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WO2001010845A1 - Nouvelles diketo-piperazines - Google Patents

Nouvelles diketo-piperazines Download PDF

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Publication number
WO2001010845A1
WO2001010845A1 PCT/EP2000/007707 EP0007707W WO0110845A1 WO 2001010845 A1 WO2001010845 A1 WO 2001010845A1 EP 0007707 W EP0007707 W EP 0007707W WO 0110845 A1 WO0110845 A1 WO 0110845A1
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WO
WIPO (PCT)
Prior art keywords
compounds
bond
alkyl
mmol
aminomethylphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2000/007707
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German (de)
English (en)
Inventor
Norbert Schaschke
Luis Moroder
Robert Huber
Wolfram Bode
Christian Sommerhoff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Max Planck Gesellschaft zur Foerderung der Wissenschaften
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
Max Planck Gesellschaft zur Foerderung der Wissenschaften
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Priority to AU62811/00A priority Critical patent/AU6281100A/en
Publication of WO2001010845A1 publication Critical patent/WO2001010845A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to new diketopiperazines which are used in the pharmaceutical industry for the manufacture of medicaments.
  • the invention relates to compounds of the formula I.
  • A1 and A2 are the same or different and -C (O) -, -NH-, -O- (oxygen), -S- (sulfur),
  • A3 and A4 are the same or different and -NH-, -OC (O) -, -C (0) -0 -, -C (0) -NH-, -NH-C (O) -,
  • M represents a diketopiperazine component selected from the following overview
  • B1 denotes a bond or 1-4C-alkylene
  • B2 represents a bond or 1-4C-alkylene
  • B3 and B4 are identical or different and are a bond, 1-4C-alkylene or -C (R11) R12, wherein R1 1 and R12 are connected together and with inclusion of the carbon atom to which both ge ⁇ , are a spiro-linked 3 -, 4-, 5- or 6-membered saturated hydrocarbon ring material ⁇ represent
  • Y1 and Y2 are the same or different and represent a group from the following overview
  • X is selected from one of the following groups
  • R2 is hydrogen or 1-4C-alkyl
  • R3 represents hydrogen, 1-4C-alkyl or a group from the overview below
  • R31 denotes hydrogen, 1-4C-alkyl or 1-4C-aikoxy
  • R32 is hydrogen, 1-4C-alkyl, 1-4C-alkoxycarbonyl, phenyl-1-4C-alkoxycarbonyl,
  • Carboxyl, mono- or di-1-4C-alkylamino-carbonyl and R33 are hydrogen, 1-4C-alkyl, 1-4C-alkylsulfonyl or hydroxymethylcarbonyl,
  • R4 represents 1-4C-alkylcarbonyl, phenyl-1-4C-alkylcarbonyl or a group from the overview below
  • R41 is hydrogen or 1 -4C-alkyl
  • R42 denotes 1-4C-alkyl, adamantyl, phenyl or phenyl-1-4C-alkyl,
  • R5 represents hydrogen, 1-4C-alkyl or a group from the overview below
  • R6 denotes hydrogen, -C (0) -OR61 or -C (0) -NHR61, where R61 denotes 1 -4C-alkyl or phenyl-1 -4C-alkyl, and wherein in a direct way between the terminal nitrogen atoms 20 to 40, preferably 25 to 40 bonds must be present, as well as the salts of these compounds, all those compounds are excluded, in which one or more of the variables B1, B2, B3 or B4 assume the meaning of a bond and are therefore used for the direct linkage of two heteroatoms, two carbonyl groups or two sulfonyl groups would come.
  • 1 -4C-alkylene stands for straight-chain or branched 1-4C-alkylene radicals, for example the methylene- (-CH 2 -), ethylene- (-CH 2 -CH 2 -), trimethylene- (-CH 2 -CH 2 -CH 2 -), tetramethylene- (-CH 2 -CH 2 -CH 2 -CH 2 -), 1, 2-dimethyethylene- [-CH (CH 3 ) -CH (CH 3 ) -], 1, 1-dimethylethylene- [-C (CH 3 ) 2 -CH 2 -], 2,2-dimethylethylene- [-CH 2 -C (CH 3 ) 2 -], isopropylidene [-C (CH 3 ) 2 -] or the 1- Methylethylene residue [-CH (CH 3 ) -CH 2 -].
  • 1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms.
  • Example ⁇ are wise mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • 1-4C-alkoxy stands for radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical with 1 to 4 carbon atoms. Examples include the butoxy, iso-butoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
  • 1 -4C-alkoxycarbonyl represents a carbonyl group to which one of the 1-4C-alkoxy radicals mentioned above is attached.
  • the methoxycarbonyl [CH 3 0-C (0) -] and the ethoxycarbonyl group [CH 3 CH 2 0-C (0) -] may be mentioned.
