WO2002034283A2 - Vegh inhibitors and their use - Google Patents

Vegh inhibitors and their use Download PDF

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Publication number
WO2002034283A2
WO2002034283A2 PCT/EP2001/012369 EP0112369W WO0234283A2 WO 2002034283 A2 WO2002034283 A2 WO 2002034283A2 EP 0112369 W EP0112369 W EP 0112369W WO 0234283 A2 WO0234283 A2 WO 0234283A2
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WIPO (PCT)
Prior art keywords
formula
compound
substituted
alkyl
amino
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PCT/EP2001/012369
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French (fr)
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WO2002034283A3 (en
Inventor
Karl Baumann
Carolyn Ann Foster
Philipp Lehr
Josef Gottfried Meingassner
Berndt Oberhauser
Erwin Paul Schreiner
Barbara Wolff-Winiski
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Novartis Ag
Novartis Pharma Gmbh
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Priority claimed from GB0026345A external-priority patent/GB0026345D0/en
Priority claimed from GB0029113A external-priority patent/GB0029113D0/en
Priority claimed from GB0102380A external-priority patent/GB0102380D0/en
Priority claimed from GB0102379A external-priority patent/GB0102379D0/en
Priority claimed from GB0102839A external-priority patent/GB0102839D0/en
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Priority to AU2002223649A priority Critical patent/AU2002223649A1/en
Publication of WO2002034283A2 publication Critical patent/WO2002034283A2/en
Publication of WO2002034283A3 publication Critical patent/WO2002034283A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • VEGF-inhibitors vascular endothelial cell growth factor
  • VEGF-inhibitors vascular endothelial cell growth factor
  • VEGF-inhibitors exhibit pharmacological activity and are therefore useful as pharmaceuticals, e.g. in the treatment or prophylaxis of VEGF-mediated events.
  • VEGF-inhibitors may be useful in the treatment or prophylaxis of pathogenic processes, e.g.
  • angiogenesis and neovascularization that contribute to diseases, e.g. including arteriosclerosis, cancer, chronic transplant rejection, psoriasis, rheumatoid arthritis and eye diseases, such as proliferative retinopathies and macular degeneration.
  • diseases e.g. including arteriosclerosis, cancer, chronic transplant rejection, psoriasis, rheumatoid arthritis and eye diseases, such as proliferative retinopathies and macular degeneration.
  • Inhibitors of the stimulated expression of cellular adhesion molecules especially inhibitors of VCAM-1 relative to E-selectin and ICAM-1 expression, exhibit pharmacological activity and are therefore useful as pharmaceuticals.
  • the effect on VCAM-1 expression inhibition occurs at both transcriptional and posttranscriptional levels.
  • inhibitors of the stimulated expression of cellular adhesion molecules are useful for the treatment or prophylaxis of disease processes which involve expression of cellular adhesion molecules.
  • These disease processes include many acquired and inherited diseases/disorders where leucocyte trafficing plays a prominent role in the pathogenic process, most notably acute and chronic inflammation (e.g. allergy, asthma, psoriasis, reperfusion injury, rheumatoid arthritis and septic shock) and autoimmune states (e.g. multiple sclerosis).
  • Other indications include tumor metastasis (e.g. melanoma, osteocarcinoma) and allograft/xenograft rejection, since it is known that inhibition of vascular adhesion molecules can greatly improve the prognosis of these processes.
  • inhibitors of the expression of cellular adhesion molecules have therapeutic potential in hyperproliferatJve skin diseases (e.g.
  • Inhibitors of the expression of cellular adhesion molecules are active in inhibiting TNF ⁇ - or IL6-induced HIV production in the U1 monocytic cell line, as evaluated by p24 ELISA and are therefore also useful in the treatment of immunodeficiences and virally caused diseases, especially in the treatment of AIDS.
  • inhibitors of adhesion molecule expression especially VCAM-1 expression inhibitors, additionally act as VEGF-inhibitors.
  • Compounds which act as inhibitors of adhesion molecule expression and additionally as VEGF-inhibitors offer potential for the treatment of many disease states.
  • the present invention provides the use of inhibitors of adhesion molecule expression in the preparation of a medicament for the treatment of vascular endothelial cell growth factor-mediated diseases, e.g. including diseases as described above, e.g. diseases wherein processes, e.g. capillary nonperfusion, angiogenesis, neovascularization, tumor growth and metastasis, contribute to the pathogenesis or severity of said disease, such as
  • - eye diseases involving vision impairment or loss e.g. proliferative retinopathies and macular degeneration, including ischemic retinopathies, uveoretinitis and degenerative eye diseases,
  • the present invention provides the use of inhibitors of adhesion molecule expression in the preparation of a medicament for the treatment of eye diseases leading to vision impairment or loss, such as proliferative retinopathies and macular degeneration, including ischemic retinopathies, uveoretinitis and degenerative eye diseases.
  • Treatment includes therapeutical treatment and prophylaxis.
  • Cyclopeptides are cyclic molecules comprising amino acid residues linked together by peptide bonds, cyclopeptolides further comprise one hydroxy substituted carboxylic acid residue which is linked through its hydroxyl substituent to the neighbouring acid residue by an ester linkage. Cyclopeptolides are e.g. described in WO 96/03430 and in WO 97/19104 for use as inhibitors of adhesion molecule expression. According to the finding of the present invention cyclopept(ol)ides act additionally as VEGF-inhibitors.
  • cyclopept(ol)ides e.g. compounds of formula l p , l r and l s , which are VEGF- inhibitors and additionally act as inhibitors of adhesion molecule expression.
  • Inhibitors of adhesion molecule expression which, according to the present invention, act additionally as VEGF-inhibitors, thus include cyclopeptides and cyclopeptolides, e.g. such as described above.
  • the present invention provides the use of cyclopept(ol)ides, e.g. including cyclopeptolides of WO 96/03430 and WO 97/19104, e.g. of formula I, and of formula l p , and l r and cyclopeptides of formula l s , in the preparation of a medicament for the treatment of vascular endothelial cell growth factor-mediated diseases.
  • cyclopept(ol)ides e.g. including cyclopeptolides of WO 96/03430 and WO 97/19104, e.g. of formula I, and of formula l p , and l r and cyclopeptides of formula l s , in the preparation of a medicament for the treatment of vascular endothelial cell growth factor-mediated diseases.
  • Cyclopeptolides as described in WO 96/03430 and WO 97/19104 are of formula I, and in another aspect the present invention provides a compound of formula r— A - B - R ⁇ eu - Leu - Z - X - Y-
  • A is - a glycolic acid residue optionally ⁇ -substituted by methyl or vinyl, optionally substituted by
  • R 3 is hydrogen or optionally arylsubstituted alkyl
  • CONR 4 R 5 wherein R and R 5 are the same or different and represent hydrogen or alkyl or form together with the nitrogen to which they are attached a 3- to 6-membered ring, optionally containing a second heteroatom
  • COR 7 wherein R 7 represents hydrogen or lower alkyl, CSNH 2 , or alkyl, optionally substituted by
  • R 9 is hydrogen, alkoxy, alkyl or benzyl
  • R 10 is hydrogen or halogen
  • Rn is hydrogen or methyl and ⁇ is a single or double bond
  • X is an ⁇ -amino-substituted (C 2 - ⁇ 4 )carboxylic acid residue
  • Y is an ⁇ -amino- or N-methyl- ⁇ -amino substituted (C 2 . 10 )carboxylic acid residue
  • glycolic acid residue which is optionally ⁇ -substituted by methyl, which methyl is optionally substituted by amino, hydroxy, chloro, alkoxy, optionally substituted thiazolyl, optionally substituted vinyl, cyclopropyl, CSNH 2 or -C ⁇ CH;
  • Z is preferably a tryptophan residue of formula II, wherein R 9 is hydrogen, alkoxy, alkyl or benzyl, R ⁇ 0 is hydrogen or halogen and Rn is hydrogen or methyl; X is preferably an ⁇ -amino-substituted (C 2 .
  • X is an ⁇ -amino- ⁇ - or ⁇ -(C 1 - 4 ) alkyl-, especially methyl-, substituted octanoic or butyric acid residue
  • Y is preferably an N-methyl- ⁇ -amino-substituted (C 2 .io)carboxylic acid residue, more preferably Y is an N-methyl-alanine or N-methyl-valine residue.
  • the compounds of formula I comprise asymmetric C-atoms and substituents attached to asymmetric C-atoms may be in either in the R or in the S configuration.
  • the present invention provides the use as defined above of the compound 5- [8,11-Diisobutyl-14-(1-methoxy-1 H-indol-3-ylmethyl)-7,13,19,20-tetramethyl-5,17-bis-(2-methyl- hexyl)-3,6,9,12,15,18,21 -heptaoxo-1-oxa-4,7,10,13,16,19-hexaaza-cycloheneicos-2-yl]-pent-2- enoic acid methyl ester and of a compound of formula
  • R ⁇ A , M and R 3A are as defined in TABLE 1 below, and ⁇ is a double bond in No.1 to 34, 36 and 38 to 46 and a single bond in No. 35 and 37;
  • R 4A is methoxy in No. 1 to 16, 18 to 30, and 40 to 44, hydrogen in No. 17; 37 and 45, methyl in No. 31 and 46, ethyl in No. 32, benzyl in No. 33 and 35, a group of formula -CH 2 C(CH 3 ) 3 in No. 34, isopropyl in No.36, n-propoxy in No. 38; ethoxy in No. 39; and
  • R 5A is hydrogen in No. 1 to 39 and 41 to 46 and Br in No. 40; e.g. compounds such as exemplified in WO 96/03430 and WO 97/19104:
  • a compound of formula I includes a compound of formula IA.
  • novel cyclopeptolides which are inhibitors of adhesion molecule expression, especially VCAM-1 relative to ICAM-1 and E-selectin expression inhibitors, and additionally act as VEGF-inhibitors, e.g. compounds of formula l p , l r and l s .
  • a substituent in ⁇ -position of an ⁇ -hydroxy-substituted butyric acid residue in the meaning of A in a compound of formula I includes a substituent R 6 as defined above and we have found that
  • R 6 may be also selected from the groups
  • R 2p is alkyl substituted by CF 3 ,
  • R 3p is alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl or acyloxyalkyl
  • R p is alkyl, e.g. alkyl substituted by a sugar residue
  • R 5p is hydrogen or a substitutent, e.g. in position 2 of the ring system; such as alkyl, cyanoalkyl, alkoxyalkyl,
  • R 6p is hydrogen or a substituent, e.g. hydroxy, and of formula
  • R 7p is hydrogen or a substitutent, such as alkyl, e.g. (C ⁇ alkyl.
  • the present invention provides a compound, i.e. a cyclopeptolide, of formula
  • R 1p is selected from the groups
  • R 2p is alkyl substituted by CF 3 ,
  • R 3p is alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl or acyloxyalkyl,
  • R 4p is alkyl
  • R 5p is hydrogen or a substitutent, such as alkyl, cyanoalkyl, alkoxyalkyl, e.g. in position 2 of the ring system;
  • R 6p is hydrogen or a substituent, e.g. hydroxy
  • R 7p is hydrogen or a substitutent, such as alkyl, e.g. (C ⁇ alkyl; and R' 2p is hydrogen, alkyl, alkoxy or aralkyl, preferably alkoxy, such as methoxy.
  • the present invention provides a compound of formula l p , wherein R' 2p is methoxy and R ⁇ p is as defined in TABLE 2:
  • a compound of formula I includes a compound of formula IA, and, generically, a compound of formula l D .
  • the present invention provides a compound, i.e. a cyclopeptolide, of formula
  • a r is a glycolic acid residue; e.g. which is ⁇ -substituted by alkyl, which alkyl is optionally substituted by aryl, optionally protected hydroxy, cyano, heterocyclyl, iminoaminocarbenyl,, diazoketone or a group -COR, wherein R is OH, alkyl, alkoxy, alkenyloxy, amino;
  • B r is an ⁇ -amino- ⁇ -methyl-substituted octanoic acid residue
  • Leu * is leucin or N-methyl leucin, preferably N-methyl leucin
  • Leu is leucin
  • D r is a tryptophan residue, e.g. of formula
  • R 2r is hydrogen, alkoxy, alkyl or aralkyl
  • R 3r is hydrogen or halogen
  • R 4r is hydrogen or alkyl
  • — is a single bond or a double bond
  • X r is an ⁇ -amino-substituted (C 2 - ⁇ 4 )carboxylic acid residue
  • Y r is an ⁇ -amino- or N-methyl- ⁇ -amino substituted (C 2 , ⁇ 0 )-carboxylic acid residue wherein position ⁇ is trisubstituted, e.g. in addition to the ⁇ -amino- or N-methyl- ⁇ -amino substitution further disubstituted.
  • R ⁇ r is alkyl, e.g. unsubstituted alkyl; or substituted alkyl, e.g. including alkyl substituted by
  • heterocyclyl e.g. including a 5 or 6 membered ring (system) having 2 to 3 heteroatoms selected from N,O and S, such as a thiazolyl, oxadiazolyl, oxazolyl, e.g. unsubstituted heterocyclyl or substituted heterocyclyl, e.g. including heterocyclyl substituted by
  • alkyl e.g. (C ⁇ - 6 )alkyl, alkoxycarbonylalkyl, alkoxyalkyl, cyanoalkyl;
  • alkoxy e.g. (C ⁇ - 5 )alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkylcarbonyloxyalkoxy; alkyl, e.g. including hydroxyalkyl, alkoxyalkyl;
  • alkoxycarbonyloxyalkoxy e.g. which alkyloxycarbonyloxyalkoxy is further substituted by a sugar residue
  • D r is preferably a tryptophan residue of formula ll r , wherein R 2r is hydrogen, R 3r is hydrogen;
  • R r is alkoxy, such as methoxy; and - ⁇ is a double bond;
  • X r is preferably an ⁇ -amino (C 4 - 8 )carboxylic acid residue substituted in position ⁇ and/or ⁇ , e.g. by alkyl, such as (C ⁇ alkyl, e.g. an ⁇ -amino-butyric or octanoic acid residue, preferably octanoic acid residue, preferably substituted in position ⁇ by alkyl, such as methyl;
  • Y r is preferably a group of formula
  • R 5r is H or alkyl, e.g methyl
  • R 6r is alkyl, e.g. methyl
  • (C ⁇ -6)alkyl e.g. unsubstituted alkyl or alkyl substituted by - aryl, hydroxy or acyloxy, e.g. (C ⁇ - 6 )alkylcarbonyloxy or heterocyclylcarbonyloxy, e.g. imidazolylcarbonyloxy;
  • alkenyl e.g. (C 2 _s)alkenyl, such as (C 3 . 5 )alkenyl;
  • R 6r and R 7r together form a cycloalkyl ring, e.g. spiro attached to that carbon atom of the ring system where R 6r and R 7r are attached.
  • the present invention provides a compound of formula
  • R ⁇ r , R 5 r , R 6r and R 7r are as defined above and R 2
  • Ar has the meaning of R 2r , preferably methoxy.
  • the present invention provides a compound, i.e. a cyclopeptide, of formula
  • a s is an ⁇ -amino carboxylic acid residue
  • B s is an ⁇ -amino- ⁇ -methyl-substituted octanoic acid residue
  • Leu * is leucin or N-methyl leucin, preferably N-methyl leucin
  • Leu is leucin
  • D s is a tryptophan residue, e.g of formula wherein
  • R 2s is hydrogen, alkoxy, alkyl or aralkyl
  • R 3s is hydrogen or halogen
  • R 4s is hydrogen or alkyl
  • ⁇ z is a single bond or a double bond
  • X s is an ⁇ -amino-carboxylic acid residue, e.g. an ⁇ -amino-substituted (C 2 . ⁇ )carboxylic acid residue.
  • a s is preferably a group of formula
  • R 1s is alkyl or alkenyl, preferably alkyl
  • D s is preferably a tryptophan residue of formula ll s , wherein R 4s is hydrogen, R 3s is hydrogen; R 2s is alkoxy, such as methoxy; and _ ⁇ _ is a double bond; and
  • X s is preferably an ⁇ -amino (C 4 . 8 )carboxylic acid residue, e.g. substituted in position ⁇ and/or ⁇ , e.g. by alkyl, such as (C ⁇ - )alkyl, such as an ⁇ -amino-butyric or octanoic acid residue, preferably octanoic acid residue, preferably substituted in position ⁇ by alkyl, such as methyl.
  • the present invention provides a compound of formula wherein R ⁇ s and R 2s are as defined above.
  • a compound of formula l s includes a compound of formula IA S .
  • R ⁇ s is preferably alkyl and R 2s is preferably methoxy.
  • Ri s is more preferably substituted alkyl, e.g. substituted by a group CY' s R's, wherein Y' s is S or O, preferably O; and
  • R' s is H, OH, alkyl, alkenyl, cycloalkyl, aryl, alkoxy, e.g. (C ⁇ alkoxy, alkenyloxy, cycloalkyloxy, e.g. (C 3 . 7 )cycloalkoxy, alkylthio, arylthio, amino, e.g. unsubstituted and substituted amino, e.g. amino substituted by one or more alkyl, e.g. (C ⁇ - 6 )alkyl or alkoxy, e.g. (C ⁇ alkoxy; or R' s is heterocyclyl, e.g.
  • a cycloalkyl e.g. (C ⁇ cycloalkyl, ring or spiro attached to another hetercyclic ring, e.g. a piperidine ring spiro attached to (Cs ⁇ cycloalkyl, or 1 ,3- dioxacycloalkyl, such as 1 ,3-dioxa(C- 5 - 6 )cycloalkyl, e.g. including unsubstituted heterocyclyl and substituted heterocyclyl, e.g. substituted by one or more groups, such as conventional in organic chemistry, e.g. substiuted by heterocyclyl, e.g.
  • alkyl includes (d ⁇ alkyl, such as (C ⁇ alkyl, e.g. (C M )alkyl.
  • Lower alkyl includes (C ⁇ alkyl.
  • Cycloalkyl includes (C 3 . 7 )cycloalkyl.
  • Aryl includes phenyl.
  • Heterocyclyl includes a 5 or 6 membered ring system having 1 to 4 heteroatoms, such as 1 to 3, e.g. selected from N, O, S. Heterocyclyl e.g.
  • Alkenyl includes (C 2 - 22 )alkenyl, e.g. (C 2 - 6 )alkenyl.
  • Acyl includes alkylcarbonyl. Hydroxy includes unprotected hydroxy and protected hydroxy.
  • Amino includes unsubstituted amino or substituted amino, e.g. including protected amino, e.g. amino substituted by one or two alkyl, aryl, alkoxy. Any group may be substituted or unsubstituted, e.g.
  • subsitutents includes groups as conventional in organic chemistry, such as halogen, amino, nitro, cyano, hydroxy, cycloalkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, heterocyclyl, acyl and thioacyl, e.g. a group of formula CY'R', wherein Y' is S or O and R' is H, OH, amino, alkyl, alkenyl, cycloalkyl, aryl, alkoxy, e.g. (C ⁇ alkoxy, alkenyloxy, alkylthio, arylthio or heterocyclyl.
  • groups as conventional in organic chemistry such as halogen, amino, nitro, cyano, hydroxy, cycloalkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, heterocyclyl, acyl and thioacyl, e.g.
  • the present invention beside cyclic pept(ol)ides includes open chain pept(ol)ides corresponding to cyclic pept(ol)ides as described herein, wherein a bond of the cyclic compound is split; e.g. the present invention includes open chain peptolides according to compounds of formula I; e.g. open chain compounds obtainable by either cleavage of the ester bond between residues Y and A or cleavage of an amide linkage between any other adjacent pair of the acid residues.
  • the present invention provides the use of a compound of formula
  • a compound of the present invention includes a compound in any form, e.g. in free form, in the form of a salt, in the form of a solvate and in the form of a salt and a solvate.
  • the present invention provides a compound of formula l p , l r , l s , IA r and IA S in the form of a salt, or in the form of a salt and in the form of a solvate, or in the form of a solvate; e.g. and or in the form of an ester.
  • a salt of a compound of the present invention includes a pharmaceutically acceptable salt, e.g. including a metal salt or an acid addition salt.
  • Metal salts include for example alkali or earth alkali salts;
  • acid addition salts include salts of a compound of the present invention with an acid, e.g. hydrogen fumaric acid, fumaric acid, naphthalin-1 ,5-sulphonic acid, hydrochloric acid, deuterochloric acid; preferably hydrochloric acid.
  • a compound of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa.
  • a compound of the present invention in free form or in the form of a salt and in the form of a solvate may be converted into a corresponding compound in free form or in the form of a salt in unsolvated form; and vice versa.
  • a compound of the present invention may be converted into an ester and vice versa, in case of the presence of a group which is convertible into an ester, such as of a carboxylic acid group.
  • a compound of formula of the present invention may be in the form of an ester such as a physiologically-hydrolysable and -acceptable ester.
  • physiologically-hydrolysable and - acceptable esters as used herein is meant an ester in which the -COO- group of a carboxylic acid group is esterified and which is hydrolysable under physiological conditions to yield an acid which is itself is physilogically tolerable at dosages to be administered.
  • the term "a compound of the present invention in the form of an ester" is thus to be understood as defining regular pro-drug forms of compounds of the present invention.
  • a compound of the present invention in the form of a salt or a solvate or an ester exhibit a similar order of pharmaceutical activity as a compound of the present invention in free from.
  • a compound of of the present invention may exist in the form of isomers and isomeric mixtures thereof, e.g. optical isomers, epimers, cis trans configurated isomers, conformers.
  • a compound of the present invention e.g. contains asymmetric carbon atoms and may thus exist in the form of diastereoisomeris and epimers and mixture thereof. Isomeric, diastereoisomeric and epimeric mixtures may be separated as appropriate, e.g. according to a method as conventional, to obtain pure isomers.
  • Pure isomers may also be produced as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as described herein.
  • the present invention includes a compound of the present invention in any isomeric form and in any isomeric mixture, e.g. R-forms, S-forms and mixtures of R- and S- forms.
  • Any compound mentioned herein, e.g. including compounds according to the present invention may be obtained as appropriate, e.g. according to, e.g. analogously, to a process as conventional, e.g. as described in WO 96/03430 or in WO 97/19104, e.g. or as described herein.
  • the present invention provides a process for the production of a compound of formula l r comprising deprotonating the ⁇ -carbonyl atom in Y' r in a compound of formula
  • a r , B r , Leu * , Leu, D r and X r are as defined above and Y' r is an ⁇ -amino- or N-methyl- ⁇ - amino substituted (C 2 . 10 )-carboxylic acid residue wherein position ⁇ is in addition to the ⁇ - amino- or N-methyl- ⁇ -amino substitution further monosubstituted; e.g. Y' is a group of formula
  • R 5r and R 6r are as defined above; and reacting a deprotonated compound of formula 11 lr- with an electrophile, e.g. including a compound of formula R 7r X' r , wherein R 7r is as defined above and X' r is a leaving group, e.g. bromide; to obtain a compound of formula l r .
  • an electrophile e.g. including a compound of formula R 7r X' r , wherein R 7r is as defined above and X' r is a leaving group, e.g. bromide
  • a compound of formula l r is preferably produced by reacting a solution of a compound of formula lll r in a solvent which is inert under the reaction conditions, e.g. tetrahydrofurane, e.g. in the presence of a co-solvent, with a compound of formula R 7r X' r , wherein R 7r is as defined above and X' r is bromide, in the presence a base, e.g. phosphazene base P 4 -t-But, at appropriate temperature, preferably at low temperature.
  • a base e.g. phosphazene base P 4 -t-But
  • R 1r is an oxadiazolyl, e.g. an oxadiazol-2-yl, e.g. which oxadiazolyl is unsubstituted or substituted, e.g. substituted in position 5, e.g. by alkyl, such as (C 1 - 4 )alkyl.
  • a compound of formula l r obtained may be isolated and purified, e.g. according to a method as conventional.
  • a compoud of formula lll r may be obtained according to a method as conventional, e.g. by fermentative production of a cyclic peptide structure as an intermediate which may be chemically converted as desired; e.g. according to a method as conventional; or by chemical synthesis; e.g. according to a method as conventional, e.g. in peptide synthesis; e.g. according to a method as disclosed in WO 97/19104 or WO 96/03430; or as described herein. If desired a group R ir in a compound of formula l r obtained may be converted further to obtain a compound of formula l r wherein R ⁇ r has another meaning than in the compound obtained according to the above described procedures.
