EP0456758A1 - Ligands de recepteurs d'anaphylatoxines - Google Patents

Ligands de recepteurs d'anaphylatoxines

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Publication number
EP0456758A1
EP0456758A1 EP90903567A EP90903567A EP0456758A1 EP 0456758 A1 EP0456758 A1 EP 0456758A1 EP 90903567 A EP90903567 A EP 90903567A EP 90903567 A EP90903567 A EP 90903567A EP 0456758 A1 EP0456758 A1 EP 0456758A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
amino
group
arginyl
lysyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90903567A
Other languages
German (de)
English (en)
Other versions
EP0456758A4 (en
Inventor
Megumi Kawai
Yat Sun Or
Paul E. Wiedeman
Jay R. Luly
Mikel P. Moyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0456758A1 publication Critical patent/EP0456758A1/fr
Publication of EP0456758A4 publication Critical patent/EP0456758A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/472—Complement proteins, e.g. anaphylatoxin, C3a, C5a
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to organic compounds that
  • polypeptide is generated by cleavage of the alpha-chain of native C5 at a specific site by convertases (proteolytic enzymes) of the blood complement system as well as by enzymes of the coagulation system.
  • convertases proteolytic enzymes
  • degradation products are capable of triggering diverse inflammatory reactions.
  • the neutrophil response to C5a is the best defined.
  • Cell surface receptors specific for C5a have been demonstrated on the neutrophil (Chenoweth, D. E.; Hugli, T. E. Proc. Natl . Acad. Sci . U. S. A . 1978, 15 r 3943-3947.
  • C5a may also be important in mediating inflammatory effects of phagocytic mononuclear cells that accumulate at sites of chronic inflammation
  • C5a and C5a des-Arg can induce chemotaxis in monocytes (Ward, P. A. J. Exp . Med.
  • erythematosus erythematosus, ulcerative colitis, and forms of hepatic cirrhosis, chronic hepatitis, and glomerulonephritis, in certain shock states, during hemodialysis, and
  • certain compounds of the present invention can reduce or prevent anaphylatoxin-mediated inflammation.
  • Other compounds of the present invention are agonists that mimic anaphylatoxin activity, and assist the body in building its defense mechanism against invasion by infectious agents and malignancy. Additionally, these compounds may influence the immunoregulatory effects of anaphylatoxin.
  • anaphylotoxin activity modifying compounds of the formula A-B-D-E-G-J-L-M-Q-T and the pharmaceutically acceptable salts, esters, or
  • A is R 1 -R 2 -R 3 ;
  • B is selected from R 4 -R 5 -R 6 , R 31 , R 32 , R 35 and R 37 ;
  • D is selected from R 7 -R 8 -R 9 , R 31 , R 32 , R 35 and R 37 ;
  • E is selected from R 10 -R 11 -R 12 , R 31 , R 32 , R 35 and R 37 ;
  • G is selected from R 13 -R 14 -R 15 , R 31 , R 32 , R 35 and R 37 ;
  • J is selected from R 16 -R 17 -R 18 , R 31 , R 32 , R 35 and R 37 ;
  • L is selected from R 19 -R 20 -R 21 , R 31 , R 32 , R 35 and R 37 ;
  • M is selected from R 22 -R 23 -R 24 , R 31 , R 32 , R 35 and R 37 ;
  • Q is selected from R 25 -R 26 -R 27 , R 31 , R 32 , R 35 and
  • T is R 28 -R 29 -R 30 ;
  • B and D taken together, optionally represent a group selected from R 33 , R 34 , R 38 , R 39 , R 40 , R 41 , R 42 , and
  • D and E taken together, optionally represent a group selected from R 33 , R 34 , R 38 , R 39 , R 40 , R 41 , R 42 , and
  • E and G taken together, optionally represent a group selected from R 33 , R 34 , R 38 , R 39 , R 40 , R 41 , R 42 , and
  • G and J taken together, optionally represent a group selected from R 33 , R 34 , R 38 , R 39 , R 40 , R 41 , R 42 , and
  • J and L taken together, optionally represent a group selected from R 33 , R 34 , R 38 , R 39 , R 40 , R 41 , R 42 , and
  • L and M taken together, optionally represent a group selected from R 33 , R 34 , R 38 , R 39 , R 40 , R 41 , R 42 , and
  • M and Q taken together, optionally represent a group selected from R 33 , R 34 , R 38 , R 39 , R 40 , R 41 , R 42 , and
  • R 23 -R 24 -R 25 ; or R 26 -R 27 -R 28 independently optionally represent R 36 .
  • the group Ri is selected from the group consisting of amino, (lower alkyl) amino, dialkylammo, (arylalkyl) amino, hydroxy, alkoxy, aryloxy, arylalkoxy, acetamido, thioalkoxy, halogen, aryl, lower alkyl, arylalkyl, (heterocyclic) alkyl, heterocyclic, arylamino, and hydrogen.
  • aryl lower alkyl, arylalkyl or (heterocyclic) alkyl.
  • R 4 is selected from the group consisting of >CH 2 , >O, >S, and >NR 101 where R 101 is hydrogen, lower alkyl, arylalkyl, alkenyl, hydroxy or alkoxy, with the proviso that when R 4 is >O or >S then R 1 , R 2 and R 3 taken together represent a group selected from lower alkyl, arylalkyl, aryl or hydrogen.