  • Phenyl-1-4C-alkoxycarbonyl stands for one of the aforementioned 1-4C-alkoxy radicals to which a phenyl ring is attached.
  • the benzyioxycarbonyl radical may be mentioned, for example.
  • mono- or di-1-4C-alkylaminocarbonyl radicals contain a mono- or di-1-4C-alkylamino radical.
  • examples include the N-methyl, the N, N-dimethyl, the N-ethyl, the N-propyl, the N, N-diethyl and the N-isopropylaminocarbonyl radical.
  • 1-4C-Alkylsulfonyl stands for a sulfonyl group to which one of the 1-4C-alkyl radicals mentioned above is bonded.
  • the methylsulfonyl radical (CH 3 S0 2 -) may be mentioned.
  • 1-4C-Alkylcarbonyl represents a radical which is called one of the above ge ⁇ addition to the carbonyl 1-4C-alkyl radicals contains.
  • the acetyl radical may be mentioned.
  • Phenyl-1-4C-alkyl represents one of the abovementioned phenyl-substituted 1-4C-alkyl radicals. Examples include the phenethyl and benzyl radicals.
  • Phenyl-1-4C-alkylcarbonyl stands for a radical which, in addition to the carbonyl group, contains one of the phenyl-1-4C-alkyl radicals mentioned above.
  • the phenylacetyl radical may be mentioned, for example.
  • M, Y1, Y2, X, R3, R4 and R5 contain chemical formulas such as
  • Bonds that are not linked on one side mean that the building block is connected to the rest of the molecule at this point. Binding that is not linked on both sides means that there are several positions on this building block via which the connection to the rest of the molecule can take place.
  • terminal nitrogen atom means in each case one nitrogen atom in the groups designated Y1 and Y2.
  • the terminal nitrogen atom is either a terminal amino group of the substituent X or the amino group of the 2-amino-pyrid-5-yl group.
  • That number of bonds at ⁇ According to the invention under the direct route between the nitrogen atoms which act in the as Y1 or Y2 groups defined as terminal nitrogen atoms, seen that obtained by counting the bonds which represent the shortest possible connection line between the terminal nitrogen atoms, becomes.
  • the direct path here includes 30 ties.
  • Suitable salts for compounds of the formula I - depending on the substitution - are all acid addition salts or all salts with bases. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics.
  • water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, it sigklare ⁇ , trifluoroacetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) - benzoic acid, butyric acid , Sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid
  • salts with bases can also be used.
  • examples of salts with bases which may be mentioned are alkali (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, with the salt production also being used here Bases are used in an equimolar or a different ratio.
  • Pharmacologically incompatible salts which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
  • the compounds according to the invention and also their salts if they are isolated, for example, in crystalline form, can contain different amounts of solvents.
  • the invention therefore also includes all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
  • A1 and A2 are identical or different and -C (O) -, -NH-, -O- (oxygen), -C (0) -NH-, -NH-C (O) -,
  • A3 and A4 are the same or different and -NH-, -OC (O) -, -C (0) -0-, -C (0) -NH-, -NH-C (O) - or a bond
  • M represents a diketopiperazine component selected from the following overview
  • B1 denotes a bond or 1-4C-alkylene
  • B2 represents a bond or 1-4C-alkylene
  • B3 and B4 are the same or different and represent a bond or 1-4C-alkylene
  • Y1 and Y2 are the same or different and represent a group from the following overview
  • X is selected from one of the following groups
  • R2 is hydrogen or 1-4C-alkyl
  • R3 is hydrogen, 1-4C-alkyl or benzyl, or wherein R2 and R3 together and including the nitrogen atom to which both are attached represent a group from the following overview
  • R33 is hydrogen or 1-4C-alkyl
  • R4 is 1-4C-alkylcarbonyl
  • R5 is hydrogen or 1-4C-alkyl
  • 20 to 40, preferably 25 to 40, bonds must be present directly between the terminal nitrogen atoms, and the salts of these compounds, excluding all those compounds in which one or more of the variables B1, B2, B3 or B4 assume the meaning of a bond and this would result in the direct linking of two heteroatoms or two carbonyl groups.
