CN101043882A - Use of peptide compounds for treating bone cancer pain, chemotherapy- and nucleoside-induced pain - Google Patents

Abstract

The present invention is directed to the use of a class of peptide compounds having the formula for treating tumor pain, in particular bone cancer pain, for treating chemotherapy-induced and nucleoside-induced pain.

Description

Peptide compounds for treating osteocarcinoma pain, chemotherapy-and the new purposes of nucleoside-inductive pain

The present invention relates to peptide compound treatment relaxing tumor pain, especially osteocarcinoma pain, the purposes of inductive pain of therapeutical chemistry therapy and the inductive pain of treatment nucleoside.

Known some peptide has central nervous system (CNS) activity, and useful in the treatment of epilepsy and other CNS obstacle.At United States Patent (USP) the 5th, 378, these peptides of describing in No. 729 have formula (Ia) structure:

Formula (Ia)

Wherein

R is hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, aryl, aromatic yl elementary alkyl, heterocycle, heterocycle low alkyl group, low alkyl group heterocycle, low-grade cycloalkyl, low-grade cycloalkyl low alkyl group, and R is not substituted or by at least one electron withdraw group or electron donating group-substituted;

R ₁Be hydrogen or low alkyl group, low-grade alkenyl, low-grade alkynyl, aromatic yl elementary alkyl, aryl, heterocycle low alkyl group, heterocycle, low-grade cycloalkyl, low-grade cycloalkyl low alkyl group, be not substituted separately or replaced by electron donating group or electron withdraw group; And

R ₂And R ₃Be hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, aromatic yl elementary alkyl, aryl, heterocycle, heterocycle low alkyl group, low alkyl group heterocycle, low-grade cycloalkyl, low-grade cycloalkyl low alkyl group or Z-Y independently, wherein, R ₂And R ₃Can not be substituted or by at least one electron withdraw group or electron donating group-substituted;

Z is O, S, S (O) _a, NR ₄, PR ₄Or chemical bond;

Y is hydrogen, low alkyl group, aryl, aromatic yl elementary alkyl, low-grade alkenyl, low-grade alkynyl, halogen, heterocycle, heterocycle low alkyl group, and Y can not be substituted or replaced by electron donating group or electron withdraw group, condition is when Y is halogen, and Z is a chemical bond, or

ZY is NR together ₄NR ₅R ₇, NR ₄OR ₅, ONR ₄R ₇, OPR ₄R ₅, PR ₄OR ₅, SNR ₄R ₇, NR ₄SR ₇, SPR ₄R ₅Or PR ₄SR ₇, NR ₄PR ₅R ₆Or PR ₄NR ₅R ₇,

R ₄, R ₅And R ₆Be hydrogen, low alkyl group, aryl, aromatic yl elementary alkyl, low-grade alkenyl or low-grade alkynyl independently, wherein, R ₄, R ₅And R ₆Can not be substituted or by electron withdraw group or electron donating group-substituted; With

R ₇Be R ₆Or COOR ₈Or COR ₈

R ₈Be hydrogen or low alkyl group or aromatic yl elementary alkyl, and aryl or alkyl can not be substituted or by electron withdraw group or electron donating group-substituted; And

N is 1-4; And

A is 1-3.

United States Patent (USP) the 5th, 773 also discloses the additional compounds that is applicable to treatment CNS obstacle for No. 475.These chemical compounds are the N-benzyl-2-amino-3-methoxyl group-propionic acid amide .s with formula (IIa) structure:

Formula (IIa)

Wherein

Ar is the aryl that is not substituted or is replaced by halogen; R ₃It is lower alkoxy; And R ₁It is methyl.

Patent US 5.378.729 and US 5.773.475 are incorporated herein by reference thus.Yet, do not have one piece to describe these chemical compounds and be used for the treatment of relaxing tumor pain in these patents, osteocarcinoma pain especially, the purposes of inductive pain of therapeutical chemistry therapy and the inductive pain of treatment nucleoside.

WO 02/074297 relates to formula (IIa) chemical compound and is applicable to purposes in the pharmaceutical composition of the treatment allodynia relevant with peripheral nerve characteristic of disease pain in preparation, and wherein, Ar is the phenyl that can be replaced by at least one halogen, R ₃Be lower alkoxy and the R that contains 1-3 carbon atom ₁It is methyl.

WO 02/074784 relates to the formula (Ia) that shows anti-nociception character or/and formula (IIa) chemical compound is used for the treatment of dissimilar and acute pain and chronic pain symptom, especially be non-neuropathic inflammatory pain, for example the rheumatoid arthritis pain is or/and the purposes of Secondary cases inflammatory osteoarthritis pain.

Not having at present a kind ofly all has efficiently analgesic exist to multiple pain symptom.Owing to cause that the mechanism of inflammatory pain or neuropathic pain is different, be difficult to identify chemical compound with comprehensive analgesic effect.We only are the mechanism that has just begun to be familiar with different pain symptoms, as if such as the pain or the inductive pain of nucleoside of cancer pain (for example osteocarcinoma pain of tumor inducing), chemotherapy-induced, it all has different molecule origins.Description is used for the treatment of antidepressant, anticonvulsant or the opioid compounds of several groups of chemical compounds of pain less than the common mode about their treatment pain symptom effects.This is difficult to the activity of prediction noval chemical compound in various pain symptoms, and also need be in the detailed sign in the multiple pain animal model.

The neuropathic pain that periphery or central nervous system injury or dysfunction cause later on remains the clinical problem of a difficulty, in default of effective treatment (Bennett, 1994; Murphy and Reid, 2001).Anticonvulsant is used for handling neuropathic pain (Sindrup and Jenssen, 1999 of some forms; Jensen, 2002).SPM 927 (R-2-acetylaminohydroxyphenylarsonic acid N-benzyl-3-methoxy propyl amide) also is called harkoseride or ADD 234037, is a kind of new anticonvulsant.It belongs to the aminoacid of a series of functionalization, and it is the new anticonvulsant of a class (people such as Kohn, 1991) that these aminoacid have been synthesized.

Present studies show that SPM 927 in cancer pain, especially in the rat model of the pain of osteocarcinoma pain, chemotherapy-induced and the inductive pain of nucleoside analog analgesic effect is arranged.

Bone is the 3rd modal metastasis site after the lung regulating liver-QI, also is the main position of suffering from patient's metastatic disease of breast carcinoma, carcinoma of prostate and pulmonary carcinoma.The bone injury that metastatic disease caused also causes serious bone pain, and this is the main clinical problem in the cancer patient.The characteristic that such pain increases the weight of owing to its intermittence, carrying out property and gene motion is so be difficult to treatment.The cardinal symptom of this model pain is the unusual pain of machinery.Thermal hyperalgesia and mechanical hyperalgesia are as different measured being confirmed by two hind leg load-bearing people such as (, 2002) Medhurst.The treatment of people patient's bone pain is limited to the use of opioid to a great extent, and effectively the effect of opioid is very little, and effective dose produces a series of weak side effect.Therefore, clinically need the new treatment that can be used in the bone pain that prevention, treatment and ameliorate tumor cause.The therapy of the bone pain that candidate's treatment tumor causes can be assessed with rat model, because be superior for test to the behavior reaction rat of pain stimulation.Model relates to the terminal point that uses the pain assessment and inject rat breast cancer cell people such as (, 2002) Medhurst in the bone marrow gap of proximal tibia, and carry out this after tumour transplatation the 7th to 15 day.

The pain of chemotherapy-induced is and neurotoxicity medicine such as the vinca alkaloids neuropathic pain of the relevant a kind of form of vincristine for example, and has the feature of the unusual and pain perception obstacle of pain perception.The clinical antitumor efficacy of vincristine is subject to the neuropathic development of a kind of blended sensorimotor (people such as Casey, 1973, people such as Tanner, 1998 people such as grade, 1998), and this disease appears at two main stages (people such as Weiss, 1974).In early days the stage, the periphery aixs cylinder is damaged by vincristine, and The main symptoms is paraesthesia and pain perception obstacle.Late the stage, when longer-term gave higher dosage, this disease more frequently took place, the aixs cylinder forfeiture, and main clinical finds it is the motor function forfeiture.As if described vincristine rat model reflect the neuropathic commitment of chemotherapy that early stage vincristine causes.Although basic mechanism also is not familiar with fully, this mechanism is described to cause the structural deterioration of aixs cylinder microtubule cytoskeleton and the increase of no myelin sensation neurite caliber people such as (, 2002) Quasthoff.These results prove the hyperpathia that the change of micro-tubular structure in the nociception sensory neuron follows vincristine to cause.

The inductive painful peripheral neurophaty of nucleoside analog is being acknowledged as the important source (Cohen, 2002) of the individual sickness rate that infects HIV (human immunodeficiency virus) (HIV).Thisly weak side effect can be forced shorten or even end treatment people such as (, 1999) Yatvin of AIDS (acquired immune deficiency syndrome (AIDS)).This neuropathic characteristics are greatly seldom to involve both hands about the intensive biped calcination sense of discomfort that broke out in the tenth week of treatment, and this sense of discomfort reaches serious intensity people such as (, 1989) Dubinsky through the time in a few days.Although report that mitochondrial toxicity helps this neuropathic development, this neuropathic potential biochemical mechanism waits clearly to determine.Recently, the report rat has been arranged, and (ddC (2 ' with antiretroviral nucleoside analog AIDS medicine, 3 '-zalcitabine), ddl (2 ', 3 '-didanosine) or d4T (2 ', 3 '-two dehydrogenations-3 '-deoxyribosylthymine)) the poisoning meeting causes enhanced nociception (people such as Joseph, 2004) in the rat body.As if the mechanism that relates to be different from the mechanism in other models of finding to help metabolism or toxic pain peripheral neurophaty because anti-hyperalgesic medicine in these models effectively.The inhibitor of protein kinase A, Protein kinase C, protein kinase G, p42/p44-mitogen-activated protein kinase (ERK1/2) and nitricoxide synthase is to not effect of peripheral neurophaty, and the super quick not effect that nucleoside reverse transcriptase inhibitor is caused.Intracellular Ca2+ regulator (TMB-8 and Quin-2) is only to have to reverse this super quick medicine of poisoning animal, and this points out the effect of intracellular Ca2+ in such neuropathic pain strongly.

Chemotherapy is for example used the treatment of vinca alkaloids such as vincristine or with paclitaxel, suramin, cisplatin, carboplatin or oxaliplatin treatment, is used to treat cancer and HIV patient.In addition, HIV or/and tumor patient also with the treatment of antiretroviral agent or antiviral agents.

Also do not report formula (Ib) or/and the chemical compound of formula (IIb) is used for the treatment of the purposes of relaxing tumor pain (particularly osteocarcinoma pain), the inductive pain of therapeutical chemistry therapy and the inductive pain of treatment nucleoside.

Therefore, the present invention relates to formula (Ib) or/and the described chemical compound of formula (IIb) be used for prevention in preparation, alleviate or/and treat relaxing tumor pain (particularly relevant relaxing tumor pain), osteocarcinoma pain with AIDS, during tumour progression by the pain that produces at the infiltration of bone, internal organs, soft tissue or nerve or pressure thereon or/and for example shift inductive pain, but be not limited to, the osteocarcinoma pain that transfer causes, suffer from breast cancer, among the patient of carcinoma of prostate or pulmonary carcinoma by the purposes in the pharmaceutical composition that shifts the inductive pain of disease.The invention still further relates to formula (Ib) or/and chemical compound (IIb) is used for prevention, alleviates or/and the inductive pain of therapeutical chemistry therapy in preparation, for example, but be not limited to, the neuropathic pain that chemotherapy causes, the inductive pain of vinca alkaloids, the inductive pain of vincristine or/and by paclitaxel, suramin, cisplatin, carboplatin or/and the purposes in the pharmaceutical composition of the inductive pain of oxaliplatin.The invention still further relates to formula (Ib) or/and chemical compound (IIb) is used for preventing, alleviating in preparation or/and treat the purposes of the pharmaceutical composition of following pain: nucleoside-or/and nucleoside analog-inductive pain, for example, but be not limited to, ucleosides or/and the inductive painful peripheral neurophaty of nucleoside analog, antitumor or/and the inductive pain of antiviral nucleoside analogue or/and antiretroviral nucleoside analog in the AIDS treatment for example, for example AZT (3 '-azidothymidine AZT), ddC, ddl are or/and the inductive pain of d4T.

The invention still further relates to formula (Ib) or/and chemical compound (IIb) preparation be used for preventing, alleviating or/and treat relaxing tumor pain, chemotherapy-induced pain or/and by at least a nucleoside or/and the purposes of the pharmaceutical composition of the inductive pain of at least a nucleoside analog.

Surprisingly, in the neuropathic pain model that osteocarcinoma pain model that tumor causes, neuropathic pain model that chemotherapy causes and nucleoside analog cause, (Ib) or/and the application of chemical compound (IIb), particularly (R)-2-acetamide-N-benzyl-3-methoxy propyl amide (SPM 927) has reduced machinery and thermal hyperalgesia and machinery and heat anomaly pain.

The compounds of this invention has general formula (Ib) structure

Formula (Ib)

Wherein

R is hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, aryl, aromatic yl elementary alkyl, heterocycle, heterocycle low alkyl group, low alkyl group heterocycle, low-grade cycloalkyl or low-grade cycloalkyl low alkyl group, and R is not substituted or by at least one electron withdraw group and/or at least one electron donating group-substituted;

R ₁Be hydrogen or low alkyl group, low-grade alkenyl, low-grade alkynyl, aromatic yl elementary alkyl, aryl, heterocycle low alkyl group, low alkyl group heterocycle, heterocycle, low-grade cycloalkyl, low-grade cycloalkyl low alkyl group, be not substituted separately or replaced by at least one electron donating group and/or at least one electron withdraw group;

And

R ₂And R ₃Be hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, aromatic yl elementary alkyl, aryl, halogen, heterocycle, heterocycle low alkyl group, low alkyl group heterocycle, low-grade cycloalkyl, low-grade cycloalkyl low alkyl group or Z-Y independently, wherein, R ₂And R ₃Can not be substituted or by at least one electron withdraw group and/or at least one electron donating group-substituted;

Z is O, S, S (O) _a, NR ₄, NR ' ₆, PR ₄Or chemical bond;

Y is hydrogen, low alkyl group, aryl, aromatic yl elementary alkyl, low-grade alkenyl, low-grade alkynyl, halogen, heterocycle, heterocycle low alkyl group, low alkyl group heterocycle, and Y can not be substituted or replaced by at least one electron donating group and/or at least one electron withdraw group, condition is when Y is halogen, Z is a chemical bond, or

ZY is NR together ₄NR ₅R ₇, NR ₄OR ₅, ONR ₄R ₇, OPR ₄R ₅, PR ₄OR ₅, SNR ₄R ₇, NR ₄SR ₇, SPR ₄R ₅, PR ₄SR ₇, NR ₄PR ₅R ₆, PR ₄NR ₅R ₇Or N ⁺R ₅R ₆R ₇,

R ' ₆Be hydrogen, low alkyl group, low-grade alkenyl or low-grade alkenyl, its can not be substituted or by at least one electron withdraw group or/and at least one electron donating group-substituted;

R ₄, R ₅And R ₆Be hydrogen, low alkyl group, aryl, aromatic yl elementary alkyl, low-grade alkenyl or low-grade alkynyl independently, wherein, R ₄, R ₅And R ₆Can not be substituted independently or by at least one electron withdraw group or/and at least one electron donating group-substituted;

R ₇Be R ₆Or COOR ₈Or COR ₈, wherein, R ₇Can not be substituted or by at least one electron withdraw group or/and at least one electron donating group-substituted;

R ₈Be hydrogen or low alkyl group or aromatic yl elementary alkyl, and aryl alkyl can not be substituted or by at least one electron withdraw group or/and at least one electron donating group-substituted; And

N is 1-4; And

A is 1-3.

Preferred chemical compound of the present invention has general formula (IIb) structure

Formula (IIb)

Wherein

Ar is an aryl, phenyl especially, and it is not substituted or is replaced by at least one halogen; R ₃Be-CH ₂-Q, wherein, Q is a lower alkoxy; And R ₁Be low alkyl group, methyl especially.

The invention still further relates to pharmaceutical composition, it comprises according to formula (Ib) or/and the chemical compound of formula (IIb), it is applicable to prevention, alleviates or/and treat relaxing tumor pain, particularly relevant relaxing tumor pain, osteocarcinoma pain with AIDS, in the pain that produces by infiltration in bone, internal organs, soft tissue or nerve or pressure thereon during the tumour progression or/and shift inductive pain, for example, but be not limited to, the osteocarcinoma pain that transfer causes is by the inductive pain of transfer disease among the patient who suffers from breast carcinoma, carcinoma of prostate or pulmonary carcinoma.The invention still further relates to pharmaceutical composition, it comprises according to formula (Ib) or/and the chemical compound of formula (IIb), it is applicable to prevention, alleviates or/and the inductive pain of therapeutical chemistry therapy, for example, but be not limited to, the neuropathic pain that chemotherapy causes, the inductive pain of vinca alkaloids, the inductive pain of vincristine or/and paclitaxel, suramin, cisplatin, carboplatin or/and the inductive pain of oxaliplatin.The invention still further relates to pharmaceutical composition, it comprises according to formula (Ib) or/and the chemical compound of formula (IIb), it is applicable to prevention, alleviate or/and treat nucleoside-or/and nucleoside analog-inductive pain, for example, but be not limited to, ucleosides or/and the inductive painful peripheral neurophaty of nucleoside analog, antitumor or/and the inductive pain of antiviral nucleoside analogue or/and antiretroviral nucleoside analog in the AIDS treatment for example, for example AZT, ddC, ddl are or/and the inductive pain of d4T.

The invention still further relates to pharmaceutical composition, it comprises according to formula (Ib) or/and the chemical compound of formula (IIb), it is applicable to prevention, alleviate or/and treat relaxing tumor pain, chemotherapy-induced pain or/and by at least a nucleoside or/and the inductive pain of at least a nucleoside analog.

" low alkyl group " refers to during when independent use or with other group coupling and contains 1 to 6 carbon atom, especially contains the low alkyl group of 1 to 3 carbon atom, and can be straight or branched.These groups comprise methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, hexyl etc.

" lower alkoxy " is to contain 1 to 6 carbon atom, especially contains the lower alkoxy of 1 to 3 carbon atom, and can be straight or branched.These groups comprise methoxyl group, ethyoxyl, propoxyl group, butoxy, isobutoxy, tert-butoxy, amoxy, hexyloxy etc.

" aromatic yl elementary alkyl " comprises for example benzyl, phenethyl, phenylpropyl, propyloxy phenyl base, benzene butyl, benzhydryl, 1,1-two phenethyls, 1,2-two phenethyls etc.

Term " aryl " when independent use or unite when using, refers to and contains 6 to 18 ring carbon atoms and the aromatic group of 25 ring carbon atoms altogether at the most, and comprises multi-nucleus aromatic compound.These aryl can be monocycle, dicyclo, three rings or multi-ring, and are condensed ring.When being used for herein, multi-nucleus aromatic compound refer to comprise contain 10-18 ring carbon atom and at the most altogether the dicyclo of 25 carbon atoms and tricyclic condensed aromatic ring the system.Aryl comprises phenyl and multi-nucleus aromatic compound, for example naphthyl, anthryl, phenanthryl, azulene base etc.Aryl also comprises as groups such as ferrocenyls.Aryl can not be substituted or by following electrophilic or/and the donor residues single group replace or be polysubstituted.

" low-grade alkenyl " is the alkenyl that contains 2 to 6 carbon atoms and at least one two key.These groups can be straight or branched, and can be Z type or E type.These groups comprise vinyl, acrylic, 1-butylene base, isobutenyl, crotyl, 1-pentenyl, (Z)-pentenyl, (E)-pentenyl, (Z)-4-methyl-pentenyl, (E) 4-methyl-pentenyl, pentadienyl, for example 1,3-or 2,4-pentadienyl etc.

Term " low-grade alkynyl " is the alkynyl that contains 2 to 6 carbon atoms, and can be straight or branched.It comprises these groups, as acetenyl, propinyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 3-methyl-1-pentene alkynyl, 3-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base etc.

Term " low-grade cycloalkyl " when independent use or unite when using, is to contain 3 to 18 ring carbon atoms and the cycloalkyl of 25 carbon atoms altogether at the most.Cycloalkyl can be monocycle, bicyclo-, three rings or multi-ring, and ring is condensed.Cycloalkyl can be fully saturated or fractional saturation.Example comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, ring decyl, cyclohexenyl group, cyclopentenyl, cyclo-octene base, cycloheptenyl, naphthalane base, hydrogenation indanyl, indanyl, fenchyl, pinene base, adamantyl etc.Cycloalkyl comprises cis or trans.Cycloalkyl can not be substituted or by following electron withdraw group or/and the donor residues single group replace or be polysubstituted.In addition, on the interior position that substituent group can be in the bridge joint second cycle line or outer.

Term " electrophilic and give electronics " refers to substituent group respectively with respect to the hydrogen electrophilic or the ability of giving electronics, if hydrogen atom has occupied intramolecular same position.These terms are well-known to those having ordinary skill in the art, and by J.March, John Wiley and Sons discuss at Advanced Organic Chemistry, New York, and NY, in the 16-18 page or leaf (1985), discussion wherein is incorporated herein by reference.Electron withdraw group comprises halogen, comprises bromine, fluorine, chlorine, iodine etc.; Nitro, carboxyl, low-grade alkenyl, low-grade alkynyl, formoxyl, carboxamido, aryl, quaternary ammonium, haloalkyl is as trifluoromethyl, aryl low-grade alkane acidyl, alkoxy carbonyl group etc.Electron donating group comprises these groups such as hydroxyl, and lower alkoxy comprises methoxyl group, ethyoxyl etc.; Low alkyl group is as methyl, ethyl etc.; Amino, lower alkyl amino, two (low alkyl group) amino, aryloxy group is as phenoxy group, sulfydryl, lower alkylthio, low alkyl group sulfydryl, disulphide (low alkyl group disulfide group) etc.It will be understood by those of skill in the art that some in the above-mentioned substituent group can be counted as electron donating group or electron withdraw group under different electrochemical conditions.And the present invention also pays close attention to the substituent combination in any that is selected from above-mentioned group.

Term " halogen " comprises fluorine, chlorine, bromine, iodine etc.

Term " acyl group " comprises the low-grade alkane acidyl that contains 1 to 6 carbon atom, and can be straight or branched.These groups comprise for example formoxyl, acetyl group, propiono, bytyry, isobutyryl, uncle's bytyry, valeryl and caproyl.

When using in this article, heterocyclic group comprises at least one sulfur, nitrogen or oxygen annular atoms, but also can comprise several described atoms in ring.The heterocyclic group that the present invention pays close attention to comprises heteroaromatics and saturated and heterocyclic compound fractional saturation.These heterocyclics can be monocycle, bicyclo-, three rings or multi-ring and be condensed ring.They can preferably comprise 18 annular atomses at the most, and 17 ring carbon atoms and 25 carbon atoms altogether altogether at the most at the most.Heterocyclics is also intended to comprise so-called benzheterocycle compounds of group.Typical heterocycle comprises furyl, thienyl, pyrazolyl, pyrrole radicals, the methylpyrrole base, imidazole radicals, indyl, thiazolyl,  azoles base, isothiazolyl, different  azoles base, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazole radical, isoquinolyl, benzofuranyl, benzothienyl, morpholinyl, the benzoxazol base, tetrahydrofuran base, pyranose, indazolyl, purine radicals, indolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolidinyl, the furazan base, N-methylindole base, the methylfuran base, pyridazinyl, pyrimidine radicals, pyrazinyl, pyridine radicals, epoxy, aziridine base (aziridino), oxetanyl, azetidinyl, nitrogenous heterocyclic N-oxide is as pyridine radicals, the N-oxide of pyrazinyl and pyrimidine radicals etc.Heterocyclic group can not be substituted or by electron withdraw group or/and the donor residues single group replace or be polysubstituted.

Preferred heterocycle is thienyl, furyl, pyrrole radicals, benzofuranyl, benzothienyl, indyl, methylpyrrole base, morpholinyl, pyridine radicals, pyrazinyl, imidazole radicals, pyrimidine radicals or pyridazinyl.Preferred heterocycle is 5 or 6-unit heterocyclics.Particularly preferred heterocycle is furyl, pyridine radicals, pyrazinyl, imidazole radicals, pyrimidine radicals or pyridazinyl.Most preferred heterocycle is furyl and pyridine radicals.

Preferred chemical compound be those wherein n be 1 chemical compound, but two (n=2), three (n=3) and tetrapeptide (n=4) are also included within the scope of the invention.

The preferred value of R is an aromatic yl elementary alkyl, benzyl especially, especially wherein its phenyl ring be not substituted or by electron donating group or/and those groups that electron withdraw group such as halogen (for example F) replace.

Preferred R ₁Be H or low alkyl group.Most preferred R ₁Group is a methyl.

The preferred electron substituent group of giving is or/and electron-withdrawing substituent is halogen, nitro, alkanoyl, formoxyl, aromatic yl silane terephthalamide yl, aroyl, carboxyl, alkoxy carbonyl group, formamido group, cyano group, sulfonyl, sulfoxide, heterocyclic radical, guanidine, quaternary ammonium, low-grade alkenyl, low-grade alkynyl, sulfonium salt, hydroxyl, lower alkoxy, low alkyl group, amino, lower alkyl amino, two (low alkyl group) amino, amino low alkyl group, sulfydryl, mercaptoalkyl, alkylthio group and alkyl disulfide group.Term " sulfide " comprises sulfydryl, mercaptoalkyl and alkylthio group, and term disulphide comprises the alkyl disulfide group.The particularly preferred electronics of giving is or/and electron withdraw group is halogen or lower alkoxy, most preferably fluorine or methoxyl group.These preferred substituted can be present in formula (Ib) or/and on any one group (IIb), for example R, the R of this paper definition ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ' ₆, R ₇, R ₈And/or R ₅₀

Represent R ₂And R ₃The ZY group comprise hydroxyl, alkoxyl, for example methoxyl group, ethyoxyl, aryloxy group, for example phenoxy group; Thio alkoxy, for example sulfo-methoxyl group, thio ethoxy; Thio-aryloxy, for example sulfo-phenoxy group; Amino; Alkylamino, for example methylamino, ethylamino; Virtue is amino, for example anilino-; Rudimentary dialkylamino, for example dimethylamino; Trialkyl ammonium salts, diazanyl; Alkyl diazanyl and aryl diazanyl, for example N-methyl diazanyl, N-phenyl diazanyl, alkoxy carbonyl group diazanyl, aralkoxycarbonyl diazanyl, aryloxy carbonyl diazanyl, hydroxylamino, for example N-hydroxylamino (NH-OH), lower alkoxy amino [(NHOR ₁₈), R wherein ₁₈Be low alkyl group], N-low alkyl group hydroxylamino [(NR ₁₈) OH, wherein R ₁₈Be low alkyl group], N-low alkyl group-O-low alkyl group hydroxylamino, i.e. [N (R ₁₈) OR ₁₉, R wherein ₁₈And R ₁₉Be low alkyl group independently] and O-hydroxylamino (O-NH ₂); Alkyl amido is acetylamino for example; Trifluoroacetamido; Rudimentary alcoxyl amino, for example NH (OCH ₃); And heterocyclic amino group, for example pyrazoles amino.

Represent R ₂And R ₃Preferred heterocyclic group be the monocycle 5-of following formula or 6-unit heterocyclic moiety:

Or its corresponding fractional saturation or complete saturated form, wherein, n is 0 or 1; With

R ₅₀Be H or electron withdraw group or electron donating group;

A, E, L, J and G are CH independently, or are selected from the hetero atom of N, O, S;

But when n was 0, G was CH, or was selected from the hetero atom of NH, O and S, condition be among A, E, L, J and the G maximum two be hetero atom.

When n was 0, above heteroaryl moieties was 5 yuan of rings, and if n is 1, heterocyclic moiety is 6 yuan of monocyclic heterocycles parts.Preferred heterocyclic moiety is that those belong to monocyclic above-mentioned heterocycle.

If above-described ring comprises the azo-cycle atom, the N-oxide form is also included within the scope of the invention so.

Work as R ₂Or R ₃When being the heterocycle of following formula, it can be by ring carbon atom and main chain bonding.When n is 0, R ₂Or R ₃Also can pass through azo-cycle atom and main chain bonding in addition.

Other preferred R ₂And R ₃Part is a hydrogen, aryl, phenyl for example, aralkyl, for example benzyl and alkyl.

It should be understood that preferred R ₂And R ₃Group can not be substituted or given electronics or/and the electron-withdrawing group single group replaces or be polysubstituted.Preferred R ₂And R ₃Be hydrogen independently, be not substituted or by electron withdraw group or/and electron donating group, the low alkyl group, N-hydroxylamino, N-low alkyl group hydroxylamino, N-low alkyl group-O-low alkyl group and the alkyl hydroxylamino that replace of lower alkoxy (for example methoxyl group and ethyoxyl etc.) for example.

Preferred R ₂And R ₃One of be hydrogen.

Preferred n is 1.

More preferably n=1, R ₂And R ₃One of be hydrogen.Particularly preferably be, in this embodiment, R ₂Be hydrogen, R ₃Be low alkyl group or ZY; Z is O, NR ₄Or PR ₄Y is hydrogen or low alkyl group; ZY is NR ₄NR ₅R ₇, NR ₄OR ₅, ONR ₄R ₇,

Or

In another particularly preferred embodiment, n=1, R ₂Be hydrogen, R ₃Be low alkyl group, the NR that not to be substituted or to be given the replacement of electronics or electron withdraw group ₄OR ₅Or ONR ₄R ₇

In another particularly preferred embodiment, n=1, R ₂Be hydrogen, R ₃Be low alkyl group, the NR that is not substituted or is replaced by hydroxyl or lower alkoxy ₄OR ₅Or ONR ₄R ₇, R wherein ₄, R ₅And R ₇Be hydrogen or low alkyl group independently, R is an aromatic yl elementary alkyl, and this aryl can not be substituted or be replaced by electron withdraw group, R ₁It is low alkyl group.In this embodiment, most preferably aryl is the phenyl that is not substituted or is replaced by halogen.

Preferred R ₂Be hydrogen, R ₃Be hydrogen, be not substituted or by at least one alkyl or ZY that replaces for electronics or electron withdraw group.In this preferred embodiment, more preferably R ₃Be hydrogen, be not substituted or by the alkyl of electron donating group-substituted for example methyl or NR ₄OR ₅Or ONR ₄R ₇, wherein, R ₄, R ₅And R ₇Be hydrogen or low alkyl group independently.Preferred electron donating group is a lower alkoxy, especially methoxy or ethoxy.

Preferred R ₂And R ₃Be hydrogen, low alkyl group or ZY independently;

Z is O, NR ₄Or PR ₄

Y be hydrogen or low alkyl group or

ZY is NR ₄R ₅R ₇, NR ₄OR ₅, ONR ₄R ₇,

Or

Also preferred R is an aromatic yl elementary alkyl.For R, most preferred aryl is a phenyl.Most preferred R group is a benzyl.In preferred embodiments, aryl can not be substituted or replaces for electronics or electron withdraw group.If the aryl rings among the R has been substituted, most preferably it is replaced by electron withdraw group, especially on aryl rings.For R, most preferred electron withdraw group is a halogen, especially fluorine.

Preferred R ₁Be low alkyl group, methyl especially.

More preferably R is an aromatic yl elementary alkyl, R ₁It is low alkyl group.

Further preferred chemical compound is formula (Ib) chemical compound, and wherein n is 1; R ₂Be hydrogen; R ₃Be hydrogen, low alkyl group, especially methyl, it replaces for electronics or electron withdraw group, or ZY; R is an aryl, aromatic yl elementary alkyl, and benzyl for example, wherein aryl is not substituted or replaces R for electronics or electron withdraw group ₁It is low alkyl group.In this embodiment, more preferably R ₃Be hydrogen, can be by low alkyl group, the especially methyl of electron donating group such as lower alkoxy (for example methoxyl group and ethyoxyl etc.) replacement, NR ₄OR ₅Or ONR ₄R ₇, wherein, these groups define as mentioned.

Used most preferred is formula (IIb) chemical compound:

Formula (IIb)

Wherein

Ar is an aryl, phenyl especially, and it is not substituted or by at least one electron donating group or electron withdraw group, especially halogen replaces,

R ₁Be low alkyl group, especially contain the low alkyl group of 1-3 carbon atom; With

R ₃As defined herein, but hydrogen especially, low alkyl group, it is not substituted or is replaced by at least one electron donating group or electron withdraw group, or ZY.Even more preferably, in this embodiment, R ₃Be hydrogen, be not substituted or by the alkyl of electron donating group-substituted, NR ₄OR ₅Or ONR ₄R ₇R most preferably ₃Be CH ₂-Q, wherein Q is a lower alkoxy, especially contains the lower alkoxy of 1-3 carbon atom; NR ₄OR ₅Or ONR ₄R ₇, R wherein ₄Be hydrogen or the alkyl that contains 1-3 carbon atom, R ₅Be hydrogen or the alkyl that contains 1-3 carbon atom, R ₇Be hydrogen or the alkyl that contains 1-3 carbon atom.

Most preferred R ₁Be CH ₃Most preferred R ₃Be CH ₂-Q, wherein, Q is a methoxyl group.

Most preferred aryl is a phenyl.Most preferred halogen is a fluorine.

Most preferred comprises:

(R)-2-acetylaminohydroxyphenylarsonic acid N-benzyl-3-methoxyl group-propionic acid amide.;

O-methyl-N-acetyl group-D-serine--luorobenzyl-amide;

O-methyl-N-acetyl group-D-serine-right-luorobenzyl-amide;

N-acetyl group-D-phenylglycine benzyl amide;

D-1,2-(N, O-dimethyl hydroxylamino)-2-acetamide acetic acid benzyl amide;

D-1,2-(O-methyl hydroxylamino)-2-acetylaminoacetic acid benzyl amide.

It should be understood that R described herein ₁, R ₂, R ₃, R and n the various combination and permutation of Ma Kushi group all within the scope of the invention.And the present invention also comprises chemical compound and compositions, and it comprises R ₁, R ₂, R ₃, each the Ma Kushi group among n and the R one or more key elements and various combination thereof.Therefore, for example, that the present invention pays close attention to is R ₁Can be above listed substituent one or morely, associating arbitrarily and all R ₂, R ₃With the R substituent group, with regard to each value of n.

Be used for chemical compound of the present invention and can comprise one or more asymmetric carbons, and can have racemic form and optically active form.Configuration around each asymmetric carbon can be D or L type.Prior art is known, and in the Cahn-Prelog-Ingold naming system, the configuration that centers on chiral carbon atom also can be described as R or S.The present invention also pays close attention to all the various configurations around each asymmetric carbon, comprises the mixture of various enantiomers and diastereomer and racemic mixture and enantiomer, the mixture of diastereomer or both mixture.

In main chain, with radicals R ₂And R ₃There is unsymmetry on the carbon atom that connects.When n was 1, The compounds of this invention had the following formula structure

Wherein, R, R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ' ₆, R ₇, R ₈, R ₅₀, Z and Y as previously defined.

When being used for herein, although can there be other chiral centre in intramolecularly, the term configuration will refer to and center on and R ₂And R ₃The configuration of the carbon atom that connects.Therefore, when referring to particular configuration for example when D or L, should be appreciated that to refer to and R ₂And R ₃The D or the L stereoisomer of the carbon atom that connects.Yet, also comprise all possible enantiomer and the diastereomer of other chiral centre (if any) that is present in the chemical compound.

The compounds of this invention relates to all optical isomers, promptly The compounds of this invention be L-stereoisomer or D-stereoisomer (with R ₂And R ₃The carbon atom place that connects).These stereoisomers can L and the mixture of D stereoisomer, and for example racemic mixture is found.Preferred D stereoisomer.

The formula of R configuration (III) chemical compound more preferably, preferred enantiomeric pure in fact, wherein substituent R is the benzyl that is not substituted or is replaced by at least one halogen group, wherein R ₃Be CH ₂-Q, wherein Q contains the lower alkoxy of 1-3 carbon atom and R wherein ₁It is methyl.Preferred R is unsubstituted benzyl, or by the benzyl of at least one halogen group (being fluorin radical) replacement.

According to substituent group, The compounds of this invention also can form addition salts.All these forms is all considered to comprise the mixture of stereoisomer form within the scope of the invention.

The preparation of compound used therefor is described in United States Patent (USP) the 5th, 378, and No. 729 and the 5th, 773, in No. 475, the two content is introduced into as a reference.

Being used for chemical compound of the present invention, or/and (IIb) described, is useful with himself form as formula (Ib), or because of it because existence of free amine group has alkalescence, can use with the form of salt.Therefore, formula (Ib) or/and (IIb) chemical compound and many kinds acid (mineral acid and organic acid comprise pharmaceutically acceptable acid) form salt.The salt that forms with the acceptable acid of treatment can be used for the preparation of preparation certainly, and wherein the water solubility of Zeng Jiaing is best.

These pharmaceutically acceptable salts also have therapeutic efficiency.These salt comprise mineral acid for example hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, Metaphosphoric acid, nitric acid and vitriolic salt, and the organic acid salt of tartaric acid, acetic acid, citric acid, malic acid, benzoic acid, perchloric acid, glycolic, gluconic acid, succinic acid, aromatic sulfonic acid (for example p-methyl benzenesulfonic acid, benzenesulfonic acid), phosphoric acid and malonic acid etc. for example.

The invention still further relates to prevention, alleviate or/and treat and comprise the human above-mentioned disease of mammal or the method for the patient's condition, comprise and use at least a formula (Ib) or/and (IIb) chemical compound.

The used chemical compound of preferred the present invention uses with the treatment effective dose.

The doctor will determine the only dosage of therapeutic agent of the present invention, and this dosage will change with form of medication and selected specific compound, and in addition, it will change with the patient who is treated, patient age, the disease type of being treated.The doctor wishes to improve dosage with little increment, until the optimum efficiency that reaches in this case to be lower than the low dose of begin treatment of chemical compound optimal dose in fact usually.When the composition oral administration, the activating agent that needs are relatively large produces and the identical effect of parenteral in a small amount.In the mode identical with comparable therapeutic agent, this chemical compound is useful, and other therapeutic agent of dosage level and these usually adopt have an identical order of magnitude.

In preferred embodiments, The compounds of this invention to the amount administration of every day of the every kg body weight of about 100mg, more preferably arrives the every kg body weight of the about 10mg amount of every day with about 1mg with about 1mg.This dosage can be adjusted by the doctor, replys so that optimal treatment to be provided.Have this demand the patient can with 50mg/ days at least, preferred 200mg/ days at least, more preferably at least 300mg/ days, most preferably 400mg/ days The compounds of this invention dosage is treated at least.Usually, have this demand the patient can with maximal dose 6g/ days, more preferably maximal dose 1g/ days, most preferably maximal dose 600mg/ days dosage is treated.Yet in some cases, may need higher or lower dosage.

In a further preferred embodiment, increase daily dose, further keeping this predetermined daily dose in the therapeutic process until reaching predetermined daily dose.

In a further preferred embodiment, but use the dosage that several separate every day.For example, but use dosage every day three times, preferred every day two doses.More preferably use single dose every day.

In a further preferred embodiment, can use the amount of The compounds of this invention, it causes the plasma concentration of 0.1 to 15 μ g/ml (paddy) and 5 to 18.5 μ g/ml (peak), is calculated by treatment curee's average with most.

Formula (Ib) is or/and (IIb) the chemical compound mode administration that can suit, for example by in oral, intravenous (water miscible), intramuscular, the sheath or the subcutaneous route administration.Preferred oral is or/and intravenous administration.

Can prepare pharmaceutical composition of the present invention and be used for above-mentioned therapeutic scheme, especially be used for the treatment of with above-mentioned dosage, to reach above-mentioned plasma concentration, the administration cycle that is used for describing in detail with above-mentioned embodiment of the present invention is or/and route of administration.

In a further preferred embodiment, the invention described above treatment has the mammal of this demand to comprise that human method comprises to use The compounds of this invention, unite and be used for prevention, alleviate or/and treat viral infection, for example retroviral infection comprises the HIV infection of AIDS; Cancer, for example breast carcinoma, carcinoma of prostate, pulmonary carcinoma, osteocarcinoma, transfer disease; Or/and by other activating agent of the tumour progression that causes at bone, internal organs, soft tissue or intranueral infiltration or the pressure on it.The compounds of this invention and the administration together of other activating agent promptly with the single dose form, maybe can be distinguished administration, promptly with isolating dosage form.Therefore, pharmaceutical composition of the present invention can comprise the invention described above chemical compound, and can comprise and be used for prevention, alleviate or/and treat viral infection, and for example retroviral infection comprises the HIV infection of AIDS; Cancer, for example breast carcinoma, carcinoma of prostate, pulmonary carcinoma, osteocarcinoma, transfer disease; Or/and by other activating agent of the tumour progression that causes at bone, internal organs, soft tissue or intranueral infiltration or the pressure on it.Pharmaceutical composition can comprise the single dose form, maybe can comprise isolating dosage form, and this isolating dosage form comprises first compositions and second compositions, and this first compositions comprises the invention described above chemical compound and this second compositions comprises other activating agent.

The compounds of this invention can be used for preparing aforementioned pharmaceutical compositions.

Formula (Ib) or/and (IIb) chemical compound can be for example with inert diluent or with absorbable edible carrier oral administration, or it can be wrapped into hard or soft shell gelatin capsules, or it can be pressed in flakes, maybe it directly can be mixed in the fool of food.For oral therapeutic administration, formula (Ib) or/and (IIb) reactive compound can with the excipient fusion, use can absorb forms such as sheet, buccal tablet, lozenge, capsule, elixir, suspensoid, syrup and wafer.Said composition and preparation should comprise at least 1% formula (Ib) or/and (IIb) reactive compound.The percent of compositions and preparation can change certainly, can be aptly between described unitary weight about 5 to about 80% between.In the useful compositions of this treatment, formula (Ib) or/and (IIb) amount of reactive compound be to obtain the amount of suitable dosage.Preferred composition of the present invention or preparation comprise about 10mg to the formula between the 6g (Ib) or/and (IIb) reactive compound.

Tablet, lozenge, pill and capsule etc. also can comprise following composition: binding agent, for example tragakanta, arabic gum, corn starch or gelatin; Excipient, for example dicalcium phosphate; Disintegrating agent, for example corn starch, potato starch and alginic acid etc.; Lubricant, for example magnesium stearate; And sweeting agent, can add for example sucrose, lactose or glucide; Or flavoring agent for example Herba Menthae, wintergreen oil or Fructus Pruni pseudocerasi flavoring agent.When dosage unit form was capsule, it also can comprise liquid-carrier except above types of material.

Various other materials can be used as the physical form that there is or otherwise changes dosage unit in coating.For example, tablet, pill or capsule can carry out coating with Lac, sugar or the two.Syrup or elixir can comprise reactive compound, as the sucrose of sweeting agent, as the methyl parahydroxybenzoate of antiseptic and propyl p-hydroxybenzoate, dyestuff and flavoring agent for example Fructus Pruni pseudocerasi or orange flavor.Certainly, preparing the used any material of any dosage unit form should be pharmaceutical purity, and used amount is nontoxic in fact.In addition, reactive compound can be impregnated in slow releasing preparation and dosage form.For example, pay close attention to slow release formulation, wherein active component combines with ion exchange resin, and this resin can be chosen wantonly with diffuser screen obstacle coating and carry out coated with the release characteristics that changes resin.

But reactive compound is parenteral or intraperitoneal administration also.Also can in glycerol, liquid, Polyethylene Glycol and composition thereof and in oil, prepare dispersion.Under common storage and service condition, these preparations comprise the growth of antiseptic with prophylaxis of microbial.

The medicament forms that is suitable for the injectable use comprises aseptic aqueous solution (water miscible) or dispersion and is used for preparing the sterilized powder of aseptic injection with solution or dispersion temporarily.In all cases, dosage form must be aseptic, and must be mobile, and flowability will reach the degree that is easy to inject.Make and condition of storage under, preparation must be stable, and must prevent for example contamination of antibacterial and fungus of microorganism.Carrier can be to comprise for example solvent or the disperse medium of water, ethanol, polyhydric alcohol (for example glycerol, propylene glycol and liquid macrogol etc.), its suitable mixture and vegetable oil.Can be for example by using coating such as lecithin, for dispersion by keeping required particle diameter and by using surfactant to keep suitable flowability.Can for example parabens, chlorobutanol, phenol, sorbic acid and thimerosal wait to reach and prevent microbial action by various antibacterial and antifungal.Under many circumstances, preferably include isotonic agent, for example sucrose or sodium chloride.Postpone absorbent by using in compositions, for example aluminum monostearate and gelatin can realize that the prolongation of Injectable composition absorbs.

Mix in the appropriate solvent with above various other compositions (as required) of enumerating by reactive compound,, prepare aseptic injection solution then by filtration sterilization with aequum.In general, comprise basic disperse medium and be selected from the sterile carrier of above required other composition of enumerating, prepare dispersion by various sterile active compositions are mixed.Prepare the sterilized powder of aseptic injection with solution for being used to, preferred manufacturing procedure is that the vacuum drying freeze drying technology adds any other required composition, by its previous aseptic filtration formulations prepared from solutions.

When being used for herein, " pharmaceutically acceptable carrier " comprises any He all solvents, disperse medium, coating, antibacterial and the antifungal that are used for pharmaceutically active substance, isotonic agent and the absorption delay agent of knowing in this area.Any conventional media or reagent are except inconsistent with active component, and its use in therapeutic combination all is taken into account.The active component of augmenting also can mix compositions.

Preparation dosage unit form or be easy to administration and the uniform parenteral compositions of dosage is particularly advantageous.Dosage unit form used herein refers to the physical separation unit that is suitable for subject mammalian subject with single dose; Each unit comprises as calculated the active substance with the scheduled volume that produces required therapeutic effect, unites required pharmaceutical carrier.The characteristic of new dosage unit form of the present invention is subjected to following factor domination and directly depends on following factor: (a) unique property of active substance and the particular treatment effect that will reach, (b) inherent limitation in the preparation technique field, for example this active substance is used for the treatment of the active substance of curee's disease alive of suffering from the patient's condition, suffers damage as this paper institute is disclosed in detail healthy in this patient's condition.

Main active is mixed into above-described unit dosage forms with effective dose and suitable pharmaceutical acceptable carrier, is used for convenient and effectively administration.Unit dosage forms can for example comprise the main reactive compound of about 10mg to about 6g amount.Statement in proportion, reactive compound is present in about 1 usually to about 750mg/ml carrier.Augment composition of active components for comprising, decide dosage with reference to the administering mode of common dose and described composition.

When being used for herein, term " patient " or " curee " refer to homoiothermic animal, preferred mammal, and for example cat, Canis familiaris L., horse, milch cow, pig, mice, rat and primates comprise the people.Preferred patient is the people.

Term " treatment " refers to the alleviation pain relevant with the disease or the patient's condition, or cures or alleviate the disease of patient or the patient's condition.

The compounds of this invention suffers from the patient of aforementioned type obstacle with effective dose.This tittle equals treatment effective dose mentioned above.

The following example has shown that SPM 927 reduces the character in machinery and thermal hyperalgesia and machinery and the heat anomaly pain in the neuropathic pain model of the osteocarcinoma pain model of tumor inducing, chemotherapy-induced and the inductive neuropathic pain model of nucleoside analog.

Used material is SPM 927, and it is the synonym of Harkoseride.The standard chemical name is (R)-2-acetamide-N-benzyl-3-methoxy propyl amide.

Brief Description Of Drawings

Fig. 1 has described the test of mechanical allodynia in the osteocarcinoma pain model (rat).Handle the osteocarcinoma rat with the SPM 927 (10mg, 20mg and 40mg) that increases concentration, and itself and the osteocarcinoma rat of morphine processing, osteocarcinoma rat and the control rats that does not have to handle (having only cell) are compared.

Fig. 2 has described the test of hot pawl stimulation in the 14th and 15 day in the osteocarcinoma pain model (rat).Handle the osteocarcinoma rat with the SPM 927 (3mg, 10mg and 30mg) that increases concentration, and, not have the osteocarcinoma rat of processing (having only cell) and control rats to compare itself and the osteocarcinoma rat that morphine is handled.

Fig. 3 has described the test of load-bearing difference in the osteocarcinoma pain model (rat).Handle the osteocarcinoma rat with the SPM 927 (10mg, 20mg and 40mg) that increases concentration, and itself and the osteocarcinoma rat of morphine processing, osteocarcinoma rat and the control rats that does not have to handle (having only cell) are compared.

Fig. 4 has described in the pain model (rat of handling with vincristine) in chemotherapy-induced, with morphine (3mg/kg) relatively, increase the influence of the SPM 927 (3mg/kg, 10mg/kg and 30mg/kg) of concentration to the heat anomaly pain of cryostat test.

Fig. 5 has described in the pain model (rat of handling with vincristine) in chemotherapy-induced, with morphine (3mg/kg) relatively, increase the influence of the SPM 927 (3mg/kg, 10mg/kg and 30mg/kg) of concentration to the heat anomaly pain of 38 ℃ of hot plate tests.

Fig. 6 has described in the pain model (rat of handling with vincristine) in chemotherapy-induced, with morphine (3mg/kg) relatively, increase the influence of the SPM 927 (3mg/kg, 10mg/kg and 30mg/kg) of concentration to the thermal hyperalgesia of 52 ℃ of hot plate tests.

Fig. 7 has described in the pain model (rat of handling with vincristine) in chemotherapy-induced, with morphine (3mg/kg) relatively, increase the influence of the SPM 927 (3mg/kg, 10mg/kg and 30mg/kg) of concentration to the mechanical hyperalgesia of pawl pressure test.

Fig. 8 has described in the pain model (rat of handling with vincristine) in chemotherapy-induced, compare with morphine (3mg/kg), increase the influence of the SPM 927 (3mg/kg, 10mg/kg and 30mg/kg) of concentration the mechanical allodynia of Frey hair irritant test.

Fig. 9 has described in the inductive pain model of nucleoside (rat of handling with ddC), compare the effect of SPM927 (3mg/kg, 10mg/kg and 30mg/kg) in heat anomaly pain test (cryostat) that the intraperitoneal of increase concentration gives with the effect of morphine (the subcutaneous 3mg/kg that gives).

Figure 10 has described in the inductive pain model of nucleoside (rat of handling with ddC), compare with the effect of morphine (the subcutaneous 3mg/kg of giving), increase SPM927 (3mg/kg, 10mg/kg and 30mg/kg) that the intraperitoneal of concentration gives and test effect in (in the D20 wiping) at mechanical allodynia.

Figure 11 has described in the inductive pain model of nucleoside (rat of handling with ddC), with the effect of morphine (the subcutaneous 3mg/kg that gives) relatively, increase SPM 927 (3mg/kg, 10mg/kg and 30mg/kg) that the intraperitoneal of concentration gives and test effect in (von Frey hair) at mechanical allodynia.

Figure 12 has described in the inductive pain model of nucleoside (rat of handling with ddC), compare the effect of SPM927 (3mg/kg, 10mg/kg and 30mg/kg) in thermal hyperalgesia test (52 ℃ of hot plates) that the intraperitoneal of increase concentration gives with the effect of morphine (the subcutaneous 3mg/kg that gives).

Figure 13 has described in the inductive pain model of nucleoside (rat of handling with ddC), compare the effect of SPM927 (3mg/kg, 10mg/kg and 30mg/kg) in mechanical hyperalgesia test (pawl pressure) that the intraperitoneal of increase concentration gives with the effect of morphine (the subcutaneous 3mg/kg that gives).

Embodiment

The system in the rat of having checked in the neuropathic pain model that osteocarcinoma pain model that tumor causes, neuropathic pain model that chemotherapy causes and nucleoside analog cause gives the effect of SPM 927.In these models, SPM 927 has reduced machinery and thermal hyperalgesia and machinery and heat anomaly pain.Confirmed that SPM 927 is useful and generally speaking more effective than morphine as the neuropathic analgesics of treatment osteocarcinoma pain, chemotherapy-and nucleoside-cause.

Material and method

The osteocarcinoma rat model

Cell culture

Containing RPMI-1640 (Gibco, 500ml), 10% heat-inactivated hyclone (Hyclone), L-glutaminate (final concentration 2mM, from Gibco) and the culture medium of antibiotic solution (final concentration 100U/ml penicillin and 100ug/ml streptomycin sulfate are from Gibco) in cultured cell.By briefly being exposed to 0.1% trypsin Gibco) from tissue culture flasks, discharge cell, be prepared as follows then and be used for injection: about 1,200rpm centrifuge cell 10 minutes.With the phosphate buffered saline (PBS) that is deposited in calcic not or magnesium that obtains (PBS, Mediatech) in washed twice.To finally precipitate and be resuspended among the PBS and use hematimeter to carry out cell counting.With cell dilution to reach the final concentration that is used to inject and on ice keeping, up to injecting.

Surgical operation

After the quarantine of one week, with culture medium or 3 * 10 ⁴Homologous gene MRMT-1 rat breast cancer cell is expelled in the pulp cavity of proximal tibia of every rat.On program, at first with ketamine/xylazine with Animal Anesthesia, the hair of right shank position is shaved light, is handled and clean with 70% alcoholic solution with iodine solution.Carrying out 1-cm beak-tail on the skin of the first half of tibia cuts.Carry out flush end and dissect, guarantee minimal damage muscle or blood vessel to expose tibia.Use the 23-gage needle, 1-3mm penetrates tibia under knee joint.So that can pushing the angle of the intermedullary canal of bone downwards, pin inserts pin.In case open to the path of intermedullary canal, just the blunt pin that is connected on the 5 μ l Hamilton syringes is taken out and replaced to the 23-gage needle.With the culture medium+medium of 3 μ l volumes or tumor cell+media injections in intramedullary cavity.Inject cancerous cell lentamente, take out syringe simultaneously, make cell can fill the space in the described chamber.After the injection, use bone wax with the injection site closure.Use surgical staples with wound closure then.Undergoing surgery, nurse the back and observation, up to animal regains consciousness.

Behavior measure

Administration

At the 8th or 15 day, preceding 20 minutes of beginning test mechanical allodynia and before beginning to test thermal hyperalgesia about 40 minutes, rat gave medium, reference compound or the tester of single injection.Based on the pharmacological activity of SPM 927, test need be no more than 90 minutes and carry out after drug treating.At the 9th day, beginning to test load-bearing preceding 20 minutes, rat gives reference compound or tester.

Nociception is estimated

At the 7th, 8,14 and 15 day, carry out the pain evaluation test.At the 7th, 14 day, carry out the baseline evaluation.All animals were accepted peritoneal injection saline in about 20 minutes before baseline test.Began in about 20 minutes in test/reference substance injection back at the 8th, 15 day, animal is stood a series of nociception evaluations.All animals of the inferior ordered pair of test keep identical.At first animal is carried out mechanical allodynia evaluation, estimate thermal hyperalgesia then.At the 9th and 15 day, animal experience load test.At first animal is carried out baseline load-bearing reaction evaluating.After the base line measurement, rat ejection testing/reference substance and after at least 20 minutes, animal experiences another time load-bearing analysis.

The machinery allodynia

Baseline (the 7th day) and the 8th day, on all animals affected (right side) hind leg, carry out the Von Frey test of mechanical allodynia.In this test, rat is placed little lucite (plexiglas) case with metal wire mesh.After the about 10 minutes customs,, by using the series of thin nylon fiber at the bottom of the cage, and push down the sole of the foot surface of rear solid end from following.At duration of test, rat is unrestricted and do not arrested.The diameter of silk thread provides the logarithmic scale of exerting pressure and therefore provides discovers the linear of intensity and interval scale.Have the fiber of weak power and at first test, and under the normality threshold that most of rats detect.Just begun to make in the various situations of the required power of monofilament lines bending in use, tested each strong fiber continuously.When mentioning its pawl when the rat response pressure, next the size of record silk thread also uses more weak silk thread.According to " on-down (up-down) " method of Chapman, measure the withdrawal threshold value, described method comprises uses bigger and less continuously fiber to concentrate on the threshold value of withdrawing.The remarkable increase of allodynia be based on cell mean relatively.

The test of thermal hyperalgesia

The animal experience is at baseline (the 7th, 14 day) and the 8th, 15 day test thermal hyperalgesia.Every rat is placed in the lip-deep independent lucite compartment of heated glass of rising about 10 minutes with custom.When animal is static, is directed to fiber-optics heating source below the described glass and aims at the right back pawl of animal.Open infrared beam and when rat was mentioned or move its pawl, light beam was closed automatically.Timer record in the machine moves hiding of foot, and this is hidden and is counted as representing that animal discovers the time of the pain that is caused by heat.If rat was not moved in 25 seconds, thermal source is closed automatically, guarantees not damage of pawl.Only test affected rear solid end.For every rat, repeat this process at least 2 times, be separated by about 3 minutes at every turn.If it is hide each other within 2 seconds, that they are average.If the difference of hiding is greater than 2 seconds, the test rat hides for twice and average these two numerals up to having within 2 seconds.The cell mean of hiding of the withdrawal pawl between the comparable group, lower hiding are represented more pain sensitivity.

Load-bearing

After animal in the 4-6 group turned to the drug treating group more at random, at the 9th, 15 day all animals experience load test.The load-bearing of affected hind leg is evaluated as the difference of comparing homonymy body weight that limb bears with the offside limb.During experiment, rat is placed the lucite compartment, design this compartment and make each rear solid end rest on the independent transducer pad, the distribution of body weight on every pawl of this transducer pad record animal.Obtain 5 readings from every pawl, then that they are average, the result is expressed as load-bearing difference (WBD; Offside reading-homonymy reading).Distribute rat based on body weight that day after arrival, every group of 8 animals.The average weight of checking every group satisfies inhomogeneity supposition to guarantee meansigma methods and standard deviation.Based on the 8th day Von Frey test result, the animal in the 4-6 group is turned to the new processed group of bearing test more at random, with any deviation that prevents that they previous set of dispense from being caused.Animal in the 1-3 group is still at them in specified group, because these are not accept the animal that SPM 927 handles.

The inductive pain model of vincristine

Animal is handled

For this research, use 86 female Dark Agouti rats (150-200g) (Harlan, Gannat, France).Their groupings are raised (3 animals of every cage) and maintain temperature (21-22 ℃) and the light-dark of putting upside down circulated in the room of (12h/12h), can freely obtain food and water with control.Guide according to the rules carries out all experiments.By from the 1st day to the 5th day, the 8th day to the 12nd day and inject vincristine the 15th day to the 16th day every day (0.15mg/kg/d i.p.), reaches vincristine and poisons.At the 17th day, make animal experience behavior test and accept pharmacology's processing.With the rat random assortment of vincristine-poisoning in 5 experimental grouies (every group of 11 rats): 1. vincristine/medium, i.p.; 2. vincristine/SPM 927 (3mg/kg), i.p.; 3. vincristine/SPM 927 (10mg/kg), i.p; 4. vincristine/SPM 927 (30mg/kg), i.p.; 5. vincristine/morphine (3mg/kg), s.c..Before implementing behavior test 30 and 45 minutes, inject SPM 927 and morphine respectively.

Cryostat test (heat anomaly pain)

Animal is placed on the ice platform, this platform cold water (4 ℃) surface about 1cm down that submerges, the skin of the hairiness of animal foot and nothing mao contacts with cold water like this.Preceding the hiding of record first set reaction (licking pawl, moving jaws, jete) is 30 seconds by (cut off) time.

Hot plate test (heat anomaly pain/hyperpathia)

Animal is put in the glass cylinder on the hot plate (Bioblock, France) that is adjusted to 38 ℃ or 52 ℃.Hiding of record first set reaction (lick pawl, moving jaws, jete or takeoff to escape heat), be 30 seconds deadline.

Von Frey hair irritant test (mechanical allodynia)

Rat is placed on the metal grid floor.Insert von Frey filament (Bioseb, France) and it is applied to the sole of the foot surface of rear solid end by the grid floor, carry out the nociception test.Test is made up of the application of repeatedly different von Frey filaments (frequency is 1-1.5 second).Filament from 10g to 100g is used von Frey filament.Animal one is moved its rear solid end, just writes down mechanical allodynia threshold value, stops test and record number of filaments.

Pawl pressure test (mechanical hyperalgesia)

Use Randall-Selitto pawl pressure apparatus (Bioseb, France) to quantize the nociception flexion reflex, described pawl pressure apparatus applies the mechanical force of linear increase to the back side of rat hind paw.Power when mechanical wounding sensitivity threshold value defined is withdrawn its pawl for the rat of representing with gram.Cutoff pressure is set at 250 grams.

Data analysis

Use ANOVA, then post-hoc analyzes (DunnettShi check), relatively the behavioral data of the group of each single time point.

The inductive pain of nucleoside

Animal, ddC poison and experimental group

For this research, use 50 male Sprague Dawley (～220g) rat (Janvier, Le Genest-St-lsle, France).Rat grouping is raised (3 animals of every cage) and is maintained the temperature (21-22 ℃) with control and the light-dark of putting upside down circulated in the room of (12h/12h), can freely obtain food and water.Guide according to the rules carries out all experiments.Reach poisoning by single injection ddC (50mg/kg is in the I.V. tail vein).At the 10th day and the 20th day, animal was stood behavior test and accepts the pharmacology and handle.The rat that ddC-is poisoned is assigned randomly in 5 experimental grouies (every group of 10 rats): 1. contrast/medium .ip, 2.ddC/ medium, i.p.; 3.ddC/SPM 927 (3mg/kg), i.p.; 3.ddC/SPM 927 (10mg/kg), i.p; 4.ddC/SPM 927 (30mg/kg), i.p.; 5.ddC/ morphine (3mg/kg), s.c..Before implementing behavior test 30 and 45 minutes, inject SPM 927 and morphine respectively.

The 20th day wipe test

(speed is 1-2/ second with using oscillating movement; 30 seconds) the hair of the continuous wiping lower limb of the vertical applicator of Cotton Gossypii, the side of body and following back.Carry out wiping with being not more than mobile applicator by the required power of hair, so only disturb hair.The sounding and the appropriate effect that produce for the escape wiping are counted.

The result

The osteocarcinoma rat model

The machinery allodynia

Fig. 1 has described after baseline test and the drug treating group reaction to Von Frey filament.For processed group, the statistical analysis significantly different (p＜0.01) that uses 2-factor ANOVA altogether to carry out, single significantly not different for baseline effect vs. Treatment Effects.Relatively list-factor the ANOVA of the group of " the having only cell " after " processings " and each processed group checks demonstration, morphine group (p＜0.01), and 20 is significantly different with the mechanical allodynia level of 927 groups of 40mg/kg SPM (p＜0.05).The 5mg/kg morphine the has been handled all round reversing allodynia that when baseline is tested, shows.In addition, confirmed between " handling the back " data that health and injection tumor " having only cell " organized, to have the difference (p＜0.01) of highly significant.Also there is significant difference (p＜0.01) between the value behind " having only cell " group and the baseline value of morphine group and the dosage.

Thermal hyperalgesia

The data (Fig. 2) of the 14th and 15 day hot pawl test show, the baseline of removing their pawls of the group of all injection tumors hide for.Confirm this highly significant with two-factor ANOVA, wherein drug effect is that acting on p＜0.05 of p＜0.0001 and processing is remarkable." have only cell " for " not having cell " group vs. and organize, the preceding data of baseline or processing are significantly different, and (Dunnett ' spost-hoc checks; P＜0.001), other group shows there is not difference each other.In addition, for " not having cell " vs. (Dunnett ' s that " has only cell "; P＜0.001) and " having only cell " vs.SPM927 30mg/kg dosage (Dunnett ' s; P＜0.001), handles back group difference.The morphine matched group does not show significant difference, shows that morphine increases the trend of hiding that pawl is removed although have.

Mechanical hyperalgesia

Figure (Fig. 3) has shown 2-factor ANOVA altogether, and this ANOVA has shown significant group of difference, 0＜0.001.Deduct homonymy (the injection tumor) body weight that lower limb bore because load-bearing difference is defined as the body weight that contralateral leg bears, higher numeral will be presented at more body weight on the unaffected pawl, and 0 meaning is meant that the equal body weight on two pawls distributes.The base-line data of collecting has shown positive number, and it shows that these animals all are placed on more body weight on their the unaffected pawl.Compare with " having only cell " group, morphine group and 40mg/kg SPM are presented at the amounts of handling the body weight of placing the back on their offside pawls for 927 groups and reduce (p＜0.05) significantly, organize relatively with " having only cell ".

The inductive pain of vincristine

The cryostat test

As shown in FIG. 4, between 6 groups, observed significant significant difference (p＜0.05, Anova check).With the control animal contrast that shows the score of about 14 second time, in the cryostat test, show the threshold of lacking very much hide (about 9 seconds) with vincristine-animal of media processes.Handle the remarkable increase (p＜0.05, DunnettShi check) that vincristine-animals cause that threshold is hidden with SPM 927, it becomes and the threshold of control animal is hidden really quite, especially for 10 and the treatment dosage of 30mg/kg.Yet with 3mg/kg, threshold is hidden and is hidden less times greater than the threshold of vincristine-animal, although do not reach significant difference.Morphine is handled the threshold of vincristine-animal hidden to extend to and is higher than the level that the threshold that obtains from control rats is hidden far away.

38 ℃ of hot plate tests

The threshold that Fig. 5 is presented at vincristine-animal in hot plate (38 ℃) test threshold that significantly is shorter than control animal hide (p＜0.05, DunnettShi check) of hiding.With 3,10 and the SPM 927 of 30mg/kg handle vincristine-rats and cause threshold (p＜0.05, the DunnettShi check) increase of hiding significantly.With 10 and the treatment dosage of 30mg/kg, the behavior performance of STZ-rat becomes and can compare with the behavior performance of control animal.Similar with the SPM 927 of 30mg/kg to 10, the morphine of 3mg/kg is hidden the threshold of STZ-animal and is extended to the level that can hide and compare with the threshold of control rats.

52 ℃ of hot plate tests

As illustrated in fig. 6, the pawl of vincristine-rat the withdrawal pawl withdrawal that significantly is shorter than control animal hide (p＜0.05, DunnettShi check) of hiding.Compare with the animal of medium-processing, handle the remarkable increase (p＜0.05, DunnettShi check) that vincristine-rat causes that the pawl withdrawal is hidden with SPM 927.With 3 and 10, the effect that obtains of the dosage of 30mg/kg can compare with the effect of contrast.

The pawl pressure test

Compare with the behavior performance of control animal, use Randall ﹠amp; Selitto analgesia meter (analgesy-meter), vincristine-animal have confirmed the tangible pawl withdrawal reduction (Fig. 7) of hiding.With 10 and 30mg/kg, hide and significantly increase (p＜0.05, DunnettShi check) but handle pawl withdrawal that vincristine-rats cause vincristine-rat without the SPM 927 of 3mg/kg dosage.In this test, morphine is handled the behavior performance (p＞0.05, DunnettShi check) that does not change vincristine-rat.

The test of Von Frey filament

In this test (Fig. 8), with the withdrawal of the pawl of control rats hide (about 60g) compare the pawl withdrawal of vincristine-rat the significantly shortening (about 20g) of hiding.Handling the pawl withdrawal that has prolonged the vincristine rat with SPM 927 hides.Reached with 10 and the significance level (p＜0.05, DunnettShi check) of 30mg/kg treatment dosage with the difference of the group of medium-processing.The behavior performance that morphine is handled vincristine-rat returns to the level that can compare with the behavior performance of matched group.

The inductive pain rat model of nucleoside

Heat anomaly pain

As shown in FIG. 9, between 6 groups, observed significant significant difference (p＜0.05, Anova check).In cryostat test,, show the threshold of lacking very much hide (about 11 seconds) with the ddC-animal of media processes with the control animal contrast that shows about 20 seconds time score.Handle the remarkable increase (p＜0.05, DunnettShi check) that the ddC-animals cause that threshold is hidden with SPM 927, for 3 proof loads (3,10 and 30mg/kg), it becomes really and threshold of control animal is hidden quite.The morphine processing is hidden the threshold of ddC-animal and is extended to and the suitable level of hiding from the threshold of control rats acquisition.

Wipe test at the 20th day

Figure 10 is presented at the result of the wipe test that carried out in the 20th day.With SPM 927 (with 3,10 and 30mg/kg) animal of handling shows that the total degree that cries significantly increases (p＜0.05, DunnettShi check).Here again, the morphine of 3mg/kg can significantly reduce the total degree that the ddC-animal cries.

Von Frey filament test at the 10th day

In this test (Figure 11), with the withdrawal of the pawl of control rats hide (about 85g) compare the pawl withdrawal of ddC-rat the significantly shortening (about 50g) of hiding.Handling the pawl withdrawal that has prolonged the ddC rat with SPM 927 hides.Reached with 3,10 and the significance level (p＜0.05, DunnettShi check) of 30mg/kg treatment dosage, to the level suitable with the difference of the group of medium-processing with matched group.The behavior performance that the morphine of 3mg/kg is handled the ddC-rat returns to and the similar level of matched group.

52 ℃ of hot plate tests at the 20th day

As illustrated in fig. 12, the pawl of ddC-rat the withdrawal pawl withdrawal that significantly is shorter than control animal hide (p＜0.05, DunnettShi check) of hiding.With compare with the animal of medium-processing, only the SPM 927 with 30mg/kg dosage handles the remarkable increase (p＜0.05, DunnettShi check) that the ddC-rats cause that the pawl withdrawal is hidden.Can compare with untreated media pack with the effect that 10mg/kg dosage obtains with 3.After morphine was handled, it is similar to the behavior performance of control animal that the behavior of ddC-rat performance becomes.

Pawl pressure test at the 10th day

Compare with the behavior performance of control animal, use Randall ﹠amp; The analgesia meter of Selitto, ddC-animal have confirmed the remarkable reduction (Figure 13) that withdrawal is hidden.Handling pawl withdrawal that the ddC-rats cause the ddC-rat with the SPM 927 of whole 3 dosage (3,10 and 30mg/kg) hides and significantly increases (p＜0.05, DunnettShi check).Morphine is handled the behavior performance (p＜0.05, DunnettShi check) that has increased the ddC-rat again.

Conclusion

After single dose gave, system SPM 927 had produced anti-allodynia of dose dependent and anti-hyperpathia effect in the pain model of rat osteocarcinoma pain model, chemotherapy-induced and the inductive pain model of nucleoside.Therefore, SPM 927 and as in formula (Ib) or/and (IIb) disclosed allied compound be applicable among the treatment mankind with the pain during the cancer of chemotherapy and ucleosides treatment back, for example osteocarcinoma pain.

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Claims (35)

1. The compound with the structure of formula (Ib) or its pharmaceutically acceptable salt is used for the preparation and is suitable for preventing, alleviating or/and treating tumor pain, chemotherapy-induced pain or/and by at least one nucleoside or/and Use of at least one pharmaceutical composition for nucleoside analog-induced pain,

in R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocycle, heterocycle lower alkyl, lower alkylheterocycle, lower cycloalkyl, or lower cycloalkyl Lower alkyl, and R is unsubstituted or substituted by at least one electron-withdrawing group or/and at least one electron-donating group; _R is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, lower cycloalkane Lower alkyl groups, each unsubstituted or substituted by at least one electron-donating group or/and at least one electron-withdrawing group; R _{and R} are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halogen, heterocycle, heterocycle lower alkyl, lower alkylheterocycle, lower Cycloalkyl, lower cycloalkyl lower alkyl or ZY, wherein R ₂ and R ₃ may be unsubstituted or substituted by at least one electron-withdrawing group or/and at least one electron-donating group; and wherein R ₂ and R ₃ The heterocycle in is furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidinyl, Pyrrolinyl, piperazinyl, quinolinyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuranyl, pyranyl base, indazolyl, purinyl, indolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridyl Azidinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridinyl, oxetanyl, azetidinyl, or when N is present in a heterocycle, its N-oxide thing; Z is O, S, S(O) _a , NR ₄ , NR ₆ ' or PR ₄ or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halogen, heterocycle, heterocycle lower alkyl, lower alkyl heterocycle, and Y can be unsubstituted or Substituted by at least one electron-donating group or/and at least one electron-withdrawing group, where the heterocyclic ring has the same meaning as in _R2 or _R3 , and with the proviso that when Y is halogen, Z is a chemical bond, or ZY together Yes NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ , PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ , PR ₄ NR ₅ R ₇ or N ⁺ R ₅ R ₆ R ₇ ,

R ₆ ' is hydrogen, lower alkyl, lower alkenyl or lower alkynyl, which may be unsubstituted or substituted by at least one electron-withdrawing group or/and at least one electron-donating group; R ₄ , R ₅ and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, wherein R ₄ , R ₅ and R ₆ may be independently unsubstituted or substituted by at least one electron-withdrawing group or/and at least one electron-donating group; and R ₇ is R ₆ or COOR ₈ or COR ₈ , wherein R ₇ may be unsubstituted or substituted by at least one electron-withdrawing group or/and at least one electron-donating group; _R is hydrogen or lower alkyl or aryl lower alkyl, and the aryl or alkyl may be unsubstituted or substituted by at least one electron withdrawing group or/and at least one electron donating group; and n is 1-4; and a is 1-3. 2. The use according to claim 1, wherein the tumor pain is AIDS-related tumor pain, bone cancer pain, produced during tumor progression by infiltration in or pressure on bone, viscera, soft tissue or nerves Pain induced by metastatic disease, pain induced by metastases, bone cancer pain caused by metastases, or/and pain induced by metastatic disease in patients with breast, prostate, or lung cancer, where chemotherapy-induced pain is chemotherapy-induced neuropathic pain, Vinca alkaloid-induced pain or/and vincristine-induced pain, or/and wherein the nucleoside or/and nucleoside analog-induced pain is nucleoside or/and nucleoside analog-induced painful peripheral neuropathy, Pain induced by antineoplastic drugs or/and antiviral nucleoside analogs, pain induced by antiviral nucleoside analogs in AIDS treatment or/and pain induced by AZT, ddC, ddl or/and d4T. 3. Use according to any one of claims 1-2, wherein one of _R2 and _R3 is hydrogen. 4. Use according to any one of claims 1-3, wherein n is 1 . 5. Use according to any one of claims 1-4, wherein one of _R2 and _R3 is hydrogen, and n is 1. 6. Use according to any one of claims 1-5, wherein R is aryl lower alkyl and _R is lower alkyl. 7. Use according to any one of claims 1-6, wherein R ₂ and R ₃ are independently hydrogen, lower alkyl or ZY; Z is O, NR ₄ or PR ₄ ; Y is hydrogen or lower alkyl or ZY is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ ,

or

8. Use according to claim 7, wherein R ₂ is hydrogen, and R ₃ is lower alkyl or ZY; Z is O, NR ₄ or PR ₄ ; Y is hydrogen or lower alkyl; ZY is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ ,

or

9. Use according to any one of claims 1-8, wherein R is hydrogen, and _R is a lower alkyl group which may be unsubstituted or substituted _by at least one electron-donating group or/and at least one electron-withdrawing group , NR ₄ OR ₅ or ONR ₄ R ₇ . 10. The use according to any one of claims 1-9, wherein R ₃ is lower alkyl which is unsubstituted or substituted by hydroxyl or lower alkoxy, NR ₄ OR ₅ or ONR ₄ R ₇ , wherein R ₄ , R ₅ and R ₇ are independently hydrogen or lower alkyl, R is aryl lower alkyl which may be unsubstituted or substituted with at least one electron-withdrawing group, and R ₁ is lower alkyl. 11. Use according to any one of claims 1-10, wherein aryl is phenyl and is unsubstituted or substituted by halogen. 12 - Use according to any one of claims 1-11, wherein said compound is (R)-2-Acetamido-N-benzyl-3-methoxy-propionamide; O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; N-acetyl-D-phenylglycine benzamide; D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide benzamide acetate; or D-1,2-(O-methylhydroxyamino)-2-acetylaminoacetic acid benzylamide. 13. The use of any one of claims 1-12, wherein the compound has the structure of formula (IIb)

in Ar is phenyl which is unsubstituted or substituted by at least one halogen group; R ₃ is CH ₂ -Q, wherein Q is a lower alkoxy group containing 1-3 carbon atoms, and R ₁ is a lower alkyl group containing 1-3 carbon atoms; or a pharmaceutically acceptable salt thereof. 14. Use according to claim 13, wherein Ar is unsubstituted phenyl. 15. Use according to claim 13 or 14, wherein halogen is fluorine. 16. The use according to claims 13 to 15, wherein _R3 is CH2 _- Q, wherein Q is an alkoxy group having 1 to 3 carbon atoms, and Ar is an unsubstituted phenyl group. 17. The use of any one of claims 1-16, wherein the compound is in the R configuration and has the following structure

in R is benzyl unsubstituted or substituted by at least one halogen group; R ₃ is CH ₂ -Q, wherein Q is a lower alkoxy group containing 1-3 carbon atoms, and R ₁ is methyl; or a pharmaceutically acceptable salt thereof. 18. The use according to claim 17, which is substantially enantiomerically pure. 19. Use according to claim 17 or 18, wherein R is unsubstituted benzyl. 20. Use according to claims 17 to 19, wherein halogen is fluorine. 21. Use according to claims 17 to 20, wherein _R3 is CH2 _- Q, wherein Q is an alkoxy group having 1 to 3 carbon atoms, and R is unsubstituted benzyl. 22. The use according to claim 1 or 2, wherein the compound of formula (Ib) is (R)-2-acetamido-N-benzyl-3-methoxypropionamide or a pharmaceutically acceptable salt thereof. 23. