EP0804463A1 - Neurokinin (tachykinin)-antagonisten - Google Patents

Neurokinin (tachykinin)-antagonisten

Info

Publication number
EP0804463A1
EP0804463A1 EP95919392A EP95919392A EP0804463A1 EP 0804463 A1 EP0804463 A1 EP 0804463A1 EP 95919392 A EP95919392 A EP 95919392A EP 95919392 A EP95919392 A EP 95919392A EP 0804463 A1 EP0804463 A1 EP 0804463A1
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
phenyl
pro
compound according
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Withdrawn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
EP95919392A
Other languages
German (de)
English (en)
French (fr)
Inventor
Gerd Schnorrenberg
Franz Esser
Horst Dollinger
Birgit Jung
Georg Speck
Erich Buerger
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.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE4445939A external-priority patent/DE4445939A1/de
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of EP0804463A1 publication Critical patent/EP0804463A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to new amino acid derivatives of the general formula I.
  • the compounds are valuable neurokinin
  • EP 394 989 and EP 443 132 and WO 94/05 693 describe peptides with neurokinin antagonistic activity.
  • the compounds according to the invention differ from these peptides essentially in the terms R 1 , A 2 , R 5 and
  • CDI carbonyldiimidazole
  • DCCI dicyclohexylcarbodiimide
  • Hpa homophenylalanine
  • PPA polyphosphoric acid
  • Trp (for) formyl-protected triptophan
  • Met (0) methionine, in which S is oxidized to the sulfoxide.
  • the invention relates to new amino acid derivatives
  • R 11 represents -C (O) -, -CH 2 -C (O) -, -SO 2 - or -CH 2 -SO 2 -;
  • Pro (OH) such as 3-hydroxyproline (Pro (30H)) and 4-hydroxyproline (Pro (40H)), D- or L-azetidine-2-carboxylic acid (Azt), D- or L-thioproline (Tpr ), D- or L-aminoproline (Pro (NH 2 )) such as 3-aminoproline (Pro (3NH 2 )) and 4-aminoproline
  • L-aspartic acid (Asp), D- or L-glutamine (Gln), D- or L-asparagine (Asn), D- or L-lysine (Lys), D- or L-arginine (Arg), D- or L-histidine (His), D- or L-ornithine (Orn), D- or L-hydroxypiperidine carboxylic acid such as 5-hydroxypiperidine-2-carboxylic acid, D- or L-mercaptoproline
  • Pro (SH) such as 3-mercaptoproline (Pro (3SH)) and 4-mercaptoproline (Pro (4SH)), Tpr (O), Met (O), Tpr (O 2 ) or Met (O 2 ), means and their geometric isomers, the hydroxyl and amino groups present can be protected by customary protective groups (for example acyl, carbamoyl or aralkyl (in particular benzyl);
  • B is the group - A 2 - NR 2 R 3 - or -R 5 ; is a lipophilic ⁇ -amino acid which is a phenyl, 1, 2 or 3 times substituted phenyl, heteroaryl, cyclohexyl or
  • Cyclopentyl group a naphthyl group or a mono- or di-C 1-3 alkylamino group, and this ring group or
  • Amino group is separated from the backbone of the amino acid by a 1- to 8-membered chain (the substituents of the
  • Phenyl group are independently halogen, trihalomethyl, alkoxy, alkyl, cyano or 1-pyrrolidinyl and in the 1- to 8-membered chain the links of the chain -CHR 4 , -C (O) -, -O-, -S- and / or -NR 4 -, which are arranged so that one of the following 3 types of chain results
  • Chain links is 1 to 8, and R 4 represents hydrogen, alkyl, aryl or aralkyl, wherein
  • substituted phenyl or naphthyl substituted phenyl or naphthyl; the substituents of the phenyl group are independently halogen, trihalomethyl, alkoxy, alkyl or cyano; and the
  • Alkyl group contains 1 to 3 carbon atoms; (where, if a chain contains more than one -CHR 4 group, only in one of these -CHR 4 groups R 4 can be alkyl, aryl or aralkyl) or
  • R 2 and R 3 are independently alkyl
  • Arylalkyl, heteroaryl or hydroxy (where aryl is phenyl, 1, 2 or 3 times substituted phenyl or naphthyl; the substituents of the phenyl group independently of one another are halogen, trihalomethyl, alkoxy, alkyl, alkylthio, hydroxy, nitro, trifluoromethoxy, dialkylamino or
  • Heteroaryl represents indolyl, pyridyl, pyrrolyl, imidazolyl or thienyl; and the alkyl or alkoxy group 1 to