  • the present invention provides a process for the production of a compound of formula l s comprising the steps a) subjecting a compound of formula
  • a W o is an ⁇ -hydroxy-substituted butyric acid residue
  • B o is an ⁇ -amino- ⁇ -methyl- substituted octanoic acid residue
  • Leu * is leucin or N-methyl leucin, Leu is leucin
  • C W o is a tryptophan residue
  • X W o i an ⁇ -amino-substituted (C 2 . ⁇ 4 ) carboxylic acid residue
  • Ywo is an ⁇ -amino- or ⁇ -methylamino-substituted (C 2 . i4 ) carboxylic acid residue, which is a compound of formula I of WO 96/03430, e.g.
  • step b) splitting off a residue Awo in a compound obtained in step b) to obtain a corresponding compound wherein A o is removed and B o is an ⁇ -amino- ⁇ -methyl-substituted octanoic acid residue wherein the amine group in position ⁇ is free, e.g.
  • step b) by treatment of a compound obtained in step b) with methanesulfonic acid chloride/N-methyl morpholine and N-ethylthiourea; d) converting in a compound obtained in step c) the free amine group in an ⁇ -amino- ⁇ -methyl- substituted octanoic acid residue in the meaning of B o to obtain a compound of step c) wherein the amine group in position ⁇ in a group Bwo is acylated, e.g. acylated by a group
  • step c) e.g. by reaction of a compound obtained in step c) with an acid of formula INT s -OH, e.g. in the presence of a coupling agent; e) ring formation, e.g. ring closuring of a compound obtained in step d), e.g. reductive, to obtain a compound of formula l s , wherein the substitutents are as defined above, e.g.
  • a compound of formula l s obtained may be isolated and purified, e.g. according to a method as conventional.
  • a compound of formula may be subjected to ring formation to obtain a compound of formula IA S wherein R ⁇ s and R 2s are as defined above.
  • the compounds of the present invention exhibit pharmacological activity and are therefore useful as pharmaceuticals.
  • the compounds of formula I, l p , l r and l s are inhibitors of the stimulated expression of cellular adhesion molecules, especially inhibiting VCAM-1 relative to E-selectin and ICAM-1 expression, and additionally are inhibitors of the growth factor VEGF expression.
  • Assays which may be used to detect the inhibition of VCAM-1 , ICAM-1 and E- selectin expression by the compounds of the present invention are e.g. described in WO 97/19104 and the compounds of the present invention show activitiy in assays as described in WO 97/19104.
  • Assays appropriate for the determination of downregulation of VEGF expression e.g. assays to assess potential for VEGF-inhibition, are e.g. as follows:
  • U-138 MG cells a non-tumorigenic human glioblastoma cell line, displays phenotypic characteristics of primary human glioblastoma cells (Ponten and Maclntyre, 1968, Acta Path Microbiol Scand 74:465-486) and are used for the human VEGF soluble ELISA.
  • U-138 MG cells constitutively express VEGF, which can be upregulated under hypoxic culture conditions and switching the culture medium from a low to high concentration of fetal calf serum (FCS). Dose-response and time-course experiments are performed to determine the optimal conditions for inducing VEGF protein, whose secreted form (VEGF 165 isoform) is determined by soluble ELISA.
  • FCS fetal calf serum
  • CM Minimum essential medium with Earie's salts [MEM; Gibco #61100] supplemented with 10% FCS, 2.2 g/l NaHCO 3 , 1 mM sodium pyruvate, non-essential amino acids, 100 U/ml penicillin and 100 mg/ml of streptomycin).
  • the cells are reseeded every 3-4 days at a 1 :10 splitting ratio and given fresh CM every 3 days.
  • the culture medium is replaced with 150 ⁇ l/well of DMEM/F12 assay medium supplemented with 5% FCS and containing either (1) appropriate concentrations of the test compound, (2) corresponding concentrations of solvent/methanol-extracted medium, or (3) DMEM/F12 assay medium alone (5% FCS).
  • the cells are incubated for 48 hr at 37° C. Each 96-well assay is performed with duplicate wells. After 48 hours in these 'low-to-high' serum conditions, the cell culture supernatants are transfered to a 96-well V-bottom plate (Costar # 3896) and spun down at 4° C for 15 min., 3000 x g, for subsequent analysis in the VEGF solid phase ELISA.
  • Cvtotoxicity Control (cell loss based on nuclear stain): After harvesting the culture supernatants, the U-138 MG cell monolayer is fixed in 2% paraformaldehyde for 15 min at room temperature (RT) and rinsed in distilled water (Aquadest). The monolayer is covered with a 33% Giemsa solution in Aquadest for 2 min at RT. The wells are washed with Aquadest and air dried for at least 15 min. Microscopic evaluation is used to check that only the nuclei are stained, with essentially no cytoplasmic staining. Giemsa absorbance values are read on a microtiter plate reader at 550 nm and corrected for "blank" values (rows without cells) at 690 nm.
  • Human VEGF Solid Phase ELISA Harvested supernatant samples from the U-138 MG cells are evaluated for levels of VEGF ⁇ 65 protein using a commercially-available human VEGF ELISA (R &D Systems #DVE00), according to manufacture's instructions.
  • the compounds of the present invention show activity in such assays.
  • a compound of the present invention may be administered in the form of a pharmaceutical composition.
  • a therapeutic, e.g. pharmaceutical, composition comprising a compound of formula l p , l r or l s , e.g. at least one compound, e.g. a therapeutically effective amount of at least one compound of formula l p , l r or l s ; beside one or more pharmaceutically acceptable carriers, diluents and/or excipients.
  • the present invention provides the use of a compound of formula I, l p , l r or l s , e.g. including a compound of formula IA, IA r and IA S , such as a compound of formula l p , l r or l s , e.g. including a compound of formula IA r and IA S , e.g. in the form of a salt, or in the form of a salt and in the form of a solvate, or in the form of a solvate; and/or in the form of an ester; in the treatment, e.g. therapy or prophylaxis, of diseases wherein processes e.g.
  • capillary nonperfusion angiogenesis, neovascularization, tumor growth and metastasis contribute to the pathogenesis or severity of said disease, such as - eye diseases involving vision impairment or loss, such as proliferative retinopathies and macular degeneration, including ischemic retinopathies, uveoretinitis and degenerative eye diseases,
  • - solid tumor malignancies and other cancers e.g. Kaposi's sarcoma, - psoriasis, rheumatoid arthritis
  • a method for the treatment e.g. or prophylaxis; of such diseases comprising administering a therapeutically or prophylactically effective amount of a compound of formula l p , l r or l s , e.g. including a compound of formula IA r and IA S , e.g.
  • compositions according to the present invention may be for parenteral, oral, aerosol or topical use, e.g. administration, and may comprise one or more pharmaceutically acceptable carriers, diluents and/or excipients; and may comprise one or more additives; e.g. stabilisers and the like.
  • Appropriate dosage ranges of the compounds of the present invention in therapeutical use may be dependent on e.g. the condition or disease involved, whether the use is for treatment or prophylaxis, the mode of administration, the route of administration. In general satisfactory results may be obtained, e.g.
  • dosages of from about 0.05 to about 10 mg/kg/day preferably from about 0.1 to about 7.5 mg/kg/day, more preferably from about 0.1 to about 2 mg/kg/day;
  • parenteral administration e.g. by i.v. drip or infusion
  • dosages from about 0.01 to about 5 mg/kg/day preferably from about 0.05 to about 1 mg/kg/day and more, preferably from about 0.1 to about 1.0 mg/kg/day may be appropriate; e.g. administered once, or, in divided doses, 2 to 4 times a day.
  • Suitable daily dosages for human patients include thus from about 2.5 to about 500 mg p.o., preferably from about 5 to about 250 mg p.o., more preferably from about 5 to about 100 mg p.o.; or from about 0.5 to about 250 mg i.v., preferably from about 2.5 to about 125 mg i.v. and more preferably from about 2.5 to about 50 mg i.v..
  • the compounds of the present invention may be administered by any appropriate route, including enteral, parenteral and topical and by inhalator administration.
  • Appropriate enteral administered forms include solutions for drinking, tablets or capsules.
  • Appropriate parenteral forms include injectable solutions or suspensions.
  • Appropriate forms for topical administration include e.g. creams, lotions; e.g.
  • Appropriate unit dosage forms for oral administration may comprise from 1 to 50 mg of a compound of the present invention, e.g. from 1 to 10 mg.
  • a compound of the present invention may be administered to larger mammals, for example humans, e.g. by similar modes of administration; e.g. at similar or lower dosages; than known standards for indications, e.g. indications as described above.
  • a compound of the present invention may be used for pharmaceutical treatment according to the present invention alone, or in combination with one or more other pharmaceutically active agents.
  • Such other pharmaceutically active agents include compounds which enhances the effectiveness of a compound of the present invention in a diseases as defined above.
  • Combinations include fixed combinations, in which two or more pharmaceutically active agents are in the same formulation; kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g. with instruction for co- administration; and free combinations in which the pharmaceutically active agents are packaged separately, but instruction for simultaneous or sequential administration are given.
  • the present invention provides a compound as defined in any one of examples 26 to 104.
  • HATU [O-(7-azabenzotriazol-1-yl)]-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
  • BOP (Benzotriazol-1 -yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate
  • P -t-Bu Phosphazene Base P 4 -t-Bu (1 M-solution in n-hexane, FLUKA Art.Nr. 79421) Flash column chromatography is carried out on silica gel.
  • a compound of formula l p is as defined above, wherein R 1p is as defined in examples 1 to 25 (TABLE 2) and R 2p is methoxy. According to Examples 26 to 84, the production of compounds of formula
  • a solution of 150 mg of a compound obtained in example 2 A) in 10 ml of propionitrile is treated with 10 mg of rhodium(ll)acetate, the mixture obtained is stirred for ca. 20 hours at RT and EtAc is added.
  • the mixture obtained is extracted with brine, the organic layer obtained is dried, the solvent is evaporated off and the evaporation residue is subjected to flash column chromatography.
  • a compound of formula l p is obtained wherein R p is as defined in Table 2 under "Ex. 16", in the form of a powder. 13 C-NMR: 172.95; 171.99; 171.04; 170.48; 170.43; 168.37; 168.26 (carbonyls); 164.63 / 150,77 / 123.03 (oxazol).
  • Rip is as defined in Table 2 under "Ex. 17”: 13 C-NMR: 172.96; 172.00; 171.05; 170.48; 170.44; 168.37; 168.27 (carbonyls); 160.42 / 150.93 / 123.24 (oxazol).
  • R 1p is as defined in Table 2 under "Ex. 18": 13 C-NMR: 172.93; 172.03; 171.05; 170.48; 170.42; 168.28; 168.25 (carbonyls); 154.11 / 152.71 / 123.74 (oxazol), 115.84 (-CN).
  • EXAMPLE 19 13 C-NMR: 172.96; 172.00; 171.05; 170.48; 170.44; 168.37; 168.27 (carbonyls); 160.42 / 150.93 / 123.24 (oxazol).
  • EXAMPLE 18 R 1p is as defined in Table 2 under
  • R 1p is as defined in Table 2 under "Ex. 19": 13 C-NMR: 172.94; 172.02; 171.03; 170.47; 170.42; 168.31 ; 168.27 (carbonyls); 160.14 / 152.20 / 123.52 (oxazol); 66.01 (oxazolyl-CH2O-); 58.77 (-OCH3).
  • 13 C-NMR 172.94; 172.02; 171.03; 170.47; 170.42; 168.31 ; 168.27 (carbonyls); 160.14 / 152.20 / 123.52 (oxazol); 66.01 (oxazolyl-CH2O-); 58.77 (-OCH3).
  • Example 20 13 C-NMR: 172.94; 172.02; 171.03; 170.47; 170.42; 168.31 ; 168.27 (carbonyls); 160.14 / 152
  • R 1p is as defined in Table 2 under "Ex. 22": 1 :1 Mixture of 2 conformers.
  • R ⁇ p is as defined in Table 2 under "Ex. 23": 1 :1 mixture of 2 conformers; 3 C-NMR(125.8 MHz, CDCI3): 180.302, 179.913, 173.921 , 173.084, 172.495, 172.444, 171.479, 170.803, 169.707, 169.587, 169.508, 169.466, 169.362, 169.024, 168.497, 168.309, 168.233, 132.546, 132.372, 124.274, 123.740, 122.924, 122.580, 122.395, 121.882, 120.257, 119.773,
  • EXAMPLE 24 R 1p is as defined in Table 2 under "Ex. 24": 1 :1 mixture of 2 conformers; 13 C-NMR(125.8 MHz, CDCI 3 ): 173.857, 173.161 , 172.469, 171.430, 170.826, 170.720, 169.573, 169.476, 169.321, 169.280, 169.200, 168.632, 168.385, 168.102, 165.177, 164.598, 132.576, 132.305, 124.283, 123.754, 122.937, 122.601 , 122.419, 122.003, 120.201 , 119.711 , 119.082, 118.514, 108.972, 108.715, 108.526, 106.798, 75.017, 74.644, 66.648, 65.849, 65.557, 65.272, 61.446, 59.766, 59.559, 57.326, 48.024, 47.909, 47.350, 47.113,
  • R ⁇ p is as defined in Table 2 under "Ex. 25": 1 :1 mixture of 2 conformers; 13 C-NMR(125.8 MHz, CDCI 3 ): 176.866, 176.382, 173.954, 173.096, 172.479, 172.443, 171.473, 170.813, 170.761 , 169.873, 169.640, 169.569, 169.482, 169.044, 168.470, 168.264, 132.574, 132.371 , 124.282, 123.750, 122.
  • Triacetoxy-1 ,1-dihydro-1 ,2-benziodoxol-3(1 H)-one (Des Martin periodinane) and 360 ⁇ l of pyridine are added and the mixture obtained is stirred at RT for ca. 3 hours.
  • the organic layer is dried and the solvent is evaporated off.
  • the evaporation residue obtained is subjected to chromatography.
  • Example 52 Production of a compound of formula lA ⁇ r , wherein R 5E ⁇ r , ⁇ E x. and R 7EXr are as defined in example 51 and R 1EXr is -CH 2 -CH 2 -COOH
  • a compound of example 51 is saponified by treatment with NaOH in a mixture of THF/water.
  • a compound of formula 51 wherein R 1EXr is -CH 2 -CH 2 -COOH is obtained.
  • 13 C-NMR 173.931 , 173.383,171.804,171.728, 171.649, 170.681 , 168.510, 168.407, 132.152, 123.980, 123.224, 122.744, 120.537, 119.947, 119.530, 108.637, 107.027, 75.260, 66.206, 64.095, 60.931 , 60.628, 57.734, 48.182, 47.410, 47.147, 38.865, 37.323, 36.903, 36.754, 36.359, 33.106, 30.631 , 30.341 , 29.218, 28.977, 28.852, 28.663, 28.391 , 28.184, 26.064, 24.947, 23.875, 2
  • a compound of example 50 is treated with carbonyldiimidazole in apolar solvent, a compound of example 50 formula I, wherein wherein R 7E x r is a group of
  • reaction mixture obtained is diluted with 600 ml of EtAc/cyclohexane (1 :1) and washed with aqueous 1 M NaH 2 PO 4 solution.
  • the phases obtained are separated, the organic layer is dried, the solvent is evaporated off, the evaporation residue obtained is subjected to chromatography and size exclusion.
  • Compound-containing fractions are subjected to lyophilisation from dioxane.
  • R 5EXr and R 6E ⁇ . are CH 3
  • the evaporation residue obtained is subjected to gel permeation chromatography (Sephadex LH-20, methanol/EtAc 1 :1). The product fractions obtained are evaporated.
  • the evaporation residue obtained is treated with 1.5 ml of THF and the solution obtained is treated with 5 mg of tetrakis-triphenylphosphine palladium and 42 ⁇ l of pyrrolidine at 0° for ca. 1 hours.
  • the mixture obtained is diluted with EtAc, washed with diluted hydrochloric acid, Na 2 CO 3 solution and brine, dried and the solvent is evaporated off.
  • the evaporation residue obtained is dissolved in 1 ml of toluene, 200 ⁇ l of TFA are added and the mixture obtained is stirred for ca. 4 hours at RT.
  • the mixture obtained is diluted with EtAc, the mixture obtained is washed with diluted hydrochloric acid, NaHCO 3 solution and brine, dried and the solvent is evaporated off.
  • the evaporation residue obtained is mixed with 2 ml of acetonitrile and diisopropylethylamine is added to adjust a slightly basic pH.
  • the mixture obtained is added to a solution of 57 mg of [O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate and 9 ⁇ l of diisopropylethylamine in 10 ml of acetonitrile during ca. 10 hours.
  • the mixture obtained is diluted with EtAc and the organic phase is washed and dried and the solvent is evaporated off.
  • the evaporation residue is subjected to silica gel chromatography (gradient toluene/methanol 0.5% to 3%) and gel permeation chromatography.
  • a compound of formula EX69C is obtained in the form of a solid.
  • R 5E ⁇ r and R 6EX . are CH 3
  • a compound of formula EX79-i may be obtained according to example 13, "Production of a compound of formula EX13.”
  • EX.37 1 H-NMR: 173.222, 172.925, 171.863, 171.483, 170.651 , 168.357, 168.304, 132.138, 123.874, 123.271 , 122.784, 119.937, 119.084, 108.759, 106.872, 74.877, 66.243, 64.177, 60.697, 57.732, 51.772, 48.184, 47.360, 47.116, 38.816, 38.741 , 37.480, 36.854, 36.757, 36.380, 30.536, 29.969, 29.223, 29.028, 28.958, 28.876, 28.631 , 28.394, 26.078, 24.942, 23.845, 23.590, 23.101 , 22.926, 22.807, 22.013, 20.452, 19.109, 19.042, 18.866, 17.981 , 14.527, 14.464, 14.408.
  • EX.49 3 C-NMR: 172.976, 171.873, 171.594, 170.549, 169.129, 168.498, 168.138, 142.772, 132.215, 123.817, 123.265, 122.855, 120.971, 119.840, 119.081, 108.814, 106.838, 106.603, 73.950, 66.240, 64.161, 60.925, 57.850, 48.060, 47.492, 47.215, 36.781, 36.719, 36.463, 31.246, 30.556, 29.196, 29.041 , 28.956, 28.817, 28.699, 28.040, 24.939, 23.747, 23.686, 23.047, 22.924, 22.791, 22.145, 20.463, 19.176, 18.881, 14.455, 14.402.
  • EX.58 13 C-NMR: 172.793, 171.624, 171.490, 170.701 , 170.218, 169.325, 167.941 , 167.887, 132.224, 131.875, 123.513, 122.874, 122.404, 119.651 , 119.241 , 118.561 , 108.417, 106.504, 73.725, 65.830, 63.691 , 60.454, 57.505, 47.744, 47.085, 46.937, 38.462, 37.150, 36.386, 36.083, 30.265, 28.802, 28.632, 28.583, 28.562, 28.372, 28.019, 27.789, 24.583, 23.388, 23.213, 22.657, 22.542, 22.408, 21.767, 20.041 , 19.527, 18.824, 18.633, 18.470, 14.029, 13.991 , 10.537.
  • EX.60 13 C-NMR: 177.138, 177.013, 173.056, 172.225, 171.901 , 170.629, 170.130, 169.670, 168.371 , 168.011 , 132.232, 123.833, 123.298, 122.835, 120.058, 118.994, 108.819, 106.795, 74.283, 66.231 , 63.823, 60.837, 57.822, 48.092, 47.312, 47.184, 38.730, 37.373, 36.847, 36.695, 36.487, 31.158, 29.180, 29.006, 28.961 , 28.872, 28.695, 28.431 , 28.203, 27.215, 27.094, 24.936, 23.873, 23.767, 23.497, 23.029, 22.790, 22.748, 22.089, 21.856, 20.395, 19.381 , 19.096, 18.850, 17.429, 14.432, 14.383,
  • EX.62 13 C-NMR: 179.987, 176.986, 173.064, 172.211, 171.894, 170.644, 170.141, 169.600, 168.384, 167.999, 132.217, 123.832, 123.292, 122.809, 120.030, 118.987, 108.809, 106.785, 74.385, 66.229, 63.826, 60.796, 57.830, 48.087, 47.337, 47.196, 38.678, 37.367, 36.846, 36.671, 36.499, 31.146, 29.177, 29.006, 28.964, 28.873, 28.731, 28.438, 28.134, 27.922, 27.151, 24.945, 23.701 , 23.483, 23.018, 22.837, 22.791 , 22.754, 22.093, 21.971, 20.393, 19.908, 19.096, 18.861, 17.412, 14.426, 14.383, 13.772.
  • EX.63 13 C-NMR:180.133, 176.986, 173.063, 172.210, 171.891, 170.683, 170.141, 169.597, 168.377, 168.007, 132.160, 123.825, 123.289, 119.997, 118.992, 108.591, 106.771, 74.371, 66.227, 66.056, 63.825, 60.773, 57.821, 48.083, 47.328, 47.182, 38.676, 36.847, 36.668, 31.155, 29.181, 29.008, 28.962, 28.419, 27.098, 25.771, 24.941, 23.766, 23.477, 23.012, 22.836, 22.792, 22.092, 21.946, 20.396, 19.090, 18.850, 17.405, 14.433, 14.391, 13.846.
  • EX.72 13 C-NMR: 207.23, 173.42; 171.93; 171.71 ; 171.13; 170.72; 168.59; 168.37 (carbonyls); 75.39; 64.10, 60.64; 57.72; 48.29; 47.43; 47.16 (alpha-C's); 72.06 ((CH3)2CHO-); 73.47 (-CH2O-).
  • EX.73 13 C-NMR: 07.28, 173.35; 171.95; 171.73; 171.13; 170.69; 168.54; 168.38 (carbonyls); 75.57; 64.11 , 60.68; 57.76; 48.26; 47.43; 47.18 (alpha-C ' s); 66.21 (CH3CH2O-).
  • EX.75 13 C-NMR: 172.98; 172.05; 171.95; 171.14; 170.50; 168.42; 168.24 (carbonyls); 160.25 / 151.70 / 122.85 (oxazol).
  • EX.77 13 C-NMR: 172.96; 172.08; 171.99; 171.11 ; 170.4;168.37; 168.25 (carbonyls); 160.04 / 153.08 / 123.30 (oxazol); 65.94 (oxazolyl-CH2O-); 57.8 (-OCH3).
  • EX.78 13 C-NMR: 172.93; 172.06; 172.01 ; 171.12; 170.48; 168.33; 168.23 (carbonyls); 153.94 / 153.58 / 123.64 (oxazol), 115.80 (-CN).
  • the solvent of the organic layer obtained is evaporated off and the evaporation residue obtained is heated with 12.5 g of N-ethylthiourea in 45 ml of dry ethanol under argon atmosphere at ca. 80° for ca. 48 hours. From the mixture obtained the solvent is evaporated off. To the evaporation residue obtained 300 ml of toluene are added and the mixture obtained is extracted with 20% aqueous K 2 HPO 4 . the organic layer obtained is dried, the solvent is evaporated off and the evaporation residue is subjected to chromatography. A compound of formula IV EXs in the form of an 1 : 2 mixture of 2 conformers is obtained.
  • the evaporation residue obtained is dissolved in 1.8 I of acetonitrile, the solution obtained is cooled to 0° and 5.3 g of a coupling reagent (BOP, equivalent to HATU) and 2.6 ml of DIEA are added and the mixture obtained is stirred at RT for ca. 24 hours. From the mixture obtained the solvent is evaporated off, the evaporation residue obtained is dissolved in EtAc, the mixture obtained is extracted with 1 M aqueous HCI, saturated NaHCO 3 solution and brine, the solvent of the organic layer obtained is evaporated off and the evaporation residue obtained is subjected to chromatography.
  • BOP a coupling reagent
  • a compound of formula IA S wherein R 2s is methoxy and R 1s is a group -CH 2 -COOtert.butyl in the form of a 4:1 mixture of 2 conformers is obtained.
  • step F 50 mg of compound obtained in example 85, step F) is treated with piperidine and HATU in DMF and to the mixture obtained DIEA is slowly added at ca. 0°. The mixture obtained is left for ca. 1.5 hours and a mixture of EtAc/c-Hex (1/2) is added. The mixture obtained is extracted with 1 M aqueous HCI, saturated NaHCO 3 solution and brine, the solvent is evaported off and the evaporation residue obtained is subjected to chromatography.
