NZ247914A - Peptides having bradykinin antagonist activity, their preparation and compositions - Google Patents
Peptides having bradykinin antagonist activity, their preparation and compositionsInfo
- Publication number
- NZ247914A NZ247914A NZ247914A NZ24791493A NZ247914A NZ 247914 A NZ247914 A NZ 247914A NZ 247914 A NZ247914 A NZ 247914A NZ 24791493 A NZ24791493 A NZ 24791493A NZ 247914 A NZ247914 A NZ 247914A
- Authority
- NZ
- New Zealand
- Prior art keywords
- residue
- radical
- arg
- formula
- carbonyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/18—Kallidins; Bradykinins; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- 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
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Compounds of formula (I): <IMAGE> in which X, X', A1, A2, A3, A4, A5, A6, A7, A8, A 9 and Y are as defined in the description. Medications.
Description
New Zealand Paient Spedficaiion for Paient Number £47914
24 7 9 1 4
Priority Date(s): ... {
Complete Specification Filed:
Class: Attkllft.. faJ.X-30. 1*3-....
Publication Date: .PP.Q, P.O. Journal, No: A3&7
NEW ZEALAND PATENTS ACT, 1953
No.:
Date:
COMPLETE SPECIFICATION
NEW PEPTIDE COMPOUNDS HAVING BRADYKININ-ANTAGONIST ACTIVITY, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS WHICH CONTAIN THEM
We, ADIR ET COMPAGNIE, a French body corporate, of 1 rue Carle Hebert, F-92415, Courbevoie, Cedex, France,
hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
(followed by page la)
* 24 7 9 1 4
The present invention relates to new peptide compounds having bradykinin-antagonist activity, to a process for their preparation and to the pharmaceutical compositions which contain them.
Bradykinin, a natural nonapeptide, is known as a mediator of inflammatory and painful reactions, as well as in hypotensive states.
Bradykinin has, in addition, contractive effects on smooth muscle, especially that of the trachea, uterus or intestine. 10 In clinical medicine, bradykinin has been implicated in the physiopathoiogy of shock states, inflammatory reactions, asthma and bronchial hyperreactivity, allergic or viral rhinitis, pancreatitis, arthritis, postgastrectomy dumping syndrome, psoriasis, hereditary angioneurotic-edema and 15 migraine.
Bradykinin antagonists have been described in the literature for the treatment of physiopathological situations in which high concentrations of bradykinin could be demonstrated, as in the case of septic shock (Robinson et al., Am. J. Med. 59-61, 20 1975), arthritis (Shavura et al., Arch. Int. Pharmacodyn. 262-279, 1983), asthma, allergic rhinitis and many other inflammatory and allergic reactions (Bradykinin antagonists: ^ Basic and Clinical research (1991) ed. R. Burch, Marcel Dekker Inc., N. York).
This applies especially to the compounds described by Stewart and Vavrek in Patents WO 86/07,263 and WO 89/01,781*, who demonstrated that the replacement of the proline at position 7 £ of bradykinin by a D-phenylalanine enabled an antagonist activity to be obtained. Patents EP 0,370,453 and EP 0,413,277 30 describe bradykinin antagonists obtained by replacement of the proline at position 7 by a D-phenylalanine or a tetrahydroiso-quinoline-3-carbonyl residue and modification of the C- and N-terminal functions of the peptide.
The present invention describes bradykinin antagonists which 35 are new not only in respect of the novel modifications of position A7 of bradykinin and other amino acid substitutions in different positions, but also in respect of the introduction of substituents on the N- and C-terminal
. '
,/-v V
/
2
24 7 9 1 4
functions of the peptide. These various modifications endow the compounds of the invention with especially intense pharmacological activities.
More specifically, the present invention relates to compounds of general formula (I):
in which:
X and X* , the substituents of the terminal amino group of the peptide of formula (I), which may be identical or different, represent:
- a hydrogen atom,
- a 4-guanidinobenzoyl radical (Gba), unsubstituted or substituted on the phenyl ring with one or more halogen atoms or hydroxyl, mercapto, linear or branched (Ci~C6) alkyl, linear or branched (Ci-Cg) alkylthio or linear or branched (C1-C6) alkoxy radicals,
- a linear or branched (C1-C6) alkyl radical,
- a (C6-C12) aryl radical,
- a linear or branched {C1-C6) alkoxycarbonyl radical,
- a linear or branched (C1-C6) alkylsulfonyl radical,
- a 9-fluorenylmethyloxycarbonyl radical,
- a linear or branched (C1-C6) guanidinoacyl radical, unsubstituted or substituted with an amino radical/
- or a radical of formula
Ai and Ag, which may be identical or different, represent:
x\
,/A1-A2-A3-A4-A5-A6-A7-A8-A9-Y
A '
(i)
H2N-(CH2)n-CH.
XC0 -
in which n is between 1 and 6
a bond,
a residue of formula
\*24FEB1»K
3
24 7 9 14
/NH -
Rl-(CH2)n-CH
XC0 -
in which n represents an integer between 1 and 6 and Ri an amino or guanidino radical,
or any basic amino acid, unsubstituted or substituted on its side chain,
A2 and A3, which may be identical or different, represent:
- a bond,
- a proline (Pro), hydroxyproline (Hyp), 2-azabi-cyclo[2.2.2]octane-3-carbony1 (Abo), 2-azabi-cyclo[2.2.1]heptane-3-carbonyl (Abh), homoproline (hPro), 3,4-dehydroproline (dhPro), sarcosine (Sar), N-methylphenylglycine (NMePgl), azetidine- 2-carbonyl (Azt) or alanine (Ala) residue,
A4 represents a bond or a glycine (Gly) or sarcosine (Sar) residue or a residue of the formula:
in which m is an integer between 2 and 8,
A5 represents a bond or a phenylalanine (Phe), P~(2-thienyl) alanine (Thi), 0-cyclohexylalanine (Cha)., 0-naphthylalanine (Nal), J3-furylalanine tFur), 0-pyranylalanine (Pra) or p-pyridylalanine (Pyr) residue,
A6 represents a bond or any amino acid residue,
A7 any one of the following residues:
-NH-(CH2)m-CO-
A
B
C .
