CN1461217A - Novel uses of non-peptide bombesin receptor antagonists for treating anxiety and panic disorders - Google Patents

Novel uses of non-peptide bombesin receptor antagonists for treating anxiety and panic disorders Download PDF

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CN1461217A
CN1461217A CN00820082A CN00820082A CN1461217A CN 1461217 A CN1461217 A CN 1461217A CN 00820082 A CN00820082 A CN 00820082A CN 00820082 A CN00820082 A CN 00820082A CN 1461217 A CN1461217 A CN 1461217A
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罗伯特·D·平诺克
马丁·C·普里查德
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Warner Lambert Co LLC
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Abstract

New uses have been found for compounds of formula (I) in which Ar, Ar1, R1, R2, R3, R4, R5, R6, R7, R8, R9, j, k, l, m and n are as defined in the description. These uses for the diagnosis, prevention, or treatment of anxiety, social phobia and panic disorders, pulmonary hypertension, lung repair and lung development disorders, prostate cancer, pancreatic cancer, hepatic porphyria, visceral pain, gastrointestinal secretory disturbances including duodenal ulcer and Helicobacter pylori infection and neuropathic pain. There is also disclosed a method for diagnosing or treating cancers using a radiolabelled compound of Formula (I), and also a method for treating cancers using a conjugate of a compound of Formula (I) with a cytotoxic agent.

Description

Non-peptide bombesin receptor antagonists is to the new application of treatment anxiety and panic disorders
Technical field
The invention relates to the application in making of medicine that bombesin receptor antagonists uses new indication.Also method about utilizing bombesin receptor antagonists to diagnose, treat or prevent.
Technical background
Four amphibious decapeptide bombesins (BB) belong to the peptide of new class, shared structure uniformity (Dutta A.S. (1993) in their C-end order Small Peptides:Chemistry, Biology ， ﹠amp; Clinical Studies, the 2nd chapter, pp66-82, Elsevier).
Decapeptide neuromedin B (NMB), neuromedin C (NMC) and 27 residue aminoacid, the peptide (GRP) that discharges Gastrin. be the peptide of the class bombesin of certified three kinds of mammals (people (1991) such as Battey J., Trends Neurosa.14:524).Think that NMB and GRP are by acting on corresponding preferred NMB (BB 1) receptor and preferred GRP (BP 2) receptor, can transmit the biological agent of transmitting in various peripheries and center (people (1990) such as Lebacq Verheyden A. Handbook of Experimental Pharmacology95 (part II): 71).In the International Patent Application WO 98/07718 non-peptide bombesin receptor antagonists has been described.
Invention is concise and to the point
Have now found that the chemical compound that is described among the WO 98/07718 and relevant chemical compound can be used for diagnosis, prevention and the treatment of following disease, for example anxiety and panic disorders, pulmonary hypertension, lung are repaired and lung development imbalance, carcinoma of prostate, cancer of pancreas, hepatic porphyria, visceral pain, gastrointestinal secretion disorder, vomiting or anorexia.Employed in the present invention bombesin receptor antagonists described in International Patent Application WO 98/07718 is disclosed in herein as a reference.
Therefore, the invention provides a kind of prevention or Therapeutic Method that utilizes the various diseases that bombesin receptor antagonists can improve treatment, comprise the panic deficiency disorder of anxiety, social phobia, pulmonary hypertension, lung is repaired and the lung development deficiency disorder, carcinoma of prostate, cancer of pancreas, hepatic porphyria, visceral pain, the gastrointestinal secretion imbalance, vomiting or anorexia, inflammatory pain, neuropathic pain, cancer pain, postoperative pain, nervi trigeminus pain, the herpetic pain of acute herpetic and back, described method comprises bombesin receptor antagonists or its pharmaceutically acceptable salt of the patient of this treatment of needs being used the formula I of effective dose.
Figure A0082008200071
Wherein: i is 0 or 1, and k is 0 or 1, and l is 0,1,2, or 3, m is 0 or 1, n is 0,1 or 2,
Ar is phenyl, pyridine radicals or pyrimidine radicals, respectively is unsubstituted, or can by be selected from alkyl, halogen, alkoxyl, acetyl group, nitro, amino ,-CH 2NR 10R 11, cyano group ,-CF 3,-NHCONH 2And-CO 2R 12In 1～3 substituent group replace:
R 1Be straight chain, side chain or the cyclic alkyl of hydrogen or 1～7 carbon atom,
R 8Be hydrogen or and the R of 3～7 carbon atoms arranged 1The ring that forms,
R 2Be straight chain, the side chain of hydrogen or 1～8 carbon atom, or cyclic alkyl, it also can contain 1～2 oxygen or nitrogen-atoms,
R 9Be hydrogen or by 3～7 carbon atoms and R 2The ring that forms, it can contain aerobic or nitrogen-atoms; Perhaps R 2And R 9Can be carbonyl together,
Ar 1Can be to be selected from Ar separately and also can to comprise pyridine radicals-N-oxide, indyl, imidazole radicals, and pyridine radicals,
R 4, R 5, R 6And R 7Each all is to be selected from hydrogen and low alkyl group, R individually 4Also can with R 5Form the covalent bond of 2～3 atoms, it can comprise oxygen or nitrogen-atoms,
R 3Can be selected from Ar individually, or hydrogen, hydroxyl ,-NMe 2, N-methyl-pyrrole radicals, imidazole radicals, N-methyl-imidazole radicals, tetrazole radical, N-methyl-tetrazole radical, thiazolyl ,-CONR 13R 14, alkoxyl,
Figure A0082008200073
, or
Wherein: p is 0,1 or 2, Ar 2Be phenyl or pyridine radicals,
R 10, R 11, R 12, R 13And R 14Each is selected from straight chain, side chain or the cyclic alkyl of hydrogen or 1-7 carbon atom individually.
The present invention is also about utilizing a kind of disease that is used for improving diagnosis, prevention or the treatment of treatment by above-mentioned bombesin receptor antagonists of formula I compound.
The present invention also about the method for treatment mammal tumor is provided, comprises that to a kind of compositions of administration, said composition contains the formula I chemical compound that suppresses dose,tumor, the perhaps conjugate of formula I chemical compound and cytotoxic agent.
The present invention and then a kind of method of in-vivo diagnostic imaging of the tissue that mammal is had a cell surface bombesin receptor is provided, this method comprises the radio-labelled compound of the present invention to administration diagnostic imaging amount, because said chemical compound manyly has the bombesin receptor of the tissue of this recipient cell to combine with having, so can further detect radiation image.Especially the present invention is about the method that exists to mammal diagnosis mammal tumor, and this method comprises the formula I chemical compound to administration diagnostic imaging amount, and selectively detects the image of the tissue with many cells that bombesin receptor arranged.
Another aspect of the present invention, provide the method for the cancerous cell in a kind of vitro detection mammalian tissues, this method comprises mammiferous tissue sample, contact certain hour with the formula I chemical compound of in-vitro diagnosis imaging amount, and make under chemical compound and the bonded condition of cancerous cell being enough to, detect this combination.
Accompanying drawing is described
Fig. 1 illustrates the effect ([A]: the % time that is open arm of chemical compound 1 (with 10mg/kg, 1h peritoneal injection before the test) to the rat behavior on the positive labyrinth that is placed on raising; [B]: the % number that enters out arm; [C]: open the arm concluding time; Veh: carrier).
Fig. 2 shows by rat under high light, not familiar condition, the effect of 1 pair of used time of social interaction of chemical compound.
Fig. 3 shows by the rat effect (Veh: carrier) of 1 pair of used time of chemical compound when opening wide the sand ground central authorities of field test.
Fig. 4 shows chemical compound 1 in the Cavia porcellus young stock and is isolating-inducing effect in the frightened pattern of sounding.
Fig. 5 shows in the Cavia porcellus young stock effect of isolating-inducing benzene first phenodiazine (a) in the frightened pattern of sounding or fluoxetine (b).
Detailed description of the preferred embodiments
The chemical compound that uses among the present invention is the chemical compound of above-mentioned formula I.Preferred compound is the chemical compound of formula II.
Figure A0082008200091
Wherein:
Ar is a unsubstituted phenyl, or by the phenyl that is selected from 1 or 2 substituent group replacement in isopropyl, halogen, nitro and the cyano group,
R 4, R 5And R 6Be hydrogen,
R 7Be methyl or hydrogen,
R 3Be 2-pyridine radicals or hydroxyl and
Ar 1Be indyl, pyridine radicals, pyridine radicals-N-oxide or imidazole radicals.
Another kind of preferred compound is the chemical compound of formula I.
Wherein: Ar is unsubstituted phenyl,
R 1Be the cyclopenta or the tert-butyl group,
R 4And R 5Be hydrogen,
R 7Be methyl,
R 6Be hydrogen,
R 3Be to have 2 substituent phenyl of isopropyl, unsubstituted phenyl, or formula
Figure A0082008200092
Ar 1It is indyl.
Another kind of preferred compound is the chemical compound of formula I,
Wherein: Ar is 2,6-diisopropyl-phenyl, and 4-nitro-phenyl and 4-cyano group-phenyl,
R 4, R 5And R 6Be hydrogen,
R 7Be methyl,
R 2Be hydrogen or cyclohexyl and
R 3Be hydroxyl, pyridine radicals.
Figure A0082008200101
, or
Figure A0082008200102
The alkyl group of the chemical compound that uses among the present invention except special specified form, comprises straight chain, the side chain of 1-8 carbon atom, or the ring-type carbochain.Representative groups be methyl, ethyl, propyl group, isopropyl, just-propyl group, just-butyl, isobutyl group, the second month in a season-butyl, tert-butyl, 2-methyl hexyl, just-amyl group, 1-methyl butyl, 2,2-dimethylbutyl, 2-methyl amyl, 2,2-dimethyl propyl, just-hexyl and other.
The low-grade alkyl group of compound used therefor comprises the group with 1-6 carbon atom among the present invention.
The group of naphthene base of compound used therefor is the group with 3-7 carbon atom among the present invention.They can replace with 1-3 the group that is selected from halogen, nitro, alkyl and the alkoxyl.
The alkoxy grp of compound used therefor among the present invention except other has explanation, comprises two kinds of carbochains of the straight chain and the side chain of 1-6 carbon atom.Representative groups is methoxyl group, ethyoxyl, propoxyl group, different-propoxyl group, the second month in a season-butoxy and hexyloxy.
Term " halogen " is meant fluorine, chlorine, bromine, iodine and astatine, comprises their radionuclide.
Term " Ar " is meant and comprises replacement or unsubstituted phenyl.Substituent group comprises one or more following substituent groups, such as halogen, nitro, alkyl, alkoxyl and other bases, as described or the present technique personnel known.
Term " amine " is free amine group, alkylated amines and acylated amine.
Preferred chemical compound be selected from following:
(S) N-cyclohexyl methyl-2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
N-cyclohexyl methyl-2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-N-methyl-propionic acid amide.,
N-cyclohexyl methyl-2-[3-(2,6-diisopropyl-phenyl)-1-methyl-urea groups]-3-(1H-indol-3-yl)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-2-methyl-3-(1-oxygen-pyridine-2-yl)-N-(1-pyridine-2-base-cyclohexyl methyl)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-2-methyl-3-pyridine-2-base-N-(1-pyridine-2-base-cyclohexyl methyl)-propionic acid amide.,
2-[3-(2-tert-butyl-phenyl)-urea groups]-N-cyclohexyl methyl-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
N-cyclohexyl methyl-2-[3-(2,6-two chloro-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
N-cyclohexyl methyl-2-[3-(2,6-dimethoxy-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
N-cyclohexyl methyl-2-[3-(2,6-dimethylamino-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
(S) N-cyclohexyl methyl-3-(1H-indol-3-yl)-2-methyl-2-[3-(4-nitro-phenyl)-urea groups]-propionic acid amide.,
N-cyclohexyl methyl-2-[3-(2,2-dimethyl-1-phenyl-propyl group)-urea groups]-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
[S-(R *, R *)] 3-(1H-indol-3-yl)-2-methyl-2-{3-[1-(4-nitro-phenyl)-ethyl]-urea groups }-N-(1-pyridine-2-base-cyclohexyl methyl)-propionic acid amide.,
N-(2,2-dimethyl-4-phenyl-[1,3] diox-5-yl)-3-(1H-indol-3-yl)-2-methyl-2-[3-(1-phenyl-cyclopentyl-methyl)-urea groups]-propionic acid amide.,
(S)-N-(2,6-diisopropyl-phenyl)-2-[3-(2,2-dimethyl-1-phenyl-propyl group)-urea groups]-3-(1H-indol-3-yl)-propionic acid amide.,
(R)-N-(2,6-diisopropyl-phenyl)-2-[3-(2,2-dimethyl-1-phenyl-propyl group)-urea groups]-3-(1H-indol-3-yl)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-N-(2,2-dimethyl-4-phenyl-[1,3] diox-5-yl)-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
N-cyclohexyl-2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
N-(2-cyclohexyl-ethyl)-2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-N-(3-methyl-butyl)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-N-(3-phenyl-propyl group)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-N-(1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-N-(2-phenyl-cyclohexyl)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-N-dihydroindene-1-base-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-N-(1-hydroxyl-cyclohexyl methyl)-3-(1H-indol-3-yl)-2-methyl-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridine-2-base-cyclohexyl methyl)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-N-(6,7,8,9-tetrahydrochysene-5H-benzocyclohepta-5-yl)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-N-phenyl-propionic acid amide.,
N-(1-hydroxyl-cyclohexyl methyl)-3-(1H-indol-3-yl)-2-methyl-2-[3-(4-nitro-phenyl)-urea groups]-propionic acid amide.,
2-[3-(4-cyano group-phenyl)-urea groups]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridine-2-base-cyclohexyl methyl)-propionic acid amide.,
(S) 3-(1H-indol-3-yl)-2-methyl-2-[3-(4-nitro-phenyl)-urea groups]-N-(1-pyridine-2-base-cyclohexyl methyl)-propionic acid amide.,
(S) 3-(1H-indol-3-yl)-2-methyl-N-(1-pyridine-2-base-cyclohexyl methyl)-2-[3-(4-trifluoromethyl-phenyl)-urea groups]-propionic acid amide.,
(S) 4-(3-{2-(1H-indol-3-yl)-1-methyl isophthalic acid-[(1-pyridine-2-base-cyclohexyl methyl)-carbamoyl]-ethyl }-urea groups)-benzoic acid ethyl ester,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-3-(1H-imidazol-4 yl)-N-(1-pyridine-2-base-cyclohexyl methyl)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-2-methyl-N-(1-pyridine-2-base-cyclohexyl methyl)-3-(2-trifluoromethyl-phenyl)-propionic acid amide.,
2-[3-(2,6-diisopropyl-phenyl)-urea groups]-2-methyl-3-(2-nitro-phenyl)-N-(1-pyridine-2-base-cyclohexyl methyl)-propionic acid amide.,
(S) 3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridine-2-yl)-cyclohexyl methyl]-2-methyl-2-[3-(4-nitro-phenyl)-urea groups]-propionic acid amide. and
N-cyclohexyl methyl-2-[3-(2,6-diisopropyl-phenyl)-urea groups]-2-methyl-3-pyridine-2-base-propionic acid amide..
After, (S) 3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridine-2-yl)-cyclohexyl methyl]-2-methyl-2-[3-(4-nitro-phenyl)-urea groups]-propionic acid amide. is also referred to as chemical compound 1.
Used chemical compound among the present invention in above-mentioned formula I, according to their structure, can have a plurality of chiral centres.Especially the chemical compound that uses among the present invention can be with diastereomer, and the mixture of diastereomer perhaps exists with blended or independent optical antipode.It is considered herein that the chemical compound that can use all these forms.
The chemical compound that uses among the present invention comprises the acceptable salt of solvate, hydrate, medicine of formula I chemical compound, and polymorph (different crystalline lattice is described thing).
Optimum is to form salt, the acceptable salt of medicine comprises acetate, benzene sulfonate, benzoate, bicarbonate, biatrate, bromide, calcium acetate, camsilate, carbonate, chloride, citrate, dihydrochloride, edetate, ethanedisulphonate, Estolate, esilate, fumarate, gluceptate, gluconate, glutamate, Glu, the glycollyl arsanilate, hexyl resorcin salt, Hai Baming salt (hydrabamine), hydrobromide, hydrochloride, hydroxynaphthoic acid salt, iodide, the 2-isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, mucate, naphthalene sulfonate, nitrate, embonate (4,4 '-di-2-ethylhexylphosphine oxide (3-hydroxyl-2-naphthoate)), pantothenate, phosphate/phosphor acid hydrogen salt, Polygalacturonate, Salicylate, stearate, basic acetate, succinate, sulfate, tannate, tartrate, the q-dramamine, the triethyl group iodine salt, the benzyl star, chloroprocaine, choline, diethanolamine, ethylene diamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc (also can be referring to " pharmaceutical salts ", people (1997) such as Bergs S.M. J.P ham.Sci.66:1-19, introduce herein for referencial use).
Term " patient " or " object " are meant mammal, are meant the mankind especially.
Carrying out method of the present invention is by to the formula I of administration effective dose chemical compound, in the chemotherapy indication, uses the conjugate of formula I chemical compound and cytotoxic agent, or the acceptable salt of its medicine is to diagnose, to prevent and treat above-mentioned any disease.This effective dose generally is that per kilogram object body weight is about 1-300mg.For the adult of a 70kg, general dosage be every day about 1mg to 5g.In addition, doses of radiolabelled compounds depends on the specific activity of radionuclide.
Another aspect of the present invention, provide a kind of to above-mentioned listed indication treatment or the pharmaceutical composition of prevention usefulness, described compositions contains the bombesin receptor antagonists of formula I, at least with a kind of pharmaceutically acceptable carrier or excipient.For by compound used therefor pharmaceutical compositions of the present invention, inert, pharmaceutically acceptable carrier can be that solid also can be a liquid.The preparation of solid form comprises powder, tablet, particle dispersion, capsule, medicated bag, pessulum and comprises the suppository of vaginal suppository.Solid carrier can be one or more materials that can be used as in diluent, pastil, solubilizing agent, lubricant, suspending agent, binding agent or the tablet disintegrant, and it also can be a kind of encapsulant.In powder, carrier be a kind of grind very thin solid, and form mixture with fine ground active component.In tablet, active component needs the carrier of bond property to mix with suitable ratio with having, and is pressed into the shape of wanting and size.
In order to prepare vaginal suppository or suppository,,, and for example be dispersed in wherein active the composition by stirring such as the mixture fusion of fatty glyceride and cocoa butter at first with low-fusing wax.Then the uniform mixture of fusion is poured in the mould of suitable size, and made its cooling and curing.Ointment also is preferred pharmaceutical composition, can be prepared by the used chemical compound of the present invention equally.
Powder and tablet preferably contain 5%～about 70% active component, suitable carrier is magnesium carbonate, magnesium stearate, Talcum, lactose, sucrose, pectin, dextrin, starch, Tragacanth, methylcellulose, sodium carboxymethyl cellulose, low melt wax, cocoa butter, or the like.
Terms " formulation " be comprise with active component with prepare as the encapsulant of carrier, a kind of capsule is provided, wherein actively forms (having or do not have other carriers) and surround, so carrier and it combines by carrier, equally also can prepare medicated bag.
Tablet, powder, medicated bag and capsule can be used as and be suitable for oral solid formulation shape.
Liquid form preparation comprises solution, suspension and emulsion.As the example that is suitable for the liquid preparation that the intestines and stomach takes, the sterilized water or the water-propylene glycol solution of reactive compound can be proposed.Liquid preparation also can be the solution in the Polyethylene Glycol aqueous solution.Oral aqueous solution can be by preparing solubilization of active ingredient in water.If desired, can add suitable toner, pastil, stabilizing agent and thickening agent.By levigated active component known other suspending agents in cohesive material such as natural rubber polymer, resin, methylcellulose, sodium carboxymethyl cellulose and medicine preparation technique are dispersed in the water, can be made into water slurry.
Preferred drug substances is with unit dosage form.In this form, preparation is divided into the unit dose of the active component that contains Sq.Unit dosage form can be a kind of packaged preparation, and packing contains the preparation of discrete magnitude, for example, package troche, capsule and be contained in bottle or ampoule bottle in powder.Unit dosage form also can be capsule, medicated bag or a tablet itself, perhaps can be this packaged form of any suitable number.
Just as already mentioned, formula I chemical compound can be used to diagnose, prevent and treat the disease of various situations, provides as follows about the further details of this application.
1) anxiety, panic attack and social phobia
Anxiety neurosis is a kind of common symptom, and benzodiazepine is the main therapeutic agent to this disease.The U.S. the most frequently used for this purpose be chlorine diaza oxide, benzene first phenodiazine , oxazepan, L0, prazepam and ALprazolanic.Yet, the benzodiazepine that controls anxiety neurosis also can cause sedation, the side effect that they have muscle-loose, calmness-hypnosis and forget, they also can strengthen the effect of alcohol, all may develop their deviation of effect, after using continually for a long time, will cause the anxiety bounce-back in case stop using, life-time service benzodiazepine especially along with the increase of dosage, can cause dependency.Therefore, need this dependence trend of reduction to treatment for anxiety.
Recent findings, the peptide of the suggestion class bombesin (people (1996) such as Plamondon H. that in nervous and anxiety, can play a role Soc.Neurosci.22:Abstract 181.13): will be used for GRP receptor and NMB receptor to the antianaphylactic oligonucleotide infusion of the mRNA mouse ventricles of the brain (i.c.v), surpass 2 days and measure by the receptor autoradiography, the result reduces the density of bombesin binding site in the brain.When comparing with control animal, with the acid-treated mouse of antianaphylactic oligonucleoside, add the anxiety field (anxiogenicfields of an elevated plus maze) in labyrinth or on the anxiety field in the avette labyrinth in flute profile tunnel (trough-tunnel ovalmaze), obviously consume more time in a high position.This just reflects the anxiety effect of processing.Prove that by the materia medica method chemical compound of the present invention is useful on treatment anxiety Panic disorder, below enumerates some examples.