  • aryl is phenyl, 1, 2 or 3 times substituted phenyl or naphthyl
  • Alkyl contains 1 to 3 carbon atoms
  • R 6 stands in what R 6 is aralkyl, diarylalkyl (in these groups aryl is phenyl or naphthyl and alkyl
  • N-phenylalkylpiperidinyl in which the phenyl groups mentioned are unsubstituted or contain 1, 2 or 3 substituents which independently of one another are (C 1 -C 5 ) -alkyl, preferably methyl,
  • R7 represents hydrogen or (C 1 -C 5 ) alkyl
  • X represents 0 or H 2 ;
  • Y and Z are independently hydrogen
  • (C 1 -C 5 ) alkyl preferably methyl
  • R 5 also for an amine of formula IV
  • R 6 , R 7 , Y and Z have the meaning given above and
  • R 8 represents hydrogen and R 9 represents hydroxy, (C 1 -C 5 ) alkoxy, phenyl- (C 1 -C 5 ) alkyloxy,
  • Substance P antagonism as well as neurokinin A or
  • Compounds of the general formula I can therefore be used either as internal salts, as salts with pharmaceutically usable inorganic acids such as hydrochloric acid,
  • organic acids such as maleic acid,
  • Fumaric acid, citric acid, tartaric acid or acetic acid or as salts with pharmaceutically usable bases such as alkali or alkaline earth metal hydroxides or
  • organic amines such as Diethylamine, triethylamine, triethanolamine and others available.
  • the chirality centers in the new amino acid derivatives can each have the R, S or R, S configuration.
  • partially saturated 6-ring used in the definition of R 1 is understood to mean a 6-ring which has two double bonds or preferably one
  • the bridged or unbridged ring described in the definition of R 1 can have 1 to 5 (C 1 -C 3 ) alkyl groups
  • alkyl groups each replace one or two H atoms of the CH 2 groups forming the ring and in two adjacent CH 2 groups, a maximum of 3 H atoms are replaced by alkyl groups. It follows from this that the group R 1 contained in compound 1, for example, does not exceed 5
  • Said bridge preferably connects positions 1 and 4, 2 and 5 or in particular 3 and 6, based on position 1 of the ring, which is connected to R 11 .
  • the bridge preferably connects 2 carbon atoms of the ring. If R 1 is a heterocyclic ring containing N, R 1 is preferably connected to R 11 via a C atom.
  • Heteroaryl group stands for a mono-, bi- or
  • the group may contain 1 or 2 substituents (C 1-3 alkyl) or an oxo group or an alkoxy group.
  • Heteroaryl groups can also be attached to the chain in positions other than those specified.
  • the "1 to 8-link chain” contained in A 2 consists, as explained above, of one to 8 links, which are understood to mean the following groups: -CHR 4 -, -C (O) -, -O-, -S -, -NR 4 -.
  • the chain is attached to the ⁇ -carbon atom of the amino acid (A 2 ).
  • R 4 (as stated above) represents hydrogen, alkyl, aryl or aralkyl, R 4 is preferably
  • the chain preferably contains 1 to 5, in particular 1 to 4, links.
  • R 1 and R 11 are as defined above,
  • Pro (OH) such as 3-hydroxyproline (Pro (30H)) and 4-hydroxyproline (Pro (40H)), D- or L-azetidine-2-carboxylic acid (Azt), D- or L-thioproline (Tpr ), D- or L-aminoproline (Pro (NH 2 )) such as 3-aminoproline (Pro (3NH 2 )) and 4-aminoproline
  • L-lysine (Lys), D- or L-arginine (Arg), D- or L-histidine (His), D- or L-ornithine
  • D- or L-hydroxypiperidine carboxylic acid such as 5-hydroxypiperidine-2-carboxylic acid, D- or L-mercaptoproline
  • Carbamoyl or aralkyl (especially benzyl) can be protected; and when B is the group - A 2 - NR 2 R 3
  • a 2 is a lipophilic amino acid, which is a
  • Di-C 1-3 alkylamino group contains, and this
  • Phenyl group independently of one another halogen
  • Arylalkyl, heteroaryl or hydroxy in which aryl is phenyl, 1, 2 or 3 times substituted phenyl or naphthyl; the substituents of the phenyl group are independently halogen, trihalomethyl, alkoxy, alkyl or cyano; heteroaryl is indolyl, pyridyl, pyrrolyl, Imidazolyl or thienyl; and the alkyl or
  • Alkoxy group contains 1 to 3 carbon atoms) or the group
  • aryl is phenyl, 1, 2 or 3 times substituted phenyl or naphthyl; the substituents of the phenyl group are independently halogen, trihalomethyl, alkoxy, alkyl or cyano).
  • R 1 - R 11 - A 1 - A 2 - NR 2 R 3 la are preferred in which
  • R 1 and R 11 are as defined above and / or
  • a 1 is an amino acid that is one or 2 polar
  • s in the side chain carries, such as OH, COOH, NH 2 , guanidine, CONH 2 , SH; especially what the functional group in the side chain of A 1 is OH and / or in which A 1 is pro, 4-hydroxyproline,
  • a 2 is an acyclic or cyclic amino acid such as (O-benzyl) Ser, (O-subst. Benzyl) Ser, (O-Benzyl) Thr, cyclohexylalanine, homophenylalanine, 3- (1-pyrrolyl) alanine,
  • Phenyl groups can be substituted 1, 2 or 3 times and the substituents independently of one another halogen, trihalomethyl, alkoxy, alkyl or
  • Methoxy groups are substituted) or pyridylmethyl; preferably compound wherein R 2 is methyl and R 3 is benzyl or alkoxybenzyl, especially where R 3 is 2-methylbenzyl; or where the group
  • Phenyl group is preferably in position 2 and when W is the group -CH (phenyl) 2 , the
  • Phenyl groups are each substituted by a halogen, preferably by fluorine, the two phenyl groups in the -CH (phenyl) 2 group preferably being substituted identically, preferably in the p-position.
  • a 1 is an amino acid that is one or 2 polar
  • functional group (s) in the side chain carries, such as OH, COOH, NH 2 , guanidine, CONH 2 , SH; in particular in which the functional group in the side chain of A 1 is OH and / or in which A 1 is pro, 4-hydroxyproline,
  • Preferred compounds of the invention are those in which R 5 is a group of the general
  • R 7 , X, Y and Z are as defined above.
  • Y and Z independently of one another methoxy, hydrogen
  • R 11 is -CH 2 SO 2 or preferably -C (O) -.
  • amino acids given are preferably in
  • the receptor affinity for the NK 1 receptor (substance 1)
  • the NK 2 binding test is carried out on transfected A20 cells which express the human NK 2 receptor.
  • the displacement of 125 J -BN-Neosolinin A is determined.
  • the IC 50 values thus obtained are:
  • Compound 1 for example, contains as group R 1 -R 11 - the (+) - camphorocarboxylic acid group.
  • the compounds of the invention are valuable neurokinin (tachykinin) antagonists that both
  • Substance P antagonism as well as neurokinin A or neurokinin B antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases:
  • Treatment or prevention of inflammatory and allergic diseases of the respiratory tract such as asthma, chronic bronchitis, emphysema, rhinitis, cough, eyes, such as conjunctivitis and ulcerative colitis,
  • the skin such as dermatitis, urticaria, psoriasis
  • the gastrointestinal tract such as ulcerative colitis, Crohn's disease, irritable colon, M.
  • Hirschsprung of the joints such as rheumatoid arthritis, reactive
  • migraine depression
  • epilepsy epilepsy
  • NK 1 and NK 2 values are of a similar order of magnitude.
  • the invention therefore also relates to the use of the compounds according to the invention as medicines and
  • the compounds according to the invention can be administered intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation, transdermally, if desired by iontophoresis or enhancers known from the literature
  • Salts possibly with the usual substances such as solubilizers, emulsifiers or other auxiliaries brought into solution, suspension or emulsion.
  • Solvents come e.g. in question: water,
  • physiological saline solutions or alcohols e.g.
  • the connections can be made through implants, for example from polylactide, polyglycolide or
  • Polyhydroxybutyric acid or intranasal preparations can be applied.
  • the compounds of the invention can be any organic compounds of the invention.
  • Peptide chemistry can be made by gradually adding the respective amino acids, respectively
  • R 1 - R 11 - A 1 - A 2 - NR 2 R 3 la can be built up from the parts R 1 -R 11 OH, HA 1 -OH, HA 2 -OH and HN (R 3 ) R 2 , the Sequence of couplings from right to left, from left to right or by coupling the units