D
E
F
2 4 FEB 1994;;
24 7 9 f
H—N
H
ch3—n
N
(R represents radical)
a linear or branched (Ci~C6)
or A7
represents a methylphenylalanine residue (MePhe) or a tetrahydroisoquinoline-3-carbonyl residue (Tic) (on condition that, in this case, X represents a p-guanidinobenzoyl radical and X' a hydrogen atom),
As represents a bond, an octahydroindole-2-carbonyl (Oic), proline (Pro), hydroxypro1ine (Hyp), 2-aza-bicyclo[2.2.2]octane-3-carbonyl (Abo), 2-azabi-cyclo[2.2.1]heptane-3-carbonyl (Abh), homoproline (hPro), 3,4-dehydroproline (dhPro), sarcosine (Sar), N-methylphenylglycine (NMePgl), azetidine-2-carbonyl (Azt) or alanine (Ala) residue or any one of the residues A to R defined for A7,
Y, a substituent of the terminal carbonyl group of the peptide of formula (I), represents a hydroxyl or linear or branched (C1-C6) alkoxy radical or an amino radical (unsubstituted or substituted with one or two linear or v"
> 2 4FEB 1994
24 79 1
branched (C1-C6) alkyl radicals or phenyl radicals - it being possible for each of the alkyl or phenyl radicals itself to be substituted with an amino, guanidino or ureido radical),
or alternatively the carbonyl-terminal group of the peptide of formula (I) is reduced to the corresponding alcohol (ol),
and their addition salts with a pharmaceutically acceptable acid or base,
on the understanding that:
when X represents a p-guanidinobenzoyl radical, X' a hydrogen atom, Ai an arginine residue (Arg), A2 a proline residue (Pro), A3 a hydroxyproline residue (Hyp), A4 a glycine residue (Gly), A5 a p-(2-thienyl)alanine residue (Thi), A6 a serine residue (Ser), As an octahydroindole-2-carbonyl residue (Oic), Ag an arginine residue (Arg) and Y a hydroxyl radical, then A7 is other than a tetrahydroisoquinoline-3-carbonyl residue (Tic) of D or L configuration with respect to its a carbon,
each peptide bond -CO-NH- of the peptide of the formula (I) can be optionally replaced by a pseudopeptide bond chosen from -CH2-NH, -CH2-S-, -CH2-SO-, -CH2-S02-, -NH-CO-or -CH=CH-,
each amino acid of the peptide sequence being optically pure and the a carbon of each amino acid having the D or L configuration.
Among pharmaceutically acceptable acids, there may be mentioned, hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulfonic and camphoric acids, and the like.
> 1 ;<'V'
/
/'
■ v
6
24 7 9 1 4
Among pharmaceutically acceptable bases, there may be mentioned/ sodium hydroxide, potassium hydroxide, triethylamine, tert- butylamine, and the like.
The expression "any amino acid" used in the present application includes both natural amino acids and so-called non-proteinogenous amino acids which are commonly used by a person skilled in the art in the synthesis of synthetic analogs of natural peptides.
Among natural amino acids, there may be mentioned, glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamine, glutamic acid, arginine, ornithine and lysine.
Among non-proteinogenous amino acids, there may be mentioned, norleucine, norvaline, alloisoleucine, homoarginine, thiaproline, dehydroproline, hydroxyproline, homoserine, cyclohexylglycine, phenylglycine, amino-n- butyric acid, cyclohexylalanine, aminophenylbutyric acid, phenylalanines mono-, di- or trisubstituted on the phenyl group at the ortho, meta or para position with group(s) chosen from (C1-C6) alkyl, (C1-C6) alkoxy, halogen, trifluoromethyl, nitro, amino, mono-or di(Ci~C6 alkyl)amino or alternatively a methylenedioxy group, fJ-(2- and 3- thienyl) alanine, fS-(2- and 3-furyl)alanine, ji-(2-, 3- and 4-pyridyl)alanine, ji-{2- and 3-benzothienyl)alanine, p-(l- and 2-naphthyl)alanine, O-alkyl derivatives of serine, threonine, and tyrosine," S-alkylcysteines, all amino acids of D configuration, isomers of natural amino acids of L configuration, and the like. The invention also extends to the process for preparing the compounds of formula (I), which may be obtained by various methods such as sequential solid- phase synthesis, the synthesis of fragments and their coupling in solution, enzymatic synthesis and genetic synthesis by cloning and expression of genes in transformed bacteria, or by various combinations of these techniques.
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24j9 1 4
The general methods of solid-phase peptide synthesis have been described by B.W. ERICKSON and R.B. MERRIFIELD ("The Proteins", Solid-Phase Peptide Synthesis, 3rd edition, 257-527, 1976).
