Biomeasure Incorporated

The Administrators of the Tulane Educational Fund

Societe De Conseils De Recherches Et D'applications Scientifiques (s.c.r.a.s.)

Societe De Conseils De Recherches Et D'applications Scientifiques Sas

Tulane Univ. Medical Ctr.

John E Taylor

David H Coy

Sun H Kim

Jacques-Pierre Moreau

Zheng Xin Dong

Dennis Bigg

Jacques Pommier

Anne-Marie Liberatore

Arthur E Bogden

Sylviane Moreau

Susan R Keyes

Wojciech J Rossowski

The present invention is directed to a novel class of cyclic polypeptides of the formula: (R)-AA-cyclo[AA-AA-AA-AA-AA-Cys]-AA-R, pharmaceutically acceptable salts thereof, wherein the variables are as defined in the specification, which inhibit the effects of urotensin-II and are useful for treating a variety of diseases and/or conditions characterized by an excess of urotensin-II including ischaemic heart disease, congestive heart failure, portal hypertension, variceal bleeding, hypotension, angina pectoris, myocardial infarction, ulcers, anxiety, schizophrenia, manic depression, delirium, dementia, mental retardation and/or dyskinesias.

Urotensin-II agonists and antagonists

The invention concerns the use of pyrido-thieno-triazolo-diazepins for preparing a medicine for treating pathological conditions or diseases involving one of the growth hormone release inhibiting factor receptors. The invention also concerns novel pyrido-thieno-triazolo-diazepins and therapeutic compositions containing them.

Use of diazepines for preparing medicines for treating pathological conditions or diseases involving one of the growth hormone release inhibiting factor receptors

A cyclic peptide analog of somatostatin wherein a disulfide bond links the N-terminus residue and the C-terminus residue.

Cyclic peptide analogs of somatostatin

A linear peptide which is an analog of a naturally occurring, biologically active peptide having an active site and a binding site responsible for the binding of the peptide to a receptor on a target cell, cleavage of a peptide bond in the active site to the naturally occurring peptide being unnecessary for in vivo biological activity, the analog having a non-peptide bond instead of a peptide bond between an amino acid of the active site and an adjacent amino acid, and having the same binding site as the naturally occurring peptide, so that the analog is capable of acting as a competitive inhibitor of the naturally occurring peptide by binding to the receptor and, by virtue of the non-peptide bond, failing to exhibit the in vivo activity of the naturally occurring peptide.

Bradykinin analogs with non-peptide bond

Opioid peptides including those of the formula ##STR1## in which A.sub.1 is the identifying group of an amino acid selected from 3,4-dihydroxyphenylalanine, 3,4-dimethoxyphenylalanine, azatyrosine, and 2,6-dimethyltyrosine; A.sub.2 is the identifying group of an amino acid selected from D-Ala and D-Arg; A.sub.3 is H, or the identifying group of an amino acid selected from of 3,4-dihydroxyphenylalanine and 3,4-dimethoxyphenylalanine, A.sub.4 is H, cyclohexylmethyl, the identifying group of an amino acid selected from 3,4-dihydroxyphenylalanine, 3,4-dimethoxyphenylalanine, Phe, and substituted Phe with its benzene ring substituted by halogen, NO.sub.2, OH, or CH.sub.3 ; A.sub.5 is the identifying group of a D- or L-amino acid selected from Leu, Nle, Lys, Met and Met(O), or is deleted together with R.sub.4 --CH attached thereto; each R.sub.1 and R.sub.2 is --H, --C(NH.sub.2).dbd.NH, or C.sub.1-12 alkyl; R.sub.3 is ##STR2## R.sub.4 is ##STR3## and R.sub.5 is --(CH.sub.2).sub.n+1 OH, ##STR4## wherein m is 0-6, n is 0-6, and X is H, C.sub.1-12 alkyl, C.sub.6-12 aryl, C.sub.7-18 aralkyl, C.sub.7-18 alkaryl, C.sub.7-18 alkayl, C.sub.6-17 pyridylalkyl, or C.sub.6-17 alkylpyridyl; provided that when one of R.sub.1 and R.sub.2 is --C(NH.sub.2).dbd.NH, the other must be H; or a pharmaceutically acceptable salt thereof.

Opioid peptides

A cyclic octapeptide of the formula: ##STR1## wherein: A.sup.1 is D-Nal or D-Trp; A.sup.3 is Phe, F.sub.5 -Phe, or X-Phe wherein X is a halogen, NO.sub.2, CH.sub.3, or OH; A.sup.5 is --NH--CH(Y)--CO-- wherein Y is (CH.sub.2).sub.m --R.sub.4 --N(R.sub.5)(R.sub.6) or (CH.sub.2).sub.n --R.sub.4 --NH--C(R.sub.7)--N(R.sub.5) (R.sub.6); A.sup.6 is the D-- or L-- isomer of Thr, Leu, Ile, Nle, Val, and Abu; A.sup.8 is Nal or Trp; m is 1, 2, or 3; n is 1, 2, 3, 4 or 5; each of R.sub.1 and R.sub.2, independently, is H, E, COE, or COOE wherein E is C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, phenyl, naphthyl, C.sub.7-12 phenylalkyl or alkylphenyl, C.sub.8-12 phenylalkenyl or alkenylphenyl, C.sub.8-12 phenylalkynyl or alkynylphenyl, C.sub.11-20 naphthylalkyl or alkylnaphthyl, C.sub.12-20 naphthylalkenyl or alkenylnaphthyl, or C.sub.12-20 naphthylalkynyl or alkynylnaphthyl, provided that when one of R.sub.1 or R.sub.2 is COE or COOE, the other must be H; R.sub.4 is C.sub.6 H.sub.4 or absent; R.sub.7 is .dbd.NR.sub.8, .dbd.S, or .dbd.O; and each of R.sub.3, R.sub.5, R.sub.6, and R.sub.8, independently, is H or E.

