~
H C!~ ~4' RS H r-i a ~
a E a ~ q =~ ~-t E- > O 0 O O O O O o o 0 O O O O O m Qx lD [r N ~0 lD \D d' d' N1' N N N X
Q-- q a EXAMPLE 5: Combination Treatment Using Compound 103793 and Paclitaxel in the CX-1 Human Tumor Xenograft Model The Q2dx3; 5, 12 and 19 dosing regimen described above S was used in this example. Paclitaxel was administered IV
one hour after Compound (xvii) was administered IV. The optimal single dose of both paclitaxel and Compound (xvii) can be determined from Table 3.

EXAMPLE 6: Combination Treatment Using Compound 103793 and Paclitaxel in the PC-3 Human Tumor Xenograft Model The Q2dx3; 5, 12 and 19 dosing regimen described above was used in this example. Paclitaxel was administered IP
one hour after Compound (xvii) was administered IV. The optimal single dose of both paclitaxel and Compound (xvii) was not determined.

RESULTS:
The results obtained using the Human Xenograft Model to assess anti-tumor efficacy of the combination therapy of the present invention are presented in Tables 2-4. The data presented represents results from preliminary experiments. The data in Table 2 show that the optimal combination of compound (xvii) and paclitaxel was 15 mg/kg and 10 mg/kg respectively, in the LX-1 model. The combination resulted in some regressions and tumor growth delay. However, the same combination schedule in the CX-1 model did not result in any advantage over the single drug treatment as shown in Table 3.
In the PC-3 model, there was no beneficial effect of the combination as compared to single drug treatment.
However, the optimal dose for single dose administration was not determined.

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a H
a a U
a H

o a X

r-{ (~f lD lD lD lD lfl lD l0 a 41 ~~ 0 H o o U
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(y r(j \ lf) 01 N O N (Y) Ln 0 a M O

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z w U~ O o O o aH '\'HQ
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f-i ^
a E.H~ N N (N
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~.- o 0 0 0 0 0 o a U ?C H .~ m a~ rn N

Q b^ v ~ ~ ., r~n ~ Ln Ln O -~ > o o in i.n = Ln Ln = r~
R+ y H ~1 N rl [- N H [- x E?C iz~
O N
U a W N
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Z
0 co 04 rl rf N
OU
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x = c ~
H W N t~ M
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U
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Lin =~ ~n .
o=H> 0 o 0 0 0 0 0 o ayH Q M M M M x E ?CQ
N
U CY