The solid-phase synthesis may be carried out on an automated apparatus which performs in a repetitive and programmable manner deprotection, coupling and washing cycles needed for the sequential introduction of the amino acids into the peptide chain. The amino acid, preferably C-terminal, is attached to a resin conventionally used for the preparation of polypeptides, preferably a polystyrene crosslinked using 0.5 to 3.0 % of divinylbenzene and equipped with activated residues such as chloromethylene or hydroxymethylene which enable the first amino acid to be attached covalently to the resin. The appropriate choice of resin enables a C-terminal carboxylic acid, amide or alcohol function to be formed after synthesis.
The amino acids are then introduced one by one in the order determined by the operator. Each synthesis cycle corresponding to the introduction of an amino acid entails a deprotection, preferably N-terminal, of the peptide chain, successive washes designed to remove the reactants or to swell the resin, a coupling with activation of the amino acid and further washes.
Each of these operations is followed by a filtration, accomplished by means of the presence of a glass sinter incorporated in the reactor in which the synthesis "takes place.
The coupling reagents used are standard reagents of peptide synthesis, such as dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) or benzotriazol- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or alternatively diphenylphosphoryl azide (DPPA).
Activation by mixed anhydride formation is also possible.
Each amino acid is introduced into the reactor in approximately four-fold excess with respect to the degree of substitution of the resin, and in an approximately equivalent amount with respect to .the coupling agents. The coupling reaction may be checked at each step of the synthesis by the
: 2 4FEB 5994,'
24 7 9 ? 4
ninhydrin reaction test described by E. KAISER et al. (Analyt. Biochem., 34, 595, 1970).
After assembly of the peptide chain on the resin, treatment with a strong acid such as trifluoroacetic acid or hydrofluoric acid in the presence of anisole, ethanedithiol or 2-raethylindole serves to separate the peptide from the resin and also to free the peptide, where appropriate, from its protective groups. The compound is then purified by standard purification techniques, in particular chromatographic techniques.
The peptides of the present invention may also be obtained by the coupling in solution of selectively protected peptide fragments, which may be prepared either on a solid phase or in solution. The use of protective groups and the means of taking advantage of their differential stability are similar to the solid-phase methods, except for the attachment of the peptide chain to the resin. The C-terminal carboxyl group is protected, for example, by a methyl ester or an amide function. The methods of activation during coupling are also similar to those employed in solid-phase synthesis. The synthesis of peptides containing pseudopeptide bonds such as -CH2-NH-, -CH2-S-, -CH2-SO-, -CH2-S02-, -NH-CO- or -CH=CH-is performed either by solution methods or in a combined procedure with solid-phase synthesis using standard methods of organic chemistry. Thus, for example, the introduction of the -CH2-NH- bond is accomplished by preparing in solution the aldehyde Fmoc-NH-CHR-CHO according to the technique described by FEHRENTZ and CASTRO (Synthesis, 676-678, 1983) and condensing it with the growing peptide chain, either on a solid phase according to the technique described by SASAKI and COY (Peptides, 8, 119-121, 1988), or in solution. The compounds of formula (I) possess very advantageous pharmacological properties, especially bradykinin-antagonist properties. On this basis, they may be used beneficially in a number of therapeutic indications such as traumas, grazes, burns, skin eruptions, eczema, erythema, edema, sore throat, arthritis, asthma, allergies, rhinitis, anaphylactic shock,
2 4 FEB <994 a.
24 7 9 1 4
inflammations, arterial hypotension, pains, pruritus and insufficiency of spermatozoal mobility.
The subject of the present invention is also pharmaceutical compositions containing as active principle at least one compound of general formula (I) or one of its addition salts with a pharmaceutically acceptable acid or base, alone or in combination with one or more non-toxic, inert excipients or vehicles.
Among the pharmaceutical compositions according to the invention, there may be mentioned, more especially, those which are suitable for oral, parenteral or nasal administration, simple or sugar-coated tablets, sublingual tablets, sachets, packets, hard gelatin capsules, suppositories, creams, ointments, skin gels, aerosols, ampoules containing preparations to be swallowed or injected, etc.
The dosage varies according to the patient's age and weight, the nature and severity of the disorder and also the administration route.
The latter can be oral (including inhalation and sublingual administration), nasal, rectal, parenteral or transdermal. Generally speaking, the dosage ranges between 0.1 g/kg and 5 mg/kg for a treatment administered in one or several doses per 24 hours.
The examples which follow illustrate the invention and in no way limit it.
In the examples below, the amino acids whose abbreviations begin with a capital letter are of the L configuration. The amino acids whose abbreviations begin with a lower-case letter are of the D configuration.