  • A1 and A2 are identical or different and are -C (0) -NH- or -NH-C (O) -,
  • A3 and A4 are the same or different and are -C (0) -NH- or a bond
  • B1 1-4C-alkyls means
  • B2 means 1-4C-alkylene
  • B3 and B4 are the same or different and represent a bond or 1-3C-alkylene
  • Y1 and Y2 are the same and represent a group selected from the following overview
  • A1 and A2 are identical or different and are -C (0) -NH- or -NH-C (O) -,
  • A3 and A4 are the same or different and are -C (0) -NH- or a bond
  • B1 means 1-4C-alkylene
  • B2 means 1-4C-alkylene
  • B3 and B4 are the same or different and represent a bond or 1-2C-alkylene
  • Y1 and Y2 are the same and represent a group selected from the following overview
  • Preferred compounds of the formula I are (3S, 6S) -3,6-di- (4- ⁇ 3- [1- (4-carbamimidoylbenzyl) -2-oxo-2-piperidinethylcarbamoyl] propanoylamino ⁇ - butyl) -1, 4H-2,5-dioxopiperazin; (3S, 6S) -3,6-di- ⁇ 4- [2-acetylamino-3- (4-aminomethylphenyl) propanoyiamino] butyl ⁇ -1, 4H-2,5-dioxopiperazine; (3S, 6R) -3,6-di - ( ⁇ [2- (4-aminomethylphenyl) -1-methoxycarbonylethylcarbamoyl] methylcarbamoyl ⁇ methyl) -1, 4H-2,5-dioxopiperazine; (3S, 6S) -3,6
  • An embodiment of the preferred compounds of the formula I are (3S, 6S) -3,6-di- (4- ⁇ 3- [1- (4-carbamimidoylbenzyl) -2-oxo-2-piperidinethylcarbamoyl] propanoylamino ⁇ - butyl) -1, 4H-2,5-dioxopiperazine;
  • the compounds of the formula I are chiral compounds with several centers of chirality.
  • the invention therefore includes all conceivable pure diastereomers and enantiomers as well as their mixtures in any mixing ratio, including the racemates.
  • the compounds of the formula I are composed of a large number of divalent (M, A1, A2, A3, A4, B1, B2, B3, B4) and two mono-oriented building blocks (Y1 and Y2). In principle, their synthesis can proceed from any of these building blocks. In the case of largely symmetrical compounds of the formula I, the structure starting from the central building block M is appropriate, while in the case of predominantly unsymmetrical compounds of the formula I the synthesis starting from one of the end groups Y1 or Y2 can be advantageous.
  • the building blocks are always linked according to the same pattern known to the person skilled in the art.
  • ether and thioether bridges can be made by the Williamson method.
  • Keto bridges can, for example, be part of larger building blocks, such as. B. the 1, 3-dichloroacetone are introduced.
  • Sulfonyl bridges can be obtained, for example, by oxidation of thioether bridges.
  • ester bridges A large number of methods are known for the construction of ester bridges.
  • An example is the reaction of acids with alcohols, preferably using H 2 S0 4 or p-toluenesulfonic acid as a catalyst; or with the addition of a dehydrating agent, such as molecular sieve or a carbodiimide.
  • a dehydrating agent such as molecular sieve or a carbodiimide.
  • the reaction of acid chloride with alcohols can also be mentioned here.
  • amide bridges There are also a number of known methods for the preparation of amide bridges.
  • the reaction of acid chlorides with primary or secondary amines may be mentioned here as an example.
  • sulfonamide bridges can be built up from sulfonic acid chlorides and primary or secondary amines.
  • Carbamate bridges can e.g. B. by reaction of chiocarbonic acid esters with amines.
  • the chlorocarbonic acid esters in turn can be built up from alcohols and phosgene.
  • Another variant for building carbamate bridges is the addition of alcohols to isocyanates.
  • carbonate bridges can be produced from chlorocarbonic acid esters by reaction with alcohols (instead of amines).
  • Carbamide bridges can e.g. B. by the reaction of isocyanates with amines.
  • indandemates such as, for example, 2,5-diminoxane-2-carboxylic acid, tetrahydro-2,4a, 6,8a-tetraaza-anthracene-3,7,9, 10-tetraone building block can, for example, starting from 3,5-B ⁇ smethylam ⁇ nop ⁇ peraz ⁇ n-2,5-d ⁇ on by introducing a protective group on the amino groups (eg with tert-butyloxycarbonyl), activation of the piperazine nitrogen (eg with (i) iodoacetic acid , (n) Hydroxysuccinimide / Dicyclohexylcarbodnmid) and subsequent ring closure reaction
  • a protective group on the amino groups eg with tert-butyloxycarbonyl
  • piperazine nitrogen eg with (i) iodoacetic acid , (n) Hydroxysuccinimide / Dicyclohexylcarbodnmid
  • the desired chirality of the diketopiperazine building block can be set via the choice of amino acid chirahacy; in addition, access to asymmetrical diketopiperazine building blocks is also possible when using two different amino acids
  • Reaction Schemes 2, 3 and 4 show examples of the preparation of compounds of the formula I. Any suitable stereochemistry of the compounds of the formula I can be prepared by a suitable choice of the chirality of the starting compounds.
  • Reaction Scheme 5 shows the preparation of compounds of the formula I having an asymmetrical structure
  • the substances according to the invention are isolated and purified in a manner known per se, for example in such a way that the solvent is distilled off in vacuo and the residue obtained is re-installed in a suitable solvent or subjected to one of the customary cleaning methods, such as, for example, column chromatography on a suitable carrier material
  • Salts are obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as Ethanol or isopropanol), which contains the desired acid or base, or to which the desired acid or base is subsequently added.