The following compounds were prepared and can be prepared according to the Examples:
3. Xaa Val Xab Pro Xac 4. Xaa Val Xab Pro Xad S. Xaa Val Xab Pro Xae 6. Xaa Val Xab Pro Xaf 7. Xaa Val Xab Pro Xag 8. Xaa Val Xab Pro Xah 9. Xaa Val Xab Pro Xai 10. Xaa Val Xab Pro Xak 11. Xaa Val Xab Pro Xal 12. Xaa Val Xab Pro Xam 13. Xaa Val Xab Pro Xan 14. Xaa Val Xab Pro Xao 15. Xaa Val Xab Pro Xap 16. Xaa Val Xab Pro Xaq 17. Xaa Val Xab Pro Xar 18. Xaa Val Xab Pro Xas 19. Xaa Val Xab Pro Xat 20. Xaa Val Xab Pro Xau 21. Xaa Val Xab Pro Xav 22. Xaa Val Xab Pro Xaw 23. Xaa Val Xab Pro Xax 24. Xaa Val Xab Pro Xay 25. Xaa Val Xab Pro Xaz 26. Xaa Val Xab Pro Xba 27. Xaa Val Xab Pro Xbb 28. Xaa Val Xbc Pro Xay 29. Xaa Val Xab Pro Xbd 30. Xaa Val Xab Pro Xbe 31. Xaa Val Xab Pro Xbf 32. Xaa Val Xab Pro Xbg 33. Xaa Val Xab Pro Xbh 34. Xaa Val Xab Pro Xbi 35. Xaa Val Xab Pro Xbk 36. Xaa Val Xab Pro Xbl 37. Xaa Val Xab Pro Xbm 38. Xaa Val Xab Pro Xbn 39. Xaa Val Xab Pro Xbo 40. Xaa Val Xab Pro Xbp 41. Xaa Val Xab Pro Xbq 42. Xaa Val Xab Pro Xbr 43. Xaa Val Xab Pro Xbs 44. Xaa Val Xab Pro Xbt 45. Xaa Val Xab Pro Xbu 46. Xaa Val Xab Pro Xbv 47. Xaa Val Xab Pro Xbw 48. Xaa Val Xab Pro Xbx 49. Xaa Val Xab Pro Xby 50. Xaa Val Xab Pro Xbz 51. Xaa Val Xab Pro Xca 52. Xaa Val Xab Pro Xcb 53. Xaa Val Xab Pro Xcc 54. Xaa Val Xab Pro Xcd 55. Xaa Val Xab Pro Xce 56. Xaa Val Xab Pro Xcf 57. Xaa Xdf Xab Pro Xay 58. Xaa Val Xab Pro Xch 59. Xaa Val Xab Pro Xci 60. Xaa Val Xab Pro Xck 61. Xaa Val Xab Pro Xcl 62. Xaa Val Xab Pro Xcm 63. Xaa Val Xab Pro Xcn 64. Xaa Val Xab Pro Xco 65. Xaa Val Xab Pro Xcp 66. Xaa Val Xab Pro Xcq 67. Xaa Val Xab Pro Xcr 68. Xaa Val Xab Pro Xcs 69. Xaa Val Xab Pro Xct 70. Xaa Val Xab Pro Xcu 71. Xcw Val Xab Pro Xcv 72. Xcx Val Xab Pro Xcv 73. Xaa Val Xab Pro Pro Xcy 74. Xaa Val Xab Pro Pro Xcz 75. Xaa Val Xda Pro Xcv 76. Xaa Xdb Xab Pro Xcv 77. Xdc Val Xab Pro Xcv 78. Xaa Ile Xab Pro Xcv 79. Xdd Val Xab Pro Xcv 80. Xde Val Xab Pro Xcv 81. Xaa Xdf Xab Pro Xcv 82. Xaa Val Xab Pro Xcg 83. Xaa Val Xab Pro Pro Xdg 84. Xaa Val Xab Pro Pro Xdh 85. Xaa Val Xab Pro Pro Xdi 86. Xaa Val Xab Pro Pro Xdk 87. Xaa Val Xdl Pro Xcv 88. Xde Val Xab Pro Xay 89. Xaa Val Xdl Pro Xay 90. Xaa Val Xab Pro Xdm 91. Xaa Val Xab Pro Xdn 92. Xaa Val Xab Pro Xdo 93. Xaa Val Xab Pro Xdp 94. Xaa Val Xab Pro Xdq 95. Xaa Val Xab Pro Pro Xdr 96. Xaa Val Xab Pro Xds 97. Xaa Val Xbc Pro Xcv 98. Xaa Ile Xab Pro Xay 99. Xcw Val Xab Pro Xay 100. Xaa Val Xbc Pro Xal 101. Xaa Val Xdl Pro Xal 102. Xaa Xdf Xab Pro Xal 103. Xaa Ile Xab Pro Xal 104. Xdd Val Xab Pro Xal 105. Xde Val Xab Pro Xal 106. Xcx Val Xab Pro Xcy 107. Xcw Val Xab Pro Xal 108. Xcx Val Xab Pro Xal 109. Xcw Val Xab Pro Xav 110. Xcx Val Xab Pro Xav 111. Xcw Val Xab Pro Xaw 112. Xcx Val Xab Pro Xaw 113. Xab Val Xab Pro Xay 114. Xab Val Xab Pro Xcv 115. Xab Val Xab Pro Xal 116. Xab Val Xab Pro Xam 117. Xab Val Xab Pro Xan 118. Xab Val Xab Pro Xao 119. Xab Val Xab Pro Xav 120. Xab Val Xab Pro Xaw 121. Xab Val Xab Pro Xat 122. Xab Val Xab Pro Xau 123. Xab Val Xab Pro Xbf 124. Xab Val Xab Pro Xbm 125. Xab Val Xab Pro Xbn 126. Xab Val Xab Pro Xbo 127. Xab Val Xab Pro Xch 128. Xaa Val Xab Pro Xdt 129. Xaa Val Xab Pro Xdu 130. Xaa Val Xab Pro Xdv 131. Xaa Val Xab Pro Xdw 132. Xaa Val Xab Pro Xdx 133. Xaa Val Xab Pro Xdy 134. Xaa Val Xab Pro Xdz 135. Xaa Val Xab Pro Xea 136. Xaa Val Xab Pro Xeb 137. Xaa Val Xab Pro Xec 138. Xaa Val Xab Pro Xed 139. Xaa Val Xab Pro Xef 140. Xaa Val Xab Pro Xeg 141. Xaa Val Xab Pro Xeh 142. Xaa Val Xab Pro Xei 143. Xaa Val Xab Pro Xek 144. Xaa Val Xab Pro Xel 145. Xaa Val Xab Pro Xem 146. Xaa Val Xab Pro Xen 147. Xaa Val Xab Pro Xeo 148. Xaa Val Xab Pro Xep 149. Xaa Val Xab Pro Xeq 150. Xaa Val Xab Pro Xer 151. Xaa Val Xab Pro Xcq 152. Xaa Val Xab Pro Pro Val Phe 153. Xaa Val Xab Pro Xet Val Phe NH2 154. Xaa Val Xer Pro Pro Val Phe NH2 155. Xaa Val Xbc Pro Pro Val Phe NH2 156. Xaa Ile Xab Pro Pro Val Phe NH2 157. Xaa Leu Xab Pro Pro Val Phe NH2 158. Xde Val Xab Pro Pro Val Phe NH2 159. Xdd Val Xab Pro Pro Val Phe NH2 160. Xes Val Xab Pro Pro Val Phe NH2 161. Xeu Val Xab Pro Pro Val Phe NH2 162. Xaa Val Xab Pro Pro Phe Phe NH2 163. Xaa Val Xab Pro Pro Val NH2 163. Xaa Val Xab Pro Xev 165. Xaa Val Xab Pro Pro NH2 166. Xaa Val Xab Pro Pro 167. Xaa Val Xab Pro Xew 168. Xaa Val Xab Xex 169. Xdd Val Xab Pro Pro NH2 170. Xaa Xdf Xab Pro Pro NH2 171. Xaa Val Xab Pro Xey 172. Xaa Val Xab Pro Xez 173. Xfa Val Xab Pro Pro Val Phe NHZ
174. Xaa Val Xab Pro Pro Xfb oL` ~ = CA 02282720 1999-09-01 . .. ...,-57-_ 7.~'i . X GQ ~/~ :I 11Gh = r..~i 1'.~C
~ i .. . ~...G uG, X :D ?ro X f .r..
_ / . . Xaa vG i -xQc .-_/ Ci . A G G V G 1- Xab - r..I 7r _/., . X-G v-= 1 Xab rro X_a _e 0 . XGG YGl L1GL P=o Xih 181. Xaa Val XGh Pro X:l 132. Xaa VG1 XaJ P'_'c X_-1 ~. Xaa Val Xcl Pro Pro Nr_, 184. Xaa VG? X-Ek Prc Prc NP', 185. Xaa Val Xil- Pro X=h Xaa Val Xik Pro X~h 167. Xcx Val Xab Pro Xfh 188. XaG VG" Xab Pro Pro Xd-'L" Phe NH, 15- 1-8 c' . Xaa Val XGS'i PrO -'-- Leu Phe 2174H-;
190. Xaa Val Xab P=C prO Tle 7~hC NH, .;~2D_ 5: SEQUENCE IDEN"TIFIC.z=CN OF COMPOUNDS PREPARED
ACCORDING TO THE -7X_~.MPLES AND CCNT~AINE:D IN TTriE
FIGURE

