CN1812997A - Pharmaceutical composition - Google Patents

Abstract

The present invention describes parenteral pharmaceutical compositions comprising a somatostatin analogue and novel somatostatin analogues.

Description

Pharmaceutical composition

The present invention relates to comprise the parenteral pharmaceutical composition of somatostatin analogs and new somatostatin analogs.

Somatostatin is a kind of tetradecapeptide with following structure.

Since separating and having identified somatostatin, the research work that is intended to seek more effective and more stable analogue is continuing always.

In WO 97/25977, somatostatin analogs is described.Said somatostatin analogs comprises the aminoacid sequence of formula I

-(D/L)Trp-Lys-X ₁-X ₂- I

X wherein _lBe formula (a) or group (b)

R wherein ₁Be randomly substituted phenyl,

R ₂Be-Z ₁-CH ₂-R ₁,-CH ₂-CO-O-CH ₂-R ₁,

Or

Z wherein ₁Be O or S, and

X ₂Be at C _αThe a-amino acid that has aromatic yl residue on the side chain, or being selected from the amino acid unit of Dab, Dpr, Dpm, His, (Bzl) HyPro, thienyl-Ala, cyclohexyl-Ala and tert-butyl-Ala, the Lys residue of said sequence is equivalent to the Lys of natural somatostatin-14 ⁹Residue.

Here used somatostatin analogs refers to straight chain or the cyclic peptide derived from the natural somatostatin-14 that comprises formula I sequence, wherein, there is one or more amino acid unit deleted and/or replaced by one or more other amino acid group and/or have one or more functional groups to be replaced and/or one or more group is replaced by one or more other isosteric group by one or more other functional group.Say to overview, this term covered binding affinity to defined at least a the somatostatin receptor hypotype hereinafter comprising in the nM scope with the natural somatostatin-14 of following formula I sequence all carried out the derivative of modifying.

The preferred wherein somatostatin analogs of residue shown in the sequence of top defined formula I on 8 to 11 of somatostatin-14.

The top disclosed somatostatin analogs that more preferably comprises six peptide units, the residue on 3 to 6 of said six peptide units comprises the sequence of formula I.More preferably, residue on 1 and 2 of six peptide units of these somatostatin six peptides can be any in the residue well known in the prior art, for example as A.S.Dutta at Small Peptides, the 19th volume, 292-354, Elsevier, disclosed residue in 1993, or as for example Phe of somatostatin-14 ⁶And/or Phe ⁷Substituent those residues.

Cyclic somatostatin six peptides more preferably, for example comprise the residue that is numbered on 3 to 6 of 1 to 6 six peptide units and said six peptide units have above cyclic somatostatin six peptides of aminoacid sequence of formula shown I, for example compound of formula Ia

X wherein ₁And X ₂As defined above,

A be selected from following residue of divalent: Pro,

With-NR _4a-CH ₂-CO-,

R wherein ₃Be NR ₈R ₉-C _2-6Alkylidene group, guanidine radicals-C _2-6Alkylidene group or C _2-6Alkylidene group-COOH, R _3aBe H, C _1-4Alkyl or have R independently ₃A kind of in the given implication, R _3bBe H or C _1-4Alkyl, R _aBe OH or NR ₅R ₆, R _bBe-(CH ₂) _1-3-or-CH (CH ₃)-, R ₄Be H or CH ₃, R _4aBe randomly the ring on substituted benzyl, R ₅And R ₆Be H, C independently of one another _1-4Alkyl, omega-amino--C _1-4Alkylidene group, ω-hydroxyl-C _1-4Alkylidene group or acyl group, R ₇Be direct bond or C _1-6Alkylidene group, R ₈And R ₉Be H, C independently of one another _1-4Alkyl, ω-hydroxyl-C _2-4Alkylidene group, acyl group or CH ₂OH-(CHOH) _c-CH ₂-(wherein c is 0,1,2,3 or 4), perhaps R ₈And R ₉Form together with coupled nitrogen-atoms and can comprise other heteroatomic heterocyclic group, R ₁₁Be randomly the ring on substituted benzyl ,-(CH ₂) _1-3-OH, CH ₃-CH (OH)-or-(CH ₂) _1-5-NR ₅R ₆, ZZ _aIt is natural or non-natural a-amino acid unit.

Particularly preferably be the compound of the formula II of free form, salt form or protected form

Wherein the configuration on the C-2 is (R) or (S) or its mixture, and

Wherein R is NR ₁R ₂-C _2-6Alkylidene group or guanidine-C _2-6Alkylidene group, and R ₁And R ₂Be H or C independently of one another _1-4Alkyl.

R is NR preferably ₁R ₂-C _2-6Alkylidene group.The compound of preferred formula II is that the wherein R of free form, salt form or protected form is the compound of 2-amino-ethyl, i.e. ring [{ 4-(NH ₂-C ₂H ₄-NH-CO-O-) Pro}-Phg-DTrp-Lys-Tyr (4-Bzl)-Phe] (being called as compd A here) and ring [{ 4-(NH ₂-C ₂H ₄-NH-CO-O-) Pro}-DPhg-DTrp-Lys-Tyr (4-Bzl)-Phe].Phg refers to-HN-CH (C ₆H ₅)-CO-, Bzl refers to benzyl.

The compound of these free forms, salt form or protected form is called as " compound of the present invention " hereinafter.

Because the proteolytic degradation effect of somatostatin analogs of the present invention, very good is that it is carried out systemic delivery, for example parenteral admin.But parenteral admin may be very painful at medicine-feeding part, and is especially true when repeat administration.

Find now to comprise The compounds of this invention and tartaric parenteral compositions table and reveal and make us interested character especially, for example have good tolerability and very high stability.

The compound of the present invention of protected form is equivalent to wherein that at least one amino is protected and can be by it being gone protection, thereby preferably obtains the somatostatin analogs of the compound of formula II in the physiological conditions protection of going down.Suitable amido protecting group has for example at " blocking group in the organic synthesis (Protective Groups in Organic Synthesis) ", T.W.Greene, J.Wiley; Sons NY (1981), the group described in the 219-287, the content of the document here is introduced into as a reference.The example of such amido protecting group has ethanoyl.

Compound of the present invention can exist with for example free form or salt form.Salt comprises acid salt, for example the salt that forms with mineral acid, polymer acid or organic acid, for example salt that becomes with hydrochloric acid, acetate, lactic acid, aspartic acid, phenylformic acid, succsinic acid or pamoic acid.Acid salt can exist with the form of unit price or divalent salts, and what this depended on adding is 1 equivalent or 2 normal acid.Preferred salt is lactic acid salt, aspartate, benzoate, succinate and embonate, comprises its single salt or disalt, more preferably aspartic acid disalt and pamoic acid list salt.

Compound of the present invention can be prepared with ordinary method.

First aspect present invention provides a kind of The compounds of this invention and tartaric parenteral composition of comprising.

According to the present invention, the concentration of The compounds of this invention in the present composition typically is every ml composition about 0.05 to about 1mg, and particularly 0.1 to 1mg/ml.

Compound of the present invention (in the amount of free form) and tartaric ratio are generally about 0.001 to about 2, and preferred about 0.05 to about 0.6 (w/w).

The content of compound of the present invention in the present composition is about 0.005% to about 0.1% of said preparation gross weight.

Tartrate is preferably tiny crystalline form.More preferably use D (-) or the crystallization of L (+) tartrate.Tartaric amount be preferably said preparation about 0.01% to about 1.5%, preferred about 0.01% to about 0.3%, more preferably from about 0.15%w/w.The volumetric molar concentration of tartrate in final composition is preferably about 10mM.

According to the present invention, except that tartrate and compound of the present invention, said pharmaceutical composition also preferably comprises a kind of basic component, described basic component is to transfer to about 4 to about 4.5 with the pH with this tartrate buffered pharmaceutical composition, and preferred about 4.2 mode is selected and joined in the said composition.

Preferably a kind of alkali of said basic component, for example sodium hydroxide or potassium hydroxide, perhaps for example sodium bicarbonate, yellow soda ash, saleratus or salt of wormwood of basic salt.The add-on of preferred basic component can make the pharmaceutical composition of gained have the above-mentioned pH value that is cushioned.

Pharmaceutical composition of the present invention is preferably based on water.

Composition of the present invention can also comprise tension regulator such as N.F,USP MANNITOL, sodium-chlor, glucose, dextrose, sucrose or glycerine.This tension regulator is N.F,USP MANNITOL preferably.

The amount of tension regulator is selected to regulate with the isotonicity to the present composition, for example, N.F,USP MANNITOL can be preferably said composition weight about 1% to about 5% weight, be preferably about 4.95% weight.The ratio that exists of N.F,USP MANNITOL is generally N.F,USP MANNITOL: tartrate is about 20 to about 40, preferred about 33.

Composition of the present invention can comprise other vehicle commonly used in the parenteral composition so that required stability and curative effect to be provided.Said vehicle can comprise for example oxidation inhibitor or sanitas.

Can protect promoting agent that oxygenolysis does not take place with oxidation inhibitor, particularly under heat-killed acceleration environment.Oxidation inhibitor can be selected from any in the compound known in the state of the art.Equally, can determine the amount of used oxidation inhibitor with routine test.Composition of the present invention does not preferably comprise oxidation inhibitor.

When being prepared to multiple dose vials, cartridge or syringe, can in said composition, add for example phenol of sanitas.Composition of the present invention does not preferably comprise sanitas.

Can be about these and other vehicle and the method mentioned here with reference to lot of documents, particularly can be referring to handbook of pharmaceutical excipients (Handbook of Pharmaceutical Excipients), second edition, Ainley Wade and Paul J.Weller chief editor, American PharmaceuticalAssociation, Washington, USA and Pharmaceutical Press, London; With Lexikon derHilfsstoffe f ü r Pharmazie, Kosmetik and angrenzende Gebiete, the H.P.Fiedler chief editor, the 4th edition, Editio Cantor, Aulendorf and version early, it here is introduced into as a reference.

Composition of the present invention preferably only comprises compound of the present invention, the compound of formula II for example, and for example compd A is as activeconstituents.

The method that is used to prepare the present composition can be an ordinary method known in the art or based on these class methods, people such as L.Lachman for example, the theory and practice of industrial pharmacy (TheTheory and Practice of Industrial Pharmacy), the 3rd edition, 1986, people such as H.Sucker, Pharmazeutische Technologie, Thieme, 1991, Hager ' s Handbuch derpharmazeutischen Praxis, the 4th edition (Springer Verlag, 1971) and Remington ' sPharmaceutical Sciences, the 13rd edition, method described in the version of (Mack Publ., Co., 1970) or renewal.

Typically, compound of the present invention, tartrate and described other optional composition are dissolved in the aqueous solvent (preferred water for injection), and its pH are regulated with alkali with institute's expense.Then, water with the solution dilution of gained to required final volume.Can with sterile filters for example Millipak  strainer the solution of gained is filtered.In above-mentioned preparation process, preferred displacement is fallen oxygen (air) and is contacted with the solution of The compounds of this invention to avoid it.This point is normally undertaken by with nitrogen for example the container that holds this solution being purified.Can under carbonic acid gas or other rare gas element, pack to prevent degraded this pharmaceutical composition, preferably under carbonic acid gas, pack, for example it is loaded into bottle for example vial, ampoule, for example glass ampoule or syringe be for example in the pre-filled syringe, and it is carried out steam sterilizing or heat sterilization.

Can with ordinary method under aseptic condition with this solution lyophilize, thereby obtain a kind of sterile injection powder, before facing administration can by with the solvent of this powder and aequum for example water for injection mix and it reassembled into the required solution that is used for parenteral admin.

In addition, the present invention also provides a kind of on the other hand and has been buffered to about 4 to about 4.5, the composition of the parenteral admin of preferred about 4.2 pH, it comprises as the compd A of activeconstituents or its pharmaceutically useful salt, lactic acid salt, list-or two-aspartate, succinate for example, preferred aspartic acid disalt.

These compositions can comprise with above-mentioned and comprise the identical component of component that tartaric composition comprises, and wherein replace said tartrate/tartrate with other damping fluid such as acetate/acetate, lactic acid salt/lactic acid, Glycin/HCl.

Compound of the present invention can be used for

A) prevent treat that its cause of disease comprises or with GH excessive secretion and/or the too high relevant illness of IGF-1, for example can be used for treating acromegaly and I type or type ii diabetes, especially its complication, vascular disease for example, diabetic proliferative retinopathy, diabetic macular edema, ephrosis, neuropathy and dawn phenomenon, and other discharge relevant metabolic disorder with Regular Insulin or hyperglycemic-glycogenolytic factor, for example fat, morbid obesity or hypothalamic obesity or hyperinsulinism (hyperinsulinemic) obesity for example

B) treatment intestines fistula of skin and ductus pancreaticus fistula of skin, irritable bowel syndrome, inflammatory diseases, Graves disease for example, inflammatory bowel, psoriasis or rheumatoid arthritis, multicystic kidney disease, dumping syndrome, watery diarrhea syndrome, the diarrhoea relevant with AIDS, the diarrhoea that chemotherapy causes, the tumour of acute or chronic pancreatitis and secretion gastrointestinal hormone ` (GEP tumour for example, VIPoma for example, glucagonoma of pancreas, insulinoma, innocent tumour etc.), the lymphocyte malignant tumour, for example lymphoma or leukemia, hepatocellular carcinoma and gastrointestinal hemorrhage, for example varix esophagorrhagia

C) prevention or treatment vasculogenesis, above-mentioned inflammatory diseases, comprise inflammatory eye disease, macular edema, for example cystoid macular edema, spontaneous cystoid macular edema, the overflowing property macular degeneration relevant, illness and the proliferative retinopathy relevant with choroidal neovascularization with the age

D) prevention or antagonism vascular graft disease, for example allotransplantation or xenotransplantation vascular lesion, grafting vessel atherosclerosis for example, for example organ transplantation, the heart for example, lung, the heart-lung associating, liver, grafting vessel atherosclerosis in kidney or the transplantation of pancreas, or be used for prevention or treatment vein transplantation thing is narrow, restenosis behind the blood vessel injury and/or vascular occlusion, said blood vessel injury is for example operated as Percutaneous Transluminal Angioplasty by conduit operation or blood vessel curettement, the blood vessel injury that other invasive operation of the integrity of laser therapy or destruction tunica intima or endothelium causes

E) tumour such as the pituitary tumor of the somatostatin receptor expressed or gathered in treatment, Cushing's disease for example, stomach-intestines pancreatic neoplasm, innocent tumour, central nervous system, breast, tumor of prostate (the hormone intractable prostate cancer that comprises late period), ovary or colon tumor, small cell lung cancer, pernicious intestinal obstruction, chromaffinoma, kidney, skin carcinoma, neuroblastoma, pheochromocytoma, medullary thyroid shape knurl, myelomatosis, lymphoma, He Jiejinshi and non_hodgkin lymphoma, bone tumor with and metastatic tumor, and autoimmunity or inflammatory conditions, for example rheumatoid arthritis, Graves disease or other inflammatory eye disease.

Composition of the present invention is preferred for treating acromegaly and cancer, for example Cushing's disease.