The abbreviations used in the examples are as follows:
Gba in place of 4-guanidinobenzoyl,
Arg in place of the arginine residue,
Pro in place of the proline residue,
dhPro in place of 3,4-dehydroproline,
Hyp in place of the hydroxyproline residue,
Gly in place, of the glycine residue,
Thi in place of the f}-(2-thienyl)alanine residue
24 7 9 14
Ser in place of the serine residue, * *
Tic in place of the tetrahydroisoquinoline-3-carbonyl residue,
Oic in place of the octahydroindole-2-carbonyl residue,
[3,2-c]ttp in place of the (6R)-4,5,6,7-tetrahydrothieno[3,2-
c]pyridine-6-carboxylic acid residue. Dpr in place of the 2,3-diaminopropionic acid residue,
Gpr in place of the 2-amino-3-guanidinopropionic acid
residue,
Dbu in place of the 2,4-diaminobutyric acid residue,
Sar in place of the sarcosine residue,
Aoc in place of the 8-aminooctanoic acid residue,
[3,4-c]ttp in place of the (6R)-4,5,6,7-tetrahydrothieno[3,4-
c]pyridine-6-carboxylic acid residue,
[2,3-c]ttp in place of the (6R)-4,5,6,7-tetrahydrothieno[2,3-
c]pyridine-6-carboxylic acid residue,
[2,3-c]tfp in place of the (6R)-4,5,6,7-tetrahydrofuro[2,3-
c]pyridine-6-carboxylic acid residue, 20 [3,4-c]tfp in place of the (6R)-4,5,6,7-tetrahydrofuro[3,4-
c]pyridine-6-carboxylic acid residue,
[3,2-c]tfp in place of the ( 6R)-4,5,6,7-tetrahydrofuro[3,2-
£ c]pyridine-6-carboxylic acid residue,
[2,3-c]tpp in place of the (6R)-4,5, 6,7-tetrahydro-3H-
pyrrolo[2,3- c]pyridine-6-carboxylic acid residue,
[3,4-c]tpp in place of the (6R)-4,5, 6,7-tetrahydro-2H-
pyrrolo[3,4- c]pyridine-6-carboxylic acid residue, [3,2-c]tpp in place of the (6R)-4,5,6,7-tetrahydro-lH-
pyrrolo[3,2- c]pyridine-6-carboxylic acid residue, 30 [2m]tpp in place of the (6R)-2-methyl-4,5,6,7-tetrahydro-
2H- pyrrolo[3,4-c]pyridine-6-carboxylic acid residue,
[lm]tpp in place of the (6R)-l-methyl-4,5,6,7-tetrahydro-
1H- pyrrolo[3,2-c]pyridine-6-carboxylic acid 35 residue,
[3m]tpp in place of the (6R)-3-methyl-4,5,6,7-tetrahydro-
3H- py.rrolo [2 ,3-c] pyr idine-6-carboxylic acid residue, ...
V > c N r ' / c
/v
Jr.
fa^FtBTW.
24 7 9 1 4
[3m]tip in place of the (6R)-3-methyl-4,5,6,7-tetrahydro-
3H- imidazo[5,4-c]pyridine-6-carboxy1ic acid residue,
[lm]tip in place of the (6R)-l-methyl-4,5,6,7-tetrahydro-
1H- imidazo[4,5-c]pyridine-6-carboxylic acid residue,
[l,7]tna in place of the (6R)-5,6,7,8-tetrahydro-l,7-
naphthyridine-6-carboxylic acid residue, [2,7]tna in place of the (6R)-5,6,7,8-tetrahydro-2,7-
naphthyridine-6-carboxylic acid residue, [3,7]tna in place of the (6R)-5,6,7,8-tetrahydro-3,7-
naphthyridine-6-carboxylic acid residue, [4,7]tna in place of the (6R)-5,6,7,8-tetrahydro-4,7-
naphthyridine-6-carboxylic acid residue, epc in place of the 5-ethoxypiperidine-2-carboxylic acid residue,
Gbu in place of the 2-amino-4-guanidinobutyric acid residue.
Example 1: Gba-Arg-dhPro-Hyp-Gly-Thi-Ser-tic-Oic- Arg-OH hexafluoroacetate
The compound of Example 1 is synthesized from 2 g of a resin substituted with 0.33 mmol/g of Fmoc-Arg- (Pmc)-OH and according to the following repetitive protocol:
Operation no. Function Solvent/
Reactant washing DMF
deprotection 20% piperi-
dine/DMF deprotection 20% piperi-dine/DMF DMF
dichloro-methane activated protected
1
2
4
washing washing coupling amino acid
Repetition/ time
2 x 2 min 1 x 5 min
1 x 15 min
3 x 3 x
2 min 2 min
1 x 90 min
/- X c
V
-24FEB19M
12
2* 7 9 1
7
8
washing DMF
washing isopropyl
3 x 2 min 3 x 2 min
9
alcohol washing dichloro methane
3 x 2 min
Each of these operations, performed in 30 ml of solvent with agitation at room temperature, is followed by filtration through a glass sinter incorporated in the glass cell (reactor) in which the synthesis progresses. The filter retains the resin to which the growing peptide chain is attached.
The chosen protected amino acids were introduced in the following order: Fmoc-Oic-OH, Fmoc-tic-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thi-OH, Fmoc-Gly-OH, Fmoc-Hyp(tBU)-OH, Fmoc-dhPro-OH and Fmoc-Arg(Pmc)-OH.
The activation for the purpose of coupling (operation 6) is obtained in each cycle by dissolving 4 equivalents (2.64 mmol) of the protected amino acid with 360 mg of HOBt in 30 ml of DMF, and then, after 30 minutes at room temperature, by adding 618 mg of DCC. This solution is then introduced immediately into the reaction cell with 10 ml of dichloromethane.
At the end of the eight cycles corresponding to the sequential attachment of eight amino acids, and with C-terminal arginine, a nonapeptide protected on its side chains and attached to the resin has thereby been obtained. After treatment 'under conditions identical to those described for the previous cycles with 4-guanidinobenzoic acid, the resin is then treated with a mixture of trifluoroacetic acid (18 ml), dichloromethane (1 ml) and anisole (1 ml) for 90 minutes at room temperature. The filtrate and the solvents used for washing the resin (3 x 20 ml of dichloromethane) are combined and evaporated to dryness. The product is suspended in ether, filtered off and dried, then purified by preparative HPLC on a Ci8 column (internal diameter: 47 mm, length: 300 mm) and lyophilized.