Compound Number(s) SEQ ID NO: 2A, 3-56, 52-72, 75, 77, 79-80, 82, 87-94, 96-97, 99-101, 104- , _5'_, 164, 167, 171-172, 175-182, 185-187, and Co=our-ds -4-xv_i of 2 5 *_he - cure 73-74, 83-86, 95, 174 3 76,81,102 4 78, 98, 103 5 152, 154-155, 158-161, 173 6 _53 7 BBC-038.?CT CA 02282720 1999-09-01 16~ , 1B, 2E, 165-166, 169, 183 1 7 0 1-~
18s lop 17 Examples fcr the MS-characterizGtion of the synthesized novel comzounds are listed below:
EXP-MPLE Fast atom bombardment MS ar_alvsis 3. 565 4. 579 5= 593 6. 607 7. 621 8. 635 1i= 607 12. 607 13= 621 14. 649 15. 635 16. 635 17. 635 19 . 621 .iiviENDcD SV.E!

20. 621 21. 635 22. 635 25. 633 26. 647 27. 661 31. 623 32. 671 33. 667 34. 681 35. 655 36. 655 37. 669 38. 621 39. 635 41. 649 42. 621 43. 633 44. 667 45. 607 46. 647 47. 668 48. 655 49. 669 50. 685 51. 629 52. 625 53. 721 55. 579 58. 623 61. 597 62. 621 63. 609 64. 625 65. 635 66. 591 67. 715 68. 685 69. 685 70. 591 71. 607 72. 621 74. 706 75. 579 76. 579 77. 579 78. 607 79. 607 80. 607 81. 607 82. 637 83. 692 84. 706 85. 706 86. 706 87. 607 90. 635 92. 659 93. 617 94. 636 95. 678 128. 671 131. 625 139. 625 151. 637 152. 798 153. 810 154. 812 155. 812 156. 812 157. 812 258. 812 159. 811 160. 825 161. 881 162. 845 163. 649 164. 737 165. 550 166. 551 167. 731 168. 550 169. 566 170. 566 171. 635 172. 704 173. 853 174. 740 175. 619 176. 845 177. 649 178. 691 179. 717 180. 641 181. 579 182. 595 183. 566 184. 566 185. 669 186. 656 187. 669 188. 811 189. 812 190. 812 The symbols used in the description of the compounds of Formula I have the following meanings:
Xaa: N,N-Dimethylvaline Xab: N-Methylvaline Xac:
N NH

OI
Xad:

Xae: N NH

Xaf:
N

Xag:
N
NH

Xah: N CH3 Xai: N

Xak: N rJH CH3 Xa 1 : N NH

Xam : N NH

Xan: N
NH
'~,C CH3 Xao:

O

Xap: N NH\/~~i'CH3 Xaq:

. ~ ~

Xar : CH3 N /NH

Xas: N
NH
l ~~ CH3 Xat: N r NH

Xau: N NHCH
I ~ 3 Xav: CH3 N NH I,< CH3 Xaw: H3C

NH\

Xax: N rNHCH=CH2 Xay : CH3 N NH

Xaz:
/N NH
O
Xba:
/N NH
O

Xbb:

/ N
rNH
O

Xbc: N-Methyl-isoleucine OJ
Xbd: I
N N
/ ~

O

i Xbe: 0 N N

Xbf :
N N

Xbg: N N

Xbh:

N NH 30 ~

Xbi:
N NH
O
/
Xbk:
NH
I f Xb1:

/ N NH

Xbm: N NH

+

Xbn:
N NH
I
CH3 \ CH3 xbo: CH
N
/NH

Xbp:
N /-NH

i Xbq: CH3 Xbr : CH3 Xbs:

Xbt:

Xbu:

/N 30 i NH CH3 Xbv:

/N /NH,~

Xbw N NH
I

Xbx: N NH
I I \

XbY: N NH

OH
Xbz.
/N NH

I = ~ \

Xca:

/N NH
1 ~

S
Xcb:

N NH_ CH3 Xcc: Proline adamantyl(Z)amide Xcd:

~ I~ NH\/\

Xce:
/ N N

Ir Xcf:

N ~ N CH3 I

Xcg:

NH
0 CH3 ~ OH

Xch: rS

,N N
( OH

Xci:

~
Xck: N N `
O

F
Xcl:

/N NJ
Xcm: I~

/N ~NHJ
Xcn:

i Xco:

S
N NH

Xcp:

/ N
NH
O

Xcq: N
/ NH

Xcr:
/N NH O ~

OH
Xcs: N
/ NH

OH

Xct: N NH 5 I 1 Xcu:
N

Xcv:

I

Xcw: N-Methyl-N-ethyl-valine Xcx: N,N-Diethylvaline Xcy:

N' 1f NH CH3 IOI

XCZ : H3C-4,~ H3 NH

O

Xda: N-Methyl-2-aminobutyroyl Xdb: 2-aminobutyroyl Xdc: N,N-Dimethyl-2-aminobutyroyl Xdd: N,N-Dimethyl-2-tert.butyZglycine Xde: N,N-Dimethyl-isoleucine Xdf: 2-tert.butylglycine Xdg: H3Cl,~,_,,--CH3 NH rCH3 Xdh: H3C-,,,-I,--CH3 0 ITCH3 .

Xdi: H3C\j N ,,~y NH rCH3 Xdk:

-N NH ,,rCH3 Xdl: N-Methyl-2-tert.butylglycine Xdm: N

Xdn : CH3 N
NH~ C= N

Xdo:
N NH

Xdp : CH3 N NH,,, / C = CH

Xdq: N NH~ CONHZ

Xdr: - NH ," / CONHCH2CH2CH3 Xds: I \/ CH3 i Xdt: N
N
i OCH3 O

Xdu : N NH _\C]

Xdv : CH3 N NH \0 Xdw: CH3 N NH ,,,~ / CH3 I

F

Xdx: N /NH CH3 Xdy: N NH "J',~CH3 F

.40 CH3 Xdz: I = \ CH3 F
~

Xea: N. h'K

1 ~

F

C"r_3 ~':e C :
~,N /2vn I C =3 F

C"3 xed:
hr.r F

CF:3 Xee: /t' /~\

F

CFi3 Xe`_ . CF3 SUBSTITUTE SHEET (RULE 26) Ci Xea: h / \ O
Cl l oC~3 .
Xeh: ~
f C=3 xei 10 C :3 N N' =\ CE'3 Xe1.: /~ N'r.~ CF:3 C-v3 C1 ~

Cu3 GH3 X em : / A / NFx u Cq3 Mll Xert : : M.:
0 C''3 SUBSTITUTE SHEET (RULE 26) Xeo: N
NH
O

Xep: CH3 N NH
~
i CH3 O

Xeq: \

O

Xer: N-Methylleucine Xes: N-Acetyl-N-methylvaline Xet: pipecolinic acid Xeu: N,N-Dibutylvaline /
\1 Xev: 0 N
HN
CN~~

~ O
Xew: N
N(Bzl)2 Xex: N NH S--/

Xey: O
N N
~</ 31 S

O N,N
Xez: N I~~S~CF3 Fi Xfa: N,N-dipropylvaline O
Xf b : "- NH

~~CH3)2 Xfc: 0 6"jt, NH
~ . O
Xfd : OCH3 NH ~

0 N_N
Xf e: il, CH3 NH S

Xff: ~ 0 NH

/

Xfg: ~ O
N

\
Xfh: l O

I O
Xfi. N
~

~ O
N
Xfj . N.CH3 Xfk: N-Ethylvaline Xfl: N-Methyl-3-tert-butylalanine EQUIVALENTS
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 herein. Such equivalents are intended to be encompassed in the scope of the following claims.