  • R 7 , R 10 , R 13 , R 16 , R 19 , R 22 , R 25 are independently selected from >CH 2 and >NR 50 where R 50 is selected from the group consisting of hydrogen, lower alkyl, arylalkyl, aryl, hydroxy and alkoxy.
  • R 28 is selected from the group consisting of >O, >S, >CH 2 , and >NR 109 where R 109 is selected from hydrogen, lower alkyl, (heterocyclic) alkyl, and arylalkyl, with the proviso that when R 27 is >SO 2 or >P(O)X, then R 28 is >O or >NR 109 .
  • R 29 is selected from the group consisting of hydrogen, lower alkyl, arylalkyl, and >NR 110 where R 110 is selected from hydrogen, lower alkyl, aryl, and arylalkyl, with the provisos that (i) when R 28 is >O, or >S then R 29 is lower alkyl or arylalkyl, and (ii) when R 29 is hydrogen, lower alkyl, or arylalkyl then R 30 is absent.
  • R 30 is selected from the group consisting of hydrogen, aryl, lower alkyl, and arylalkyl.
  • R 31 is a group having the structure
  • n and n are integers independently selected from 0, 1 and 2.
  • R 32 is a group having the structure
  • R 33 is a group having the structure
  • t and v are integers independently selected from 0, 1,
  • R 34 is a group having the structure
  • r and s are integers independently selected from 0, 1, 2 and 3.
  • R 35 is a group having the structure
  • f is and integer of 0 to 3
  • R is selected from hydrogen and lower alkyl, with the provisos that (i) when f is 0, X is at C-2 and R is at C-3 or C-4; (ii) when f is 1, X is at C-2 and R is at C-3, C-4 or C-5 and C-3, 4 are saturated or unsaturated; (iii) when f is 2, X is at C-2, C-3 or C-4 and R is at C-2, C-3, C-4, C-5 or C-6 when the position is unoccupied by X and C-3, 4 or C-4, 5 are saturated or unsaturated; and (iv) when f is 3, X is at C-2, C-3 or C-4 and R is at C-2, C-3, C-4, C-5, C-6 or C-7 when the position is unoccupied by X and C-3,4 or C-4, 5 or C-5,6 are saturated or unsaturated.
  • R 36 is a group having the structure
  • g is an integer of from 0 to 3.
  • R 37 is a group having the structure
  • h is 0 or 1 and j is 0 or 1 with the proviso that either h or j must be 1.
  • R 38 is a group having the structure
  • R 39 is a group having the structure
  • R 40 is a divalent group having the structure
  • R 41 is a divalent group having the structure
  • R 42 is a divalent group having the structure
  • R 43 is a divalent group having the structure
  • k is an integer of from zero to two.
  • R 1 and R 2 taken together, optionally may represent a group selected from aryl, heterocyclic, or hydrogen.
  • R 6 and R 7 ; R 9 and R 10 ; R 12 and R 13 ; R 15 and R 16 ; R 18 and R 19 ; R 21 and R 22 ; and R 24 and R 25 ,. each pair taken together, may optionally and independently represent a group selected from >CH 2 , -(CH 2 ) 3 -, -CH CH-,
  • R 29 and R 30 taken together, optionally represent a group selected from hydrogen, hydroxy, or alkoxy, with the proviso that when R 28 is >O or >S then R 29 and R 30 , taken together, represent hydrogen.
  • R 1 , R 2 and R 3 taken together, optionally represent a group selected from lower alkyl, arylalkyl, alkenyl, aryl, hydroxy, alkoxy, hydrogen, an N-terminal protecting group or peptide fragment of 1-8 residues similarly protected wherein each of the amino acids comprising the peptide fragment is independently selected from the 20 naturally occuring amino acids.
  • R 1 , R 2 , R 3 and R 4 taken together, optionally represent a group selected from hydrogen, lower alkyl, arylalkyl, aryl, heterocyclic, or H2NC(O)-, with the proviso that when R 5 is >CH 2 then R 1 , R 2 , R 3 and R 4 , taken together, may not be hydrogen.
  • R 27 , R 28 , R 29 and R 30 taken together, optionally, represent a group selected from hydrogen, lower alkyl, aryl, or arylalkyl.
  • R 1 , R 2 , R 3 , R 4 and R 5 taken together, optionally represent an aryl or heterocyclic group.
  • R 95 , R 96 , R 205 , R 206 , R 215 , R 216 , R 225 , R 226 , R 235 , R 236 , R 305 , R 306 , R 315 , R 316 , R 335 and R 336 are
  • alkyl independently selected from the group consisting of hydrogen, lower alkyl, aryl, arylalkyl, (cycloalkyl) alkyl, amidoalkyl, (carboxyamido) alkyl, ureidoalkyl, (heterocyclic) alkyl,- and halosubstituted alkyl.
  • R 99 , R 202 , R 211 , R 221 , R 231 , R 302 , R 311 , R 321 and R 331 are independently selected from hydrogen and lower alkyl.
