HK1240952A1

HK1240952A1 - Beta-hairpin peptidomimetics

Info

Publication number: HK1240952A1
Application number: HK18100476.3A
Authority: HK
Inventors: D．奥伯莱希特; A．路德; F．贝尔纳迪尼; G．丹伊奥德; A．勒德雷尔
Original assignee: 波利弗尔股份公司
Priority date: 2014-09-30
Filing date: 2015-09-29
Publication date: 2018-06-01

Description

Beta-hairpin peptidomimetics

The present invention provides β -hairpin peptidomimetics having gram-negative antimicrobial activity and is encompassed by but not specifically disclosed in the general disclosure of WO02/070547 a1 and WO2004/018503 a 1.

The β -hairpin peptidomimetics of the invention are cyclo [ P ] compounds of the general formula (I)¹-P²-P³-P⁴-P⁵-P⁶-P⁷-P⁸-P⁹-P¹⁰-P¹¹-P¹²-T¹-T²]And pharmaceutically acceptable salts thereof, wherein P¹To P¹²，T¹And T²Are elements as described below.

Furthermore, the present invention provides efficient synthetic methods whereby these compounds can be prepared, if desired, in parallel library form. In addition, the β -hairpin peptidomimetics of the invention exhibit improved potency, reduced red blood cell hemolysis and reduced or absent cytotoxicity.

The leading cause of death worldwide and the leading cause of death in developed countries is infectious disease. They are caused by the presence of pathogenic microorganisms, including pathogenic viruses and pathogenic bacteria. The problem of bacterial resistance to established antibiotics has stimulated strong interest in the development of new antimicrobial agents with new modes of action (d.obrecht, j.a.robinson, f.bernadini, c.bishang, s.j.demanco, k.moehle, f.o.gombert, curr.med.chem.2009,16, 42-65; h.breithaupt, nat.biotechnol.1999,17, 1165-.

One of the growing unmet medical needs is represented by gram-negative bacteria, which cause 60% of iatrogenic pneumonia (r.frechette, ann.rep.med.chem., Elsevier,2007,349-64). A broad spectrum of beta lactamase (ESBL) producing gram negative bacteria also compromise the utility of many pro-line beta-lactam drugs (s.j.projan, p.a.bradford, curr.opin.microbiol.,2007,10, 441). The lack of suitable new compounds is forcing clinicians to use previously abandoned antibiotics such as polymyxin E, despite its well-known toxicity problems (m.e. falagas, s.k.kasiakou, crit.care,2006,10, R27). Therefore, new approaches are needed to treat resistant strains (h.w. boucher, g.h.talbot, j.s.bradley, j.e.edwards jr, d.gilbert, l.b.rice, m.scheld, b.spellberg, j.bartlett, IDSA port on development Pipeline, CID 2009,48,1), especially of Klebsiella pneumoniae (Klebsiella pneumoniae), Acinetobacter baumannii (Acinetobacter baumannii) and Escherichia coli (Escherichia coli).

One class of antibiotics that has emerged is based on natural cationic peptides (T.Ganz, R.I.Lehrer, mol.Medicine today 1999,5, 292-. These include disulfide-bridged β -hairpin and β -sheet peptides (such as antimicrobial peptides [ V.N.Kokryakov, S.S.L.Harwig, E.A.Panyuch, A.A.Shevchenko, G.M.Aleshina, O.V.Shamova, H.A.Korneva, R.I.Lehrer, FEBS Lett.1993,327,231-236], limulus antimicrobial peptides [ T.Nakamura, H.Furunaka, T.Miyata, F.Tokunaga, T.Muta, S.Iwanagaga, M.Niwa, T.Takao, Y.Shimonishi, J.biol.chem.1988,263, 09-16713], and defensins [ R.I.Lehreren, A.K.dermin, Y.Shimonishi, J.biol.chem.1988,263, 16713], and defensins [ R.I.Lechen. T.K.103, T.11. T.H.Biokuchen. peptide, T.11. T.H.Biokuwana, T.11. peptide, T.A.A.A.11, T.A.A.11. Biokuwann.11. peptide, T.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.L.L.A.L.L.A.A.A.A.A.L.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.T.T.T.T.A.A.A.A.T.T., more complex mechanisms of action such as involvement in receptor-mediated signal transduction cannot be excluded at present (M.Wu, E.Maier, R.Benz, R.E.Hancock, Biochemistry 1999,38, 7235-7242).

Among the compounds described below, a strategy was introduced to stabilize the β -hairpin conformation of backbone-cyclic cationic peptidomimetics, which exhibit gram-negative antimicrobial activity, in particular against gram-negative pathogens called ESKAPE pathogens (l.b. rice, j.infect.dis.2008,197, 1079). This involves grafting a hairpin sequence onto the template, which functions to constrain the peptide cyclic backbone in a hairpin shape. The introduction of additional β -strand linkages may further enhance the rigidity of the hairpin.

Template-binding hairpin mimetics have been described in the literature (D.Obrecht, M.Altorfer, J.A.Robinson, adv.Med.chem.1999,4, 1-68; J.A.Robinson, Syn.Lett.2000,4,429-441) and the ability to generate β -hairpin peptidomimetics using combinatorial and parallel synthesis methods has also been determined (L.Jiang, K.Moehle, B.Dhanapaal, D.Obrecht, J.A.Robinson, Helv.Chim.acta.2000,83, 3097-3112). Antibacterial template-fixed peptidomimetics and methods for their synthesis have been described in international patent applications WO02/070547 a1, WO2004/018503 a1, WO2007/079605 a2 and WO2012/016595 a1, but these molecules do not show a potent gram-negative antimicrobial activity against klebsiella pneumoniae (klebsiella pneumoniae) and/or Acinetobacter baumannii (Acinetobacter baumannii) and/or Escherichia coli (Escherichia coli).

The present invention relates to novel beta-hairpin peptidomimetics of formula (I),

ring [ P ]¹-P²-P³-P⁴-P⁵-P⁶-P⁷-P⁸-P⁹-P¹⁰-P¹¹-P¹²-T¹-T²]

(I)

Wherein an individual element T or P is linked to the nitrogen (N) of the next element in one of two directions from the carbonyl (C ═ O) point of attachment and wherein

T¹Is a natural or non-natural D α -amino acid containing optionally substituted side chains forming a four or five membered heterocyclic ring or a bicyclic ring system comprising α -carbon and α -amino atoms;

T²is a natural or non-natural L α -amino acid containing optionally substituted side chains forming a five-or six-membered heterocyclic or bicyclic system comprising α -carbon and α -amino atoms, or a natural or non-natural aliphatic L α -amino acid containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain, or a natural or non-natural aromatic L α -amino acid containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain, or a natural or non-natural basic L α -amino acid containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain comprising at least one amino function;

P¹natural or unnatural aliphatic L α -amino acids having a total of from 1 to 25 carbon atoms and/or heteroatoms in the individual side chain, or natural or unnatural aromatic L α -amino acids having a total of from 1 to 25 carbon atoms and/or heteroatoms in the individual side chain, or natural or unnatural L α -amino acids having a total of from 1 to 25 carbon atoms and/or heteroatoms in the individual side chain comprising at least one urea function, amide function, ester function, sulfone function or ether function, or natural or unnatural alcohol-containing L α -amino acids having a total of from 1 to 25 carbon atoms and/or heteroatoms in the individual side chain;

P²natural or non-natural aromatic L α -amino acids containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain, or natural or non-natural basic L α -amino acids containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain comprising at least one amino function;

P³，P⁸and P¹⁰Independently a natural or non-natural aliphatic L α -amino acid containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain, or a natural or non-natural aromatic L α -amino acid containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain;

P⁴natural or unnatural aliphatic L α -amino acids containing a total of 1 to 25 carbon atoms and/or heteroatoms in the individual side chains, or natural or unnatural basic L α -amino acids containing a total of 1 to 25 carbon atoms and/or heteroatoms in the individual side chains comprising at least one amino function, or natural or unnatural L α -amino acids containing a total of 1 to 25 carbon atoms and/or heteroatoms in the individual side chains comprising at least one urea function, amide function, ester function, sulfone function or ether function, or natural or unnatural alcohol-containing L α -amino acids containing a total of 1 to 25 carbon atoms and/or heteroatoms in the individual side chains;

P⁵is a natural or non-natural basic L α -amino acid containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain comprising at least one amino function, or a natural or non-natural L α -amino acid containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain comprising at least one urea, amide, ester, sulfone or ether function, or a natural or non-natural alcohol-containing L α -amino acid containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain;

P⁶is Gly, or a natural or non-natural basic D or L α amino acid containing a total of 1 to 25 carbon and/or hetero atoms in a single side chain comprising at least one amino function;

P⁷is a natural or non-natural basic L α -amino acid, included inA total of 1 to 25 carbon and/or heteroatoms in a single side chain of at least one amino function;

P⁹，P¹¹and P¹²Independently a natural or non-natural L α -amino acid, containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain;

P²and P¹¹Together and/or P⁴And P⁹Together, can form natural or unnatural crosslinked D or L α -amino acids, each containing a total of 1 to 12 carbon atoms and/or heteroatoms in a single side chain, which together link P by covalent interactions (interchain linkages)²And P¹¹And/or P⁴And P⁹；

Or a tautomer or rotamer thereof, or a salt or hydrate or solvate thereof;

and with the proviso that

If no interchain connection is formed;

and is

T¹Is a natural or non-natural D α -amino acid containing an optionally substituted side chain forming a five-membered heterocyclic or bicyclic ring system comprising α -carbon atoms and α -amino atoms;

then

T²Is a natural or non-natural aliphatic L α -amino acid having a total of 1 to 25 carbon atoms and/or heteroatoms in a single side chain, or a natural or non-natural aromatic L α -amino acid having a total of 1 to 25 carbon atoms and/or heteroatoms in a single side chain, or of the formula AA10^aThe L α -amino acid of (1).

A particular embodiment of the invention relates to compounds of the general formula (I), in which

T¹Is a D α -amino acid residue of one of the formulae

T²Is an L α -amino acid residue of one of the formulae

P¹Is an L α -amino acid residue of one of the formulae

P²Is an L α -amino acid residue of one of the formulae

P³，P⁸And P¹⁰Independently is an L α -amino acid residue of one of the formulae

P⁴Is an L α -amino acid residue of one of the formulae

P⁵Is an L α -amino acid residue of one of the formulae

P⁶Is Gly, or the L or D α amino acid residue of the formula

P⁷Is an L α -amino acid residue of the formula

P⁹，P¹¹And P is¹²Independently is an L α -amino acid residue of one of the formulae

P²And P¹¹Together and/or P⁴And P⁹Together are able to form a di (amino acid) -structure based on a linkage between two linking chains of L-or D- α -amino acid residues of one of the formulae

R^AlkIs C_1-12-an alkyl group; c_2-12-an alkenyl group; a cycloalkyl group; cycloalkyl-C_1-6-an alkyl group; or C_1-6-alkoxy-C_1-6-alkyl, provided that it contains less than 26 carbon and/or heteroatoms;

R^Aris- (CR)¹R⁴)_nR¹⁹；-(CH₂)_nO(CH₂)_mR¹⁹；-(CH₂)_nS(CH₂)_mR¹⁹(ii) a Or- (CH)₂)_nNR¹⁴(CH₂)_mR¹⁹With the proviso that less than 26 carbons are presentAn atom and/or a heteroatom;

R^Amis- (CR)¹R¹³)_qNR¹⁵R¹⁶；-(CH₂)_qC(＝NR¹³)NR¹⁵R¹⁶；-(CH₂)_qC(＝NOR¹⁷)NR¹⁵R¹⁶；-(CH₂)_qC(＝NNR¹⁵R¹⁶)NR¹⁷R¹⁸；-(CR¹R¹³)_qNR²C(＝NR¹⁷)NR¹⁵R¹⁶；-(CR¹R¹³)_qN＝C(NR¹⁵R¹⁶)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mNR¹⁵R¹⁶；-(CH₂)_nO(CH₂)_mC(＝NR¹⁷)NR¹⁵R¹⁶；-(CH₂)_nO(CH₂)_mC(＝NOR¹⁷)NR¹⁵R¹⁶；-(CH₂)_nO(CH₂)_mC(＝NNR¹⁵R¹⁶)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mNR¹C(＝NR¹⁷)NR¹⁵R¹⁶；-(CH₂)_nO(CH₂)_mN＝C(NR¹⁵R¹⁶)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mNR¹⁵R¹⁶；-(CH₂)_nS(CH₂)_mC(＝NR¹⁷)NR¹⁵R¹⁶；-(CH₂)_nS(CH₂)_mC(＝NOR¹⁷)NR¹⁵R¹⁶；-(CH₂)_nS(CH₂)_mC(＝NNR¹⁵R¹⁶)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mNR¹C(＝NR¹⁷)NR¹⁵R¹⁶(ii) a Or- (CH)₂)_nS(CH₂)_mN＝C(NR¹⁵R¹⁶)NR¹⁷R¹⁸Under the condition thatContaining less than 26 carbon atoms and/or heteroatoms;

R^Am1is- (CR)¹R¹³)_qNR¹⁵R¹⁶With the proviso that less than 26 carbon atoms and/or heteroatoms are present;

R^Hetis- (CR)¹R¹³)_qOR¹⁴；-(CR¹R¹³)_qSR¹⁵；-(CR¹R¹³)_qSO₂R¹⁵；-(CR¹R¹³)_qSO₂NR¹R¹⁴；-(CR¹R¹³)_qSO₂NR¹⁵R¹⁶；-(CR¹R¹³)_qNR¹⁴SO₂R¹⁵；-(CR¹R¹³)_qNR¹⁴SO₂NR¹⁵R¹⁶；-(CH₂)_nO(CH₂)_mOR¹⁴；-(CH₂)_nO(CH₂)_mSR¹⁵；-(CR¹R¹³)_qCOOR¹⁵；-(CR¹R¹³)_qCONR¹⁵R¹⁶；-(CR¹R¹³)_qNR¹⁵R²⁷(ii) a Or- (CR)¹R¹³)_qNR²CONR¹⁵R¹⁶With the proviso that less than 26 carbon atoms and/or heteroatoms are present;

R^OHis- (CR)¹R¹³)_qOH；-(CR¹R¹³)_qSH；-(CH₂)_nO(CH₂)_mOH；-(CH₂)_nS(CH₂)_mOH；-(CH₂)_nNR¹(CH₂)_mOH; hydroxy-C_1-8-an alkyl group; hydroxy-C_2-8-an alkenyl group; hydroxy-cycloalkyl; or hydroxy-heterocycloalkyl, provided that it contains less than 26 carbon and/or heteroatoms;

z is- (CH)₂)_n-S-S-(CH₂)_m-；-(CH₂)_nCH＝CH(CH₂)_m-；-(CH₂)_nCONR¹(CH₂)_m-；-(CH₂)_nNR¹CO(CH₂)_m-(ii) a Or- (CH)₂)_nNR¹CONR²(CH₂)_m-Provided that it contains less than 25 carbon and/or heteroatoms;

R¹，R²and R³Independently is H; CF (compact flash)₃；C_1-8-an alkyl group; c_2-8-an alkenyl group; or aryl-C_1-6-an alkyl group;

R⁴，R⁵，R⁶，R⁷and R⁸Independently is H; f; CF (compact flash)₃；C_1-8-an alkyl group; c_2-8-an alkenyl group; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; aryl-C_1-6-an alkyl group; heteroaryl-C_1-6-an alkyl group; - (CHR)¹³)_oOR¹⁵；-O(CO)R¹⁵；-(CHR¹³)_oSR¹⁵；-(CHR¹³)_oNR¹⁵R¹⁶；-(CHR¹³)_oOCONR¹⁵R¹⁶；-(CHR¹³)_oNR¹CONR¹⁵R¹⁶；-(CHR¹³)_oNR¹COR¹⁵；-(CHR¹³)_oCOOR¹⁵；-(CHR¹³)_oCONR¹⁵R¹⁶；-(CHR¹³)_oPO(OR¹)₂；-(CHR¹³)_oSO₂R¹⁵；-(CHR¹³)_oNR¹SO₂R¹⁵；-(CHR¹³)_oSO₂NR¹⁵R¹⁶；-(CR¹R¹³)_oR²³(ii) a Or- (CHR)¹)_nO(CHR²)_mR²³(ii) a Or

R⁴And R²(ii) a Or R⁵And R⁶Together can form: o; NR ═ NR¹；＝NOR¹；＝NOCF₃(ii) a Or- (CHR)¹)_p-；

R⁴And R⁵；R⁶And R⁷；R⁷And R⁸(ii) a Or R⁶And R⁹Together can form: - (CHR)¹)_p-；-(CH₂)_nO(CH₂)_m-；-(CH₂)_nS(CH₂)_m-(ii) a Or- (CH)₂)_nNR¹(CH₂)_m-；