SEQUENCE LISTING
(1) GENERAL INFORMATION:

(i) APPLICANT: BASF Aktiengesellschaft (ii) TITLE OF INVENTION: Dolastatin-15 Derivatives in Combination With Taxanes (iii) NUMBER OF SEQUENCES: 17 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Borden Ladner Gervais LLP
(B) STREET: 60 Queen Street (C) CITY: Ottawa (D) PROVINCE: Ontario (E) COUNTRY: Canada (F) POSTAL CODE: K1P 5Y7 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: PatentIn Release #1.0, Version #1.30 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER: 2,282,720 (B) FILING DATE: 1-September-1999 (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 08/819,101 (B) FILING DATE: 13-MAR-1997 (viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: Joachim T. Fritz (B) REGISTRATION NUMBER: 4173 (C) REFERENCE/DOCKET NUMBER: PAT 44979W-1 (ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 613-237-5160 (B) TELEFAX: 613-787-3558 (2) INFORMATION FOR SEQ ID N0:1:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:
Xaa Val Xaa Pro Xaa (2) INFORMATION FOR SEQ ID NO:2:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:
Xaa Xaa Xaa Pro Xaa (2) INFORMATION FOR SEQ ID NO:3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:
Xaa Val Xaa Pro Pro Xaa (2) INFORMATION FOR SEQ ID NO:4:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:
Xaa Xaa Xaa Pro Xaa (2) INFORMATION FOR SEQ ID NO:5:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:
Xaa Ile Xaa Pro Xaa (2) INFORMATION FOR SEQ ID NO:6:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:
Xaa Val Xaa Pro Pro Val Phe (2) INFORMATION FOR SEQ ID NO:7:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:
Xaa Val Xaa Pro Xaa Val Phe (2) INFORMATION FOR SEQ ID NO:8:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:
Xaa Ile Xaa Pro Pro Val Phe (2) INFORMATION FOR SEQ ID NO:9:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:
Xaa Leu Xaa Pro Pro Val Phe (2) INFORMATION FOR SEQ ID NO:10:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:
Xaa Val Xaa Pro Pro Phe Phe (2) INFORMATION FOR SEQ ID NO:l1:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:
Xaa Val Xaa Pro Pro Val (2) INFORMATION FOR SEQ ID NO:12:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:
Xaa Val Xaa Pro Pro (2) INFORMATION FOR SEQ ID NO:13:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:
Xaa Val Xaa Xaa (2) INFORMATION FOR SEQ ID NO:14:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:
Xaa Xaa Xaa Pro Pro (2) INFORMATION FOR SEQ ID NO:15:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:
Xaa Val Xaa Pro Pro Xaa Phe (2) INFORMATION FOR SEQ ID NO:16:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:
Xaa Val Xaa Pro Pro Leu Phe (2) INFORMATION FOR SEQ ID NO:17:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:
Xaa Val Xaa Pro Pro Ile Phe

Claims (34)

-93-What is claimed is:

1. A pharmaceutical composition comprising: a therapeutically effective amount of a first compound which is paclitaxel, taxotere, modified taxane or a taxoid analog; and a therapeutically effective amount of a second compound, wherein the second compound is of Formula I
R1 R2 N-CHX-CO-A-B-D-(E)g-(F)t-(G)u-K (I) wherein:
R1 is alkyl, cycloalkyl, alkylsulfonyl, fluoroalkyl, or aminosulfonyl;

R2 is hydrogen, alkyl, fluoroalkyl or cycloalkyl;

R1-N-R2 together may be a pyrrolidino or piperidino residue;

A is a valyl, isoleucyl, leucyl, allo-isoleucyl, 2,2-dimethylglycyl, 2-cyclopropylglycyl, 2-cyclopentylglycyl, 3-tert-butylalanyl, 2-tert-butylglycyl, 3-cyclohexylalanyl, 2-ethylglycyl, 2-cyclohexylglycyl, norleucyl or norvalyl residue;

B is a N-alkyl-valyl, -norvalyl, -leucyl, -isoleucyl, -2-tert-butylglycyl, -3-tert-butylalanyl, -2-ethylglycyl, -2-cyclopropylglycyl, -2-cyclopentylglycyl, -norleucyl or -2-cyclohexylglycyl residue;

D is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue;

E is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methyl prolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue;

F and G are independently prolyl, homoprolyl, hydroxyprolyl, thiazolidinyl-4-carbonyl, 1-aminopentyl-1-carbonyl, valyl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl, N-methylphenylalanyl, tetrahydrosioquinolyl-2-histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl, norleucyl, norvalyl, neopentylglycyl, trytophanyl, glycyl, 2,2-dimethylglycyl, alanyl, .beta.-alanyl or 3-naphthylalanyl residues;

X is hydrogen, alkyl, cycloalkyl, -CH2-cyclohexyl or arylalkyl;

s, t and u are independently 0 or 1; and K is hydroxy, alkoxy, phenoxy, benzyloxy or a substituted or unsubstituted amino moiety;
and the salts thereof with physiologically tolerated acids.

