MXPA00003289A - Methods and compositions for treating rheumatoid arthritis - Google Patents

Abstract

The present invention provides compositions and methods for the treatment of rheumatoid arthritis in a subject wherein one or more compounds of Formula (I) as defined herein alone or in combination with one or more other antiarthritic drugs provide suppression of rheumatoid arthritis.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS BACKGROUND OF THE INVENTION Rheumatoid arthritis is generally considered an autoimmune disease believed to be associated with the activity of self-reactive T cells (see, Harris, ED, Jr., The New England Jounal of Medicine, 322: 1277- 1289 (1990)). Despite advances in treatment, rheumatoid arthritis remains a serious health problem. Although rarely fatal, arthritis is a major cause of morbidity, loss of work time, loss of productivity and decreased quality of life. Rheumatoid arthritis causes severe pain and loss of joint mobility and can make it difficult to perform even simple tasks. Current treatment methods and regimens for rheumatoid arthritis include the administration of non-steroidal anti-inflammatory drugs such as acetylsalicylic acid (aspirin), ibuprofen, naproxen and other compounds, gold compounds, penicillin, methotrexate, cytotoxic compounds (e.g. , azotrioprine), 4-aminoquinoline compounds and immunoregulators. However, improved rheumatoid arthritis treatments are needed that can suppress or ameliorate symptoms such as inflammation, swelling, abnormal neovascularization, bone erosion or erosion of cartilage. Preferably, an improved method of treatment should be able to be combined with other treatment methods, should work quickly to cause regression or stabilization of symptoms and should be well tolerated. Preferably, such a treatment regimen should also be useful in prophylaxis in susceptible individuals.

COMPENDIUM OF THE INVENTION This invention relates to the derivatives of dolastatin-15, its preparation and use in the treatment of rheumatoid arthritis, in mammals, for example, in humans. The dolastatin-15 derivatives of the present invention are the compounds of Formula I: Rx R "N-CHX-CO-A-B-D- (E) 3- (F) t- (G) u- (I) Formula I is described in more detail more . Several examples of compounds of Formula I are specifically presented herein. For example, the compounds of Formula I may be those in which R 1 and R 2 are each. e? _ixo / X is i.sopropi. HÍTI_Í O x xo, sec-butyl or tert-butyl; s is 1; t and u are each 0; a is valery, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or 2-tert-butylglycyl; D is thiazolidinylcarbonyl, 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 R -N-R6, wherein R5 is hydrogen or C1-C alkoxy and R is a monovalent radical such as (1) - or (2) -adamantyl; (CH2) v-phenyl with v = 1; a, a-dimethylbenzyl; a straight or branched chain hydroxyalkyl group of C? -C12, such as -C (CH3) 2 -CH2-CH2-0H, also known as 3-hydroxy, 1,1-dimethylpropyl; a C3-C10 cycloalkyl group such as bicyclo [3.3.0] octa-l-yl, 1-methylcyclopentyl or 1-ethylcyclohexyl or a straight or branched chain alkyl group of C1-C12 such as: -C (CH3) 3, also known as tert-butyl; -C-CH2 CH3, also known as 1,1-dimethylpropyl; (CH 3) 2 -C- (CH 2 CH 3) 2 also known as 1-methyl-1-ethylpropyl; (CH 3) 3 -CH-C (CH 3) 3 also known chorus (S) - or (R) -l-methyl-2,2-dimethyl-propyl; I. '' CH3-CH-CH (CH3) 2 also known as (S) - or (R) -l-ethyl-2-methylpropyl; I C2H5 s -CH-CH (CH3) 2, also known as l-isopropyl-2-methylpropyl; or -CH- (CH 3) 2 -C (CH 3) 2 -CH (CH 3) 2, also known as 1,1-dimethyl-2-methylpropyl; »-CH (CH3) 2, also known as isopropyl; -CH (CH3) CH2CH3, also known as sec-butyl [(S) or (R)]; or -CH- (CH 3) CH (CH 3) 2 also known as 1,2-dimethylpropyl.

This invention also relates to methods for the treatment of rheumatoid arthritis, in mammals, for example, a human, in which one or more of the dolastatin-15 derivatives described herein are used. In the method of the present invention, one or more of the dolastatin-15 derivatives are administered alone or in a pharmacologically acceptable carrier, in a therapeutically effective amount to treat rheumatoid arthritis in a mammal having or susceptible to rheumatoid arthritis. In another aspect of the invention one or more dolastatin-15 derivatives are administered in combination with one or more other anti-arthritic drugs to a mammal having or being susceptible to rheumatoid arthritis. In a specific embodiment, two or more dolastatin-15 derivatives are administered alone or in combination with one or more other antiarthritic drugs to a mammal having or being susceptible to rheumatoid arthritis. The administration of two or more derivatives of -dolastatin-15 or the administration of the derivative (s) of dolastatin-15 in combination with one or more of other antiarthritic drugs improve the treatment of rheumatoid arthritis. For example, a combination provides a greater or lesser deletion of side effects, and / or may allow the administration of a lower dose of the known antiarthritic drugs to produce the same effect produced with a higher dose. The other antiarthritic drugs may be, but are not limited to, one or more of the following: (1) a non-spheroidal anti-inflammatory compound such as acetylsalicylic (aspirin), ibuprofen or naproxen; (2) an organic gold derivative such as sodium thiolate and gold, aurothioglucose or auranofin; (3) D-penicillamine; (4) a 4-aminoquinoline compound such as hydroxychlorofin; (5) azathioprine; (6) methotrexate; (7) cyclosporin; (8) an angiogenesis inhibitor like AGM-1470 (Ingber et al., Na ture 348, (1990) 555); (9) monoclonal antibodies to T cells; (10) monoclonal antibodies to adhesion molecules; (11) monoclonal antibodies to cytokines and growth factors; (12) the tumor necrosis factor receptor (TNFR) -IgG; (13) IL-1 receptor antagonists; and (14) _XCE inhibitors. Also the subject of this invention are pharmaceutical compositions comprising one or more Dolastatin-15 derivatives of Formula I alone or in combination with one or more other anti-arthritic drugs. The pharmaceutical composition may optionally include a carrier, diluent or pharmaceutically acceptable compound that aids in processing, for example, binders, fillers and preservers.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents the compounds i-xvii, as examples of dolastatin-15 derivatives having the structure of Formula I. Figure 2 is a graph showing the average arthritic record as a function of the number of days after immunization with type II collagen for mice treated with saline (control), dexamethasone (normal treatment) and compound ii of Figure 1. The treatment was started on day 26 after immunization and was completed on day 35 after immunization. Figure 3 is a graph showing the average arthritic record as a function of the number of days after immunization with collagen type II, for mice treated with vehicle (control), dexamethasone (normal treatment) and compound ii of Figure 1. Treatment started on day 48 after immunization It lasted 21 days. Figure 4 depicts a graph showing the degree of synovitis and damage to cartilage determined by histopathological analysis for mice treated with vehicle, dexamethasone (normal treatment) and compound ii of Figure 1. Mice were treated beginning on day 48 after treatment. immunization with collagen type II and the treatment lasted 21 days. Necropsy was performed on day 71 after immunization.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to dolastatin-15 derivatives useful in the treatment of rheumatoid arthritis in a mammal. The dolastatin-15 derivatives of the invention are compounds having the structure shown in Formula I, as described below. The compound is administered in a therapeutically effective amount. As used herein, the term "therapeutically effective amount" refers to an amount sufficient to obtain the desired biological response. In this invention, the desired biological response of the treatment is the suppression of rheumatoid arthritis. As used herein, "deletion" includes any or all of the following: (1) improvement of existing symptoms; (2) prevention or reduction of the speed of progress of symptom; (3) prevention or delay of the onset or appearance of the disease in a susceptible individual, that is, prophylaxis. Symptoms usually associated with rheumatoid arthritis include, but are not limited to, inflammation, swelling, abnormal neovascularization, bone erosion, and cartilage erosion. When a therapeutically effective amount of a compound derived from dolastatin-15 of Formula I is administered, one or more of these symptoms are suppressed.