R⁹Is H; f; CF (compact flash)₃；C_1-8-an alkyl group; c_2-8-an alkenyl group; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; aryl-C_1-6-an alkyl group; heteroaryl-C_1-6-an alkyl group; - (CHR)¹³)_rOR¹⁵；-O(CO)R¹⁵；-(CHR¹³)_rSR¹⁵；-(CHR¹⁰)_rNR¹⁵R¹⁶；-(CHR¹³)_rOCONR¹⁵R¹⁶；-(CHR¹³)_rNR¹CONR¹⁵R¹⁶；-(CHR¹³)_rNR¹COR¹⁵；-(CHR¹³)_oCOOR¹⁵；-(CHR¹³)_oCONR¹⁵R¹⁶；-(CHR¹³)_rPO(OR¹)₂；-(CHR¹³)_rSO₂R¹⁵；-(CHR¹³)_rNR¹SO₂R¹⁵；-(CHR¹³)_rSO₂NR¹⁵R¹⁶；-(CR¹R¹³)_oR²³(ii) a Or- (CHR)¹)_rO(CHR¹)_oR²³；

R¹⁰，R¹¹And R¹²Independently is H; f; cl; br; i; CF (compact flash)₃；OCF₃；OCHF₂；CN；NO₂；C_1-8-an alkyl group; c_2-8-an alkenyl group; an aryl group; a heteroaryl group; aryl-C_1-6-an alkyl group; heteroaryl-C_1-6-an alkyl group; - (CHR)¹³)_oOR¹⁵；-O(CO)R¹⁵；-(CHR¹³)_oSR¹⁵；-(CHR¹³)_oNR¹⁵R¹⁶；-(CHR¹³)_oOCONR¹⁵R¹⁶；-(CHR¹³)_oNR¹CONR¹⁵R¹⁶；-(CHR¹³)_oNR¹COR¹⁵；-(CHR¹³)_oCOOR¹⁵；-(CHR¹³)_oCONR¹⁵R¹⁶；-(CHR¹³)_oPO(OR¹)₂；-(CHR¹³)_oSO₂R¹⁵；-(CHR¹³)_oNR¹SO₂R¹⁵；-(CHR¹³)_oSO₂NR¹⁵R¹⁶(ii) a Or- (CR)¹R¹³)_oR²³；

R¹³Is H; f; CF (compact flash)₃；C_1-8-an alkyl group; c_2-8-an alkenyl group; a cycloalkyl group; a heterocycloalkyl group; cycloalkyl-C_1-6-an alkyl group; heterocycloalkyl-C_1-6-an alkyl group; an aryl group; a heteroaryl group; aryl-C_1-6-an alkyl group; heteroaryl-C_1-6-an alkyl group; - (CHR)¹)_oOR¹⁵；-OCOR¹；-(CHR¹)_oNR¹⁵R¹⁶；-COOR¹⁵；-CONR¹⁵R¹⁶；-SO₂R¹⁵(ii) a or-SO₂NR¹⁵R¹⁶；

R¹⁴Is H; CF (compact flash)₃；C_1-8-an alkyl group; c_2-8-an alkenyl group; a cycloalkyl group; a heterocycloalkyl group; cycloalkyl-C_1-6-an alkyl group; heterocycloalkyl-C_1-6-an alkyl group; an aryl group; a heteroaryl group; aryl-C_1-6-an alkyl group; heteroaryl-C_1-6-an alkyl group; cycloalkyl-aryl; heterocycloalkyl-aryl; cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl; aryl-heterocycloalkyl; heteroaryl-cycloalkyl; heteroaryl-heterocycloalkyl; - (CHR)¹)_oOR¹⁵；-(CHR¹)_oSR¹⁵；-(CHR¹)_oNR¹⁵R¹⁶；-(CHR¹)_oCOOR¹⁵；-(CHR¹)_oCONR¹⁵R¹⁶(ii) a Or- (CHR)¹)_oSO₂R¹⁵；

R¹⁵，R¹⁶，R¹⁷And R¹⁸Independently is H; c_1-8-an alkyl group; c_2-8-an alkenyl group; c_1-6-an alkoxy group; a cycloalkyl group; a heterocycloalkyl group; cycloalkyl-C_1-6-an alkyl group; heterocycloalkyl-C_1-6-an alkyl group; an aryl group; a heteroaryl group; aryl-C_1-6-an alkyl group; heteroaryl-C_1-6-an alkyl group; cycloalkyl-aryl; heterocycloalkyl-aryl; cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl; aryl-heterocycloalkyl; heteroaryl-cycloalkyl; or heteroaryl-heterocycloalkyl;

or structural element-NR¹⁵R¹⁶and-NR¹⁷R¹⁸Can independently form: a heterocycloalkyl group; aryl-heterocycloalkyl; or heteroaryl-heterocycloalkyl;

R¹⁹is an aryl radical of one of the formulae

Or a radical of one of the formulae

X, X 'and X' are independently CR²⁰(ii) a Or N;

R²⁰and R²¹Independently is H; f; cl; br; i; OH; NH (NH)₂；NO₂；CN；CF₃；OCHF₂；OCF₃；C_1-8-an alkyl group; c_2-8-an alkenyl group; an aryl group; a heteroaryl group; aryl-C_1-6-an alkyl group; heteroaryl-C_1-6-an alkyl group; - (CH)₂)_oR²²；-(CH₂)_oOR¹⁵；-O(CO)R¹⁵；-O(CH₂)_oR²²；-(CH₂)_oSR¹⁵；-(CH₂)_oNR¹⁵R¹⁶；-(CH₂)_oOCONR¹⁵R¹⁶；-(CH₂)_oNR¹CONR¹⁵R¹⁶；-(CH₂)_oNR¹COR¹⁵；-(CH₂)_oCOOR¹⁵；-(CH₂)_oCONR¹⁵R¹⁶；-(CH₂)_oPO(OR¹)₂；-(CH₂)_oSO₂R¹⁴(ii) a Or- (CH)₂)_oCOR¹⁵；

R²²Is an aryl radical of the formula

R²³，R²⁴And R²⁵Independently is H; f; cl; br; i; OH; NH (NH)₂；NO₂；CN；CF₃；OCHF₂；OCF₃；C_1-8-an alkyl group; c_2-8-an alkenyl group; - (CH)₂)_oOR¹⁵；-O(CO)R¹⁵；-(CH₂)_oNR¹R¹⁵；-(CH₂)_oCOOR¹⁵；-(CH₂)_oCONR¹R¹⁵；

R²⁶Is H; ac; c_1-8-an alkyl group; or aryl-C_1-6-an alkyl group;

R²⁷is-CO (CR)¹R¹³)_qR¹⁵；

n and m are independently integers from 0 to 5, provided that n + m.ltoreq.6;

o is 0 to 4; p is 2 to 6; q is 1 to 6; and r is 1 to 3;

or a pharmaceutically acceptable salt thereof;

and with the proviso that

If no interchain connection is formed;

and is

T¹Is of the formula AA1^D；AA2^D(ii) a Or AA3^DD α -amino acid residue of one of;

then

T²Is AA 7; AA 8; or AA10^aThe L α -amino acid residue of (1).

Each individual radical "R" having the same index x of 1 to 27^x"is independently selected at each occurrence in a particular formula, and thus they can be the same or different.

As used in this specification, the term "alkyl" alone or in combination (i.e., as a further group such as "aryl-C_1-6-alkyl ") designates a saturated, linear or branched hydrocarbon residue and may be optionally substituted. The term "C_x-y-alkyl "(x and y are each an integer) means an alkyl group as defined hereinbefore, containing from x to y carbon atoms. E.g. C_1-6Alkyl contains 1 to 6 carbon atoms. Representative examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.

The term "alkenyl", alone or in combination, designates a straight-chain or branched hydrocarbon residue containing at least one or up to four ethylenic double bonds depending on the chain length. The alkenyl moiety is optionally substituted and each double bond can independently exist as an E or Z configuration, all of which are part of the present invention. The term "C_x-y-alkenyl "(x and y are each an integer) means an alkenyl group as defined hereinbefore, containing from x to y carbon atoms.

The term "cycloalkyl", alone or in combination, refers to a saturated or partially unsaturated alicyclic moiety having from 3 to 10 carbon atoms and which may be optionally substituted. Examples of such moieties include, but are not limited to, cyclohexyl, norbornyl, decahydronaphthyl, and the like.

The term "heterocycloalkyl", alone or in combination, describes a saturated or partially unsaturated monocyclic or bicyclic moiety having from 3 to 9 ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen, or sulfur. The term includes, for example, morpholino, piperazino, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, octahydro-1H-indolyl, 1, 7-diazaspiro [4.4] nonanyl, and the like. The heterocycloalkyl ring may be optionally substituted.

The term "aryl" alone or in combination, designates an aromatic carbocyclic hydrocarbon residue containing one or two six-membered rings such as phenyl or naphthyl, which may be optionally substituted with up to three substituents such as Br, Cl, F, CF₃，OH，OCF₃，OCHF₂，NH₂，N(CH₃)₂，NO₂，CN，C_1-6-alkyl radical, C_2-6-alkenyl, phenyl or phenoxy.

The term "heteroaryl", alone or in combination, denotes an aromatic heterocyclic residue containing one or two five-and/or six-membered rings, at least one of which contains up to three heteroatoms selected from O, S and N, whereby the heteroaryl residue or a tautomeric form thereof may be attached via any suitable atom. The heteroaryl ring is optionally substituted, for example as indicated above for "aryl".

The term "aryl-C_x-y-alkyl "as used herein means C as defined hereinbefore_x-y-an alkyl group substituted by an aryl group as defined hereinbefore. aryl-C_x-yRepresentative examples of-alkyl moieties include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.

The term "heteroaryl-C_x-y-alkyl "as used herein means C as defined hereinbefore_x-y-alkyl, which is heteroaromatic as defined hereinbeforeAnd (4) substituting the group. heteroaryl-C_x-yExamples of-alkyl groups include pyridin-3-ylmethyl, (1H-pyrrol-2-yl) ethyl and the like.

The term "aryl-cycloalkyl", as used herein, refers to a cycloalkyl group, as defined hereinbefore, substituted by, or fused with, an aryl group, as defined hereinbefore. Examples of aryl-cycloalkyl moieties include, but are not limited to, phenylcyclopentyl, 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrahydronaphthyl, and the like.

The term "aryl-heterocycloalkyl", as used herein, refers to a heterocycloalkyl group, as defined above, substituted with or fused to an aryl group, as defined above. Examples of aryl-heterocycloalkyl moieties include, but are not limited to, indolinyl, 1,2,3, 4-tetrahydroquinolinyl, and the like.

The term "heteroaryl-cycloalkyl", as used herein, refers to a cycloalkyl group, as defined hereinbefore, substituted by or fused with a heteroaryl group, as defined hereinbefore. Examples of heteroaryl-cycloalkyl moieties include, but are not limited to, 5,6,7, 8-tetrahydroquinolinyl and the like.

The term "heteroaryl-heterocycloalkyl", as used herein, refers to a heterocycloalkyl group, as defined above, substituted with or fused to a heteroaryl group, as defined above. Examples of heteroaryl-heterocycloalkyl moieties include, but are not limited to, 4- (thiazol-2-yl) piperazinyl, 5,6,7, 8-tetrahydro-1, 6-naphthyridinyl, and the like.

The terms "cycloalkyl-aryl", "heterocycloalkyl-aryl", "cycloalkyl-heteroaryl", and "heterocycloalkyl-heteroaryl", as used herein, are defined similarly to the terms "aryl-cycloalkyl", "aryl-heterocycloalkyl", "heteroaryl-cycloalkyl" and "heteroaryl-heterocycloalkyl" as previously defined, but are attached in the opposite direction, e.g., the term refers to 2- (piperazin-1-yl) thiazolyl instead of 4- (thiazol-2-yl) piperazinyl, the rest being the same.

The terms "hydroxy", "alkoxy" and "aryloxy", alone or in combination, refer to-OH, -O-alkyl and-O-aryl, respectively, wherein alkyl or aryl is as defined above. The term "C_x-yAlkoxy (x and y are each an integer) means as beforean-O-alkyl group, as defined herein, containing from x to y carbon atoms attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. Examples of the aryloxy group include, for example, a phenoxy group. For the avoidance of doubt, for example the term "hydroxy-C_1-8Alkyl "represents in particular a group such as hydroxymethyl, 1-hydroxypropyl, 2-hydroxypropyl or 3-hydroxy-2, 3-dimethylbutyl.

The term "optionally substituted" is generally intended to mean a group, such as, but not limited to, C_x-y-alkyl radical, C_x-yAlkenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C_x-y-alkoxy and aryloxy groups may be substituted with one or more substituents independently selected from amino (-NH)₂) Dimethylamino, nitro (-NO)₂) Halogen (F, Cl, Br, I), CF₃Cyano (-CN), hydroxy, methoxy, ethoxy, phenyloxy, benzyloxy, acetoxy, oxo (═ O), carboxy, carboxamide, methyl, ethyl, phenyl, benzyl, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate.

In the context of the present invention, the term "natural or non-natural alpha-amino acid" generally comprises any natural alpha-amino acid such as proteinogenic amino acids (examples are listed below), natural or semisynthetic derivatives thereof as well as alpha-amino acids of entirely synthetic origin. The term also includes alpha-amino acids, which are optionally substituted at the alpha-nitrogen of the amino acid, such as but not limited to acetylation or alkylation, e.g., methylation, or benzylation.

The term "aliphatic α -amino acid" refers to an α -amino acid having an aliphatic side chain, such as, but not limited to, alanine, valine, leucine, isoleucine, n-octylglycine and the like.

The term "aromatic alpha-amino acid" refers to an alpha-amino acid having a side chain comprising an aromatic or heteroaromatic group, such as, but not limited to, phenylalanine, tryptophan, histidine, O-methyl-tyrosine, 4-trifluoromethyl-phenylalanine, 3, 4-dichloro-homophenylalanine, and the like.

The term "basic α -amino acid" refers to α -amino acids having a side chain comprising at least one amino group, such as, but not limited to, lysine, ornithine, and the like, and further substituted derivatives thereof. The aforementioned amino groups can be substituted with amidino groups to form alpha-amino acids such as, but not limited to, arginine, homoarginine, and the like, and further substituted derivatives thereof, or with diaminomethine groups.

The term "crosslinked alpha-amino acid" refers to an alpha-amino acid having a side chain comprising a functionality capable of being crosslinked to a second alpha-amino acid by a covalent bond, such as, but not limited to, cysteine, homocysteine, and the like.

The term "alcohol-containing α -amino acid" refers to an α -amino acid having a side chain comprising an alcohol or thiol group, i.e., a hydroxyl or sulfhydryl functional group, such as, but not limited to, serine, threonine, and the like.

For the avoidance of doubt, the term "single side chain" in the context of an α -amino acid refers to a structure in which the α -carbon of the amino acid is covalently linked to (in the chain) carbonyl (C ═ O) and nitrogen (N) groups and to one hydrogen (H) and one variable side chain, for example as defined hereinbefore. "Single side chain" may also include heterocyclic structures containing an alpha-amino atom, such as but not limited to proline, 2-pipecolic acid, and the like.

For the avoidance of doubt, the term "heteroatom" refers to any atom that is not carbon or hydrogen.

Descriptors L and D refer to the stereochemistry at the alpha-position of the alpha-amino acid, respectively, and are used in accordance with the Fischer-Rosanoff rule of IUPAC.

The peptidomimetics of the invention can also be diastereomers (e.g., epimers) of the compounds of formula (I) if the specific stereochemistry of the chiral center is not determined in the specification. These stereoisomers can be prepared by modifying the process described below, using the appropriate isomer (e.g. epimer/enantiomer) of the chiral starting material. Where stereochemistry is not indicated above, each individual epimer as well as mixtures of the two are part of the present invention.

Yet another embodiment of the invention may also include compounds that are equivalent to compounds of formula (I) except that one or more atoms are replaced with an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g., enrichment²H(D)、³H、¹¹C、¹⁴C、¹²⁷I, etc. These isotopic analogs and pharmaceutical salts and formulations thereof are considered to be useful agents in therapy and/or diagnosis, for example, but not limited to, fine-tuning the half-life time in vivo can result in optimized dosing regimens.

A further embodiment of the present invention relates to derivatives of the general formula (I), in particular

T¹Is D α -amino acid residue AA1^D；AA12^D；AA7^D；AA8^D；AA10^D(ii) a Or AA11^D；

T²Is an L α -amino acid residue of one of the formulae

AA 1; AA 7; AA 8; or AA10^a；

Or a pharmaceutically acceptable salt thereof.

Alternative embodiments of the present invention relate to derivatives of the general formula (I), among others

P¹Is an L α -amino acid residue of one of the formulae

AA 7; or AA 8;

P²is an L α -amino acid residue of one of the formulae

AA 8; or AA10

P⁵Is an L α -amino acid residue of the formula

AA 10; or AA 11;

P⁶is Gly, or the amino acid residue D or L α of the formula

AA10；

P⁹Is an L α -amino acid residue of one of the formulae

AA 7; AA 8; AA 10; or AA 11;

P¹¹is an L α -amino acid residue of one of the formulae

AA 7; AA 9; AA 10; or AA 11;

P¹²is an L α -amino acid residue of one of the formulae

AA 7; AA 8; AA 10; or AA 11;

P²and P¹¹Together and/or P⁴And P⁹Together can form the formula AA13 or AA13^DAn interchain linkage of one of the (amino acid) -structures;

or a pharmaceutically acceptable salt thereof.

