| 摘要 |
<p>#CMT# #/CMT# Peptide derivatives and peptidomimetic (D) and their stereoisomer forms, E/Z-isomers, enantiomers, enantiomeric mixture, diastereomers, diastereomeric mixture, racemates, tautomers, anomers, keto-enol-forms, betaine forms, prodrugs, solvate, hydrate or their salts, are new. #CMT# : #/CMT# Peptide derivatives and peptidomimetic (D) of formula (I-III), and their stereoisomer forms, E/Z-isomers, enantiomers, enantiomeric mixture, diastereomers, diastereomeric mixture, racemates, tautomers, anomers, keto-enol-forms, betaine forms, prodrugs, solvate, hydrate or their salts, are new, where (I) excludes compounds having X and X1a are hydrogen and Y 1>is hydroxy. MS : acceptor substituted olefin of formula (-CH(R 1>)(R 2>)-CH(R 3>)(R 4>)-(CO) m-CH(Z 3>)=C(Z 1>)(Z 2>)); E : e.g. -CH 2-, -CF 2-, -C 2H 4-, -CH 2-CF 2-, -CF 2-CH 2-, -CH=CH-, -CH(OH)-CH 2-, -C(=O)-CH 2-, -CH 2-NH-, -CH 2-O-, -CH(OH)-CH 2-NH-, -P(=O)(OH)-NH-, -P(=O)(OH)-O- or -P(=O)(OH)-S-; m : 0 or 1; either Z 1>-Z 3>e.g. CO-(1-6C-alkyl), -COO-(1-6C-alkyl) (both preferred), -CO-R 6>, -CO-R 7>, -CO-(1-6C-haloalkyl), -CO-(3-10C-heteroaryl), -CO-(6-15C-aryl), -COO-(1-6C-haloalkyl), -COO-(3-10C-heteroaryl), -COO-(6-15C-aryl), -CN, -F, -Cl, -COOH, -CO-NH(1-6C-alkyl), -CO-N(1-6C-alkyl)(1-6C-alkyl), -CO-NH 2, -CH 2CN, -CH 2F, -CHF 2, -CF 3, -OCF 3, -CH 2-CF 3, -CF 2-CF 3, -NO 2, -CS-(1-6C-alkyl), -CS-N(1-6C-alkyl)(1-6C-alkyl), -OS-NH 2, -SO-N(1-6C-alkyl)(1-6C-alkyl), -SO 2-N(1-6C-alkyl)(1-6C-alkyl), SO 2-OH, -O-P(O)(OH) 2, -O-P(O)(O-1-6C-alkyl)(O-1-6C-alkyl), -P(O)(O-1-6C-alkyl)(O-1-6C-alkyl) or -CF 2-P(O)(O-1-6C-alkyl)(O-1-6C-alkyl); or Z 2>+Z 3>e.g. -CO-O-CH 2-, -CO-O-CO- or -CO-NH-CO-; either Q, Q 1>a side chain residue of a natural amino acid; or Q+X1a, Q 1>+X1b : a propylenyl group; Y 1>e.g. OH, amino, 1-6C-alkylamino, 1-6C-dialkylamino, 1-6C-alkoxy, 1-6C-alkyl, 1-6C-haloalkyl, 3-10C-heteroaryl, 6-15C aryl, a peptidomimetic group of up to 60 carbon atoms or amine bond bounded peptide residue of up to 6 amino acids; either X1a, X1b : H or 1-6C alkyl; or N+X+X1a : e.g. amino, 1-10C alkylamino, 6-12C aralkyloxycarbonylamino, 1-10C-dialkylamino, 2-6C-nitrogen heterocycle, 3-5C nitrogen heteroaryl or a part of peptidomimetic residue of up to 60 carbon atoms; and X : amine bond bounded peptide residue of up to 6 amino acids; and R 1>-R 4>e.g. H, -OH, -OCH 3, -OC 2H 5, -OC 3H 7, -O-cyclo-C 3H 5, -OCH(CH 3) 2, -OC(CH 3) 3, -OC 4H 9, -OPh, -OCH 2-Ph, -OCPh 3, -SH, -SCH 3, -SC 2H 5, -SC 3H 7, -S-cyclo-C 