COMPOUNDS OF FORMULA I A number of short peptides with important activity as inhibitors of cell growth have been isolated from the Indian Ocean hare Dolabella auriculari (Bai, et al., Biochem Pharmacology, 40: 1859-1864 (1990); Bec with et al., J. Nati. Cancer Inst., 85: 483-488 (1993) the references mentioned therein). These include dolastatins-1-10 (U.S. Patent No. 4,816,444, published for Pettit et al.) And dolastatin-15 (European Patent Application No. 398,558). Dolastatin-15, for example, markedly inhibits the growth of the P388 lymphocytic leukemia cell line of the National Cancer Institute, a strong predictor of efficacy against different types of human maleinities. This compound, however, is only present in trace amounts in the sea hare and is difficult to isolate, its synthesis is expensive and it has little solubility in water. The compounds of Formula I are derivatives of dolastatin-15. It has been determined that, surprisingly, the compounds of Formula I are useful in a method for the treatment of rheumatoid arthritis. The dolastatin-15 derivatives of Formula I, which are employed in the method of the present invention, can be synthesized as described herein and in related co-pending application USSN 08 / 472,453, filed on June 7, 1995, the teachings of which are incorporated into the present in their integrity. The dolastatin-15 derivatives of Formula I generally consist of L-amino acids, but may also contain one or more D-amino acids, as described in related co-pending application USSN 08 / 472,453 filed on June 7, 1995. The compounds Formula I may also be present as physiologically compatible co-acid salts 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, alonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid acetylglycine. For the purposes of the present invention, the term "monovalent radical" is intended to understand an electrically neutral molecular fragment capable of forming a covalent bond with a second neutral molecular fragment.The monovalent radicals include the hydrogen atom, alkyl groups (e.g. methyl, ethyl, propyl and tert butyl), cycloalkyl groups, hydroxyalkyl groups, adamantyl group, halogen atoms (for example, fluorine, chlorine bromine), aryl groups (for example, phenyl groups, benzyl naphthyl) and alkoxy groups (for example , methoxy ethoxy groups) Two monovalent radicals in adjacent atoms with sigma bond can also form a pi bond between the adjacent atoms Two monovalent radicals can also be linked together, for example by a polymethylene linked to form a cyclic structure. , the unit -N (R) R ', where R and R' are monovalent radicals can, together with the nitrogen atom, form a hetero ring In addition, two monovalent radicals bound 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: i is alkyl, such as C1-C3; cycloalkyl with cyclopropyl; alkylsulfonyl, such as d C1-C3; fluoroalkyl such as fluoroethyl, difluoroethyl, fluoroisopropyl; aminosulfonyl which may be substituted by alkyl as may be methyl; it is hydrogen; alkyl such as C? ~ C3 fluoroalkyl, such as fluoroethyl, difluoroethyl, fluroisopropyl; cycloalkyl as cyclopropyl; R ^ N-R2 together may be a pyrrolidino piperidino residue; A is a valyl residue, iosoleucyl, leucyl, isoleucyl, 2, 2-dimethylglycyl, 2-cyclopropylglycyl, 2-cyclopentylglycyl, 3-tert-butylalanyl, 2-tert-butylglycyl, 3-cyclohexyl-alanyl, 2-ethylglycyl, 2-cyclohexylglycyl, norleucyl or norvalyl.; B is a residue N-alkyl-valyl, norvaldyl, -leucyl, Isoleucyl, -2-tert-butylglycyl; -3-tert-butylalanyl, -2-ethylglycyl, -2-cyclopropylglycyl, -2-cyclopentylglycyl, norleucyl or -2-cyclohexylglycyl, where N-alkyl is preferably N-methyl or N-ethyl; D is a prolyl residue, homoprolyl, hydroxyprolyl, 3, 4-dehydroprolyl, 4-fluoropropyl, 3 methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidin-2-carbonyl, 3, 3-dimethylprolyl, 4,4-difluoropropyl, oxazolidin-4-carbonyl thiazolidin-4-carbonyl; E is prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidin-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidin-4. carbonyl or thiazolidin-4-carbonyl; F and G are independently selected from the group consisting of prolyl, homoprolyl, hydroxyprolyl, thiazolidin-4-carbonyl, 1-aminopentyl-1-carbonyl, valeyl, 2-tert-butyl-glycyl, isoleucyl, leucyl, 3-cyclohexylalanyl, -phenylalanyl, N residues. methylphenylalanyl, tetrahydroisoquinolyl-2 histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl, norleucyl, norvalyl, neopentylglycyl, tritophanyl [sic], glycyl, 2,2-dimethylglycylalanyl, β-alanyl and 3-naphthylalanyl; X is hydrogen, alkyl (such as C1-C5), cycloalkyl (C3-C7), -CH2-cyclohexyl arylalkyl (such as benzyl or phenethyl); s, t, and u are independently 0 or 1; Y K is hydroxy, (C 1 -C 4) alkoxy, phenoxy, benzyloxy a substituted or unsubstituted amino moiety. In addition, the compounds of Formula I may be present as a salt thereof with physiologically tolerated acids. A subclass of compounds of this invention includes compounds of Formula I wherein R 1 -N-R 2 is a pyrrolidinyl or piperidinyl residue. Another subclass of compounds of this invention include compounds of Formula I wherein K is an amino portion of the formula R -NR, wherein: R is hydrogen, or hydroxy, or C1-C7 alkoxy or benzyloxy or phenyloxy or linear hydroxyalkyl or branched from C? C12, such as 3-hydroxy-1, 1-dimethylpropyl, or linear or branched C1-C7 alkyl (which may be substituted by one or more fluorine atoms), C3-C10 cycloalkyl, which may be bicyclo [ 3.3.0 octa-yl, 1-methylcyclopentyl or 1-methylcyclohexyl; benzyl (which may be substituted by substituents which can independently be CF3 halogen, C1-C4 alkyl, cyano, hydroxy, N (CH3) 2 COOMe, COOEt, COOiPr or C00NH2); R is hydrogen, linear or branched C1-C12 alkyl (which may be substituted by one or more fluorine atoms), linear or branched hydroxylalkyl of C? -C? , how can to be 3-hydroxy-1, 1-dimethylpropyl, or C3C-cycloalkyl or, as it may be, bicyclo [3.3. Ojocta-1-yl, or 1-methylcyclopentyl or 1-methylcyclohexyl; or - (CH2) V C3-C7 cycloalkyl (v = 0, 1, 2 or 3), or norephedril, or norseudoephedrile, or quinolyl or pyrazyl or -CH2-benzimidazolyl or (1) -adamantyl, or (2) -admantyl , CH-adamantyl, or alpha-methyl-benzyl, or alpha dimethylbenzyl, or - (CH2) v ~ phenyl (v = 0, 1, 2 or 3; qu can be substituted by up to 2 substituents which can independently be CF3, nitro , C 1 -C 7 alkylsulfonyl, C 1 -C 4 alkoxy, phenoxy, benzoxy, halogen, C 1 -C 4 alkyl which can form a cyclic system, cyanohydroxy, N (CH 3) 2, COOMe, COOEt, COOiPr, or COONH 2), or - (CH2) m-naphthyl (= 0 or 1; or CH) w-benzhydryl (= 0, 1 or 2); or biphenium or picolyl or -benzothiazolyl or benzisothiazolyl or benzopyrazolyl or benzooxazolyl or - (CH 2) m-fluorenyl (m = 0 or 1); pyrimidyl or - (CH 2) m-indanyl (m = 0 or 1); or - (CH2CH20) and CH3 (y = 0, 1, 2, 3, 4 or 5), or- (CH2CH20) and -CH2CH3 (y = 0, 1, 2, 3, 4 or 5), or NH- C6-H5 (which may be substituted by up to two substituents which can independently be 'CF3, nitro, C1-C7 alkylsulfonyl d, C1-C4 alkoxy, halogen, C1- C4 alkyl which can form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr or COONH2), or -NCH3-C6H5 or -NH-CH2-C6H5 or NCH3-CH2-C6H5 [sic] or 5-membered heteroaryl which can be substituted by up to two substituents which can independently be CF3, nitro ', thiomethyl, thioethyl cycloalkyl of C3-C6, -CH2-COOEt, alkylene group of C3 C4 forming a dicyclic system with the 7-phenyl heterocycle; or -CHR-5-member heterocycle (which can be substituted by up to two substituents which can be independently CF3, nitro, cyano halogen COOMe, COOEt, COOiPr, CONH2, C 1 -C 4 alkyl / C 1 -C 4 alkoxy, phenyl, benzyl, naphthyl or C 1 alkylsulfonyl? C7 [R = hydrogen, linear or branched C 1 -C 5 alkyl benzyl; or R 7 and R 5 together form a group - (CH 2) 3- or (CH2) 4-) • This subclass includes the compounds of Formula I e where s, t and u are independently 0 or 1; R 1, R 2 and X or lower alkyl, A is an amino acid lower alkyl [sic] B is an amino acid lower alkyl substituted on the N by a lower alkyl; D, E, F, G, and K are as already defined with the foregoing in mind, three series of these compounds can thus be represented by the following Formulas II III and IV: R ^ N-CXH-CO-AB-Pro-Pro-FGK II R1R2N-CXH-CO-AB-Pro-Pro-FK III R ^ N-CXH-CO-AB-Pro-Pro-K IV -CHR-5-member heteroaryl can, for example be represented by one of the following residues CH2 ^ CH2 ^ CH2"^ CHa ^ CH2 \ - ^ ^ ^ ^ COQEe COOMß COOS = i CONHBzl CONE2 -NR CHR-5-member heterocycle can, for example, be represented by the following residues: -membered heteroaryl can, for example, be represented by the following residues: In another subclass of compounds of this invention, R -N R together can form structures selected from the group consisting of: - ~ > N - -N s = o -N - N - -OQ Yet another subclass of compounds of this invention includes, for example, the compounds of Formula I, where s, t and u are 1 and K is a hydroxy, alkoxy, phenoxy or benzyloxy portion. Yet another subclass of compounds of this invention includes, for example, the compounds of Formula I, where s, and t are 1, u is 0 and K is a hydroxy portion, alkoxy, phenoxy or benzyloxy. Another subclass of compounds of this invention includes, for example, the compounds of Formula I, wherein s e 1, t and u are 0 and K is a hydroxy, alkoxy, phenoxy benzyloxy portion. In the specific modalities, a compound of Formula I is that in which R 1 and R are each methyl ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t u are each 0; A is valery, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or 2-tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl or 3,4-dehydropropyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxy-prolyl; and K is a substituted amino moiety having the formula R -N-R. In another embodiment, the dolastatin-15 derivative is a compound of Formula I in which R and R are each a methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; is 1; t and u are each 0; A is valery, isoolethyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or 2-tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydropropyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxy-prolyl; and K is a substituted amino moiety having the formula R -N-R, wherein R 5 is hydrogen or C 1 -C 4 alkoxy and R 6 is a linear or branched alkyl group of C 1 -C 12 or a hydroxyl group linear or branched alkyl of C? -C? 2, represented for example by the following monovalent radicals: -C (CH3) 2-CH2-CH2-OH, also known as 3-hydroxy-l, 1-dimetiprolyl, -C (CH3) 3, also known as tert-butyl; -C-CH CH3, also known as 1,1-dimethyloprolyl; (CH 3) 2 -C- (CH 2 CH 3) 2 also known as 1-methyl-1-ethylpropyl; CH 3 -CH-C (CH 3) also known as co (S) - or (R) -l-α-tyl-2,2-dimethylpropyl; I CH3 -CH-CH (CH3) 2, also known as (S) - or (R) -l-ethyl-2-methylpropyl C2H5-CH-CH (CH3) 2, also known as l-isopropyl-2-methylbutyl; or I -CH- (CH 3) 2 -C (CH 3) -CH (CH 3) 2, also known as 1,1-dimethyl-2-methylpropyl; -C (CH3) 2 / also known as isopropyl; -C (CH) CHCH3, also known as sec-butyl (S) - or (R) -C- (CH3) CH (CH3) 2 also known as 1,2-dimethylpropyl.

In another embodiment, the dolastatin-15 derivative of the invention is a compound of Formula I, wherein R 1 and R are each methyl or ethyl; X is isopropyl, sec-butyl tert-butyl; s is 1; t and u are each 0; A is valery, isoleucyl or 2-tert-butylglycyl; B is N-methylvalil, 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 hydroxy-prolyl; and K is a substituted amino moiety having the formula R-NR, wherein R is hydrogen or C1-C alkoxy and R is a monovalent radical such as a C3-C10 cycloalkoxy group (eg, cyclobutyl, cyclopentyl, cyclohexyl 1- methylcyclopentyl, or 1-methylcyclohexyl bicyclo [3.3.0] octa-l-yl); a group (1) - or (2) -adamantyl (CH) v-phenyl with v = 1; or, α-dimethylbenzyl; In another embodiment, the dslastatin-15 derivative of the invention is a compound of Formula I in which R 1 and JR are each methyl; X is isopropyl, s is 1; t and u are each one 0; A is valilo; B is N-methylvalyl; D is prolyl; The prolyl; K is a substituted amino moiety having the formula R -N-R, wherein R is hydrogen and R is a tert-butyl group; this compound corresponds to compound i shown in Figure 1. The results of the use of compound ii of Formula I are described in Examples 3 and 4 and are depicted graphically in Figures 2, 3 and 4.