  • a suitable solvent for example a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as Ethanol or is
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporation of the solvent by acidification into the free compounds which can in turn be converted into salts.
  • pharmacologically non-contractual salts can be converted into pharmacologically contractual salts
  • RT stands for room temperature, min for minutes, h for hours, over for calculated, HOBt for 1-hydroxy-1 H-benzot ⁇ azole, DCC for N, N'-dicyclohexylcarbodnmid, EDC for N ' - (3rd -D ⁇ methylam ⁇ nopropyl) -N-ethylcarbod ⁇ m ⁇ d, DIEA for dnsopropylethylamine, TFA for T ⁇ f- luoracetic acid, HOSu for N-hydroxysuccinimide, Z-OSu for N- (benzyloxycarbonyloxy) -succ ⁇ n ⁇ m ⁇ d, RP- HPLC for reverse phase high pressure liquid chromatography Chromatography, high pressure liquid chromatography and ESI-MS for electrospray mass spectrometry.
  • the compounds mentioned by way of example and their salts are a preferred subject of the invention
  • the crude product is isolated by precipitation from MeOH / ethyl acetate and purified by preparative RP-HPLC (Nucleosil 5 C-18 (Macherey-Nagel); eluents: (A) 0.1% aqueous TFA, (B) 0.08% TFA in acetonitrile ; Elution profile: 0-5 min isocratic 5% B, 5-10 min linear gradient from 5% B to 18% B, 10-90 min linear gradient from 18% B to 60% B) and lyophilized.
  • the crude product obtained is purified by preparative RP-HPLC (Nucleosil 5 C-18 (Macherey-Nagel), eluents: (A) 0.1% aqueous TFA, (B) 0.08% TFA in acetonitrile; elution profile 0-5 min isocratic 3% B, 5-90 min linear gradient from 3% B to 60% B) and lyophilized.
  • the crude product obtained is purified by preparative RP-HPLC (Nucleosil 5 C-18 (Macherey-Nagel), eluent (A) 0.1% water) TFA, (B) 0.08% TFA in acetonitrile; Elution profile: 0-5 min isocratic 5% B, 5-10 min linear gradient from 5% B to 18% B, 10-90 min linear gradient from 18% B to 60% B) and lyophilized.
  • MeO-DLPhe (3-H, N-CH z ) -Glv-crDAsp-Aspl-Glv-DLPhe (3-H z N-CH z ) -OMe ⁇ 2TFA or r (3S, 6R) -3,6-Di - ((r2- (3-aminomethylphenyl) -1-methoxycarbonylethylcarbamovn-methylcarbamoyl> -methyl) -1.4H-2,5-dioxopiperazinx2TFAl
  • MeO-DLPhe (3-BOC-HN-CH 2 ) -Gly-c [DAsp-Asp] -Gly-DLPhe (3-BOC-HN-CH 2 ) -OMe (75.0 mg, 0.08 mmol, A28 ) are dissolved in 10 ml of 95% trifluoroacetic acid and the cleavage cooled with an ice bath subjected. After 4 h the acid is removed in vacuo, the residue is treated with toluene (3 times) and the title compound is isolated as a colorless powder by precipitation from isopropanol / tert-butyl methyl ether.
  • MeO-DLPhe (3-H, N-CH ? ) -Glv-crAsp-Asp1-Glv-DLPhe (3-H z N-CH z ) -OMe ⁇ 2TFA or r (3S, 6S) -3,6-Di - ( ⁇ f2- (3-aminomethylphenyl) -1-methoxycarbonylethylcarbamovn-methylcarbamoyl ⁇ -methyl) -1, 4H-2,5-dioxopiperazinx2TFAl
  • MeO-DLPhe (3-H z N-CH ? ) -Ss-Ala-crDAsp-Aspl-ß-Ala-DLPhe (3-H z N-CH z ) -OMe ⁇ 2TFA or
  • H-Lys (BOC) -OMe ⁇ HCI (9.84 g, 31, 9 mmol) are dissolved in 130 ml DMF, neutralized with NMM (3 51 ml, 31 9 mmol) and with stirring with Z-Lys (BOC) -OSu (15.25 g, 31, 9 mmol) added After 16 h, the solvent is removed in a high vacuum, the oil obtained is taken up in ethyl acetate, the ethyl acetate phase in succession with 5% strength KHS0 4 solution, 5% strength NaHC0 3 solution , Water and saturated sodium chloride solution, dried over Na 2 S0 4 and concentrated.
  • H-DLPhe (3-CN) -OMe ⁇ HCI (15.0 g, 62.3 mmol, A11) and 6.6 g (62.3 mmol) Na 2 CO 3 are placed in 300 ml dioxane / water 1: 1 and 15.7 g (71.6 mmol) of N-ethoxycarbonyl phthalimide were added to the solution with stirring. After 1 h, another 6.8 g (31.1 mmol) of N-ethoxycarbonylphthalimide are added.