Analysis of the product obtained is carried out after decomposition of the latter into amino acids by hydrolysis in
\
c
24FEBJ994
24 7 9 1 4
6N hydrochloric acid for 18 hours at 110°C, and quantitative assay of the amino acids obtained by HPLC. This analysis complies with the standards normally required.
Analysis Arg Hyp Ser Gly dhPro Oic tic Calculated 2 111 11 1
Found 1.99 0.94 0.93 1.1 1.1 0.96 1.00
Mass spectrum (FAB): MH+, m/z = 1307
The examples which follow were prepared using the procedure described in Example 1.
Example 2: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[3,2-c]tpp-Oic-Arg trifluoroacetate
The resin substituted with Fmoc-Oic-Arg(Pmc)-OH is condensed after deprotection using piperidine in the same manner as in Example 1 with Fmoc-tpp-OH. This intermediate is obtained from Thi-OH in three steps:
thienylalanine hydrochloride is obtained in a methanol solution saturated with HC1;
cyclization of the thienylalanine hydrochloride in a 40% solution of HCHO in water, with stirring for 2 h at 110°C followed by 15 h at 60°C;
protection at the Na position with the fluorenyl-methyloxycarbonyl group (Fmoc).
Analysis Arg Hyp Ser Gly Pro Oic Thi calculated 2 1 1 1 1 11
found 2.09 1.01 0.97 0.99 1.01 1.000.96
Mass spectrum (FAB): MH+, m/z = 1315
Example 3: arg-Arg-Pro-Hyp-Gly-Thi-Ser-[3,2-c]ttp-Oic-Arg trifluoroacetate
Analysis
Arg
Hyp
Ser
Gly
Pro
Oic
Thi
[3,2-c]ttp calculated
3
1
1
1
1
1
1
1
found
2.79
1.02
o o
1.05
1.06
1.03
0.99
1.04
s
•)
24 7 9 1 4
Mass spectrum (FAB): MH+, m/z = 1309
Example 4: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-tic-Oic-Dpr-OH
Analysis Arg Hyp Ser Gly Pro Oic tic Thi calculated 11111111
found 0.99 1.07 0.95 0.97 1.03 1.08 0.92 1.00
Mass spectrum (FAB): MH+, m/z = 1239
Example 5: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-tic-Oic-Gpr-OH
Analysis Arg Hyp Tic Oic Pro Gly Ser calculated 11111 11
found 0.97 0.93 1.02 1.00 1.06 1.03 0.99
Mass spectrum (FAB): MH+, m/z = 1281
Example 6: Gba-Dbu-Pro-Hyp-Gly-Thi-Ser-tic-Oic-Dbu-OH
Analysis Dbu Oic Tic Ser Gly Hyp Pro calculated 2 1111 11
found 2.03 1.01 0.99 0.91 1.07 1.02 1.03
Mass spectrum (FAB): MH+, m/z = 1196
Example 7: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[3,4-c]ttp-Oic- Arg-OH Example 8: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[2,3-c]ttp-Oic- Ar§-OH Example 9: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[2,3-c]tfp-Oic- Arg-OH Example 10: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[3,4-c]tfp-Oic- Arg-OH Example 11: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[3,2-c]tfp-Oic- Arg-OH Example 12: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[2,3-c]tpp-Oic- Arg-OH Example 13: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[3,4-c]tpp-Oic- Arg-OH Example 14: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[3,2-c]tpp-Oic- Arg-pH
\ K.
■ V
14 FEBB94
24 7 9 1 4
Example 15: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[ 3m] tpp-Oic-Arg-OH Example 16: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[ 2m] tpp-Oic-Arg-OH Example 17: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[ lm] tpp-Oic-Arg-OH Example 18: Gba-Arg-Pro-Hyp-Gly-Thi-Ser- [ 3m] tip-Oic-Arg-OH Example 19: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[ lm] tip-Oic-Arg-OH Example 20: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[1,7]tna-Oic-Arg- OH Example 21: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[2,7]tna-Oic-Arg- OH Example 22: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[3,7]tna-Oic-Arg- OH Example 23: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[4,7]tna-Oic-Arg- OH Example 24: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-epc-Oic-Arg-OH Example 25: arg-Arg-Pro-Hyp-Gly-Thi-Ser-[3,2-c]tfp-Oic- Arg-OH Example 26: arg-Arg-Pro-Hyp-Gly-Thi-Ser-[3,4-c]tpp-Oic- Arg-OH Example 27: arg-Arg-Pro-Hyp-Gly-Thi-Ser-[2,3-c]tpp-Oic- A"rg-0H Example 28: arg-Arg-Pro-Hyp-Gly-Thi-Ser-[ 3m]tpp-Oic-Arg-OH Example 29: arg-Arg-Pro-Hyp-Gly-Thi-Ser-[ 2m] tpp-Oic-Arg-OH Example 30: arg-Arg-Pro-Hyp-Gly-Thi-Ser-[lm]tip-Oic-Arg-OH Example 31: arg-Arg-Pro-Hyp-Gly-Thi-Ser-[3,4-c]ttp-Oic- Arg-OH Example 32: arg-Arg-Pro-Hyp-Gly-Thi-Ser-[2,3-c]ttp-Oic- Arg-OH Example 33: Gba-Arg-Pro-Hyp-Gly-Thi-Ser-[3,2-c]ttp-Oic- Gpr-OH
\ « u ^ • «
c-
2 4FEBS994,.