  • the compounds of the invention can be any organic compounds of the invention.
  • Amino acids or partial amino acid sequences step by step condensed and the peptides thus obtained are in free form or in the form of the desired salts
  • Solid phase syntheses the fluorenylmethoxycarbonyl group (Fmoc) is preferred.
  • the side chain of arginine is protected by protonation in the case of conventional synthesis, in the case of
  • R 1 - R 11 - A 1 - R 5 Ib become the components R 1 -R 11 OH, the amino acid
  • the acid R 1 -R 11 OH can optionally be used first
  • a suitably protected form of HA 1 -OH can be coupled and condensed with the amine HR 5 after deprotection, or the suitably protected amino acid HA 1 -OH can first be reacted with HR 5 and, after deprotection of this product, coupled with R 1 -R 11 OH become.
  • the base bodies of the amines HR 5 according to the invention can be obtained by processes known per se:
  • Suitable protective groups are base stable
  • a compound of general formula XI is reduced with ring closure (e.g. analogously to that of A.L.
  • connection X can be made accordingly
  • Phthalimide group introduced and after cleavage of the protective groups and reduction of the nitro group cyclized to (substituted or unsubstituted) 3-amino-2-indolinone:
  • Connection IIb can take place as indicated above.
  • Acetamidomalonklarediethylester be converted to compound XIX and then to XX.
  • the reduction of compound XX to compound XXI can e.g. by hydrogen in the presence of Pd-Mohr in a solution of MeOH and water under pressure.
  • the ring closure for the preparation of compound XXII can be carried out with polyphosphoric acid with stirring and heating.
  • phthaloyl-phenylalanine is coupled with the amine H 2 NR 6 and then cyclized in a kind of Pictet-Spengler reaction with formaldehyde. Finally, the phthaloyl group is split off, for example by treatment with hydroxylamine:
  • R 6 , Y and Z are as defined above can be according to G-Leclerc et al., J. Med. Chem. 29, 2427 (1986).
  • substituted or unsubstituted 3-bromoquinoline is first converted into the corresponding N-oxide, then rearranged to quinolin-2-one and finally the amino group is introduced with ammonia under pressure (in the bomb tube):
  • the substituent R 6 can be introduced as described above for the compound Ila.
  • R 6 is as defined above and R 8 is hydroxy
  • R 9 is hydrogen, according to R. Wei.chert, Arkiv Kemi.
  • Acetaminomalonic acid monoethyl ester reacted with substituted or unsubstituted 2-nitrobenzaldehyde, then hydrolyzed, the nitro group reduced and finally cyclized:
  • R 9 (C 1 -C 5 ) alkoxy, phenyl- (C 1 -C 5 ) alkyloxy,
  • alkylated This alkylation can be carried out by first protecting the exocyclic N with, for example, trifluoroacetyl, carrying out the alkylation with, for example, alkyl bromide and then removing the protective group by, for example, hydrolysis.
  • Diisopropylethylamine was adjusted to pH 9.5 and then 3.8 g of tetramethyluronium tetrafluoroborate were added and the mixture was stirred for 24 hours. The solution was evaporated in a high vacuum, the residue was taken up in ethyl acetate and extracted twice with 10% KHCO 3 solution and saturated NaCl solution, dried and evaporated.
  • the Boc protecting group was removed as described in the preparation of 2b. 4.7 g of the hydrochroride 2d were obtained as a beige powder.
  • 2d was synthesized as in Example 2. 0.63 g of 2d (1.34 mmol) and 0.26 g of (-) camphoric acid were dissolved in 25 ml of DMF, the pH was adjusted to 8 by adding 0.38 ml of TEA, and 0.48 g of TBTU admitted. The mixture was stirred at room temperature overnight and then evaporated to dryness on a Rotavapor.
  • 0.63 g of 2d (1.34 mmol) and 0.26 g of (-) camphoric acid were dissolved in 25 ml of DMF, the pH was adjusted to 8 by adding 0.38 ml of TEA, and 0.48 g of TBTU admitted. The mixture was stirred at room temperature overnight and then evaporated to dryness on a Rotavapor.
  • TEA 0.38 ml
  • TBTU 0.48 g