  • a compound of formula IA S wherein R 2s is methoxy and R ⁇ s is a group of

Abstract

The use of inhibitors of adhesion molecule expression, e.g. cyclopeptolides or cyclopeptides, in the preparation of a medicament for the treatment of vascular endothelial cell growth factormediated diseases and novel cyclopeptolides and cyclopeptides.

Description

VEGF inhibitors
The present invention relates to inhibitors of the expression of the vascular endothelial cell growth factor (VEGF-inhibitors). VEGF is a secreted protein produced by a variety of cells in vascularized tissues where it plays a critical role in angiogenesis (formation of new blood vessels) by stimulating endothelial cell growth and modulating capillary permeability. Because of these activities, VEGF may play a prominent role in inflammatory processes and disease pathogenesis. VEGF-inhibitors exhibit pharmacological activity and are therefore useful as pharmaceuticals, e.g. in the treatment or prophylaxis of VEGF-mediated events. VEGF-inhibitors may be useful in the treatment or prophylaxis of pathogenic processes, e.g. capillary nonperfusion, angiogenesis and neovascularization that contribute to diseases, e.g. including arteriosclerosis, cancer, chronic transplant rejection, psoriasis, rheumatoid arthritis and eye diseases, such as proliferative retinopathies and macular degeneration.
Cellular adhesion molecules, such as ICAM-1 , are expressed on the surface of endothelial cells and keratinocytes, in response to pro-inflammatory mediators including TNFα, IFNγ, IL1 and LPS. Corresponding counter-ligands, e.g. LFA-1 , VLA-4 and SLEX, are expressed on the surface of circulating blood cells. Transendothelial migration of leucocytes during inflammatory processes, as well as extravascular cell-cell interactions, are regulated as a result of the interactions between these adhesion molecules and their counterligands. Inhibitors of the stimulated expression of cellular adhesion molecules, especially inhibitors of VCAM-1 relative to E-selectin and ICAM-1 expression, exhibit pharmacological activity and are therefore useful as pharmaceuticals. The effect on VCAM-1 expression inhibition occurs at both transcriptional and posttranscriptional levels. Thus inhibitors of the stimulated expression of cellular adhesion molecules are useful for the treatment or prophylaxis of disease processes which involve expression of cellular adhesion molecules.
These disease processes include many acquired and inherited diseases/disorders where leucocyte trafficing plays a prominent role in the pathogenic process, most notably acute and chronic inflammation (e.g. allergy, asthma, psoriasis, reperfusion injury, rheumatoid arthritis and septic shock) and autoimmune states (e.g. multiple sclerosis). Other indications include tumor metastasis (e.g. melanoma, osteocarcinoma) and allograft/xenograft rejection, since it is known that inhibition of vascular adhesion molecules can greatly improve the prognosis of these processes. In addition, inhibitors of the expression of cellular adhesion molecules have therapeutic potential in hyperproliferatJve skin diseases (e.g. psoriasis) as well as various malignancies. Inhibitors of the expression of cellular adhesion molecules are active in inhibiting TNFα- or IL6-induced HIV production in the U1 monocytic cell line, as evaluated by p24 ELISA and are therefore also useful in the treatment of immunodeficiences and virally caused diseases, especially in the treatment of AIDS.
We have found that inhibitors of adhesion molecule expression, especially VCAM-1 expression inhibitors, additionally act as VEGF-inhibitors. Compounds which act as inhibitors of adhesion molecule expression and additionally as VEGF-inhibitors offer potential for the treatment of many disease states.
In one aspect the present invention provides the use of inhibitors of adhesion molecule expression in the preparation of a medicament for the treatment of vascular endothelial cell growth factor-mediated diseases, e.g. including diseases as described above, e.g. diseases wherein processes, e.g. capillary nonperfusion, angiogenesis, neovascularization, tumor growth and metastasis, contribute to the pathogenesis or severity of said disease, such as
- eye diseases involving vision impairment or loss, e.g. proliferative retinopathies and macular degeneration, including ischemic retinopathies, uveoretinitis and degenerative eye diseases,
- arteriosclerosis associated with chronic transplant rejection and coronary heart disease, - solid tumor malignancies and other cancers, e.g. Kaposi's sarcoma,
- psoriasis, rheumatoid arthritis.
In another aspect the present invention provides the use of inhibitors of adhesion molecule expression in the preparation of a medicament for the treatment of eye diseases leading to vision impairment or loss, such as proliferative retinopathies and macular degeneration, including ischemic retinopathies, uveoretinitis and degenerative eye diseases.
Treatment includes therapeutical treatment and prophylaxis.
Cyclopeptides are cyclic molecules comprising amino acid residues linked together by peptide bonds, cyclopeptolides further comprise one hydroxy substituted carboxylic acid residue which is linked through its hydroxyl substituent to the neighbouring acid residue by an ester linkage. Cyclopeptolides are e.g. described in WO 96/03430 and in WO 97/19104 for use as inhibitors of adhesion molecule expression. According to the finding of the present invention cyclopept(ol)ides act additionally as VEGF-inhibitors.
The content of WO 96/03430 and WO 97/19104 is introduced herein by reference. We have also found cyclopept(ol)ides, e.g. compounds of formula lp, lr and ls, which are VEGF- inhibitors and additionally act as inhibitors of adhesion molecule expression.
Inhibitors of adhesion molecule expression which, according to the present invention, act additionally as VEGF-inhibitors, thus include cyclopeptides and cyclopeptolides, e.g. such as described above.
In another aspect the present invention provides the use of cyclopept(ol)ides, e.g. including cyclopeptolides of WO 96/03430 and WO 97/19104, e.g. of formula I, and of formula lp, and lr and cyclopeptides of formula ls, in the preparation of a medicament for the treatment of vascular endothelial cell growth factor-mediated diseases.
Cyclopeptolides as described in WO 96/03430 and WO 97/19104 are of formula I, and in another aspect the present invention provides a compound of formula r— A - B - R^eu - Leu - Z - X - Y-
wherein: A is - a glycolic acid residue optionally α-substituted by methyl or vinyl, optionally substituted by
- halogen.alkoxy, optionally protected hydroxy or amino, CSNH2, vinyl, -C≡CH, thiazolyl or COOR2, wherein R2 is H or lower alkyl, optionally substituted by
- alkyl, halogen, cycloalkyl, optionally substituted thiazolyl, -C≡CH or COOR2 wherein R2 is as defined above; - an α-hydroxy-substituted butyric or valeric acid residue β-substituted by
- halogen, alkoxy, optionally protected hydroxy or amino, CSNH2) vinyl, -C≡CH, thiazolyl or COOR2, wherein R2 is H or lower alkyl, optionally substituted by
- alkyl, halogen, cycloalkyl, optionally substituted thiazolyl, -C≡CH or COOR2, wherein R2 is as defined above; or - an α-hydroxy-substituted butyric acid residue optionally γ-substituted by R6, wherein R6 is
- CN, COOR3, wherein R3 is hydrogen or optionally arylsubstituted alkyl, CONR4R5, wherein R and R5 are the same or different and represent hydrogen or alkyl or form together with the nitrogen to which they are attached a 3- to 6-membered ring, optionally containing a second heteroatom, COR7, wherein R7 represents hydrogen or lower alkyl, CSNH2, or alkyl, optionally substituted by
- azido, halogen, alkoxy, optionally protected hydroxy or amino, CSNH2, thiazolyl, vinyl, which may be substituted by alkyl, halogen or CN, cycloalkyl, tetrazolyl, -C≡CH, or COOR'2, wherein R'2 is hydrogen or lower alkyl, optionally substituted by alkyl, halogen, cycloalkyl, optionally substituted thiazolyl, -C≡CH or COOR"2, wherein R"2 is hydrogen or lower alkyl, B is an α-amino-γ-methyl-substituted octanoic acid residue; R. is hydrogen or methyl; Z is a tryptophan residue, e.g. of formula
Figure imgf000005_0001
wherein R9is hydrogen, alkoxy, alkyl or benzyl, R10is hydrogen or halogen, Rn is hydrogen or methyl and ^^ is a single or double bond, X is an α-amino-substituted (C2-ι4)carboxylic acid residue, and Y is an α-amino- or N-methyl-α-amino substituted (C2.10)carboxylic acid residue; in the preparation of a medicament for the treatment of vascular endothelial cell growth factor- mediated diseases.
In formula I the C-terminal to N-terminal orientation of the amino acid residues is in the clockwise direction, and the peptolide ester bond is between residues A and Y. In a compound of formula I A is preferably
- a glycolic acid residue which is optionally α-substituted by methyl, which methyl is optionally substituted by amino, hydroxy, chloro, alkoxy, optionally substituted thiazolyl, optionally substituted vinyl, cyclopropyl, CSNH2 or -C≡CH;
- an α-hydroxy-substituted butyric or valeric acid residue which is optionally β-substituted by amino, hydroxy, chloro, alkoxy, optionally substituted thiazolyl, optionally substituted vinyl, cyclopropyl, CSNH2 or -C≡CH;
- an α-hydroxybutyric acid residue, which is γ-substituted by - CN, optionally protected CH2OH, COOR2, wherein R2> is hydrogen or optionally arylsubstituted alkyl, CONR3'R4>, wherein R3> and R4> are the same or different and are hydrogen or alkyl, or R3> and R < together with the nitrogen to which they are attached form a 5 or 6- membered ring optionally containing a second heteroatom, CORff, wherein Rff is hydrogen, or -CH=CH2; alkyl optionally substituted by
- azido, halogen, alkoxy, optionally protected amino or hydroxy, vinyl, optionally substituted by alkyl, halogen or CN; cycloalkyl, tetrazolyl, -C≡CH, optionally substituted thiazolyl, or CSNH2; Z is preferably a tryptophan residue of formula II, wherein R9 is hydrogen, alkoxy, alkyl or benzyl, Rι0 is hydrogen or halogen and Rn is hydrogen or methyl; X is preferably an α-amino-substituted (C2.14)carboxylic acid residue, more preferably X is an α-amino-β- or γ-(C1-4) alkyl-, especially methyl-, substituted octanoic or butyric acid residue, Y is preferably an N-methyl-α-amino-substituted (C2.io)carboxylic acid residue, more preferably Y is an N-methyl-alanine or N-methyl-valine residue.
E.g. the compounds of formula I comprise asymmetric C-atoms and substituents attached to asymmetric C-atoms may be in either in the R or in the S configuration.
In another aspect the present invention provides the use as defined above of the compound 5- [8,11-Diisobutyl-14-(1-methoxy-1 H-indol-3-ylmethyl)-7,13,19,20-tetramethyl-5,17-bis-(2-methyl- hexyl)-3,6,9,12,15,18,21 -heptaoxo-1-oxa-4,7,10,13,16,19-hexaaza-cycloheneicos-2-yl]-pent-2- enoic acid methyl ester and of a compound of formula
Figure imgf000006_0001
wherein RιA, M and R3Aare as defined in TABLE 1 below, and ^ is a double bond in No.1 to 34, 36 and 38 to 46 and a single bond in No. 35 and 37; R4A is methoxy in No. 1 to 16, 18 to 30, and 40 to 44, hydrogen in No. 17; 37 and 45, methyl in No. 31 and 46, ethyl in No. 32, benzyl in No. 33 and 35, a group of formula -CH2C(CH3)3 in No. 34, isopropyl in No.36, n-propoxy in No. 38; ethoxy in No. 39; and R5A is hydrogen in No. 1 to 39 and 41 to 46 and Br in No. 40; e.g. compounds such as exemplified in WO 96/03430 and WO 97/19104:
TABLE 1
Figure imgf000007_0001
Figure imgf000008_0001
A compound of formula I includes a compound of formula IA.
We also have found novel cyclopeptolides which are inhibitors of adhesion molecule expression, especially VCAM-1 relative to ICAM-1 and E-selectin expression inhibitors, and additionally act as VEGF-inhibitors, e.g. compounds of formula lp, lr and ls.
A substituent in γ-position of an α-hydroxy-substituted butyric acid residue in the meaning of A in a compound of formula I includes a substituent R6 as defined above and we have found that
R6 may be also selected from the groups
- -COO-R2p, wherein R2p is alkyl substituted by CF3,
- -CO-CH2-O-R3p, wherein R3p is alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl or acyloxyalkyl,
- -COO-CH2-O-CO-R4p, wherein R p is alkyl, e.g. alkyl substituted by a sugar residue;
- of formula
Figure imgf000009_0001
wherein R5p is hydrogen or a substitutent, e.g. in position 2 of the ring system; such as alkyl, cyanoalkyl, alkoxyalkyl,
-C(=N-R6p)NH2, wherein R6p is hydrogen or a substituent, e.g. hydroxy, and of formula
Figure imgf000009_0002
wherein R7p is hydrogen or a substitutent, such as alkyl, e.g. (C^alkyl.
In another aspect the present invention provides a compound, i.e. a cyclopeptolide, of formula
Figure imgf000009_0003
wherein
R1p is selected from the groups
- -CH2-CH2-COO-R2p, wherein R2p is alkyl substituted by CF3,
- -CH2-CH2-CO-CH2-O-R3p, wherein R3p is alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl or acyloxyalkyl,
- -CH2-CH2-COO-CH2-O-CO-R4p, wherein R4p is alkyl,
- of formula
Figure imgf000010_0001
wherein R5p is hydrogen or a substitutent, such as alkyl, cyanoalkyl, alkoxyalkyl, e.g. in position 2 of the ring system;
- -CH2-CH2-C(=N-R6p)NH2, wherein R6p is hydrogen or a substituent, e.g. hydroxy,
- a group of formula
Figure imgf000010_0002
wherein R7p is hydrogen or a substitutent, such as alkyl, e.g. (C^alkyl; and R'2p is hydrogen, alkyl, alkoxy or aralkyl, preferably alkoxy, such as methoxy.
In another aspect the present invention provides a compound of formula lp, wherein R'2p is methoxy and Rιp is as defined in TABLE 2:
TABLE 2
Figure imgf000010_0003
Figure imgf000011_0001
Figure imgf000012_0001
A compound of formula I includes a compound of formula IA, and, generically, a compound of formula lD. In another aspect the present invention provides a compound, i.e. a cyclopeptolide, of formula
Ar-Br-Leu*-Leu-Dr-Xr-Yr
wherein
Ar is a glycolic acid residue; e.g. which is α-substituted by alkyl, which alkyl is optionally substituted by aryl, optionally protected hydroxy, cyano, heterocyclyl, iminoaminocarbenyl,, diazoketone or a group -COR, wherein R is OH, alkyl, alkoxy, alkenyloxy, amino;
Br is an α-amino-γ -methyl-substituted octanoic acid residue;
Leu* is leucin or N-methyl leucin, preferably N-methyl leucin,
Leu is leucin;
Dr is a tryptophan residue, e.g. of formula
Figure imgf000013_0001
wherein
R2ris hydrogen, alkoxy, alkyl or aralkyl,
R3r is hydrogen or halogen,
R4r is hydrogen or alkyl, and
— is a single bond or a double bond, Xr is an α-amino-substituted (C2-ι4)carboxylic acid residue, and Yr is an α-amino- or N-methyl-α-amino substituted (C2,ι0)-carboxylic acid residue wherein position α is trisubstituted, e.g. in addition to the α-amino- or N-methyl-α-amino substitution further disubstituted.
In formula lr the ester bond is between residues A. and Yr. In a compound of formula lr Ar is preferably a group of formula
Figure imgf000014_0001
wherein
Rιr is alkyl, e.g. unsubstituted alkyl; or substituted alkyl, e.g. including alkyl substituted by
- cyano, a diazoketone, e.g. a group of formula -CO-CH=N+=N";
- heterocyclyl, e.g. including a 5 or 6 membered ring (system) having 2 to 3 heteroatoms selected from N,O and S, such as a thiazolyl, oxadiazolyl, oxazolyl, e.g. unsubstituted heterocyclyl or substituted heterocyclyl, e.g. including heterocyclyl substituted by
- alkyl, e.g. (Cι-6)alkyl, alkoxycarbonylalkyl, alkoxyalkyl, cyanoalkyl;
- a group CORr', wherein Rr' is
- OH, alkoxy, e.g. (Cι-5)alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkylcarbonyloxyalkoxy; alkyl, e.g. including hydroxyalkyl, alkoxyalkyl;
- alkenyloxy, amino, iminoaminocarbenyl, e.g. a group -C(=NR8r)NH2, wherein R8r is a substituent, e.g. hydroxy;
- alkoxycarbonyloxyalkoxy, e.g. which alkyloxycarbonyloxyalkoxy is further substituted by a sugar residue;
Dr is preferably a tryptophan residue of formula llr, wherein R2r is hydrogen, R3r is hydrogen;
R r is alkoxy, such as methoxy; and -^ is a double bond; Xr is preferably an α-amino (C4-8)carboxylic acid residue substituted in position β and/or γ, e.g. by alkyl, such as (C^alkyl, e.g. an α-amino-butyric or octanoic acid residue, preferably octanoic acid residue, preferably substituted in position γ by alkyl, such as methyl; Yr is preferably a group of formula
Figure imgf000014_0002
wherein
R5r is H or alkyl, e.g methyl;
R6r is alkyl, e.g. methyl;
R?r is
- alkyl, (Cι-6)alkyl,e.g. unsubstituted alkyl or alkyl substituted by - aryl, hydroxy or acyloxy, e.g. (Cι-6)alkylcarbonyloxy or heterocyclylcarbonyloxy, e.g. imidazolylcarbonyloxy;
- alkenyl, e.g. (C2_s)alkenyl, such as (C3.5)alkenyl;
- a group -CHO or hydroxyiminocarbenyl, e.g. a group -C=N-OH, or
R6r and R7r together form a cycloalkyl ring, e.g. spiro attached to that carbon atom of the ring system where R6r and R7r are attached.
In another aspect the present invention provides a compound of formula
Figure imgf000015_0001
wherein Rιr, R5 r, R6r and R7r are as defined above and R2|Ar has the meaning of R2r, preferably methoxy.
A compound of formula lr includes a compound of formula IAr.
In another aspect the present invention provides a compound, i.e. a cyclopeptide, of formula
-As-Bs-Leu*-Leu-Ds-X-
wherein
As is an α-amino carboxylic acid residue;
Bs is an α-amino-γ -methyl-substituted octanoic acid residue;
Leu* is leucin or N-methyl leucin, preferably N-methyl leucin,
Leu is leucin;
Ds is a tryptophan residue, e.g of formula
Figure imgf000016_0001
wherein
R2s is hydrogen, alkoxy, alkyl or aralkyl, R3s is hydrogen or halogen, R4s is hydrogen or alkyl, ^z is a single bond or a double bond, and Xs is an α-amino-carboxylic acid residue, e.g. an α-amino-substituted (C2.ι )carboxylic acid residue.
In formula lr and in formula ls the N-terminal to C-terminal orientation of the amino acid residues is in the clockwise direction.
In a compound of formula ls
As is preferably a group of formula
Figure imgf000016_0002
wherein R1s is alkyl or alkenyl, preferably alkyl,
Ds is preferably a tryptophan residue of formula lls, wherein R4s is hydrogen, R3s is hydrogen; R2s is alkoxy, such as methoxy; and _^_ is a double bond; and
Xs is preferably an α-amino (C4.8)carboxylic acid residue, e.g. substituted in position β and/or γ, e.g. by alkyl, such as (Cι- )alkyl, such as an α-amino-butyric or octanoic acid residue, preferably octanoic acid residue, preferably substituted in position γ by alkyl, such as methyl.
In another aspect the present invention provides a compound of formula
Figure imgf000017_0001
wherein Rιs and R2s are as defined above.
A compound of formula ls includes a compound of formula IAS. In a compound of formula IAS, Rιs is preferably alkyl and R2s is preferably methoxy. Ris is more preferably substituted alkyl, e.g. substituted by a group CY'sR's, wherein Y's is S or O, preferably O; and
R's is H, OH, alkyl, alkenyl, cycloalkyl, aryl, alkoxy, e.g. (C^alkoxy, alkenyloxy, cycloalkyloxy, e.g. (C3.7)cycloalkoxy, alkylthio, arylthio, amino, e.g. unsubstituted and substituted amino, e.g. amino substituted by one or more alkyl, e.g. (Cι-6)alkyl or alkoxy, e.g. (C^alkoxy; or R's is heterocyclyl, e.g. including a 5 or 6 membered ring system containing 1 to 4 heteroatoms selected from N, O and S; preferably from N and O; preferably aliphatic heterocyclyl, such as a pyrrolidine, piperidine, piperazine, hexahydro-1H-azepine, morpholine; including an anelleted heterocyclic ring system, e.g. a heterocyclic ring anelleted with a cycloalkyl ring, e.g. piperidine annelleted with cyclohexyl; and including spiro heterocyclyl, such as a heterocyclic ring spiro attached to another ring, e.g. such as a cycloalkyl, e.g. (C^cycloalkyl, ring or spiro attached to another hetercyclic ring, e.g. a piperidine ring spiro attached to (Cs^cycloalkyl, or 1 ,3- dioxacycloalkyl, such as 1 ,3-dioxa(C-5-6)cycloalkyl, e.g. including unsubstituted heterocyclyl and substituted heterocyclyl, e.g. substituted by one or more groups, such as conventional in organic chemistry, e.g. substiuted by heterocyclyl, e.g. pyrrolidinyl, piperidinyl, alkyl. More preferably preferably R's is OH, amino, alkoxy or heterocyclyl. If not otherwise defined herein alkyl includes (d^alkyl, such as (C^alkyl, e.g. (CM)alkyl. Lower alkyl includes (C^alkyl. Cycloalkyl includes (C3.7)cycloalkyl. Aryl includes phenyl. Heterocyclyl includes a 5 or 6 membered ring system having 1 to 4 heteroatoms, such as 1 to 3, e.g. selected from N, O, S. Heterocyclyl e.g. includes heterocyclyl anellated with another ring (system) and e.g. heterocylclyl spiro attached to another ring (system). Alkenyl includes (C2-22)alkenyl, e.g. (C2-6)alkenyl. Acyl includes alkylcarbonyl. Hydroxy includes unprotected hydroxy and protected hydroxy. Amino includes unsubstituted amino or substituted amino, e.g. including protected amino, e.g. amino substituted by one or two alkyl, aryl, alkoxy. Any group may be substituted or unsubstituted, e.g. subsitutents includes groups as conventional in organic chemistry, such as halogen, amino, nitro, cyano, hydroxy, cycloalkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, heterocyclyl, acyl and thioacyl, e.g. a group of formula CY'R', wherein Y' is S or O and R' is H, OH, amino, alkyl, alkenyl, cycloalkyl, aryl, alkoxy, e.g. (C^alkoxy, alkenyloxy, alkylthio, arylthio or heterocyclyl.
The present invention beside cyclic pept(ol)ides includes open chain pept(ol)ides corresponding to cyclic pept(ol)ides as described herein, wherein a bond of the cyclic compound is split; e.g. the present invention includes open chain peptolides according to compounds of formula I; e.g. open chain compounds obtainable by either cleavage of the ester bond between residues Y and A or cleavage of an amide linkage between any other adjacent pair of the acid residues.
In another aspect the present invention provides the use of a compound of formula
H - Z - X - Y - A - B - RιLeu - Leu-OR7o IV or HA - B - RiLeu - Leu - Z - X - Y-OR^ V wherein R7o is hydrogen or alkyl, and Z, X, Y, A, B, R^eu and Leu are as defined above, in the preparation of a medicament for the therapy, e.g. or prophylaxis, of vascular endothelial growth factor (VEGF)-mediated diseases.
Compounds provided by the present invention, including the compounds provided for the VEGF-inhibition use of the present invention, are hereinafter designated as "compound(s) of the present invention". A compound of the present invention includes a compound in any form, e.g. in free form, in the form of a salt, in the form of a solvate and in the form of a salt and a solvate. In another aspect the present invention provides a compound of formula lp, lr, ls, IAr and IAS in the form of a salt, or in the form of a salt and in the form of a solvate, or in the form of a solvate; e.g. and or in the form of an ester.
A salt of a compound of the present invention includes a pharmaceutically acceptable salt, e.g. including a metal salt or an acid addition salt. Metal salts include for example alkali or earth alkali salts; acid addition salts include salts of a compound of the present invention with an acid, e.g. hydrogen fumaric acid, fumaric acid, naphthalin-1 ,5-sulphonic acid, hydrochloric acid, deuterochloric acid; preferably hydrochloric acid.