Can in standard clinical or animal experiment, confirm the activity and the characteristic of the present composition.

The optimal dose of the present composition will change according to the illness of for example being treated (for example disease type or resistance), used medicine, required effect and administering mode certainly.

When by successive administration, the significant quantity of compound can be divided in for some time and given for two or three times, as for example intravenous drip, intramuscular or subcutaneous injection or for example continuous subcutaneous input of subcutaneous input are given by parenteral admin, preferably carry out administration by subcutaneous injection or input, total per daily dose can be distributed in during the whole administration or in its portion of time.When by the subcutaneous injection administration, most preferably being administered three times weekly was administered three times to every day, preferably weekly twice to high to once a day or twice.Compound of the present invention can also be with for example subcutaneous form administration of injecting.

Composition of the present invention preferably is suitable for subcutaneous administration.

After injection, the local tolerance of the present composition is fine.Specifically, the parenteral admin of the present composition, for example subcutaneous injection only produces slight burning sensation or does not have the sensation of burning sensation in the injection site.

After injection, except that good local tolerance, composition of the present invention also shows satisfactory stability.For example, after storing for 4 weeks under 60 ℃, the degraded of product is less than 2.5%.For example, if under the lucifuge condition when under 8 ℃, storing for 2 ℃, composition of the present invention was stable in 24 months.Two aspartates with compd A can be observed special satisfactory stability.

Usually, can be by per injection about 0.01 to about 1.2mg, preferred about 0.1 to about 0.6mg compound of the present invention, or with about 0.001 dosage to about 0.009mg/kg the weight of animals/sky be administered once every day or with height to every day four times divided doses carry out administration, for example subcutaneous administration can obtain gratifying result.Therefore, for the patient, suitable per daily dose is that about 0.1mg is to about 0.6mg compound of the present invention, for example compound of formula II, for example compd A.

Come composition of the present invention is described with the following examples.

Embodiment 1 to 7:

Tartrate and N.F,USP MANNITOL are dissolved in the water for injection, with nitrogen this solution are purified simultaneously.Then, to two aspartates that wherein add compd A, the pH of this solution is transferred to 4.20 and to wherein adding water for injection to 1.0ml with sodium hydroxide.Under aseptic condition, this solution is filtered with the Millipak-200  sterile filters of aperture≤0.22 μ m, fill it in the ampoule and it is sterilized with autoclave.

	Embodiment 1	Embodiment 2	Embodiment 3	Embodiment 4
					Two aspartates of compd A (amount that is equivalent to compd A)	0.251 (0.200)	0.315 (0.251)	0.376 (0.300)	0.472 (0.376)
The tartrate crystallization	1.501	1.501	1.501	1.501
					N.F,USP MANNITOL	49.500	49.500	49.500	49.500
1N injection sodium hydroxide	To pH 4.20	To pH 4.20	To pH 4.20	To pH 4.20
					Water for injection	Add to 1ml	Add to 1ml	Add to 1ml	Add to 1ml

	Embodiment 5	Embodiment 6	Embodiment 7
				Two aspartates of compd A (amount that is equivalent to compd A)	0.752 (0.600)	0.786 (0.627)	1.129 (0.900)
The tartrate crystallization	1.501	1.501	1.501
				N.F,USP MANNITOL	49.500	49.500	49.500
1N injection sodium hydroxide	To pH 4.20	To pH 4.20	To pH 4.20
				Water for injection	Add to 1ml	Add to 1ml	Add to 1ml

The present invention provides the new compound of the formula III of free form, salt or complex form or protected form on the other hand

Wherein R is NR ₁R ₂-C _2-6Alkylidene group or guanidine-C _2-6Alkylidene group, and

R ₁And R ₂Be H or C independently of one another _1-4Alkyl.

R is NR preferably ₁R ₂-C _2-6Alkylidene group.A kind of compound of preferred formula III is that wherein R is free form, salt or the complex form of 2-amino-ethyl or the compound of protected form, is also referred to as ring [{ 4-(NH ₂-C ₂H ₄-NH-CO-O-) Pro}-DPhg-DTrp-Lys-Tyr (4-Bzl)-Phe], and be called as compd B here.Phg and Bzl are as defined above.

The compound of these free forms, salt or complex form or protected form is called as " new compound of the present invention " hereinafter.

The compound of the formula III of protected form, for example compd B is equivalent to wherein that at least one amino is protected and can be by going protection, preferably goes down protection and produces molecule above the compound of formula III at physiological conditions.Suitable amido protecting group is for example at " blocking group in the organic synthesis ", T.W.Greene, J.Wiley﹠amp; Sons NY (1981), disclosed group among the 219-287, the content of the document here is introduced into as a reference.The example of such amido protecting group has ethanoyl.

When the compound of formula III, when for example compd B exists with complex form, its be easily on the side chain amino of Pro, have a kind of chelation group and with the compound of the formula III of detectable element or the complexing of radiation treatment element.The compd B that has chelation group is called as the compd B that yoke closes here.

The example of chelation group comprises the group that for example derives from many-aminopolycanboxylic acid or acid anhydrides, for example derives from for example diethylene triaminepentaacetic acid(DTPA) (DTPA) of non-annularity part, ethylene glycol-0,0 '-two (2-amino-ethyl)-N, N, N ', N '-tetraacethyl (EGTA), N, N '-two (hydroxybenzyl) quadrol-N, the group of N '-oxalic acid (HBED) and triethylenetetraaminehexaacetic acid (TTHA), derive from substituted DTPA, the group of for example right-isothiocyanato-benzyl-DTPA, derive from macrocyclic ligand, for example 1,4,7,10-tetraazacyclododecanand-N, N ', N ", N -tetraacethyl (DOTA); 1; 4; 8,11-tetraazacyclododecane tetradecane-N, N '; N " N -tetraacethyl (TETA) or 1,4,7,10-tetraazacyclododecane tridecane-N, N ', N ", the group of N -tetraacethyl (TITRA).

This chelation group can be directly connected on the side chain amino of Pro or by a kind of spacer and connect thereon.Suitable spacer comprises spacer known in the art, GB-A-2 for example, and disclosed spacer in 225,579, the aminocarboxylic acid residue of divalent of β-Ala for example for example perhaps derives from the residue of divalent of 6-amino-caproic acid.

Preferred chelation group is the group that derives from DTPA, DOTA or TETA.Most preferably derive from the chelation group of DTPA or DOTA.

Detectable element refers to any element that shows the character that can arrive by the in-vivo diagnostic technology for detection, preferable alloy ion, but the metal ion of emission sense radiation or can influence the metal ion of NMR relaxivity for example.The radiation treatment element refers to emission has the ray of beneficial effect to the illness of being treated any element.

Suitable element comprises for example heavy element or rare earth ion, for example cat scan (the axial x-ray tomography gamma radiography of computer control) used element, paramagnetic ion, for example Gd ³⁺, Fe ³⁺, Mn ²⁺And Cr ²⁺, fluorescence metal ion, for example Eu ³⁺, and radionuclide, for example the radioactivity lanthanon is particularly launched gamma-ray radionuclide, launches Beta-ray radionuclide, launches Alpha-ray radionuclide, is launched Auger-e ^-The radionuclide of the radionuclide of ray or emission positron, for example ⁶⁸Ga, ¹⁸F or ⁸⁶Y.

The suitable gamma-ray radionuclide of emission comprises the nucleic that is used for diagnostic techniques.Launch gamma-ray radionuclide and advantageously had 1 hour to 40 days, preferred 5 hours to 4 days, more preferably transformation period of 12 hours to 3 days.The radio isotope that the example has gallium, indium, technetium, ytterbium, rhenium, terbium, lutetium, thallium and a samarium for example ⁶⁷Ga, ¹¹¹In, ^99mTc, ¹⁶¹Tb, ¹⁶⁹Yb, ¹⁸⁶Re or ¹⁷⁷Lu.