  • R 100 is selected from the group consisting of hydrogen, lower alkyl, arylalkyl, (cycloalkyl) alkyl, aminoalkyl,
  • R 201 is selected from the group consisting of hydrogen, lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl) alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamido) alkyl, (carboxyhydrazino) alkyl, ureidoalkyl, (heterocyclic) alkyl, (thioalkoxy) alkyl,
  • R 203 , R 213 , R 223 , R 233 , R 303 , and R 313 are independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, arylalkyl, (cycloalkyl) alkyl,
  • R 203 , R 213 , R 223 , R 233 , R 303 , or R 313 may be a vinyl group or have a heteroatom directly attached to the nitrogen or separated from it by one
  • R 210 is hydrogen, lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl) alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl, (carboxyamido) alkyl,
  • ureidoalkyl (carboxyhydrazino) alkyl, (heterocyclic) alkyl, (thioalkoxy) alkyl, sulfhydrylalkyl, (aminothioalkoxy) alkyl, (thioarylalkoxy) alkyl, protected sulfhydrylalkyl, or
  • R 220 , R 230 , R 301 , R 310 , and R 330 are independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, aryl, arylalkyl, (cycloalkyl) alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, guanidinoalkyl, carboxyalkyl,
  • R 320 and R 323 are selected from the group consisting of hydrogen, lower alkyl, alkenyl, aryl, benzyl,
  • R 340 , R 341 , R 342 , and R 343 are independently selected from hydrogen and lower alkyl
  • R 344 and R 345 are independently selected from hydrogen, lower alkyl, and halosubstituted lower alkyl, with the proviso that R 323 may not be a vinyl group or have a heteroatom directly attached to the nitrogen or separated from it by one methylene unit.
  • R 325 and R 326 are independently selected from the group consisting of hydrogen, lower alkyl, aryl, (cycloalkyl) alkyl,
  • R 345 are as defined above.
  • R 201 and R 202 R 210 and R 211 , R 220 and R 221 , R 230 and R 231 , R 301 and R 302 , R 310 and R 311 , R 320 and R 321 , and R 330 and R 331 , each pair taken together, independently may
  • C5a is the most active of a class of biologically active peptides which serves to amplify and exacerbate inflammation. While C5a contains 74 amino acid residues, it has been found in accordance with the present invention that oligopeptides containing as few as eight amino acid residues are also actively bound by C5a receptors.
  • peptidomimetic compounds i.e. compounds which mimic the activity of peptides
  • certain groups replace the ⁇ -carbon, carbonyl group, and amide-nitrogen group of the individual amino acids in oligopeptides are also actively bound by C5a receptors.
  • alkyl refers to monovalent straight chain or branched chain groups of 1 to 12 carbon atoms, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • lower alkyl refers to straight or branched chain alkyl groups containing from 1 to 8 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
  • alkylene refers to divalent groups of from one to twelve carbon atoms derived by the removal of two hydrogen atoms from straight or branched saturated hydrocarbons. Examples include -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(C 2 H 5 )-, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-,
  • alkenyl refers to straight or branched chain groups of 2 to 12 carbon atoms containing a carbon-carbon double bond, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, and the like.
  • halosubstituted alkyl refers to an alkyl group as described above substituted with one or more
  • halogens including, but not limited to chloromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like.
  • halo and halogen are used herein to mean groups derived from the elements fluorine, chlorine, bromine, or iodine .
  • cycloalkyl refers to cyclic groups, of 3 to 8 carbons, including, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • (cycloalkyl) alkyl refers to a cycloalkyl group appended to a lower alkyl group, including, but not limited to cyclohexylmethyl and cyclohexylethyl.
  • alkoxy refers to an alkyl group as defined above, attached to the remainder of the molecule through an oxygen atom. Alkoxy groups include, for example, methoxy, ethoxy, isopropoxy, n-butoxy, sec-but ⁇ xy, isobutoxy, tert-butoxy, and the like.
  • sulfhydrylalkyl refers to a -SH group appended to a lower alkyl group, as previously defined.
  • protected sulfhydrylalkyl refers to a
  • S-Acm S-acetamidomethyl
  • thioalkoxy refers to an alkyl group, as previously defined, attached to the remainder of the molecule through a sulfur atom.
  • thioalkoxy groups include, but are not limited to, thiomethoxy,
  • (thioalkoxy) alkyl refers to a thioalkoxy group, as just defined, appended to a " lower alkyl group .
  • (thioarylalkoxy) alkyl refers to a group of the structure R 420 -S- appended to a lower alkyl where R 420 is an arylalkyl group as defined below ⁇
  • aryl refers to substituted and unsubstituted carbocyclic aromatic groups including, but not limited to phenyl, 1- or 2-naphthyl, fluorenyl, (1,2)-dihydronaphthyl, (1,2,3,4)-tetrahydronaphthyl, indenyl, indanyl, and the like, wherein the aryl group may be
  • arylalkyl refers to an aryl group, as previously defined, appended to an alkyl group, including, but not limited to benzyl, 1- and
  • phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl,
  • benzyl refers specifically to to phenyl substituted methyl in which the phenyl group may be substituted with 1, 2, or 3 substituents independently selected from halo, nitro, cyano, alkyl of from one to twelve carbon atoms, alkoxy, aroyl, and halosubstituted alkyl, and the like.
  • aryloxy refers to an aryl group as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Aryloxy includes, but is not limited to phenoxy, 1-naphthoxy, 2-naphthoxy and the like.