A compound of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa. A compound of the present invention in free form or in the form of a salt and in the form of a solvate may be converted into a corresponding compound in free form or in the form of a salt in unsolvated form; and vice versa.
A compound of the present invention may be converted into an ester and vice versa, in case of the presence of a group which is convertible into an ester, such as of a carboxylic acid group.
A compound of formula of the present invention may be in the form of an ester such as a physiologically-hydrolysable and -acceptable ester. By physiologically-hydrolysable and - acceptable esters as used herein is meant an ester in which the -COO- group of a carboxylic acid group is esterified and which is hydrolysable under physiological conditions to yield an acid which is itself is physilogically tolerable at dosages to be administered. The term "a compound of the present invention in the form of an ester" is thus to be understood as defining regular pro-drug forms of compounds of the present invention.
A compound of the present invention in the form of a salt or a solvate or an ester exhibit a similar order of pharmaceutical activity as a compound of the present invention in free from. A compound of of the present invention may exist in the form of isomers and isomeric mixtures thereof, e.g. optical isomers, epimers, cis trans configurated isomers, conformers. A compound of the present invention e.g. contains asymmetric carbon atoms and may thus exist in the form of diastereoisomeris and epimers and mixture thereof. Isomeric, diastereoisomeric and epimeric mixtures may be separated as appropriate, e.g. according to a method as conventional, to obtain pure isomers. Pure isomers may also be produced as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as described herein. The present invention includes a compound of the present invention in any isomeric form and in any isomeric mixture, e.g. R-forms, S-forms and mixtures of R- and S- forms.
Any compound mentioned herein, e.g. including compounds according to the present invention may be obtained as appropriate, e.g. according to, e.g. analogously, to a process as conventional, e.g. as described in WO 96/03430 or in WO 97/19104, e.g. or as described herein.
In another aspect the present invention provides a process for the production of a compound of formula lr comprising deprotonating the α-carbonyl atom in Y'r in a compound of formula
Ar-Br-Leu*-Leu-Dr-Xr-Y'r
III, wherein Ar, Br, Leu*, Leu, Dr and Xr are as defined above and Y'r is an α-amino- or N-methyl-α- amino substituted (C2.10)-carboxylic acid residue wherein position α is in addition to the α- amino- or N-methyl-α-amino substitution further monosubstituted; e.g. Y' is a group of formula
Figure imgf000020_0001
wherein R5r and R6r are as defined above; and reacting a deprotonated compound of formula 11 lr- with an electrophile, e.g. including a compound of formula R7rX'r, wherein R7r is as defined above and X'r is a leaving group, e.g. bromide; to obtain a compound of formula lr.
A compound of formula lr is preferably produced by reacting a solution of a compound of formula lllr in a solvent which is inert under the reaction conditions, e.g. tetrahydrofurane, e.g. in the presence of a co-solvent, with a compound of formula R7rX'r, wherein R7r is as defined above and X'r is bromide, in the presence a base, e.g. phosphazene base P4-t-But, at appropriate temperature, preferably at low temperature.
A compound of formula lr wherein R5r, R6r and R7r are as defined above and Rir is a group of formula -C(=N-OH)-NH2 or oxadiazolyl, may be obtained, e.g. by reaction of a compound of formula lr wherein R1r is a group of formula =CH-CH2-CN and R5r, R6r and R7r are as defined above with hydroxylamine to obtain a compound of formula lr wherein R1r is a group of formula -C(=N-OH)-NH2 and R5r, R6r and R7r are as defined above; which compound may be further reacted, e.g. with a trimethyloxymethyl, e.g. unsubstituted or further substitued, e.g. substituted by alkyl, such as (Chalky!; to obtain a compound of formula lr, wherein R1r is an oxadiazolyl, e.g. an oxadiazol-2-yl, e.g. which oxadiazolyl is unsubstituted or substituted, e.g. substituted in position 5, e.g. by alkyl, such as (C1-4)alkyl. A compound of formula lr obtained may be isolated and purified, e.g. according to a method as conventional.
A compoud of formula lllr may be obtained according to a method as conventional, e.g. by fermentative production of a cyclic peptide structure as an intermediate which may be chemically converted as desired; e.g. according to a method as conventional; or by chemical synthesis; e.g. according to a method as conventional, e.g. in peptide synthesis; e.g. according to a method as disclosed in WO 97/19104 or WO 96/03430; or as described herein. If desired a group Rir in a compound of formula lr obtained may be converted further to obtain a compound of formula lr wherein Rιr has another meaning than in the compound obtained according to the above described procedures.
In another aspect the present invention provides a process for the production of a compound of formula ls comprising the steps a) subjecting a compound of formula
Awo-Bwo-Leu*-Leu-Cwo-Xw0-Ywo "~|
■wo
wherein AWo is an α-hydroxy-substituted butyric acid residue; B o is an α-amino-γ-methyl- substituted octanoic acid residue; Leu* is leucin or N-methyl leucin, Leu is leucin; CWo is a tryptophan residue, XWo i an α-amino-substituted (C2.ι4) carboxylic acid residue and Ywo is an α-amino- or α-methylamino-substituted (C2.i4) carboxylic acid residue, which is a compound of formula I of WO 96/03430, e.g. obtainable from a fermentation broth of a fungal strain NRRL 21123 as described in WO 96/03430, to ring opening; e.g. by treatment with sodium tetrahydroborate, to obtain a diol of formula lWo> wherein the bond between AWo and YWo is opened and wherein AWo is an α-hydroxy-substituted butyric acid residue which α-hydroxy-group is free, Ywo is 1-hydroxy-2-amino- or 2-methylamino- substituted (C2.1 )alkyl and BWo- Leu*, Leu, C and XWo are as defined above; b) replacing in a compound obtained in step a) the residue YWo by a group which may be
(e.g. reductively) removed, e.g. an allyloxy group; e.g. replacing the 1 -hydroxy-2-amino- or 2-methylamino-substituted (C2.14)alkyl in the meaning of YWo in a compound obtained in step a) by an allyloxy group, e.g. by treatment with allyl alcohol/methane sulfonic acid and N-methyl morpholine; c) splitting off a residue Awo in a compound obtained in step b) to obtain a corresponding compound wherein A o is removed and B o is an α-amino-γ-methyl-substituted octanoic acid residue wherein the amine group in position α is free, e.g. by treatment of a compound obtained in step b) with methanesulfonic acid chloride/N-methyl morpholine and N-ethylthiourea; d) converting in a compound obtained in step c) the free amine group in an α-amino-γ-methyl- substituted octanoic acid residue in the meaning of B o to obtain a compound of step c) wherein the amine group in position α in a group Bwo is acylated, e.g. acylated by a group
Figure imgf000022_0001
e.g. by reaction of a compound obtained in step c) with an acid of formula INTs-OH, e.g. in the presence of a coupling agent; e) ring formation, e.g. ring closuring of a compound obtained in step d), e.g. reductive, to obtain a compound of formula ls, wherein the substitutents are as defined above, e.g. forming an amide bond between a residue Xwo and a residue BWo in the presence of a coupling agent, thereby removing the allyloxy group in a residue YWo and removing the acyl group in a group BWo> e-9- in the presence of tetrakis(triphenylphosphane)-palladium.
A compound of formula ls obtained may be isolated and purified, e.g. according to a method as conventional. E.g. for the preparation of a compound of formula IAS wherein R1s and R2s are as defined above, a compound of formula
Figure imgf000023_0001
may be subjected to ring formation to obtain a compound of formula IAS wherein Rιs and R2s are as defined above.
The compounds of the present invention exhibit pharmacological activity and are therefore useful as pharmaceuticals. E.g. the compounds of formula I, lp, lr and ls are inhibitors of the stimulated expression of cellular adhesion molecules, especially inhibiting VCAM-1 relative to E-selectin and ICAM-1 expression, and additionally are inhibitors of the growth factor VEGF expression. Assays which may be used to detect the inhibition of VCAM-1 , ICAM-1 and E- selectin expression by the compounds of the present invention are e.g. described in WO 97/19104 and the compounds of the present invention show activitiy in assays as described in WO 97/19104. Assays appropriate for the determination of downregulation of VEGF expression, e.g. assays to assess potential for VEGF-inhibition, are e.g. as follows:
A) Human VEGF soluble ELISA
U-138 MG cells, a non-tumorigenic human glioblastoma cell line, displays phenotypic characteristics of primary human glioblastoma cells (Ponten and Maclntyre, 1968, Acta Path Microbiol Scand 74:465-486) and are used for the human VEGF soluble ELISA. U-138 MG cells constitutively express VEGF, which can be upregulated under hypoxic culture conditions and switching the culture medium from a low to high concentration of fetal calf serum (FCS). Dose-response and time-course experiments are performed to determine the optimal conditions for inducing VEGF protein, whose secreted form (VEGF165 isoform) is determined by soluble ELISA.
I. Growth conditions: U-138 MG cells are grown in T-75 flasks (Nunc) coated with 0.2% gelatin under standard conditions (37°C, 5% CO2) with 1.5 x 106 cells/ml culture medium (CM = Minimum essential medium with Earie's salts [MEM; Gibco #61100] supplemented with 10% FCS, 2.2 g/l NaHCO3, 1 mM sodium pyruvate, non-essential amino acids, 100 U/ml penicillin and 100 mg/ml of streptomycin). After mild trypsinization (0.25% trypsin + 0.1 % EDTA for 5 min) and resuspension in CM, the cells are reseeded every 3-4 days at a 1 :10 splitting ratio and given fresh CM every 3 days. II. Experimental conditions: 96 well flat-bottom microtiter plates are precoated with 0.2% gelatin and seeded with 3 x 104 U-138 MG cells/well in 200 μl of assay growth medium, defined as 1 :1 ratio of DMEM [Gibco #52100-047; supplemented with 3.7 g/l NaHCO3] and Nutrient Mixture Ham's F12 [Gibco #21700-091 ; supplemented with 1.176 g/l NaHCO3] containing 0.8% FCS The cells are incubated for 24 hours in these high-density, 'serum-starvation' conditions. The following day the culture medium is replaced with 150 μl/well of DMEM/F12 assay medium supplemented with 5% FCS and containing either (1) appropriate concentrations of the test compound, (2) corresponding concentrations of solvent/methanol-extracted medium, or (3) DMEM/F12 assay medium alone (5% FCS). The cells are incubated for 48 hr at 37° C. Each 96-well assay is performed with duplicate wells. After 48 hours in these 'low-to-high' serum conditions, the cell culture supernatants are transfered to a 96-well V-bottom plate (Costar # 3896) and spun down at 4° C for 15 min., 3000 x g, for subsequent analysis in the VEGF solid phase ELISA.
III. Cvtotoxicity Control (cell loss based on nuclear stain): After harvesting the culture supernatants, the U-138 MG cell monolayer is fixed in 2% paraformaldehyde for 15 min at room temperature (RT) and rinsed in distilled water (Aquadest). The monolayer is covered with a 33% Giemsa solution in Aquadest for 2 min at RT. The wells are washed with Aquadest and air dried for at least 15 min. Microscopic evaluation is used to check that only the nuclei are stained, with essentially no cytoplasmic staining. Giemsa absorbance values are read on a microtiter plate reader at 550 nm and corrected for "blank" values (rows without cells) at 690 nm.
IV. Human VEGF Solid Phase ELISA: Harvested supernatant samples from the U-138 MG cells are evaluated for levels of VEGFι65 protein using a commercially-available human VEGF ELISA (R &D Systems #DVE00), according to manufacture's instructions.
The compounds of the present invention show activity in such assays. A compound of the present invention may be administered in the form of a pharmaceutical composition.
In another aspects the present invention provides the therapeutical use of a compound of formula lp, lr and ls; e.g. the use of a compound of formula lp, lr and ls as a pharmaceutical;
- a therapeutic, e.g. pharmaceutical, composition comprising a compound of formula lp, lr or ls, e.g. at least one compound, e.g. a therapeutically effective amount of at least one compound of formula lp, lr or ls; beside one or more pharmaceutically acceptable carriers, diluents and/or excipients.
In another aspect the present invention provides the use of a compound of formula I, lp, lr or ls, e.g. including a compound of formula IA, IAr and IAS, such as a compound of formula lp, lr or ls, e.g. including a compound of formula IAr and IAS, e.g. in the form of a salt, or in the form of a salt and in the form of a solvate, or in the form of a solvate; and/or in the form of an ester; in the treatment, e.g. therapy or prophylaxis, of diseases wherein processes e.g. capillary nonperfusion, angiogenesis, neovascularization, tumor growth and metastasis contribute to the pathogenesis or severity of said disease, such as - eye diseases involving vision impairment or loss, such as proliferative retinopathies and macular degeneration, including ischemic retinopathies, uveoretinitis and degenerative eye diseases,
- arteriosclerosis associated with chronic transplant rejection and coronary heart disease,
- solid tumor malignancies and other cancers, e.g. Kaposi's sarcoma, - psoriasis, rheumatoid arthritis; and a method for the treatment; e.g. or prophylaxis; of such diseases comprising administering a therapeutically or prophylactically effective amount of a compound of formula lp, lr or ls, e.g. including a compound of formula IAr and IAS, e.g. in the form of a salt, or in the form of a salt and in the form of a solvate, or in the form of a solvate; and/or in the form of an ester; optionally in the form of a pharmaceutical composition, to a subject; e.g. to a patient, in need of such treatment.
Pharmaceutical compositions according to the present invention may be for parenteral, oral, aerosol or topical use, e.g. administration, and may comprise one or more pharmaceutically acceptable carriers, diluents and/or excipients; and may comprise one or more additives; e.g. stabilisers and the like. Appropriate dosage ranges of the compounds of the present invention in therapeutical use may be dependent on e.g. the condition or disease involved, whether the use is for treatment or prophylaxis, the mode of administration, the route of administration. In general satisfactory results may be obtained, e.g. in oral administration, at dosages of from about 0.05 to about 10 mg/kg/day, preferably from about 0.1 to about 7.5 mg/kg/day, more preferably from about 0.1 to about 2 mg/kg/day; Alternatively, for parenteral administration, e.g. by i.v. drip or infusion, e.g. dosages from about 0.01 to about 5 mg/kg/day, preferably from about 0.05 to about 1 mg/kg/day and more, preferably from about 0.1 to about 1.0 mg/kg/day may be appropriate; e.g. administered once, or, in divided doses, 2 to 4 times a day. Suitable daily dosages for human patients include thus from about 2.5 to about 500 mg p.o., preferably from about 5 to about 250 mg p.o., more preferably from about 5 to about 100 mg p.o.; or from about 0.5 to about 250 mg i.v., preferably from about 2.5 to about 125 mg i.v. and more preferably from about 2.5 to about 50 mg i.v.. The compounds of the present invention may be administered by any appropriate route, including enteral, parenteral and topical and by inhalator administration. Appropriate enteral administered forms include solutions for drinking, tablets or capsules. Appropriate parenteral forms include injectable solutions or suspensions. Appropriate forms for topical administration include e.g. creams, lotions; e.g. at a concentration range of 0.01 - 10 %, preferably from 0.1 to 1 %, by weight in such a topical formulation. Appropriate unit dosage forms for oral administration may comprise from 1 to 50 mg of a compound of the present invention, e.g. from 1 to 10 mg. A compound of the present invention may be administered to larger mammals, for example humans, e.g. by similar modes of administration; e.g. at similar or lower dosages; than known standards for indications, e.g. indications as described above.
A compound of the present invention may be used for pharmaceutical treatment according to the present invention alone, or in combination with one or more other pharmaceutically active agents. Such other pharmaceutically active agents include compounds which enhances the effectiveness of a compound of the present invention in a diseases as defined above. Combinations include fixed combinations, in which two or more pharmaceutically active agents are in the same formulation; kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g. with instruction for co- administration; and free combinations in which the pharmaceutically active agents are packaged separately, but instruction for simultaneous or sequential administration are given. In another aspect the present invention provides a compound as defined in any one of examples 26 to 104.
In the following examples all temperatures are in degree Centigrade and are uncorrected. The following abbreviations are used:
EX.: Example m.p.: melting point
DCC: dicyclohexylcarbodiimide DMF: N,N-dimethylformamide
THF: tetrahydrofurane DIEA: diisopropylethylamine
EtAc: ethyl acetate c-Hex: cyclohexane
TFA: trifluoro acetic acid RT = room temperature
HATU: [O-(7-azabenzotriazol-1-yl)]-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate BOP: (Benzotriazol-1 -yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate P -t-Bu: Phosphazene Base P4-t-Bu (1 M-solution in n-hexane, FLUKA Art.Nr. 79421) Flash column chromatography is carried out on silica gel.
According to Examples 1 to 25 a compound of formula lp is as defined above, wherein R1p is as defined in examples 1 to 25 (TABLE 2) and R2p is methoxy. According to Examples 26 to 84, the production of compounds of formula
Figure imgf000027_0001
wherein RIEXΓ. RSEXΓ, RSEX. and R7Eχr are as defined in the corresponding examples (TABLE 3 to TABLE 10), is described. According to Examples 85 the production of a compound of formula IAS as defined above, wherein R2s is methoxy and R1s is as defined in the corresponding example, is described. According to examples 86 to 104 the production of a compound of formula
Figure imgf000028_0001
wherein REXΛS is as defined in TABLE 11 , is described. The production of a compound of formula
Figure imgf000028_0002
is carried out according to WO 96/03430, example 3, Compound A. The production of a compound of formula IIA wherein RnA is hydrogen, a group of formula -CH2-CH=CH or a group of formula -CH2-O-CO-C(CH3)3; is known, see e.g. WO97/19104; e.g. a compound IIA wherein RnA is a group of formula -CH2-CH=CH2 or a group of formula -CH2-O-CO-C(CH3)3 may be obtained by reaction of a compound of formula IIA, wherein RnA is hydrogen, with a compound of formula Br-CH2-CH=CH2, or CI-CH2-O-CO-C(CH3)3, in the presence of phosphazane P4, in THF at -78°. Compound of formula
Figure imgf000029_0001
If not otherwise indicated 1 H-NMR Spectra are determined in DMSO-d6 (500 MHz), and 13C-NMR Spectra in DMSO-d6 (125.8 MHz). In most cases only selected signals of the major conformation are given.
Example 1
Production of a compound of formula lp wherein R1p = -CH2-CH2-COO-CH2-CH2-CF3
To a solution of 100 mg of compound A of example 3 of WO 96/03430, 15 mg of DMAP, 0.4 ml of 3,3,3-trifluoro-1-propanol and 50 mg of DCC are added and the mixture obtained is stirred at RT for ca. 18 hours. To the mixture obtained a mixture of EtAc/c-HEX is added and the mixture obtained is extracted with saturated NaH2PO solution. The organic layer obtained is dried, the solvent is evaporated off, the evaporation residue is subjected to chromatography, the fraction comprising the product is poured over a LH20 column and the organic solution obtained is subjected to lyophilisation. A compound of formula lp wherein R1p = -CH2-CH2-COO-CH2-CH2-CF3 in the from of an 1 :1 mixture of 2 conformers is obtained. 13C-NMR(125.8 MHz, CDCI3): 173.670, 173.160, 172.486, 172.345, 172.085, 171.824, 171.412, 170.939, 169.771 , 169.664, 169.641 , 169.107, 168.397, 168.344, 168.008, 132.453, 132.256, 124.161 , 123.757, 122.829, 122.513, 122.411 , 121.947, 119.959, 119.668, 118.845, 118.401 , 108.655, 108.441 , 106.801 , 74.493, 73.609, 66.905, 65.788, 65.505, 64.662, 61.160, 59.891 , 59.522, 57.302, 57.200, 47.996, 47.854, 47.263, 47.210, 46.913, 46.421 , 41.262, 39.855, 39.660, 39.186, 38.996, 38.261 , 37.568, 37.107, 36.982, 36.897, 36.838, 33.464, 33.383, 33.227, 33.151 , 30.740, 30.153, 29.441 , 29.350, 29.314, 29.144, 29.100, 28.801 , 28.674, 28.580, 27.299, 25.876, 25.230, 24.692, 24.438, 24.198, 23.937, 23.681 , 23.509, 23.180, 22.992, 22.970, 22.891 , 22.783, 22.369, 21.865, 21.673, 19.797, 19.651 , 19.273, 19.224, 19.055, 14.136, 14.107, 14.069, 14.040, 13.946, 13.580.
Example 2
Production of a compound of formula lp wherein R1p = -CH2-CH2-CO-CH2-O-CH3
Figure imgf000030_0001
2.0 g of an solution of a compound of example 5 of WO 96/03430 in 30 ml of THF, cooled in an ice bath is treated with 0.33 ml of triethylamine and 0.29ml of 2-methyl- propyichloroformate. To the mixture obtained 15 ml of an 1 M etheral diazomethane solution is added and the mixture obtained is stirred at RT for ca. 15 hours. To the mixture obtained saturated aqueous NaHCO3 and EtAc are added and the phases formed are separated. The organic layer obtained is washed, dried, the solvent is evaporated off and the evaporation residue is subjected to flash column chromatography. A compound of formula lp wherein R1 = -CH2-CH2-CO-C=N+=N" in the form of an amorphous powder is obtained. 13C-NMR: 194.22, 173.61 ; 171.62; 171.1 ; 170.57; 170.55; 168.91 ; 168.15 (carbonyls); 75.5; 60.71 , 59.12; 57.67; 48.36; 46.87; 46.69 (alpha-C's)
Figure imgf000031_0001
To a solution of 200 mg of a compound of formula lp wherein R1fg = -CH2-CH2-CO-C=N+=N" in 5ml of dry methanol, 0.05ml of borontrifluoride-diethyletherat are added and the mixture obtained is stirred at room temperature for ca. 3 hours. To the mixture obtained saturated aqueous NaHCO3 and EtAc are added and the phases formed are separated. The organic layer obtained is washed, dried, the solvent is evaporated off and the evaporation residue is subjected to flash column chromatography. A compound of formula lp wherein Ri = -CH2- CH2-CO-CH2-CO-CH3 in the form of an amorphous powder is obtained. 13C-NMR: 207.04, 173.57; 171.58; 170.99; 170.57; 170.54; 168.84; 168.18 (carbonyls); 75.34; 60.76, 59.05; 57.68; 48.31 ; 46.90; 46.68 (alpha-C's); 77.47(-CH2O); 58.91 (-OMe).
Analogously as described in example 2, but using appropriate starting materials, compounds of formula lp, wherein Rιp is as defined in examples 3 to 8, are obtained:
EXAMPLE 3: R,p = -CH2-CH2-CO-CH2-O-CH2-CH3
13C-NMR: 206.99, 173.62; 171.65; 170.98; 170.58; 170.54; 168.87; 168.18 (carbonyls);
75.66; 60.73, 58.93; 57.67; 48.33; 46.90; 46.65 (alpha-C's); 66.50(CH3CH2O); 75.39 (-
COCH2O-). EXAMPLE 4: R,p = -CH2-CH2-CO-CH2-O-CH(CH3)2
13C-NMR: 206.81 , 173.69; 171.61 ; 170.96; 170.59; 170.56; 168.91 ; 168.18 (carbonyls);
75.51 ; 60.70, 58.95; 57.65; 48.35; 46.89; 46.64 (alpha-C's); 71.88 ((CH3)2CHO-); 73.52
(2H; -OCH2-).
EXAMPLE 5: R,p = -CH2-CH2-CO-CH2-O-C(CH3)3 13C-NMR: 206.71 , 173.73; 171.57; 170.96; 170.59; 170.58; 168.93; 168.20 (carbonyls);
75.49; 60.69, 59.00; 57.66; 48.35; 46.89; 46.63 (alpha-C's); 66.50((CH3)3CO-).
EXAMPLE 6: R,p = -CH2-CH2-CO-CH2-O-cyclobutyl
1HNMR: 4.6/1.87/1.72/1.64/1.62/1.46 (6 x m; 5 x 1H, 1 x 2H; cyclobutyloxy).
EXAMPLE 7: R,p = -CH2-CH2-CO-CH2OH 13C-NMR: 210.03, 173.49; 171.70; 170.99; 170.55; 170.52; 168.78; 168.19 (carbonyls);
75.29; 60.82; 58.86; 57.68; 48.20; 46.88; 46.66 (alpha-C's); 68.09 (CH2OH) .