In a further particular embodiment of the invention, the elements of the general formula (I) are defined as follows

T¹Is that^DPro；^DAzt; or^DTic；

T²Is Pro; pic; oic; tic; ala; abu; leu; ile; val; nva; NMeAla; NMeAbu; NMeLeu; NMeIle; NMeVal; tyr; phe; trp; dab; dap; orn; or Lys;

P¹is Ala; abu; leu; ile; val; nva; nle; cpa; cpg, respectively; phe; tyr; or Trp;

P²is Tyr; phe; trp; dab; dap; orn; lys; or Arg;

P³is Val; tBuGly; ala; leu; ile; val; nva; tyr; phe; or Trp;

P⁴is Ala; val; abu; leu; ile; nva; dab; dap; orn; lys; arg; asn; gln; thr; homotype Thr; ser; or Hse;

P⁵is Orn; dap; dab; lys; arg; thr; homotype Thr; ser; or Hse;

P⁶is Gly; dab;^DDab；Dap；^DDap；Orn；^DOrn；Lys；^Dlys; arg; or^DArg；

P⁷Is Dab; dap; orn; lys; or Arg;

P⁸is Trp; phe; tyr; phg; leu; ile; val; nva; abu; or Ala;

P⁹is Ala; abu; leu; ile; val; nva; tyr; phe; trp; dab; dap; orn; lys; arg; ser; thr; homotype Thr; or Hse;

P¹⁰is Val; tBuGly; ala; leu; ile; nva; abu; chg; phg; tyr; phe; or Trp;

P¹¹is Ala; val; abu; nva; leu; ile; ser; thr; homotype Thr; hse; asn; gln; asp; glu; dab; dap; orn; lys; or Arg;

P¹²is Val; ala; abu; nva; leu; ile; tyr; his; phe; trp; dab; dap; orn; lys; arg; ser; thr; homotype Thr; or Hse;

P²and P¹¹Together and/or P⁴And P⁹Together, can form an interchain linking di (amino acid) -structure based on the linkage of two L-or D-amino acid residues, which is performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfide linkage; or Dap, Dab, Orn, or Lys side chain is linked to an Asp, Glu, or hGlu side chain by a lactam linkage; or the Dap, Dab or Orn side chain is linked to the Dap, Dab or Orn side chain by a urea linkage;

or a pharmaceutically acceptable salt thereof;

provided that

If no interchain connection is formed;

and is

T¹Is that^DPro; or^DTic；

Then

T²Is Ala; abu; leu; ile; val; nva; NMeAla; NMeAbu; NMeLeu; NMeIle; NMeVal; tyr; phe; trp; dab; dap; orn; or Lys.

In a further particular embodiment of the invention, the elements of the formula (I) are defined as follows

T¹Is that^DPro; or^DAzt；

T²Is Pro; ala; leu; NMeAla; tyr; phe; dab; dap; orn; or Lys;

P¹is Leu; ile; val; cpa; cpg, respectively; phe; or Trp;

P²is Tyr; dab; dap; or Lys;

P³is Val; tBuGly; or Tyr;

P⁴is Ala; val; dab; arg; asn; or Thr;

P⁵is Orn; dap; dab; or Thr;

P⁶is Gly; dab; or^DDab；

P⁷Is Dab;

P⁸is Trp; phe; or Leu;

P⁹is Ala; tyr; dab; dap; ser; or Thr;

P¹⁰is Val; tBuGly; chg; phg; or Tyr;

P¹¹is Ala; val; ser; thr; asp; glu; dap; dab; or Lys;

P¹²is Val; tyr; his; dab; ser; or Thr;

P²and P¹¹Together and/or P⁴And P⁹Together capable of forming a chain based on the linkage of two L-or D-amino acid residuesInter-linked di (amino acid) -structures, the linkage being performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfide linkage; or the Dap, Dab or Lys side chain is linked to the Asp or Glu side chain by a lactam linkage; or the Dap or Dab side chain is linked to the Dap or Dab side chain by a urea linkage;

or a pharmaceutically acceptable salt thereof;

provided that

If no interchain connection is formed;

and is

T¹Is that^DPro；

Then

T²Is Ala; leu; NMeAla; tyr; phe; dab; dap; orn; or Lys.

T¹Is that^DPro; or^DAzt；

T²Is Pro; leu; NMeAla; tyr; phe; dab; dap; orn; or Lys;

P¹is Leu; ile; val; phe; or Trp;

P²is Dab; dap; or Lys;

P³is Tyr;

P⁴is Ala; dab; or Arg;

P⁵is Orn; dap; dab; or Thr;

P⁶is Dab; or^DDab；

P⁷Is Dab;

P⁸is Trp; or Leu;

P⁹is Ala; or Dab;

P¹⁰is Val; tBuGly; or Phg;

P¹¹is Ala; ser; asp; glu; dap; dab, or Lys;

P¹²is Val; tyr; his; ser; or Thr;

P²and P¹¹Together and/or P⁴And P⁹Together, can form an interchain linking di (amino acid) -structure based on the linkage of two L-or D-amino acid residues, which is performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfide linkage; or the Dap, Dab or Lys side chain is linked to the Asp or Glu side chain by a lactam linkage; or the Dap side chain is connected with the Dap side chain through urea connection;

or a pharmaceutically acceptable salt thereof;

provided that

If no interchain connection is formed;

and is

T¹Is that^DPro；

Then

T²Is Leu; NMeAla; tyr; phe; dab; dap; orn; or Lys.

In yet another particular embodiment of the invention, the elements of formula (I) are defined as follows

T¹Is that^DPro；^DAzt; or^DTic；

P²is Tyr; phe; trp; dab; dap; orn; lys; or Arg;

P³is Val; tBuGly; ala; leu; ile; val; nva; tyr; phe; or Trp;

P⁵is Orn; dap; dab; lys; arg; thr; homotype Thr; ser; or Hse;

P⁷Is Dab; dap; orn; lys; or Arg;

P⁸is Trp; phe; tyr; phg; leu; ile; val; nva; abu; or Ala;

P¹⁰is Val; tBuGly; ala; leu; ile; nva; abu; chg; phg; tyr; phe; or Trp;

P²and P¹¹Together and/or P⁴And P⁹Together form an interchain linking di (amino acid) -structure based on the linkage of two L-or D-amino acid residues, said linkage being performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfide linkage; or Dap, Dab, Orn, or Lys side chain is linked to an Asp, Glu, or hGlu side chain by a lactam linkage; or Dap, Dab or Orn side chains with Dap, Dab orThe Orn side chains are connected by urea linkages;

or a pharmaceutically acceptable salt thereof.

T¹Is that^DPro; or^DAzt；

T²Is Pro; ala; leu; NMeAla; tyr; phe; dab; dap; orn; or Lys;

P¹is Leu; ile; val; cpa; cpg, respectively; phe; or Trp;

P²is Tyr; dab; dap; or Lys;

P³is Val; tBuGly; or Tyr;

P⁴is Ala; val; dab; arg; asn; or Thr;

P⁵is Orn; dap; dab; or Thr;

P⁶is Gly; dab; or^DDab；

P⁷Is Dab;

P⁸is Trp; phe; or Leu;

P⁹is Ala; tyr; dab; dap; ser; or Thr;

P¹⁰is Val; tBuGly; chg; phg; or Tyr;

P¹¹is Ala; val; ser; thr; asp; glu; dap; dab; or Lys;

P¹²is Val; tyr; his; dab; ser; or Thr;

P²and P¹¹Together and/or P⁴And P⁹Together form an interchain linking di (amino acid) -structure based on the linkage of two L-or D-amino acid residues, said linkage being performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfideConnecting; or the Dap, Dab or Lys side chain is linked to the Asp or Glu side chain by a lactam linkage; or the Dap or Dab side chain is linked to the Dap or Dab side chain by a urea linkage;

or a pharmaceutically acceptable salt thereof.

T¹Is that^DPro; or^DAzt；

T²Is Pro; NMeAla; tyr; dab; dap; orn; or Lys;

P¹is Leu; ile; val; phe; or Trp;

P²is Dab; dap; or Lys;

P³is Tyr;

P⁴is Ala; dab; or Arg;

P⁵is Orn; dap; dab; or Thr;

P⁶is Dab; or^DDab；

P⁷Is Dab;

P⁸is Trp; or Leu;

P⁹is Ala; or Dab;

P¹⁰is Val; tBuGly; or Phg;

P¹¹is Ala; ser; asp; glu; dap; dab, or Lys;

P¹²is Val; tyr; his; ser; or Thr;

P²and P¹¹Together and/or P⁴And P⁹Together form an interchain linking di (amino acid) -structure based on the linkage of two L-or D-amino acid residues, which is performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfide linkage; or Dap, Dab or Lys sideThe chain is connected with the Asp or Glu side chain through lactam connection; or the Dap side chain is connected with the Dap side chain through urea connection;

or a pharmaceutically acceptable salt thereof.

T¹Is that^DPro；^DAzt; or^DTic；

P²is Tyr; phe; trp; dab; dap; orn; lys; or Arg;

P³is Val; tBuGly; ala; leu; ile; val; nva; tyr; phe; or Trp;

P⁵is Orn; dap; dab; lys; arg; thr; homotype Thr; ser; or Hse;

P⁷Is Dab; dap; orn; lys; or Arg;

P⁸is Trp; phe; tyr; phg; leu; ile; val; nva; abu; or Ala;

P¹⁰is Val; tBuGly; ala; leu; ile; nva; abu; chg; phg; tyr; phe; or Trp;

or a pharmaceutically acceptable salt thereof;

provided that

If T is¹Is that^DPro; or^DTic；

Then

T¹Is that^DPro; or^DAzt；

T²Is Pro; ala; leu; NMeAla; tyr; phe; dab; dap; orn; or Lys;

P¹is Leu; ile; val; nle; phe; or Trp;

P²is Tyr; dab; dap; or Lys;

P³is Val; tBuGly; or Tyr;

P⁴is Ala; val; dab; arg; asn; or Thr;

P⁵is Orn; dap; dab; or Thr;

P⁶is Gly; dab; or^DDab；

P⁷Is Dab;

P⁸is Trp; phe; or Leu;

P⁹is Ala; tyr; dab; dap; ser; or Thr;

P¹⁰is Val; tBuGly; chg; phg; or Tyr;

P¹¹is Ala; val; ser; thr; asp; glu; dap; dab; or Lys;

P¹²is Val; tyr; his; dab; ser; or Thr;

or a pharmaceutically acceptable salt thereof;

provided that

If T is¹Is that^DPro；

Then

T²Is Ala; leu; NMeAla; tyr; phe; dab; dap; orn; or Lys.

T¹Is that^DPro; or^DAzt；

T²Is Pro; leu; tyr; or Phe;

P¹is Val; or Phe;

P²is Dap;

P³is Tyr;

P⁴is Dab;

P⁵is Orn; or Dap;

P⁶is that^DDab；

P⁷Is Dab;

P⁸is Trp；

P⁹Is Dab;

P¹⁰is tBuGly;

P¹¹is Ala; or Ser;

P¹²is Ser; or Thr;

or a pharmaceutically acceptable salt thereof;

provided that

If T is¹Is that^DPro；

Then

T²Is Leu; tyr; or Phe.

T¹Is that^DPro；^DAzt; or^DTic；

T²Is Dab; dap; orn; or Lys;

P²is Tyr; phe; or Trp;

P³is Val; tBuGly; ala; leu; ile; val; nva; tyr; phe; or Trp;

P⁴is Ala; val; abu; leu; ile; nva; asn; gln; thr; homotype Thr; ser; or Hse;

P⁵is Orn; dap; dab; lys; or Arg;

P⁶is Dab;^DDab；Dap；^DDap；Orn；^DOrn；Lys；^Dlys; arg; or^DArg；

P⁷Is Dab; dap; orn; lys; or Arg;

P⁸is Trp; phe; tyr; phg; leu; ile; val; nva; abu; or Ala;

P⁹is Ala; abu; leu; ile; val; nva; tyr; phe; trp; ser; thr; homotype Thr; or Hse;

P¹⁰is Val; tBuGly; ala; leu; ile; nva; abu; chg; phg; tyr; phe; or Trp;

P¹¹is Ala; val; abu; nva; leu; ile; ser; thr; homotype Thr; hse; asn; gln; asp; or Glu;

P¹²is Val; ala; abu; nva; leu; ile; tyr; his; phe; trp; ser; thr; homotype Thr; or Hse;

P²and P¹¹Together and/or P⁴And P⁹Together form an interchain linking di (amino acid) -structure based on the linkage of two L-or D-amino acid residues, which is performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfide linkage; or Dap, Dab, Orn, or Lys side chain is linked to an Asp, Glu, or hGlu side chain by a lactam linkage; or the Dap, Dab or Orn side chain is linked to the Dap, Dab or Orn side chain by a urea linkage;

or a pharmaceutically acceptable salt thereof.

T¹Is that^DPro; or^DAzt；

T²Is Dab; dap; orn; or Lys;

P¹is Leu; ile; val; cpa; cpg, respectively; phe; or Trp;

P²is Tyr;

P³is Val; tBuGly; or Tyr;

P⁴is Ala; val; asn; or Thr;

P⁵is Orn; dap; or Dab;

P⁶is Dab; or^DDab；

P⁷Is Dab;

P⁸is Trp; phe; or Leu;

P⁹is Ala; tyr; ser; or Thr;

P¹⁰is Val; tBuGly; chg; phg; or Tyr;

P¹¹is Ala; val; ser; thr; asp; or Glu;

P¹²is Val; tyr; his; ser; or Thr;

P²and P¹¹Together and/or P⁴And P⁹Together form an interchain linking di (amino acid) -structure based on the linkage of two L-or D-amino acid residues, which is performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfide linkage; or the Dap, Dab or Lys side chain is linked to the Asp or Glu side chain by a lactam linkage; or the Dap or Dab side chain is linked to the Dap or Dab side chain by a urea linkage;

or a pharmaceutically acceptable salt thereof.

T¹Is that^DPro；

T²Is Dab; dap; orn; or Lys;

P¹is Leu;

P³is Tyr;

P⁴is Ala;

P⁵is Orn; or Dab;

P⁶is Dab; or^DDab；

P⁷Is Dab;

P⁸is Trp;

P⁹is Ala;

P¹⁰is Val;

P¹²is Val;

P²and P¹¹Together form an interchain linking di (amino acid) -structure based on the linkage of two L-or D-amino acid residues, which is performed as follows: the Cys side chain is connected with the Cys side chain through disulfide linkage;

or a pharmaceutically acceptable salt thereof.

The following provides a list of abbreviations corresponding to commonly employed amino acid abbreviations, the amino acids or residues of amino acids being suitable for the purposes of the present invention.

Although these amino acids are specifically indicated, it is still clear to the skilled person that derivatives of these amino acids have similar structural and physicochemical properties, thus having functional analogues of similar biological activity and thus still forming part of the gist of the present invention.