2. The composition of Claim 1 further comprising a pharmaceutically acceptable carrier.

3. The composition of Claim 1 wherein for the compound of Formula I, K is a substituted amino moiety having the formula R5-N-R6 wherein:

R5 is hydrogen; hydroxy; C1-7 alkoxy;
benzyloxy; phenyloxy; fluorine- substituted or unsubstituted C1-7- linear or branched alkyl; C1-12 linear or branched hydroxyalkyl;
C3-10-cycloalkyl; unsubstituted benzyl or mono-, di- or tri substituted benzyl, wherein the substituents are independently CF3, nitro, C1-7 alkylsulfonyl, C1-4 alkoxy, phenoxy, benzoxy, halogen, C1-4-alkyl, cyano, hydroxy, N(CH3)2, COOMe, COOEt, COOiPr, or COONH2;

R6 is hydrogen; fluorine-substituted or unsubstituted C1-12 linear or branched alkyl;
C1-12 linear or branched hydroxyalkyl; C3-10-cycloalkyl; - (CH2)v-C3-7- cycloalkyl (v=0, 1, 2, or 3); norephedryl;
norpseudoephedryl; quinolyl; pyrazyl; -CH2-benzimidazolyl ; (1) -adamantyl; (2)-adamantyl; -CH2-adamantyl; alpha-methyl-benzyl; alpha-dimethylbenzyl; -(CH2)v-phenyl (v=0, 1, 2, or 3) wherein the phenyl group is unsubstituted or mono- or di-substituted and the substituents are independently CF3, nitro, C1-7 alkylsulfonyl, C1-4 alkoxy, phenoxy, benzoxy, halogen, C1-4-alkyl or fused alkyl, cyano, hydroxy, N(CH3)2, COOMe, COOEt, COOiPr, or COONH2; -(CH2)m-naphthyl (m=0 or 1); -(CH2)w-benzhydryl (w=0, 1, or 2); biphenyl; picolyl; benzothiazolyl;
benzoisothiazolyl; benzopyrazolyl;
benzoxazolyl; - (CH2)m-fluorenyl (m=0 or 1);
pyrimidyl; - (CH2)m-indanyl (m=0 or 1); -(CH2CH2O)y-CH3 (y=0, 1, 2, 3, 4, or 5); -(CH2CH2O)y -CH2CH3 (y=0, 1, 2, 3, 4, or 5); NH-phenyl wherein the phenyl group is unsubstituted or mono- or di-substituted and the substituents are independently CF3, nitro, C1-7 alkylsulfonyl, C1-4 alkoxy, halogen, C1-4 alkyl or fused alkyl, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH2;
-NCH3-C6H5; -NH-CH2-C6H5; -NCH3-CH2-C6H5; 5-membered unsubstituted or mono- or di-substituted heteroaryl wherein the substituents are CF3, nitro, thiomethyl, thioethyl, C3-6-cycloalkyl, -CH2-COOEt, or C3-4-alkylene group forming a bicylic system with the heterocycle; phenyl; or -CHR7-5-membered heteroaryl wherein the heteroaryl group is unsubstituted or mono-or di-substituted wherein the substituents are independently CF3, nitro, cyano, halogen, COOMe, COOEt, COOiPr, CONH2, C1-4-alkyl, C1-4-alkoxy, phenyl, benzyl, naphthyl, or C1-7-alkylsulfonyl; and R7 is hydrogen, linear or branched C1-5 alkyl, benzyl, or R7 and R5 together form a group -(CH2)3- or -(CH2)4- .

4. The composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 2-ethylglycyl, 1-isoleucyl or 2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched alkyl group the monovalent radical of which is:

-C(CH3)3;
-C(CH3)2-CH(CH3)2;
-CH(CH3)2;

-CH(CH3)CH2CH3; or -CH(CH3)CH(CH3)2.

5. The composition of Claim 4 wherein the monovalent radical is -C(CH3)3.

6. The composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -1-isoleucyl or -2-tertbutylglycyl; D
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a monovalent radical which is(CH2)v-phenyl or .alpha.,.alpha.-dimethylbenzyl, wherein v is 1.

7. The composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -1-isoleucyl or 2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched hydroxyalkyl.

8. The composition of Claim 7 wherein R6 is 3-hydroxy-1,1-dimethylpropyl.

9. The composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -1-isoleucyl or -2-tertbutylglycyl; D
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having.the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C3-10 cycloalkyl which is (1)-adamantyl, (2)-adamantyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1-methylcyclohexyl or bicyclo [3.3.0]octa-1-yl.