Cyclic octapeptide neuromedin B receptor antagonists

Peptide derivatives containing one or more substituents separately linked by an amide, amino or sulfonamide bond to an amino group on either the N-terminal end or side chain of a biologically active peptide moiety. The peptide derivatives have relatively enhanced biological activity when compared to the corresponding peptide alone.

Therapeutic peptide derivatives

A method of selectively inhibiting biochemical activity of cells induced by neuromedin B. The method includes the step of contacting cells which contain neuromedin B receptor with a cyclic octapeptide, D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH.sub.2, or an analog thereof.

Neuromedin B receptor antagonists which demonstrate selectivity

A bradykinin analog which contains nine or ten amino acid residues and at least one [CH.sub.2 NH] pseudopeptide bond, the analog being useful as an antagonist or agonist of the naturally occuring bradykinin.

Peripheral benzodiazepines (BZDs) are useful in treating disorders caused by abnormal level of peripheral benzodiazepene receptor activity and having, in one aspect, the formula: ##STR1## wherein each X, X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, and X.sub.8, independently, is hydrogen, halogen (F, Cl, Br, I), C.sub.1 -C.sub.4 straight or branched alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, hydroxy, nitro, cyano, amino, or trifluoromethyl; R.sub.1 =H, C.sub.1 -C.sub.4 alkyl, cyclo C.sub.3 -C.sub.5 alkyl, C.sub.1 -C.sub.4 alkenyl, CH.sub.2 --CO.sub.2 H, or CH.sub.3 --C.dbd.O; R.sub.2 =a member of the group of the formula (Ia) ##STR2## wherein each R.sub.3, R.sub.4, R.sub.8, R.sub.9, R.sub.10 and R.sub.11, independently, can be any of the groups listed as possibilities for X.sub.1 -X.sub.8, and can be attached at any available ring carbon atom, said R.sub.2 group being bonded to (CH.sub.2) in via any available ring carbon atom; n=0 or 1; and m=an integer between 1 and 4 provided that m is at least 1 when n=0.

2H-1,3,4-benzotriazepin-2-ones

A method of treating a mammal suffering from cancer by administering to the mammal somatostatin or an analog thereof, the analog being a hexapeptide analog or higher, in a dosage of at least 25 .mu.g/kg/day.

Treatment of small cell lung cancer with somatostatin analogs

BZDs of the general formula 1: ##STR1## where: R represents H, alkyl, alkenyl, cycloalkyl or cycloalkenyl each with up to 8 carbon atoms, phenylalkyl with an alkylene chain of 1 to 3 carbon atoms and optionally substituted on the phenyl radical with one or two substituents selected from the group consisting of Cl, Br, F, CN, CF.sub.3, NO.sub.2, lower alkyl, and OCH.sub.3, or represents a phenyl radical which is optionally substituted with one or two substituents selected from the group consisting of Cl, F, Br, CN, I, CF.sub.3 NO.sub.2, lower alkyl and OCH.sub.3, or represents a 5-membered or 6-membered heterocyclic radical with 1 or 2 heteroatoms from the group consisting of O, N and S; R.sub.1 represents H or, together with R.sub.2, forms a bond; R.sub.2 and R.sub.4 independently of one another represent H, or an alkyl radical with 1 to 6 carbon atoms, or represent a phenylalkyl radical with an alkyl chain of 1 to 3 carbon atoms and optionally substituted on the phenyl radical with one or two substituents selected from the group consisting of Cl, Br, F, CN, CF.sub.3, NO.sub.2, CH.sub.3, C.sub.2 H.sub.5 and OCH.sub.3, or R.sub.2 together with R.sub.1, forms a bond; R.sub.3 is (CH.sub.2).sub.n CH or (CH.sub.2).sub.n --CR.sub.14 .dbd.CR.sub.14, where n is between 0 and 5 inclusive and R.sub.14 .dbd.HOL a bond; R.sub.5 and R.sub.6 independently of one another represent H, Cl, F, Br, NO.sub.2, CN, CF.sub.3, lower alkyl, or OCH.sub.3 ; R.sub.7 and R.sub.9 are independently CH.sub.2 or C.dbd.0; R.sub.8 is ##STR2## where p and q are independently between 0 and 4 and the sum of p and q is 4 or less; and R.sub.11 and R.sub.12 are independently H or a lower alkyl of between 1 and 5 carbon atoms.

Growing community of inventors

Upton, MA, United States of America

John E Taylor