Animal and medicament are taken
Male Hooded Lister rat (200-250g) or male TO mice (20-25g) with 6 groups of stable breedings.With the weigh common marmoset (callithrix jacchus) of 280-380g of paired stable breeding.All animals are all under bright/dark circulation in 12 hours, with food and the random stable breeding of water.
Except other has explanation, generally all be preceding 40 minutes in test, by lumbar injection (i.p) or subcutaneous injection (s.c) administration medicament, be the cubical content of 1ml/kg for rat and Adeps seu carnis Rhiopithecus roxellanae, for mice the cubical content of 10ml/kg.
A) mice is bright/the camera bellows test
Device is the chest of an open-top, long 45cm, and wide 27cm and high 27cm are divided into (3/5) greatly by dividing plate, little (2/5) district, dividing plate prolongs high 20cm people (1989) Pharmacol.Biochem.Behav.32:777-785 such as () costall B. than wall.Along floor level, have the opening of 7.5 * 7.5cm in the center of dividing plate.Little case chamber painted black, big case chamber painted white.The red illumination laboratory is used with the illumination of the tungsten lamp of 60W in the white box chamber, each mice is tested by the center that is placed on the white area, and made it be accustomed to new environment 5 minutes, is determined at time of spending in the illumination points (people (1989) such as Kilfoil T. Neuropharmacol.28:901-905).
B) the high-order X maze test of Mus
Method A: the high-order X labyrinth of standard (people (1984) such as Handley S.L. Naunyn- Schiedeberg Arch.Pharmacol.327:1-5), as people such as Field (1991) Br.J. Pharmacol.Be automatization described in 102 Suppl:304P.Animal is placed on towards the center, X labyrinth of opening one of arm.In order to determine the anxiety effect, in 5 minutes experimental period, be determined at out arm enter and half time spent that finishes (people (1989) such as Costall Br.J.Phamacol.96Suppl.:312P).
The result: (Fig. 1) in preceding 60 minutes Mus groups of test with 10mg/kg dosage peritoneal administration chemical compound 1, with the Mus group who receives only carrier relatively, open the % that spends the time in the arm place significantly increases in the labyrinth, detecting out the time quantum that arm finishes to spend also obviously increases.
C) people of Adeps seu carnis Rhiopithecus roxellanae monkey threatens test
In 2 minutes test period, write down by animal lest frightening the sum (people stands in from the about 0.5m of Adeps seu carnis Rhiopithecus roxellanae monkey case place, and stares the into eyes of Adeps seu carnis Rhiopithecus roxellanae monkey) that stimulates the figure's variation that occurs.Record figure's variation is to stare slit, afterbody attitude, and in case/high level makes odor identification, piloerection retreats and the back shape that overarches.Each animal is before drug treating and stand twice threatening the date of test after handling and stimulate., at least 2 hours, carry out subcutaneous medicament and handle after (control) threatening first.Pretreatment time to every kind of chemical compound is 40 minutes.Analyze the difference between record twice with the one way analysis of variance after the Dunnett ' test.
D) conflict test of rat
Training rat group depression bar is to obtain food in the operating room.Scheme program comprises: following operation hockets, signal by opening chamber light, at interval 30s changes, and carries out the cycle of not punishing in 4 times 4 minutes and signals with the punishment in three times 3 minutes (carrying the impact of food to foot by following) of constant proportion 5 by close chamber's light.Every Mus is adjusted the ballistic degree of foot, compare with replying of punishment not, obtain about 80～90% the inhibition of replying, the Mus group receives the saliferous carrier in the date of training.
F) social interaction of rat test
Method: the social interaction playground is annular (diameter 70cm), is made the high 30cm of wall by white pmma.Playground is by being positioned at intense light source (350lux) direct irradiation of playground top.A photographing unit also is installed directly over playground, is connected with video recorder in the adjacent chamber, for carrying out the duration of test record with post analysis.
Rat is matched by body weight, to guarantee that a pair of member's weight difference is less than 10g.Mus is being put into preceding 60 minutes of playground, two Mus of every centering are being carried out the peritoneal injection 5 minutes of carrier (n=10) or various dosetest chemical compound (n=10/ group).By the not clear observer of drug treating being recorded in the time of spending in the active social survey (Mus is followed the trail of and arrangement smelling with one's nose).For drug treating, test between 10:00～14:00 with random order, after each test, to wipe the whole playground of examination.Utilize unidirectional ANOVA analytical data, subsequently each species diversity is carried out Post-hoc Duncan ' s test.
Result:, p＜0.01 (Fig. 2) with 3.75 and 7.5mg/kg[F (2,27)=7.2] chemical compound 1 of injection obviously increased the social interaction ability of rat.With regard to percentage ratio increased, two kinds of dosage were close.For not effect of locomotor activity, this just proves that the effect for the ability of social interaction is selectable.
G) rat opens wide the test in place
Method: unlimited playground is annular (diameter 70cm), is made the high 30cm of wall by white pmma.By be positioned at playground directly over intense light source (350lux) irradiation playground.The photographing unit that is connected with the video recorder of adjacent chamber also be installed in playground directly over, for later analysis is carried out the duration of test record.Base plate is divided into internal ring and outer shroud with line.Behind the dosed administration 60 minutes, each Mus was placed on the playground center 5 minutes, and stays to detect.By the not clear observer of drug treating is recorded near time of spending the playground periphery and the time of spending at the playground inner region, when 4 pawls of animal during all in the zone, just think in interior playground, equally, when 4 pawls are all in outer shroud, just think at the periphery place.In the time that inner region is spent, be to represent, and analyze by unidirectional ANOVA with the percentage ratio of total time in interior exterior domain, subsequently each species diversity is carried out Post-hoc Duncan ' s test.
The result: (Fig. 3) with control animal relatively, carry out the Mus of peritoneal injection chemical compound 1 with 3.75mg/kg, crossing the percentage ratio of time in the inner region moderate of playground obviously increases, the effect of this reaction treatment anxiety.
H) isolate the sound producing pattern that the Cavia porcellus young stock causes anxiety
The psychosis pattern of animal usually with rat or mice as experimental animal.Yet, say that with regard to this point the laboratory animal that Cavia porcellus is best suited for is because they have and human similar center 5HT 1DReceptor causes that by temporary transient isolation parent the Cavia porcellus sounding is to influencing the test model of behavior.Know that also the chemical compound that can suppress to isolate cry in the anxiety pattern of this Cavia porcellus is the sign of clinical effect.
Method: with 5 minutes isolation time quantitative assay Cavia porcellus young stock (2-14 days ages) distress call, they and they mother and junior partner are met again.Proof box is made of the sound reduction box of white inner wall, white illumination.By means of mini-loud hailer and DAT recorder, the sound that record sends on the DAT tape.After carrying out 3 trial tests for three days on end, at first utilize the Standard Selection young stock of 500 sounds of minimum emission.As positive control, comprise the inhibitor fluoxetine of benzene first diaza and picked-up 5-hydroxy tryptamine.Every young stock reception test chemical compound (chemical compound 1,1-30mg/kg, intraperitoneal (i.p.) injection, in 50% cyclodextrin, benzene first phenodiazine 0.1-1mg/kg, subcutaneous injection (s.c.) in hydroxy methocel (CMC), perhaps fluoxetine 1-10mg/kg, subcutaneous injection, in water carrier), and before isolating, return to home cage 30 minutes with parent.As positive control, parallel test every day benzene first phenodiazine (1mg/kg).To every group, carry out computational analysis several difference that shouts a shout before and after treatment by paired t test.The percentage ratio that uses Kruskall-Wallis analysis of experiments cry number to reduce carries out the Mann-Whitney test subsequently between carrier and various dose.