Ala L-alanine

Arg L-arginine

Asn L-asparagine

Asp L-aspartic acid

Cit L-citrulline

Cys L-cysteine

Gln L-Glutamine

Glu L-glutamic acid

Gly glycine

His L-histidine

Ile L-isoleucine

Leu L-leucine

Lys L-lysine

Met L-methionine

Orn L-Ornithine

Phe L-phenylalanine

Pro L-proline

Ser L-serine

Thr L-threonine

Trp L-Tryptophan

Tyr L-tyrosine

Val L-valine

Abu (S) -2-aminobutyric acid

Agp (S) -2-amino-3-guanidinopropionic acid

Ala (tBu) (S) -2-amino-4, 4-dimethylpentanoic acid

Ala (4 butoxy PhUr) (S) -2-amino-3- (3- (4-butoxyphenyl) ureido) propionic acid

Ala (cHex) (S) -2-amino-3-cyclohexylpropionic acid

Ala (cPr) (S) -2-amino-3-cyclopropylpropionic acid

Ala (iPrUr) (S) -2-amino-3- (3-isopropylureido) propionic acid

Ala (2ClPhUr) (S) -2-amino-3- (3- (2-chlorophenyl) ureido) propanoic acid

Ala (4ClPhUr) (S) -2-amino-3- (3- (4-chlorophenyl) ureido) propanoic acid

Ala (2 furyl) (S) -2-amino-3- (furan-2-yl) propionic acid

Ala (3 furyl) (S) -2-amino-3- (furan-3-yl) propionic acid

Ala (1Im) (S) -2-amino-3- (1H-imidazol-1-yl) propionic acid

Ala (2Im) (S) -2-amino-3- (1H-imidazol-2-yl) propionic acid

Ala (Ppz) (S) -2-amino-3- (piperazin-1-yl) propionic acid

Ala (cPr) (S) -2-amino-3-cyclopropylpropionic acid

Ala (pyrazinyl) (S) -2-amino-3- (pyrazin-2-yl) propionic acid

Ala (1 pyrazolyl) (S) -2-amino-3- (1H-pyrazol-1-yl) propionic acid

Ala (3 pyrazolyl) (S) -2-amino-3- (1H-pyrazol-3-yl) propionic acid

Ala (2Pyrimidin) (S) -2-amino-3- (Pyrimidin-2-yl) propionic acid

Ala (4Pyrimidin) (S) -2-amino-3- (Pyrimidin-4-yl) propionic acid

Ala (5Pyrimidin) (S) -2-amino-3- (Pyrimidin-5-yl) propionic acid

Ala (3PyrMeUr) (S) -2-amino-3- (3- (pyridin-3-ylmethyl) ureido) propionic acid

Ala (2Quin) (S) -2-amino-3- (quinolin-2-yl) propionic acid

Ala (3Quin) (S) -2-amino-3- (quinolin-3-yl) propionic acid

Ala (4Quin) (S) -2-amino-3- (quinolin-4-yl) propionic acid

Alb(s) -2-amino-3-ureidopropionic acid

tBuGly (S) -2-amino-3, 3-dimethylbutyric acid

Bbta (S) -2-amino-3- (1-benzothien-3-yl) propionic acid

Bip (S) -2-amino-3- (4-biphenylyl) propionic acid

Cha (S) -2-amino-3-cyclohexylpropionic acid

Chg (S) -2-amino-2-cyclohexylacetic acid

Cpa (S) -2-amino-3-cyclopentylpropionic acid

Cpg (S) -2-amino-2-cyclopentylacetic acid

Dab (S) -2, 4-diaminobutyric acid

Dab (Ac) (S) -4-acetylamino-2-aminobutyric acid

Dab (cPr) (S) -2-amino-4- (cyclopropylamino) butanoic acid

Dab (iPr) (S) -2-amino-4- (isopropylamino) butanoic acid

Dab (2PyrMe) (S) -2-amino-4- (pyridin-2-ylmethylamino) butyric acid

Dap (S) -2, 3-diaminopropionic acid

Dap (Ac) (S) -3-acetylamino-2-aminopropionic acid

Dap (AcThr) (S) -3- ((2S,3R) -2-acetylamino-3-hydroxybutanamido) -2-aminopropionic acid

Dap (cPr) (S) -2-amino-3- (cyclopropylamino) propionic acid

Dap (iPr) (S) -2-amino-3- (isopropylamino) propionic acid

Dap(MeSO₂) (S) -2-amino-3- (methylsulfonylamino) propionic acid

Dap (2,3-OH propionyl) (2S) -2-amino-3- (2, 3-dihydroxypropionamido) propionic acid

Dap (Thr) (S) -2-amino-3- ((2S,3R) -2-amino-3-hydroxybutanamido) -propionic acid

Gly (cPr) (S) -2-amino-2-cyclopropylacetic acid

hAla (1Im) (S) -2-amino-3- (1H-imidazol-1-yl) -butyric acid

hAla (2Im) (S) -2-amino-3- (1H-imidazol-2-yl) -butyric acid

hArg (S) -2-amino-6-guanidinohexanoic acid

hCha (S) -2-amino-4-cyclohexylbutyric acid

hCys, hCy (S) -2-amino-4-mercaptobutanoic acid

hHis (S) -2-amino-4- (1H-imidazol-5-yl) butanoic acid

hLeu (S) -2-amino-5-methylhexanoic acid

hLys (S) -2, 7-diaminoheptanoic acid

h2Pal (S) -2-amino-4- (pyridin-2-yl) -butyric acid

h3Pal (S) -2-amino-4- (pyridin-3-yl) -butyric acid

h4Pal (S) -2-amino-4- (pyridin-4-yl) -butyric acid

hSer, Hse (S) -2-amino-4-hydroxybutyric acid

hTRp (S) -2-amino-4- (1H-indol-3-yl) butanoic acid

hTyr (S) -2-amino-4- (4-hydroxyphenyl) butanoic acid

His (Me) -2-amino-3- (1-methyl-1H-imidazol-5-yl) propionic acid

His (Bn) (S) -2-amino-3- (1-benzyl-1H-imidazol-5-yl) propionic acid

Lys (Bz) (S) -2-amino-6-benzoylaminocaproic acid

Lys (Me) -2-amino-6- (methylamino) hexanoic acid

Lys (Nic) (S) -2-amino-6- (nicotinamido) hexanoic acid

Met(O₂) (S) -2-amino-4- (methylsulfonyl) butanoic acid

1Nal (S) -2-amino-3-naphthalen-1-ylpropionic acid

2Nal (S) -2-amino-3-naphthalen-2-ylpropionic acid

Nle (S) -2-amino-hexanoic acid

Nle (6OBn) (S) -2-amino-6- (benzyloxy) hexanoic acid

NMeGly N-methyl glycine

NMeAla L-N-methylalanine

NMeAbu N-methyl- (S) -2-aminobutyric acid

NMeVal L-N-methylvaline

NMeLeu L-N-methylleucine

NMeIle L-N-methylisoleucine

Nva (S) -2-aminopentanoic acid

Octg (S) -2-aminodecanoic acid

Oic (2S,3aS,7aS) -octahydro-1H-indole-2-carboxylic acid

Orn (Ac) (S) -5-acetylamino-2-aminopentanoic acid

Orn (cPr) (S) -2-amino-5- (cyclopropylamino) pentanoic acid

Orn (iPr) (S) -2-amino-5- (isopropylamino) pentanoic acid

2Pal (S) -2-amino-3- (pyridin-2-yl) propionic acid

3Pal (S) -2-amino-3- (pyridin-3-yl) propionic acid

4Pal (S) -2-amino-3- (pyridin-4-yl) propionic acid

Phe (2Cl) (S) -2-amino-3- (2-chlorophenyl) propionic acid

Phe (3Cl) (S) -2-amino-3- (3-chlorophenyl) propionic acid

Phe (4Cl) (S) -2-amino-3- (4-chlorophenyl) propionic acid

Phe(3,4Cl₂) (S) -2-amino-3- (3, 4-dichlorophenyl) propionic acid

Phe (2F) (S) -2-amino-3- (2-fluorophenyl) propionic acid

Phe (3F) (S) -2-amino-3- (3-fluorophenyl) propionic acid

Phe (4F) (S) -2-amino-3- (4-fluorophenyl) propionic acid

Phe(3,4F₂) (S) -2-amino-3- (3, 4-difluorophenyl) propionic acid

Phe (3CN) (S) -2-amino-3- (3-cyanophenyl) propionic acid

Phe (4CN) (S) -2-amino-3- (4-cyanophenyl) propionic acid

Phe(2CF₃) (S) -2-amino-3- (2- (trifluoromethyl) phenyl) propanoic acid

Phe(3CF₃) (S) -2-amino-3- (3- (trifluoromethyl) phenyl) propionic acid

Phe(4CF₃) (S) -2-amino-3- (4- (trifluoromethyl) phenyl) propanoic acid

Phe(3,4(CF₃)₂) (S) -2-amino-3- (3, 4-bis (trifluoromethyl) phenyl) propanoic acid

Phe (4COOMe) (S) -2-amino-3- (4- (methoxycarbonyl) phenyl) propionic acid

Phe(4NH₂) (S) -2-amino-3- (4-aminophenyl) propionic acid

Phe (3OH) (S) -2-amino-3- (3-hydroxyphenyl) propionic acid

Phg (S) -2-amino-2-phenylacetic acid

Pic (S) -piperidine-2-carboxylic acid

Pip 4-aminopiperidine-4-carboxylic acid

Pro((4R)NH₂) (2S,4R) -4-Aminopyrrolidine-2-carboxylic acid

Pro((4S)NH₂) (2S,4S) -4-Aminopyrrolidine-2-carboxylic acid

Pro ((3R) OH) (2S,3R) -3-hydroxypyrrolidine-2-carboxylic acid

Pro ((3S) OH) (2S,3S) -3-hydroxypyrrolidine-2-carboxylic acid

Pro ((4R) OH) (2S,4R) -4-hydroxypyrrolidine-2-carboxylic acid

Pro ((4S) OH) (2S,4S) -4-hydroxypyrrolidine-2-carboxylic acid

Pro ((4R) OBn) (2S,4R) -4- (benzyloxy) pyrrolidine-2-carboxylic acid

Pro ((4S) OBn) (2S,4S) -4- (benzyloxy) pyrrolidine-2-carboxylic acid

Sar; NMeGly N-methyl glycine

Ser (Bn) (S) -2-amino-3- (benzyloxy) propionic acid

Ser (Me) (S) -2-amino-3-methoxy-propionic acid

Thi (S) -2-amino-3- (thien-2-yl) propionic acid

Homotype Thr (2S,3S) -2-amino-3-hydroxybutyric acid

Thr (Bn) (2S,3R) -2-amino-3- (benzyloxy) butyric acid

Thr (Me) (2S,3R) -2-amino-3- (methyloxy) butanoic acid

Thz (R) -thiazolidine-4-carboxylic acid

Thz(5,5Me₂) (R) -2, 2-dimethylthiazolidine-4-carboxylic acid

Tic (S) -1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid

Tic (7OH) (S) -7-hydroxy-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid

Trp (7Aza) (S) -2-amino-3- (1H-pyrrolo [2,3-b ] pyridin-3-yl) propionic acid

Trp (5Br) (S) -2-amino-3- (5-bromo-1H-indol-3-yl) propionic acid

Trp (6Br) (S) -2-amino-3- (6-bromo-1H-indol-3-yl) propionic acid

Trp(6CF₃) (S) -2-amino-3- (6- (trifluoromethyl) -1H-indol-3-yl) propionic acid

Trp (5Cl) (S) -2-amino-3- (5-chloro-1H-indol-3-yl) propionic acid

Trp (6Cl) (S) -2-amino-3- (6-chloro-1H-indol-3-yl) propionic acid

Trp (5,6Cl) (S) -2-amino-3- (5, 6-dichloro-1H-indol-3-yl) propionic acid

Trp (5OH) (S) -2-amino-3- (5-hydroxy-1H-indol-3-yl) propionic acid

Tyr (Bn) (S) -2-amino-3- (4- (benzyloxy) phenyl) propionic acid

Tyr (Me) -2-amino-3- (4-methoxyphenyl) propionic acid

Tyr (Ph) (S) -2-amino-3- (4-phenoxyphenyl) propionic acid

Tyr (4OHPh) (S) -2-amino-3- [4- (4-hydroxyphenoxy) phenyl ] propanoic acid

Tyr (3F) (S) -2-amino-3- (3-fluoro-4-hydroxyphenyl) propionic acid

Tza (S) -2-amino-3- (thiazol-4-yl) propionic acid

Abbreviations for the D-isomers, examplesSuch as^DLys corresponds to the 2-position epimer of the appropriate amino acid described above. The same applies to the general description of amino acids, e.g. with AA1^DAA1 as the corresponding α -epimer.

In a preferred embodiment of the invention, the β -hairpin peptidomimetics are selected from the group of β -hairpin peptidomimetics of the general formula (I) which are present at P²And P¹¹With disulfide, lactam or urea linkages therebetween:

cyclo (-Leu-Cys-Tyr-Ala-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dab-)；

Cyclo (-Leu-Cys-Tyr-Ala-Dab-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dab-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Lys-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Orn-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dab-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dap-)；

Cyclo (-Ile-Cys-Tyr-Dab-Orn-^DDab-Dab-Leu-Dab-Val-Cys-Tyr-^DPro-Pro-)；

Cyclo (-Val-Cys-Tyr-Dab-Dap-Dab-Trp-Dab-tBuGly-Cys-Thr-^DPro-Pro-)；

Cyclo (-Val-Cys-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-Cys-Ser-^DPro-NMeAla-)；

Cyclo (-Ile-Cys-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Cys-Ser-^DPro-Pro-)；

Cyclo (-Ile-Cys-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Cys-Ser-^DPro-Tyr-)；

Cyclo (-Val-Dab-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-Asp-Thr-^DAzt-Pro-)；

Cyclo (-Phe-Dab-Tyr-Arg-Orn-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Trp-Dab-Tyr-Dab-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Trp-Dab-Tyr-Dab-Trp-Dab-tBuGly-Asp-Ser-^DAzt-Pro-)；

Cyclo (-Val-Dab-Tyr-Dab-^DDab-Dab-Trp-Dab-Phg-Asp-Ser-^DPro-Pro-)；

Cyclo (-Val-Dab-Tyr-Dab-Thr-Dab-Trp-Dab-tBuGly-Asp-His-^DPro-Pro-)；

Cyclo (-Leu-Glu-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Dap-Ser-^DPro-Pro-)；

Cyclo (-Leu-Glu-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Dab-Ser-^DPro-Pro-)；

Cyclo (-Leu-Glu-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Lys-Ser-^DPro-Pro-)；

Cyclo (-Leu-Asp-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Dap-Ser-^DPro-Pro-)；

Cyclo (-Leu-Asp-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Dab-Ser-^DPro-Pro-)；

Cyclo (-Leu-Asp-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Dab-Ser-^DPro-Pro-)；

Cyclo (-Leu-Asp-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Lys-Ser-^DPro-Pro-)；

Cyclo (-Leu-Asp-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Lys-Ser-)^DPro-Pro-)；

Cyclo (-Leu-Dap-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Glu-Ser-^DPro-Pro-)；

Cyclo (-Leu-Lys-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Glu-Ser-^DPro-Pro-)；

Cyclo (-Val-Dab-Tyr-Dab-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dap-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Glu-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dab-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Glu-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dap-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dab-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Lys-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Glu-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Dap-Ser-^DPro-Pro-)；

Cyclo (-Leu-Lys-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dap-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dab-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Val-^DCys-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-^DCys-Ser-^DPro-Pro-)；

Cyclo (-Val-Hcy-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-Cys-Ser-^DPro-Pro-)；

Cyclo (-Val-Dap-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-Dap-Ser-^DPro-Pro-)；

Or a pharmaceutically acceptable salt thereof;

and/or

Beta-hairpin peptidomimetics selected from the general formula (I)

Cyclo (-Val-Dap-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-Ser-Thr-^DAzt-Pro-)；

Cyclo (-Phe-Dap-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Ala-Ser-^DPro-Leu-)；

Cyclo (-Phe-Dap-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Ala-Ser-^DPro-Phe-)；

Cyclo (-Phe-Dap-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Ala-Ser-^DPro-Tyr-)；

Or a pharmaceutically acceptable salt thereof.

In a further preferred embodiment of the invention, in P²And P¹¹β -hairpin peptidomimetics of the general formula (I) having disulfide linkages therebetween are selected from:

cyclo (-Leu-Cys-Tyr-Ala-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dab-)；

Cyclo (-Leu-Cys-Tyr-Ala-Dab-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dab-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Lys-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Orn-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dab-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dap-)；

Or a pharmaceutically acceptable salt thereof.

According to the invention, these β -hairpin peptidomimetics can be prepared by a process comprising the following steps:

a) coupling a suitably functionalized solid support with a suitably N-protected derivative of an amino acid located at position T as defined above in the desired end product¹Or T²Or P¹To P¹²(ii) a Any functional groups that may be present in the N-protected amino acid derivative are similarly suitably protected;

(b) removing the N-protecting group from the product obtained in step (a);

(c) coupling the product thus obtained with a suitably N-protected derivative of an amino acid located in the desired end product at the position of the next element (T or P) following-COOH to-NH according to formula (I)₂A counterclockwise or clockwise sequence of orientations; any functional groups that may be present in the N-protected amino acid derivative are similarly suitably protected;

(d) removing the N-protecting group from the product thus obtained;

(e) repeating steps (c) and (d) until all amino acid residues have been introduced;

(f) selectively deprotecting one or several protected functional groups present in the molecule, if desired, and chemically converting the reactive groups thus liberated;

(g) removing the product thus obtained from the solid support;

(h) cyclizing the product cleaved from the solid support;

(i) selectively deprotecting one or several protected functional groups present in the molecule, if desired, and chemically converting the reactive groups thus liberated;

(j) removing any protecting groups present on the functional groups of any members of the chain of amino acid residues, and any protecting groups that may be additionally present in the molecule, if desired;

(k) if desired, performing additional chemical transformations on one or more reactive groups present in the molecule; and

(l) If desired, removing any protecting groups present on the functional groups of any members of the chain of amino acid residues, and if desired, any protecting groups that may be additionally present in the molecule; and is

(m) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable or unacceptable salt thus obtained into the corresponding free compound of formula (I) or into a different pharmaceutically acceptable salt.

Enantiomers of the compounds defined hereinbefore also form part of the invention. These enantiomers can be prepared as follows: the above process is modified in that the enantiomers of all chiral starting materials are used.