The dolastatin-15 derivative of the present invention can optionally be administered in a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known to those skilled in the art. The choice of a carrier to be determined in part by the specific compound of Formula I, as well as by the particular method used to administer the dolastatin-15 derivative. Also, the object of this invention is the pharmaceutical composition containing one or more dolastatin-15 derivatives of the Formula I alone or in combination with one or more other anti-arthritic drugs, such as those described herein. The pharmaceutical composition can optionally include a pharmaceutically acceptable carrier, diluent or a compound that aids in processing, for example, binder fillers and preservatives. In another aspect, the present invention comprises a method for the treatment of rheumatoid arthritis of a mammal using the dolastatin-15 derivatives of Formula I. For the purposes of this invention, the phrase "rheumatoid arthritis treatment method" and " suppressed rheumatoid arthritis "can be used interchangeably. As used herein, the term "deletion" includes any or all of the following: (1) improvement of existing symptoms; (2) prevention, reduction of the rate of progress of symptoms (3) prevention or delay of onset or onset of the disease in a susceptible individual, that is, prophylaxis The treatment method of the present invention is to administer a therapeutically effective amount of one or more compounds of Formula I. The compounds of Formula I can be administered alone or with a pharmaceutically acceptable carrier or diluent suitable for the desired route of administration. The administration can be by any of the means that are traditional for pharmacists, including oral parenteral means such as subcutaneous, intravenous, intramuscular, intraperitoneal, nasal or rectal. Tale pharmaceutical compositions can also contain other therapeutically active ingredients. In another aspect of the invention one or more dolastatin-15 derivatives are administered alone or in combination with one or more other antiarthritic drugs in a mammal having or being susceptible to rheumatoid arthritis. The administration of one or more derivatives of dolastatin-15 e combination with one or more other antiarthritic drugs improve the treatment of rheumatoid arthritis. For example, a combination provides greater or lesser deletion of adverse examples and / or may make it possible to administer a lower dose of the known arthritic medicament to produce the same effect. The other antiarthritic drugs may be, but are not limited to, the following: (1) non-steroidal anti-inflammatory compounds such as acetylsalicylic acid (aspirin), ibuprofen or naproxen; (2) an organic derivative of gold such as sodium and gold thiomalate, aurothioglucose or auranofin; (3) D-penicillamine; (4) u 4-aminoquinoline compound such as hydroxychlorofine; (5) azathioprine; (6) methotrexate; (7) cyclosporin; (8) or angiogenesis inhibitor such as AGM-1470 (Ingber col., Nature 348, (1990) 555); (9) monoclonal antibodies to T cells; (10) monoclonal antibodies to adhesion molecule; (11) monoclonal antibodies to cytokines growth factors; (12) tumor necrosis factor-factor (TNFR) -IgG receptors; (13) IL-1 receptor antagonists; and ICE inhibitors. In a specific embodiment, at least two or more dolain-15 derivatives are administered alone or in combination with one or more other antiarthritic drugs to a mammal having or susceptible to rheumatoid arthritis. The dosage administered to the mammal, as can be a human, includes a therapeutically effective amount of a compound of Formula I, as described herein. The dosage can be determined in an empirical form, using the known methods, and factors such as biological activity, mechanism of action, toxicity profile of the particular compounds that are used will depend; the means of administration; l age, health and body weight of the recipient; the nature, duration and degree of the symptoms; the frequency of treatment; the administration of other treatments and the desired effect. A common daily dose of the compounds of Formula I will be from about 1 to about 100 milligrams per kilogram of body weight per oral administration and from about 1 to about 100 milligrams per kilograms of body weight per parenteral administration. The dolain-15 derivatives of the present invention can be administered in conventional liquid solid dosage forms, for example, in co-coated (film) or uncoated tablets, capsules, powders, granules, suppositories or solutions. These are produced in a traditional way. The active subces can, for this purpose, be processed with traditional pharmaceutical auxiliaries such as binders for tablets, fillers, preservatives, tablet disintegrants, flow regulators, wetting agent plastifiers, dispersants, emulsifiers, solvents, suned release compositions. , antioxidants and propellant gases (see, H. "Sucker et al., Pharmazeutisch Technologie, Thieme-Verlag, Stuttgart, 1978.) Administration forms obtained in this manner will usually range from about 1 to about 90%. in weight of the subce active If administered more than a derivative of dolain-15, it can be administered at the same time (simultaneously) or at separate times (in sequence), provided that they are administered in such order and at suitable intervals to produce the desired therapeutic effect. If two or more dolain-15 derivatives are administered at the same time, these may be administered separately (as individual derivatives) or in physical combination (as a mixture or combination). The same is the case when one or more derivatives of dolain-1 are administered with one or more other antiarthritic drugs. These can be administered simultaneously or sequentially and individually or as a combination or mixture. Pharmaceutical compositions that include one or more dolain-15 derivative or one or more dolain-15 derivatives one or more other antiarthritic drugs are also subject of this invention. The compounds of Formula I are described in detail in the foregoing. In a particular embodiment, the method of the invention utilizes a dolain-1 derivative of Formula I in which Ri and R2 are each methyl ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t u are each 0; A is valery, isoleucyl or 2-tert-butylglycyl; B is N-methylvalil, 1-isoleucyl or 2-ter Butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl or 3,4-dehydroprolyl; E is prolyl, thiazolidinyl-4-carbonyl homoprolyl, 3,4-dehydroprolyl or hydroxy-prolyl; and K is a substituted amino moiety having the formula R -N-R. In another embodiment, the method of the invention utilized derivative of dolastatin-15 of Formula I, in which R R 2 are each methyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is vally 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 thiazolinidyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl hydroxy-prolyl; and K is an amino substituted portion having the formula R -N-R, wherein R is hydrogen or C1-C alkoxy and R is a linear or branched C1-C12 alkyl group or a linear or branched hydroxyalkyl group of C? -C? represented, for example, by the following monovalent radicale: -C (CH3) 2-CH-CH2-OH, also known as 3-hydroxy-l, 1-dimetiprolyl, -C (CH3) 3, also known as tert-butyl; -C-CH2 CH3, also known as • 1,1-dimethyloprolyl; (CH 3) 2 -C- (CH CH 3) 2 also known as 1-methyl-1-ethylpropyl; I CH3 -CH-C (CH3) 3 also known as (S) - or (R) -l-methyl-2,2-dimethylpropyl; I CH3 -CH-CH (CH3) z, also known as (S) - or '(R) -l-ethyl-2-methylpropyl C2H5-CH-CH (CH3) 2, also known as l-isopropyl-2-methylbutyl; or -CH- (CH 3) 2 -C (CH 3) 2 ~ CH (CH) 2, also known as 1,1-dimethyl-2-methylpropyl; -C (CH3) 2, also known as isopropyl; -C (CH3) CHCH3, also known as sec-butyl (S) - or (R) -C- (CH3) CH (CH3) also known as 1,2-dimethylpropyl.

In another embodiment, the method of the invention utilizes a compound of Formula I, wherein R 1 and R 2 are each a methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; is 1; t and u are each 0; A is valery, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or 2-tert-butylglycyl; D is prolyl, thiazolidinyl-4-carbonyl or 3,4-dehydropropyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxy-prolyl; and K is a substituted amino moiety having the formula R -N-R, e where R 5 is hydrogen or C 1 -C 4 alkoxy and R 6 is a monovalent radical such as a cycloalkyl group of C 3 -C? (eg, cyclobutyl cyclopentyl, cyclohexyl or 1-methylcyclohexyl 1-methylcyclohexyl or bicyclo [3.3.0] octa-1-yl, a group (1) - or (2) -adamantyl; (CH) v-phenyl with v 1 or, α-dimethylbenzyl. In another embodiment, the method of the invention utilizes a dolastatin-15 derivative of Formula I in which R and R are each methyl; X is isopropyl; s is 1; t and u are each one 0; A is valilo; B is N-methylvalyl; D is prolyl; The prolyl; and K is a substituted amino moiety having the formula R -N-R, wherein R is hydrogen and R is a tert-butyl group. This compound corresponds to compound i depicted in Figure 1. The use of compound ii in the treatment of rheumatoid arthritis is described in Examples 3 and 4 with the results depicted in Figures 2, 3 and 4.

METHODS OF SYNTHESIS Compounds of Formula I can be prepared by the known methods of peptide synthesis as described herein and, in the application of US Pat. No. 08 / 470,453 filed June 1995 , the teachings of which are incorporated and the present as reference. The peptides may be assembled in sequence from individual amino acids or by linking small suitable peptide fragments. In the sequence assembly, the peptide chain extends step by step, starting at the C-terminus, or amino acid per step. In the copulation of fragments, what fragments of different lengths can be linked together, and the fragments can also be obtained by sequential assembly from amino acids or by coupling even shorter peptide fragments. Both in the sequential assembly and in the coupling of fragments it is necessary to link the units forming an amide bond, which can be achieved by a variety of enzymatic and chemical methods. The methods described herein for the formation of peptide amide bonds are also suitable for the formation of non-peptide amide bonds. The chemical methods for the formation of the amide bond are described in detail in the standard references on chemistry of the peptides which includes Müller, 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 Syntesis, 85-128, John iley & Sons, New York, (1976); Practice or Peptide Synthesis, M. Bodanszky, A. Bodanszky Springer-Verlag, 1994 and other normal works in the chemistry of peptides. Preferred methods include the azide method, the symmetrical and combined anhydride method, the use of active in situ or preformed active esters, the use of urethane-protected N-carboxy anhydrides of the amino acids and the formation of amide bonds using coupling reagents, such as dicyclohexy carbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloyl chloruride, l-ethyl hydrochloride -3- (3-dimethylaminopropyl) carbodiimide (EDCI), N-propan phosphonic anhydride (PPA), N, N-bis (2-oxo-3-oxazolidinyl) amidophosphoryl chloride (BOP-C1), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) diphenylphosphorylazide (DPPA), castro reagent (BOP PyBop), salts of 0-benzotroiazolyl-N, N, N ', N' tetramethyluronium (HBTU), O-azabenzotroiazolyl salts N, N, N ', N' -tetramethyluronium (TATU) diethylphosphoryl cyanide (DEPCN), 2, 5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglichs reagent, HOTDO), and 1,1'-carbonyldiimidazole (CDI). The coupling reagents can be used alone or in combination with additives such as N, N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazo (HOBt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccimid (HOSu) or 2-hydroxypyridine. Although the use of protecting groups is generally not necessary in the enzymatic synthesis of peptides, the reversible protection of reactive groups not included in the formation of the amide bond is necessary for both reagents in chemical synthesis. For the chemical synthesis of peptide Usually, three conventional protective group techniques are used: the techniques of benzyloxy carbonyl (Z), t-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc). In each case it is identified from the protecting group on the a-amino group of the chain extender unit. A detailed review of the amino acid protecting groups is provided in Müller, Methoden der organischen Chemi vol. XV / 2, 1-364, Tjie e Verlag, Stuttgart, (1974). The units used to assemble the peptide chain can be reacted in solution, suspension or by a method similar to that described in Merrifield in J. Amer. Chem. Soc. 85 (1963) 2149. In one method, the peptides are assembled sequentially or by coupling fragments using the protective group technique Z, Boc or Fmoc, with one of the reagents in the Merrifield technique being joined to an insoluble polymeric support (also mentioned as resin onwards). It usually causes the assembly of the peptide sequentially on the polymeric support using the Boc or Fmoc protecting group technique, with the peptide chain growing covalently bound at the C-terminus to the insoluble resin particles. This procedure allows the elimination of reagents and byproducts by filtration, eliminating the need for intermediate recrystallization.