  • the reaction mixture was concentrated in vacuo to a small volume, the precipitated phthalhydrazide was centrifuged off, the methanol phase was concentrated, the oil obtained was dissolved in water and the precipitate which had formed was removed by centrifugation.
  • the pH of the water phase was adjusted to about 10
  • chloroform 5 times 100 ml
  • the combined chloroform phases dried over Na 2 S0 4 and concentrated.
  • the oil obtained is dissolved in methanol, the pH is adjusted to about 3 with 6N HCl in dioxane and concentrated.
  • the title compound is then precipitated from Iso - propanol / ferf-butylmethyl ether obtained as a colorless powder.
  • Z-DLPhe (4-CN) pip (1.00 g, 2.55 mmol, A16), hydroxylamine hydrochloride (0.27 g, 3.82 mmol) and DIEA (0.66 ml, 3.82 mmol ) are suspended in 20 ml of ethanol and heated under reflux in an oil bath, a colorless precipitate forming after a short time. After 2 h the reaction mixture in Cooled ice bath, the precipitate was filtered off, washed a little with cold ethanol and finally with dnsopropyl ether and petroleum ether, the hydroxyamidine being obtained as a colorless powder.
  • H-DLPhe (4-CN) -OH ⁇ HCI (1.50 g, 6.23 mmol) and BOC-Gly-OH (1.31 g, 7.47 mmol) and DIEA (1.07 ml, 6.23 mmol) ) are placed in 50 ml of chloroform and coupled using EDC (1.43 g, 7.47 mmol) / HOBt (1.01 g, 7.47 mmol) while cooling in an ice bath.
  • BOC-Gly-DLPhe (4-CN) -OMe (2.02 g, 5.57 mmol) are dissolved in 50 ml of 95% trifluoroacetic acid and subjected to the cleavage with ice-bath cooling. After 3 h the acid is removed in vacuo, the residue dissolved in methanol with 6N HCl in dioxane, concentrated and treated several times with toluene.
  • H-DLPhe (3-BOC-HN-CH 2 ) -OMe ⁇ HCI (0.70 g, 2.03 mmol, A14) are dissolved in 30 ml of chloroform, neutralized with DIEA (0.35 ml, 2.03 mmol) and with 0.80 g (2.63 mmol) Z-Gly-OSu added. After 16 h the solvent is removed in vacuo, the residue is taken up in ethyl acetate, the ethyl acetate phase is washed in succession with 5% KHS0 4 solution, 5% NaHC0 3 solution, water and saturated saline solution, dried over Na 2 S0 4 and constricted.
  • H-Gly-DLPhe (4-CN) -MeO ⁇ HCI (0.62 g, 2.09 mmol, A22) dissolved in 20 ml DMF were neutralized with DIEA (0.36 ml, 2.09 mmol), c [Asp ( OH) -Asp (OH)] (0.20 g, 0.87 mmol, A4) and coupled in the presence of PyBOP (1.08 g, 2.09 mmol).
  • H-Gly-DLPhe (4-CN) -MeO ⁇ HCI (0.62 g, 2.09 mmol, A22) dissolved in 20 ml DMF are neutralized with DIEA (0.36 ml, 2.09 mmol), c [DAsp ( OH) -Asp (OH)] (0.20 g, 0.87 mmol, A7) and in the presence of EDC (0.40 g, 2.09 mmol) / HOBt (0.23 g, 1.74 mmol ) coupled.
  • the solvent mixture is drawn off in a high vacuum, methanol is added, briefly sonicated, the colorless precipitate is centrifuged off, washed in succession with methanol, ferf-butyl methyl ether and petroleum ether and dried in vacuo.
  • the title compound is obtained as a colorless powder.
  • H-Gly-DLPhe (3-BOC-HN-CH 2 ) -OMe ⁇ HCI (0.125 g, 0.312 mmol, A14) dissolved in 10 ml DMF are neutralized with DIEA (0.054 ml, 0.312 mmol), c [Asp (OH) - Asp (OH)] (0.030 g, 0.130 mmol, A4) added and coupled in the presence of EDC (0.059 g, 0.312 mmol) / HOBt (0.042 g, 0.312 mmol).
  • the sodium salt is dissolved in 150 ml THF / Waser (1 2) and treated with Amberlyst 15 until the pH is approx. 3.
  • the ion exchanger is filtered off, the solvent was removed in vacuo and the residue was treated with toluene (3 times).
  • the title compound is isolated from ethyl acetate / petroleum ether as a colorless, finely crystalline material.