The methods of the invention can advantageously be performed as parallel array synthesis, resulting in a library of β -hairpin peptidomimetics of the invention. The parallel synthesis allows one to obtain a series of multiple (typically 12 to 576, typically 96) compounds described previously, in moderate to high yields, with defined purity, minimizing the formation of dimer and polymer by-products. Thus, the proper choice of functionalized solid support (i.e., solid support and linker molecule), the site of cyclization, plays a key role.

The functionalized solid support is conveniently derived from polystyrene crosslinked with preferably 1-5% divinylbenzene; polystyrene coated with polyethylene glycol spacers (Tentagel)^TM) (ii) a And polyacrylamide resins (see also D.Obrecht, J. -M.Villalgord, "Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compounds", Tetrahedron Organic Chemistry Series, Vol.17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by a linker, which is a bifunctional spacer molecule containing at one end an immobilization group for attachment to the solid support and at the other end a selectively cleavable functional group for subsequent chemical transformation and cleavage procedures. For the purposes of the present invention, 2 types of linkers were used:

type 1 linkers are designed to release the amide group under acidic conditions (H.rink, tetrahedron Lett.1987,28, 3783-. This type of linker forms an amide of the amino acid carboxyl group; examples of resins functionalized by the linker structure include 4- [ ((((2, 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) aminomethyl ] PS resin, 4- [ (((2, 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) aminomethyl ] -4-methylbenzhydrylamine PS resin (Rink amide MBHA PS resin), and 4- [ ((((2, 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) aminomethyl ] benzhydrylamine PS-resin (Rink amide BHA PS resin). Preferably, the support is derived from polystyrene cross-linked with most preferably 1-5% divinylbenzene, and functionalized by a 4- (((2, 4-dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetamido) linker.

The type 2 linker is designed to eventually release the carboxyl group under acidic conditions. This type of linker forms an ester of the acid labile amino acid carboxyl group, typically the acid labile benzyl, benzhydryl and trityl esters; examples of such linker structures include 2-methoxy-4-hydroxymethylphenoxy (Sasrin)^TMLinker), 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy (Rink linker), 4- (4-hydroxymethyl-3-methoxyphenoxy) butanoic acid (HMPB linker), trityl and 2-chlorotrityl. Preferably, the support is derived from polystyrene cross-linked with most preferably 1-5% divinylbenzene and functionalized by a 2-chlorotrityl linker.

In the case of parallel array synthesis, the method of the invention can advantageously be carried out as described below, but it will be readily apparent to the skilled person how to adjust these procedures in the case where it is desired to synthesize a single compound of the invention.

A number of reaction vessels equal to the total number of compounds synthesized by the parallel method (typically 12 to 576, typically 96) are loaded with 25 to 1000mg, preferably 60mg of a suitably functionalized solid support, preferably 1 to 5% cross-linked polystyrene or Tentagel resin.

The solvent used must be capable of swelling the resin and includes, but is not limited to, Dichloromethane (DCM), Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene, Tetrahydrofuran (THF), ethanol (EtOH), Trifluoroethanol (TFE), isopropyl alcohol, and the like. Solvent mixtures containing at least one component polar solvent (e.g., 20% TFE/DCM, 35% THF/NMP) are useful for ensuring high reactivity and solvation of resin-bound peptide chains (G.B. fields, C.G. fields, J.Am.chem.Soc.1991, 113, 4202. sub.4207).

With the development of various linkers that release a C-terminal carboxylic acid group under mildly acidic conditions without affecting the acid labile groups protecting the functional groups in the side chains, the synthesis of protected peptide fragments has advanced significantly. 2-methoxy-4-hydroxybenzyl alcohol-derived linker (Sasrin)^TMlinker, Mergler et al, Tetrahedron Lett.1988,294005-4008) can be cleaved with dilute trifluoroacetic acid (0.5-1% TFA in DCM) and is stable to Fmoc deprotection conditions during peptide synthesis, and additional protecting groups of the Boc/tBu-type are also suitable for this protection scheme. Other linkers suitable for the method of the invention include 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy-linker which is very labile to superacids (Rink linker, H.rink, Tetrahedron Lett.1987,28, 3787-; 4- (4-hydroxymethyl-3-methoxyphenoxy) butanoic acid-derived linker (HMPB-linker,&riniker,1991, Peptides 1990: Proceedings of the Twenty-First European Peptide Symposium,131) which was also cleaved with 1% TFA/DCM to yield Peptide fragments containing all acid labile side chain protecting groups; and, 2-chlorotrityl chloride linker (Barlos et al, T)etrahydron lett.1989,30, 3943-: 2: 7) the mixture was subjected to peptide stripping for 30 minutes.

Suitable protecting groups for amino acids and their respective residues are for example,

for amino groups (e.g. also including lysine side chain amino groups)

Cbz benzyloxycarbonyl

Boc tert-butyloxycarbonyl

Fmoc 9-fluorenylmethoxycarbonyl

Alloc allyloxycarbonyl radical

Teoc trimethylsilyl ethoxycarbonyl

Tc Trichloroethoxycarbonyl

Nps O-Nitrophenylsulphonyl radical

Trt triphenylmethyl or trityl

ivDe 1- (4, 4-dimethyl-2, 6-dioxocyclohex-1-ylidene) -3-methylbutyl;

for carboxyl groups (for example also including aspartic acid and glutamic acid side chain carboxyl groups): conversion into esters with alcoholic components

tBu tert-butyl

Bn benzyl group

Me methyl group

Ph phenyl

Pac phenacyl

Allyl radical

Tse Trimethylsilylethyl group

Tce Trichloroethyl

Dmab 4-N- (1- [ dimethyl-2, 6-dioxocyclohexylidene ] -3-methylbutyl) -aminobenzyl;

for guanidino (e.g. also including arginine side chain guanidino)

Pmc 2,2,5,7, 8-pentamethyl chroman-6-sulfonyl

Ts tosyl (i.e. p-tosyl)

Cbz benzyloxycarbonyl

Pbf pentamethyl dihydrobenzofuran-5-sulfonyl;

and for hydroxyl groups (e.g. also including threonine and serine side chain hydroxyl groups)

tBu tert-butyl

Bn benzyl group

Trt trityl radical

Alloc allyloxycarbonyl.

9-fluorenylmethoxycarbonyl- (Fmoc) -protected amino acid derivatives are preferably used as building blocks for the construction of the β -hairpin loop mimetics of the invention for deprotection, i.e. cleavage of the Fmoc group, 20% piperidine in DMF or 2% DBU/2% piperidine and CH in DMF can be used₂Cl₂25% hexafluoroisopropanol.

The amount of reactants, i.e. amino acid derivatives, is usually 1 to 20 equivalents based on the functionalized solid support initially weighed into the reaction tube (typically 0.1 to 2.85 meq/g for polystyrene resins) in milliequivalents/gram (meq/g) loading. Additional equivalents of reactants can be used to drive the reaction to completion in a reasonable time, if desired. Preferred workstations, however without limiting them, are the combinatorial chemical station of Labsource, Symphony and MultiSyn technology's-Syro synthesizer of Protein Technologies, the latter additionally being equipped with a transfer unit and a reservoir vessel during the process of removing the fully protected linear peptide from the solid support. The overall synthesizer is capable of providing a controlled environment, for example the reaction can be carried out at temperatures other than room temperature and under an inert gas atmosphere (if desired).

Amides of carboxylic acidsThe bond formation requires activation of α -carboxyl group in the acylation step, where the activation is carried out by a commonly used carbodiimide, such as dicyclohexylcarbodiimide (DCC, Sheehan)&Hess, J.Am.chem.Soc.1955,77,1067-1068) or diisopropylcarbodiimide (DIC, Sarantakis et al biochem.Biophys.Res.Commun.1976,73,336-342), the dicyclohexylurea and diisopropylurea obtained are insoluble and soluble, respectively, in the solvents generally used. In a variant of the carbodiimide process, 1-hydroxybenzotriazole (HOBt,&geiger, chem. Ber 1970,103,788-798) as an additive to the coupling mixture. HOBt prevents dehydration, inhibits racemization of activated amino acids and acts as a catalyst to promote slow coupling reactions. Certain phosphonium reagents have been used as direct coupling agents, such as benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP, Castro et al, Tetrahedron Lett.1975,14, 1219-; Synthesis,1976,751-752), or benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (Py-BOP, Coste et al, Tetrahedron Lett.1990,31,205-208), or 2- (1H-benzotriazol-1-yl-) 1,1,3, 3-tetramethyluronium tetrafluoroborate (TBTU), or hexafluorophosphate (HBTU, Knorr et al, Tetrahedron Lett.1989,30, 1927-1930); these phosphonium reagents are also suitable for forming HOBt esters in situ with protected amino acid derivatives. More recently, diphenoxyphosphoryl azide (DPPA) or O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TATU) or O- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU)/7-aza-1-hydroxybenzotriazole (HOAt, Carpino et al, tetrahedron Lett.1994, 35, 2279-, postpresentation, Gordon Conference, 2002, 2 months) have also been used as coupling reagents, and 1,1,3, 3-bis (tetramethylene) chlorouronium hexafluorophosphate (PyClU) is particularly useful for coupling N-methylated amino acids (je, e.frerot, p.jouin, b.castro, Tetrahedron lett.1991, 32, 1967) or pentafluorophenyl diphenyl phosphonite (s.chen, j.xu, Tetrahedron lett.1991, 32, 6711).

Since a near quantitative coupling reaction is required, it is desirable to have experimental evidence showing completion of the reaction. After each coupling step, the ninhydrin test (Kaiser et al, anal. biochemistry 1970,34,595) can be easily and quickly performed, wherein a positive colorimetric reaction on a resin-bound peptide or peptide aliquot qualitatively indicates the presence of a primary amine. The chemical nature of Fmoc allows spectrophotometric detection of the Fmoc chromophore with base release (Meienhofer et al, int.J. peptide Protein Res.1979, 13, 35-42).

Excess reagents, solvents and byproducts were washed from the resin-bound intermediate in each reaction vessel by repeated exposure to pure solvent.

The washing procedure is repeated up to about 30 times (preferably about 5 times), and the removal efficiency of the reagents, solvents and by-products is monitored by methods such as TLC, GC, LC-MS or examination of the washings.

The above procedure was repeated for each successive transformation: the resin-bound compound is reacted with a reagent in a reaction well, followed by removal of excess reagent, byproducts, and solvent until the final resin-bound fully protected linear peptide is obtained.

Before the fully protected linear peptide is removed from the solid support, one or more protected functional groups in the molecule may be selectively deprotected and the reactive groups thus released appropriately substituted, if desired. To achieve this effect, the functional group concerned must initially be protected by a protecting group and be able to be selectively removed without affecting the remaining protecting groups present. Alloc (allyloxycarbonyl) is an example of the amino protecting group, which can be for example by Pd ° and phenylsilane/CH₂Cl₂Selectively removed without affecting the remaining protecting groups present in the molecule, such as Fmoc. The reactive groups thus liberated can then be used with an appropriate test for introducing the desired substituentsAnd (4) treating with an agent. Thus, for example, an amino group can be acylated by an acylating agent corresponding to the acyl substituent to be introduced.

After detachment of the fully protected linear peptide from the solid support, the individual solutions/extracts are then manipulated as needed to isolate the final compound. Typical manipulations include, but are not limited to, evaporation, concentration, liquid/liquid extraction, acidification, basification, neutralization or additional reactions in solution.

The solution containing the fully protected linear peptide derivative which has been cleaved from the solid support is neutralized with a base and evaporated. The cyclization is then carried out in solution using solvents such as DCM, DMF, dioxane, THF, etc. Various coupling reagents mentioned earlier as activators for amide bond formation can be used for the cyclization. The duration of the cyclization is about 6 to 48 hours, preferably about 16 hours. The reaction is followed, for example, by RP-HPLC (reverse phase high performance liquid chromatography). The solvent is then removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a water immiscible solvent such as DCM, and the solution is extracted with water or a mixture of water miscible solvents to remove any excess coupling agent.

Finally, the fully protected peptide derivative was treated with 95% TFA, 2.5% H₂O, 2.5% TIS or 87.5% TFA, 2.5% DODT, 5% thioanisole, 5% H₂O or yet another combined treatment of the capture agent, causing cleavage of the protecting group. The cleavage reaction time is generally 30 minutes to 12 hours, preferably about 2.5 hours. The volatiles were evaporated to dryness and the crude peptide was dissolved in 20% AcOH/water and extracted with isopropyl ether or other suitable solvent. The water layer was collected and evaporated to dryness, and the fully deprotected cyclic peptide was obtained. Alternatively, the deprotected cyclic peptide can be precipitated and used with cold Et₂And O washing.

Certain compounds of the invention of formula (I) require additional synthetic steps. These transformations can be applied to fully protected or partially deprotected linear or cyclic peptides that are attached to or have been released from a solid support; or to the final deprotected molecule.

Various methods are known for forming inter-strand connections, including: J.P.Tam et al, Synthesis 1979, 955-957; stewart et al, Solid Phase Peptide Synthesis,2d ed, Pierce chemical company, Rockford, IL, 1984; ahmed et al, j.biol.chem.1975,250, 8477-8482; and m.w.pennington et al, Peptides, pages 164-; c.e. schafmeister et al, j.am. chem. soc.2000,122, 5891. The most widely known linkage is a disulfide bridge formed by, for example, cysteine and homocysteine, which are located opposite the β -strand.

For example, the formation of disulfide bridges can be performed after assembly of the linear peptide on the resin: for example, a10 equivalent iodine/DMF solution is used on the trityl-protected cysteine amino acid residue for 1.5 hours, and the oxidation step is repeated with fresh iodine solution for an additional 3 hours. Alternatively, disulfide bridge formation can be performed in solution after backbone cyclization but before peptide deprotection: for example, 2 equivalents of iodine/hexafluoroisopropanol/CH on trityl-protected cysteine amino acid residues₂Cl₂The mixture solution was left for 1 hour, and then 1M aqueous vitamin C solution was added to quench the oxidation reaction. Disulfide bridges may also be formed after deprotection of the backbone cyclized peptide: for example, a mixture of DMSO and acetic acid solution is applied with 5% NaHCO₃Buffering to pH 5-6 for 4 hr; or stirred in water for 24 hours after adjusting to pH 8 with ammonium hydroxide solution.

Yet another well-established interchain linkage is formed by lactam bridges as follows: the side chains carrying amino groups, such as ornithine and lysine, are linked to the side chains carrying carboxyl groups of glutamic acid and aspartic acid residues, respectively, located opposite the beta-chain, via amide linkages. The preferred protecting group for the pendant amino groups of ornithine and lysine is allyloxycarbonyl (alloc), while the preferred protecting group for the pendant carboxyl groups of aspartic acid and glutamic acid is allyl ester (allyl).

For example, lactam bridge formation can be performed after assembly of the linear peptide on the resin: 0.2 equivalent of tetrakis (triphenyl-phosphine) palladium (0) (10 mM)/anhydrous CH was applied₂Cl₂And 10 equivalents of phenylsilane to selectively remove alloc-and allyl-protecting groups from the amino and carboxyl functional groups of the side chain of the amino acid residue to be attached. After repeating the above procedure, lactam bridges were formed as follows: 4 equivalents of DIPEA/DMF and subsequently 2 equivalents of HATU/DMF were added.

By using appropriate orthogonal protecting group strategies, lactam bridges can also be formed at later stages of synthesis, for example after deprotection of the backbone cyclized peptide.

The inter-chain connections can also be established as follows: the side chain amino groups of amino acid residues located in opposite positions of the beta-strand, e.g., L-1, 3-diaminopropionic acid and ornithine, are linked to a reagent such as N, N-carbonylimidazole or bis (N-succinimidyl) carbonate to form a cyclic urea. Allyloxycarbonyl (alloc) can be preferably used as an orthogonal protecting group for amino functions.

For example, the formation of urea bridges can be performed in solution after backbone cyclization but before complete deprotection of the peptide: 30 equivalents of phenylsilane and 0.2 equivalent of tetrakis (triphenylphosphine) -palladium (0) CH are applied₂Cl₂And (3) solution. After removal of the alloc protecting group and precipitation of the selectively deprotected peptide, the urea bridge is formed as follows: CH with 6 equivalents of DIPEA₂Cl₂Solution and subsequent dropwise addition of 1.2 equivalents of CH of bis (N-succinimidyl) carbonate₂Cl₂And (3) solution.

More recently, yet another type of interchain linkage based on 1, 4-disubstituted 1,2, 3-triazole containing alkanediyl has been introduced. The connection is obtained as follows: 1, 3-dipolar cycloaddition between the side chain omega-alkyne group of an amino acid residue, e.g., L-propargylglycine, and the side chain omega-azide group of an amino acid residue, e.g., (S) -2-amino-4-azidobutanoic acid, the two residues being located in opposite positions of the beta-chain.

For example, the formation of the above triazole-containing bridge proceeds as follows: cyclizing the purified fully deprotected backbone to the peptide at H₂O/tBuOH, 4.4 equivalents of CuSO₄x5H₂A mixture of O and 6.6 equivalents of vitamin C was stirred for 12 hours.