  • arylalkoxy refers to an arylalkyl group as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • aroyl refers to an aryl group as defined above, attached to the parent molecule through a carbonyl group. Examples include benzoyl and substituted benzoyl.
  • alkylamino refers to a group having the structure -NH (alkyl) where the alkyl portion is as defined above.
  • Alkylamino groups include, for example, methylamino, ethylamino, isopropylamino and the like.
  • dialkylammo refers to a group having the structure -N (alkyl) (alkyl) where the two alkyl groups may be the same or different and are as previously defined.
  • aminoalkyl refers to a group having the structure -NR 342 R 343 appended to a lower alkyl , group, as previously defined.
  • the groups R 342 and R 343 are independently selected from hydrogen, lower alkyl, aryl and arylalkyl . Additionally, R 342 and R 343 taken together, may optionally be -(CH 2 ) mm - where mm is an integer of from 2 to 6.
  • amidoalkyl refers to a group having the structure -NR 344 C (O)R 345 appended to a lower alkyl group, as previously defined.
  • the groups R 344 and R 345 are independently selected from hydrogen, lower, alkyl, aryl, arylalkyl, and halosubstituted alkyl. Additionally, R. 3 , 44 and R 345 taken together may optionally be -(CH 2 ) kk - where kk is an integer of from 2 to 6.
  • (aminothioalkoxy) alkyl refers to H 2 N-Rx-S-Ry- where Rx and Ry are alkylene groups, as previously defined, and may be the same or different.
  • carboxyalkyl refers to a carboxyl group, -CO 2 H, appended to a lower alkyl group, as previously defined.
  • (carboxyamido) alkyl refers to a group of the formula -C (O)NR 340 R 341 , appended to a Lower alkyl group, as previously defined.
  • the groups R 340 and R 341 are independently selected from hydrogen, lower alkyl, aryl and arylalkyl. Alternatively, R 340 and R 341 taken together may optionally be -(CH 2 ) pp - wherein pp is an integer of from 2 to 6.
  • (carboxyhydrazino) alkyl refers to a group having the structure -C(O)NR 425 NHR 430 appended to a lower alkyl group, as previously defined.
  • the groups R 425 and R 430 are independently selected from hydrogen, lower alkyl, aryl and arylalkyl.
  • R 346 , R 347 , and R 348 are independently selected from hydrogen, lower alkyl, and aryl.
  • ureidoalkyl refers to a group having the structure -NHC(O)NH 2 appended to a lower alkyl group, as previously defined.
  • heterocyclic refers to any 5- or 6-membered ring containing from one to three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the 5-membered ring has 0 to 2 double bonds and the 6-membered ring has 0 to 3 double bonds, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, wherein the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring.
  • heterocycles include, but are not limited to pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,
  • pyrazolidinyl imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazoyl, oxazolidinyl, isoxazolyl,
  • (heterocyclic) alkyl refers to a heterocyclic group, as previously defined, appended to an alkyl group as previously defined.
  • hydroxyalkyl refers to -OH appended to a lower alkyl group.
  • naturally occuring amino acid refers to an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, gl ⁇ tamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanme, proline, serine,
  • N-terminal protecting group refers to those groups intended to protect the N-terminus against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the final compounds or to increase the solubility of the final compounds and includes, but is not limited to acyl, acetyl, pivaloyl, tert-butylacetyl, tert-butyloxycarbonyl (Boc), carbobenzyloxycarbonyl (Cbz) , benzoyl groups or an L- or D-aminoacyl residue, which may itself be N-protected similarly.
  • anaphylatoxin is used herein to mean C5a, C4a, C3a, or the corresponding des-Arg degradation products.
  • pharmaceutically acceptable salt refers to non-toxic acid addition salts such as salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, malic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • Other pharmaceutically acceptable salts include inorganic nitrate, sulfate, acetate, malate, formate, lactate, tartrate, succinate, citrate, p-toluenesulfonate, and the like, including, but not limited to cations based on the alkali and alkaline earth metals, such as sodium,
  • ammonium lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,
  • esters of the compounds of this invention include C 1 to C 6 alkyl esters wherein the alkyl group is straight or branched chain. Acceptable esters also include C 5 to C 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C 1 to C 4 alkyl esters are preferred. Esters of the compound of formula I may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C 1 to C 6 alkyl amines and secondary C 1 to C 6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 to C 3 alkyl primary amides and C 1 to C 2 dialkyl secondary amides are preferred. Amides of the compound of formula I may be prepared according to
  • chiral centers can exist at R 2 , R 5 , R 8 , R 11 , R 14 , R 17 , R 20 , R 23 and R 26 .
  • these groups comprise the ⁇ -carbon atom of an ⁇ -amino acid, the natural configuration is
  • Particular stereoisomers are prepared by selecting the starting amino acids or amino acid analogs having the desired stereochemistry and reacting these starting ⁇ materials by the methods detailed below.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods detailed below and resolved by techniques well known in the organic chemical arts.
  • R 4 , R 7 , R 10 , R 13 , R 16 , R 19 , R 22 , and R 25 are independently selected from >NH and >N- (lower alkyl).