The result: under all research dosage, chemical compound 1 has reduced significantly isolates the cry that causes.In test preceding 30 minutes, only inject chemical compound 1, (1-30mg/kg i.p.) increases the percentage ratio that cry reduces, with MED (Fig. 4: with the percentage ratio ecbatic of decreased average ± SEM of 10mg/kg along with dosage.To vehicle group *P＜0.05, Kruskull-Wallis test, Mann-Whitney test subsequently).This effect is better than the viewed effect (MED=1mg/kg of benzene first phenodiazine ; Fig. 5).Because sedation, so do not comprise the higher dosage of this chemical compound in the research.Fluoxetine also can obviously reduce cry number (Fig. 5) with the minimum effective dose (MED) of 10mg/kg.Clearly anxiety and antidepressant drug can both reduce the isolation cry of being sent by Cavia porcellus.Bombesin antagonist chemical compound 1 is effective as these chemical compounds, shows that there are certain potentiality in this compounds as novel anxiety/antidepressant medicament.
2) pulmonary hypertension
People (Lancet (1996) 348:1243) such as Hurel S.J. point out that the GRP receptor antagonist is injected among the patient who suffers the pulmonary hypertension misery, just can reduce the lung systolic pressure subsequently.Chemical compound of the present invention confirms to can be used for treating pulmonary hypertension by the standard drug method.
3) disorders of lung repairing and lung development
Several researchs emphasize that all GRP and GRP receptor repair and effect in lung development (people (1997) such as Spurzem J.R. at the lung behind the injury of lung Am J.Respir.Cell.Mol.Biol.16:209-211, people (1996) such as WangD. Am.J.Respir.Cell.Mol.Biol.14:409-416; Spindel E.R., the same 14:407-408).Injury of lung comprises the peptide amount of bringing out the class bombesin that causes increasing lung because of smoking.By people's such as Cutz E. discovery ( Pediatrics(1996) 98:668-72), propose that parent smoking may make the propagation of baby's nervus pulmonalis endocrine cell and the syndrome (SIDS) (as what the immunoreactive percentage ratio of bombesin is measured) that makes baby's sudden death, and the malfunction that proposes these cells can be made contributions to the pathophysiology of SIDS according to tracheal epithelium.Prove that by standard drug method chemical compound of the present invention can be used for treating the disorders of lung repairing and lung development.
4) treatment cancer
Also about the treatment method for cancer, it comprises to patient or object, particularly mammal in the present invention, and is especially human, uses the formula I chemical compound of effective dose, preferably with the conjugated formula I chemical compound of cytotoxic agent.This method is specially adapted to the cancer that its tumor cell has the cell surface bombesin receptor, comprises some carcinoma of prostate or cancer of pancreas.
When the formula I chemical compound that uses direct labelling during, preferably use Ar that halogen replaces as radionuclide in therapeutic purposes.The halogen radionuclide that is used for the treatment of is the radionuclide of β-radiation or alpha radiation preferably.Ar halogenic substituent for the best for the treatment of cancer comprises 131I, 211At, 76Br and 77Br, 131I is especially good.
The formula I chemical compound that Ar is replaced by the radionuclide halogen is easy to preparation by the fragrant replacement of the electrophilic of corresponding on-radiation chemical compound, and wherein Ar is replaced by halogen or active group.This halogen is Br or I preferably, and best active group comprises tributyl tin, trimethyl silyl, tert-butyl dimethyl silane, etc.
The conjugate of formula I chemical compound and cytotoxic agent, especially preferably R in formula I chemical compound 3Be hydroxyl or amino.In this case, chemical compound of the present invention can pass through two functional moieties easily, as glutamic acid etc., is connected with cytotoxic agent, forms conjugate.Suitable cytotoxic agent comprises the chemical compound as amycin (doxorubicin), anticancer chemotherapy, as Merck Index, and the 12nd edition, 1996, P describes among the MISC-10.
The present invention also proposes to use the conjugate of formula I chemical compound and radionuclide, is used for the preferred radionuclide emission α or the beta-particle of radiation treatment method, comprises 188Re, 131I, 221At, 212Pb, 212Bi, 76Br, 77Br or the like (for example, The Merck Index, the 12nd edition, 1996, page MISC-93).Use usual method can prepare said conjugate.For example, can utilize two functional chelating agen, as three succinums (trisucein) (people (1993) such as Safavy A. Bioconj.Chem.4:194-8), exist according to people such as SafavyA. Cancer(1997) 80 (Suppl): the method that adopts among the 2354-9, make radionuclide, as 188Re is connected with formula I chemical compound.Conjugate breaks in the time of can adopting it in entering tumor cell and discharges the compound form of cytotoxic agent, chemical compound transforms rapidly in vivo, to produce the parent compound of following formula, for example, be hydrolyzed by in entering target cell the time, this chemical compound is ideal.
The method that the present invention treats mammal tumor comprises the of the present invention at least a compound compositions that mammal is applied the inhibition dose,tumor.The amount of this inhibition tumor is an amount at least a in the objectification compound, and this amount is enough to make chemical compound to be positioned tumor site, to reduce growth of tumor or size.This dosage is 0.1～500mmol/kg body weight.Preferred dose is 5～50mmol/kg body weight.
Pattern according to radionuclide can change the radioactivity metering.Yet, when considering radioactivity amount, can use from 1 millicurie (mCi) to about 800mCi.Preferably can use 10～600mCi.Yet when considering dosage, the specific activity of radioactive compound should be taken into account.This specific activity is preferably very high, and is for example right 123The chemical compound of I-labelling, specific activity are at least about 1000～about 50000Ci/mM.Right 123The specific activity of the chemical compound of I-labelling is preferably about 10000～about 22000Ci/mM.
A) carcinoma of prostate
Bombesin has brought out moving (the Aprikian A.G.et al. (1996) of intracellular calcium current specially by the GRP receptor in the mankind's prostate gland cancer cell J.Mol.Endocrinol16:297～306).Regulating action plays in this bombesin family that has just proposed neuropeptide in the biology of carcinoma of prostate.Use antibody to improve growth (the Hoosein N.M. (1993) that anti-bombesin suppresses prostate cancer cell line Cancer Bull.45:436-411).Prove that by standard drug method chemical compound of the present invention can be used for the diagnosis and the treatment of carcinoma of prostate.
B) cancer of pancreas
Pancreatic cell normal and tumor contains special GRP receptor, and it expresses more (Hajri A.et al. (1996) in pernicious pancreatic tissue Dancreas12:25～35).But the propagation of the peptide stimulating human pancreatic cancer cell of class bombesin (people such as Wang Q.J. Int.J.Caneer(1996) 68:528-34).Therefore, can use bombesin receptor antagonists treatment cancer of pancreas.And, can use radiolabelled bombesin receptor antagonist treatment cancer of pancreas.Prove that by standard drug method chemical compound of the present invention can be used for treating cancer of pancreas.
5) porphyria of liver
The main clinical manifestation of hepatic porphyria is the nerve symptom, comprises abdominal pain, neuropathy and spirit interference.Think between acute phase of disease, in the systemic circulation,, comprise the increase of GRP, cause nerve symptom (people (1997) such as Medenica R. by some the intestines and stomach and poly-peptide neurotransmitter Cell mol. Biol.43:9-27).Therefore, can reduce the effect that these are attached to the poly-peptide of bombesin receptor with the bombesin receptor antagonists treatment, and alleviate the symptom of acute porphyria.Materia medica method by standard proves that chemical compound of the present invention can be used for the treatment of hepatic porphyria.
6) visceral pain
By proving that with following materia medica method the chemical compound that uses among the present invention is applicable to visceral pain.
The colon of stimulation in rats
Under anesthesia, rat is carried out tracheostomy, carotid artery is made cannulation, with the monitoring blood pressure.Interior colon was injected behind 0.6% acetic acid 45 minutes, carry out colon expand (75mmHg, 30s).Reduce proof colon pain by the blood pressure of measuring after these colons expand.The subcutaneous injection test compound after 30 minutes, carries out 6 colons again and expands then.By the comparison that blood pressure during between pre-processing period and afterwards handling reduces, calculate anti-nocuous percentage ratio.Make in this way, chemical compound 1 is with the anti-nocuity of 10mg/kg generation 57%.
7) secretion of the intestines and stomach is disturbed
Proved that GRP is an of great value instrument in the interference that detects the intestines and stomach secretory function, comprised those and duodenal ulcer diseases associated and helicobacter pylori (Helicobacter pylori) infection (people (1995) such as McColl K.E. Aliment.Pharmacol.Ther.9:341-7).The result is that radiolabelled bombesin receptor antagonist can be used for diagnosing these diseases.Other gastrointestinal function, as gallbladder contraction, pancreatic secretion, the activeness of stomach function regulating-esophagus can be regulated control by GRP, and radiolabelled bombesin receptor antagonist can be used for diagnosing these diseases.Materia medica method by standard proves that chemical compound of the present invention can be used for the intestines and stomach and secretes interferential treatment.
8) vomiting
Bombesin exists with high concentration in Rana nigromaculata skin.As the part of protective reaction, when the Predator swallowed, Amphibian can secrete the urgency material, and in mammal, bombesin is to be distributed in widely in the GI road, and it can cause stomach activeness and excretory variation there.Bombesin receptor antagonists of the present invention can reduce nausea and vomiting, and therefore, is effectively in the treatment vomiting, and is especially more effective to the patient who takes anticarcinogen.Can use the effect of following materia medica method proof The compounds of this invention in the treatment vomiting.
Cisplatin (cisplatin) brings out the antagonism of ferret vomiting
As comparing with control animal, utilize following method, bring out the ferret vomiting by cisplatin in the body (cisplatin), prove the emesis characteristic of compound used therefor among the present invention.Use intravenous injection cisplatin (30mg/kg).At preceding 30 minutes of cisplatin of injection, behind injection emetic 45 minutes again, the general chemical compound by the injection research of parenteral road.Along with the emetic material of administration, during 5 hours, observe the ferret in each cage continuously.In the attack times of every animal nausea and vomiting of viewing duration record, to the result of each processed group with on average ± S.E.M represents.Utilize unidirectional variation analysis (ANOVA) assessment, (PEG200, the 0.5ml/kg) significant difference that exists between the processing carry out the t-test of Student subsequently with the The compounds of this invention processing with carrier.
9) apositia
Bombesin causes the reduction of mice ingestion of glucose.In the mice that lacks the GRP receptor, bombesin no longer shows this effect (people such as Hampton L. Proc.Natl.Acad.Soi.USA.95:3188-92,1998).The bombesin receptor antagonists that the present invention uses can increase the feed behavior, and is therefore effective in the treatment apositia, such as the apositia of cancer patient.When comparing,, prove the appetizing effect of using compound used therefor of the present invention in the body by measuring food intake and the weight increase of mice with comparing animals.
10) pain
By the application of following materia medica method proof The compounds of this invention in treatment pain.
A) antler glue brings out hyperpathia and the allodynia of rat
(the 100 μ l of 20mg/ml) are administered in the plantar surfaces of toe of rear solid end with antler glue, measure hyperpathia and allodynia to external heat and mechanical stimulus.
B) pattern after the ovariohysterectomy of surgical pain
Intra-operative by nose cone keep with different fluorane (for inducing action with 5%, for maintenance is anaesthetized with 2%) and 1: 4O 2/ NO 2Mixture to anaesthetize female rat.At intra-operative animal is placed on the constant temperature blanket.In finea alba, carry out ovariohysterectomy by center line abdominal incision (2cm is long).Use single clamp technology that ligamentum ovarium and cervix uteri are sewed up with 5.0 silk threads.On stomach wall, do 4 simple interruptions and sew up (5.0).With 4 wound clips sealing skins, with the plain wound of handling of local antibacterial.
Be the symptom of internal organs injury, the test after animal is undergone surgery after the operation, is placed on animal in the independent lucite cage at once, and with 30 minutes one batch record abdominal part postures.The posture of record is the position of the back of a bow, moves inward the contraction of relevant abdominal muscles with hind leg, and the stretching of health and low abdominal part are to the extruding on floor.For the symptom about and allodynia irritated in the disease feel of rear solid end, animal also can be tested.
C) the neuropathic pain pattern of diabetes initiation
As described in early days, use single peritoneal injection streptozotocin (50mg/kg) bring out rat (250-300g) produce diabetes (people such as Courteix, 1993, Pain53:81-88).The similar isotonic saline solution injection of control animals received.
D) the slow compression injury pattern of neuropathic pain
By Bennett and Xie, PainDescribe in early days among the 33:87-107 (1988), bring out slow compression injury (CCI).Simply say, with pentobarbital sodium 60mg/kg peritoneal injection anesthetized rat.Pass through bicepsfemoris, use blunt dissection to make left sciatic be exposed to thigh thigh by-level, and, prick 4 ligation of knot (silk threads of 4.0 braidings) loosely near trident one side of ischium, with at a distance of the ligation of 1mm gap pine loose ground, then muscle is sealed with stratiform around it.Can measure pain threshold by several method.
1) thermal hyperalgesia
Before administration with after different time points, rat is used the test of Vgo Basile vola, then with people such as Hargreaves (1998) PainThe assessment thermal hyperalgesia of improving one's methods of 32:77-78.Make animal get used to the device that on high-order glass platform, constitutes by 3 independent lucite boxes.Movably infrared source is set below estrade, and concentrates on the desired pawl.The waiting time that the record claw is regained.Have one from 22.5s to the automatic cut-out point that prevents tissue injury.
2) Static allodni
Use Semmes-Weinstein Von Frey hair measurement mechanical anaphylaxis.Put animal into bottom in the cage of gauze, make bottom, before beginning experiment, make them have the knack of this environment near their claw.The toe face of the right back pawl by making animal according to the growth order of power (0.7,1.2,1.5,2,3.6,5.5,8.5,11.8,15.1 and 29g), contacts with Von Frey hair and to reach 6s.Reply in case establish withdrawal, the Von Frey hair that the next one is fallen begins, and claw is tested once more, till not replying generation.Mention claw with the power of the highest 29g, and bring out and reply, thus, the expression cut-out point.Record brings out replys the threshold value (PWT) of needed lowest force (in g) as the claw withdrawal.
11) diagnostic symptom
The invention provides a kind of method of in-vivo diagnostic imaging of the mammalian tissues that is used to have the cell surface bombesin receptor, comprise The compounds of this invention, and detection have many imaging that the tissue of bombesin receptor cell is arranged to a kind of diagnostic imaging amount of mammal administration.Especially the invention provides the cancer that is used to detect some type, for example the method for carcinoma of prostate and cancer of pancreas.