Depending on its purity, the final product obtained according to the above procedure can be used directly for biological tests or must be further purified, for example by preparative HPLC.

As mentioned previously, it is possible thereafter, if desired, to convert the thus obtained fully deprotected cyclic product into a pharmaceutically acceptable salt, or to convert the thus obtained pharmaceutically acceptable or unacceptable salt into the corresponding free product or a different pharmaceutically acceptable salt. Any of these manipulations can be performed by methods well known in the art.

In general, the building blocks of the peptidomimetics of the invention can be synthesized according to literature methods known to those skilled in the art or are commercially available. All other corresponding amino acids have been described as unprotected or Boc-or Fmoc-protected racemates, (D) -or (L) -isomers. It will be appreciated that the unprotected amino acid building blocks can be readily converted to the corresponding Fmoc-protected amino acid building blocks required in the present invention by standard protecting group manipulations. Reviews describing the general synthesis of alpha-amino acids include: duthaller, tetrahedron (report)1994,349, 1540-1650; R.M.Williams, "synthetic optical active α -amino acids", Tetrahedron Organic Chemistry Series, Vol.7, J.E.Baldwin, P.D.Magnus (Eds.), Pergamon Press, Oxford 1989. Particularly useful methods for synthesizing optically active alpha-amino acids of interest in the present invention include kinetic resolution with hydrolases (M.A. Verhovskaya, I.A. Yamskov, Russian chem.Rev.1991,60, 1163-. Kinetic resolution with hydrolytic enzymes involves: hydrolysis of amides and nitriles by aminopeptidases or nitrilases, cleavage of N-acyl groups by acyltransferases, and hydrolysis of esters by lipases or proteases. It is widely described that certain enzymes result in particular in the pure (L) -enantiomer, whereas other enzymes produce the corresponding (D) -enantiomer (for example: R.Duthaler, Tetrahedron Report 1994,349, 1540-1650; R.M.Williams, "Synthesis of optically active. alpha. -amino acids", Tetrahedron Organic Chemistry Series, Vol.7, J.E.Baldwin, P.D.Magnus (Eds.), Pergamon Press, Oxford 1989).

The β -hairpin peptidomimetics of the invention can be used in a wide range of applications in order to inhibit the growth of microorganisms or to kill microorganisms, resulting in a desired therapeutic effect in humans or other mammals due to their similar etiology. In particular, they can be used to inhibit the growth of or kill gram-negative bacteria such as Klebsiella pneumoniae (Klebsiella pneumoniae) and/or Acinetobacter baumannii (Acinetobacter baumannii) and/or Escherichia coli (Escherichia coli).

They can be used, for example, as disinfectants or preservatives for materials such as food, cosmetics, pharmaceuticals and other nutrient-containing materials.

The beta-hairpin peptidomimetics of the invention can also be used to treat or prevent diseases involving microbial infections in plants and animals.

For use as a disinfectant or preservative, the β -hairpin peptidomimetics can be added to the desired material alone, as a mixture of several β -hairpin peptidomimetics or in combination with other antimicrobial agents.

The β -hairpin peptidomimetics of the invention can be used to treat or prevent infections or diseases involving said infections, in particular iatrogenic infections caused by gram-negative bacteria involving diseases such as Ventilator Associated Pneumonia (VAP), Hospital Acquired Pneumonia (HAP), Health Care Associated Pneumonia (HCAP); catheter-related and non-catheter-related infections such as Urinary Tract Infections (UTIs) or bloodstream infections (BSIs); respiratory diseases such as cystic fibrosis, emphysema, asthma or pneumonia; skin or soft tissue diseases such as infections involved in surgical wounds, traumatic wounds or burns; gastrointestinal diseases such as epidemic diarrhea, enterocolitis causing necrosis, cecostitis, infections related to gastroenteritis or pancreatitis; infections involved in eye diseases such as keratitis and endophthalmitis; infections involved in otic disorders such as otitis; infections involved in CNS diseases such as brain abscesses and meningitis or encephalitis; infections involved in bone diseases such as osteochondritis and osteomyelitis; infections involved in cardiovascular diseases such as endocarditis and pericarditis; or infections involved in urogenital conditions such as epididymitis, prostatitis, and urethritis. They can be administered alone, as a mixture of several β -hairpin peptidomimetics, in combination with other antimicrobial or antibiotic agents, or anticancer or antiviral (e.g. anti-HIV) agents, or in combination with other pharmaceutically active agents. The β -hairpin peptidomimetics can be administered alone or as a pharmaceutical composition.

The β -hairpin peptidomimetics of the invention may be administered alone or may be administered as an appropriate formulation with carriers, diluents or excipients well known in the art.

Pharmaceutical compositions comprising the beta-hairpin peptidomimetics of the invention can be prepared by: conventional mixing, dissolving, granulating, making coated tablet, grinding, emulsifying, encapsulating, embedding or lyophilizing. The pharmaceutical compositions may be formulated in conventional manner: one or more physiologically acceptable carriers, diluents, excipients or adjuvants are used which facilitate processing of the active β -hairpin peptidomimetics into pharmaceutically useful formulations. Suitable formulations depend on the chosen method of administration.

For topical administration, the β -hairpin peptidomimetics of the present invention may be formulated as solutions, gels, ointments, creams, suspensions, and the like, as is known in the art.

Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.

For injections, the β -hairpin peptidomimetics of the invention may be formulated in suitable solutions, preferably in physiologically compatible buffers such as Hink solution, ringer's solution, or physiological saline buffer. The solution may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the β -hairpin peptidomimetics of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, prior to use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation, as is known in the art.

For oral administration, complexes can be readily formulated by combining the active β -hairpin peptidomimetics of the invention with pharmaceutically acceptable carriers well known in the art. The carrier allows the beta-hairpin peptidomimetics of the invention to be formulated as tablets, pills, troches, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. For oral formulations such as powders, capsules and tablets, suitable excipients include fillers such as sugars, for example lactose, sucrose, mannitol and sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agent; and a binder. If desired, disintegrating agents such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added. The solid dosage forms may be sugar coated or enteric coated using standard techniques, if desired.

For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, and the like. In addition, a flavoring agent, a preservative, a coloring agent, and the like may be added.

For buccal administration, the compositions may be in the form of conventionally formulated tablets, lozenges, and the like.

For administration by inhalation, the β -hairpin peptidomimetics of the invention are conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer, using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to administer a metered amount. Capsules and cartridges of, for example, gelatin, containing a powder mix of a β -hairpin peptidomimetic of the invention and a suitable powder base such as lactose or starch may be formulated for use in an inhaler or insufflator.

The compounds may also be formulated in rectal or vaginal compositions such as suppositories, with suitable suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the β -hairpin peptidomimetics of the invention can also be formulated as depot preparations. The long acting formulation may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. To prepare the depot formulations, the β -hairpin peptidomimetics of the invention can be formulated with suitable polymeric or hydrophobic substances (e.g., emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble salts.

In addition, other drug delivery systems such as liposomes and emulsions well known in the art may be used. Certain organic solvents such as dimethylsulfoxide also can be used. Additionally, the β -hairpin peptidomimetics of the invention may be delivered using a sustained release system such as a solid polymeric semipermeable matrix containing the therapeutic agent (e.g., a stent for coating). Various sustained release materials are identified and known to those skilled in the art. Depending on the chemical nature, sustained release capsules can release the compound for weeks up to 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stabilization may be used.

Since the β -hairpin peptidomimetics of the invention may contain charged residues, they may be included in the above formulations as such or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in water and other protic solvents than the corresponding free form.

The β -hairpin peptidomimetics of the invention, or compositions thereof, are generally used in an amount effective to achieve the desired purpose. It is understood that the amount depends on the particular application.

For example, for use as a disinfectant or preservative, an antimicrobially effective amount of a β -hairpin peptidomimetic of the invention or a composition thereof is applied or added to the material to be disinfected or preserved. An antimicrobially effective amount means an amount of a β -hairpin peptidomimetic of the invention or a composition thereof that inhibits or kills a target microbial population. Although an antimicrobially effective amount depends on the particular application, for use as a disinfectant or preservative, the β -hairpin peptidomimetics of the invention or compositions thereof are typically added or applied in relatively low amounts to the substance to be disinfected or preserved. Generally, the beta-hairpin peptidomimetics of the invention comprise less than about 5% by weight, preferably less than 1% by weight and more preferably less than 0.1% by weight of the disinfectant solution or substance to be preserved. Using the results of in vitro testing, e.g., as provided in the examples, one of ordinary skill in the art is able to determine an antimicrobially effective amount of a particular β -hairpin peptidomimetic of the invention for a particular administration without undue experimentation.

For use in treating or preventing microbial infections or diseases involving such infections, the β -hairpin peptidomimetics of the invention or compositions thereof are administered or administered in a therapeutically effective amount. By a therapeutically effective amount is meant an amount effective to ameliorate the symptoms of, or to ameliorate, treat or prevent a microbial infection or disease associated therewith. One skilled in the art will be able to determine a therapeutically effective amount, particularly after reviewing the detailed disclosure provided herein.

In the case of disinfectants and preservatives, for topical administration to treat or prevent bacterial and/or viral infections, a therapeutically effective dose can be determined using in vitro test results such as provided in the examples. Treatment may be administered when the infection is visible, or even when it is not visible. One of ordinary skill in the art will be able to determine a therapeutically effective amount to treat a topical infection without undue experimentation.

For example, in animal models can be formulated to achieve circulating β -hairpin peptidomimetic concentration ranges, including in cell culture determined IC₅₀(i.e., the concentration of test compound that is lethal to 50% of the cell culture). The above information can be used to more accurately determine useful doses in humans.

Initial dosages can also be determined from in vivo data, such as animal models, using techniques well known in the art. One of ordinary skill in the art can readily optimize human dosing based on animal data.

The dose administered as an anti-infective agent can be adjusted individually to provide plasma levels of the β -hairpin peptidomimetics of the invention sufficient to maintain a therapeutic effect. Therapeutically effective serum levels may be achieved by administering multiple doses per day.

In the case of topical administration or selective administration, the effective local concentration of the β -hairpin peptidomimetics of the invention may not be related to the plasma concentration. One of ordinary skill in the art would be able to optimize therapeutically effective topical dosages without undue experimentation.

The amount of β -hairpin mimetic administered will, of course, depend on the subject to be treated, the subject's weight, the severity of the patient, the mode of administration and the judgment of the prescribing physician.

Antimicrobial treatment may be repeated intermittently when infection is detectable or even when infection is not detectable. Treatment may be provided alone or in combination with other drugs, such as anti-HIV agents or anti-cancer agents or other antimicrobial agents.

Generally, a therapeutically effective dose of the beta-hairpin peptidomimetics described herein will provide therapeutic benefit without causing substantial toxicity.

Toxicity of the β -hairpin peptidomimetics of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining LD₅₀(dose lethal to 50% of the population) or LD₁₀₀The data obtained from these cell culture tests and animal studies can be used to obtain a range of non-toxic doses for use in humans the dose of the β -hairpin mimetic of the invention is preferably within a range of circulating concentrations that include an effective dose that is nearly non-toxic or non-toxicAn internal variation. The precise formulation, route of administration and dosage can be selected by The individual physician with reference to The patient (see, e.g., Fingl et al 1975, In: The pharmacological basis of Therapeutics, Ch.1, p.1).

The following examples illustrate the invention but are not to be construed as limiting its scope in any way.

Abbreviations:

ac acetyl;

BSA bovine serum albumin;

boc tert-butyloxycarbonyl;

DCHA dicyclohexylamine;

DEAD azodicarboxylic acid diethyl ester;

DIPEA diisopropylethylamine;

DMEM Dulbecco modified Eagle Medium;

DODT 3, 6-dioxa-1, 8-octane dithiol;

FCS fetal calf serum;

fmoc fluorenylmethyloxycarbonyl;

HATU O- (7-aza-benzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate;

HBSS Hank buffered saline;

HBTU O- (benzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate;

HCTU O- (6-chlorobenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate;

hepes 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid;

HFIP hexafluoroisopropanol

HOAt 1-hydroxy-7-azabenzotriazole;

IMDM Iscove modified Dulbecco's medium;

(benzotriazol-1-yloxy) trispyrrolidinylphosphonium hexafluorophosphate;

TIS triisopropylsilane;

TPP triphenylphosphine;

RPMI Roswell Park mental Institute medium;

rt, room temperature.

Examples

1. Peptide synthesis

1.1 general synthetic procedure

The general methods for synthesizing peptidomimetics of the present invention are illustrated below. This is intended to illustrate the concept in principle and not to limit or restrict the invention in any way. The skilled person can easily modify these procedures, in particular but not limited to, selecting different starting positions within the ring system, which all allow the preparation of the claimed cyclic peptidomimetic compounds of the invention.

Coupling the first protected amino acid residue to the resin

In a dry flask, 2-chlorotrityl chloride resin (polystyrene, 1% cross-linked; loading: 1.4mMol/g) was added to anhydrous CH₂Cl₂Middle inflation for 30 min (7mL CH)₂Cl₂Per g resin). Anhydrous CH with addition of 0.8 equivalents Fmoc-protected amino acid and 6 equivalents DIPEA₂Cl₂A solution of/DMF (4/1) (10mL per g of resin). After shaking at room temperature for 2-4 hours, the resin was filtered off and successively CH was added₂Cl₂，DMF，CH₂Cl₂DMF and CH₂Cl₂And (6) washing. Then, anhydrous CH was added₂Cl₂A solution of/MeOH/DIPEA (17: 2: 1) (10mL per g of resin). After shaking for 3X 30 min, the resin was filtered off in a pre-weighed sinter funnel, followed by CH₂Cl₂，DMF，CH₂Cl₂，MeOH，CH₂Cl₂，MeOH，CH₂Cl₂(2x) and Et₂O (2x) wash. The resin was dried under high vacuum overnight. The final mass of the resin was calculated prior to treatment control.

The loading is generally between 0.6 and 0.7 mMol/g.

The following pre-loaded resins were prepared: fmoc-dab (Boc) -2-chlorotrityl resin, Fmoc-^DDab (Boc) -2-chlorotrityl resin, Fmoc-Trp (Boc) -2-chlorotrityl resin and Fmoc-Pro-2-chlorotrityl resin.

Synthesis of fully protected peptide fragments

The synthesis was carried out on a Syro-peptide synthesizer (MultiSynTech GmbH) with 24 to 96 reaction vessels. In each vessel, 0.04mMol of the above resin was placed in each vessel and the resin was added to CH₂Cl₂And 15 min in DMF.

The following reaction cycles were programmed and performed:

steps 5 to 9 are repeated to add each amino acid residue.

After the synthesis of the fully protected peptide fragment is terminated, one of the procedures a-D as described below is then followed, depending on what interchain linkages as described below are to be formed.

Finally, the peptide was purified by preparative reverse phase LC-MS, as described below.

Procedure a: cyclization and work-up of backbone cyclized peptides without interchain linkages

Cleavage, backbone cyclization and deprotection

After assembly of the linear peptide, the resin was dissolved in 1mL of 1% TFA/CH₂Cl₂(v/v; 0.14mMol) for 3 minutes. After filtration, the filtrate was combined with 1mL of 20% DIPEA/CH₂Cl₂(v/v; 1.15mMol) neutralization. This procedure was repeated four times to ensure that the cleavage was complete. Alternative lysis methods include: the resin was dissolved in 1mL of 20% HFIP/CH₂Cl₂(v/v; 1.9mMol) for 30 minutes, filtered and the procedure repeated. Resin with 1mL CH₂Cl₂Washed three times. Will contain CH of the product₂Cl₂The layer was evaporated to dryness.

The fully protected linear peptide was solvated in 8mL anhydrous DMF. Then, 2 equivalents of HATU and 2 equivalents of HOAt/anhydrous DMF (1-2mL) and 4 equivalents of DIPEA/anhydrous DMF (1-2mL) were added to the peptide, followed by stirring for about 16 hours. The volatiles were removed by evaporation. The crude cyclic peptide was dissolved in 7mL CH₂Cl₂And washed three times with 4.5mL 10% acetonitrile/water (v/v). Then the CH is₂Cl₂The layer was evaporated to dryness.

To completely deprotect the peptide, 7mL of cleavage mix TFA/DODT/thioanisole/H was added₂O (87.5:2.5: 5: 5) or TFA/TIS/H₂O (95:2.5:2.5), the mixture is kept at room temperature for 2.5-4 hours until the reaction is complete. The reaction mixture was evaporated to near dryness, and 7mL of cold Et was used₂Precipitation of the peptide by O/pentane, finally 4mL of cold Et₂The O/pentane washes were 3 times.

Procedure B: cyclization and work-up of backbone cyclized peptides with disulfide inter-chain linkages

Formation of disulfide inter-chain linkages

After linear peptide cleavage, backbone cyclization, and deprotection, the deprotected cyclic peptide was treated with 0.5mL DMSO in 9.5mL H as described in the corresponding section of procedure A₂O/AcOH solution (95: 5; with NH)₄HCO₃Adjusted to pH 6) at rt for 24 hours to form disulfide bridges. After this time, the reaction mixture was evaporated to dryness.