EXAMPLE 8: RIp = -CH2-CH2-CO-CH2-O-CH2-CH2OH
13C-NMR: 173.57; 171.66; 170.99; 170.58; 170.56; 168.84; 168.19 (carbonyls); 76.27; 60.65;
58.90; 57.68; 48.32; 46.90; 46.66 (alpha-C's); 73.09/70.28(2x-CH2O-). Example 9
Production of a compound of formula lp wherein R1p = -CH2-CH2-COO-CH2-OCH3
200 mg of a solution of a compound of example 5 of WO 96/03430 in 20 ml of toluene, cooled in an ice bath, is treated with 0.21 ml of P4-t-Bu and 100 mg of chloromethylmethyl- ether and the mixture obtained is stirred for ca. 1 hour at ca. 5°. To the mixture obtained aqueous HCI and EtAc are added, the phases formed are separated, the organic layer is washed , dried, the solvent is evaporated off and the evaporation residue is subjected to flash column chromatography. A compound of formula lp wherein Ri = -CH2-CH2-COO-CH2- O-CH3 in the form of an amorphous powder is obtained. 13C-NMR: 173.28; 171.82; 171.08; 170.53; 170.52; 168.60; 168.12 (ring carbonyls); 172.32 (-C(=O)O-); 90.04 (-OCH2O-); 57,32 (-CH2OCH3).
Analogously as described in example 9 but using appropriate starting materials compounds of formula lp wherein Rιp is as defined in the examples 10 to 12 are obtained:
EXAMPLE 10: Rlp = -CH2-CH2-COO-CH2-O-CH2-CH3
13C-NMR: 173.28; 171.81 ; 171.09; 170.52 ; 170.52 (2x); 168.61 ; 168.12 (ring carbonyls);
172.34 (-C(=O)O-); 88.77 (-OCH2O-); 65.55 (-OCH2CH3).
EXAMPLE 11 : R,p = -CH2-CH2-COO-CH2-O-CH2-CH2-OCH3 13C-NMR: 173.28; 171.81 ; 171.08; 170.53; 170.53; 168.60; 168.12 (ring carbonyls); 172.27 (-
C(=O)O-); 88.97 (-OCH2O-); 71.45/69.29 (-OCH2CH2OJ.
EXAMPLE 12: R,p = -CH2-CH2-COO-CH2-O-CO-C(CH3)3
13C-NMR: 173.18; 171.86; 171.10; 170.51 ; 170.45; 168.49; 168.05 (ring carbonyls); 171.64 (-
C(=O)O-); 176.77. (-C(=O)O-); 79.71 (-OCH2O-). EXAMPLE 13
Production of a compound of formula lp wherein R1p is as defined in Table 2 under
"Ex. 13"
To a solution of 200 mg of a compound of example 5 of WO 96/03430 in 20 ml of toluene,
0.21 ml of P -t-Butyl and 240 mg of a compound of formula
Figure imgf000032_0001
is added. The mixture obtained is stirred for ca. 15 minutes at ca. 5° and aqueous HCI and EtAc are added. The phases formed are separated, the organic layer is washed, dried and the solvent is evaporated off. The evaporation residue obtained is subjected to molecular size exclusion chromatography (Sephadex®-LH20, eluent: methanol) and flash column chromatography. A compound of formula lp wherein Rιp is as defined in Table 2 under "Ex. 13" is obtained. 3C-NMR: 173.27; 171.85; 171.61 ; 170.54; 170.30; 168.56; 168.02 (ring carbonyls); 171.08 (-C(=O)O-); 82.02 (-OCH2O-); 153.76 (-O(C=O)O-); 101.88; 82.02; 78.73; 77.57; 70.04; 64.02 (C1-C6-sugar part). Production of a compound of formula EX13 To a solution of 2.4 g of a compound of formula
Figure imgf000033_0001
and 3 ml of pyridine in 70 ml of CH2CI2, cooled to ca. 5°, 0.6 ml of chloromethyl chloroformate are added, the mixture obtained is stirred for ca. 3 hours at RT and aqueous 1 N HCI and Etac are added. The phases formed are separated, the organic layer is washed, dried and the solvent is evaporated off. To the evaporation residue obtained, dissolved in acetone/acetonitrile, 15 g of Nal and 60 mg of 18-crown-6 are added and the mixture obtained is kept at ca. 60° for ca. 2 hours. To the mixture obtained, cooled down to RT, EtAc and water are added, the phases formed are separated, the organic layer is washed, dried and the solvent is evaporated off. A compound of formula EX13 is obtained and used without further purification.
Example 14
Production of a compound of formula lp wherein Rιp is as defined in Table 2 under
"Ex. 14" To 246 mg of the cyclopeptolide obtained according to Example 13 in 16 ml of CH3CN, 2 ml of aqueous hydrogenfluoride (40w/w%) are added, the mixture obtained is stirred for ca. 90 minutes at RT, saturated aqueous NaHCO3 and EtAc are added and the phases formed are separated. The organic layer obtained is washed, dried and the solvent is evaporated off. The evaporation residue is subjected to flash column chromatography and filtration through Sephadex®-LH20 (eluent:methanoI). The fractions comprising a compound of formula lp, wherein R1p is as defined in Table 2 under "Ex. 14", are subjected to lyophilisation from benzene. 13C-NMR: 173.27; 171.84; 171.09; 170.51 ; 170.48; 168.59; 168.06 (ring carbonyls); 171.71 (-C(=O)O-); 82.19 (-OCH2O-); 153.84 (-O(C=O)O-); 103.35; 77.32; 77.16; 73.87; 70.51 ; 61.53 (C1 -C6-sugar part).
Example 15
Production of a compound of formula lp wherein R1p is a compound of formula
Figure imgf000034_0001
is carried out analogously to the method described in example 14, but using the appropriate starting materials. 13C-NMR: 173.27; 171.71 ; 171.09; 170.51 ; 170.48; 168.59; 168.06 (ring carbonyls); 171.84 (-C(=O)O-); 82.18 (-OCH2O-); 153.84 (-O(C=O)O-); 99.13; 73.73; 73.29; 72.37; 70.70; 61.36 (C1-C6-sugar part).
Example 16
Production of a compound of formula lp wherein R1p is a compound of formula
Figure imgf000034_0002
A solution of 150 mg of a compound obtained in example 2 A) in 10 ml of propionitrile is treated with 10 mg of rhodium(ll)acetate, the mixture obtained is stirred for ca. 20 hours at RT and EtAc is added. The mixture obtained is extracted with brine, the organic layer obtained is dried, the solvent is evaporated off and the evaporation residue is subjected to flash column chromatography. A compound of formula lp is obtained wherein R p is as defined in Table 2 under "Ex. 16", in the form of a powder. 13C-NMR: 172.95; 171.99; 171.04; 170.48; 170.43; 168.37; 168.26 (carbonyls); 164.63 / 150,77 / 123.03 (oxazol).
Analogously as described in example 16 but using appropriate starting materials compounds of formula lp wherein Rιp is as defined in the examples 17 to 19 are obtained: EXAMPLE 17
Rip is as defined in Table 2 under "Ex. 17": 13C-NMR: 172.96; 172.00; 171.05; 170.48; 170.44; 168.37; 168.27 (carbonyls); 160.42 / 150.93 / 123.24 (oxazol). EXAMPLE 18 R1p is as defined in Table 2 under "Ex. 18": 13C-NMR: 172.93; 172.03; 171.05; 170.48; 170.42; 168.28; 168.25 (carbonyls); 154.11 / 152.71 / 123.74 (oxazol), 115.84 (-CN). EXAMPLE 19
R1p is as defined in Table 2 under "Ex. 19": 13C-NMR: 172.94; 172.02; 171.03; 170.47; 170.42; 168.31 ; 168.27 (carbonyls); 160.14 / 152.20 / 123.52 (oxazol); 66.01 (oxazolyl-CH2O-); 58.77 (-OCH3). Example 20
Production of a compound of formula lp wherein R1p = -CH2-CH2-C(=N-OH)NH2 4 g of compound A of example 3 of WO 96/03430, 2.76 g of hydroxylamin hydrochloride, 14 ml of triethylamine in 40 ml of isopropanol are sonicated for 30 minutes at RT and the mixture obtained is stirred at ca. 60° for ca. 7 hours. To the mixture obtained 600 ml of EtAc/c-HEX (1 :1) are added and the mixture obtained is washed with 1 M NaH2PO solution. The organic layer obtained is dried, the solvent is evaporated off, the evaporation residue obtained is subjected to chromatography on silica gel and size exclusion on Sephadex LH20 (methanol) and lyophilisation from dioxane. A compound of formula lp wherein R1p = -CH2- CH2-C(=N-OH)NH2 in the form of a powder is obtained, m.p. = 109-114°. Example 21
Production of a compound of formula lp wherein Rιp is as defined in Table 2 under "Ex. 21 " To 150 mg of a compound of formula lp wherein Rιp = -CH2-CH2-C(=N-OH)NH2, dissolved in 2 ml of dry toluene, 100 μl of trimethylorthopropionate and 5 μl of methanesulfonic acid are added, the mixture obtained is stirred at ca. 60°C for ca. 7 hours, the solvent is evaporated off, the evaporation residue obtained is subjected to chromatography on silica gel, size exclusion on Sephadex LH20 (methanol) and lyophilisation from dioxane. A compound of formula lp wherein R1p is as defined in Table 2 under "Ex. 21", in the form of a 1 :1 mixture of 2 conformers, in the form of a powder is obtained.
13C-NMR(125.8 MHz, CDCI3): 180.954, 180.577, 173.827, 173.105, 172.434, 172.421 , 171.479, 170.779, 169.710, 169.596, 169.523, 169.499, 169.351 , 169.024, 168.478, 168.281 , 168.231 , 132.454, 132.275, 124.195, 123.660, 122.926, 122.577, 122.359, 121.841 , 120.254, 119.747, 118.943, 118.279, 108.715, 108.662, 108.458, 106.639, 74.128, 73.647, 66.794, 65.852, 65.565, 65.005, 61.273, 59.786, 59.7576, 57.270, 48.076, 47.705, 47.225, 47.203, 46.908, 46.281 , 41.191 , 39.919, 39.835, 39.663, 38.999, 38.097, 37.642, 37.480, 37.363, 37.138, 37.997, 36.947, 36.897, 36.824, 29.473, 29.414. Analogously as described in example 21 but using appropriate starting materials compounds of formula lp wherein R1p is as defined in examples 22 to 25 are obtained: EXAMPLE 22
R1p is as defined in Table 2 under "Ex. 22": 1 :1 Mixture of 2 conformers. 13C-NMR(125.8 MHz, CDCI3):180.130, 179.739, 173.918, 173.094, 172.487, 172.444, 171.479, 170.831 , 170.804, 169.707, 169.594, 169.517, 169.481 , 169.370, 169.033, 168.497, 168.309, 168.237, 132.541 , 132.366, 124. 268, 123.737, 122.926, 122.587, 122.396, 121.883, 120.259, 119.777, 1 18.972, 118.346, 108.759, 108.723, 108.472, 106.757, 74.102, 73.666, 66.854, 65.808, 65.522, 65.156, 61.300, 59.829, 59.627, 57.323, 48.120, 47.782, 47.301 , 47.270, 46.992, 46.368, 41.246, 39.926, 39.881 , 39.731 , 39.066, 38.249, 37.657, 37.507, 37.356, 37.148, 37.026, 36.924, 36.876, 29.486, 29.470, 29.348, 29.212, 29.115, 29.016, 28.797, 28.716, 28.549, 28.465, 28.425, 27.822, 25.280, 24.745, 24.458, 24.212, 24.080, 23.689, 23.487, 23.144, 23.020, 22.995, 22.920, 22.887, 22.820, 22.533, 22.422, 21.931 , 21.768, 20.116, 20.091 , 19.822, 19.562, 19.311 , 19,263, 19.104, 14.147, 14.110, 14.076, 14.050, 13.852, 13.651 , 13.611 , 13.555. EXAMPLE 23
Rιp is as defined in Table 2 under "Ex. 23": 1 :1 mixture of 2 conformers; 3C-NMR(125.8 MHz, CDCI3): 180.302, 179.913, 173.921 , 173.084, 172.495, 172.444, 171.479, 170.803, 169.707, 169.587, 169.508, 169.466, 169.362, 169.024, 168.497, 168.309, 168.233, 132.546, 132.372, 124.274, 123.740, 122.924, 122.580, 122.395, 121.882, 120.257, 119.773,
118.966, 118.345, 108.767, 108.718, 108.469, 106.762, 74.077, 73.651 , 66.869, 65.801 , 65.514, 65.166, 61.298, 59.830, 59.625, 57.319, 48.121 , 47.783, 47.305, 47.270, 46.998, 46.372, 41.251 , 39.940, 39.879, 39.730, 39.073, 38.255, 37.655, 37.512, 37.354, 37.154, 37.031 , 36.930, 36.874, 29.486, 29.471 , 29.217, 29.115, 29.026, 28.796, 28.712, 28.599, 28.573, 28.546, 27.835, 28.546, 27.835, 26.277, 26.266, 25.281 , 24.745, 24.459, 24.214, 24.085, 23.686, 23.483, 23.150, 23.016, 22.994, 22.918, 22.524, 22.418, 22.194, 22.162, 21.932, 21.766, 19.822, 19.561 , 19.321 , 19.266, 19.100, 14.145, 14.105, 14.073, 14.047, 13.849, 13.557, 13.479. EXAMPLE 24 R1p is as defined in Table 2 under "Ex. 24": 1 :1 mixture of 2 conformers; 13C-NMR(125.8 MHz, CDCI3): 173.857, 173.161 , 172.469, 171.430, 170.826, 170.720, 169.573, 169.476, 169.321, 169.280, 169.200, 168.632, 168.385, 168.102, 165.177, 164.598, 132.576, 132.305, 124.283, 123.754, 122.937, 122.601 , 122.419, 122.003, 120.201 , 119.711 , 119.082, 118.514, 108.972, 108.715, 108.526, 106.798, 75.017, 74.644, 66.648, 65.849, 65.557, 65.272, 61.446, 59.766, 59.559, 57.326, 48.024, 47.909, 47.350, 47.113, 46.910, 46.134, 41.241 , 40.088, 39.963, 39.890, 39.720, 39.074, 38.905, 38.218, 37.668, 37.345, 37.265, 37.161 , 37.001 , 36.845, 29.500, 29.324, 29.241 , 29.131 , 28.942, 28.753, 28.685, 28.621 , 27.941 , 25.279, 24.760, 24.483, 24.232, 24.035, 23.692, 23.526, 23.148, 23.021 , 22.999, 22.972, 22.896, 22.831 , 22.498, 21.940, 21.720, 19.813, 19.541 , 19.337, 19.153, 14.160, 14.121 , 14.080, 14.048, 13.703, 13.354. EXAMPLE 25
Rιp is as defined in Table 2 under "Ex. 25": 1 :1 mixture of 2 conformers; 13C-NMR(125.8 MHz, CDCI3): 176.866, 176.382, 173.954, 173.096, 172.479, 172.443, 171.473, 170.813, 170.761 , 169.873, 169.640, 169.569, 169.482, 169.044, 168.470, 168.264, 132.574, 132.371 , 124.282, 123.750, 122. 936, 122.609, 122.397, 121.908, 120.261 , 119.766, 119.011 , 118.372, 108.839, 108.728, 108.491 , 106.760, 74.502, 73.828, 66.741 , 65.808, 65.516, 65.323, 61.323, 59.837, 59.660, 57.319, 48.111 , 47.801 , 47.274, 46.983, 46.276, 41.232, 39.986, 39.874, 39.712, 39.065, 38.948, 38.241 , 37.652, 37.434, 37.329, 37.179, 37.020, 36.935, 36.864, 29.466, 29.359, 29.326, 29.218, 29.120, 28.964, 28.782, 28.693, 28.552, 27.903, 25.285, 24.744, 24.464, 24.211 , 24.099, 23.681 , 23.480, 23.153, 23.019, 22.994, 22.915, 22.809, 22.586, 22.452, 21.938, 21.756, 19.819, 19.534, 19.315, 19.274, 19.109, 14.145, 14.105, 14.070, 14.040, 13.845, 13.505, 12.322. Example 26 Production of a compound of formula lAecr, wherein RιEXr, R5Exrand R6Eχ. are CH3, and R7Eχr is -CH2-CH=CH2
To a solution of 100 mg of a compound of formula IAEXΓ, wherein R1EXr, R5Eχrand R6EXr are CH3, and R7EXr is hydrogen, allyl bromide in dry THF and 0.6 ml of P -t-But is added at -78 ° and the mixture obtained is stirred for ca. 3 hours and treated with 100 μl of acetic acid. The mixture obtained is diluted with toluene and the mixture obtained is extracted with aqueous NaH2PO4 and brine. The organic layer is separated off, dried and the solvent is evaporated off. The evaporation residue obtained is purified by pouring over sephadex (LH20) and chromatography over silica gel. A compound of formula IAEXr, wherein RιEXr, R5EXrand R6EX. are CH3 and R7EXr is -CH2-CH=CH2 is obtained. 1H-NMR: 8.60 (d, J=10.0Hz, 1 H), 8.31 (d, J=6.0Hz, 1 H), 7.58 (d, J=9.6Hz, 1 H), 7.52 (d, J=8.0Hz, 1 H), 7.41 (d, J=8.3Hz, 1 H), 7.36 (s, 1 H), 7.19 (t, J=7.6Hz, 1 H), 7.03 (t, J=7.5Hz, 1 H), 5.51 (m, 1 H), 5.05 (d, J=15.5Hz, 1 H), 5.02 (d, J=9.9Hz, 1 H), 4.93 (td, J=9.8, 4.7Hz, 1 H), 4.75 (dd, J=9.1 , 5.6Hz, 1 H), 4.66 (m, 1 H), 4.56 (q, J=7.0Hz, 1 H), 4.17 (m, 1 H), 4.11 (dd, J=9.7, 5.4Hz, 1 H), 3.99 (s, 3H), 3.26 (dd, J=15.0, 5.6Hz, 1 H), 3.00 (dd, J=15.0, 9.1 Hz, 1 H), 2.89 (s, 3H), 2.75 (s, 3H), 2.47 (dd, J=13.6, 7.3Hz, 1 H), 2.41 (dd, J=13.6, 6.8Hz, 1 H), 2.40 (s, 3H), 1.62 (t, J=7.0Hz, 2H), 1.27 (s, 3H), 0.93 (d, J=6.5Hz, 3H), 0.92 (d, J=6.6Hz, 3H), 0.85 (d, J=6.6Hz, 3H), 0.83 (t, J=7.2Hz, 3H), 0.82 (t, J=7.0Hz, 3H), 0.77 (d, J=6.5Hz, 3H), 0.49 (d, J=6.6Hz, 3H), 0.03 (d, J=6.6Hz, 3H), -0.16 (ddd, J=13.6, 10.6, 3Hz, 1 H).
Analogously as described in example 26 but using appropriate starting materials the compounds of formula IAEXr, wherein RιEXr, R5EXr, R6EXr and R7EXr are as described in TABLE 3, are obtained:
TABLE 3
Figure imgf000038_0001
Figure imgf000039_0001
Example 44
Production of a compound of formula IAEXΓ wherein R1EXr is -CH2-CH2-CO-NH2, R5EXrand
Reεxr are CH3, and R7EXr is -CH2-CH=CH2
A compound of formula IAEXr, wherein RιEXr is -CH2-CH2-COOH, R5EXrand R6EXr are CH3, and R7EXΓ is -CH2-CH=CH2 is heated in a mixture of tert-butanol/water and HCI, the mixture obtained is treated with isobutyl chlorformate in the presence of an amine in apolar solvent and quenched with aqueous ammonium hydroxide. A compound of formula lAεxr wherein R1EXr is -CH2-CH2-CO-NH2, RSEXΓ and R6EXr are CH3, and R7EXr is -CH2-CH=CH2 is obtained. 13C-NMR: 173.545, 173.044, 171.873, 171.481 , 171.378, 170.740, 168.770, 168.611 , 133.014, 132.166, 124.034, 123.272, 122.683, 119.721 , 108.555, 107.140, 75.931 , 66.174, 64.172, 60.643, 57.713, 50.592, 48.356, 47.465, 47.137, 40.944, 38.926, 37.379, 36.991 , 36.822, 36.358, 31.673, 30.991 , 29.210, 28.956, 28.811 , 28.633, 28.475, 26.085, 24.971 , 23.896, 23.430, 23.070, 22.974, 22.826, 21.910, 20.488, 19.366, 18.818, 14.458, 14.389. Example 45
Production of a compound of formula IAEX-, wherein R1EXr and R5EXr are as defined in example 36 and R7EXr is -CH2OH The compound of example 36 is stirred at temperatures from RT to 50° in 50 ml of methanol together with 150 mg of lithium carbonate. The mixture obtained is diluted with cyclohexane:EtAc = 2:1 and the mixture obtained is extracted with saturated NaHPO4. The organic layer obtained is dried and the solvent is evaporated off. The residue obtained is purified by chromatography on silica gel and sephadex (LH20). A compound of example 36 wherein R7Eχr is -CH2OH is obtained, m.p.: 130-135 °. Example 46
Production of a compound of formula IAiΞXr, wherein R1EXr and R5EXr are as defined in example 36 and R7EXr is -CHO To a solution of 400 mg of a compound of example 45 in CH2CI2, 192 mg of 1 ,1 ,1-
Triacetoxy-1 ,1-dihydro-1 ,2-benziodoxol-3(1 H)-one (Des Martin periodinane) and 360 μl of pyridine are added and the mixture obtained is stirred at RT for ca. 3 hours. The mixture obtained is diluted with cyclohexane:EtAc = 2:1 and the mixture obtained is extracted with sat. NaHPO . The organic layer is dried and the solvent is evaporated off. The evaporation residue obtained is subjected to chromatography. A compound of example 45, wherein R7Eχr is -CHO obtained. 13C-NMR (CDCI3): 194.299, 182.091 , 170.177, 170.105, 167.547, 167.260, 132.5, 122.693, 121.877, 119.826, 119.063, 108.488, 108.375, 107.671 , 105.208, 71.878, 67.958, 65.821 , 65.654, 61.718, 57.499, 48.354, 47.802, 42.564, 40.896, 40.485, 37.564, 37.178, 36.855, 36.394, 32.542, 31.406, 30.875, 29.680, 29.564, 29.449, 29.348, 29.294, 29.229, 29.056, 28.958, 28.838, 25.603, 25.095, 24.547, 23.333, 23.183, 22.986, 22.921 , 21.861 , 21.622, 19.687, 19.562, 19.284, 18.811, 18.702, 16.498, 15.251 , 14.103. Example 47
Production of a compound of formula IAEXΓ, wherein RιEXr and R5EXr are as defined in example 36 and R7EXr is -C=N-OH To a solution of 250 mg of a compound of example 46 in 20 ml of THF, 30 mg of NaOAc and 27 mg of NH2OH in the form of a hydrochloride, dissolved in 5 ml of water, are added and the mixture obtained is stirred at 60° for ca. 1 hour. The mixture obtained is diluted with cyclohexane:EtAc = 2:1 and the mixture obtained is extracted with saturated NaHPO4. The organic layer obtained is dried, the solvent is evaporated off and the evaporation residue obtained is subjected to chromatography on silica gel and sephadex (LH20/MeOH). A compound of example 46, wherein R7EXΓ is -C=N-OH is obtained. Example 48
Production of a compound of formula IAEXΓ, wherein RιEXr and R5EXr are as defined in example 28 and R7Eχr is -CH2-CH2-CH2OH A compound of example 28 is treated with borane dimethylsulfide complex at 0° and oxidatively worked up with Na2Cθ3/H2θ2. A compound of example 28, wherein R7EXr is -CH2- CH2-CH2OH is obtained. 13C-NMR: 174.168, 172.083, 171.677, 171.422, 168.792, 168.709, 122.431 , 119.732, 108.198, 106.389, 74.275, 65.056, 64.264, 61.433, 61.008, 58.160, 39.499, 39.026, 36.760, 36.686, 36.638, 35.759, 33.136, 29.971 , 29.130, 29.082, 28.885, 28.566, 27.994, 27.539, 26.728, 24.646, 23.572, 22.836, 22.675, 22.640, 22.554, 21.693, 21.075, 18.975, 18.070, 18.018, 17.668, 13.118, 13.058.