The used chemical compound of the present invention is attached on the cell surface bombesin receptor and to above-mentioned cancerous cell with to having the cell of bombesin receptor, presents intensive cell-specific and affinity.In one embodiment, the present invention is meant the method that is used to detect mammal tumor, comprises the above-mentioned formula I chemical compound to administration diagnostic imaging amount, and the hold-up of the chemical compound of observation in mammalian tissues.The present invention also provides a kind of method that is used for cancer diagnosis, usage flag, the preferred formula I bombesin receptor antagonists that uses the radioisotope labeling that is suitable for imaging.Exist by people (1991) such as Michelot J.M. J.Nucl. Med.The radionuclide example that is suitable for imaging has been described among the 32:1573-80.The preferred radionuclide that is used for diagnostic imaging is not launched the particle as α, β one class.When being used for diagnostic imaging, the halogenic substituent that can use Ar is as radionuclide.And described halogen radionuclide carrying group is preferred for the group of diagnostic imaging, mainly is the radionuclide of radiation γ, and it can use the radioactivity image formation method, for example by the scintiscan Imaging, and detects.The ray that the radionuclide of this radiation γ sends is enough to will detect by tissue penetration.Be used for the preferred halogenic substituent of the Ar group of diagnostic imaging, comprise 123I, 124I, 125I, 131I, 18F, 76Br and 77Br.The better group that is used for diagnostic imaging comprises 123I, 125I and 18F, 123I is particularly preferred for diagnostic imaging.
Chemical compound of the present invention generally on some cancerous cell types, is attached on the special cell receptor, and this cancerous cell comprises cancer of pancreas, carcinoma of prostate and relevant cell.The bombesin receptor that the bonded cell receptor example of this chemical compound is a cell surface.In the detection of receptors bind, proved the binding characteristic of compound used therefor among the present invention, as described in the WO 98/07718.
According to the present invention, the interior method that detects mammal tumor or contain the cell surface bombesin receptor of body comprises to mammal applying a kind of compositions that contains at least a The compounds of this invention of diagnostic imaging amount.This diagnostic imaging amount is the dosage of at least a purpose chemical compound, and it can make chemical compound be enough to be positioned tumor or tissue, can detect tumor or tissue.This dosage is every liter of chemical compound 1 μ g～1g, and its dosage is 1ng～10 μ g/kg body weight.For diagnostic imaging, the preferred dose of The compounds of this invention is about 10ng～about 2 μ g/kg.And, for diagnostic imaging, should consider the radioactive dosage used, preferably use the radioactive compound of about 0.1mCi～about 20mCi.
Just as described in this article, use radioactivity seeker, for example γ-radioactivity seeker can detect tumor or the tissue with one or more The compounds of this invention labellings.A kind of such method is to use scintigraphy.Also can utilize the X tomography x, the X tomography x (SPECT) or the positron emission X tomography x (PET) that calculate of single photon emission for example is to improve video picture.
In another embodiment, the invention provides a kind of external detection method that is used for the cancerous cell of mammalian tissues sample, comprise any chemical compound among the formula I of mammiferous tissue sample and in-vitro diagnosis imaging amount or the formula II is contacted a period of time, be enough to make chemical compound to be attached to cell surface bombesin receptor on the cancerous cell, and detecting this combination.Collect sample, for example vivisection of collection organization or body fluid by method known to the skilled.For example sample can be cut into slices with microtome knife, to be easy to microscopy and to observe bonded chemical compound.The also available suitable fixative of sample is fixed, before or after cultivating, with the liver mass of a kind of chemical compound of the present invention with the improvement sample tissue.The condition that is enough to make chemical compound be attached to cell surface bombesin receptor on the cancerous cell comprises the conditions of tissue culture of standard, that is, but sample In vitro culture and in Physiological Medium, cultivating with a kind of chemical compound of the present invention.This condition is known to the technical staff.Another kind method is that sample can be fixed, then wait ooze or physiological buffer in, cultivate with chemical compound of the present invention.At least a vitro detection cancerous cell amount that is used for, the amount of The compounds of this invention is 1ng/l～1000 μ g/l.Preferred amounts is 1 μ g/l～100 μ g/l.
When chemical compound of the present invention was used for the in-vitro diagnosis cancer, the substituent group that can use Ar was as radionuclide.Preferred substituted radionuclide for the in-vitro diagnosis cancer comprises 125I, 18F ,- 14COOH ,- 14CH 3, 3H etc.For detection in conjunction with a kind of cell of The compounds of this invention, can in the presence of selected compounds, cultivate sample, washing then, and count with the scintillation counter of standard.Another kind method is that sample is immersed in the photographic emulsion, after several days, carries out signal detection under optical microscope, as the silver particles of exposure.

Claims (24)

1. the manufacturing of formula I chemical compound or the acceptable salt of its medicine any used medicine in handling, prevent or diagnose anxiety and panic disorders, social phobia, pulmonary hypertension, lung repairing and lung development disorders, carcinoma of prostate, cancer of pancreas, hepatic porphyria, visceral pain, gastrointestinal secretion imbalance, inflammatory pain, neuropathy pain, cancer pain, postoperative pain, nervi trigeminus pain, the herpetic pain of acute herpetic pain and back is used
Wherein: j is 0 or 1, and k is 0 or 1, and l is 0,1,2, or 3, m is 0 or 1, n is 0,1 or 2,
Ar is phenyl, pyridine radicals or pyrimidine radicals, and every kind can be unsubstituted, perhaps be selected from alkyl, halogen, alkoxyl, acetyl group, nitro, amino ,-CH 2NR 10R 11, cyano group ,-CF 3,-NHCONH 2And-CO 2R 12In 1～3 substituent group replace.
R 1Be straight chain, side chain or the cyclic alkyl of a hydrogen or 1-7 carbon atom,
R 8Be hydrogen or with by the R of 3-7 carbon atom 1The ring that forms,
R 2Be hydrogen or with straight chain, side chain or the cyclic alkyl of 1-8 carbon atom, it also can contain 1-2 oxygen or nitrogen-atoms,
R 9Be a hydrogen or 3-7 carbon atom and R 2The ring that forms, it can contain aerobic or nitrogen-atoms; Perhaps R 2And R 9Can become carbonyl together,
Ar 1Can be to be selected among the Ar separately, and also can comprise pyridine radicals-the N-oxide, indyl, imidazole radicals, and pyridine radicals,
R 4, R 5, R 6And R 7Each all is to be selected from hydrogen and low alkyl group, R individually 4Also can with R 5Form the covalent bond of 2-3 atom, it can comprise oxygen or nitrogen-atoms.
R 3Can be selected from Ar individually, or hydrogen, hydroxyl ,-N-Me 2, N-methyl-pyrrole radicals, imidazole radicals, N-methyl-imidazole radicals, tetrazole radical, N-methyl-tetrazole radical, thiazolyl ,-CONR 13R 14, alkoxyl,
Figure A0082008200031
Figure A0082008200032
, or
Figure A0082008200033
Wherein: p is 0,1 or 2, Ar 2Be phenyl or pyridine radicals,
R 10, R 11, R 12, R 13And R 14Each all is straight chain, side chain or the cyclic alkyl that is selected from hydrogen individually or 1-7 carbon atom arranged.
2. according to the application of claim 1, feature is, chemical compound is the chemical compound of formula II,
Figure A0082008200034
Wherein:
Ar is unsubstituted phenyl or the phenyl that replaced by 1 or 2 substituent group that is selected from isopropyl, halogen, nitro and the cyano group,
R 4, R 5And R 6Be hydrogen,
R 7Be methyl or hydrogen,
R 3Be 2-pyridine radicals or hydroxyl and
Ar 1Be indyl, pyridine radicals, pyridine radicals-N-oxide and imidazole radicals.