Procedure C: cyclization and work-up of peptides with backbone cyclization of lactam interchain linkages

Formation of lactam interchain linkages

After assembly of the linear peptides, the resin was in 5mL of freshly distilled CH₂Cl₂Medium swelling for at least 15 minutes. To selectively remove alloc-and allyl-protecting groups from amino and carboxyl functions, respectively, 0.2 equivalents of tetrakis (triphenyl-phosphine) palladium (0) (10 mM)/anhydrous CH were added₂Cl₂And 10 equivalents of phenylsilane. After shaking the reaction mixture at rt for 15 minutes, the resin was filtered off, a fresh solution of the reagent was added and the procedure was repeated. In use of CH₂Cl₂DMF and Et₂After subsequent washing of the resin, the resin was expanded in 5mL of DMF. 1mL of DIPEA/DMF solution (24.6. mu.l DIPEA/1mL of DMF, 4 equivalents) was added followed by 1mL of HATU/DMF solution (27.4mg HATU/DMF, 2 equivalents). After stirring the reaction mixture overnight, the resin was filtered with DMF and CH₂Cl₂And (4) thoroughly washing.

Cleavage, backbone cyclization and deprotection of the modified peptide were performed as described in the corresponding section of procedure a.

Procedure D: cyclization and work-up of peptides with backbone cyclization of urea inter-chain linkages

Formation of urea inter-chain linkages

After cleavage and backbone cyclization as described in the corresponding part of procedure A, the fully protected peptide was dissolved in 10mLCH₂Cl₂0.2mL of phenylsilane (30 equiv.) and tetrakis (triphenylphosphine) -palladium (0) (0.2 equiv.) of 1mL CH were added₂Cl₂And (3) solution. The mixture was stirred at rt for 45 minutes to complete the removal of the alloc protecting group. After evaporation to a final volume of 2mL, the peptide was quenched with 40mL of cold Et₂And (4) precipitating O/pentane. Cold Et for precipitation₂O/Pentane 3 times, dissolve the air-dried solid in 30mL anhydrous CH₂Cl₂. After addition of 6 equivalents of DIPEA, 10mL of anhydrous CH will be dissolved in 25 minutes₂Cl₂Bis (N-succinimide) of (C)Mesityl) carbonate (1.2 equivalents) was added dropwise to the reaction mixture. After stirring for 1 hour at rt, 10. mu.l of ethylenediamine (2.5 equivalents) and 10mL of H were then added₂O to quench excess bis (N-succinimidyl) carbonate. After discarding the aqueous phase, the organic phase was evaporated to dryness and the modified peptide was deprotected as described in the corresponding part of procedure a.

Purification procedure (preparative reverse phase LC-MS)

The compound was purified by reverse phase chromatography using a Phenomenex Gemini NX-C18 column, 30X 100mm, 5 μm (Cat No.00D-4435-U0-AX) or a Waters Xbridge C18OBD column, 30X 100mm, 5 μm (Cat No. 186002982).

The mobile phases used were:

a: 0.1% TFA in water/acetonitrile 95/5v/v

B: acetonitrile solution of 0.1% TFA

The gradient slope used for the preparative run was adjusted each time based on analytical LC-MS analysis of the crude product. For example, typical operations are performed as follows: using a Phenomenex column, flow rate 35mL/min, gradient 0-1 min 0% B, 1.1 min 25% B to a final 8 min 45% B (retention time: 5.96 min in this case).

And (3) detection: MS and UV @220nm

The collected fractions were evaporated using a Genevac HT4 evaporator or a Buchi system.

Alternatively, for larger quantities, the following LC-purification system was used:

column: waters Xbridge C18OBD column, 50X 250mm, 10 μm (Cat No.186003900)

Mobile phase A: 0.1% TFA/water

Mobile phase B: acetonitrile

Flow rate: 150mL/min

And (3) detection: UV @220nm

After lyophilization, the product was obtained as a white to off-white powder and analyzed by HPLC-ESI-MS as described below. Analytical data after preparative HPLC purification are shown in table 1.

1.2 analytical methods

Analytical method A:

analytical HPLC retention times (RT, min) were determined as follows: using an Ascentis Express C8 column, 100X3mm, 2.7 μm, the following solvent A (H)₂O + 0.1% TFA) and B (CH)₃CN + 0.085% TFA) and gradient: 0-0.1 min: 95% of A, 5% of B; 11 minutes: 15% A, 85% B; 11.02-12.5 minutes: 3% a, 97% B; 12.55-13.5 min: 95% A, 5% B, flow rate 1.3mL/min at 55 ℃.

Analysis method B:

analytical HPLC retention times (RT, min) were determined as follows: using an Ascentis Express C8 column, 100X3mm, 2.7 μm, the following solvent A (H)₂O + 0.1% TFA) and B (CH)₃CN + 0.085% TFA) and gradient: 0-0.1 min: 95% of A, 5% of B; 7 minutes: 15% A, 85% B; 7.02 min: 3% a, 97% B; 7.02-7.5 minutes: 3% a, 97% B; 7.52-7.75 minutes: 95% A, 5% B, flow rate 1.4mL/min at 55 ℃.

Analysis method C:

analytical HPLC retention times (RT, min) were determined as follows: using an Ascentis Express C8 column, 100X3mm, 2.7 μm, the following solvent A (H)₂O + 0.1% TFA) and B (CH)₃CN + 0.085% TFA) and gradient: 0-0.1 min: 95% of A, 5% of B; 7 minutes: 45% A, 55% B; 7.02 min: 3% a, 97% B; 7.02-7.5 minutes: 3% a, 97% B; 7.52-7.75 minutes: 95% A, 5% B, flow rate 1.4mL/min at 55 ℃.

Analysis method D:

analytical HPLC retention times (RT, min) were determined as follows: using an Ascentis Express C18 column, 50X3mm, 2.7 μm, the following solvent A (H)₂O + 0.1% TFA) and B (CH)₃CN + 0.085% TFA) and laddersDegree: 0-0.05 min: 97% A, 3% B; 3.4 minutes: 45% A, 55% B; 3.45 min-3.65 min: 3% a, 97% B; 3.67-3.7 minutes: 97% A, 3% B, flow rate 1.3mL/min at 55 ℃.

Analysis method E:

analytical HPLC retention times (RT, min) were determined as follows: using an Ascentis Express C18 column, 50X2.1mm, 2.7 μm, the following solvent A (H)₂O + 0.1% TFA and B (CH)₃CN + 0.085% TFA) and gradient: 0-0.05 min: 97% A, 3% B; 3.3 min: 15% A, 85% B; 3.32 minutes: 3% a, 97% B; 3.32-3.55 min: 3% a, 97% B; 3.57-3.7 minutes: 97% A, 3% B, flow rate 1.6mL/min at 55 ℃.

1.3 synthetic peptide procedure

Example 1 is shown in table 1.

The peptide was synthesized according to the general procedure starting with the amino acid (S) -2-amino-4- (tert-butoxycarbonylamino) butyric acid, which was grafted onto a resin (Fmoc-dab (Boc) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above, which was the following sequence: resin-Dab-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷After cleavage from resin, backbone cyclization and deprotection, disulfide β -chain linkages were formed as indicated in procedure B finally, the peptide was purified by preparative reverse phase LC-MS as described above the product was obtained after lyophilization as a white to off-white powder characterized by HPLC-MS analytical data see ex.1 of table 1.

Examples 2-6 are shown in Table 1.

The peptides were synthesized according to the general procedure starting with the amino acid (R) -2-amino-4- (tert-butoxycarbonylamino) butanoic acid, which was grafted onto a resin (Fmoc-^DDab(Boc) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above, which was the following sequence: resin-^DDab-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷After cleavage from resin, backbone cyclization and deprotection, disulfide β -chain linkages were formed as indicated in procedure B finally, the peptide was purified by preparative reverse phase LC-MS as described above the product was obtained after lyophilization as a white to off-white powder characterized by HPLC-MS analytical data see ex.2-6 of table 1.

Examples 7-9 are shown in Table 1.

The peptide was synthesized according to the general procedure starting with the amino acid (S) -2-amino-4- (tert-butoxycarbonylamino) butyric acid, which was grafted onto a resin (Fmoc-dab (Boc) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above, which was the following sequence: resin-Dab-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸After cleavage from resin, backbone cyclization and deprotection, disulfide β -chain linkages were formed as indicated in procedure B finally, the peptide was purified by preparative reverse phase LC-MS as described above the product was obtained after lyophilization as a white to off-white powder characterized by HPLC-MS analytical data see ex 7-9 of table 1.

Examples 10 and 11 are shown in Table 1.

The peptide was synthesized according to the general procedure starting with the amino acids Fmoc-trp (boc) -OH, which were grafted onto a resin (Fmoc-trp (boc) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above, which was the following sequence: resin-Trp-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹After cleavage from resin, backbone cyclization and deprotection, disulfide β -chain linkages were formed as indicated in procedure B finally, the peptide was purified by preparative reverse phase LC-MS as described above the product was obtained after lyophilization as a white to off-white powder characterized by HPLC-MS analytical data see ex.10, 11 of table 1.

Examples 38 and 39 are shown in Table 1.

The peptide was synthesized according to the general procedure starting with the amino acid L-proline, which was grafted onto the resin (Fmoc-Pro-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above, which was the following sequence: resin-Pro-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹After cleavage from resin, backbone cyclization and deprotection, disulfide β -chain linkages were formed as indicated in procedure B finally, the peptide was purified by preparative reverse phase LC-MS as described above the product was obtained after lyophilization as a white to off-white powder characterized by HPLC-MS analytical data see ex.38, 39 of table 1.

Examples 12-33 are shown in Table 1.

The peptide was synthesized according to the general procedure starting with the amino acid (S) -2-amino-4- (tert-butoxycarbonylamino) butyric acid, which was grafted onto a resin (Fmoc-dab (Boc) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above, which was the following sequence: resin-Dab-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸Lactam β -chain linkages were then formed as indicated in procedure C, after cleavage from the resin, backbone cyclizationAnd deprotection, the peptide was purified by preparative reverse phase LC-MS, as described above. The product was obtained after lyophilization as a white to off-white powder, characterized by HPLC-MS. See Ex.12-33 of Table 1 for analytical data.

Examples 34-37 are shown in Table 1.

The peptide was synthesized according to the general procedure starting with the amino acid L-proline, which was grafted onto the resin (Fmoc-Pro-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above, which was the following sequence: resin-Pro-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹After cleavage from resin, backbone cyclization and deprotection, the peptide was purified by preparative reverse phase LC-MS as described above the product was obtained after lyophilization as a white to off-white powder characterized by HPLC-MS.

Example 40 is shown in table 1.

The peptide was synthesized according to the general procedure starting with the amino acid L-proline, which was grafted onto the resin (Fmoc-Pro-2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above, which was the following sequence: resin-Pro-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹After deprotection, the peptide was purified by preparative reverse phase LC-MS as described above the product was obtained after lyophilization as a white to off-white powder characterized by HPLC-MS.

Example 41 is shown in table 1.

The peptide was synthesized according to the general procedure starting with the amino acid (S) -2-amino-4- (tert-butoxycarbonylamino) butyric acid, which was grafted onto a resin (Fmoc-dab (Boc) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above, which was the following sequence: resin-Dab-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹-P⁸. After cleavage from the resin, backbone cyclization and deprotection, the peptide was purified by preparative reverse phase LC-MS as indicated in procedure a, as described above. The product was obtained after lyophilization as a white to off-white powder, characterized by HPLC-MS. See table 1 for ex.41 for analytical data.

Examples 42-44 are shown in Table 1.

The peptide was synthesized according to the general procedure starting with the amino acids Fmoc-trp (boc) -OH, which were grafted onto a resin (Fmoc-trp (boc) -2-chlorotrityl resin). The linear peptide was synthesized on a solid support according to the procedure described above, which was the following sequence: resin-Trp-P⁷-P⁶-P⁵-P⁴-P³-P²-P¹-T²-T¹-P¹²-P¹¹-P¹⁰-P⁹. After cleavage from the resin, backbone cyclization and deprotection, the peptide was purified by preparative reverse phase LC-MS as indicated in procedure a, as described above. The product was obtained after lyophilization as a white to off-white powder, characterized by HPLC-MS. See Ex.42-44 in Table 1 for analytical data.

2. Biological method

2.1 preparation of peptides

The lyophilized peptide was weighed on a microbalance (Mettler MT5) and dissolved in sterile water to a final concentration of 1 mg/mL. The stock solution was kept at +4 ℃ protected from light.

2.2 antimicrobial Activity of peptides

The selective antimicrobial activity of peptides was determined in 96-well plates (Greiner, polystyrene) by slight modification by standard NCCLS broth microdilution methods (National Committee for Clinical Laboratory Standards 1993.methods for dilution of antimicrobial properties tests for bacteria that grow aerobic bacteria, 3rd ed. applied standard M7-A6; National Committee for Clinical Laboratory Standards, Wayne, PA). An inoculum of the microorganisms was diluted into Mueller-Hinton II (MH, cation-adjusted) broth and compared to a 0.5McFarland standard, providing approximately 10⁶Individual Colony Forming Units (CFU)/mL. Aliquots of the inoculum (90 μ l) were added to 10 μ l MH broth + P-80 (polysorbate 80, 0.002% final concentration) containing peptides in serial two-fold dilutions. The antibiotic selectivity of the peptides was determined using the following microorganisms: escherichia coli (Escherichia coli) ATCC 25922, Klebsiella pneumoniae (Klebsiella pneumoniae) ATCC 13883 and Acinetobacter baumannii (Acinetobacter baumannii) DSM 30008. The antimicrobial activity of the peptide was expressed as the Minimum Inhibitory Concentration (MIC) in μ g/mL, at which no visible growth was observed after incubation at 35 ℃ for 18-20 hours.

2.3 hemolysis

Peptides were tested for hemolytic activity on human red blood cells (hRBC). Fresh hRBC were washed three times with Phosphate Buffered Saline (PBS) and centrifuged at 3000x g for 5 minutes. The compound (100. mu.g/mL) was incubated with 20% hRBC (v/v) at 37 ℃ for 1 hour with shaking at 300 rpm. The final red blood cell concentration was about 0.9x 10⁹Individual cells/mL. 0% and 100% cell lysis was measured in PBS containing 0.001% acetic acid and 2.5% Triton X-100/H, respectively₂hRBC in the presence of O. The samples were centrifuged and the supernatant diluted 8-fold in PBS buffer and the Optical Density (OD) was measured at 540 nm. 100% dissolution value (OD)₅₄₀H₂O) provides an OD of about 0.5-1.0₅₄₀。

The percent hemolysis was calculated as follows: (OD)₅₄₀peptide/OD₅₄₀H₂O)x100％。

The results described for experiments 2.2-2.3 are shown in table 2 below.