The suitable Beta-ray radionuclide of emission comprises the nucleic that is used for the radiation treatment application, for example ⁹⁰Y, ⁶⁷Cu, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁶⁹Er, ¹²¹S n, ¹²⁷Te, ¹⁷⁷Lu, ¹⁴³Pr, ¹⁹⁸Au, ¹⁰⁹Pd, ¹⁶⁵Dy, ¹⁴²Pr or ¹⁵³Sm.

The suitable Alpha-ray radionuclide of emission is the nucleic that is used for the treatment of, for example ²¹¹At, ²¹²Bi or ²⁰¹Tl.

The compound of formula III, for example compd B can exist with for example free or salt form.Salt comprises the acid salt that forms with mineral acid, polymer acid or organic acid, for example salt that becomes with hydrochloric acid, acetate, lactic acid, aspartic acid, phenylformic acid, succsinic acid or pamoic acid.Acid salt can exist with the form of unit price or divalent salts, and this depends on that what add is 1 equivalent or 2 normal acid in the compd B of free alkali form.Preferred salt is lactic acid salt, aspartate, benzoate, succinate and embonate, comprises its single salt and disalt, more preferably aspartic acid disalt and pamoic acid list salt.

When having hydroxy-acid group in the chelation group, the compound of the formula III that yoke closes, for example the compd B that closes of yoke can also exist with the form of for example an alkali metal salt such as sodium or sylvite or replacement or unsubstituted ammonium salt.

The present invention also comprises a kind of compound for preparing formula III, for example method of compd B.It can prepare with the method that is similar to currently known methods, for example:

A) peptide that will protect, straight chain that combine with polymkeric substance or that do not protect form is can access the compound of formula III, and for example the mode of compd B is carried out cyclization, randomly remove protecting group then,

B) in order to prepare the compound of the formula III that yoke closes, the compd B that closes of yoke for example, with chelation group and the protected or compound of the formula III of protected form not, for example compd B couples together, and randomly removes blocking group then,

Reclaim then formed free form, salt form or randomly with detectable element or the radiation treatment element compound of the formula III of complexing mutually, the compound of the formula III that closes of compd B or yoke for example, for example compd B that closes of yoke.

Because this linear peptides will be by cyclisation, thus select which kind of amino acid on the C-terminal position as peptide chain to begin not be key, as long as the compound of aminoacid sequence in this linear peptides and required formula III, for example the sequence in the compd B is corresponding gets final product.But some other the factor that may have causes a kind of initial amino acid than another kind more preferably.When the compound for preparing formula III by solid phase synthesis; for example during compd B; preferably first amino acid is connected to resin by suitable connection base; for example on the resin based on polystyrene that can obtain by commercial sources; said connection base is for for example connecting base by cracked under the mild conditions that this side chain protected is kept perfectly; for example SASRIN or replacement or unsubstituted connection base based on trityl; 4-(hydroxyl-phenylbenzene-methyl)-phenylformic acid for example; one of them phenyl can randomly be substituted, and is for example replaced by Cl.Can finish the structure of required peptide chain with usual manner, for example, the amino acid unit that can use terminal amino group wherein to be protected by Fmoc-, existing side chain is amino, and for example Boc or CBO protect with different amino protecting groups.Preferably the peptide with straight chain carries out cyclization in the mode that can form key between Tyr (4-Bzl)-OH and Phe, for example Phe-{4-(NHR ₁-C ₂H ₄-NH-CO-O-) Pro}-DPhg-DTrp (R ₂)-Lys (ε-NHR ₃)-Tyr (4-Bzl)-OH or its functional derivatives, wherein R ₁, R ₂And R ₃It is respectively amino protecting group.Cyclization step a) can be finished with currently known methods easily, for example finishes via trinitride, active ester, mixed acid anhydride or carbodiimide.Remove protecting group then, for example by removing protecting group with the trifluoroacetic acid cracking or by hydrogenization.

The cyclisation of peptide also can directly be carried out on solid carrier, and first amino acid is N α-and the form of the terminal protection of C-, and is connected thereto by a side chain (for example epsilon-amino functional group of Lys) or by skeletal fixation.Then, the sequence that can synthesize this straight chain according to solid phase synthesis (SPPS) process of standard.After terminal protecting group cracking with C-, with peptide according to for example above description cyclization.Then, the cracking from the resin of cyclic peptide is got off and it is gone protection.

If necessary, can be incorporated on this amino acid at the side chain that said peptide cyclisation step will be present on the Pro before or after a).Therefore, can be to transforming as the Pro of initial amino acid or initial straight chain or cyclic peptide (Pro in the wherein various situations is all replaced by the OH ring on ring), thus provide wherein Pro by NHR respectively ₁-C ₂H ₄The compound of the formula III that-NH-CO-O-replaces, for example compd B or required Pro unit or corresponding linear peptides.

The compound of the formula III that yoke closes, for example the complexing action of the compd B that closes of yoke can be by the compound of formula III that yoke is closed, the compd B that closes of yoke and the compound that can produce detectable or radiation treatment element accordingly metal-salt for example for example, preferred water-soluble salt reacts to be finished.This reaction can be with carrying out with the currently known methods similar methods, Perrin for example, Organic Ligand, Chemical Data Series 22.NY Pergamon Press (1982); Krejcarit and Tucker, Biophys.Biochem.Res.Com. 77: 581 (1977) and Wagner and Welch, J.Nucl.Med. 20: 428 (1979) disclosed methods.

Come the new compound of formula III of the present invention is described with the following examples.All temperature all are ℃.

Abbreviation:

AcOH=acetate

Boc=uncle-butoxy-carbonyl

Bzl=benzyl

CBO=carbobenzoxy-(Cbz)

DIPCI=N, N '-DIC

DIPEA=diisopropyl ethyl amine

DMF=dimethyl formamide

DPPA=diphenyl phosphoryl azide

Fmoc=fluorenylmethyloxycarbonyl

HOBT=I-hydroxybenzotriazole

Osu=N-hydroxy-succinamide

TFA=trifluoroacetic acid

THF=tetrahydrofuran (THF)

Embodiment 8:

Ring [{ 4-(NH ₂-C ₂H ₄-NH-CO-O-) Pro}-DPhg-DTrp-Lys-Tyr (4-Bzl)-Phe]

A) Fmoc-Pro (4-OCO-NH-CH ₂-CH ₂-NH-Boc)-OH synthetic

Hydrochloric acid L-L-Hydroxyproline methyl ester and Fmoc-Osu are at room temperature reacted in 1.0N aqueous sodium carbonate/THF.After reacting completely, Fmoc-Pro (4-OH)-Ome is separated by precipitation.Then, Fmoc-Pro (4-OH)-Ome is added drop-wise in the solution of triphosgene (0.6 equivalent) in THF, thereby obtains a kind of chlorine carbonic ether intermediate.After 1 hour, to wherein adding dimethyl aminopyridine (1.0 equivalent) and N-Boc-diaminoethanes (6.0 equivalent) and should reacting at room temperature and stir.After reaction finishes, under vacuum, remove and desolvate and the Fmoc-Pro (4-OCO-NH-CH of gained ₂-CH ₂-NH-Boc)-Ome extracts with the biphasic system of ethyl acetate/0.1M HCl, thereby obtains crude product (MH ⁺=554), by it being carried out purifying with the ethyl acetate crystallization.Then, by with handling in 1NNaOH Zai diox/water this methyl esters being cracked into free acid and with product Fmoc-Pro (4-OCO-NH-CH ₂-CH ₂-NH-Boc)-OH purifying on silicagel column, [(M+Na)] ⁺=562).