Protected amino acids can be bound to any suitable polymer, which must be insoluble in the solvents used and have a stable physical form that allows filtration. The polymer must contain a functional group to which it can be covalently bound to the first protected amino acid. A wide range of polymer are suitable for this purpose, for example, cellulose, polyvinyl alcohol, polymethacrylate, sulfonated polystyrene, chloromethylated styrene / divinylbenzene copolymer (Merrifield resin), 4-metibezhydrylamine resin (MBHA resin), phenylacetamidomethyl resin (Para resin), benzyloxy-benzyl alcohol resin, benzhydrylamine resin (BHA resin), 4- (hydroxymethyl) -benzoyl-oxymethyl-resin, Breipohl d resin and col. , (Tetrahedron Letters 28 (1987) 565; supplied by BACHEM), 4- (2,4-dimethoxyphenylaminomethyl) phenoxy resin (supplied by Novabioche) or o-chlorotritil-resin (supplied by Biohellas). Suitable solvents for peptide synthesis include any solvent that is inert under the reaction conditions, for example, water, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, diclsromethane (DCM), 1,4- dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) mixtures of these solvents. The synthesis of the peptides in the polymeric support it can be carried out in a suitable inert organic solvent in which the amino acids obtained and the initial materials used are soluble. Particularly useful solvents are, for example, DMS, DCM, NMP, acetonitrile, DMSO and mixtures thereof, due to their swelling properties of the resin. After synthesis, the peptide is separated (commonly known as dissociation) from the polymeric support. The conditions under which this dissociation is performed are well known in the art of peptide synthesis depends in part on the type of resin that is used. The dissociation reactions commonly used are catalyzed by acid or palladium, the acid-catalysed cleavage being carried out in, for example, anhydrous acid fluoride, liquid, anhydrous trifluoromethanesulfonic acid, dilute or concentrated trifluoroacetic acid and mixtures of acetic acid / dichloromethane / trifluoroethanol . Palladium catalyzed dissociation can be carried out in THF or THF-DCM mixture in the presence of a weak base such as morpholine. Certain protecting groups also dissociate under these conditions. Partial deprotection of the peptide may also be necessary before certain derivatization reactions. For example, the dialkylated peptides in the N-terminus can to be prepared by coupling the appropriate N, N-dialkylamino acid for the peptide in solution or in the polymeric support or by reductive alkylation of the peptide bound to the resin in DMF / 1% 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 different non-natural amino acids as well as the different non-amino acid moieties described herein can be obtained from commercial sources or synthesized from commercially available materials using methods known in the art. For example, the building blocks of amino acids with portions R 1 and R 2 they can be prepared according to E. Wuenshc, Huben Weyl. Methoden der organischen Chemie vol. XV / 1, p. 306, Thieme Verlag, Stuttgart, (1974) and the literature mentioned in it. The peptides with gamma or delta lactam bridges can be prepared by incorporating the appropriate lactate bridge dipeptide co-units (R. Freidinger, J. Org. Chem. (1982) 104-109) in the peptide chain. Peptides co-dipeptide building blocks containing thiazole-oxazole-, thiazolin- or oxazolin can be prepared by incorporating suitable dipeptide units (P. Jouin et al., Tetrahedron Letters (1992), pp. 2087-2810; P. Wipf et al. , Tetrahedron Letters (1992), pp. 907-910; WR Tully, J. Med '. Chem. (1991), P 2060-2065; U. Schmidt et al., Synthesis (1987), pp 233-236) in the peptide chain. The following procedures are proposed to illustrate the methods useful for the preparation of the compounds of formula I. When applicable, the amino acids are abbreviated using the codes of three known letters. Other meanings used are: Me3Val = N, N dimethylvaline, MeVal = N-methylvaline, TFA = acid trifluoroacetic, Ac = acetic acid, Bu = butyl, Ethyl, Me = methyl, Bzl = benzyl, Nal = 3-naphthylalanine Cha = 3-cyclohexylalanine, Npg = neopentylglycine, Abu = 2-aminobutyryl, Dab = 2,4-diaminobutyryl, iPr = isopropyl.

GENERAL SYNTHESIS PROCEDURES I. The compounds of Formula I of the present invention are synthesized by traditional solution synthesis using standard Z and Boc methodology as described above or by standard methods of solid fas synthesis in an automatic synthesizer model. 431A from supplier APPLIED BIOSYSTEMS. The apparatus used different synthetic cycles for the protective groups of Boc and Fmoc.

In the case of solid phase synthesis, the N, N dialkylpenta- or hexapeptide acids are released from the solid support and are also copied with the C-terminal amines. corresponding in solution. B0P-C1 and PyBro were used as reagents for coupling the amino acid after the N-methylamino acids. The reaction times were increased in correspondence. For the reductive alkylation of the N-terminals, the peptide-resin was deprotected at the N-terminus and then was reacted with a three-fold molar excess of the aldehyde or ketone in DMF / 1% acetic acid with the addition of three equivalents of NaCNBH3. After finishing the reaction time (negative Kaise test) the resin was washed several times with water, isopropanol, DMF and dichloromethane. In solution synthesis, the use of NC amino acids protected with Boc (N-tert-butyloxycarbonyl amino acid-N carboxy-anhydrides), NCA amino acids protected with (N-benzyloxycarbonyl amino acid-N-carboxy anhydrides), or the use of pivaloyl as a condensing agent respectively is more advantageous for coupling the amino acid after the N-methylamino acids. The reductive alkylation of the N-termini can, for example, be carried out by the reaction of peptides or amino acids deprotected at the N-terminus with the corresponding aldehydes or ketone using aCNBH3 or hydrogen, Pd / C. a) Synthetic cycle for the Boc protective group technique: 1. 30% trifluoroacetic acid in DCM 1 x 3 min. 2. 50% trifluoroacetic acid in DCM l x l min. 3. Washing with DCM 4. Diisopropylethylamine 5% in DCM 5 x 1 min . 5% Diisopropylethylamine in NMP 'l x l min 6. Washing with NMP 5 x 1 min 7. Addition of the protected, preactivated amino acid (DCC and 1 equivalent of HOBt in NMP / DCM); Peptide copulation (first part) 1 x 30 min 8. Addition of DMSO to the reaction mixture until it contains 20% DMSO by volume; Peptide copulation (second part) 1 x 16 min 9. Addition of 3.8 equivalents of diisopropylethylamine to the reaction mixture; Peptide copulation (third part) 1 x 7 min . Washing with DCM 3 x 1 min 11. If the conversion is incomplete, Repetition of the coupling (again up to 6) 12. Acetic anhydride at 10%, Diisopropylethylamine at 5% in DCM 1 x 2 min 13. 10% acetic anhydride in DCM 1 x 4 min 14. Washing with DCM 4 x 1 min 15. Return to 1.

B0P-C1 and PyBrop were used as reagents for the coupling of the amino acids after the N-methylamino acids. The reaction times were increased in correspondence. In the synthesis and solution, the use of NCA amino acids protected with BO (N-tert-butyloxy-amino acid-N-carboxy-anhydrides) Z-protected NCA amino acids respectively is advantageous for this type of coupling. b) Synthetic cycle for the protectant group technique Fmoc 1. Washing with DMF 1 x 2 min. 2. Piperidine 20% in DMF 1 x 4 min. 3. Piperidine 20% in DMF 1 x 16 min 4. Washing with DMF 5 x 1 min 5. Addition of the protected amino acid, preactivated (activation by 1 equivalent of TBTU and 5 equivalents of DIPEA in DMF); Peptide copulation 1 x 61 min 6. Washing with DFM 3 x 1 min 7. IF the conversion is incomplete, Repetition of the coupling (return to 5) 10% acetic anhydride in DMF 1 x 8 min Wash with DMF 3 x 1 min . Return to 2.

BOP-C1 and PyBrop were used as reagents for coupling in the amino acid after the N-methylamino acids. The reaction times increase correspondingly. 11. N-terminal Reductive Alkylation The peptide-resin prepared in the previous Ib was deprotected at the N-terminus (steps 2-4 in Ib or 1- in) and then reacted with a triple-mole excess of aldehyde or ketone in DMF / 1% 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 chlorine ethane.

III. Treatment of the peptide-resins obtained as in the II. The peptide-resin was dried under reduced pressure and. transferred to a reaction vessel of a TEFLON HF apparatus (supplied with PENINSULA). The addition of a scrubber, for example, anisole (1 ml / g of resin), and in the case of peptides containing tryptophan from a thio or eliminating the indole formyl group, for example, ethane dithiol (0.5 ml / g resin) was followed by condensation in acid fluoride (10 ml / g resin) with cooling with liquid N2. The mixture was allowed to warm to 0 ° C and stirred at this temperature for 45 minutes, the acid fluoride was then distilled under reduced pressure, and the residue was washed with ethyl acetate to remove the remaining scavenger. The peptide was extracted with 30% acetic acid and filtered, and the filtrate was lyophilized.

IV. Treatment of the peptide-resins obtained as in Ib and II The peptide-resin was dried under reduced pressure and then subjected to one of the following dissociation procedures, depending on the composition of the amino acid (Wade, Tregear, Howard Florey Fmoc Workshop Manual, Melbourne 1985).

Conditions of dissociation: TFA Debugger Reaction time 1. 95% 5% water 1.5 h 2. 95% 5% ethanediol / anisole (1: 3) 1.5 h The suspension of the peptide-resin in the appropriate TF mixture was stirred at room temperature during established time and then the resin was filtered and washed with TFA and DCM. The filtrate and washings were concentrated, and the peptide was precipitated by the addition of diethyl ether. After cooling in an ice bath, the precipitate was filtered, taken up in 30% acetic acid and lyophilized.

V. When an O-chlorotityl-resin (supplied with 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 one hour. The resin is then filtered with suction and perfectly washed with the dissociation 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.

SAW. Purification and characterization of the peptides. The purification was carried out by gel chromatography (SEPHADEX G-10, G-15 / HOAc at 10%, SEPHADEX LH20 / MeOH) medium pressure chromatography (stationary phase: HD-SIL C-18, 20-45 microns, 100 angstrom, mobile phase: gradient with A = 0.1% TFA / MeOH, B = 0.1% TFA / water) or preparative HPLC (stationary phase: water, Delta-Pak C-18, 15 mieras, 100 angstrom; mobile phase: gradient with A = 0.1% TFA / MeOH, B = 0.1% 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 in gradient, buffered with 0.1% TFA, 40 ° C). The characterization was by amino acid analysis and fast atomic bombardment mass spectroscopy.

SPECIFIC SYNTHETIC PROCEDURE 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-methylamino acid was coupled with PyBrop as a coupling reagent. After the iterative synthetic cycles were completed, the peptide-resin was subjected to N-terminal deprotection (steps 2-4 in Ib), and furthermore, it reacted with aqueous formaldehyde solution as II and then dried under reduced pressure. The resulting resin was subjected to dissociation with TFA 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 by methodology in traditional solution phase. 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-Orne 66. 25 g (250 mmol) of Z-MeVal-OH were dissolved in 250 ml of anhydrous dichloromethane. After the 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) of pivaloyl chloride were added. After stirring for 2.5 hours, 41.89 g (250 mmol) of H-Pro-OMe-HCl in 250 ml of dichloromethane, neutralized with 36. 41 ml (262.5 mmol) of triethylamine at 0 ° C were added to the reaction mixture. Stirring was continued for 2 hours at -25 ° C and overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed thoroughly with saturated aqueous solution of aHC? 3 (3X), water (IX), 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 the product were obtained.