3H 5, -SCH(CH 3) 2, -SC(CH 3) 3, -NO 2, -F, -Cl, -Br, -I, -N 3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COOH 3, -COC 2H 5or -COC 3H 7. Independent claims are included for: (1) tetrapeptide derivatives of formula (IV); and (2) a pharmaceutical composition comprising (A) and at least a carrier, auxiliary material or solvent. Either Q, Q 1>, Q 2>a side chain residue of a natural amino acid; or Q+X1b, Q 1>+X1c, Q 2>+X1d : a propylenyl residue; and X1b, X1c, X1d : H or 1-6C alkyl. #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Immunosuppressive; Gastrointestinal-Gen; Antiinflammatory; Thrombolytic; Anticoagulant; Neuroprotective; Anticonvulsant; Nootropic; Antiparkinsonian; Ophthalmological; Antiseborrheic; Dermatological; Antipsoriatic; Fungicide. #CMT#MECHANISM OF ACTION : #/CMT# Transglutaminase inhibitor. Test details are described but no results given. #CMT#USE : #/CMT# (D) are useful for the treatment or prophylaxis of celiac disease, fibrosis, thrombosis, neurodegenerative disorders, Huntington's chorea, Parkinson disease, Alzheimer's disease, cataract, acne, psoriasis, skin aging, candidiasis and other transglutaminase dependent diseases (claimed). #CMT#ADVANTAGE : #/CMT# (D) increases the absorption of the nutrients by inhibiting the gluten content in the food, such that the massive impact preferably weight loss, anemia, diarrhea, vomiting, loss of appetite and fatigue in the patient is avoided. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Disclosed): Preparation of (D) comprises reacting amino acid (glutamic acid) at C-terminal and N-terminal with protection groups e.g. tert-butyloxycarbonyl; selectively reducing the side chain to aldehyde in the presence of diisobutylaluminum hydride; reacting the aldehyde with phosphorane to form Michael system; introducing a peptide residue, peptide analog, amino-acid-analog or one or two alkyl groups, after acid induced splitting of the protection groups at the N-terminal end by means of trifluoroacetic acid; adding any peptidic or peptide like groups at the C-terminal and at the N-terminal of the amino acid-Michael system to form alkyloxycarbonylethenyl-Michael system. Preferred Components: (IV) is preferably tetrapeptide derivative of formula (V). Preferred Composition: The pharmaceutical composition further comprises an active substance comprising vitamins, minerals, trace elements, peptidase, cytokine, monoclonal antibodies and zonulin. #CMT#[Image]#/CMT# #CMT#DEFINITIONS : #/CMT# Full