  • R 202 and R 205 are selected from the group consisting of hydrogen and lower alkyl;
  • R 203 is selected from the group consisting of lower alkyl, alkenyl, arylalkyl, (cycloalkyl) alkyl, amidoalkyl, (carboxyamido) alkyl,
  • R 203 may not be a vinyl group or have a heteroatom directly attached to the nitrogen or separated from it by one
  • R 206 is selected from the group consisting of lower alkyl; aryl; arylalkyl; (cycloalkyl) alkyl;
  • amidoalkyl (carboxyamido) alkyl; (heterocyclic) alkyl; and halosubstituted alkyl.
  • R 210 is selected from the group consisting of arylalkyl; aminoalkyl; guanidinoalkyl;
  • R 211 and R 215 selected from hydrogen and lower alkyl
  • R 213 is selected from the group consisting of arylalkyl; aminoalkyl
  • R 213 may not have a herteroatom directly attached to the nitrogen or separated from it by one methylene unit; and R 216 is selected from arylalkyl and (heterocyclic) alkyl.
  • R 336 is selected from arylalkyl and (heterocyclic)- alkyl;
  • R 330 is selected from the group consisting of
  • arylalkyl aminoalkyl, guanidinoalkyl, (heterocyclic) alkyl and (aminothioalkoxy) alkyl; and R 331 is hydrogen or lower alkyl.
  • the compounds of the present invention serve to modulate the activity of anaphylatoxin.
  • Certain compounds of the present invention function as anaphylatoxin antagonists, while others function as agonists.
  • the antagonist compounds of the present invention block the anaphylatoxin receptor and prevent anaphylatoxin activity, which makes those compounds useful in the treatment and prevention of injurious
  • anaphylatoxin is involved.
  • Disease states in which anaphylatoxin is involved include asthma, bronchial allergy, chronic inflammation, systemic lupus erythematosus, vasculitis, serum sickness, angioedema, rheumatoid arthritis, osteoarthritis, gout, bullous skin diseases, hypersensitivity pneumonitis,
  • idiopathi ⁇ pulmonary fibrosis immune complex-mediated glomerulonephritis, psoriasis, allergic rhinitis, adult respiratory distress syndrome, acute pulmonary disorders, endotoxin shock, hepatic cirrhosis, pancreatitis,
  • inflammatory bowel diseases including Crohn's disease and ulcerative colitis
  • thermal injury Gram-negative sepsis, necrosis in myocardial infarction, leukophoresis, exposure to medical devices (including but not limited to hemodialyzer membranes and extracorpeal blood circulation equipment), chronic hepatitis, transplant rejection, post-viral
  • encephalopathies and/or ischemia induced myocardial or brain injury. These compounds may also be used as prophylactics for such conditions as shock accompanying Dengue fever.
  • antibiotic and anti-inflammatory agent such as corticosteroids (e.g., methylprednisolone) and one or more of the above mentioned compounds may be employed.
  • therapeutic agents because of their ability to mimic or promote anaphylatoxin activity and are therefore useful in stimulating the inflammatory response and immune response in mammals who are deficient in this regard.
  • These agonist compounds may be used to assist the body in building its defense mechanism against invasion by infectious
  • agonists at the anaphylatoxin receptor makes them useful in treating conditions or diseases including, but not limited to cancers (including but not limited lung carcinoma),
  • the compounds of the present invention may be any organic compound having the same properties.
  • the compounds of the present invention may be any organic compound having the same properties.
  • parenteral as used herein includes
  • topically encompasses administration rectally and by inhalation spray, as well as by the more common routes of the skin and the mucous membranes of the mouth and nose .
  • compositions of this invention may be varied so as to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated.
  • dosage levels of about 0.001 mg to about 100 mg, more typically from about 0.1 mg to about 20 mg, of active compound per kilogram of body weight per day are administered daily to a mammalian host.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or
  • aqueous and nonaqueous cariers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay abdorption such as aluminum monostearate and gelatin.
  • the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alignates, gelatin,
  • polyvmylpyrrolidone sucrose, and acacia
  • humectants such as glycerol
  • disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution
  • lubricants such as .as talc, calcium stearate, magnesium
  • the dosage form may also comprise buffering agents.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, 4n a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, 4n a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsjulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions,
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzy
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • novel compounds and salts thereof of the invention can be utilized effectively as therapeutic agents.
  • the present invention further relates to
  • compositions comprising a novel compound having the general formula I or salts thereof as an active
  • the compounds of the invention may be prepared by a synthetic method of elongation of a peptide chain through condensation of one amino acid by one, or by a method of coupling fragments consisting of two or several amino acids, or by a combination of these methods in accordance with conventional peptide synthesis methods.
  • condensation of two amino acids may be effected in accordance with conventional condensation methods such as azide method, mixed acid anhydride method, symmetrical anhydride method, DCC (dicyclohexylcarbodiimide) method, active ester method (p-nitrophenyl ester method, N-hydroxysuccinimide ester method, cyanomethyl ester method and the like), Woodward reagent K method, DCC-HOBT (1-hydroxy-benzotriazole) method and the like. These condensation reactions may be done by either solution methods or solid phase synthetic methods.
  • the C-terminal amino acid is linked to an insoluble carrier.