  • H-DLPhe (3-BOC-HN-CH 2 ) -OMe ⁇ HCI (0.50 g, 1, 45 mmol, A14) dissolved in 30 ml chloroform are neutralized with DIEA (0.19 ml, 1, 45 mmol), Z -ß-Ala-OH (0.40 g, 1.74 mmol) was added and coupled in the presence of EDC (0.33 g, 1.74 mmol) / HOBt (0.24 g, 1.74 mmol).
  • EDC 0.33 g, 1.74 mmol
  • HOBt 0.24 g, 1.74 mmol
  • H-DLPhe (3-BOC-NH-CH 2 ) -OMe ⁇ HCI (1.00 g, 2.89 mmol, A14) are suspended in 25 ml of chloroform and dissolved by adding DIEA (0.50 ml, 2 89 mmol) Ac 2 0 (0.36 ml, 3.76 mmol) and DIEA (0.65 ml, 3.76 mmol) are then added with stirring. After 3 h, the solvent is removed in vacuo, and the oil obtained is dissolved in ethyl acetate Ethyl acetate phase with 5% KHS0 4 solution, 5% NaHC0 3 solution and saturated sodium chloride solution, dried over Na 2 S0 4 and evaporated in a rotary evaporator.
  • H-DLPhe (3-BOC-HN-CH 2 ) -OMe ⁇ HCI 48 mg, 0.139 mmol, A14
  • DIEA 24 ⁇ L, 0.139 mmol
  • MeO-DLPhe 3-BOC-NH -CH 2 ) -Gly-c [DAsp-Glu] (75 mg, 0.126 mmol, A45) added and coupled in the presence of EDC (27 mg, 0.139 mmol) / HOBt (17 mg, 0.126 mmol).
  • Human tryptase is a protein protease which is the predominant protein in human mast cells. Tryptase comprises eight closely related enzymes ( ⁇ 1, ⁇ 2, ⁇ 1 a, ⁇ 1 b , ß2, ß3, mMCP-7-l ⁇ ke-1, mMCP-7-l ⁇ ke-2, 85 to 99% sequence identity) (see Miller et al, J Clin Invest 84 (1989) 1 188-1195, Miller et al , J Clm Invest 86 (1990) 864-870, Vanders ce et al, Proc Natl Acad Sei, USA 87 (1990) 381 1 -3815, Pallaoro et al, J Biol Chem 274 (1999) 3355-3362) Only the ß -Tryptases (Schwartz et al, J Clin Invest 96 (1995) 270
  • Tryptase is released together with other inflammation mediators, such as histamine and proteoglycans, when human mast cells are activated. It is therefore suspected that tryptase is present in a number diseases, especially allergic and inflammatory diseases, on the one hand due to the importance of mast cells in such diseases and on the other hand, since an increased tryptase content was found in a number of such diseases. Tryptase is associated with the following diseases, among others Acute and chronic (especially inflammatory and allergen-induced) respiratory diseases various Genesis (e.g.
  • bronchitis bronchitis, allergic bronchitis, bronchial asthma, COPD
  • interstitial lung diseases diseases that are based on allergic reactions of the upper respiratory tract (throat, nose) and the adjacent regions (e.g. sinuses, conjunctiva), such as allergic conjunctivitis and allergic diseases, diseases from the arthritis (e.g.
  • autoimmune diseases such as multiple sclerosis, furthermore pentiodontitis, anaphylaxis, interstitial cystitis, dermatitis, pso ⁇ asis, scleroderma / systemic sclerosis, inflammatory bowel diseases (Crohn's disease, inflammatory bowel disease ) and other tryptase appears to be directly related in particular to the pathogenesis of asthma (Caughey, Am J Respir Cell Mol Biol 16 (1997), 621-628, R Tanaka, "The role of tryptase in allergic infection” in Protease Inhibitors, IBC Library Senes, 1979, chapters 3 3 1-3 3 23)
  • the invention further relates to the compounds according to the invention for use in the treatment and / or prophylaxis of diseases, in particular the diseases mentioned
  • the invention also relates to the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the diseases mentioned
  • the invention furthermore relates to medicaments for the treatment and / or prophylaxis of the diseases mentioned, which contain one or more of the compounds according to the invention
  • the pharmaceuticals are prepared by methods known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.
  • the compounds according to the invention are preferably also administered by inhalation.To this end, they are administered either directly as powder (preferably in micronized form) or by atomizing solutions or suspensions which contain them.
  • powder preferably in micronized form
  • atomizing solutions or suspensions which contain them.
  • the compounds according to the invention are used in particular in the form of those medicaments which are suitable for topical application.
  • suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions
  • the pharmaceuticals according to the invention are produced by methods known per se.
  • the dosage of the active ingredients in systemic therapy is between 0.1 and 10 mg per kilogram and day
  • the documented pathophysiological effects of mast cell tryptase are caused directly by the enzymatic activity of the protease. Accordingly, they are reduced or blocked by inhibitors which inhibit the enzymatic activity of tryptase.