H-MeVal-Pro-OMe 48. 9 g (130 mmol) of Z-MeVal-Pro-OMe were dissolved in 490 ml of methanol. After the addition of 10.9 ml (130 mmol) of concentrated hydrochloric acid and 2.43 g of 10% palladium / carbon, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 36.43 g of product.

Z-Val-MeVal-Pro-OMe 18. 1 g (65 mmol) of H-MeVal-Pro-OMe, 21.6 g (78 mmol) of Z-Val-N-carboxyanhydride and 22.8 ml (130 mmol) of Diisopropylethylamine were stirred in 110 ml DMF at 40 ° C for two days. After evaporation of the DMF, the dichloromethane was added and the organic phase was washed with saturated aqueous solution of NaHCO3 (3X), water (IX), 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 the addition of 1.15 g of 10% palladium / carbon, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of product. e) Z-Val-Val-MeVal-Pro-OMe . 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 the addition of 8.16 mmol (73.2 mmol) of N-methylmorpholine, 2.77 g (20.3 mmol) of HOBt and 11.74 g (61 mmol) of EDCI, the reaction mixture was stirred overnight Room temperature, diluted with dichloromethane and thoroughly washed with saturated aqueous solution of NaHCO3 (3X), water - (IX), citric acid to 5fc (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 1N solution of LiOH were added and the mixture was stirred overnight at room temperature. After the addition of 500 ml of water, the aqueous phase was washed three times with methyl 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) of N-methylmorpholine, 1.97 g (15 mmol) of HOBt and 8.33 g (43.3 mmol) of EDCI were added and the reaction mixture was stirred overnight at room temperature. The solvents were evaporated, the residue dissolved in 640 ml of dichloromethane and washed thoroughly with saturated aqueous NaH03 solution (4X), 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 33.04 g of the product. The crude product was subjected to chromatography on silica gel with 20% MeOH / hexane. 18.32 g of the desired product were obtained.

N, N-dimethyl-Val-Val-MeVal-Pro-Pro-Val-Phe-NH2 18. 32 g of Z-Val-Val-MeVal-Pro-Pro-Val-Phe-NH2 were dissolved in 80 ml of methanol. 0.4 g of 10% palladium / carbon were added under a nitrogen atmosphere and the hydrogenated reaction mixture at room temperature for 4 hours. After the addition of 6.22 ml (81.24 mmol) of a 37% aqueous solution of formaldehyde, the hydrogenation was continued for 5 hours. Filtration and evaporation of the solvent gave rise to 15.6 g of the crude product. Greater 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 the purified product as a white powder. The compound was characterized by rapid atom bombardment mass spectrometry ([m + h] = 797).

EXAMPLE 2A: N, N-dimethyl-Val-Val-NMe-Val-Pro-. { 1- [thiazole- (2) -yl] -2-phenyl} -ethylamide 4.11 g of Fmoc-Pro-p-alkoxybenzyl alcohol-resin (0.73 mmol / g substitution), corresponding to a batch size of 3 mmol, were reacted as in Ib with 4.5 mmol each of: Fmoc-N -MeVa1-OH Fmoc-Val-OH Fmoc-Val-OH The amino acid after the N-methylamino acid in this case was reacted with double coupling using PyBrop or BOP-C1 with increase in the reaction times. After the synthesis was complete. The peptide-resin was subjected to deprotection at the N-terminus (steps 2-4 in Ib), and furthermore it reacted with aqueous formaldehyde solution as in II and then dried under reduced pressure. The resin obtained from this manner was subjected to dissociation with TFA as in IV. The crude product (750 mg) was used directly for the next coupling. 100 mg of this compound reacted with 45 mg of (S) -2- [(1-amino-2-phenylethyl] thiazole and 230 mg of PyBrop with the addition of 192 microliters of DIPEA in DMF at room temperature for 2 days. The reaction mixture was purified by gel chromatography (SEPHADEX LH-20, methanol) and the product fractions were combined, 83 mg of the product were obtained.

EXAMPLE IB Me2Val-Val-MeVal-Pro-Pro-NHCH- (CH3) 2 a) Z-MeVal-Pro-Ome 66.25 g (250 mmol) of Z-MeVal-OH were dissolved in 250 ml of anhydrous dichloromethane. After the 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) of pivaloyl chloride were added. After stirring for 2.5 hours, 41.89 g (250 mmol) of H-Pro-OMe x HCl in 250 ml of dichloromethane, neutralized with 36.41 ml (262.5 mmol) of triethylamine at 0 ° C, were added to the reaction mixture. Stirring was continued for 2 hours at -25 ° C and overnight at room temperature. The reaction mixture was diluted with dichloromethane and thoroughly washed with solution saturated aqueous NaHCO3 (3X), water (IX), 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 the product were obtained. b) H-MeVal-Pro-OMe 48. 9 g (130 mmol) of Z-MeVal-Pro-OMe were dissolved in 490 ml of methanol. After the addition of 10.9 ml (130 mmol) of concentrated hydrochloric acid and 2.43 g of 10% palladium / carbon, 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) of Z-Val-N-carboxyanhydride and 22.8 ml (130 mmol) of diisopropylethylamine were stirred in 110 ml of DMF at 40 ° C. 2 days. After evaporation of the DMF, dichloromethane was added and the organic phase was washed with saturated aqueous solution of NaHCO3 (3X), water (IX), 5% citric acid (3X) and saturated NaCl solution. The 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 the addition of 1.15 g of 10% palladium / carbon, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of product. e) Z-Val-Val-MeVal-Pro-OMe . 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 the addition of 8.16 ml (73.2 mmol) of N-methylmorpholine, 2.77 g (20.3 mmol) of HOBt and 11.74 g (61 mmol) of EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and washed thoroughly with saturated aqueous solution of NaHCO3 (3X), water (IX), 5% citric acid (3X) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to produce 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 1N solution of LiOH was added and the mixture was stirred overnight at room temperature. After the addition of 500 ml of 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) of Z-Val-Val-MeVal-Pro-OH and 0.664 g (3.35 mmol) of H-Pro-NHCH (CH3) 2 were dissolved in 34 ml of anhydrous dichloromethane. After cooling to 0 ° C, 1.35 ml (12.1 mmol) of N-methylmorpholine, 0.114 g (0.84 mmol) of HOBt and 0.645 g (3.35 mmol) of EDCI were added and the reaction mixture stirred overnight at room temperature . 80 ml of dichloromethane were added and the organic phase washed Perfectly with saturated aqueous solution of NaHCO3 (3X), water (lx), 5% citric acid (3X) and saturated NaCl solution (Ix). 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.

Me2Val-Val-MeVal-Pro-Pro-NHCH (CH3) 2 1. 96 g of Z-Val-Val-MeVal-Pro-Pro-NHCH (CH3) 2 were dissolved in 11 ml of methanol. 0.54 g of 10% Pd / C were added under a nitrogen atmosphere and the reaction mixture was hydrogenated at room temperature for 4 hours. After the addition of 0.86 ml (11.24 mmol) of a 37% formaldehyde aqueous solution and 0.281 g of 10% Pd / C, the hydrogenation continued for 5 hours. Filtration and evaporation of the solvent gave rise to 2.77 g of crude product. Another purification was achieved by dissolving the peptide in water, adjusting the pH to 2 and extracting the aqueous phase 3 times with ethyl acetate. The aqueous phase was then adjusted to pH 8-9 and extracted 4 times with dichloromethane. The organic phase was dried over sodium sulfate, filtered and evaporated to yield 1.37 g of the purified product as a white foam. The compound was more purified using liquid chromatography at medium pressure (10-50% A in 10 minutes, 50-90% A in 320 minutes). The fractions containing the product were combined, lyophilized, redissolved in water and the pH adjusted to 9, with 1N LiOH. After extraction with dichloromethane, the organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The lyophilization gave rise to 500 mg of the pure product that was characterized by mass spectrometry with rapid atomic bombardment ([M + H] + = 593).

EXAMPLE 2B: Me2Val-Val-MeVal-Pro-Pro-NHC- (CH3) 3 a) Z-Val-Val-MeVal-Pro-Pro-NHC (CH3) 3 2 g (3.35 mmol) of Z-Val-Val-MeVal-Pro-OH and 0.692 g (3.35 mmol) of H-Pro-NHC (CH3) 3 were dissolved in 34 ml of anhydrous dichloromethane. After cooling to 0 ° C, 1.35 ml (12.1 mmol) of N-methylmorpholine, 0.114 g (0.84 mmol) of HOBt and 0.645 g (3.35 mmol) of EDCI were added and the reaction mixture was stirred overnight at room temperature. ambient. 80 ml of dichloromethane were added and the organic phase was washed thoroughly with saturated aqueous solution of NaHC 3 (3X), water (IX), % citric acid (3X) and saturated NaCl solution (lx). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to produce 1.8 g of the product which was used in the next reaction without further purification.

Me2Val-Val-MeVal-Pro-Pro-NHC (CH3) 3 1. 98 g of Z-Val-Val-MeVal-Pro-Pro-NHC (CH3) 3 were dissolved in 10 ml of methanol. 0.045 g of 10% Pd / C were added under a nitrogen atmosphere and the reaction mixture was hydrogenated at room temperature for 4 hours. After the addition of 0.86 ml (11.24 mmol) of a 37% formaldehyde aqueous solution and 0.252 g of 10% Pd / C, the hydrogenation continued for 5 hours. 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 minutes; 50-90% A in 320 minutes). The fractions containing the product were combined, lyophilized, redissolved in water and adjusted to pH 9 with 1N LiOH. After extraction with dichloromethane, the organic phase was dried over sodium sulphate and evaporated to dryness. The lyophilization gave rise to 547 mg of the pure product that was characterized by mass spectrometry with rapid atomic bombardment ([M + H] = 607).

EVALUATION OF THE BIOLOGICAL ACTIVITY - - - - In Vivo Methodology The dolastatin-15 derivative of Formula I, designated compound ii in Figure 1, was tested using a normal animal model for rheumatoid arthritis known as collagen-induced arthritis (CIA) (see, for example, Banerjee, and coi., The Journal of Immonology 142: 2237-2243) (1989)). The CIA is a useful animal model of rheumatoid arthritis that serves as an in vivo system for the exploration of etiologies of inflammatory synovitis and the investigation of potentially novel therapeutic interventions. Other suitable models can also be used in this invention. For example, arthritis induced by adjuvant in rats (see, for example, Ward et al., Arthritis Rheum. (1962) 5: 557-564). Collagen-induced arthritis in mice is induced by intradermal injection of type II chicken collagen emulsified in complete Freund's adjuvant, with onset of symptoms occurring normally around day 26 after immunization. In general, any regime of dosage that appears to provide an acceptable level of suppression of rheumatoid arthritis. Any acceptable method of administering medication can be determined * using techniques well known to those skilled in the art. In addition, the dolastatin-15 derivatives of Formula I can be administered in combination with other medicaments known to be useful in the treatment of rheumatoid arthritis, as described at the outset.