  • the insoluble carrier any that can produce a detachable bond by reacting with a carboxyl group in a C- terminal amino acid may be used, and the examples thereof involve, for example, halomethyl resins such as chloromethyl resin, bromomethyl resin and the like, hydroxy-methyl resin, benzhydrylamine resin, and t-alkyloxycarbonyl hydrazide resin.
  • branched chain amino and carboxyl groups at alpha and omega positions in amino acids may be protected/deprotected if necessary.
  • the protecting groups for amino groups which can be used involve, for example, benzyloxycarbonyl (Z), o-chlorobenzyloxycarbonyl ((2-Cl)Z), p-nitrobenzyloxycarbonyl (Z(NO 2 )), p-methoxy- benzyloxycarbonyl (Z(OMe)), t-butoxycarbonyl (Boc), t-amyloxycarbonyl (Aoc), isobornyloxycarbonyl,
  • Ppt diphenylphosphinothioyl
  • Mpt dimethylphosphinothioyl
  • protecting groups for carboxyl groups involve, for example, benzyl ester (OBn), cyclohexyl ester, 4-nitrobenzyl ester (OBnNO 2 ), t-butyl ester (OtBu), 4-pico ⁇ yl ester (OPic) and the like.
  • the guanidino group (N G ) in arginine may be protected with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxybenzenesulfonyl, 4-methoxy-2, 6-dimethylbenzene- sulfonyl (Mds), 1,3,5-trimethylphenylsulfonyl (Mts) and the like, and the thiol group in cysteine may be protected with benzyl, p-methoxybenzyl, triphenylmethyl, acetamidomethyl, ethylcarbamyl, 4-methylbenzyl (4-MeBn), 2, 4, 6-trimethylbenzyl (Tmb) and the like, and the hydroxyl group in serine may be protected with benzyl (Bn), t-butyl, acet
  • N-Acetylated peptides were prepared in analogy to.
  • Example 99 The following literature procedures were used to prepare N-alkyl- or N,N-dialkyl-amino acid derivatives.
  • (2S)-2-Amino-4-cyclohexylbutanoic acid A solution of (2S) -2-amino-4-phenylbutanoic acid (5 g) in 10% HOAC-H 2 O (50 mL) was hydrogenated at room temperature at 5 atms with platinum oxide (0.1 g) . Removal of catalyst by filtration and evaporation yielded 4.9 g of product. 3-(2'- Perhydronaphthyl) ⁇ alanine and 3-(1'-perhydronaphthyl) Jalanine were prepared similarly from L-3-(2'-naphthyl) ⁇ aianine and L-3-(1'-naphthyl) ⁇ alanine, respectively.
  • the compounds of the invention were prepared by standard solid phase peptide synthesis conditions as described in "Solid Phase Peptide Synthesis” by J. M. Stewart and J. D, Young, Second Edition (1984) and illustrated in Examples 1 and 2 in the experimental section.
  • the compounds of the invention may also be prepared by partial solid phase synthesis, fragment condensation methods and classical solution methods as exemplified by the methods described in "Peptide Synthesis", Second Edition, M.
  • the standard chirality descriptors "R” and “S” are used to indicate an isomerically pure center, “RS” to indicate a mixture, and “R/S” to indicate a single pure isomer of undetermined configuration.
  • the descriptor “ ⁇ ” refers to a d, 1 mixture of amino acids at the indicated residue.
  • the descriptor ⁇ X ⁇ indicates the group, X, that is a replacement for the standard peptide bond, -C(O)NH-.
  • the descriptor "*" or "**” when written in a chemical name indicates the site of a disulfide or amide linkage, respectively.
  • Boc-Arg(N-guanidino-Tos)-Merrifield resin (0.4-1.0 g) was placed in a solid phase peptide synthesis vessel and amino acids were attached to the resin sequentially in the following order: Boc-D-Alanine, Boc-Leucine, Boc-(2S)-2-Amino-3-cyclohexylpropanoic acid, Boc-(2S)-2-Amino-3-cyclohexylpropanoic acid, Boc-Alanine, (N-alpha-Boc,N-e
  • the protected peptide resin was removed from the reaction vessel by washing the resin three times with 20 mL DMF into a 30-60 mL sintered glass funnel, followed by washing the resin three. times with 20 mL methylene chloride. The resin was dried at least five hours, then weighed. Agenda A
  • the protected peptide resin of Example 1 (0.. ⁇ .. g) was treated with 1.0 mL anisole and 10 mL hydrogen fluoride (HF) for 60 minutes at 0oC.
  • the HF and anisole were removed in vacuo at 0oC, and the mixture of the peptide and resin was washed with diethyl ether (2 ⁇ 25 mL).
  • the crude peptide was extracted from the mixture by treatment with portions of 20 % aqueous acetic acid (4 ⁇ 25 mL), lyophilized to a dry amorphous powder, and purified by high performance liquid chromatography (HPLC) ⁇ column: 21.4 mm ID ⁇ 25 cm or 41.4. mm
  • DMF N,N-dimethylformamide
  • the resin was washed with an additional 10 mL of DMF, and the combined DMF solution was poured 'into 100 mL of diethylether. Upon cooling the mixture, it gradually solidified. The solid was collected by filtration, washed with 50 mL of water and dried. The dry solid obtained
  • N-alpha-Boc-N-guanidino-Tosyl-Arginine is converted to its aldehyde which is reacted with methylenetriphenyl-phosphorane using a modified literature procedure (Luly, J. R.; Dellaria, J. F.; Plattner, J. J.; Soderquist, J. L.; Yi, N. J. Org. Chem. 1987, 52, 1487) followed by hydrogenation on Pd/C to yield (4R)-N-alpha-Boc-N-guanidino-Tosyl-(4-Ethyl)Agmatine.