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP95919392A 1994-05-07 1995-05-04 Neurokinin (tachykinin)-antagonisten Withdrawn EP0804463A1 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE4416255 1994-05-07
DE4416255 1994-05-07
DE4445939A DE4445939A1 (de) 1994-05-07 1994-12-22 Neue Aminosäurederivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen (II)
DE4445939 1994-12-22
PCT/EP1995/001691 WO1995030687A1 (de) 1994-05-07 1995-05-04 Neurokinin (tachykinin)-antagonisten

Publications (1)

Publication Number Publication Date
EP0804463A1 true EP0804463A1 (de) 1997-11-05

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Application Number Title Priority Date Filing Date
EP95919392A Withdrawn EP0804463A1 (de) 1994-05-07 1995-05-04 Neurokinin (tachykinin)-antagonisten

Country Status (20)

Country Link
US (2) US5712273A (sk)
EP (1) EP0804463A1 (sk)
JP (1) JPH09512806A (sk)
CN (1) CN1147260A (sk)
AU (1) AU690275B2 (sk)
BG (1) BG100946A (sk)
CA (1) CA2189764A1 (sk)
CZ (1) CZ325496A3 (sk)
EE (1) EE9600186A (sk)
FI (1) FI964473A0 (sk)
HR (1) HRP950276A2 (sk)
HU (1) HUT75708A (sk)
IL (1) IL113625A0 (sk)
MX (1) MX9605128A (sk)
NO (1) NO964700L (sk)
NZ (1) NZ285750A (sk)
PL (1) PL317127A1 (sk)
RO (1) RO115355B1 (sk)
SK (1) SK142696A3 (sk)
WO (1) WO1995030687A1 (sk)

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FI964473A (fi) 1996-11-07
CN1147260A (zh) 1997-04-09
US5700827A (en) 1997-12-23
FI964473A0 (fi) 1996-11-07
US5712273A (en) 1998-01-27
EE9600186A (et) 1997-08-15
CA2189764A1 (en) 1995-11-16
SK142696A3 (en) 1997-06-04
WO1995030687A1 (de) 1995-11-16
HUT75708A (en) 1997-05-28
MX9605128A (es) 1997-08-30
AU690275B2 (en) 1998-04-23
NO964700D0 (no) 1996-11-06
NO964700L (no) 1996-11-06
NZ285750A (en) 1998-08-26
BG100946A (en) 1997-07-31
AU2524995A (en) 1995-11-29
HU9603082D0 (en) 1997-01-28
CZ325496A3 (en) 1997-09-17
JPH09512806A (ja) 1997-12-22
RO115355B1 (ro) 2000-01-28
IL113625A0 (en) 1995-08-31
PL317127A1 (en) 1997-03-17

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