  • a suitable measure for the affinity of a reversible inhibitor for the target protease is the equilibrium Dissociation constant K, of the enzyme-inhibitor complex. This K value can be determined via the influence of the inhibitor on the tryptase-mediated cleavage of a chromogenic peptide-p-nitroanide substrate or of a fluorogenic peptide-aminomethylcuma ⁇ n substrate
  • the dissociation constants for the tryptase inhibitor complexes are calculated under equilibrium conditions in accordance with the general suggestions of Bieth (Bieth JG, Pathophysiological Interpretation of kinetic constants of protease Inhibitors, Bull Europ Physiopath Resp 16 183-195, 1980) and the methods of Sommerhoff et al (Sommerhoff CP et al, A Kazal-type mhibitor of human mast cell tryptase isolation from the medical leech Hirudo medicinalis, charactenzation, and sequence analysis, Biol Chem Hoppe-Seyler 375 685-694, 1994)
  • Human tryptase is prepared purely from lung tissue or is produced in a recombinant manner, the specific activity of the protease determined by titration is usually a large 85% of the theoretical value. Constant amounts of tryptase are used in the presence of hepan (0.1-50 ⁇ g / ml) to stabilize the protease incubated with increasing amounts of the inhibitors. After equilibrium between the reaction partners, the remaining enzyme activity is determined after addition of the peptide p-nitroanihd substrate tos-Gly-Pro-Arg-pNA, the cleavage of which is monitored over 3 min at 405 nm the residual enzymatic activity can also be determined using fluorogenic substrates.
  • V, / Vo 1 - ⁇ E t + l t + K ⁇ app - [(E t + l t + K ⁇ app ) 2 -4E t l t ] 1 2 ⁇ / 2E t

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Abstract

Les composés de la formule (I) où M, A1, A2, A3, A4, B1, B2, B3, B4, Y1 et Y2 ont la signification donnée dans la description, sont de nouveaux inhibiteurs puissants de la tryptase.
PCT/EP2000/007707 1999-08-10 2000-08-08 Nouvelles diketo-piperazines Ceased WO2001010845A1 (fr)

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US6924305B2 (en) 2001-01-31 2005-08-02 Altana Pharma Ag Diazocine derivatives and their use as tryptase inhibitors
US6962941B2 (en) 2001-06-19 2005-11-08 Altana Pharma Ag Tryptase inhibitors
US7060716B2 (en) 2001-02-21 2006-06-13 Altana Pharma Ag Tryptase inhibitors
US7101911B2 (en) 2001-02-21 2006-09-05 Altana Pharma Ag Tryptase inhibitors
JP2013540784A (ja) * 2010-10-29 2013-11-07 ロンザ リミテッド ジケトピペラジン形成ジペプチジルリンカー
US10086013B2 (en) 2011-10-27 2018-10-02 Massachusetts Institute Of Technology Amino acid-, peptide- and polypeptide-lipids, isomers, compositions, and uses thereof
US10117934B2 (en) 2011-03-28 2018-11-06 Massachusetts Institute Of Technology Conjugated lipomers and uses thereof
US10189802B2 (en) 2008-11-07 2019-01-29 Massachusetts Institute Of Technology Aminoalcohol lipidoids and uses thereof
US10201618B2 (en) 2015-06-19 2019-02-12 Massachusetts Institute Of Technology Alkenyl substituted 2,5-piperazinediones, compositions, and uses thereof
CN113072506A (zh) * 2021-04-29 2021-07-06 陕西慧康生物科技有限责任公司 一类含天冬氨酸、谷氨酸的环二肽的合成方法
CN113214168A (zh) * 2021-04-29 2021-08-06 陕西慧康生物科技有限责任公司 一种固液联合合成含谷氨酸、天冬氨酸的环二肽的方法
CN113292508A (zh) * 2021-06-07 2021-08-24 陕西慧康生物科技有限责任公司 一类含天冬酰胺、谷氨酰胺的环二肽的合成方法
WO2025207585A1 (fr) * 2024-03-25 2025-10-02 Mccloud Josh Composition rodenticide activée par l'humidité sans danger pour l'environnement et système de distribution
WO2025217299A1 (fr) * 2024-04-10 2025-10-16 Georgia Tech Research Corporation Nouveaux lipides contenant un noyau dicétopipérazine, nanoparticule lipidique les contenant et leurs procédés d'utilisation

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WO2004030522A2 (fr) 2002-10-02 2004-04-15 Dmi Biosciences, Inc. Diagnostic et controle de maladies
CN103191409A (zh) 2003-05-15 2013-07-10 Dmi生物科学公司 T-细胞介导的疾病的治疗
EP2046778B1 (fr) * 2006-08-04 2013-12-04 Manus Pharmaceuticals (Canada) Ltd. Composés bioactifs multifonctionnels
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JP2013537195A (ja) 2010-09-07 2013-09-30 ディエムアイ アクイジション コーポレイション 疾患の治療
EP3721884A1 (fr) 2011-10-10 2020-10-14 Ampio Pharmaceuticals, Inc. Traitement de maladies articulaires dégénératives avec da-dkp (= diketopiperazine aspartyl-alanyl)
MY172699A (en) 2011-10-10 2019-12-10 Ampio Pharmaceuticals Inc Implantable medical devices with increased immune tolerance, and methods for making and implanting
CA2846394A1 (fr) 2011-10-28 2013-05-02 Ampio Pharmaceuticals, Inc. Traitement de la rhinite
MX2015010937A (es) 2013-03-15 2015-10-29 Ampio Pharmaceuticals Inc Composiciones para la movilizacion, autodireccion, expansion y diferenciacion de celulas madre y metodos para usar las mismas.