10. The composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl; X is isopropyl; s is 1; t and u are each 0; A is valyl;
B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen.

11. A use, for treating a cancer in a mammal, of a therapeutically effective amount of a first compound which is paclitaxel, taxotere, modified taxane or taxoid analogs; and a therapeutically effective amount of a second compound of Formula I:

R1 R2 N-CHX-CO-A-B-D- (E)s - (F) t -(G) -K (I) wherein:
R1 is alkyl, cycloalkyl, alkylsulfonyl, fluoroalkyl, or aminosulfonyl;

R2 is hydrogen, alkyl, fluoroalkyl or cycloalkyl;

R1-N-R2 together may be a pyrrolidino or piperidino residue;

A is a valyl, isoleucyl, leucyl, allo-isoleucyl, 2,2-dimethylglycyl, 2-cyclopropylglycyl, 2-cyclopentylglycyl, 3-tert-butylalanyl, 2-tert-butylglycyl, 3-cyclohexylalanyl, 2-ethylglycyl, 2-cyclohexylglycyl, norleucyl or norvalyl residue;

B is a N-alkyl-valyl, -norvalyl, -leucyl, -isoleucyl, -2-tert-butylglycyl, -3-tert-butylalanyl, -2-ethylglycyl, -2-cyclopropylglycyl, -2-cyclopentylglycyl, norleucyl or -2-cyclohexylglycyl residue;

D is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue;

E is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methyl prolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue;

F and G are independently prolyl, homoprolyl, hydroxyprolyl, thiazolidinyl-4-carbonyl, 1-aminopentyl-1-carbonyl, valyl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclo-hexylalanyl, phenylalanyl, N-methylphenyl-alanyl, tetrahydrosioquinolyl-2-histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl, norleucyl, norvalyl, neopentylglycyl, trytophanyl, glycyl, 2,2-dimethylglycyl, alanyl, .beta.-alanyl or 3-naphthylalanyl residues;

X is hydrogen, alkyl, cycloalkyl, -CH,-cyclohexyl or arylalkyl;

s, t and u are independently 0 or 1; and K is hydroxy, alkoxy, phenoxy, benzyloxy or a substituted or unsubstituted amino moiety;
and the salts thereof with physiologically tolerated acids, wherein the cancer is lung, breast, colon, prostate, bladder, rectal, endometrial or hematological cancer.

12. The use according to Claim 11 wherein the compound of Formula I is administrable first followed by the first compound.

13. The use acccording to Claim 11 wherein the first compound is administrable first followed by the compound of Formula I.

14. The use according to Claim 11 wherein the first compound and the compound of Formula I are administrable simultaneously.

15. The use according to Claim 11 wherein said mammal is human.

16. The use according to Claim 15 wherein for the compound of Formula I K is a substituted amino moiety having the formula R5-N-R6 wherein:
R5 is hydrogen; hydroxy; C1-7 alkoxy;
benzyloxy; phenyloxy; fluorine- substituted or unsubstituted C1-7- linear or branched alkyl; C1-12 linear or branched hydroxyalkyl;
C3-10-cycloalkyl; unsubstituted benzyl or mono-, di- or tri substituted benzyl, wherein the substituents are independently CF3, nitro, C1-7 alkylsulfonyl, C1-4 alkoxy, phenoxy, benzoxy, halogen, C1-4-alkyl, cyano, hydroxy, N(CH3)2, COOMe, COOEt, COOiPr, or COONH2;