Analogously as described in example 48 but using appropriate starting materials the compounds of formula IAEXr, wherein R1EXr, R5EXr, R6Eχr and R7EXr are as defined in TABLE 4, are obtained:
TABLE 4
Figure imgf000041_0001
Example 52 Production of a compound of formula lA^r, wherein R5Eχr, εEx. and R7EXr are as defined in example 51 and R1EXr is -CH2-CH2-COOH
A compound of example 51 is saponified by treatment with NaOH in a mixture of THF/water. A compound of formula 51 , wherein R1EXr is -CH2-CH2-COOH is obtained. 13C-NMR: 173.931 , 173.383,171.804,171.728, 171.649, 170.681 , 168.510, 168.407, 132.152, 123.980, 123.224, 122.744, 120.537, 119.947, 119.530, 108.637, 107.027, 75.260, 66.206, 64.095, 60.931 , 60.628, 57.734, 48.182, 47.410, 47.147, 38.865, 37.323, 36.903, 36.754, 36.359, 33.106, 30.631 , 30.341 , 29.218, 28.977, 28.852, 28.663, 28.391 , 28.184, 26.064, 24.947, 23.875, 23.445, 23.066, 22.936, 22.819, 21.981 , 20.465, 19.140, 19.077, 18.824, 14.468, 14.403. Example 53 Production of a compound of formula lAεx-, wherein R1EXr, R5EXrand R6Eχr are as
Figure imgf000042_0001
defined in example 50 and R7Eχ. is a group of formula
A compound of example 50 is treated with carbonyldiimidazole in apolar solvent, a compound of example 50 formula I, wherein wherein R7Exris a group of
Figure imgf000042_0002
formula is obtained. 13C-NMR: 176.868, 173.261 , 172.976, 171.978,
171.801 , 170.637, 168.466, 168.227, 164.596, 137.793, 130.732, 129.974, 123.881 , 122.745, 120.690, 119.975, 119.473, 119.057, 118.008, 108.636, 106.785, 75.114, 68.155, 66.216, 63.043, 61.990, 60.722, 60.102, 57.756, 54.200, 51.758, 48.916, 48.238, 38.182, 37.482, 36.834, 36.775, 36.395, 30.581 , 30.071 , 29.209, 28.984, 24.941 , 23.839, 22.931 , 22.805, 22.017, 20.451 , 19.165, 19.061 , 14.469, 14.402. Example 54
Production of a compound of formula lAεxr wherein RιEXr is -CH2-CH2-(C=N-OH)-NHI2, Rsεxr and R6Eχr are CH3, and R7EXr is -CH2-CH=CH2 4 g of a compound of formula IIA wherein RnA is a group of formula -CH2-CH=CH2, 2.76 g of hydroxylamin hydrochloride, 14 ml of triethylamine and 40 ml of isopropanol are sonicated for ca. 30 minutes at RT and stirred at ca. 60 ° for ca. 7 hours. The reaction mixture obtained is diluted with 600 ml of EtAc/cyclohexane (1 :1) and washed with aqueous 1 M NaH2PO4 solution. The phases obtained are separated, the organic layer is dried, the solvent is evaporated off, the evaporation residue obtained is subjected to chromatography and size exclusion. Compound-containing fractions are subjected to lyophilisation from dioxane. A compound of formula lA^ wherein R1EXr is -CH2-CH2-(C=N-OH)-NH2, R5Exrand R6EXΓ are CH3, and R7Eχr is -CH2-CH=CH2 is obtained in the form of a powder. Example 55 Analogously as described in example 54 but using appropriate starting materials a compound of formula IAEXΓ wherein R1EXr is -CH2-CH2-(C=N-OH)-NH2, R5EXrand R6EXr are CH3, and R7EXr is -CH2-O-CO-C(CH3)3 is obtained. 13C-NMR: 176.726, 172.658, 171.860, 171.472, 170.518, 170.017, 168.041 , 151.236, 131.937, 123.463, 123.053, 122.500, 119.846, 118.710, 108.443, 106.436, 73.963, 65.835, 63.873, 60.523, 57.382, 47.810, 47.081 , 46.996, 38.426, 37.048, 36.484, 36.225, 31.076, 28.781 , 28.590, 28.548, 28.326, 28.157, 26.950, 26.835, 26.499, 24.580, 23.439, 23.148, 22.696, 22.453, 22.400, 21.692,
19.956, 18.764, 17.416, 14.037, 13.969.
Example 56
Production of a compound of formula IAιrXr wherein R1EXr is a group of formula
Figure imgf000043_0001
, R5EXr and R6Eχ. are CH3, and R7Eχ. is -CH2-CH=CH2
To 150 mg of a compound obtained according to example 54, dissolved in 2 ml of dry toluene, 100 μl of trimethylorthopropionate and 5 μl of methanesulfonic acid are added and the mixture obtained is stirred at ca. 60° for ca. 7 hours. From the mixture obtained the solvent is evaporated off and the evaporation residue obtained is subjected to chromatography and size exclusion on Sephadex LH20 (methanol) Compound-containing fractions are subjected to lyophilisation. A compound of formula IAEXr wherein R1EXr is a group
of formula
Figure imgf000043_0002
is
13, obtained in the form of a powder. λ JC-NMR: 176.721 , 172.712, 171.648, 171.494, 170.717, 170.221 , 169.390, 167.942, 167.870, 132.223, 131.891 , 123.509, 122.878, 122.430, 119.670, 119.276, 118.585, 108.423, 106.516, 73.632, 65.830, 63.707, 60.489, 57.498, 47.754, 47.081 , 46.908, 40.796, 38.458, 36.405, 36.094, 30.302, 28.800, 28.637, 28.581 , 28.562, 28.341 , 28.020, 24.576, 23.381 , 23.238, 22.666, 22.542, 22.404, 21.757, 21.651 , 20.038, 18.824, 18.675, 18.526, 14.038, 13.988, 11.873.
Analogously as described in example 56 but using appropriate starting materials compounds of formula IAEXr wherein R1Exr, Rsεxr, Reεx. and R7EXr are as defined in TABLE 5 are obtained:
TABLE 5
Figure imgf000043_0003
Figure imgf000044_0001
Compounds of formula IAεχr wherein RιEXr, R5Eχr, Reεxr and R7EXr are as defined in TABLE 6 may be obtained by treatment of compounds obtained according to of examples 60 to 63 with lithium carbonate:
TABLE 6
Figure imgf000044_0002
Example 69 Production of a compound of formula lA^ wherein R1EXr is a group of formula
Figure imgf000045_0001
, RsExr is hydrogen and R6EXr and R7EXr together with the carbon atom to which they are attached form cyclopropyl (compound of formula EX69C)
A) Compound of formula EX69A
Figure imgf000045_0002
A solution of 1.8 g of the compound of example 7 of WO 97/19104 in 10 ml of methanol is treated with 1 g of NaBH4 in small portions at RT. The reaction mixture is poured onto dilute hydrochloric acid and the mixture obtained is extracted with EtAc. The organic extract obtained is washed with aqueous NaHCO3, dried and the solvent is evaporated off. The evaporation residue obtained is subjected to reversed phase chromatography (RP-8, gradient water/methanol 80 to 100% methanol). A compound of formula EX69A is obtained. B) Compound of formula EX69B
Figure imgf000045_0003
A solution of 1.87 g of a compound of formula EX69A in 10 ml of allyl alcohol is treated with 590 μl of methanesulfonic acid at 0° for ca. 5 hours and at RT for ca. 15 hours. To the mixture obtained 2.5 ml of N-methylmorpholine are added at 0° and the mixture obtained is heated to ca. 60° for ca. 6 hours. The mixture obtained is poured onto diluted hydrochloric acid and the mixture obtained is extracted with EtAc. The phases are separated and the organic layer obtained is washed with aqueous NaHCO3 solution and dried and the solvent is evaporated off. The evaporation residue obtained is subjected to chromatography. A compound of formula EX69B in the form of a solid is obtained. C) Compound of formula EX69C
Figure imgf000046_0001
To a solution of 50 mg of the compound of a compound of formula EX69B 1 ml of acetonitrile 60 mg of dimethylaminopyridine, 19 μl of TFA and 57 μl of DCC. To the mixture obtained 30 mg of N-butoxycarbonyl-aminocyclopropylcarboxylic acid are added in small portions at RT and the mixture obtained is stirred for ca, 3 hours. The mixture obtained is poured onto diluted aqueous hydrochloric acid and the mixture obtained is extracted with EtAc. The organic extract obtained is washed with aqueous NaHCO3 solution, dried and the solvent is evaporated off. The evaporation residue obtained is subjected to gel permeation chromatography (Sephadex LH-20, methanol/EtAc 1 :1). The product fractions obtained are evaporated. The evaporation residue obtained is treated with 1.5 ml of THF and the solution obtained is treated with 5 mg of tetrakis-triphenylphosphine palladium and 42 μl of pyrrolidine at 0° for ca. 1 hours. The mixture obtained is diluted with EtAc, washed with diluted hydrochloric acid, Na2CO3 solution and brine, dried and the solvent is evaporated off. The evaporation residue obtained is dissolved in 1 ml of toluene, 200 μl of TFA are added and the mixture obtained is stirred for ca. 4 hours at RT. The mixture obtained is diluted with EtAc, the mixture obtained is washed with diluted hydrochloric acid, NaHCO3 solution and brine, dried and the solvent is evaporated off. The evaporation residue obtained is mixed with 2 ml of acetonitrile and diisopropylethylamine is added to adjust a slightly basic pH. The mixture obtained is added to a solution of 57 mg of [O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate and 9 μl of diisopropylethylamine in 10 ml of acetonitrile during ca. 10 hours. The mixture obtained is diluted with EtAc and the organic phase is washed and dried and the solvent is evaporated off. The evaporation residue is subjected to silica gel chromatography (gradient toluene/methanol 0.5% to 3%) and gel permeation chromatography. A compound of formula EX69C is obtained in the form of a solid. 1H-NMR (CDCI3): 8.7277.91 a (2d, 9.5Hz; PrLeu6 NH), 7.98b/7.84a (d, 3.3Hz; thiazole), 7.49a (d, 8Hz; PrLeu2 NH), 7.4977.42° (2d, 8Hz; MMTrp 4'-H), 7.3777.35° (2d, 8Hz; MMTrp 7'-H), 7.29° (d, 9Hz; PrLeu2 NH), 7.2377.20a (2d, 3.3Hz; thiazole), 7.1877.17° (2ddd, 1 Hz, 7Hz, 8Hz; MMTrp 6'-H), 7.0176.98° (2s; MMTrp 2'-H), 6.97a (s; NH), 6.9276.91 a (2ddd, 1 Hz, 7Hz, 8Hz; MMTrp 5'-H), 6.31° (d, 12Hz; Leu NH), 6.30° (MeAla NMe), 5.94a (d, 5.5Hz; Leu NH), 5.53° (dd, 9.5Hz, 3.5Hz; CHBA α-H), 5.36a (dd, 2Hz, 10Hz; CHBA α-H), 5.24° (dd,
3.2Hz, 11.7Hz; MMTrp α-H), 4.95° (ddd, 2.5Hz, 9Hz, 12Hz; PrLeu2 α-H), 4.87a (ddd, 5.2Hz, 9.4Hz, 9.7Hz; PrLeu2 α-H), 4.67° (m; Leu α-H), 4.67a (m; PrLeu6 α-H), 4.57° (ddd, 4Hz, 9.5Hz, 11 Hz; PrLeu6 α-H), 4.54a (dd, 5Hz, 10Hz; MeLeu α-H), 4.07a (m; MMTrp α-H), 4.07a (m; Leu α-H), 4.0373.9873.96° (3s; MMTrp N1 '-OMe), 3.74° (dd, 3.3Hz, 15.6Hz; MMTrp β-H), 3.67a (m; MMTrp β-CH2), 3.50° (dd, 5.1 Hz, 10.4Hz; MeLeu α-H), 3.42° (s; NMe), 3.25° (s; MeLeu NMe), 3.19° (m; MMTrp β'-H), 2.92° (s; MMTrp NMe), 2.79c (s; NMe), 2.56a (s; MeLeu NMe), 2.39a (s; MMTrp NMe), 1.02a (d, 6.5Hz; MeLeu δ-CH3), 0.97 (m; cyPr), 0.537θ.49a (2d, 6.6Hz; Leu δ-CH3), 0.187-0.13a (2d, 6.6Hz; Leu δ'-CH3), -0.55a (ddd, 3.2Hz, 11 Hz, 14.4Hz; Leu β'-H). Example 70
Production of a compound of formula IAEX- wherein R1EXr is a group of formula
Figure imgf000047_0001
, R5Eχrand R6EX. are CH3, and R7EXr is -CH2-CH=CH2
A cooled solution of 2.0 g of a compound obtained according to Example 38 in 30 ml of THF is treated with 0.333 ml of triethylamine and 0.29 ml of 2-methyl-propylchloroformate. To the mixture obtained 15 ml of 1 M diazomethane in ether solution is added and the mixture obtained is stirred at RT for ca. 15 hours and saturated aqueous NaHCO3 and EtAc is added. The phases formed are separated and the organic layer is washed, dried and the solvent is evaporated off. The evaporation residue obtained is subjected to chromatography. A compound of formula IABO wherein RiExr is a group of formula
Figure imgf000048_0001
,R5EXrand R6EXr are CH3, and R7Eχr is -CH2-CH=CH2 is obtained. 13C-NMR: 193.72, 173.47; 171.92; 171.63; 171.15; 170.67; 168.68; 168.35 (carbonyls); 75.55; 64.13, 60.69; 57.74; 48.32; 47.41 ; 47.18 (alpha-C's); 54.23 (-CHN2). Example 71
Production of a compound of formula lAεxr wherein R1EXr is a group of formula -CH2- CH2-CO-CH2OH, R5EXrand R6EXr are CH3, and R7EXr is -CH2-CH=CH2 To a solution of 200 mg of compound obtained according to Example 38 in 20 ml of trifluoroethanol and 0.05 ml of water, 0.05 ml of borontrifluoride-diethyletherat are added in one portion, the mixture obtained is stirred for ca.15 minutes at RT and saturated aqueous NaHCO3 and ethylacetate is added. The phases obtained are separated, the organic layer is washed, dried and the solvent is evaporated off. The evaporation residue is subjected to chromatography. A compound of formula IAεχr wherein RιEXr is a group of formula -CH2-CH2- CO-CH2OH, R5εχrand R6Exr are CH3, and R7Eχr is -CH2-CH=CH2 is obtained. 13C-NMR: 210.15, 173.26; 171.88; 171.75; 171.12; 170.57; 168.48; 168.40 (carbonyls); 75.23; 64.16, 60.82; 57.81 ; 48.04; 47.44 (alpha-C's); 68.01 (-CH2OH).
Analogously as described in example 71 , but using appropriate starting materials, compounds of formula IAεχr wherein RιEXr, Rsεx., Rεεx. and R7EXr are as defined in TABLE 7 are obtained:
TABLE 7
Figure imgf000048_0002
Example 74
Production of a compound of formula IAEXΓ wherein R1EXr is a group of formula
Figure imgf000049_0001
A solution of 150 mg of a compound obtained according to example 70 in 6 ml of α-cyano- EtAc is treated with 10 mg of rhodium(ll)acetate and the mixture obtained is stirred for ca. 20 hours at RT. To the mixture obtained EtAc and brine is added, the phases obtained are separated, the organic layer obtained is dried and the solvent is evaporated off. The evaporation residue obtained is subjected to molecular size exclusion chromatography through sephadex®-LH20 (eluent methanol) and flash column chromatography (eluent. cyclohexane: 2-propanol = 4 :1). A compound of formula IAE r wherein R1EXr is a group of
formula
Figure imgf000049_0002
in the form of an amorphous powder is obtained. 13C-NMR: 172.97; 172.08; 171.95; 171.10; 170.- 168.37; 168.25 (carbonyls); 157.00 / 152.83 / 123.35 (oxazol), 168.00 (-COOEt).
Analogously as described in example 74, but using appropriate starting materials, compounds of formula IAEXr wherein R1Eχr, Rsεxr, Reεx. and R7EXr are as defined in TABLE 8 are obtained:
TABLE 8
Figure imgf000049_0003
Figure imgf000050_0002
Examples 79 and 80
Production of compounds of formula lA^- wherein RιEχr, Rsεx. and R6EXr are as defined in TABLE 9
TABLE 9
Figure imgf000050_0003
A) Compound of Example 79
To an ice bath cooled solution of 200 mg of a compound obtained according to Example 38 in 20 ml toluene is added 0.21 ml of P4-t-Butyl and 240 mg of a compound of formula
ς>Si(CH3)2(C(CH3)3)
Figure imgf000050_0001
The mixture obtained is stirred for ca. 15 minutes at ca. 5° and aqueous HCI and EtAc are added. The phases formed are separated, the organic layer is washed, dried and the solvent is evaporated off. The evaporation residue obtained is subjected to molecular size exclusion chromatography (Sephadex®-LH20, eluent: methanol) and flash column chromatography (eluent: cyclohexane:EtAc:methanol = 20:10:1). A compound of formula IAEXr wherein R1EXr, R5EXrand R6EXr are as defined in TABLE 9 under Ex. 79 is obtained.13C-NMR: 173.23; 171.98; 171.54; 170.95; 170.66; 168.41 ; 168.11 (ring carbonyls); 82.05 (-OCH2O-); 153.72 (- O(C=O)O-); 101.89; 82.05; 78.74; 77.60; 70.05; 64.03 (C1-C6-sugar part). B) Compound of Example 80
To 246 mg of the compound obtained according to Example 79 in 16 ml of acetonitrile 2 ml of aqueous hydrogenfluoride (40w/w%) are added, the mixture obtained is stirred for ca. 90 minutes at RT, saturated aqueous NaHCO3 and EtAc are added and the phases formed are separated. The organic layer obtained is washed, dried and the solvent is evaporated off. The evaporation residue is subjected to flash column chromatography (eluent: cyclohexane:EtAc:methanol=20:10:5) and filtration through Sephadex®-LH20 (eluent: methanol). The fractions comprising a compound of example 80 as defined in TABLE 9 are subjected to lyophilisation from benzene. 13C-NMR: 173.23; 171.97; 171.62; 171.01 ; 170.65; 168.44; 168.16 (ring carbonyls); 171.82 (-C(=O)O-); 82.18 (-OCH2O-); 153.81 (-O(C=O)O-); 103.35; 77.33; 77.16; 73.87; 70.52; 61.54 (C1-C6-sugar part).
A compound of formula EX79-i may be obtained according to example 13, "Production of a compound of formula EX13."
Analogously as described in example 79, but using appropriate starting materials, compounds of formula lA^ wherein RιEXr, R5εχr, Rεεxr and R7EXr are as defined in TABLE 10 are obtained:
TABLE 10
Figure imgf000051_0001
Additional compound characterization data
EX.29: 1H-NMR: 8.66 (d, J=10.0Hz, 1H), 8.34 (d, J=6.2Hz, 1H), 7.78 (d, J=9.6Hz, 1H), 7.78 (d, J=3.3Hz, 1H), 7.70 (d, J=3.3Hz, 1H), 7.57 (d, J=7.9Hz, 1H), 7.41 (d, J=8.2Hz, 1H), 7.37 (s, 1H), 7.18 (dd, J=8.2, 7.1Hz, 1H), 6.98 (dd, J=7.9, 7.1Hz, 1H), 4.96 (td, J=10.0f 5.1Hz, 1 H), 4.80 (dd, J=9.3, 5Hz, 1 H), 4.68 (td, J=8.7, 7.3Hz, 1 H), 4.62 (dd, J=10.5, 3.9Hz, 1 H), 4.15 (m, 1H), 4.13 (m, 1H), 4.00 (s, 3H), 3.26 (dd, J=15.0, 5Hz, 1H), 3.08 (dd, J=15.0, 9.3Hz, 1H), 2.98 (m, 1H), 2.97 (s, 3H), 2.84 (m, 1H), 2.79 (s, 3H), 2.40 (s, 3H), 2.09 (m, 1H), 1.91 (m, 1H), 1.65 (t, J=6.8Hz, 2H), 1.34 (s, 6H), 0.94 (d, J=6.5Hz, 3H), 0.92 (d, J=6.6Hz, 3H), 0.88 (d, J=6.5Hz, 3H), 0.86 (t, J=7.2Hz, 3H), 0.84 (t, J=7.2Hz, 3H), 0.78 (d, J=6.5Hz, 3H), 0.44 (d, J=6.6Hz, 3H), -0.13 (d, J=6.6Hz, 3H), -0.32 (ddd, J=13.7, 10.4, 3.3Hz, 1H).
EX.30: 1H-NMR: 8.64 (d, J=10.0Hz, 1H), 8.32 (d, J=6.2Hz, 1H), 7.80 (d, J=9.5Hz, 1H), 7.67 (d, J=3.3Hz, 1H), 7.59 (d, J=3.3Hz, 1H), 7.54 (d, J=7.9Hz, 1H), 7.39 (d, J=8.2Hz, 1H), 7.37 (s, 1H), 7.16 (dd, J=8.2, 7.1Hz, 1H), 6.95 (dd, J=7.9, 7.1Hz, 1H), 4.95 (td, J=9.9, 5.1Hz, 1H),
4.78 (dd, J=9.7, 5.1Hz, 1H), 4.68 (dd, J=10.1, 3.1Hz, 1H), 4.66 (td, J=8.7, 7.3Hz, 1H), 4.14 (m, 1H), 4.09 (dd, J=9.0, 6.3Hz, 1H), 3.98 (s, 3H), 3.25 (dd, J=15.1, 5.1Hz, 1H), 3.06 (dd,
J=15.1, 9.7Hz, 1H), 2.96 (m, 1H), 2.93 (s, 3H), 2.82 (m, 1H), 2.77 (s, 3H), 2.39 (s, 3H), 2.08 (m, 1H), 1.89 (m, 1H), 1.62 (m, 2H), 1.24 (s, 3H), 0.93 (d, J=6.5Hz, 3H), 0.91 (d, J=6.6Hz, 3H), 0.85 (d, J=6.5Hz, 3H), 0.84 (t, J=7.2Hz, 3H), 0.82 (t, J=7.2Hz, 3H), 0.78 (d, J=6.5Hz, 3H), 0.64 (t, J=7.2Hz, 3H), 0.43 (d, J=6.6Hz, 3H), -0.13 (d, J=6.6Hz, 3H), -0.34 (ddd, J=13.7, 10.4, 3.3Hz, 1H).
EX.31: 1H-NMR: 8.61 (d, J=10.0Hz, 1H), 8.34 (d, J=6.2Hz, 1H), 7.80 (d, J=9.5Hz, 1H), 7.67 (d, J=3.3Hz, 1H), 7.60 (d, J=3.3Hz, 1H), 7.57 (d, J=7.9Hz, 1H), 7.39 (d, J=8.2Hz, 1H), 7.34 (s, 1H), 7.16 (dd, J=8.2, 7.1Hz, 1H), 6.95 (dd, J=7.9, 7.1Hz, 1H), 4.93 (td, J=9.9, 5.1Hz, 1H),
4.79 (dd, J=9.3, 5.3Hz, 1H), 4.68 (dd, J=10.1, 3.1Hz, 1H), 4.66 (td, J=8.7, 7.3Hz, 1H), 4.18 (m, 1H), 4.10 (dd, J=8.8, 6.6Hz, 1H), 3.97 (s, 3H), 3.28 (dd, J=15.0, 5.3Hz, 1H), 3.04 (dd,
J=15.0, 9.3Hz, 1H), 2.91 (m, 1H), 2.89 (s, 3H), 2.81 (m, 1H)f 2.77 (s, 3H), 2.39 (s, 3H), 2.07 (m, 1H), 1.90 (m, 1H), 1.62 (m, 2H), 1.26 (s, 3H), 0.93 (d, J=6.5Hz, 3H), 0.91 (d, J=6.6Hz, 3H), 0.85 (d, J=6.5Hz, 3H), 0.84 (t, J=7.2Hz, 3H), 0.83 (t, J=7.2Hz, 3H), 0.81 (t, J=7.2Hz, 3H), 0.78 (d, J=6.5Hz, 3H), 0.45 (d, J=6.6Hz, 3H), -0.08 (d, J=6.6Hz, 3H), -0.26 (ddd, J=13.7, 10.4, 3.3Hz, 1H).