  • the protected peptide N-Boc-(N-Methyl)Phenylalanyl-N-epsilon-Cbz-Lysyl-(N-Methyl)Alanyl- ⁇ (2S)-2-Amino-3-cyclohexylpropanoyl ⁇ -Gylcyl-Leucyl-(N-Methyl) DAlanine is synthesized according to the procedure of Example No. 309. The above agmatine derivative is treated with 4N-HCl/Dioxane, and the resulting salt is coupled with the protected peptide using a DCC/HOBT mediated coupling procedure. The protecting groups are removed by treatment with liquid HF/anisole according to the procedure of Example 2.
  • N-Boc-(N-Methyl)Phenylalanyl-N-epsilon-Boc-Lysyl-(N-Methyl)Alanyl- ⁇ (2S)-2-Amino-3-cyclohexylpropanoyl ⁇ -Gylcyl-Leucyl-(N-Methyl) DAlanine is prepared by the method described below.
  • the peptide chain is elongated by the same method described in Example 1, except that after N-alpha-Fmoc-N-epsilon-Boc-Lysine is coupled, the sequence is stopped at agenda A-step 5.
  • the obtained N-alpha-Fmoc-N-epsilon-Boc-Lysyl-peptide resin is treated with DMF:piperidine (1:1) for 30 minutes at room temperature.
  • Example 1 After the peptide resin is washed with DMF and methylene chloride, the next synthetic protocol (Example 1, agenda A-step 3) is initiated with the exception that the N-terminal protecting group is not removed at the end of the synthesis.
  • the fully protected peptide is obtained by the procedure of Example 309.
  • the protected peptide is coupled with alpha- phenethylamine using DCC/HOBT.
  • the protecting groups are removed by treatment with 4N-HCl/dioxane to give the desired compound.
  • N-alpha-Boc-Arginine is reacted with ethylmercaptan, according to the procedure described by Yamada, S.;
  • N-alpha-Boc-Arginine is coupled with ethylamine using mixed anhydride method conditions.
  • Deprotection of the product with 4N-HCl/dioxane yields arginine ethylamide dihydrochloride which is coupled with the protected
  • Example 64 described in Example 64 with the exception that (2- pyridyDmethylamine is used instead of ethylamine.
  • the compound is prepared in analogy to Example 38.
  • the compound is prepared in analogy to Example 38.
  • N-alpha-Boc-Arginine is converted to its benzyl ester, according to the procedure described by Wang, S.-S.; Gisin,. B. F.; Winter, D. P.; Makofske, R.; Kulesha, I. D . ;
  • Example 91 The compound is prepared in analogy to Example 38.
  • Example 91 The compound is prepared in analogy to Example 38.
  • the peptide-resin obtained was washed with 10%- diisopropylethylamine (DIEA) in methylene chloride (3 x 15 mL, 45 seconds each) and methylene chloride (4 x 15 mL) .
  • DIEA diisopropylethylamine
  • the C-terminal heptapeptide is prepared under standard solid phase peptide synthesis conditions.
  • the epsilon nitrogen of lysine is protected as its Fmoc derivative which remains intact through the acidic cleavage of the
  • Racemic ( (Z) -1-Acetamido-2-phenylcyclopropane)-1-carboxylic acid is prepared from Z- acetamidocinnamic acid according to the methodology given, in, Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1988, 159-172, and the references cited therein.
  • This amino acid is then coupled in solution phase to the heptapeptide by the mixed acid anhydride method, and the Fmoc group is removed with piperidine. Separation of the diastereomeric products by HPLC furnishes the final product .
  • the C-terminal heptapeptide is prepared using standard solid phase peptide synthesis techniques.
  • the lysine is incorporated with the epsilon nitrogen protected with Fmoc which survives HF cleavage of the peptide from the resin and removal of the other protecting groups.
  • Z-Acetamidocinnamic acid is coupled to the heptapeptide in solution phase employing the mixed acid anhydride method.
  • the Fmoc group is subsequently removed with piperidine, and the crude peptide is purified by HPLC.
  • the compound was prepared in analogy to Example 38.
  • H-Leucyl-Arginyl-Alanyl-Asparaginyl-Isoleucyl-Seryl-Phenylalanyl-Lysyl-Aspartyl- ⁇ (2S) 2-Amino-3-cyclohexylpropanoyl ⁇ - ⁇ (2S)-2-Amino-3-cyclohexyIpropanoyl ⁇ -Leucyl-DAlanyl-Arginyl-OH
  • Boc-Leu-Gly-OH alkyne isostere is prepared in analogy to the procedure described in the literature ( van Marsenille, M.; Gysen, C; Tourwe, D.; van Binst, G. Bull .
  • Boc-Leucyl- ⁇ CH 2 -O ⁇ -Glycyl-OH dipeptide is prepared in analogy to the procedure described in the literature
  • Boc-Leucyl- ⁇ CH 2 -S ⁇ -Glycyl-OH dipeptide is prepared in analogy to the procedure described in the literature
  • the compound was prepared in analogy to Example 334.