/
24 7 9 14
Example 34: Gba-Gpr-Pro-Hyp-Gly-Thi-Ser-[3,2-c]ttp-Oic- Gpr-OH
Example 35: Gba-Dbu-Pro-Hyp-Gly-Thi-Ser-[3,2-c]ttp-Oic- Gpr-OH
Example 36: Gba-Gbu-Pro-Hyp-Gly-Thi-Ser-[3,2-c]ttp-Oic- Gpr-OH
Example 37: arg-Arg-Pro-Hyp-Gly-Phe-Ser-[3,2-c]ttp-Oic- Arg-OH
Example 38: arg-Arg-Pro-Hyp-Gly-Thi-Ser-Mephe-Oic-Arg-OH tetrafluoroacetate
Analysis Arg Pro Hyp Ser Gly calculated 3 1111
found 3.05 1.05 1.00 0.98 0.90
Mass spectrum (FAB): MH+, m/z = 1307
Example 39; Gba-Arg-Pro-Hyp-GlyW[CH2S]Phe-Ser-tic-Oic-Arg-OH pentafluoroacetate
Analysis
Arg
Hyp
Ser
Pro tic
Oic calculated
2
1
1
1
1
1
found
2.14
1.02
0.93
0.93
1.00
0.98
Mass spectrum (FAB)
: MH+,
m/z
= 1306
Example 40: Gba-Arg-Pro-Hyp-GlyWfC^S ] phe-Ser-tic-Oic-Arg-OH pentafluoroacetate
Example 41: Gba-Dpr-Pro-Hyp-Gly-Thi-Ser-tic-Oic-Dbu-OH trifluoroacetate
Analysis Dbu Oic tic Ser Gly Hyp Pro Dpr calculated 11111 111
found 0.98 1.08 0.98 0.94 1.02 0.94 0.98 1.08
Mass spectrum (FAB): MH+, m/z = 1183
Example 42 Gba-Arg-Pro-Hyp-Sar-Thi-Ser-tic-Oic-Arg-OH hexafluoroacetate l'
/ V
1 •< /
vV , /
24 79 1
Analysis
Arg
Hyp
Ser
Sar
Pro
Oic tic calculated
2
1
1
1
1
1
1
found
2.09
0.95
1.02
0.98
0.97
0.95
1.04
Mass spectrum (FAB)
: MH+,
m/z
= 1323
Example 43: Gba-Arg-Pro-Hyp-Aoc-tic-Oic-Arg-OH trifluoroacetate
Analysis Arg Hyp tic Oic Pro calculated 2 1111
found 1.81 1.04 1.03 1.07 1.05
Mass spectrum (FAB): MH+, m/z = 1153
PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION
Example 44: In vitro measurement of the effect of the compounds of the invention with respect to the bradykinin-induced contractile response of the smooth muscle of rabbit jugular vein
This study was carried out according to the protocol described by D. REGOLI and J. BARABE (B2 Receptor - Pharmacology of Bradykinin and related kinins, Pharm. Rev.f 32, 1, 1-46, 1980). Rings of jugular vein are suspended in organ chambers (40 ml) containing KREBS solution, which is thermostated at 37°C and oxygenated continuously by bubbling 95% 02/5% C02 through it. The isometric force developed by the rings is measured and recorded. The baseline tension is approximately 2 g. The troughs receive the concentrations of the test compound of the invention (10-8M to 10-5M), while a control trough receives the solvent. A curve of concentration versus response to bradykinin is plotted from 10_1°M to 10~5m in half-logarithm steps. The potency of the bradykinin antagonists is measured from the log dose-effect curves, enabling the pA2 (negative logarithm of the molar concentration of the compound of the invention which necessitates a doubling of the bradykinin concentration in order to .obtain the same effect) values to be determined. In this test, the compounds of the invention have
2 4 FEB 1994
Claims (10)
1. V. at time 0 immediately preceding the subcutaneous injection of carrageenan into the sole of the rat's right hind foot (type IV lambda carrageenan, Sigma, 1% solution, volume injected 0.1 ml). The volume of the foot at different time-points of the experiment is measured by plethysmography. The inhibition of the edema at time 3 hours is calculated relative to a control group which has received the vehicle, and expressed as a percentage inhibition. Under these conditions, the compounds of Examples 2 and 3 produce a 36% inhibition at time 1 hour at a dose of 0.1 mg/kg I.V., and the compound of Example 5 produces a 55% inhibition at time 1 hour at the same dose. Example 46: Pharmaceutical composition Ointment containing 5 iig/ml of the peptide of Example 1 Gba-Arg-dhPro-Hyp-Gly-Thi-Ser-tic-Oic-Arg-OH . . 50 mg Polyethylene glycol Q.S 100 ml Example 47: Solution for injection Gba-Arg-dhPro-Hyp-Gly-Thi-Ser-tic-Oic-Arg-OH . . Distilled water for injections Q.S. ...... 0.5 mg 25 / '< c . 'V , "2-4 FEB 5994r 19 WHATifWE CLAIM IS 1.A compound of formula (I): x\ ,/A1-A2-A3-A4-A5-A6-A7-A8-A9-Y (I) in which: X and X', the substituents of the terminal amino group of different, represent: a hydrogen atom, a 4-guanidinobenzoyl radical (Gba), unsubstituted or substituted on the phenyl ring with one or more halogen atoms or hydroxyl, mercapto, linear or branched (C1-C6) alkyl, linear or branched (C1-C6) alkylthio or linear or branched (C1-C6) alkoxy radicals, a linear or branched (C1-C6) alkyl radical/ a (C6-C12) aryl radical, a linear or branched (Ci~Ce) alkoxycarbonyl radical, - a linear or branched (C1-C6) alkylsulfonyl radical, a 9-fluorenylmethyloxycarbonyl radical, a linear or branched (C1-C6) guanidinoacyl radical, unsubstituted or substituted with an amino radical, or a radical of formula NH2 H2N-(CH2)n-CH XC0 - in which n is an integer between 1 and 6, Ai and Ag, which may be identical or different, represent: the peptide of formula (I), which may be identical or a bond a residue of