EXAMPLE 3: INDUCED ARTHRITIS. BY COLLAGEN - PROPHYLACTIC MODEL Mice DBA-1, which is a strain of mice susceptible to collagen-induced arthritis, were used in all experiments (see, for example, The FASEB, 2: 2950 (1988)). The mice were immunized intradermally on day 0 with 100 μg of type II chicken collagen in complete Freund's adjuvant. Three treatment groups were evaluated and consisted of animals treated with saline (control), animals treated with dexamethasone (normal treatment), and animals treated with compound ii. Treatment was started for all groups on day 26 after immunization before the onset of symptoms and ended on day 35 after immunization. Dexamethasone was injected intraperitoneally in a dose of 5 mg / kg / day, compound ii was administered orally, by means of a probe, at a dose of 50 mg / kg / day using saline as a vehicle and oral saline was administered orally once a day as a control.

ARGENTINE RECORD AVERAGE: The severity of the arthritis was recorded by daily observation of each leg. An integer scale of 0 to 5 was used to quantify the level of erythema, swelling, deformity and stiffness of the joints in each leg with 0 = normal and 5 = maximum. The sum of the 4 legs represents the average arthritic record, with a record of 20 being the maximum. The results are plotted in Figure 2. The results show that none of the animals treated with compound ii had signs of rheumatoid arthritis until six days after finishing treatment. However, animals treated with dexamethasone showed signs of rheumatoid arthritis immediately after finishing treatment.

EXAMPLE 4: COLLAGEN-INDUCED ARTHRITIS MODEL OF TREATMENT DBA-1 mice were used in all the experiments. The mice were immunized intradermally in the day 0 with 100 μg of type II chicken collagen. The onset of the symptom occurred approximately on day 35 after immunization. Three treatment groups were evaluated and consisted of animals treated with vehicle (control), animals treated with dexamethasone (normal treatment) and animals treated with compound ii. Treatment began for all groups on day 48 after immunization, when the arthritic record of all animals reached 3-4. The average arthritic records of mice in the three groups were equivalent at the start of treatment. The animals were treated for 21 days.

Dexamethasone was injected intraperitoneally in a dose of 5 mg / kg / day, compound II was orally administered orally in a dose of 50 mg / kg / day using saline as a vehicle and the vehicle was only administered by tube (0.25 mi) as control.

ARGENTINE RECORD AVERAGE: The degree of arthritis was recorded daily recording each leg. An integer scale of 0-5 was used to quantify the level of erythema, swelling, deformity and stiffness of the joints with 0 = normal and 5 = maximum. The sum of the four legs represents the average arthritic record with a record of 20 being the maximum. The results are plotted in Figure 3. The results show that the animals treated with * compound ii showed a significant decrease in the average arthritic record compared to the control (p-value less than 0.01-0.05, determined by the Mann test). -Whitney) HISTOPATHOLOGICAL RESULTS: Five mice from each treatment group underwent necropsy on day 71 after immunization and histopathology was performed on the joints of all four legs of each mouse. Synovial inflammation and damage to the cartilage of the affected joints were graded on a scale of 0-3. The results are shown in Figure 4. Treatment with compound II and dexamethasone significantly suppressed synovitis and cartilage involvement compared to animals treated with vehicle.

EXAMPLE 5: PROPHYLACTIC MODEL IN RATS OF CODYUVANTE INDUCED ARTHRITIS Male Lewis rats were immunized intradermally on day 0 with 1.2 mg of M. tuberculosis killed by heating in incomplete Freund's adjuvant. The Treatment groups (10 animals / group) consisted of animals treated with saline (control), animals treated with methotrexate (normal treatment) 1 mg / kg / day and three 'groups treated with compound II at 10, 5 and 2.5 mg / kg / day, respectively. The treatment started on the day of immunization (day 0) and was continued once every two days for a total of 12 administrations. All treatments were administered orally by gavage. The animals were evaluated on days 12, 16, 19 and 23 determining the average arthritic records in a manner similar to examples 3 and 4. On day 23 the experiment was completed and the results showed that compound ii prevented the onset of signs arthritic (legs and inflamed limbs) in a dose-dependent manner. That is, none of the animals treated with 10 mg / kg of compound ii showed signs of disease (0-10), while 2-10 animals and 7-10 animals showed signs of disease at doses 5 mg and 2.5 mg, respectively. In the control group, 7-10 animals showed signs of disease. Methotrexate prevented arthritis as expected. 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 5. 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 Xa 21. Xaa Val Xab Pro Xav 22. Xaa Val Xab Pro Xa 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 . 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 Xb 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 Pro Xay Xab 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 Xcg 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. Xc 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 lie 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 Xdp 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 lie 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 lie Xab Pro Xal 104. Xdd Val Xab Pro Xal 105. Xde Val Xab Pro Xal 106 Xc Xb Pro Val Xab 107 Xcw Val Xab Pro Xal 108. Xc Xab Pro Xal Xal 109. Xcw Val Xab Pro Xav 110 Xc Xb Xb Pro Xav Val Xab Xb Pro Xaw Xcx 112 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 Xa 122. Xab Val Xab Pro Xau 123. Xab Val Xab Pro Xbf 124. xab 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 Xe 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 10 152. Xaa Val Xab Pro Pro Val Phe 153. Xaa Val Xab Pro Xet Val Phe NH, 154. Xaa Val Xer Pro Pro Val Phe NH, 155. Xaa Val Xbc Pro Pro Val Phe NH, 156. Xaa He Xab Pro Pro Val Phe NH2 157. Xaa Leu Xab Pro Pro Val Phe NH, 158. Xde Val Xab Pro Pro Val Phe NH, 159. Xdd Val Xab Pro Pro Val Phe NH; 160. Xes Val Xab Pro Pro Val Phe NH; 161. Xeu Val Xab Pro Pro Val Phe NH; 162. Xaa Val ab Pro Pro Phe Phe NH, 163. Xaa Val Xab Pro Pro Val NHr 163. Xaa Val Xab Pro Xev 165. Xaa Val Xab Pro Pro NH; 166. Xaa Val Xab Pro Pro 20 157. Xaa Val Xab Pro Xew 168. Xaa Val Xab Xex 169. Xdd Val Xab Pro Pro NH, 170. Xaa Xdf Xab Pro Pro NH, 171. Xaa Val Xab Pro Xey 172. Xaa Val Xab Pro Xez 173. Xfa Val Xab Pro Pro Val Phe H; 174. Xaa Val Xab Pro Pro Xfb 175. Xaa Val Xab Pro Xfc 176. Xaa Val Xab Pro Xfd 177. Xaa Val Xab Pro Xfe 178. Xaa Val Xab Pro Xff 179. Xaa Val Xab Pro Xfg 180. Xaa Val Xab Pro Xfh 181. Xaa Val Xab Pro Xfi 182. Xaa Val Xab Pro Xfj 183. Xaa Val Xdl Pro Pro NH, 184. Xaa Val Xfk Pro Pro NH, 185. Xaa Val Xfl Pro Xfh 186. Xaa Val Xfk Pro Xfh 187. Xcx Val Xab Pro Xfh 188. Xaa Val Xab Pro Pro Xdf Phe NH, 189. Xaa .Val Xab Pro Pro Leu Phe NH, 190. Xaa Val Xab Pro Pro lie Phe NH, The examples for the mass spectroscopy characterization of the novel synthesized compounds are listed as follows: Example MS by bombardment Fast atomic analysis 3. 565 4. 579 5 593 6 607 7 621 8 635 11. 607 12. 607 Example MS by bombing Fast atomic analysis 13. 621 14. 649 15. 635 16. 635 17. 635 18. 635 19. 621 20. 621 21. 635 22. 635 25. 633 26. 347 27. 661 31. 623 32. 671 33. 667 31. 681 35 655 36. 655 37. 669 38. 621 39. 635 41. 649 Example MS by bombing Fast atomic analysis 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 Example MS by bombing Fast atomic analysis 70. 591 71. 607 72. 621 74. 706 75. 579 76. 579 77. 579 78. 607 79. 607 80. 607 81. 60 82. 637 83. 692 84. 706 85. 706 86. 706 87. 607 90 635 92. 659 93. • 617 94. 636 95. 678 128. 671 Example MS by bombing Fast atomic analysis 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. 887 162. 845 163. 649 164. 737 165. 550 166 551 167. 731 168. 550 169. 566 170. 566 171. 635 Example MS by bombardment Fast atomic analysis 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 the formula I have the following meanings: Xaa: N, N-dimethylvaline Xab: N-methylvaline CH3 N-Methyl - isoleucine Xbc: 3 H3C Proline adaman tyl (1) arpi? E Xcc: OH Xcn: XCO: Xcw: N-methyl-N-ethyl-valine N, N-diethylvaline Xcx: c? 3 Xda N-methyl-2-aminobutyroyl Xdb 2-aminobutyroyl Xdc N, N-dimethyl-2-aminobutyroyl Xdd N, N-dimethyl-2-tert.butylglycine Xof N, N-dimethyl-isoleucine Xdf 2-tert.butylglycine CH3 CH3 Xdl: N-methyl-2-tert.butylglycine CH3 CH3 ; Xer: N-methyleucine Xes: N-acetyl-N-methyl aline Xet: pipecolynic acid Xeu: N, N-dibutylvaline twenty Xfa: N, N-dipropylvaline Xkf: N-ethylvaline Xfl: N-methyl-3-tert-butylalanine EQUIVALENTS Those skilled in the art will recognize or may investigate using no more than usual experimentation many of the equivalents to the specific embodiments of the invention described herein. These equivalents are proposed to be included in the scope of the following clauses.

LIST OF SEQUENCES , 1) GENERAL INFORMATION (i) APPLICANT / INVENTOR: (A) NAME: BASF AKTIENGESELLSCHAFT (B) STREET: Cari Bosch Strasse 38 (C) CITY: D-67056 Ludwigshafen (D) STATE / PROVINCE: (E) COUNTRY: GERMANY (F) POSTAL CODE / ZIP: (i) APPLICANT / INVENTOR: (A) NAME: Teresa Barlozzari (B) STREET: 24 South Woodside Avenue (C) CITY: Wellesley (D) STATE / PROVINCE: Massachusetts (E) COUNTRY: EU (F) POSTAL CODE / ZIP: 02181 (i) APPLICANT / INVENTOR: (A) NAME: Subhas is Banerjee (B) STREET: 35 Hapgood Way (C) CITY: Shrewsbury (D) STATE / PROVINCE: Massachusetts (E) COUNTRY: EU (F) POSTAL CODE / ZIP: 01545 (i) APPLICANT / INVENTOR: (A) NAME: Andreas Haupt (B) STREET: 33 Catherine Drive (C) CITY: Northborough (D) STATE / PROVINCE: Massachusetts (E) COUNTRY: EU (F) ZIP / ZIP CODE: 01532 (ii) TITLE OF THE INVENTION: METHODS AND COMPOSITIONS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS (iii) NUMBER OF SEQUENCES: 17 (iv) POSTAL ADDRESS: (A) RECIPIENT: Hamilton, Brook, Smith Reynolds, PC (B) STREET: Two Militia Drive (C) CITY: Lexington (D) STATE: MA (E) COUNTRY: EU (F) POSTAL CODE : 02421 FORM OF LEGIBLE COMPUTATION: (A) TYPE OF MEDIUM: flexible disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) SOFTWARE: Patentln Relay # 1.0, version # 1.30 (vi) DATA OF THE APPLICATION- CURRENT • (A) APPLICATION NUMBER: US 08 / 944,479 (B) DATE OF: 06-OCT-1997 (C) CLASSIFICATION: (viii) ATTORNEY / ATTORNEY INFORMATION (NAME): Granaban, Patricia (B) REGISTRATION NUMBER: 32,227 (C) REFERENCE / FILE NUMBER: BBC-045A PCT (ix) TELECOMMUNICATIONS INFORMATION (A) TELEPHONE: 781-861-6240 (B) TELEFAX: 781-861-9540 (2) INFORMATION OF SEQ ID NO: 1: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 1: Xaa Val Xaa Pro Xaa 1 5 (2) INFORMATION OF SEQ ID NO: 2: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 2 Xaa Xaa Xaa Pro Xaa 1 5 [2) INFORMATION OF SEQ ID NO: 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3: Xaa Val Xaa Pro Pro Xaa 1 5 (2) INFORMATION OF SEQ ID NO: 4: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 4 Xaa Xaa Xaa Pro Xaa 1 5 (2) INFORMATION OF SEQ ID NO: 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 5: Xaa lie Xaa Pro Xaa 1 5 (2) INFORMATION OF SEQ ID NO: 6: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLT CULA: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 6: Xaa Val Xaa Pro Pro Val Phe 1 5 (2) INFORMATION OF SEQ ID NO: 7: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 7; Xaa Val Xaa Pro Xaa Val Phe 1 5 (2) INFORMATION OF SEQ ID NO: 8: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: Xaa lie Xaa Pro Pro Val Phe '1 5 (2) INFORMATION OF SEQ ID NO: 9: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 9: Xaa Leu Xaa Pro Pro Val * Phe 1 5 (2) INFORMATION OF SEQ ID NO: 10: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 10: Xaa Val Xaa Pro Pro Phe Phe 1 5 [2) INFORMATION OF SEQ ID NO: 11: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids' (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 11 Xaa Val Xaa Pro Pro Val 1 5 (2) INFORMATION OF SEQ ID NO: 12: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 12 Xaa Val Xaa Pro Pro 1 5 (2) INFORMATION OF SEQ ID NO: 13: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 13; Xaa Val Xaa Xaa 1 (2) INFORMATION OF SEQ ID NO: 14: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 14: Xaa Xaa Xaa Pro Pro 1 5 (2) INFORMATION OF SEQ ID NO: 15: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 15: Xaa Val Xaa Pro Pro Xaa Phe 1 5 (2) INFORMATION OF SEQ ID NO: 16: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 16: Xaa Val Xaa Pro Pro Leu Phe 1 5 (2) INFORMATION OF SEQ ID NO: 17: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) HEBRA: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 17 Xaa Val Xaa Pro Pro lie Phe 1 5

Claims (5)