Table 2: minimum Inhibitory Concentration (MIC) in Mueller-Hinton broth II, and hemolysis

TABLE 2 continuation of

Claims

1. A compound of the general formula (I),

ring [ P ]¹-P²-P³-P⁴-P⁵-P⁶-P⁷-P⁸-P⁹-P¹⁰-P¹¹-P¹²-T¹-T²

（I）

T¹Is natural or non-natural D α -amino acid and containsOptionally substituted side chain forming a four or five membered heterocyclic ring or bicyclic ring system comprising α -carbon and α -amino atoms;

P⁴is a natural or non-natural aliphatic L α -amino acid containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain, or a natural or non-natural basic L α -amino acid in a single side chain comprising at least one amino functionContaining a total of 1 to 25 carbon and/or heteroatoms, or natural or unnatural L α -amino acids containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain comprising at least one urea function, amide function, ester function, sulfone function or ether function, or natural or unnatural alcohol-containing L α -amino acids containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain;

P⁷is a natural or non-natural basic L α -amino acid containing a total of 1 to 25 carbon and/or heteroatoms in a single side chain comprising at least one amino function;

Or a tautomer or rotamer thereof, or a salt, or a hydrate or solvate thereof;

and provided that

If no interchain connection is formed;

and is

T¹Is a natural or non-natural D α -amino acid containing an optionally substituted side chain forming a five-membered heterocyclic or bicyclic ring system comprising α -carbon and α -amino atoms;

then

2. A compound according to claim 1, wherein

T¹Is a D α -amino acid residue of one of the formulae

T²Is an L α -amino acid residue of one of the formulae

P¹Is an L α -amino acid residue of one of the formulae

P²Is an L α -amino acid residue of one of the formulae

P⁴Is as followsL α -amino acid residue of one of the formulae

P⁵Is an L α -amino acid residue of one of the formulae

P⁶Is Gly, or the L or D α amino acid residue of the formula

P⁷Is an L α -amino acid residue of the formula

P²And P¹¹Together and/or P⁴And P⁹Together can form an interchain linked di (amino acid) -structure based on the linkage of two L-or D- α -amino acid residues of one of the formulae

R^Aris- (CR)¹R⁴)_nR¹⁹；-(CH₂)_nO(CH₂)_mR¹⁹；-(CH₂)_nS(CH₂)_mR¹⁹(ii) a Or- (CH)₂)_nNR¹⁴(CH₂)_mR¹⁹With the proviso that less than 26 carbon atoms and/or heteroatoms are present;

R^Amis- (CR)¹R¹³)_qNR¹⁵R¹⁶；-(CH₂)_qC(＝NR¹³)NR¹⁵R¹⁶；-(CH₂)_qC(＝NOR¹⁷)NR¹⁵R¹⁶；-(CH₂)_qC(＝NNR¹⁵R¹⁶)NR¹⁷R¹⁸；-(CR¹R¹³)_qNR²C(＝NR¹⁷)NR¹⁵R¹⁶；-(CR¹R¹³)_qN＝C(NR¹⁵R¹⁶)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mNR¹⁵R¹⁶；-(CH₂)_nO(CH₂)_mC(＝NR¹⁷)NR¹⁵R¹⁶；-(CH₂)_nO(CH₂)_mC(＝NOR¹⁷)NR¹⁵R¹⁶；-(CH₂)_nO(CH₂)_mC(＝NNR¹⁵R¹⁶)NR¹⁷R¹⁸；-(CH₂)_nO(CH₂)_mNR¹C(＝NR¹⁷)NR¹⁵R¹⁶；-(CH₂)_nO(CH₂)_mN＝C(NR¹⁵R¹⁶)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mNR¹⁵R¹⁶；-(CH₂)_nS(CH₂)_mC(＝NR¹⁷)NR¹⁵R¹⁶；-(CH₂)_nS(CH₂)_mC(＝NOR¹⁷)NR¹⁵R¹⁶；-(CH₂)_nS(CH₂)_mC(＝NNR¹⁵R¹⁶)NR¹⁷R¹⁸；-(CH₂)_nS(CH₂)_mNR¹C(＝NR¹⁷)NR¹⁵R¹⁶(ii) a Or- (CH)₂)_nS(CH₂)_mN＝C(NR¹⁵R¹⁶)NR¹⁷R¹⁸With the proviso that less than 26 carbon atoms and/or heteroatoms are present;

R^OHis- (CR)¹R¹³)_qOH；-(CR¹R¹³)_qSH；-(CH₂)_nO(CH₂)_mOH；-(CH₂)_nS(CH₂)_mOH；-(CH₂)_nNR¹(CH₂)_mOH; hydroxy-C_1-8-an alkyl group; hydroxy radical-C_2-8-an alkenyl group; hydroxy-cycloalkyl; or hydroxy-heterocycloalkyl, provided that it contains less than 26 carbon and/or heteroatoms;

R¹⁰，R¹¹And R¹²Independently is H; f; cl; br; i; CF (compact flash)₃；OCF₃；OCHF₂；CN；NO₂；C_1-8-an alkyl group; c_2-8-an alkenyl group; aromatic hydrocarbonA group; a heteroaryl group; aryl-C_1-6-an alkyl group; heteroaryl-C_1-6-an alkyl group; - (CHR)¹³)_oOR¹⁵；-O(CO)R¹⁵；-(CHR¹³)_oSR¹⁵；-(CHR¹³)_oNR¹⁵R¹⁶；-(CHR¹³)_oOCONR¹⁵R¹⁶；-(CHR¹³)_oNR¹CONR¹⁵R¹⁶；-(CHR¹³)_oNR¹COR¹⁵；-(CHR¹³)_oCOOR¹⁵；-(CHR¹³)_oCONR¹⁵R¹⁶；-(CHR¹³)_oPO(OR¹)₂；-(CHR¹³)_oSO₂R¹⁵；-(CHR¹³)_oNR¹SO₂R¹⁵；-(CHR¹³)_oSO₂NR¹⁵R¹⁶(ii) a Or- (CR)¹R¹³)_oR²³；

R¹⁹is an aryl radical of one of the formulae

Or a radical of one of the formulae

X, X 'and X' are independently-CR²⁰(ii) a Or N;

R²²Is an aryl radical of the formula

R²⁶Is H; ac; c_1-8-an alkyl group; or aryl-C_1-6-an alkyl group;

R²⁷is-CO (CR)¹R¹³)_qR¹⁵；

n and m are independently integers from 0 to 5, provided that n + m.ltoreq.6;

o is 0 to 4; p is 2 to 6; q is 1 to 6; and r is 1 to 3;

or a pharmaceutically acceptable salt thereof;

and provided that

If no interchain connection is formed;

and is

then

T²Is AA 7; AA 8; or AA10^aThe L α -amino acid residue of (1).

3. A compound according to claim 1 or 2, wherein

T²Is an L α -amino acid residue of one of the formulae

AA 1; AA 7; AA 8; or AA10^a；

Or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, wherein

P¹Is an L α -amino acid residue of one of the formulae

AA 7; or AA 8;

P²is an L α -amino acid residue of one of the formulae

AA 8; or AA10

P⁵Is an L α -amino acid residue of the formula

AA 10; or AA 11;

P⁶is Gly, or the amino acid residue D or L α of the formula

AA10；

P⁹Is an L α -amino acid residue of one of the formulae

AA 7; AA 8; AA 10; or AA 11;

P¹¹is an L α -amino acid residue of one of the formulae

AA 7; AA 9; AA 10; or AA 11;

P¹²is an L α -amino acid residue of one of the formulae

AA 7; AA 8; AA 10; or AA 11;

P²and P¹¹Together and/or P⁴And P⁹Together can formFormula AA 13; or AA13^DAn interchain linked di (amino acid) -structure of one of the above;

or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 4, wherein

T¹Is that^DPro；^DAzt; or^DTic；

P²is Tyr; phe; trp; dab; dap; orn; lys; or Arg;

P³is Val; tBuGly; ala; leu; ile; val; nva; tyr; phe; or Trp;

P⁵is Orn; dap; dab; lys; arg; thr; homotype Thr; ser; or Hse;

P⁷Is Dab; dap; orn; lys; or Arg;

P⁸is Trp; phe; tyr; phg; leu; ile; val; nva; abu; or Ala;

P¹⁰is Val; tBuGly; ala; leu; ile; nva; abu; chg; phg; tyr; phe; or Trp;

P¹¹is Ala; val; abu; nva; leu; ile; ser; thr; homotype Thr; hse; asn; gln; asp; glu; dab; dap; orn;lys; or Arg;

P²and P¹¹Together and/or P⁴And P⁹Together, can form a di (amino acid) -structure based on an interchain linkage of two L-or D-amino acid residues, which is performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfide linkage; or Dap, Dab, Orn, or Lys side chain is linked to an Asp, Glu, or hGlu side chain by a lactam linkage; or the Dap, Dab or Orn side chain is linked to the Dap, Dab or Orn side chain by a urea linkage;

or a pharmaceutically acceptable salt thereof;

provided that

If no interchain connection is formed;

and is

T¹Is that^DPro; or^DTic；

Then

6. A compound according to any one of claims 1 to 5, wherein

T¹Is that^DPro; or^DAzt；

T²Is Pro; ala; leu; NMeAla; tyr; phe; dab; dap; orn; or Lys;

P¹is Leu; ile; val; cpa; cpg, respectively; phe; or Trp;

P²is Tyr; dab; dap; or Lys;

P³is Val; tBuGly; or Tyr;

P⁴is Ala; val; dab; arg; asn; or Thr;

P⁵is Orn; dap; dab; or Thr;

P⁶is Gly; dab; or^DDab；

P⁷Is Dab;

P⁸is Trp; phe; or Leu;

P⁹is Ala; tyr; dab; dap; ser; or Thr;

P¹⁰is Val; tBuGly; chg; phg; or Tyr;

P¹¹is Ala; val; ser; thr; asp; glu; dap; dab; or Lys;

P¹²is Val; tyr; his; dab; ser; or Thr;

P²and P¹¹Together and/or P⁴And P⁹Together, can form a di (amino acid) -structure based on an interchain linkage of two L-or D-amino acid residues, which is performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfide linkage; or the Dap, Dab or Lys side chain is linked to the Asp or Glu side chain by a lactam linkage; or the Dap or Dab side chain is linked to the Dap or Dab side chain by a urea linkage;

or a pharmaceutically acceptable salt thereof;

provided that

If no interchain connection is formed;

and is

T¹Is that^DPro；

Then

T²Is Ala; leu; NMeAla; tyr; phe; dab; dap; orn; or Lys.

7. A compound according to any one of claims 1 to 5, wherein

T¹Is that^DPro; or^DAzt；

T²Is Pro; leu; NMeAla; tyr; phe; dab; dap; orn; or Lys;

P¹is Leu; ile; val; phe; or Trp;

P²is Dab; dap; or Lys;

P³is Tyr;

P⁴is Ala; dab; or Arg;

P⁵is Orn; dap; dab; or Thr;

P⁶is Dab; or^DDab；

P⁷Is Dab;

P⁸is Trp; or Leu;

P⁹is Ala; or Dab;

P¹⁰is Val; tBuGly; or Phg;

P¹¹is Ala; ser; asp; glu; dap; dab, or Lys;

P¹²is Val; tyr; his; ser; or Thr;

P²and P¹¹Together and/or P⁴And P⁹Together, can form a di (amino acid) -structure based on an interchain linkage of two L-or D-amino acid residues, which is performed as follows: the Cys or Hcy side chain is linked to the Cys or Hcy side chain by a disulfide linkage; or the Dap, Dab or Lys side chain is linked to the Asp or Glu side chain by a lactam linkage; or the Dap side chain is connected with the Dap side chain through urea connection;

or a pharmaceutically acceptable salt thereof;

provided that

If no interchain connection is formed;

and is

T¹Is that^DPro；

Then

T²Is Leu; NMeAla; tyr; phe; dab; dap; orn; or Lys.

8. A compound according to any one of claims 1 to 7 selected from P²And P¹¹An β -hairpin peptidomimetic of the general formula (I) having a disulfide, lactam or urea linkage therebetween:

cyclo (-Leu-Cys-Tyr-Ala-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dab-)；

Cyclo (-Leu-Cys-Tyr-Ala-Dab-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dab-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Lys-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Orn-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dab-)；

Cyclo (-Leu-Cys-Tyr-Ala-Orn-^DDab-Dab-Trp-Ala-Val-Cys-Val-^DPro-Dap-)；

Cyclo (-Ile-Cys-Tyr-Dab-Orn-^DDab-Dab-Leu-Dab-Val-Cys-Tyr-^DPro-Pro-)；

Cyclo (-Val-Cys-Tyr-Dab-Dap-Dab-Trp-Dab-tBuGly-Cys-Thr-^DPro-Pro-)；

Cyclo (-Val-Cys-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-Cys-Ser-^DPro-NMeAla-)；

Cyclo (-Ile-Cys-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Cys-Ser-^DPro-Pro-)；

Cyclo (-Ile-Cys-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Cys-Ser-^DPro-Tyr-)；

Cyclo (-Val-Dab-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-Asp-Thr-^DAzt-Pro-)；

Cyclo (-Phe-Dab-Tyr-Arg-Orn-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Trp-Dab-Tyr-Dab-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Trp-Dab-Tyr-Dab-Trp-Dab-tBuGly-Asp-Ser-^DAzt-Pro-)；

Cyclo (-Val-Dab-Tyr-Dab-^DDab-Dab-Trp-Dab-Phg-Asp-Ser-^DPro-Pro-)；

Cyclo (-Val-Dab-Tyr-Dab-Thr-Dab-Trp-Dab-tBuGly-Asp-His-^DPro-Pro-)；

Cyclo (-Leu-Glu-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Dap-Ser-^DPro-Pro-)；

Cyclo (-Leu-Glu-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Dab-Ser-^DPro-Pro-)；

Cyclo (-Leu-Glu-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Lys-Ser-^DPro-Pro-)；

Cyclo (-Leu-Asp-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Dap-Ser-^DPro-Pro-)；

Cyclo (-Leu-Asp-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Dab-Ser-^DPro-Pro-)；

Cyclo (-Leu-Asp-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Dab-Ser-^DPro-Pro-)；

Cyclo (-Leu-Asp-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Lys-Ser-^DPro-Pro-)；

Cyclo (-Leu-Asp-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Lys-Ser-)^DPro-Pro-)；

Cyclo (-Leu-Dap-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Glu-Ser-^DPro-Pro-)；

Cyclo (-Leu-Lys-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Glu-Ser-^DPro-Pro-)；

Cyclo (-Val-Dab-Tyr-Dab-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dap-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Glu-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dab-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Glu-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dap-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dab-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Lys-Tyr-Dab-Orn-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Glu-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Dap-Ser-^DPro-Pro-)；

Cyclo (-Leu-Lys-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dap-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Leu-Dab-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Asp-Ser-^DPro-Pro-)；

Cyclo (-Val-^DCys-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-^DCys-Ser-^DPro-Pro-)；

Cyclo (-Val-Hcy-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-Cys-Ser-^DPro-Pro-)；

Cyclo (-Val-Dap-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-Dap-Ser-^DPro-Pro-)；

Or a pharmaceutically acceptable salt thereof;

and/or

Beta-hairpin peptidomimetics selected from the general formula (I)

Cyclo (-Val-Dap-Tyr-Dab-Dap-^DDab-Dab-Trp-Dab-tBuGly-Ser-Thr-^DAzt-Pro-)；

Cyclo (-Phe-Dap-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Ala-Ser-^DPro-Leu-)；

Cyclo (-Phe-Dap-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Ala-Ser-^DPro-Phe-)；

Cyclo (-Phe-Dap-Tyr-Dab-Orn-^DDab-Dab-Trp-Dab-tBuGly-Ala-Ser-^DPro-Tyr-)；

Or a pharmaceutically acceptable salt thereof.

9. A diastereomer or epimer of a compound of formula (I) as defined in claim 1, which is based on one or more chiral centers not explicitly specified in formula (I), or an enantiomer of a compound of formula (I).

10. A pharmaceutical composition comprising a compound or mixture of compounds according to any one of claims 1 to 9 and at least one pharmaceutically inert carrier.

11. A pharmaceutical composition according to claim 10, in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, rectal, pulmonary or inhalation administration, particularly in the form of tablets, lozenges, capsules, solutions, liquids, gels, plasters, creams, ointments, syrups, slurries, suspensions, sprays, nebulisers or suppositories.

12. A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use as a medicament.

13. Use of a compound according to any one of claims 1 to 9 as a pharmaceutically active substance with antibiotic activity.

14. Use of a compound according to any one of claims 1 to 9 or a composition according to claim 10 or 11 for the treatment or prevention of an infection or a disease involving said infection; in particular infections related to respiratory diseases or skin or soft tissue diseases or gastrointestinal diseases or eye diseases or ear diseases or CNS diseases or bone diseases or cardiovascular diseases or genitourinary diseases, or iatrogenic infections, or catheter-related and non-catheter-related infections, or urinary tract infections, or bloodstream infections; or as a disinfectant or preservative for food, cosmetics, pharmaceuticals and other nutrient-containing materials.

15. A process for the preparation of a compound according to any one of claims 1 to 9, which comprises

(b) removing the N-protecting group from the product obtained in step (a);

(d) removing the N-protecting group from the product thus obtained;

(g) removing the product thus obtained from the solid support;

(h) cyclizing the product cleaved from the solid support;

(j) removing any protecting groups present on the functional groups of any members of the chain of amino acid residues and, if desired, any protecting groups that may be additionally present in the molecule;

(l) If desired, removing any protecting groups present on the functional groups of any members of the chain of amino acid residues and, if desired, removing any protecting groups that may otherwise be present in the molecule; and is

16. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment or prevention of an infection or a disease involving said infection; in particular infections related to respiratory diseases or skin or soft tissue diseases or gastrointestinal diseases or eye diseases or ear diseases or CNS diseases or bone diseases or cardiovascular diseases or genitourinary diseases, or iatrogenic infections, or catheter-related and non-catheter-related infections, or urinary tract infections, or bloodstream infections; or as a disinfectant or preservative for food, cosmetics, pharmaceuticals and other nutrient-containing materials.

17. Methods of treating infections or diseases or disorders associated with infections, such as, inter alia, nosocomial infections, catheter-related and non-catheter-related infections, urinary tract infections, bloodstream infections; the disease or disorder associated with infection, in particular a disease or disorder such as Ventilator Associated Pneumonia (VAP), hospital-acquired pneumonia (HAP), Health Care Associated Pneumonia (HCAP), cystic fibrosis, emphysema, asthma, pneumonia, epidemic diarrhea, necrotizing enterocolitis, cecal enteritis, gastroenteritis, pancreatitis, keratitis, endophthalmitis, otitis, brain abscess, meningitis, encephalitis, osteochondritis, pericarditis, epididymitis, prostatitis, urethritis, surgical wounds, traumatic wounds, burns, comprises administering to a subject in need thereof a pharmaceutically acceptable amount of a compound or pharmaceutical composition according to any one of claims 1 to 11.