b)H-Phe-Pro(4-OCO-NH-CH ₂-CH ₂-NH-Boc)-DPhg-DTrp(Boc)-Lys(Boc)-Tyr(Bzl)-OH

With Fmoc-Tyr (the Bzl)-O-CH that can obtain by commercial sources ₂-Ph (3-OCH ₃)-O-CH ₂(the SASRIN-resin is 2.4mM) as starting raw material and carry out by N α-deprotection (piperidines/DMF, 2: 8), with DMF repetitive scrubbing and coupling (DIPCI:4.8mM/HOBT:6mM, the standard scheme that recirculation DMF) is formed for-polystyrene resin.Amino acid derivative below the coupling: Fmoc-Lys (Boc)-OH, Fmoc-DTrp (Boc)-OH, Fmoc-DPhg-OH, Fmoc-Pro (4-OCO-NH-CH successively ₂-CH ₂-NH-Boc)-OH, Fmoc-Phe-OH.Continue or repeat coupling (2 equivalent amino acid), promptly until finding residual amino completely dissolve when ninhydrin reaction detects with feminine gender ' Kaiser ' until finishing.The protected linear peptides that will be assembled into fully from its resin carrier under the cracking before, remove N α-Fmoc protecting group from last resistates.

c)H-Phe-Pro(4-OCO-NH-CH ₂-CH ₂-NH-Boc)-DPhg-DTrp(Boc)-Lys(Boc)-Tyr(Bzl)-OH

Using CH ₂Cl ₂After the washing, with this peptide-resin transfer to pillar or on the suction filter that is carrying out stirring and by in 1 hour with the CH of 2%TFA ₂Cl ₂The of short duration processing of solution and this peptide segment is carried out cracking and wash-out.Use saturated NaHCO immediately ₃The aqueous solution neutralizes to this elutriant.Organic solution is separated and evaporated the precursor (MH that under situation about it not being further purified, this side chain is protected ⁺=1366) directly carry out cyclisation.

D) ring [Pro (4-OCO-NH-CH ₂-CH ₂-NH ₂)-DPhg-DTrp-Lys-Tyr (Bzl)-Phe-], trifluoroacetate

Above-mentioned straight chain fragment is dissolved among the DMF (4mM), is cooled to-5 ℃, with 1.5 equivalent DPPA it is handled then and under 0-4 ℃, it is stirred to reaction and finish (about 20 hours) also with 2 equivalent DIPEA.Under vacuum, solvent is almost completely removed; This enriched material is diluted with ethyl acetate, use NaHCO ₃, water washs, and is dry and with its vacuum-evaporation.

In order to go protection, this resistates is dissolved in TFA/H under 0 ℃ ₂Under cooling, stirred 30 minutes among the O 95: 5 (about 50mM) and with it.Then, make the product precipitation, filter, carry out drying with the ether washing and with it with the ether that comprises about 10 equivalent HCl.For remaining indoles-N-imino-formic acid (carbaminic acid) is decomposed fully, this product is dissolved among the 5%AcOH and with it to descend to place 15 hours at about 5 ℃, then with its lyophilize.With the preparation type RP-HPLC that uses C-1810 μ m STAGROMA post (5-25cm) it is carried out purifying, the TFA that is arranged in 70% acetonitrile with 0.5%TFA to 0.5% carries out gradient elution.The fraction that will comprise pure title compound merges, dilute with water and with its lyophilize.This lyophilize thing is dissolved in the water, uses 10%Na then ₂CO ₃The aqueous solution precipitates it.Should leach by solid-state free alkali, wash with water and its vacuum-drying at room temperature.Directly the white powder with gained prepares different salt.

Embodiment 9: the ring of salt form [{ 4-(NH ₂-C ₂H ₄-NH-CO-O-) Pro}-DPhg-DTrp-Lys-Tyr (4-Bzl)-Phe]

A. acetate

Spent ion exchange resin (for example AG 3-X4) converts it into the acetate form.MS(ESI)：m/z 524.5[M+2H] ²⁺

[α] _D ²⁰＝-41.6°；c＝0.56；AcOH 95％；T＝20C；589.3nm

B. aspartate

By being reacted in 1: 3 mixture of acetonitrile/water, the compound of 1 equivalent embodiment 8 and 1 or 2 equivalent aspartic acids undertaken to single-or the conversion of two-aspartate.The mixture of gained is freezing and with its lyophilize.

Two-aspartate can also by with the compound dissolution of embodiment 8 in water/acetonitrile 4: 1, filter, load to ion exchange resin for example on the BioRad AG4X4 post and water/acetonitrile carry out wash-out at 4: 1 and obtain.Elutriant is concentrated, freezing and with its lyophilize.

C. benzoate

Be dissolved in the conversion of carrying out in 1: 2 the mixture of acetonitrile/water to benzoate together by compound and 2 equivalent phenylformic acid with embodiment 8.The mixture of gained is freezing and with its lyophilize.

D. embonate

The compound of 1 equivalent embodiment 8 is dissolved in acetonitrile/mixture of 2: 2: 1 of THF/ water with 1 equivalent pamoic acid.The mixture of gained is freezing and with its lyophilize.

Embodiment 10:

Ring [{ 4-(DOTA-NH-C ₂H ₄-NH-CO-O-) Pro}-DPhg-DTrp-Lys-Tyr (4-Bzl)-Phe

A) ring [Pro (4-OCO-NH-CH ₂-CH ₂-NH ₂)-DPhg-DTrp-Lys (Cbo)-Tyr (Bzl)-Phe-], trifluoroacetate

This compound is to use and synthetic ring [Pro (4-OCO-NH-CH ₂-CH ₂-NH ₂)-DPhg-DTrp-Lys (Cbo)-Tyr (Bzl)-Phe-], the method that the method for trifluoroacetate is identical replaces Fmoc-Lys (Boc)-OH to carry out synthetic with Fmoc-Lys (Cbo)-OH.

B) the DOTA x 2H that 400mg is obtained by commercial sources ₂O (SYMAFEX-France) is dissolved in the 20ml water.After adding 20ml DMF, to wherein adding 170mg ring [Pro (4-OCO-NH-CH ₂-CH ₂-NH ₂)-DPhg-DTrp-Lys (CBO)-Tyr (Bzl)-Phe-], 190mg DCCI and 60mg N-hydroxy-succinamide.The suspension of gained was at room temperature placed 72 hours.After filtration, under reduced pressure remove and desolvate and the crude product of gained is carried out purifying with silica gel (use DCM/MeOH/HOAc _50%8/2/0.25--＞7/3/1 as moving phase).

C) in order to go protection, top DOTA-conjugates was at room temperature handled two hours with 5ml trifluoroacetic acid/thioanisole (9/1).After in this solution being poured into 100ml ether+5ml 3N HCl/ ether mixture, by filtering the precipitate and separate that is produced is come out.Carry out purifying with silica gel, use DCM/MeOH/HOAc _5o%7/4/2--＞7/5/4 is as moving phase.It is passed through at RP ₁₈-HPLC post (Spherisorb 250x 4.6mm) is gone up and is positioned at 90%CH with 0.1%TFA to 0.1% ₃TFA gradient elution among the CN and after carrying out the desalination step, obtain analytically pure end product.MH ⁺：1434.7

The compound of the formula III of free form or pharmacologically acceptable salt and complex form, for example compd B shown in external and in vivo test in show valuable pharmacological character, therefore can be used for treating.