formula 20 24791 4 ,NH - Rl-(CH2)n-CH XCO - in which n represents an integer between 1 and 6 and Ri an amino or guanidino radical, or any basic amino acid, unsubstituted or substituted on its side chain, A2 and A3, which may be identical or different, represent: a bond, a proline (Pro), hydroxyproline (Hyp), 2-azabi-cyclo[2.2.2]octane-3-carbonyl (Abo), 2-azabi-cyclo[2.2.1]heptane-3-carbonyl (Abh), homoproline (hPro), 3,4-dehydroproline (dhPro), sarcosine (Sar), N-methylphenylglycine (NMePgl), azetidine- 2-carbonyl (Azt) or alanine (Ala) residue, A4 represents a bond or a glycine (Gly) or sarcosine (Sar) residue or a residue of formula: in which m is an integer between 2 and 8, A5 represents a bond or a phenylalanine (Phe), p-(2 thienyl) alanine (Thi), £-cyclohexylalanine (Cha)., P naphthylalanine (Nal), f5-f urylalanine -(Fur), 0 pyranylalanine (Pra) or {J-pyridylalanine (Pyr) residue, A6 represents a bond or any amino acid residue, ^7 represents any one of the following residues: -NH-(CH2)m-C0- r / '' / - 21 - H — " IM — H ^ N-CH, I „ _ N ^ 2A79U M 0 / ^co / CO I I anct" (R represents a linear or branched (C1-C6) / CO alkyl radical) I or A7 represents a methylphenylalanine residue (MePhe) or a tetrahydroisoquinoline-3-carbonyl residue (Tic) 011 the condition that, in this case, X represents a p-guanidinobenzoyl radical and X' a hydrogen atom, As represents a bond, an octahydroindole-2-carbonyl (Oic), proline (Pro), hydroxyproline (Hyp), 2-aza-bicyclo[2.2.2]octane-3-carbonyl (Abo), 2-azabi-cyclo[2.2.1]heptane-3-carbonyl (Abh), homoproline (hPro), 3,4-dehydroproline (dhPro), sarcosine (Sar), N-methylphenylglycine (NMePgl), azetidine-2-carbonyl (Azt) or alanine (Ala) residue or any one of the residues A to R defined for A7, Y, a substituent of the terminal carbonyl group of the peptide of formula (I), represents a hydroxyl or linear or branched (C1-C6) alkoxy radical or an amino radic^0 C\*;«ssv.;22;24791A;(unsubstituted or substituted with one or two linear or branched (C1-C6) alkyl radicals or phenyl radicals - it being possible for each of the alkyl or phenyl radicals itself to be substituted with an amino, guanidino or ureido radical),;or alternatively the carbonyl-terminal group of the peptide of formula (I) is reduced to the corresponding alcohol (ol),;and its addition salts with a pharmaceutically acceptable acid or base,;on the understanding that:;when X represents a p-guanidinobenzoyl radical, X1 a hydrogen atom, Ai an arginine residue (Arg), A2 a proline residue (Pro), A3 a hydroxyproline residue (Hyp), A4 a glycine residue (Gly), A5 a f$-( 2-thienyl)alanine residue (Thi), A6 a serine residue (Ser), As an octahydroindole-2-carbonyl residue (Oic), Ag an arginine residue (Arg) and Y a hydroxyl radical, then A7 is other than a tetrahydroisoquinoline-3-carbonyl residue (Tic) of D or L configuration with respect to its a carbon,;each peptide bond -CO-NH- of the peptide of the formula (I) can be optionally replaced by a pseudopeptide" bond chosen, from -CH2-NH-, -CH2-S-, -CH2-SO-, -CH2-SO2-, -NH-CO-or -CH=CH-,;each amino acid of the peptide sequence being optically pure and the a carbon of each amino acid having the D or L configuration.;
2.A compound of formula (I) as claimed in claim 1, such that X represents a 4-guanidinobenzoyl radical (Gba) and X1 a hydrogen atom.;- 23 -;247914;
3.A compound of formula (I) as claimed in claim 1, such that A7 represents any one of the following residues:;/ co /;H— N;/;CO I;CO t;H;CO I;/;CO I;/;CO I;^ N —;N—H;/;CO I;CO I;/;CO;F — •;/ n-ch3;CO;CH3 —N N;/;M;RO;V;/;//;■ -J—CH3 .7;CO I;N;✓\ N;^ CO /;CO I;/ Nco . and;CO I;(R represents a linear or branched (C1-C6) alkyl radical);
4.A compound of formula (I) as claimed in claim 3, such that X represents a 4-guanidinobenzoyl radical (Gba) and X' a hydrogen atom.;
5.A compound of formula (I) as claimed in claim 3, such that X represents an arginyl radical and X* a hydrogen atom. t 24 247 91 4
6.A process for preparing a compound of formula (I) as claimed in claim 1, which compound may be obtained by sequential solid-phase synthesis from protected amino acids, by synthesis from peptide fragments in solution, or, Where appropriate, by a combination of these two techniques, and, if so desired, by introduction, according to standard methods of organic chemistry, of a pseudopeptide bond at any point in time during the synthesis of the peptide sequence, which compound of formula (I) is converted, if necessary, to its addition salts with a pharmaceutically acceptable acid or base. i
7.A pharmaceutical composition containing as active principle at least one compound as claimed in any one of claims 1 to 5, alone or in combination with one or more pharmaceutically acceptable excipients or vehicles.