EX.32: 1H-NMR: 8.64 (d, J=10.0Hz, 1H), 8.33 (d, J=6.0Hz, 1H), 7.78 (d, J=9.5Hz, 1H), 7.68 (d, J=3.3Hz, 1H), 7.60 (d, J=3.3Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.39 (d, J=8.1Hz, 1H), 7.34 (s, 1H), 7.16 (ddd, J=8.1, 7.1, 0.8Hz, 1H), 6.95 (ddd, J=8.0, 7.1, 0.8Hz, 1H), 5.45 (m, 1H), 5.05 (d, J=17.5Hz, 1H), 5.02 (d, J=12.0Hz, 1H), 4.95 (td, J=9.6, 5.3Hz, 1H), 4.80 (dd, J=9.8, 5.1Hz, 1H), 4.68 (dd, J=9.0, 3.6Hz, 1H), 4.65 (td, J=8.8, 7.6Hz, 1H), 4.15 (m, 1H), 4.10 (t, J=8.0Hz, 1H), 3.98 (s, 3H), 3.35 (dd, J=15.0, 5.1Hz, 1H), 3.06 (dd, J=15.0, 9.8Hz, 1H), 2.98 (ddd, J=15.8, 8.4, 6.2Hz, 1H), 2.94 (s, 3H), 2.87 (td, J=15.8, 6.3Hz, 1H), 2.77 (s, 3H), 2.53 (dd, J=13.1, 7.8Hz, 1H), 2.40 (s, 3H), 2.24 (dd, J=13.1, 6.3Hz, 1H), 2.05 (m, 1H), 1.96 (m, 1 H), 1.62 (t, J=7.0Hz, 2H), 1.26 (s, 3H), 0.94 (d, J=6.5Hz, 3H), 0.91 (d, J=6.6Hz, 3H), 0.85 (d, J=6.6Hz, 3H), 0.83 (t, J=7.2Hz, 3H), 0.82 (t, J=7.1Hz, 3H), 0.78 (d, J=6.5Hz, 3H), 0.42 (d, J=6.6Hz, 3H), -0.13 (d, J=6.6Hz, 3H), -0.35 (ddd, J=13.7, 10.4, 3.3Hz, 1H). EX.33: 1H-NMR: 8.68 (d, J=10.0Hz, 1H), 8.34 (d, J=6.2Hz, 1H), 7.87 (d, J=9.5Hz, 1H), 7.68 (d, J=3.3Hz, 1H), 7.61 (d, J=3.3Hz, 1H), 7.50 (d, J=7.9Hz, 1H), 7.40 (d, J=8.2Hz, 1H), 7.34 (s, 1H), 7.17 (dd, J=8.2, 7.1Hz, 1H), 6.96 (dd, J=7.9, 7.1Hz, 1H), 4.96 (td, J=9.9, 5.1Hz, 1H), 4.81 (dd, J=9.3, 5.3Hz, 1H), 4.78 (bs, 1H), 4.67 (m, 1H), 4.67 (m, 1H), 4.61 (bs, 1H), 4.14 (m, 1H), 4.10 (dd, J=9.6, 5.7Hz, 1H), 3.99 (s, 3H), 3.26 (dd, J=15.0, 5.3Hz, 1H), 3.07 (dd, J=15.0, 9.3Hz, 1H), 2.95 (s, 3H), 2.91 (m, 1H), 2.81 (m, 1H), 2.77 (s, 3H), 2.53 (d, J=13.0, 7.8Hz, 1H), 2.39 (s, 3H), 2.17 (d, J=13.0, 6.3Hz, 1H), 2.05 (AB, 1H), 2.05 (AB, 1H), 1.62 (m, 2H), 1.58 (s, 3H), 1.34 (s, 3H), 0.95 (d, J=6.5Hz, 3H), 0.93 (d, J=6.6Hz, 3H), 0.86 (d,
J=6.5Hz, 3H), 0.85 (t, J=7.2Hz, 3H), 0.83 (t, J=7.2Hz, 3H), 0.80 (d, J=6.6Hz, 3H), 0.41 (d, J=6.6Hz, 3H), -0.15 (d, J=6.6Hz, 3H), -0.36 (ddd, J=13.7, 10.4, 3.3Hz, 1H). EX.34: 1H-NMR: 8.64 (d, J=10.0Hz, 1H), 8.34 (d, J=6.0Hz, 1H), 7.81 (d, J=9.5Hz, 1H), 7.68 (d, J=3.3Hz, 1H), 7.59 (d, J=3.3Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.41 (d, J=8.1Hz, 1H), 7.36 (s, 1H), 7.18 (ddd, J=8.1, 7.1, 0.8Hz, 1H), 6.98 (ddd, J=8.0, 7.1, 0.8Hz, 1H), 4.97 (td, J=9.6, 5.3Hz, 1H), 4.81 (m, 1H), 4.80 (m, 1H), 4.72 (dd, J=9.1, 3.6Hz, 1H), 4.67 (td, J=8.8, 7.6Hz, 1H), 4.14 (m, 1H), 4.12 (t, J=7.2Hz, 1H), 4.00 (s, 3H), 3.36 (dd, J=15.1, 5.1Hz, 1H), 3.07 (dd, J=15.1, 9.6Hz, 1H), 3.00 (s, 3H), 2.94 (m, 1H), 2.86 (m, 1H), 2.79 (s, 3H), 2.53 (m, 2H), 2.41 (s, 3H), 2.06 (m, 1 H), 1.93 (m, 1 H), 1.64 (m, 2H), 1.63 (s, 3H), 1.58 (s, 3H), 1.26 (s, 3H), 0.95 (d, J=6.5Hz, 3H), 0.93 (d, J=6.7Hz, 3H), 0.87 (d, J=6.5Hz, 3H), 0.86 (t, J=7.2Hz, 3H), 0.84 (t, J=7Hz, 3H), 0.80 (d, J=6.5Hz, 1H), 0.44 (d, J=6.6Hz, 3H), -0.13 (d, J=6.6Hz, 3H), - 0.32 (ddd, J=13.7, 10.4, 3.3Hz, 1H).
EX.35: 1H-NMR: 8.74 (d, J=10.0Hz, 1H), 8.36 (d, J=6.1Hz, 1H), 7.82 (d, J=9.5Hz, 1H), 7.79 (d, J=3.3Hz, 1H), 7.68 (d, J=3.3Hz, 1H), 7.55 (d, J=8.0Hz, 1H), 7.42 (d, J=8.1Hz, 1H), 7.36 (s, 1H), 7.20 (m, 3H), 7.18 (dd, J=8.1, 7.1Hz, 1H), 7.01 (m, 1H), 6.98 (dd, J=8.0, 7.1Hz, 1H), 6.92 (m, 1H), 5.00 (td, J=9.7, 5.4Hz, 1H), 4.85 (dd, J=9.8, 5.1Hz, 1H), 4.73 (dd, J=8.0, 5Hz, 1H), 4.64 (td, J=8.7, 7.3Hz, 1H), 4.17 (m, 1H), 4.10 (dd, J=9.3, 7Hz, 1H), 4.00 (s, 3H), 3.32 (m, 1H), 3.18 (m, 1H), 3.07 (s, 3H), 3.03 (m, 1H), 3.01 (m, 1H), 2.85 (AB; ), 2.79 (s, 3H), 2.43 (s, 3H), 2.06 (m, 1H), 1.94 (m, 1H), 1.65 (t, J=6.8Hz, 2H), 1.26 (s, 3H), 0.94 (d, J=6.5Hz, 3H), 0.92 (d, J=6.7Hz, 3H), 0.88 (d, J=6.5Hz, 3H), 0.86 (t, J=7.2Hz, 3H), 0.77 (t, J=7.2Hz, 3H), 0.76 (d, J=6.5Hz, 3H), 0.44 (d, J=6.6Hz, 3H), -0.13 (d, J=6.6Hz, 3H), -0.38 (ddd, J=13.7, 10.4, 3.3Hz, 1H). EX.36: 1H-NMR: 8.63 (d, J=10.0Hz, 1 H), 8.33 (d, J=6.1 Hz, 1 H), 7.70 (d, J=9.2Hz, 1 H), 7.65 (d, J=3.3Hz, 1 H), 7.57 (d, J=3.3Hz, 1 H), 7.56 (d, J=7.9Hz, 1 H), 7.39 (d, J=8.2Hz, 1 H), 7.35 (s, 1 H), 7.16 (t, J=7.5Hz, 1H), 6.96 (t, J=7.5Hz, 1H), 4.98 (td, J=10.0, 5.1 Hz, 1 H), 4.78 (dd, J=10.0, 4.5Hz, 1 H), 4.67 (dd, J=10.5, 3.9Hz, 1 H), 4.67 (td, J=8.7, 7.3Hz, 1 H), 4.12 (m, 1 H), 4.10 (m, 1 H), 3.98 (s, 3H), 3.23 (dd, J=15.1 , 4.5Hz, 1 H), 3.06 (m, 1 H), 3.04 (s, 3H), 2.98 (dd, J=15.0, 8.4Hz, 1H), 2.88 (m, 1H), 2.77 (s, 3H), 2.41 (s, 3H), 2.07 (m, 1H), 1.95 (m, 1 H), 1.62 (t, J=7.0Hz, 2H), 1.36 (s, 3H), 1.12 (s, 9H), 0.93 (d, J=6.5Hz, 3H), 0.91 (d, J=6.7Hz, 3H), 0.85 (d, J=6.5Hz, 3H), 0.84 (t, J=7.2Hz, 3H), 0.82 (t, J=7.2Hz, 3H), 0.78 (d, J=6.4Hz, 3H), 0.39 (d, J=6.6Hz, 3H), -0.18 (d, J=6.6Hz, 3H), -0.44 (ddd, J=13.7, 10.4, 3.3Hz, 1 H). EX.37: 1H-NMR: 173.222, 172.925, 171.863, 171.483, 170.651 , 168.357, 168.304, 132.138, 123.874, 123.271 , 122.784, 119.937, 119.084, 108.759, 106.872, 74.877, 66.243, 64.177, 60.697, 57.732, 51.772, 48.184, 47.360, 47.116, 38.816, 38.741 , 37.480, 36.854, 36.757, 36.380, 30.536, 29.969, 29.223, 29.028, 28.958, 28.876, 28.631 , 28.394, 26.078, 24.942, 23.845, 23.590, 23.101 , 22.926, 22.807, 22.013, 20.452, 19.109, 19.042, 18.866, 17.981 , 14.527, 14.464, 14.408. EX.38: Mass Spectroscopy: ESI-MS: M.H+ 1036.6 (calc. 1036.7); M.Na-t- 1058.7 (calc. 1058.6) (M-H).2Na+ 1080.6 (calc. 1080.6) negative mode: M-H-1034.7 (calc. 1034.7) TLC: Silicagel 60 (Merck HPTLC); Rf = 0.23 in toluene:MeOH = 85:15
EX.39: 13C-NMR: 173.269, 172.956, 172.001 , 171.796, 171.024, 170.643, 168.480, 168.261, 132.683, 132.145, 123.876, 123.278, 122.780, 119.958, 119.610, 119.065, 108.766, 106.857, 74.971 , 66.241 , 64.126, 60.698, 57.751 , 51.794, 48.223, 47.362, 47.181 , 38.778, 37.448, 36.861, 36.784, 36.385, 30.783, 30.130, 29.212, 29.043, 28.963, 28.868, 28.651, 28.424, 26.065, 24.942, 23.834, 23.553, 23.086, 22.946, 22.808, 22.011 , 20.453, 19.135, 18.974, 18.844, 14.459, 14.399.
EX.40: 1H-NMR (CDCI3):8.72 (d, J=9.9Hz, 1H), 8.20 (d, J=6Hz, 1H), 7.71 (d, J=9.5Hz, 1H), 7.54 (d, J=8Hz, 1 H), 7.40 (d, J=8.1 HZ, 1 H), 7.33 (s, 1 H), 7.17 (ddd, J=8.0, 7.1 , 0.8Hz, 1 H), 6.99 (ddd, J=8.0, 7.1 , 0.8Hz, 1H), 5.52 (m, 1 H), 4.95 (ddd, J=5, 10, 4.7Hz, 1 H), 4.92 (dd, J=10.5, 4.4Hz, 1H), 4.64 (m, 1H), 4.52 (dd, J=10.3, 3.5Hz, 1 H), 4.00 (s, 3H), 3.00 (s, 3H), 2.76 (s, 3H), 2.38 (s, 3H), 1.28 (s, 3H), 0.40 (d, J=6.5Hz, 3H), -0.12 (d, J=6.5Hz, 3H), -0.51 (ddd, J=3.6, 11.1 , 14.5Hz, 1 H). EX.41: 13C-NMR 173.208, 172.553, 171.854, 171.796, 171.504, 170.667, 168.337, 168.308, 132.131, 123.877, 123.296, 122.783, 119.884, 119.049, 108.784, 106.861, 74.846, 66.239, 65.912, 64.199, 60.661, 57.738, 48.200, 47.366, 47.107, 38.876, 38.753, 37.502, 36.858, 36.748, 36.392, 30.539, 30.095, 29.220, 29.040, 28.958, 28.868, 28.643, 28.410, 26.097, 24.950, 23.834, 23.599, 23.102, 22.926, 22.806, 21.998, 20.447, 19.118, 19.074, 18.909, 17.962, 14.581, 14.463, 14.409, 10.747.
EX.42: 1H-NMR: 8.73 (d, J=10.0Hz, 1H), 8.22 (d, J=6.1Hz, 1H), 7.73 (d, J=9.5Hz, 1H), 7.55 (d, J=8.0Hz, 1H), 7.41 (d, J=8.2Hz, 1H), 7.35 (s, 1H), 7.19 (ddd, J=8.2, 7.1, 0.8Hz, 1H), 7.00 (ddd, J=8.0, 7.1 , 0.8Hz, 1 H), 5.53 (m, 1 H), 5.11 (d, J=16.0Hz, 1 H), 5.09 (d, J=10.1 Hz, 1 H), 4.96 (td, J=10.1, 4.8Hz, 1H), 4.93 (dd, J=9.8, 4.7Hz, 1H), 4.66 (td, J=8.4, 7.7Hz, 1H), 4.53 (dd, J=9.2, 3.7Hz, 1H), 4.22 (m, 1H), 4.08 (m, 1H), 4.06 (dd, J=10.7, 6.6Hz, 1H), 4.00 (s, 3H), 3.95 (dd, J=10.7, 6.6Hz, 1H), 3.18 (dd, J=15.0, 4.7Hz, 1H), 3.10 (dd, J=15.0, 9.8Hz, 1H), 3.02 (s, 3H), 2.78 (s, 3H), 2.64 (dd, J=13.0, 7.5Hz, 1H), 2.40 (s, 3H), 2.35 (m, 1H), 2.35 (m, 1H), 2.26 (ddd, J=17.1, 7.2, 4.5Hz, 1H), 1.88 (m, 1H), 1.78 (m, 1H), 1.62 (ABXY, 2H), 1.26 (s, 3H), 0.95 (d, J=6.5Hz, 3H) 0.93 (d, J=6.6Hz, 3H), 0.92 (t, J=7.3Hz, 3H), 0.87 (d, J=6.5Hz, 3H), 0.86 (t, J=7.2Hz, 3H), 0.84 (t, J=7.2Hz, 3H), 0.80 (d, J=6.5Hz, 3H), 0.42 (d, J=6.6Hz, 3H), -0.01 (d, J=6.6Hz, 3H), -0.50 (ddd, J=13.7, 10.4, 3.3Hz, 1H). EX.43: 1H-NMR: 8.72 (d, J=10Hz, 1H), 8.72 (d, J=10Hz, 1H), 8.23 (d, J=6.1Hz, 1H), 7.74 (d, J=9.5Hz, 1H), 7.55 (d, J=8Hz, 1H), 7.41 (d, J=8.1Hz, 1H), 7.35 (s, 1H), 7.18 (ddd, J=8.0, 7.1, 0.8Hz, 1H), 7.00 (ddd, J=8.0, 7.1, 0.8Hz, 1H), 5.95 (m;), 5.53 (m, 1H), 5.33 (dq, J=17.2, 1Hz; ), 5.26 (dq, J=10.8, 1Hz; ), 5.10 (d, J=17Hz, 1H), 5.07 (d, J=11Hz, 1H), 4.95 (ddd, J=5, 10, 4.7Hz, 1H), 4.92 (dd, J=10.5, 4.4Hz, 1H), 4.66 (m, 1H), 4.63 (ddt, J=14, 5.2Hz, 1H), 4.55 (ddt, J=14, 5.6Hz, 1H), 4.53 (dd, J=10.3, 3.5Hz, 1H), 4.22 (m, 1H), 4.09 (dd, J=5.4, 10Hz, 1H), 4.00 (s, 3H), 3.02 (s, 3H), 2.78 (s, 3H), 2.40 (s, 3H), 1.30 (s, 3H), 0.42 (d, J=7Hz, 3H), -0.09 (d, J=7Hz, 3H), -0.51 (ddd, J=3.6, 11.1,14.5Hz, 1 H) (In CDCI3 instead of DMSO- D6).
EX.49: 3C-NMR: 172.976, 171.873, 171.594, 170.549, 169.129, 168.498, 168.138, 142.772, 132.215, 123.817, 123.265, 122.855, 120.971, 119.840, 119.081, 108.814, 106.838, 106.603, 73.950, 66.240, 64.161, 60.925, 57.850, 48.060, 47.492, 47.215, 36.781, 36.719, 36.463, 31.246, 30.556, 29.196, 29.041 , 28.956, 28.817, 28.699, 28.040, 24.939, 23.747, 23.686, 23.047, 22.924, 22.791, 22.145, 20.463, 19.176, 18.881, 14.455, 14.402. EX.50: 1H-NMR: 8.72 (d, J=10.1Hz, 1H), 8.22 (d, J=6.2Hz, 1H), 7.77 (d, J=9.5Hz, 1H), 7.55 (d, J=7.8Hz, 1H), 7.42 (d, J=8.1Hz, 1H), 7.34 (s, 1H), 7.19 (t, J=7.6Hz, 1H), 7.02 (t, J=7.5Hz, 1H), 4.96 (m, 1H), 4.93 (m, 1H), 4.68 (dd, J=9.3, 7.5Hz, 1H), 4.57 (dd, J=10.5, 3.4Hz, 1H), 4.48 (t, J=5.6Hz, 1 H), 4.23 (m, 1 H), 4.09 (dd, J=9.9, 5.4Hz), 4.00 (s, 3H), 2.99 (s, 3H), 2.78 (s, 3H), 2.40 (s, 3H), 0.43 (d, J=6.5Hz, 3H), -0.09 (d, J=6.5Hz, 3H), -0.47 (m, 1 H). EX.51 : 13C-NMR: 173.225, 172.589, 171.885, 171.780, 171.600, 170.637, 168.417, 168.312, 132.138, 123.897, 123.264, 122.779, 119.914, 119.026, 108.790, 106.871 , 74.939, 66.240, 65.898, 64.096, 60.898, 60.731 , 60.660, 57.758, 48.195, 47.402, 47.145, 38.824, 37.447, 36.864, 33.414, 30.565, 30.190, 29.208, 29.041 , 28.972, 28.865, 28.671 , 28.417, 28.098, 26.149, 24.949, 23.821 , 23.571 , 23.486, 23.076, 22.930, 22.811 , 22.030, 21.975, 20.460, 19.327, 19.150, 19.039, 18.936, 14.463, 14.403, 10.726. EX.54: 13C-NMR: 173.057, 171.958, 171.843, 171.294, 170.781 , 168.863, 168.223, 151.543, 132.874, 132.318, 123.854, 123.395, 122.869, 120.250, 119.890, 119.065, 108.827,
106.814, 73.872, 66.222, 64.181 , 60.874, 57.783, 48.111 , 47.599, 47.212, 38.816, 36.812, 30.947, 28.671 , 28.429, 26.759, 24.935, 23.813, 23.548, 23.072, 22.915, 22.772, 22.086, 20.394, 19.196, 14.419. EX.57: 13C-NMR: 172.794, 171.579, 171.493, 170.641 , 170.196, 168.627, 167.977, 167.904, 132.208, 131.833, 123.514, 122.885, 122.385, 119.638, 119.269, 118.645, 108.367,
106.514, 74.161 , 65.817, 63.658, 60.500, 57.506, 47.808, 47.057, 46.968, 40.708, 38.525, 36.369, 36.091 , 30.191 , 28.779, 28.670, 28.572, 28.365, 28.045, 27.787, 24.583, 23.472, 23.376, 23.215, 22.662, 22.537, 22.398, 21.814, 21.743, 20.041 , 18.865, 18.691 , 18.436, 14.027, 13.974. EX.58: 13C-NMR: 172.793, 171.624, 171.490, 170.701 , 170.218, 169.325, 167.941 , 167.887, 132.224, 131.875, 123.513, 122.874, 122.404, 119.651 , 119.241 , 118.561 , 108.417, 106.504, 73.725, 65.830, 63.691 , 60.454, 57.505, 47.744, 47.085, 46.937, 38.462, 37.150, 36.386, 36.083, 30.265, 28.802, 28.632, 28.583, 28.562, 28.372, 28.019, 27.789, 24.583, 23.388, 23.213, 22.657, 22.542, 22.408, 21.767, 20.041 , 19.527, 18.824, 18.633, 18.470, 14.029, 13.991 , 10.537.
EX.59: 13C-NMR: 179.599, 172.741 , 171.635, 171.496, 170.709, 170.229, 169.341 , 167.952, 167.886, 132.237, 131.885, 123.511 , 122.883, 122.416, 119.645, 119.246, 118.574, 108.436, 106.507, 73.738, 65.839, 63.697, 60.441 , 57.514, 47.750, 47.086, 46.945, 40.830, 38.465, 37.171 , 36.391 , 36.099, 30.279, 28.812, 28.638, 28.589, 28.562, 28.383, 28.031 , 27.778, 27.566, 24.590, 23.388, 23.216, 22.660, 22.548, 22.414, 21.772, 20.049, 19.607, 18.823, 18.655, 18.472, 14.046, 13.402.
EX.60: 13C-NMR: 177.138, 177.013, 173.056, 172.225, 171.901 , 170.629, 170.130, 169.670, 168.371 , 168.011 , 132.232, 123.833, 123.298, 122.835, 120.058, 118.994, 108.819, 106.795, 74.283, 66.231 , 63.823, 60.837, 57.822, 48.092, 47.312, 47.184, 38.730, 37.373, 36.847, 36.695, 36.487, 31.158, 29.180, 29.006, 28.961 , 28.872, 28.695, 28.431 , 28.203, 27.215, 27.094, 24.936, 23.873, 23.767, 23.497, 23.029, 22.790, 22.748, 22.089, 21.856, 20.395, 19.381 , 19.096, 18.850, 17.429, 14.432, 14.383, 12.246.
EX.61: 13C-NMR: 180.929, 176.998, 173.070, 172.212, 171.898, 170.636, 170.136, 169.587, 168.387, 168.006, 132.215, 123.838, 123.297, 122.816, 120.045, 118.984, 108.812,
106.787, 74.380, 66.229, 63.826, 60.818, 57.828, 48.084, 47.333, 47.196, 38.685, 36.847, 36.678, 36.491, 31.148, 29.179, 29.008, 28.961, 28.875, 28.718, 28.434, 28.146, 27.099, 24.941 , 23.772, 23.482, 23.019, 22.841, 22.791, 22.751, 22.095, 21.978, 20.399, 19.903, 19.099, 18.830, 17.414, 14.432, 14.385, 10.838. EX.62: 13C-NMR: 179.987, 176.986, 173.064, 172.211, 171.894, 170.644, 170.141, 169.600, 168.384, 167.999, 132.217, 123.832, 123.292, 122.809, 120.030, 118.987, 108.809, 106.785, 74.385, 66.229, 63.826, 60.796, 57.830, 48.087, 47.337, 47.196, 38.678, 37.367, 36.846, 36.671, 36.499, 31.146, 29.177, 29.006, 28.964, 28.873, 28.731, 28.438, 28.134, 27.922, 27.151, 24.945, 23.701 , 23.483, 23.018, 22.837, 22.791 , 22.754, 22.093, 21.971, 20.393, 19.908, 19.096, 18.861, 17.412, 14.426, 14.383, 13.772.