R E I V I N D I C A C I O N S The use of a. composed of the formula I R1 R2 N-CHX-CO-A-B-D- (E) s- (F) t- (G) u-K (I) wherein R1 is alkyl, cycloalkyl, alkylsulfonyl, fluoroalkyl or aminosulfonyl; R 'is hydrogen, alkyl, fluoroalkyl, or cycloalkyl; 1 2 R -N-R together can be a pyrrolidino or piperidino residue; A is a valyl residue, iosoleucyl, 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; B is a N-alkyl-valyl residue, -norvalyl, -leucyl, -isoleucyl, -2-tert-butylglycyl; -3- tert-butylalanyl, -2-ethylglycyl, -2-cyclopropylglycyl, -2-cyclopentylglycyl, norleucyl or -2-cyclohexylglycyl; D is a prolyl residue, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidin-2-carbonyl, 3,3-dimethylprolyl, 4-difluoropropyl, oxazolidin-4-carbonyl or thiazolidin-4 - carbonyl; E is a prolyl residue, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidin-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidin-4-carbonyl or fiazolidin-4-carbonyl; F and G are independently selected from the group consisting of the prolyl, homoprolyl, hydroxyprolyl, thiazolidin-4-carbonyl, 1-aminopentyl-1-carbonyl, valyl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl residues , N-methylphenylalanyl, histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl, norlylenyl, norvalyl, neopentylglycyl, tritofanyl, glycyl, 2,2-dimethylglycyl-alanyl, alanyl, β-alanyl and 3-naphthylalanyl; 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 amino or substituted moiety; and salts thereof with physiologically tolerated acids, for the manufacture of a medicament for the treatment of rheumatoid arthritis in a mammal. The use according to claim 1, wherein the mammal is human. The use according to claim 2, wherein for the compound of Formula T, K is a substituted amino moiety having the formula R5-N-R6, wherein: R is hydrogen, or hydroxy, or C alco alkoxy; C7 or benzyloxy, or phenyloxy or straight or branched alkyl of C? ~ C (which may be substituted by one or more of fluorine atoms), or linear or branched hydroxyalkyl of C1-C12, or C3-C10 cycloalkyl, or benzyl (which may be substituted by up to 3 substituents which can independently be CF3, nitro, C1-C7 alkylsulfonyl, Cj-C4 alkoxy, phenoxy, benzoxy, halogen, CJ.-C4 alkyl, cyano, hydroxy, N (CH3 ) 2, COOMe, COOEt, COOiPr or COONH2); R is hydrogen, linear or branched alkyl of C? -Cj.2 (which may be substituted by one or more fluorine atoms), or linear or branched hydroxylalkyl of C? ~ C? 2 or C3-C10 cycloalkyl or - (CH2) vzc doai-quilo of C3-C7 (v = 0, 1, 2 or 3), or norefedrilo, or norseudoefedrilo, or quinolilo or pirazilo or -CH2- benzimidazolilo or (1) -adamantilo, or (2) adamantyl, -CH2-adamantyl, or alpha-methyl-benzyl, or alpha-dimethylbenzyl, or - (CH2) v_phenyl (v = 0, 1, 2 or 3; Which may be substituted by up to 2 substituents which can independently be CF 3, nitro, C 1 -C 7 alkylsulfonyl, C 1 -C 4 alkoxy, phenoxy, benzoxy, halogen, C 1 -C alkyl which can form a cyclic system, cyano, hydroxy, 15 N (CH3) 2, COOMe, COOEt, COOiPr, or COONH2), or ~ (CH2) m-naphthyl (m = 0 or 1; or -CH2) w-benzhydryl (w = 0, 1 or 2); or biphenyl or picolyl or -benzothiazolyl _? benzisothiazolyl or benzopyrazolyl or benzooxazolyl or - (CH2) m-fluorenyl (m = 0 or 1); or Pyrimidyl or - (CH 2) m-indanyl (m = 0 or 1); or - (CH2CH20)? - CH3 (y = 0, 1, 2, 3, 4 or 5), or - (CH2CH2?) and -CH2CH3 (y = 0, 1, 2, 3, 4 or 5), or NH-C6-H5 (which may be substituted by up to two substituents which can independently be 25 CF3, nitro, C1-C7 alkylsulfonyl, C ^ alkoxy- C4, halogen, C1-C4 alkyl which can form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr or COONH2), or -NCH3-C5H5 or -NH-CH2-C6H5 or - NCH3-CH2-C6H5 [sic ] or 5-membered heteroaryl (which may be substituted by up to two substituents which can independently be CF3, nitro, thiomethyl, thioethyl, C3-C6 cycloalkyl, -CH2-COOEt, C3-C4 alkylene group forming a cyclic 7-cyclic system the heterocycle), or phenyl; or -CHR-heteroaryl 5-membered (which may be substituted by up to two substituents which may independently be CF 3, nitro, cyano, halogen, COOMe, COOEt, COOiPr, CONH2, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl, benzyl, naphthyl or C 1 -C 7 alkylsulfonyl [R = hydrogen, linear or branched C 3 -C 5 alkyl, benzyl; or R 7 and R 5 together form a group - (CH 2) 3- or - (2) 4). The use according to 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 valery, 2-ethylglycyl, isoleucyl or 2-tert-butylglycol; B is N-methylvalyl, 2-ethylglycyl, isoleucyl [sic] or 2-tert-butylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl or 3,4-dehydroprolyl or; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl hydroxyprolyl or; and K is a substituted amino moiety having the formula R-N-R, wherein R is hydrogen or C1-C alkoxy and R is a straight or branched chain alkyl group of C? -C12, selected from the group of monovalent radicals consisting of: -C (CH3) 3, also known as tert-butyl; -C-CH2 CH3, also known as 1,1-dimethylpropyl; I (CH 3) 2 -C- (CH 2 CH 3) 2 also known as 1-methyl-1-ethylpropyl; (CH 3) 3 -CH-C (CH 3) 3 also known as coo (S) - or (R) -l-] tetyl-2,2-γ-γ-ethyl-propyl; I CH3 -CH-CH (CH3) 2, also known as (S) - or (R) -l-ethyl-2-methylpropyl; I C2H5-CH-CH (CH3) 2 r also known as l-isopropyl-2-methylpropyl; or
1. I -CH- (CH 3) 2 -C (CH 3) 2 ~ CH (CH 3) 2, also known as 1,1-dimethyl-2-methylpropyl; -CH (CH3) 2, also known as isopropyl; -CH (CH) CH2CH3, also known as sec-butyl [(S) or (R)]; or -CH- (CH 3) CH (CH 3) 2 also known as 1,2-dimethylpropyl. The use according to claim 4, wherein the monovalent radical is -C (CH 3) 3, also known as tert-butyl. The use according to claim 3, wherein for the compound of the Formula, R and R are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valery, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 2-ethylglycyl, 1-isoleucyl or 2-tert-butylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3-dehydroprolyl or hydroxy-prolyl; and K is a substituted amino moiety having the formula R5-NR, wherein R is hydrogen or Ci-C4 alkoxy and R is selected from the group of monovalent radicals consisting of (CH2) v-phenyl (where v = 1) a, a-dimethylbenzyl. The use according to 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 valery, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 2-ethylglycyl, 1-isoleucyl or 2-tert-butylglycyl; 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 hydroxy-prolyl; and K is a substituted amino moiety having the formula R -N-R, wherein R is hydrogen or C? -C alkoxy and R is a linear or branched hydroxyalkyl of C? -C? 2. The use according to claim 7, wherein R6 is 3-hydroxy-1,1-dimethylpropyl. The use according to claim 3, wherein for the compound of Formula I, R 1 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 valery, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 2-ethylglycyl, 1-isoleucyl or 2-tert-butylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3-dehydroprolyl or hydroxy-prolyl; and K is a substituted amino moiety having the formula R -NR, wherein R is hydrogen or C1-C4 alkoxy and R is a C3-C10 cycloalkyl selected from the group consisting of: (1) -adamantyl, (2) α-adamantyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1-methylcyclohexyl and [3.3.0] octa-1-yl. The use according to claim 4, 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 valilo; B is N-methylvalyl; D is prolyl; E is prolyl; R5 is hydrogen and R6 is tert-butyl. The use according to 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 valilo; B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen. The use of a pharmaceutical composition containing: a) a therapeutically effective amount of a compound of Formula I: R1 R2 N-CHX-CO-A-B-D- (E) s- (F) (G) -K (I) wherein: R1 is alkyl, cycloalkyl, alkylsulfonyl, fluoroalkyl or aminosulfonyl; R 'is hydrogen, alkyl, fluoroalkyl, or cycloalkyl; ~~ 1 2 R -N-R together can be a pyrrolid or piperidino residue; A is a valyl residue, iosoleucyl, 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; B is a residue N-alkyl-valyl, -norvalyl,-~~ leucyl, -isoleucyl, -2- er-butylglycyl; -3- tert-butylalanyl, -2-ethylglycyl, -2-cyclopropylglycyl, -2-cyclopentylglycyl, norleucyl or -2-cyclohexylglycyl; D is a prolyl residue, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidin-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoropropyl, oxazolidin-4-carbonyl or thiazolidin-4-carbonyl; E is a prolyl residue, homoprolyl, hydroxyprolyl, 3-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidin-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidin-4-carbonyl or thiazolidin-4-carbonyl; F and G are independently selected from the group consisting of the prolyl, homoprolyl, hydroxyprolyl, thiazolidin-4 residues carbonyl, 1-aminopentyl-1-carbonyl, valeryl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl, N-methylphenylalanyl, tetrahydroisoquinolyl-2-histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylaryl, 2-cyclohexylglycyl, norleucyl, norvalyl, neopentyl glycol, tritofanyl [sic], glycyl, 2,2-dimethylglycylalanyl, β-alanyl and 3-naphthylalanyl; 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; and b) a therapeutically effective amount of a second antiarthritic compound selected from the group consisting of: a non-steroidal anti-inflammatory compound, an organic gold derivative, D-penicillamine, 4-aminoquinoline, azathioprine, methotrexate, cyclosporin, an angiogenesis inhibitor , a monoclonal antibody for cells T, a monoclonal antibody to a molecule of adhesion, a monoclonal antibody to a cytokine or growth factor, TNFR-IgG, IL-1 receptor antagonists and ICE inhibitors, for the manufacture of a medicament for the treatment of rheumatoid arthritis in a mammal. _- A process for the manufacture of a therapeutic composition for the treatment of rheumatoid arthritis in a mammal, characterized in use, as an essential constituent of the composition, of a compound of Formula I as defined in claim 1. 14 process according to claim 13, wherein the mammal is human. 15. The invention according to any of claims 1-14 wherein for the compound of Formula I, K is a substituted amino moiety having the formula R5-N-R6, wherein: R is hydrogen, or hydroxy, or C1-C7 alkoxy or benzyloxy, or phenyloxy or linear or branched alkyl of C1-C7 (which may be substituted by one or more of fluorine atoms), or linear or branched hydroxyalkyl of C1-C12, or cycloalkyl of C3- C10, 3_ benzyl (which may be substituted by up to 3 substituents which can independently be CF 3, nitro, C 1 -C 7 alkylsulfonyl, C 1 -C 4 alkoxy, phenoxy, benzoxy, halogen, C 1 -C 4 alkyl, cyano, hydroxy, N (CH 3) 2, COOMe, COOEt, COOiPr or COONH 2); R is hydrogen, straight or branched alkyl of C1-C12 (which may be substituted by one or more fluorine atoms), or linear or branched hydroxylalkyl of C-2 or C3-C10 cycloalkyl or - (CH2) v-cycloalkyl C3-C7 (v = 0, 1, 2 or 3), or norefedril, or N-nordoudophenyl, or quinolyl or pyrazyl or -CH 2 -benzimidazolyl or (1) -adamantyl, or (2) -adamantyl, -CH 2-adamantyl, or alpha-methyl-benzyl, or alpha-dimethylbenzyl, or - (CH 2) v phenyl (v = 0, 1, 2 or 3) which may be substituted by up to 2 Substituents which can independently be CF3, nitro, C1-C7 alkylsulfonyl, Cj-C4 alkoxy, phenoxy, benzoxy, halogen, C1-C4 alkyl which can form a cyclic system, cyano, hydroxy, N (CH3) 2 , COOMe, COOEt, COOiPr, or C00NH2), or ~ (CH2) m-20 naphthyl (m = 0 or 1; or -CH2) w-benzhydryl (w = 0, 1 or 2); or biphenyl or picolyl or benzoisothiazolyl or benzopyrazolyl, benzooxazolyl or - (CH 2) m-fluorenyl (m = 0 or 1); or pyridyl or - (CH 2) m-indanyl (m = 0 or 1); or - 25 (CH2CH20) and -CH3 (y = 0, 1, 2, 3, 5) (CH2CH20) y-CH2CH3 (y = 0, 1, 2, 3, 4 or 5), or NH-C6-H5 (which may be substituted by up to two substituents which can independently be CF3, nitro, C1-C7 alkylsulfonyl , C 1 -C 4 alkoxy, halogen, C 1 -C 4 alkyl which can form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr or C00NH2), or -NCH3-C5H5 or -NH-CH2-C6H5 or -NCH3 -CH2-CgH5 [sic] or 5-membered heteroaryl (which can be substituted by up to two substituents which can independently be CF3, nitro, thiomethyl, thioethyl, C3-C6 cycloalkyl, -CH2- COOEt, C3-C4 alkylene group forming a dicyclic system with the heterocycle), or phenyl; or -CHR-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-C4 alkyl, C1-C4 alkoxy, phenyl , benzyl, naphthyl or C1-C7 alkylsulfonyl [R = hydrogen, linear or branched C1-C5 alkyl, benzyl; or R7 and R5 together form a group - (CH2) 3- or - (CH2) -). The invention according to claim 15, 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 valilo, 2- ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-ethylvalyl, 2-ethylglycyl, isoleucyl [sic] or 2-tert-butylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl or; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl hydroxyprolyl or; and K is a substituted amino moiety having the formula R 5 -N-R 6, wherein R 5 is hydrogen or C1-C4 alkoxy and R is a straight or branched chain alkyl group of C1-C12, selected from the group of monovalent radicals consisting of: -C (CH3) 3, also known as tert-butyl; -C-CH2 CH3, also known as 1,1-dimethylpropyl; I (CH3) 2 -C ~ (CH2 CH3I2 also known as 1-methyl-1-ethylpropyl; (CH3) to -C? -C (CH3) also known as (S) - or (R) -l-? Tethyl -2,2-cimethyl-propyl; I CH 3 -CH-CH (CH 3) 2, also known as (S) - or (R) -l-ethyl-2-methylpropyl; i C2H5-CH-CH (CH3) 2, also known as l-isopropyl-2-methylpropyl; or -C (CH3) 2 ~ CH (CH3) 2, also known as 1_, 1-dimethyl-2-methylpropyl; -CH (CH3) 2, also known as isopropyl; -CH (CH3) CH2CH3, also known as sec-butyl [(S) or (R)]; or -CH- (CH 3) CH (CH 3) 2 also known as 1,2-dimethylpropyl. 17. The invention according to claim 16, wherein the monovalent radical is -C (CH 3) 3, also known as tert-butyl. 18. The invention according to claim 15, wherein for the compound of the Formula, 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 valery, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 2-ethylglycyl, 1-isoleucyl or 2-tert-butylglycyl; 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 hydroxy-prolyl; and K is a substituted amino moiety having the formula R -N-R, wherein R is hydrogen or C1-C4 alkoxy and R is selected from the group of free radicals consisting of (CH2) v-phenyl (wherein = 1) a, a-dimethylbenzyl. 19. The invention according to claim 15, 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 valilo, 2- ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 2-ethylglycyl, 1-isoleucyl or 2-tert-butylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3-dehydroprolyl or hydroxy-prolyl; and K is a substituted amino moiety having the formula R -N-R, wherein R is hydrogen or C 1 -C 4 alkoxy and R is a linear or branched hydroxyalkyl of C 1 -C 12. The invention according to claim 19, wherein R 6 is 3-hydroxy-1,1-dimethylpropyl. 21. The invention according to claim 15, in-2 wherein for the compound of Formula I, R and R are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valilo,
2. 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 2-ethylglycyl, 1-isoleucyl or 2-tert-butylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl or 3,4-dehydroprqyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxy-prolyl; and K is a substituted amino moiety having the formula R-N-R, wherein R is hydrogen or C 1 -C 4 alkoxy and R is a cycloalkyl of. _ -C
3. 3-C10 selected from the group consisting of: (1) -adamantyl, (2) -adamantyl, Cyclobutyl, Cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1-methylcyclohexyl __ and [3.3.0] octa-1-yl. The invention of 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 valilo; B is N-methylvalyl; D is prolyl; E is prolyl; R5 is hydrogen and R6 is tert-butyl. The invention of 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 valilo; B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen. A pharmaceutical composition containing: a) a therapeutically effective amount of a compound of Formula I: R1 R2 N-CHX-CO-A-B-D- (E) s- (F) t- (G) u-K wherein: R1 is alkyl, cycloalkyl, alkylsulfonyl, fluoroalkyl or aminosulfonyl; ~ R "is hydrogen, alkyl, fluoroalkyl, or cycloalkyl: RX-N-R2 together can be a pyrrolidino or piperidino residue; A is a valyl residue, iosoleucyl, 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; B is a N-alkyl-valyl residue, -norvalyl, leucyl, -isoleucyl, -2-tert-butylglycyl; -3- tert-butylalanyl, -2-ethylglycyl, -2-cyclopropylglycyl, -2-cyclopentylglycyl, norleucyl- or -2-cyclohexylglycyl; D is a prolyl residue, homoprolyl, hydroxyprolyl, 3,
4. 4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl,
5. 5-methylprolyl, azetidin-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoropropyl, oxazolidin-4-carbonyl or thiazolidin-4-carbonyl; is a prolyl residue, homoprolyl, hydroxyprolyl, 3-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidin-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidin- 4-carbonyl or thiazolidin-4-carbonyl; F and G are independently selected from the group consisting of the prolyl, homoprolyl, hydroxyprolyl, thiazolidin-4-carbonyl, 1-aminopentyl-1-arbonyl, vallyl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl residues. , N-ethylphenylalanyl, tetrahydroisoquinolyl-2-histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl, norleucyl, norvalyl, neo-pentylglycyl, tritoynyl [sic], glycyl, 2,2-dimethylglycylalanyl, β-alanyl and 3- naphthylalanyl; 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; and b) a therapeutically effective amount of a second antiarthritic compound selected from the group consisting of: a non-spheroidal anti-inflammatory compound, an organic gold derivative, D-penicilla ina, 4-aminoquinoline, azathioprine, methotrexate, cyclosporine, an inhibitor of angiogenesis, a monoclonal antibody for cells T, a monoclonal antibody to an adhesion molecule, a monoclonal antibody to a cytokine or growth factor, TNFR-IgG, IL-1 receptor antagonists and ^ inhibitors ICE. The composition according to claim 24, wherein the compound has the formula as defined in any of claims 13-23. The composition according to claim 24 or 25 for use in the treatment or prophylaxis, for example, in the treatment of rheumatoid arthritis in a mammal (for example a human).