8.The pharmaceutical composition as claimed in claim 7, containing at least one active principle as claimed in any one of claims 1 to 5, which is useful as a bradykinin antagonist in the treatment of traumas of diverse origins, inflammatory disorders, pain, shock states, allergic disorders and insufficiency of spermatozoal mobility.
9. A compound of formula (I) as defined in claim 1 substantially as herein described with reference to the examples.
10. A process for preparing a compound of formula (I) as defined in claim 1 substantially as herein described with reference to the examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9207378A FR2692581B1 (en) | 1992-06-18 | 1992-06-18 | New peptide derivatives with bradykinin antagonist activity, their preparation process and the pharmaceutical compositions containing them. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ247914A true NZ247914A (en) | 1994-12-22 |
Family
ID=9430857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ247914A NZ247914A (en) | 1992-06-18 | 1993-06-17 | Peptides having bradykinin antagonist activity, their preparation and compositions |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0578521B1 (en) |
| JP (1) | JP2589937B2 (en) |
| AT (1) | ATE141615T1 (en) |
| AU (1) | AU660809B2 (en) |
| CA (1) | CA2098655A1 (en) |
| DE (1) | DE69304155T2 (en) |
| DK (1) | DK0578521T3 (en) |
| ES (1) | ES2091570T3 (en) |
| FR (1) | FR2692581B1 (en) |
| GR (1) | GR3021472T3 (en) |
| NZ (1) | NZ247914A (en) |
| ZA (1) | ZA934389B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE269310T1 (en) * | 1994-10-27 | 2004-07-15 | Fujisawa Pharmaceutical Co | PYRIDOPYRIMIDINONES, QUINOLINES AND FANNED N-HETEROCYCLES AS BRADYKININ ANTAGONISTS |
| FR2739553B1 (en) | 1995-10-06 | 1998-01-02 | Oreal | USE OF BRADYKININE ANTAGONISTS TO STIMULATE OR INDUCE HAIR GROWTH AND / OR STOP THE HAIR LOSS |
| DE19612067A1 (en) * | 1996-03-27 | 1997-10-02 | Hoechst Ag | Use of bradykinin antagonists for the manufacture of medicaments for the treatment of chronic fibrogenetic liver diseases and acute liver diseases |
| DE19642289A1 (en) | 1996-10-14 | 1998-04-16 | Hoechst Ag | Use of bradykinin antagonists for the manufacture of medicaments for the treatment and prevention of Alzheimer's disease |
| US7105172B1 (en) | 1999-11-18 | 2006-09-12 | Bolla John D | Treatment of rosacea |
| JP6424950B2 (en) * | 2015-03-24 | 2018-11-21 | 日立金属株式会社 | Composite cable, composite harness, and vehicle |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE63490B1 (en) * | 1988-11-24 | 1995-05-03 | Hoechst Ag | Peptides having bradykinin antagonist action |
| MX9100717A (en) * | 1990-08-24 | 1992-04-01 | Syntex Inc | BRADIQUININE ANTAGONISTS |
| FR2686343B1 (en) * | 1992-01-17 | 1994-03-11 | Adir Cie | NOVEL PSEUDOPEPTIDE DERIVATIVES WITH ANTAGONIST ACTIVITY OF BRADYKININE, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
-
1992
- 1992-06-18 FR FR9207378A patent/FR2692581B1/en not_active Expired - Fee Related
-
1993
- 1993-06-17 CA CA002098655A patent/CA2098655A1/en not_active Abandoned
- 1993-06-17 DE DE69304155T patent/DE69304155T2/en not_active Expired - Fee Related
- 1993-06-17 JP JP5145942A patent/JP2589937B2/en not_active Expired - Lifetime
- 1993-06-17 AT AT93401552T patent/ATE141615T1/en not_active IP Right Cessation
- 1993-06-17 ES ES93401552T patent/ES2091570T3/en not_active Expired - Lifetime
- 1993-06-17 AU AU41287/93A patent/AU660809B2/en not_active Ceased
- 1993-06-17 EP EP93401552A patent/EP0578521B1/en not_active Expired - Lifetime
- 1993-06-17 NZ NZ247914A patent/NZ247914A/en unknown
- 1993-06-17 DK DK93401552.0T patent/DK0578521T3/en active
- 1993-06-18 ZA ZA934389A patent/ZA934389B/en unknown
-
1996
- 1996-10-24 GR GR960402827T patent/GR3021472T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2692581A1 (en) | 1993-12-24 |
| AU660809B2 (en) | 1995-07-06 |
| CA2098655A1 (en) | 1993-12-19 |
| ES2091570T3 (en) | 1996-11-01 |
| DK0578521T3 (en) | 1996-12-09 |
| ZA934389B (en) | 1994-01-17 |
| DE69304155D1 (en) | 1996-09-26 |
| EP0578521B1 (en) | 1996-08-21 |
| JPH0687891A (en) | 1994-03-29 |
| ATE141615T1 (en) | 1996-09-15 |
| JP2589937B2 (en) | 1997-03-12 |
| DE69304155T2 (en) | 1997-03-20 |
| EP0578521A1 (en) | 1994-01-12 |
| GR3021472T3 (en) | 1997-01-31 |
| FR2692581B1 (en) | 1994-08-19 |
| AU4128793A (en) | 1993-12-23 |
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