Specifically, the compound of formula III, for example compd B shows interesting binding characteristic to human somatotropin's inhibin receptor (hsst).5 kinds of the somatostatin receptor hypotypes (sst1, sst2, sst3, sst4 and sst5) are cloned and identified.People such as Y.Yamada are at Proc.Nat.Acad.Sci., 89, among the 251-255 (1992) to hsst1, hsst2 and hsst3 with and sequence disclose.People such as L.Rohrer are at Proc.Acad.Sci., 90, among the 4196-4200 (1993) to hsst4 with and sequence disclose.People such as R.Panetta are at Mol.Pharmacol. 45, 417-427, in 1993 to hsst5 with and sequence be described.

Can as following disclosed, use the clone of self-selectively and stably express hsst1, hsst2, hsst3, hsst4 or hsst5, for example the film of CHO or COS cell carries out the combination test.

These films are to use known method, and for example people such as C.Bruns is at Biochem.J., 1990, 65, disclosed method is prepared in the 39-44 page or leaf.To be by the hsst selecting cell of stably express hsst1 or hsst2 or hsst3 or hsst4 or hsst5 for example CHO or COS cell preparation film with the cumulative volume of 300 μ l in triplicate with concentration increase gradually [ ¹²⁵I-Tyr ¹¹]-SRIF-14 comprises in the Hepes damping fluid (pH 7.6) of 0.5%BSA at 10mmol/l and cultivated 30 minutes down at 22 ℃.Stop cultivating and on counter, this filter being counted by quick filtration.Specificity deducts the non-specific binding that exists under 1 μ mol/l somatostatin-14 situation in conjunction with equaling total binding.These experiments are carried out in triplicate.Calculate affinity constant (K with suitable statistics and plotting program _D) and the number of binding site.

The compound of formula III, for example compd B is superincumbent has low-affinity in conjunction with in the test hsst1, hsst2 and hsst4 not being had tangible binding affinity to hsst3, hsst5 is had good avidity, result IC ₅₀Value (nM) expression (IC ₅₀=with [ ¹²⁵I-Tyr ¹¹Reach the concentration of maximum restraining effect one half in the CBA of]-SRIF-14 as the specificity radioligand).

IC ₅₀

	hsst1	hsst2	hsst3	hsst4	hsst5
						Compd B	＞1000	＞1000	22nM	840nM	0.53nM

As in vitro inhibition GH as indicated in the release of the pituicyte cultivated, the compound of formula III, for example compd B shows and suppresses the activity that GH discharges.For example, the pituitary gland frontal lobe that derives from the bull rat is cut into small pieces and it is disperseed with 0.1% trypsinase that is arranged in 20mM HEPES damping fluid.Should replenished 5% foetal calf serum, 5% horse serum, 1mM NaHCO by dispersed cell ₃, 2.5nM dexamethasone, 2.5mg/ml Regular Insulin and 20U/mlPen/Strep MEM (Gibco) in cultivated four days.On the same day of experiment, with institute's adherent cell Krebs-Ringer substratum washed twice that cushions and replenished 5mM glucose and 0.2%BSA through 20mM HEPES.Subsequently, have 3 * 10 ^-10Under the situation of M somatotropin releasing factor these cells were cultivated three hours with compd B.Be discharged into the amount of the tethelin in the said substratum with the RIA measurement.

The compound of formula III, for example compd B has suppressed the release of rat body inner growth hormone (GH).With the compd B subcutaneous administration in dopey rat.After giving this compound 1 hour, broken end was got blood.Back 6 hours of treatment to the inhibiting basis of basic GH excretory on time length of its effect of estimation.After processing, with RIA hormonal readiness was measured in the 1st hour and the 6th hour.Measure and respectively test inhibitory hormone excretory ID by mapping (log-probit) ₅₀Value is also carried out logarithmic mean with the value of gained.In this body inner model, compd B has suppressed the release of tethelin.

As indicated in the proliferation test that carries out with the various cancerous cell lines that have hsst3 and/or hsst5, the compound of formula III, for example compd B also can be used for treating the tumour of hsst3 and/or hsst5 receptor positive.

Therefore, the compound of formula III, for example compd B can be used for preventing or treats that its cause of disease comprises or with the existence of hsst3 and/or hsst5 or activate relevant illness, for example with GH excessive secretion diseases associated or illness, for example can be used for treating acromegaly or malignant cell proliferative disease, the cancerous tumour that for example has hsst3 and/or hsst5, for example following disclosed disease of compd B of closing about the complexing yoke.

For all above-mentioned indications, required dosage will change along with the severity of for example main body, administering mode and quilt treatment situation certainly.But by giving the compound of 1 μ g to 0.7mg/kg/ sky formula III, for example compd B generally just can obtain gratifying result.Suitable patient's per daily dose is that about 2 μ g are to about 50mg, preferred about 0.01 to about 40mg, for example about 0.01 compound to about 3mg subcutaneous administration, these compounds are that fractionated dose with height to days three times is to comprise for example about 0.5 μ g to about 25mg easily, for example about 2 μ g to 20mg, the compound of 2 μ g to 1.5mg formula IIIs for example, for example the form of the unit dosage form of compd B is by administration.

The compound of formula III, for example compd B can be with the form of free form or pharmacologically acceptable salt or complex form by administration.Such salt and complex compound can be prepared and show active identical activity with free cpds with ordinary method.The present invention also provides the compound of the formula III that comprises free alkali form or pharmaceutical acceptable salt or complex form, for example the pharmaceutical composition of compd B and one or more acceptable diluents or carrier.This based composition can be prepared with usual manner.The compound of formula III, for example compd B can also be with the slowly-releasing form, but for example with the spherical formula of implant, micro-capsule, microballoon or the millimicro of the polymkeric substance that comprises for example biological attack or multipolymer, with the Liposomal formulation form or with from the gel gel, for example after the body fluid with the patient interacts, can form the solid of gel or the form administration of semi-solid combination.

The compound of formula III, for example compd B or its pharmaceutically useful salt or complex compound can be by any conventional route by administrations, for example can be by parenteral admin, for example with injectable solution or suspension form (comprising for example above-mentioned slowly-releasing form) by administration, use conventional absorption enhancer to carry out oral administration, nose administration or with suppository form administration or topical, for example with eye liquid, gel, ointment or mixed suspension preparation form are by administration, for example with liposome, the form of microballoon or millimicro ball preparation for example is used under instillation or the conjunctiva or intraocular or periocular injections by administration.

According to noted earlier, the present invention also provides:

1. be used as the compound of the formula III of medicine, for example compd B or its pharmaceutically useful salt or complex compound;

Prevention or treatment need such treatment individuality here shown in the method for disease or illness, it comprises the compound of using the significant quantity formula III to said individuality, for example compd B or its pharmaceutically useful salt or complex compound; Or

3. be used to prepare the compound that is used for as the formula III of the pharmaceutical composition of top 2. times defined any methods, for example compd B or its pharmaceutically useful salt or complex compound.

Therefore, as by standard test confirmed, when with detectable element, for example launch that γ-or nucleic, fluorescence metal ion or the paramagnetic ion of positron are for example ¹¹¹In, ¹⁶¹Tb, ¹⁷⁷Lu, ⁸⁶Y, ⁶⁸Ga, Eu ³⁺, Gd ³⁺, Fe ³⁺, Mn ²⁺Or Cr ²⁺During complexing, the compound of the formula III that yoke closes, for example compd B or its pharmaceutically useful salt can be used as photographic developer, for example be used for tumour and metastatic tumor, the inflammation that shows the somatostatin receptor or autoimmune disorder, the tuberculosis that tissue that hsst3 and/or hsst5 acceptor be positive and cell such as hsst3 and/or hsst5 acceptor be positive or transplant after the development of organ rejection response, when with emission α-or the nucleic or the emission Auger-e of beta-rays ^-Nucleic, for example ⁹⁰Y, ¹⁶¹Tb, ¹⁷⁷Lu, ²¹¹At, ²¹³Bi or ²⁰¹During the Tl complexing, it can be used as the radiopharmaceuticals that is used for treating in vivo tumour that hsst3 and/or hsst5 acceptor be positive and metastatic tumor, rheumatoid arthritis and serious inflammatory conditions.

Specifically, observing compd A that yoke closes can combine with about 8 to 10 pKi value with the somatostatin receptor.With for example ¹¹¹In, ⁸⁸Y, ⁹⁰Y or ¹⁷⁷The compound of the embodiment 10 of Lu complexing combines with the binding curve of each sst hypotype according to compd B in the nM scope.

The compound of the formula III that yoke closes, for example the compd B that closes of yoke and the avidity of complex compound and hsst3 and/or hsst5 acceptor thereof can also confirm by in vivo test according to standard test methods, for example adopt GB-A-2, disclosed method in 225,579.For example the mouse or the rat that have the exocrine pancreas tumour of expressing the hsst5 acceptor were being injected back 4 hours, and for example ¹¹¹In, ⁸⁸Y, ⁹⁰Y or ¹⁷⁷The compound of the embodiment 10 of Lu complexing shows tangible tumour to be assembled.

Use 0.1 to 5mCi with the dosage of 1 to 5 μ g/kg, preferred 0.1 to 2mCi radionuclide carries out mark, for example use ¹¹¹In, ¹⁷⁷Lu, ⁸⁶Y or ¹⁶¹Tb carries out the compound of the formula III that the yoke of radiolabeled complex form closes, and for example behind the compd B that yoke closes, tumor locus becomes and can detect.

When with emission α-or the radionuclide of beta-rays or emission Auger-e ^-Nucleic when carrying out radio-labeling, the compound of the formula III that yoke closes, for example the compd B that closes of yoke shows antiproliferative and/or cytotoxic effect to the tumour cell that has hsst3 and/or hsst5 acceptor, for example in the nude mice test, showed like that.

Nude mice is inoculated with the tumour cell that has hsst5.When tumour reaches 1 to 2cm ³Volume the time, animal is divided into control group and treatment group at random.The compound of the formula III that the yoke of complex form is closed by peritoneal injection or intravenous injection, for example the compd B that closes of yoke carries out administration.The dosage of every mouse is up to 40mCi/kg.With clamp the size of tumour is measured disclosed as top.Statistical calculations adopts Xue Shengshi t check.This test in, single-dose with ⁹⁰Y or ¹⁷⁷Behind the compound of the embodiment 10 of Lu complexing, can be observed after a week that of short duration tumour is dwindled and growth of tumor has been delayed fortnight.In contrast, control group shows the successive tumor growth, and the time that its volume doubles is about seven days.

Therefore, in a series of specific or selective embodiments, the present invention also provides:

4. the compound of the formula III that closes with the yoke of detectable element complexing, for example the compd B that closes of yoke is used for surveying cell and the tissue that hsst3 and/or hsst5 are positive in individual body, for example the application of the position of the tumour that is positive and the metastatic tumor that are positive of hsst3 or hsst5 and the acceptor that writes down said complex compound target;

5. one kind is used in the individuality body surveying tissue and the cell that hsst3 and/or hsst5 are positive, the for example tumour that is positive of hsst3 or hsst5 and the method for metastatic tumor, this method comprises the compound of using the formula III that the yoke with detectable element complexing closes to said individuality, the for example compd B or its pharmaceutically useful salt that close of yoke, and the position of writing down the acceptor of described complex compound target.

The compound of the formula III that closes as the yoke of the complex form of photographic developer, for example the compd B that closes of yoke can be by for example intravenous administration, for example with the form administration of Injectable solution or suspension, preferably with the form administration of single injection.Preferably before individual administration, carry out radio-labeling facing.

For animal, the compound of the formula III that the dosage range of indication can close for the yoke of radionuclide complexing of 0.01 to 1 μ g/kg and 0.02 to 0.5mCi emission gamma-radiation, for example compd B that closes of yoke.For example for the people, shown dosage range can be 1 to 100 μ g/m for bigger animal ²With for example 1 to 100mCi/m ²Detectable element for example ¹¹¹In, ⁸⁶Y or ¹⁷⁷The compd B that the yoke of Lu complexing closes.

6. with emission α-or the nucleic of beta-rays or emission Auger-e ^-The compound of the formula III that closes of the yoke of nucleic complexing, for example the compd B that closes of yoke is used for the application of the interior therapeutic of tumour that hsst3 and/or hsst5 be positive and metastatic tumor.

7. one kind is used for the tumour and the metastatic tumor that are positive at the individuality interior therapeutic hsst3 and/or the hsst5 of needs treatments, for example treat the intrusion of described tumour or the method for the symptom relevant with such growth of tumor, this method comprise to said individual administering therapeutic significant quantity with emission α-or the nucleic or the emission Auger-e of beta-rays ^-The compound of the formula III that closes of the yoke of nucleic complexing, the compd B that closes of yoke for example.

8. the compound of the formula III that closes of yoke, for example yoke compd B or the application of its pharmaceutically useful salt in making photographic developer or radiopharmaceutical composition of closing.

Carry out radiation treatment of the present invention when using used dosage certainly will along with the concrete illness of for example being treated for example known to the normal organ of expressing hsst5 radiotoxicity, tumor size and required treatment and change.Generally speaking, this dosage is according to calculating with pharmacokinetics and radioactivity distributed data that healthy organ obtained, and based on viewed target picked-up.The compound of the formula III that closes of yoke of emission beta-rays, for example the complex compound of the compd B that closes of yoke can be repeated to carry out administration, for example repeat administration in 1 to 3 months period.

For animal, dosage range can be 20 to 100 μ g/kg and 15 to 70mCi emission α-or the nucleic of beta-rays or emission Auger-e ^-Nucleic for example ⁹⁰Y, ¹⁷⁷Lu or ¹⁶¹The compound of the formula III that the yoke of Tb phase complexing closes, for example compd B that closes of yoke.For example for the people, dosage range can be 1 to 100 μ g/m for bigger animal ²With for example 1 to 100mCi/m ²Emission α-or the nucleic of beta-rays or emission Auger-e ^-Nucleic for example ⁹⁰Y, ¹⁷⁷Lu or ¹⁶¹The compound of the formula III that the yoke of Tb phase complexing closes, for example compd B that closes of yoke.

The compound of the formula III that closes as the yoke of the complex form of radiation treatment material, for example the compd B that closes of yoke can carry out administration by the route of administration of any routine, for example intravenous administration for example carries out intravenous administration with the form of injectable solution.Can also the favourable form of passing through infusion carry out administration, for example in 15 to 60 minutes, carry out infusion.According to the residing position of tumour, can also carry out administration in as close as possible this tumor locus ground, for example carry out administration by conduit.The present invention also provide a kind of form that comprises free alkali form or pharmacologically acceptable salt or with the detectable or radiation treatment agent compound of the formula III that closes of the yoke of complexing mutually, for example compd B that closes of yoke and the pharmaceutical composition of one or more acceptable diluents or carrier.

The compound of the formula III that the compound of the formula III of complex form or yoke close, for example the compd B that closes of compd B or yoke can be used for tumour such as the pituitary tumor that hsst3 and/or hsst5 were expressed or assembled in imaging or treatment, for example adenoma or prolactinoma, stomach-intestines pancreatic neoplasm, innocent tumour, central nerve neuroma, breast tumor, tumor of prostate (the hormone intractable prostate cancer that comprises late period), ovary or colon tumor, small cell lung cancer, pernicious intestinal obstruction, chromaffinoma, kidney, skin carcinoma, neuroblastoma, pheochromocytoma, medullary thyroid shape knurl, myelomatosis, lymphoma, He Jiejinshi and non_hodgkin lymphoma, bone tumor with and metastatic tumor, and autoimmunity or inflammatory conditions, for example rheumatoid arthritis, Graves disease or other inflammatory eye disease.

Another aspect of the present invention also provides a kind of compound that comprises the formula III that yoke closes, for example the compd B that closes of yoke or the pharmaceutical composition of its complex compound and one or more pharmaceutically useful carriers or thinner.Described pharmaceutical composition can be prepared with the method for routine, and can provide with the form of test kit to be used for imaging, described test kit contains two kinds of independently reagent, a kind of is radionuclide, another kind is the compound of the formula III that closes of yoke, the compd B that closes of yoke for example, and contain and be useful on explanation with its blended teachings.For radiation treatment, the compound of the formula III that the yoke of this complex form closes, for example compd B that closes of the yoke form of the liquid preparation of heat preferably.

The compound of the formula III that is randomly closed by yoke of complex form, for example the compd B that closes of compd B or yoke can be used as unique activeconstituents and carries out administration, or for example as adjuvant and other medicines Combined Preparation.For example, the compound of formula III, for example compd B can with immunosuppressor, for example calcineurin inhibitors, for example cyclosporin A, Isa Tx247 or FK 506; MTOR inhibitor, for example rapamycin, CCI779, ABT578 or 40-O-(2-hydroxyethyl)-rapamycin; Ascosin with immunosuppression character, for example ABT-281, ASM981 or the like; Reflunomide; Endoxan; Imuran; Methotrexate; Leflunomide; Mizoribine; Mycophenolic acid or its salt, for example Myfortic ^RMycophenolic acid is ester not; 15-Gusperimus (spergualine) or its immunosuppression homologue, analogue or derivative; S1P receptor stimulant, for example FTY720; Inhibitive ability of immunity monoclonal antibody, for example monoclonal antibody of leukocyte receptors, for example monoclonal antibody of MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD58, CD80, CD86 or its part; Other immunomodulatory compounds, the reorganization binding molecule or its mutant that for example have the zone, extracellular of at least a portion CTLA4, for example extracellular part or its mutant of the CTLA4 at least that is connected with non--CTLA4 protein sequence, for example CTLA4Ig (for example being called as ATCC 68629) or its mutant, for example LEA29Y; Adhesion molecule inhibitor, for example LFA-1 antagonist, ICAM-1 or-3 antagonists, VCAM-4 antagonist or the coupling of VLA-4 antagonist.The compound of formula III, for example compd B can also with anti-inflammatory agent, GH secretogogue receptor modulators, for example ghrelin or sea sand Rayleigh (hexarelin), GH receptor antagonist, for example pegvisomant coupling.

The compound of the formula III that the randomly yoke of complex form closes for example the compd B that closes of compd B or yoke can also with the antiproliferative coupling, for example with chemotherapeutics, taxol for example, gemcitabine, cis-platinum, Zorubicin, 5 FU 5 fluorouracil or taxol coupling, with hormonal substance or antagonist, for example androgen antagonist or mitoxantrone (especially in the situation of prostate cancer), or estrogen antagonist such as letrozole (especially in the situation of mammary cancer), metabolic antagonist, plant alkaloid, biological response properties-correcting agent, preferred lymphokine or Interferon, rabbit, protein tyrosine kinase inhibitors and/or serine/threonine kinase inhibitor or have other or the material of the unknown mechanism of action, for example various esperamicin (epothilone) or esperamicin derivatives, or the mTOR inhibitor, material coupling for example recited above.

The compound of the formula III that closes when the randomly yoke of complex form is for example when the compd B that closes of compd B or yoke and other medicines Combined Preparation, and the dosage of the medicine of co-administered certainly should be along with the type of the medicine of used co-administered, employed concrete medicine, the illness of being treated etc. and changed.Term " co-administered " or " Combined Preparation " or used here similar terms refer to carries out administration with selected therapeutical agent to single patient, and comprises that wherein medicine is not necessarily with identical route of administration or the treatment plan that carries out administration in the identical time.

According to noted earlier, the present invention also comprises:

9. drug regimen, it comprises a) first kind of material, it is the compound compd B and the b that close of compd B or yoke for example of the formula III that closes of the randomly yoke of complex form) material of co-administered, for example material as defined above.

10. method as defined above, for example compd B or yoke compd B and second kind of medication combined administration of closing of the compound that this method comprises the formula III that closes of the randomly yoke of complex form that will the treatment significant quantity, for example simultaneously or administration successively, wherein said second kind of medicine is material as defined above for example.

Claims (10)

1. pharmaceutical composition that is used for parenteral admin, it comprises the somatostatin analogs and the tartrate of the aminoacid sequence that contains formula I of free form, salt form or protected form

-(D/L)Trp-LYs-X ₁-X ₂- I

X wherein ₁Be formula (a) or group (b)

R wherein ₁Be randomly substituted phenyl,

R ₂Be-Z ₁-CH ₂-R ₁,-CH ₂-CO-O-CH ₂-R ₁, Or

Z wherein ₁Be O or S, and

X ₂Be at C _αHave the a-amino acid of aromatic yl residue on the side chain or be selected from the amino acid unit of Dab, Dpr, Dpm, His, (Bzl) HyPro, thienyl-Ala, cyclohexyl-Ala and tert-butyl-Ala, the Lys residue of said sequence is equivalent to the Lys of natural somatostatin-14 ⁹Residue.

2. composition as claimed in claim 1, wherein said somatostatin analogs are the compounds of the formula II of free form, salt form or protected form

Wherein the configuration on the C-2 is (R) or (S) configuration or its mixture, and

Wherein R is NR ₁R ₂-C _2-6Alkylidene group or guanidine-C _2-6Alkylidene group, and R ₁And R ₂Be H or C independently of one another _1-4Alkyl.

3. composition as claimed in claim 1 or 2, wherein said somatostatin analogs compound are aspartate two salt forms.

4. as any described composition of claim in front, wherein the pH of said composition is transferred to about 4 to about 4.5.

5. one kind is buffered to about 4 to about 4.5 pH and comprises ring [{ 4-(NH as activeconstituents ₂-C ₂H ₄-NH-CO-O-) Pro}-Phg-DTrp-Lys-Tyr (4-Bzl)-Phe] or the composition of the parenteral admin of its pharmaceutically useful salt.

6. composition as claimed in claim 5, wherein said composition are to carry out buffered with acetate/acetate, lactic acid salt/lactic acid or Glycin/HCl buffer reagent.

7. be used to prepare the application of the medicine for the treatment of acromegaly or cancer as any described pharmaceutical composition in the claim 1 to 6.

8. application as claimed in claim 6, it is to be used to prepare the medicine for the treatment of Cushing's disease.

9. an acromegaly or method for cancer for the treatment of the individuality that needs such treatment, it comprises to said individuality uses as any described pharmaceutical composition in the claim 1 to 7.

10. the compound of the formula III of free form, salt form or complex form or protected form

Wherein R is NR ₁R ₂-C _2-6Alkylidene group or guanidine-C _2-6Alkylidene group, and R ₁And R ₂Be H or C independently of one another _1-4Alkyl, for example ring [{ 4-(NH ₂-C ₂H ₄-NH-CO-O-) Pro}-DPhg-DTrp-Lys-Tyr (4-Bzl)-Phe].