Definitions: MS : acceptor substituted olefin of formula (-CH(R 1>)(R 2>)-CH(R 3>)(R 4>)-(CO) m-CH(Z 3>)=C(Z 1>)(Z 2>)); E : -CH 2-, -CF 2-, -C 2H 4-, -CH 2-CF 2-, -CF 2-CH 2-, -CH=CH-, -CH(OH)-CH 2-, -C(=O)-CH 2-, -CH 2-NH-, -CH 2-O-, -CH(OH)-CH 2-NH-, -P(=O)(OH)-NH-, -P(=O)(OH)-O-, -P(=O)(OH)-S-, -P(=O)(OH)-CH 2-, -CH(OH)-CH 2-NH-, -C(=O)-NH-, -C(=O)-O- or -C(=O)-NX1b-; m : 0 or 1; either Z 1>-Z 3>CO-(1-6C-alkyl), -COO-(1-6C-alkyl) (both preferred), -CO-R 6>, -CO-R 7>, -CO-(1-6C-haloalkyl), -CO-(3-10C-heteroaryl), -CO-(6-15C-aryl), -COO-(1-6C-haloalkyl), -COO-(3-10C-heteroaryl), -COO-(6-15C-aryl), -COO-R 8>, -COO-R 9>, -CN, -F, -Cl, -COOH, -CO-NH(1-6C-alkyl), -CO-N(1-6C-alkyl)(1-6C-alkyl), -CO-NR 1> 0>R 1> 1>, -CO-NH 2, -CO-N(CR 1> 2>R 1> 3>R 1> 4>)(CR 1> 5>R 1> 6>R 1> 7>), -CH 2CN, -CH 2F, -CHF 2, -CF 3, -OCF 3, -CH 2-CF 3, -CF 2-CF 3, -NO 2, -CS-(1-6C-alkyl), -CS-R 1> 8>, -CS-R 1> 9>, -CS-O-(1-6C-alkyl), -CS-O-R 2> 0>, -CS-O-R 2> 1>, -CS-N(1-6C-alkyl)(1-6C-alkyl), -CS-NR 2> 2>R 2> 3>, -OS-NH 2, -CS-N(CR 2> 4>R 2> 5>R 2> 6>)(CR 2> 7>R 2> 8>R 2> 9>)-SO-R 3> 0>, -SO-R 3> 1>, -SO 2-R 3> 2>, -SO 2-R 3> 3>, -SO-CR 3> 4>R 3> 5>R 3> 6>, -SO-CR 3> 7>R 3> 8>R 3> 9>, -SO 2-CR 4> 0>R 4> 1>R 4> 2>, -SO 2-CR 4> 3>R 4> 4>R 4> 5>, -SO-N(1-6C-alkyl)(1-6C-alkyl), SO-NR 4> 6>R 4> 7>, -SO-NH 2, -SO-N(CR 4> 8>R 4> 9>R 5> 0>)(CR 5> 1>R 5> 2>R 5> 3>), -SO 2-N(1-6C-alkyl)(1-6C-alkyl), -SO 2-NR 5> 4>R 5> 5>, -SO 2-NH 2, -SO 2-N(CR 5> 6>R 5> 7>R 5> 8>)(CR 5> 9>R 6> 0>R 6> 1>), SO 2-OH, -SO 2-OR 6> 2>, -SO 2-CR 6> 3>R 6> 4>R 6> 5>, -SO 2-OCR 6> 6>R 6> 7>R 6> 8>, -O-P(O)(OH) 2, -O-P(O)(OR 6> 9>)(OR 7> 0>), -O-P(O)(O-1-6C-alkyl)(O-1-6C-alkyl), -P(O)(OR 7> 1>)(OR 7> 2>), -P(O)(O-1-6C-alkyl)(O-1-6C-alkyl), -CF 2-P(O)(OR 7> 3>)(OR 7> 4>) or -CF 2-P(O)(O-1-6C-alkyl)(O-1-6C-alkyl); or Z 2>+Z 3>CO-Z1a-CH 2-, -CO-O-CH 2-, -CO-O-CO-, -CO-NH-CO- or -Z1a-CH 2-CH 2-; Z1a : -CH 2-, -CF 2-, -C 2H 4-, -CF 2-CH 2-, -CH 2-CH 2-, -O-, -O-CH 2-, -NH- or -NH-CH 2-; either Q, Q 1>a side chain residue of a natural amino acid; or Q+X1a, Q 1>+X1b : a propylenyl group; Y 1>OH, amino, 1-6C-alkylamino, 1-6C-dialkylamino, 1-6C-alkoxy, 1-6C-alkyl, 1-6C-haloalkyl, 3-10C-heteroaryl, 6-15C aryl, a peptidomimetic group of up to 60 carbon atoms or amine bond bounded peptide residue of up to 6 amino acids, whose C-terminal carbonyl function is hydroxy, amino, 1-6C-alkylamino, 1-6C-dialkylamino, 1-6C-alkoxy, 1-6C-alkyl, 1-6C-haloalkyl, 3-10C-heteroaryl or 6-15C-aryl; either X1a, X1b : H or 1-6C alkyl; or N+X+X1a : amino, 1-10C alkylamino, 6-12C aralkyloxycarbonylamino, 1-10C-dialkylamino, 2-6C-nitrogen heterocycle, 3-5C nitrogen heteroaryl or a part of peptidomimetic residue of up to 60 carbon atoms; X : amine bond bounded peptide residue of up to 6 amino acids, whose N-terminal functional group is amino, 1-10C-alkylamino, 6-12C-aralkyloxycarbonylamino, 1-10C-dialkylamino, 2-6C-nitrogen heterocycle or 3-5C-nitrogen heteroaryl, where each of the 1-6C-alkoxy, 1-6C-alkyl, 1-10C-alkylamino, 6-12C-aralkyloxycarbonylamino, 1-10C-dialkylamino, 2-6C-nitrogen heterocycle or 3-5C nitrogen heteroaryl is substituted with up to 5 of R 8> 0>-R 8> 4>; and R 1>-R 8> 4>H, -OH, -OCH 3, -OC 2H 5, -OC 3H 7, -O-cyclo-C 3H 5, -OCH(CH 3) 2, -OC(CH 3) 3, -OC 4H 9, -OPh, -OCH 2-Ph, -OCPh 3, -SH, -SCH 3, -SC 2H 5, -SC 3H 7, -S-cyclo-C 3H 5, -SCH(CH 3)2, -SC(CH 3) 3, -NO 2, -F, -Cl, -Br, -I, -N 3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COOH 3, -COC 2H 5, -COC 3H 7, -CO-cyclo-C 3H 5, -COCH(CH 3) 2, -COC(CH 3) 3, -CO-OH, -COCN, -COOCH 3, -COOC 2H 5, -COOC 3H 7, -COO-cyclo-C 3H 5, -COOCH(CH 3) 2, -COOC(CH 3) 3, -OOC-CH 3, -OOC-C 2H 5, -OOC-C 3H 7, -OOC-cyclo-C 3H 5, -OOC-CH(CH 3) 2, -OOC-C(CH 3) 3, -CONH 2, -CONHCH 3, -CONHC 2H 5, -CONHC 3H 7, -CONH-cyclo-C 3H 5, -CONH[CH(CH 3) 2], -CONH[C(CH 3) 3], -CON(CH 3) 2, -CON(C 2H 5) 2, -CON(C 3H 7) 2, -CON(cyclo-C 3H 5) 2, -CON[CH(CH 3) 2] 2, -CON[C(CH 3) 3] 2, -NHCOCH 3, -NHCOC 2H 5, -NHCOC 3H 7, -NHCO-cyclo-C 3H 5, -NHCO-CH(CH 3) 2, -NHCO-C(CH 3) 3, -NHCO-OCH 3, -NHCO-OC 2H 5, -NH-CO-OC 3H 7, -NHCO-O-cyclo-C 3H 5, -NHCO-OCH(CH 3) 2, -NHCO-OC(CH 3) 3, -NH 2, -NHCH 3, -NHC 2H 5, -NHC 3H 7, NH-cyclo-C 3H 5, -NHCH(CH 3) 2, -NHC(CH 3) 3, -N(CH 3) 2, -N(C 2H 5) 2, -N(C 3H 7) 2, -N(cyclo-C 3H 5) 2, -N[CH(CH 3) 2] 2, -N[C(CH 3) 3] 2, -SOCH 3, -SOC 2H 5, -SOC 3H 7, -SO-cyclo-C 3H 5, -SOCH(CH 3) 2, -SOC(CH 3) 3, -SO 2CH 3, -SO 2C 2H 5, -SO 2C 3H 7, -SO 2-cyclo-C 3H 5, -SO 2CH(CH 3) 2, -SO 2C(CH 3) 3, -SO 3H, -SO 3CH 3, -SO 3C 2H 5, -SO 3C 3H 7, -SO 3-cyclo-C 3H 5, -SO 3CH(CH 3) 2, -SO 3C(CH 3) 3, -OCF 3, -OC 2F 5, -O-COOCH 3, -O-COOC 2H 5, -O-COOC 3H 7, -O-COO-cyclo-C 3H 5, -O-COOCH(CH 3) 2, -O-COOC(CH 3) 3, -NH-CO-NH 2, -NH-CO-NHCH 3, -NH-CO-NHC 2H 5, -NH-CO-NHC 3H 7, -NH-CO-NH-cyclo-C 3H 5, -NH-CO-NH[CH(CH 3) 2], -NH-CO-NH[C(CH 3) 3], -NH-CO-N(CH 3) 2, -NH-CO-N(C 2H 5) 2, -NH-CO-N(C 3H 7) 2, -NH-CO-N(cyclo-C 3H 5) 2, -NH-CO-N[CH(CH 3) 2] 2, -NH-CO-N[C(CH 3) 3] 2, -NH-CS-NH 2, -NH-CS-NHCH 3, -NH-CS-NHC 2H 5, -NH-CS-NHC 3H 7, -NH-CS-NH-cyclo-C 3H 5, -NH</p> |