EX.63: 13C-NMR:180.133, 176.986, 173.063, 172.210, 171.891, 170.683, 170.141, 169.597, 168.377, 168.007, 132.160, 123.825, 123.289, 119.997, 118.992, 108.591, 106.771, 74.371, 66.227, 66.056, 63.825, 60.773, 57.821, 48.083, 47.328, 47.182, 38.676, 36.847, 36.668, 31.155, 29.181, 29.008, 28.962, 28.419, 27.098, 25.771, 24.941, 23.766, 23.477, 23.012, 22.836, 22.792, 22.092, 21.946, 20.396, 19.090, 18.850, 17.405, 14.433, 14.391, 13.846.
EX.64: 13C-NMR: 172.727, 171.671, 171.486, 170.695, 170.220, 169.338, 167.937, 167.869, 132.231, 131.881, 123.507, 122.869, 122.395, 119.627, 119.216, 118.559, 108.421, 106.500, 73.731, 65.819, 63.679, 60.416, 57.503, 47.736, 47.084, 46.936, 40.820, 36.379, 36.091 , 30.260, 28.794, 28.621 , 28.574, 28.554, 28.370, 28.112, 28.112, 28.016, 25.396, 24.576, 23.367, 23.200, 22.636, 22.531 , 22.398, 21.759, 21.552, 20.030, 18.815, 18.648, 18.459, 14.026, 13.981, 13.442.
EX.65: 1H-NMR: 8.64 (d, J=10.0 Hz, 1H), 8.25 (d, J=6.3 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.33 (s, 1H), 7.16 (t, J=7.6 Hz, 1H), 6.98 (t, J=7.8 Hz, 1H), 5.37 (t, J=5.2 Hz, 1H), 4.94 (dt, J=9.7, 5.5 Hz, 1H), 4.79 (dd, J=10.1, 4.7 Hz, 1H), 4.68 (dd, J=10.2, 3.1 Hz, 1H), 4.66 (m, 1 H), 4.12 (dd, J=10.5, 5.1 Hz, 1H), 4.09 (m,
1H), 3.99 (s, 3H), 3.61 (d, J=5.2 Hz, 2H), 3.09 (s, 3H), 2.76 (s, 3H), 2.53 (s, 3H), 2.39 (s, 3H), 1.31 (s, 3H), 0.44 (d, J=6.6 Hz, 3H), -0.18 (d, J=6.6 Hz, 3H), -0.51 (m, 1H). EX.66: 1H-NMR: 8.65 (d, J=9.9 Hz, 1H), 8.25 (d, J=6.2 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.33 (s, 1H), 7.15 (t, J=7.3 Hz, 1H), 6.97 (t, J=7.5 Hz, 1 H), 5.37 (bs, 1 H), 4.94 (dt, J=9.7, 5.5 Hz, 1 H), 4.81 (dd, J=9.7, 5.0 Hz, 1 H), 4.69 (dd, J=10.0, 3.1 Hz, 1 H), 4.66 (m, 1 H), 4.12 (dd, J=10.5, 4.7 Hz, 1 H), 4.11 (m, 1 H), 3.99 (s, 3H), 3.60(bs, 2H), 3.18 (s, 3H), 2.89 (q, J=7.5 Hz, 2 H), 2.77 (s, 3H), 2.39 (s, 3H), 1.30 (s, 3H), 1.27 (t, J=7.5 Hz), 0.39 (d, J=6.6 Hz, 3H), -0.20 (d, J=6.6 Hz, 3H), -0.53 (m, 1 H). EX.67: 1H-NMR: 8.65 (d, J=10.0 Hz, 1 H), 8.25 (d, J=6.3 Hz, 1 H), 7.83 (d, J=9.6 Hz, 1 H), 7.46 (d, J=8.0 Hz, 1 H), 7.39 (d, J=8.2 Hz, 1H), 7.33 (s, 1 H), 7.15 (t, J=7.6 Hz, 1 H), 6.97 (t, J=7.2 Hz, 1 H), 5.36 (bt, J=4.4 Hz, 1 H), 4.94 (dt, J=9.6, 5.5 Hz, 1 H), 4.81 (dd, J=9.8, 4.9 Hz, 1 H), 4.69 (dd, J=10.0, 3.2 Hz, 1 H), 4.67 (m, 1 H), 4.12 (m, 2H), 3.98 (s, 3H), 3.59 (bd, J=4.4 Hz, 2H), 3.07 (s, 3H), 2.85 (t, J=7.4 Hz, 2 H), 2.77 (s, 3H), 2.39 (s, 3H), 1.72 (tq, J=7.3 Hz, 2H), 1.30 (s, 3H), 0.94 (t, J=7.3 Hz), 0.39 (d, J=6.6 Hz, 3H), -0.19 (d, J=6.6 Hz, 3H), -0.52 (m, 1 H).
EX.68: 1H-NMR: 8.65 (d, J=9.9 Hz, 1 H), 8.25 (d, J=6.2 Hz, 1 H), 7.83 (d, J=9.6 Hz, 1 H), 7.46 (d, J=8.0 Hz, 1 H), 7.39 (d, J=8.2 Hz, 1 H), 7.33 (s, 1 H), 7.15 (t, J=7.6 Hz, 1 H), 6.97 (t, J=7.5 Hz, 1 H), 5.37 (t, J=4.4 Hz, 1 H), 4.94 (dt, J=9.4, 5.5 Hz, 1 H), 4.81 (dd, J=9.8, 4.9 Hz, 1 H), 4.69 (dd, J=10.0, 3.2 Hz, 1 H), 4.67 (m, 1 H), 4.12 (m, 2H), 3.98 (s, 3H), 3.60(bd, J=4.4 Hz, 2H), 3.07 (s, 3H), 2.87 (t, J=7.5 Hz, 2 H), 2.76 (s, 3H), 2.39 (s, 3H), 1.68 (tt, J=7.4 Hz, 2 H), 1.34 (tq, J=7.4 Hz, 2 H), 1.30 (s, 3H), 0.88 (t, J=7.4 Hz), 0.39 (d, J=6.6 Hz, 3H), -0.19 (d, J=6.6 Hz, 3H), -0.51 (m, 1 H). EX.72: 13C-NMR: 207.23, 173.42; 171.93; 171.71 ; 171.13; 170.72; 168.59; 168.37 (carbonyls); 75.39; 64.10, 60.64; 57.72; 48.29; 47.43; 47.16 (alpha-C's); 72.06 ((CH3)2CHO-); 73.47 (-CH2O-).
EX.73: 13C-NMR: 07.28, 173.35; 171.95; 171.73; 171.13; 170.69; 168.54; 168.38 (carbonyls); 75.57; 64.11 , 60.68; 57.76; 48.26; 47.43; 47.18 (alpha-C's); 66.21 (CH3CH2O-). EX.75: 13C-NMR: 172.98; 172.05; 171.95; 171.14; 170.50; 168.42; 168.24 (carbonyls); 160.25 / 151.70 / 122.85 (oxazol).
EX.76: 13C-NMR: 172.97; 172.04; 171.98; 171.13; 170.48; 168.42; 168.22 (carbonyls); 164.40 / 151.58 / 122.71 (oxazol).
EX.77: 13C-NMR: 172.96; 172.08; 171.99; 171.11 ; 170.4;168.37; 168.25 (carbonyls); 160.04 / 153.08 / 123.30 (oxazol); 65.94 (oxazolyl-CH2O-); 57.8 (-OCH3). EX.78: 13C-NMR: 172.93; 172.06; 172.01 ; 171.12; 170.48; 168.33; 168.23 (carbonyls); 153.94 / 153.58 / 123.64 (oxazol), 115.80 (-CN).
EX.81: 13C-NMR: 173.27; 171.97; 171.78; 171.05; 170.68; 168.51 ; 168.23 (ring carbonyls); 172.19 (-C(=O)O-); 90.14 (-OCH2O-); 57,47 (-CH2OCH3). EX.82: 13C-NMR: 173.28; 171.97; 171.78; 171.04; 170.67; 168.51; 168.22 (ring carbonyls);
172.20 (-C(=O)O-); 88.91 (-OCH2O-); 65.68 (-OCH2CH3).
EX.83: 13C-NMR: 173.25; 171.98; 171.78; 171.05; 170.68; 168.48; 168.23 (ring carbonyls);
172.16 (-C(=O)O-); 89.19 (-OCH2O-); 71.38/69.35 (-OCH2CH2Oz).
EX.84: 13C-NMR: 173.21 ; 172.03; 171.83; 171.03; 170.66; 168.30; 168.15 (ring carbonyls);
171.46 (-C(=O)O-); 79.85 (-OCH2O-).
Example 85
Production of a compound of formula IAs, wherein R2s is methoxy and R1s is a group of
formula
Figure imgf000059_0001
A) Production of a compound of formula
Figure imgf000059_0002
To a solution of 30 g of a compound of formula lEχs in 300 ml of methanol 6.6 g of NaBH4 are added at 0° and the reaction mixture obtained is warmed up to RT and stirred overnight. To the mixture obtained a mixture of EtAc/c-Hex (1/2) is added and the mixture obtained is stirred with an aqueous NaH2PO4 solution for ca. 20 minutes. The phases obtained are separated and the organic layer obtained is dried, the solvent is evaporated off and the evaporation residue obtained is subjected to chromatography. A compound of formula Ilεxs in the form of a solid is obtained. B) Production of a compound of formula
Figure imgf000060_0001
To a solution of 24 g of a compound of formula llEχs in 150 ml of dry allylic alcohol 8 ml of methanesulfonic acid is added and the mixture obtained is stirred at RT overnight. To the mixture obtained 35 ml of N-methylmorpholine are added, the mixture obtained is stirred for ca. 72 hours at ca. 40°, the solvent is evaporated off and the evaporation residue obtained is subjected to chromatography. A compound of formula lllEXs in the form of a mixture of 3 conformers (0.58 : 0.27 : 0.17) is obtained. C13-NMR(125.8 MHz, CDCI3) - only selected signals: 173.641 , 173.129, 172.710, 172.515, 171.398, 169.182, 132.234, 131.920, 123.421 , 122.885, 122.132, 120.233, 119.308, 118.854, 118.253, 108.608, 106.616, 69.645, 65.602, 61.492, 51.189, 47.184, 40.018, 38.962, 37.233, 36.652, 30.900, 30.512, 29.629, 29.427, 28.939, 28.917, 24.857, 23.695, 22.950, 22.920, 22.827, 22.719, 22.231 , 19.309, 18.830, 18.712, 14.055, 13.992, 13.034. C) Production of a compound of formula
Figure imgf000060_0002
To 14 g of a compound of formula lllεχsin 150 ml of CH2CI2, cooled to 0°, 4.86 ml of N- methylmorpholine and 3.44 ml of methanesulfonic acid chloride are added and the reaction mixture obtained is allowed to warm up to RT within ca. 3 hours. To the mixture obtained 200 ml of a mixture of EtAc/c-Hex (1 :2) are added and the mixture obtained is extracted with 1 M aqueous HCI, saturated aqueous NaHCO3 solution and brine. The solvent of the organic layer obtained is evaporated off and the evaporation residue obtained is heated with 12.5 g of N-ethylthiourea in 45 ml of dry ethanol under argon atmosphere at ca. 80° for ca. 48 hours. From the mixture obtained the solvent is evaporated off. To the evaporation residue obtained 300 ml of toluene are added and the mixture obtained is extracted with 20% aqueous K2HPO4. the organic layer obtained is dried, the solvent is evaporated off and the evaporation residue is subjected to chromatography. A compound of formula IVEXs in the form of an 1 : 2 mixture of 2 conformers is obtained. C13-NMR(125.8 MHz, CDCI3): 172.839, 172.688, 172.611 , 172.073, 171.057, 169.974, 169.746, 169.490, 166.823, 166.761 , 132.252, 131.978, 131.609, 123.408, 122.907, 122.562, 122.103, 121.527, 120.259, 119.793, 118.828, 118.710, 118.602, 118.408, 118.338, 118.160, 108.625, 108.296, 106.778, 106.570, 76.330, 65.877, 65.566, 61.397, 53.839, 51.113, 50.548, 48.156, 48.031 , 47.535, 47.123, 39. 594, 39.364, 39.306, 38.823, 38.668, 37.845, 37.353, 37.307, 36.840, 36.084, 35.404, 28.926, 29.561 , 29.503, 29.383, 29.251 , 29.081 , 29.030, 28.923, 28.272, 28.224, 24.791 , 24.736, 24.445, 23.636, 23.452, 23.222, 23.098, 22.965, 22.928, 22.731 , 22.663, 21.607, 21.419, 19.114, 19.006, 18.890, 18.852, 18.555, 14.067, 13.982, 12.888, 12.847. D) Production of a compound of formula
Figure imgf000061_0001
2.8 g of a compound of formula IVEXs, 1.51 g of N-(9-fluorenyl-methoxycarbonyl)-D- asparaginic acid mono-tert.butylester and 1.89 g of HATU are dissolved in 30 ml of DMF and 1.71 ml of DIEA are slowly added at ca. 0 ° to the mixture obtained. The mixture obtained is left for ca. 1.5 hours and a mixture of EtAc/ c-Hex (1/2) is added, the mixture obtained is extracted with 1 M aqueous HCI, saturated NaHCO3 solution and brine, the solvent is evaported off and the evaporation residue obtained is subjected to chromatography.A compound of formula VEXs is obtained in the form of a solid.
E) Production of a compound of formula IAS, wherein Rg s methoxy and R-^ is a group -CHc.-COOtert.buM A compound of formula VEXs is dissolved in a mixture of 60 ml of THF and 232 μl of pyrrolidine. The mixture obtained is stirred at ca. 0° for ca. 3 hours, 1 ml of pyrrolidine is added and the mixture obtained is allowed to warm up to RT overnight. To the mixture obtained a mixture of EtAc/ c-Hex (1/2) is added, the mixture obtained is extracted with 1 M aqueous HCI and brine and from the organic layer obtained the solvent is evaporated off. The evaporation residue obtained is dissolved in 1.8 I of acetonitrile, the solution obtained is cooled to 0° and 5.3 g of a coupling reagent (BOP, equivalent to HATU) and 2.6 ml of DIEA are added and the mixture obtained is stirred at RT for ca. 24 hours. From the mixture obtained the solvent is evaporated off, the evaporation residue obtained is dissolved in EtAc, the mixture obtained is extracted with 1 M aqueous HCI, saturated NaHCO3 solution and brine, the solvent of the organic layer obtained is evaporated off and the evaporation residue obtained is subjected to chromatography. A compound of formula IAS wherein R2s is methoxy and R1s is a group -CH2-COOtert.butyl in the form of a 4:1 mixture of 2 conformers is obtained. C13-NMR(125.8 MHz, d6-DMSO): 173.077, 172.815, 172.324, 171.752, 169.695, 169.198, 169.151 , 132.033, 123.597, 123.302, 122.885, 120.178, 119.170, 108.784, 107.092, 80.286, 66.234, 62.111 , 58.539, 52.056, 49.590, 45.544, 27.264, 37.157, 36.883, 36.771 , 29.898, 29.230, 29.110, 28.762, 28.024, 25.007, 23.649, 23.369, 22.919, 22.809, 22.742, 21.586, 19.750, 19.400, 19.311 , 14.434, 14.305.
F) Production of a compound of formula IAS, wherein R? s methoxy and Rιg is a group -CHrCOOH A compound of formula IAS, wherein R2s is methoxy and R1s is a group -CH2-COOH is obtained from a compound obtained according to example 85, step E) by treatment with TFA in toluene. H1-NMR(500 MHz, d6-DMSO) - selected signals of the major conformation: 8.31 (bs, 1 H), 7.92 (bs, 1 H), 7.62 (d, J=7.7 Hz, 1 H), 7.41 (s, 1H), 7.40 (d, J=7.5 Hz, 1 H), 7.19 (t, J=7.5 Hz, 1 H), 7.07 (d, J=7.5 Hz, 1H), 4.65 (m, 3H), 4.40 (m, 2H), 4.23 (m, 1H), 3.97 (s, 3H),
2.78 (s, 3H), 0.23 (t, 6H).
G) Production of a compound of formula IAS, wherein R? s methoxy and R _ is a group of
formula
Figure imgf000063_0001
50 mg of compound obtained in example 85, step F) is treated with piperidine and HATU in DMF and to the mixture obtained DIEA is slowly added at ca. 0°. The mixture obtained is left for ca. 1.5 hours and a mixture of EtAc/c-Hex (1/2) is added. The mixture obtained is extracted with 1 M aqueous HCI, saturated NaHCO3 solution and brine, the solvent is evaported off and the evaporation residue obtained is subjected to chromatography. A compound of formula IAS, wherein R2s is methoxy and Rιs is a group of
formula
Figure imgf000063_0002
is obtained in the form of a mixture of 2 conformers. C .13 -NMR(125.8
MHz, CDCI3): 172.887, 172.585, 172.099, 171.978, 171.819, 171.610, 170.790, 169.982, 169.381 , 169.244, 168.854, 132.323, 123.396, 122.938, 122.023, 120.189, 120.077, 118.859, 118.662, 108.695, 118.616, 71.615, 65.843, 65.677, 62.517, 59.021 , 57.996, 52.115, 49.788, 48.984, 48.744, 48.343, 42.947, 40.798, 40.559, 39.769, 38.071 , 37.426, 37.368, 37.197, 36.521 , 32.499, 30.012, 29.939, 29.909, 29.769, 29.337, 29.270, 29.073, 24.963, 24.456, 24.393, 23.467, 23.022, 22.883, 22.845, 22.784, 22.037, 20.185, 19.970, 18.788, 14.020.
Analogously as described in example 85 but using appropriate starting materials, compounds of formula IAEXAs wherein REXAS ΪS as defined in TABLE 11 below, are obtained having the 1H-NMR data (500MHz; CDCI3) as shown in TABLE 11:
TABLE 11
Figure imgf000063_0003
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001

Claims

Patent Claims
1. The use of inhibitors of adhesion molecule expression in the preparation of a medicament for the treatment of vascular endothelial cell growth factor-mediated diseases.
2. The use according to claim 1 , wherein an inhibitor of adhesion molecule expression is a cyclopeptolide or a cyclopeptide.
3. The use according to claim 2, wherein a cyclopeptolide is a compound of formula i— A - B - R.Leu - Leu - Z - X - Y— ,
wherein: A is
- a glycolic acid residue optionally α-substituted by methyl or vinyl, optionally substituted by
- halogen, alkoxy, optionally protected hydroxy or amino, CSNH2, vinyl, -C≡CH, thiazolyl or COOR2, wherein R2 is H or lower alkyl, optionally substituted by
- alkyl, halogen, cycloalkyl, optionally substituted thiazolyl, -C≡CH or COOR2 wherein R2 is as defined above;
- an α-hydroxy-substituted butyric or valeric acid residue β-substituted by
- halogen, alkoxy, optionally protected hydroxy or amino, CSNH2, vinyl, -C≡CH, thiazolyl or COOR2, wherein R2 is H or lower alkyl, optionally substituted by
- alkyl, halogen, cycloalkyl, optionally substituted thiazolyl, -C≡CH or COOR2, wherein R2 is as defined above; or
- an α-hydroxy-substituted butyric acid residue optionally γ-substituted by R6, wherein R6 is - CN, COOR3, wherein R3 is hydrogen or optionally arylsubstituted alkyl, CONR4R5, wherein R and R5are the same or different and represent hydrogen or alkyl or form together with the nitrogen to which they are attached a 3- to 6-membered ring, optionally containing a second heteroatom, COR7, wherein R7 is hydrogen or lower alkyl, CSNH2, or alkyl, optionally substituted by - azido, halogen, alkoxy, optionally protected hydroxy or amino, CSNH2, thiazolyl, vinyl, which may be substituted by alkyl, halogen or CN, cycloalkyl, tetrazolyl, -C≡CH, or COOR'2, wherein R'2 is hydrogen or lower alkyl, optionally substituted by alkyl, halogen, cycloalkyl, optionally substituted thiazolyl, -C≡CH or COOR"2, wherein R"2 is hydrogen or lower alkyl, B is an α-amino-γ-methyl-substituted octanoic acid residue; RT is hydrogen or methyl; Z is a tryptophan residue,
X is an α-amino-substituted (C2.ι )carboxylic acid residue, and
Y is an α-amino- or N-methyl-α-amino substituted (C2.ι0)carboxylic acid residue.
4. The use according to any one of claims 2 to 3, wherein a cyclopeptolide or cyclopeptide is of formula lp or lr or ls as defined in claims 8 to 10.
5. The use according to any preceding claim, wherein the vascular endothelial cell growth factor-mediated disease is selected from
- eye diseases involving vision impairment or loss, - arteriosclerosis associated with chronic transplant rejection and coronary heart disease,
- solid tumor malignancies and other cancers, or
- psoriasis, rheumatoid arthritis.
6. The use according to any preceding claim, wherein the vascular endothelial cell growth factor-mediated diseases are selected from eye diseases leading to vision impairment or loss.
7. The use according to claim 6, wherein eye diseases leading to vision impairment or loss are selected from ischemic retinopathies, uveoretinitis and degenerative eye diseases.
8. A compound of formula
Figure imgf000070_0001
wherein
Rιp is selected from the group
- -CH2-CH2-COO-R2p, wherein R2p is alkyl,
- -CH2-CH2-CO-CH2-O-R3p, wherein R3p is alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl or acyloxyalkyl,
- -CH2-CH2-COO-CH2-O-CO-R4p, wherein R p is alkyl,
- of formula
Figure imgf000070_0002
wherein R5p is hydrogen or a substitutent,
- -CH2-CH2-C(=N-R6p)NH2, wherein R6p is hydrogen or a substituent,
- a group of formula
Figure imgf000070_0003
wherein R7p is hydrogen or a substitutent, and R'2p is hydrogen, alkyl, alkoxy or aralkyl.
9. A compund of formula Ar-Br-Leu*-Leu-Dr-Xr-Yr
I
wherein
Aris a glycolic acid residue,
Bris an α-amino-γ -methyl-substituted octanoic acid residue;
Leu* is leucin or N-methyl leucin, preferably N-methyl leucin,
Leu is leucin;
Dris a tryptophan residue,
Xr is an α-amino-substituted (C2-ι4)carboxylic acid residue, and
Yr is an α-amino- or N-methyl-α-amino substituted (C2.ιo)-carboxylic acid residue wherein position α is trisubstituted.
10. A compound of formula
-As-Bs-Leu*-Leu-Ds-Xs-
wherein As is an α-amino carboxylic acid residue;
Bs is an α-amino-γ -methyl-substituted octanoic acid residue;
Leu* is leucin or N-methyl leucin, preferably N-methyl leucin,
Leu is leucin;
Ds is a tryptophan residue, and Xs is an α-amino-carboxylic acid residue.
11. A compound of formula lp, lr, or ls as defined in claims 8 to 10, in the form of a salt, or in the form of a salt and in the form of a solvate, or in the form of a solvate.
12. Use of a compound of formula lp, lr or ls defined in claims 8 to 11 , as a pharmaceutical.
13. Pharmaceutical composition comprising a compound of formula lp, lr or ls, as defined in claims 8 to 11 , beside one or more pharmaceutically acceptable carriers, diluents and/or excipients.
4. A method for the treatment of diseases which are mediated by expression of adhesion molecules and/or by expression of the growth factor VEGF, which comprises administering a pharmaceutically effective amount of a compound of formula lp, lr or ls, as defined in claims 8 to 11 , to a subject in need of such treatment.
PCT/EP2001/012369 2000-10-27 2001-10-25 Vegh inhibitors and their use WO2002034283A2 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996003430A1 (en) * 1994-07-27 1996-02-08 Sandoz Ltd. Organic compounds
WO1997019104A1 (en) * 1995-11-21 1997-05-29 Novartis Ag Cyclopeptolides
WO2000038714A1 (en) * 1998-12-30 2000-07-06 Children's Medical Center Corporation The prevention and treatment of retinal ischemia and edema

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996003430A1 (en) * 1994-07-27 1996-02-08 Sandoz Ltd. Organic compounds
WO1997019104A1 (en) * 1995-11-21 1997-05-29 Novartis Ag Cyclopeptolides
WO2000038714A1 (en) * 1998-12-30 2000-07-06 Children's Medical Center Corporation The prevention and treatment of retinal ischemia and edema

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOGER D L ET AL: "Synthesis and evaluation of Aza HUN-7293" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 10, no. 15, 7 August 2000 (2000-08-07), pages 1741-1744, XP004213236 ISSN: 0960-894X *

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