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EP3310375A4 (fr) 2015-06-22 2019-02-20 Ampio Pharmaceuticals, Inc. Utilisation de fractions d'albumine de sérum humain de bas poids moléculaire pour traiter les maladies

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US6924305B2 (en) 2001-01-31 2005-08-02 Altana Pharma Ag Diazocine derivatives and their use as tryptase inhibitors
US7060716B2 (en) 2001-02-21 2006-06-13 Altana Pharma Ag Tryptase inhibitors
US7101911B2 (en) 2001-02-21 2006-09-05 Altana Pharma Ag Tryptase inhibitors
US6962941B2 (en) 2001-06-19 2005-11-08 Altana Pharma Ag Tryptase inhibitors
US10844028B2 (en) 2008-11-07 2020-11-24 Massachusetts Institute Of Technology Aminoalcohol lipidoids and uses thereof
US11414393B2 (en) 2008-11-07 2022-08-16 Massachusetts Institute Of Technology Aminoalcohol lipidoids and uses thereof
US10189802B2 (en) 2008-11-07 2019-01-29 Massachusetts Institute Of Technology Aminoalcohol lipidoids and uses thereof
JP2013540784A (ja) * 2010-10-29 2013-11-07 ロンザ リミテッド ジケトピペラジン形成ジペプチジルリンカー
US10117934B2 (en) 2011-03-28 2018-11-06 Massachusetts Institute Of Technology Conjugated lipomers and uses thereof
US12390528B2 (en) 2011-03-28 2025-08-19 Massachusetts Institute Of Technology Conjugated lipomers and uses thereof
US10933139B2 (en) 2011-03-28 2021-03-02 Massachusetts Institute Of Technology Conjugated lipomers and uses thereof
US10682374B2 (en) 2011-10-27 2020-06-16 Massachusetts Intstitute Of Technology Amino acid-, peptide- and polypeptide-lipids, isomers, compositions, and uses thereof
US10086013B2 (en) 2011-10-27 2018-10-02 Massachusetts Institute Of Technology Amino acid-, peptide- and polypeptide-lipids, isomers, compositions, and uses thereof
US11458158B2 (en) 2011-10-27 2022-10-04 Massachusetts Institute Of Technology Amino acid-, peptide- and polypeptide-lipids, isomers, compositions, and uses thereof
US10695444B2 (en) 2015-06-19 2020-06-30 Massachusetts Institute Of Technology Alkenyl substituted 2,5-piperazinediones, compositions, and uses thereof
US10201618B2 (en) 2015-06-19 2019-02-12 Massachusetts Institute Of Technology Alkenyl substituted 2,5-piperazinediones, compositions, and uses thereof
CN113072506B (zh) * 2021-04-29 2022-05-27 陕西慧康生物科技有限责任公司 一类含天冬氨酸、谷氨酸的环二肽的合成方法
CN113214168A (zh) * 2021-04-29 2021-08-06 陕西慧康生物科技有限责任公司 一种固液联合合成含谷氨酸、天冬氨酸的环二肽的方法
CN113072506A (zh) * 2021-04-29 2021-07-06 陕西慧康生物科技有限责任公司 一类含天冬氨酸、谷氨酸的环二肽的合成方法
CN113292508A (zh) * 2021-06-07 2021-08-24 陕西慧康生物科技有限责任公司 一类含天冬酰胺、谷氨酰胺的环二肽的合成方法
CN113292508B (zh) * 2021-06-07 2022-09-27 陕西慧康生物科技有限责任公司 一类含天冬酰胺或谷氨酰胺的环二肽的合成方法
WO2025207585A1 (fr) * 2024-03-25 2025-10-02 Mccloud Josh Composition rodenticide activée par l'humidité sans danger pour l'environnement et système de distribution
WO2025217299A1 (fr) * 2024-04-10 2025-10-16 Georgia Tech Research Corporation Nouveaux lipides contenant un noyau dicétopipérazine, nanoparticule lipidique les contenant et leurs procédés d'utilisation

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