  • the compound was prepared in analogy to Example 334.

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Abstract

Les composés d'oligopeptides ou les composés analogues d'oligopeptides de la formule A-B-D-E-G-J-L-M-Q-T sont des ligands pour le récepteur d'anaphylatoxine utiles dans le traitement de maladies inflammatoires. On décrit également des compositions de ligands de récepteur d'anaphylatoxine ainsi qu'un procédé permettant de moduler l'activité de l'anaphylatoxine.
EP19900903567 1989-01-31 1990-01-16 Anaphylatoxin-receptor ligands Withdrawn EP0456758A4 (en)

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US5386011A (en) * 1990-12-27 1995-01-31 Abbott Laboratories Hexapeptide anaphylatoxin-receptor ligands
US5387671A (en) * 1990-12-27 1995-02-07 Abbott Laboratories Hexa- and heptapeptide anaphylatoxin-receptor ligands
US5190922A (en) * 1991-06-04 1993-03-02 Abbott Laboratories Terminally modified tri-, tetra- and pentapeptide anaphylatoxin receptor ligands
WO1994007518A1 (fr) * 1992-09-25 1994-04-14 Abbott Laboratories Ligands de recepteurs d'anaphylatoxine contenant des restes lipophiles
US5807824A (en) * 1993-12-06 1998-09-15 Ciba-Geigy Corporation C5A receptor antagonists having substantially no agonist activity
US5837499A (en) * 1993-12-06 1998-11-17 Ciba-Geigy Corporation DNA encoding C5A receptor antagonists having substantially no agonist activity and methods of expressing same
US5614370A (en) * 1994-03-18 1997-03-25 Merck & Co., Inc. Assay to identify human C5a antagonists and agonists
US6057294A (en) * 1995-01-16 2000-05-02 Northern Sydney Area Health Service Of Pacific Highway Peptide
SE9603461D0 (sv) * 1996-09-23 1996-09-23 Astra Ab New compounds
SE9603462D0 (sv) * 1996-09-23 1996-09-23 Astra Ab New compounds
SE9603468D0 (sv) * 1996-09-23 1996-09-23 Astra Ab New compounds
US6998106B1 (en) * 1998-12-01 2006-02-14 Duke University Radioconjugation of internalizing antibodies
TW200502221A (en) 2002-10-03 2005-01-16 Astrazeneca Ab Novel lactams and uses thereof
WO2004080983A1 (fr) * 2003-03-14 2004-09-23 Astrazeneca Ab Nouveaux lactames et leurs utilisations
EP1498422A1 (fr) * 2003-07-17 2005-01-19 Jerini AG Antagonistes du Recepteur C5a
RU2346943C2 (ru) * 2003-10-24 2009-02-20 Авентис Фармасьютикалз Инк. Новые соединения и композиции в качестве ингибиторов катепсина
JP2008526915A (ja) * 2005-01-17 2008-07-24 イエリニ・アクチェンゲゼルシャフト Ｃ５ａ受容体アンタゴニスト
EP1739078A1 (fr) 2005-05-30 2007-01-03 Jerini AG Antagonistes du recepteur C5a
EP2468295A1 (fr) 2010-12-21 2012-06-27 Affiris AG Vaccins à base de peptides de la proteine C5a du complement
EP2666785A1 (fr) 2012-05-23 2013-11-27 Affiris AG Vaccins basés sur la protéine complément C5a
CN103599523B (zh) * 2013-11-25 2016-08-17 中国人民解放军第二军医大学 五肽代谢物在制备抗炎药物中的应用
US11918624B2 (en) 2020-06-10 2024-03-05 Kelsius Laboratories LLC Therapeutic composition for use in the treatment of COVID-19 and other cytokine storm associated disorders

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US4692511A (en) * 1984-07-03 1987-09-08 Immunetech Pharmaceuticals Peptide antagonists for the C5a anaphylatoxin

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CA1290097C (fr) * 1985-07-24 1991-10-01 Merck & Co., Inc. Inhibiteurs d'enzymes de type peptide

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US4692511A (en) * 1984-07-03 1987-09-08 Immunetech Pharmaceuticals Peptide antagonists for the C5a anaphylatoxin

Non-Patent Citations (4)

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Title
B. WEINSTEIN: "Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins. A Survey of recent Developments", vol. 7, 1983, pages 267-349, Marcel Dekker, Inc.; Chapter 5, A.F. SPATOLA: "Peptide backbone modifications: a structure-acitivity analysis of peptides containing amide bond surrogates" *
BIOCHEMISTRY, vol. 23, no. 4, 14th February 1984, pages 585-588, American Chemical Society; C.G. UNSON et al.: "Active site of C3a anaphylatoxin: contributions of the lipophilic and orienting residues" *
PROC. NATL. ACAD. SCI. USA, vol. 86, no. 1, January 1989, pages 292-296; K.W. MOLLISON et al.: "Identification of receptor-binding residues in the inflammatory complement protein C5a by site-directed mutagenesis" *
See also references of WO9009162A2 *

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CA2045578A1 (fr) 1990-08-01
WO1990009162A3 (fr) 1990-11-29

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