3. (S) 3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridine-2-yl)-cyclohexyl methyl]-2-methyl-2-[3-(4-nitro-phenyl)-urea groups]-propionic acid amide. or its pharmaceutically acceptable salt, at treatment prevention or diagnosis anxiety and panic disorders, social phobia, pulmonary hypertension, lung is repaired and the lung development disorders, carcinoma of prostate, cancer of pancreas, hepatic porphyria, visceral pain, the gastrointestinal secretion imbalance, inflammatory pain, neuropathy pain, cancer pain, postoperative pain, nervi trigeminus pain, the manufacturing of acute herpetic pain and back any used medicine in the herpetic pain is used.
4. according to each application among the claim 1-3, feature is, medicine is to be used for the treatment of or the medicine of the gastrointestinal secretion deficiency disorder that prevents to cause because of duodenal ulcer or helicobacter pylori infections.
5. the formula II chemical compound of the formula I chemical compound of claim 1 definition or claim 2 definition or the chemical compound of claim 3, diagnostic imaging is with the application in the manufacturing of medicine in the mammal of mammal tumor.
6. according to the application of claim 5, feature is that the group Ar in the described chemical compound is the phenyl that halogen replaced by gamma-emitting radionuclide.
7. according to the application of claim 5, feature is, the group Ar in the described chemical compound be by 123I, 124I, 125I, 131I, 18F, 76Br or 77The phenyl that Br replaces.
8. the formula II chemical compound of the formula I chemical compound of claim 1 definition or claim 2 definition or the chemical compound of claim 3, the application in the manufacturing that is used for the treatment of the medicine that carcinoma of prostate or cancer of pancreas use.
9. the application of the conjugate of the chemical compound of the formula II chemical compound of the formula I chemical compound of cytotoxin and claim 1 definition or claim 2 definition or claim 3 in the manufacturing of medicine of treatment mammal tumor usefulness.
10. the application of claim 9, feature are that conjugate enters the tumor cell implosion, and discharges cytotoxic agent.
11. the application of claim 8,9 or 10, feature are that the Ar group in the described chemical compound is the phenyl that is replaced by β radiation or alpha-emitting radionuclide halogen.
12. the application of claim 8,9 or 10, feature be, the Ar group in the described chemical compound be by 131I, 211At, 76Br or 77The phenyl that Br replaces.
13. according to the application of claim 9, feature is that conjugate comprises by chelating agen makes radionuclide be connected with formula I chemical compound.
14. according to the application of claim 13, feature is that radionuclide is 188Re.
15. according to each application among the claim 5-14, feature is that medicine is at the mammal tumor that contains the cancerous cell with cell surface bombesin receptor.
16. a method that is used for vitro detection mammalian tissues sample cancerous cell, it comprises makes described mammalian tissues sample contact with the formula I chemical compound of claim 1 definition of in-vitro diagnosis amount or the formula II chemical compound or claim 3 chemical compound of claim 2 definition.
17. according to the method for claim 16, feature is that the Ar group in the described chemical compound is the phenyl that is replaced by β radiation or alpha-emitting radionuclide halogen.
18. according to the method for claim 16, feature is, the Ar group in the described chemical compound be by 131I, 211At, 76Br or 77The phenyl that Br replaces.
19. according to the method for claim 16,17 or 18, feature is that test is the tissue sample that is used to contain the cancerous cell with cell surface bombesin receptor.
20. one kind is used for the treatment of anxiety or panic disorders, social phobia, hypertensive pulmonary vascular disease, lung is repaired and the lung development disorders, carcinoma of prostate, cancer of pancreas, hepatic porphyria, visceral pain, the gastrointestinal secretion imbalance, inflammatory pain, neuropathy pain, cancer pain, postoperative pain, nervi trigeminus pain, the method of any disease in the herpetic pain of acute herpetic pain and back, comprise to the patient who stands the treatment of above-mentioned disease and needs, administration is with formula I chemical compound or the formula II chemical compound of claim 2 definition or the chemical compound of claim 3 of claim 1 definition of effective dose, or they are at pharmaceutically acceptable salt.
22. one kind is used for prevention of anxiety or panic disorders, social phobia, pulmonary hypertension, lung is repaired and the lung development disorders, carcinoma of prostate, cancer of pancreas, hepatic porphyria, visceral pain, the gastrointestinal secretion imbalance, inflammatory pain, neuropathy pain, cancer pain, postoperative pain, nervi trigeminus pain, the method of any disease in the herpetic pain of acute herpetic pain and back, comprise to the patient who stands the treatment of above-mentioned disease and needs, administration is with formula I chemical compound or the formula II chemical compound of claim 2 definition or the chemical compound of claim 3 of claim 1 definition of effective dose, or it is at pharmaceutically acceptable salt.
23. one kind is used to diagnose anxiety or panic disorders, social phobia, hypertensive pulmonary vascular disease, lung is repaired and the lung development disorders, carcinoma of prostate, cancer of pancreas, hepatic porphyria, visceral pain, the gastrointestinal secretion imbalance, inflammatory pain, neuropathy pain, cancer pain, postoperative pain, nervi trigeminus pain, the method of any disease in the herpetic pain of acute herpetic pain and back, comprise to the patient who stands the treatment of above-mentioned disease and needs, administration is with formula I chemical compound or the formula II chemical compound of claim 2 definition or the chemical compound of claim 3 of claim 1 definition of effective dose, or it is at pharmaceutically acceptable salt.
24. treat the method that mammal tumor is used for one kind, comprise to the mammal administration with a kind of compositions, said composition contains formula I chemical compound or the formula II chemical compound of claim 2 definition or the chemical compound of claim 3 of claim 1 definition that suppresses dose,tumor, or its acceptable salt on materia medica.
25. one kind is used to diagnose the mammal method that has mammal tumor, it comprises to formula I chemical compound or the formula II chemical compound of claim 2 definition or the chemical compound of claim 3 of mammal administration with claim 1 definition of diagnosing image amount, or its acceptable salt on materia medica.
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CN103463017A (en) * 2013-09-23 2013-12-25 南京广康协生物医药技术有限公司 Application of Lycojaponicumin B in preparation of medicines for treating pancreatic cancer
CN113164552A (en) * 2018-10-04 2021-07-23 新泽西州立罗格斯大学 Methods of reducing type 2 cytokine-mediated inflammation using a neuromedin peptide

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GB0403578D0 (en) * 2004-02-18 2004-03-24 Biofocus Discovery Ltd Compounds which interact with the G-protein coupled receptor family
EP1872795A4 (en) * 2005-04-21 2009-07-22 Astellas Pharma Inc Therapeutic agent for irritable bowel syndrome
EP2100900A1 (en) * 2008-03-07 2009-09-16 Universitätsspital Basel Bombesin analog peptide antagonist conjugates

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CN103463017A (en) * 2013-09-23 2013-12-25 南京广康协生物医药技术有限公司 Application of Lycojaponicumin B in preparation of medicines for treating pancreatic cancer
CN103463017B (en) * 2013-09-23 2015-11-25 李淑兰 The application of Lycojaponicumin B in preparation treatment pancreatic cancer drug
CN113164552A (en) * 2018-10-04 2021-07-23 新泽西州立罗格斯大学 Methods of reducing type 2 cytokine-mediated inflammation using a neuromedin peptide

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