R6 is hydrogen; fluorine-substituted or unsubstituted C1-12 linear or branched alkyl;
C1-12 linear or branched hydroxyalkyl; C3-10-cycloalkyl; - (CH2)v-C3-7- cycloalkyl (v=0,1,2, or 3); norephedryl;
norpseudoephedryl; quinolyl; pyrazyl; -CH2-benzimidazolyl; (1)-adamantyl; (2)-adamantyl; -CH2-adamantyl; alpha-methyl-benzyl; alpha-dimethylbenzyl; -(CH2)v-phenyl (v=0,1,2, or 3) wherein the phenyl group is unsubstituted or mono- or di-substituted and the substituents are independently CF3, nitro, C1-7 alkylsulfonyl, C1-4 alkoxy, phenoxy, benzoxy, halogen, C1-4-alkyl or fused alkyl, cyano, hydroxy, N(CH3)2, COOMe, COOEt, COOiPr, or COONH2; -(CH2)m-naphthyl (m=0 ,or 1) ; - (CH2)w-benzhydryl (w=0,1, or 2); biphenyl; picolyl; benzothiazolyl;
benzoisothiazolyl; benzopyrazolyl;
benzoxazolyl; - (CH2)m-fluorenyl (m=0 or 1) ;
pyrimidyl; - (CH2)m-indanyl (m=0 or 1) ; -(CH2CH2O)y-CH3 (y=0,1,2,3,4, or 5) ; -(CH2CH2O)y-CH2CH3 (y=0,1,2,3,4, or 5); NH--C6H5 wherein the -C6H5 group is unsubstituted or mono- or di-substituted and the substituents are independently CF3, nitro, C1-7 alkylsulfonyl, C1-4 alkoxy, halogen, C1-4 alkyl or fused alkyl, cyano, hydroxy, COOMe, COOEt, COOiPr, and COONH2;
-NCH3-C6H5; -NH-CH2-C6H5; -NCH3-CH2-C6H5; 5-membered unsubstituted or mono- or di-substituted heteroaryl wherein the substituents are CF3, nitro, thiomethyl, thioethyl, C3-6-cycloalkyl, -CH2-COOEt, and C3-4-alkylene group forming a bicyclic system with the heterocycle; phenyl; or -CHR7-5-membered heteroaryl wherein the heteroaryl group is unsubstituted or mono-or di-substituted wherein the substituents are independently CF3 , nitro, cyano, halogen, COOMe, COOEt, COOiPr, CONH2, C1-4-alkyl, C1-4-alkoxy, phenyl, benzyl, naphthyl, and C1-7-alkylsulfonyl; and R7 is hydrogen, linear or branched C1-5 alkyl, benzyl, or R7 and R5 together form a group -(CH2)3- or -(CH2)4- .

17. The use according to Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X
is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -isoleucyl or -2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched alkyl group, the monovalent radical of which is:

-C(CH3)2-CH(CH3)2;
-CH(CH3)2;

-CH(CH3)CH2CH3; and -CH(CH3)CH(CH3)2.

18. The use according to Claim 17 wherein said monovalent radical is -C(CH3)3.

19. The use according to Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -1-isoleucyl or -2-tertbutylglycyl; D
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R3-N-R 6 wherein R3 is hydrogen or C1-C4 alkoxy and R6 is a monovalent radical which is (CH2)v-phenyl (wherein v is 1), or .alpha.,.alpha.-dimethylbenzyl.

20. The use according to Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -1-isoleucyl or -2-tertbutylglycyl; D
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched hydroxyalkyl.

21. The use according to Claim 20 wherein R6 is 3-hydroxy-1,1-dimethylpropyl.

22. The use according to Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; -,- and u are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -isoleucyl or -2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 i s hydrogen or C1-C4 alkoxy and R6 is a C3-cycloalkyl which is:
(1)-adamantyl, (2)-adamantyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1-methylcyclohexyl or bicyclo [3.3.0]octa-1-yl.

23. The use according to Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl; X is isopropyl;
s is 1; t and u are each 0; A is valyl; B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen.

24. The use according to Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl; X is isopropyl;
s is 1; t and u are each 0; A is valyl; B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen and the first compound is paclitaxel.

25. The composition of Claim 3 wherein the first compound is paclitaxel and wherein for the second compound of Formula I, R1 and R2 are each methyl; X is isopropyl; s is 1; t and u are each 0; A is valyl;
B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen.

26. The composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X
is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl, 2-ethylglycyl, or 2-tertbutylglycyl; B is N-methylvalyl, -1-isoleucyl, -2-ethylglycyl or -2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; and E is prolyl, 3-methylprolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl.

27. The use according to Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl, 2-ethylglycyl, or 2-tertbutylglycyl; B is N-methylvalyl, -1-isoleucyl, -2-ethylglycyl or -2-tertbutylglycyl; D
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; and E is prolyl, 3-methylprolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl.

28. The use of a first compound which is paclitaxel, taxotere, modified taxane or a taxoid analog and a second compound which is a compound of the Formula I
as defined in any one of claims 1 or 3 to 10, for the manufacture of a medicament for the treatment of a cancer in a mammal.

29. The use of a first compound which is paclitaxel, taxotere, modified taxane or a taxoid analog for the manufacture of a medicament for combination therapy in conjunction with a second compound, the second compound being a compound of Formula I as defined in any one of claims 1 or 3 to 10, in the treatment of a cancer in a mammal.

30. The use according to Claim 28 or 29 wherein the cancer is lung, breast, colon, prostate, bladder, rectal, endometrial, or haematological cancer.

31. The use according to Claim 29 or 30 wherein the treatment of combination therapy involves a first compound which is paclitaxel, taxotere, modified taxane or a taxoid analog, first followed by the compound of the Formula I.

32. The use according to Claim 29 or 30 wherein the treatment or combination therapy involves the compound of the Formula I, first followed by a first compound which is paclitaxel, taxotere, modified taxane or a taxoid analog.

33. The use according to any one of Claims 28 to 30 wherein the treatment or combination theraphy involves the compound of the Formula I and a first compound which is paclitaxel, taxotere, modified taxane or a taxoid analog, simultaneously.

34. The composition of Claim 1 wherein the compound of Formula I is: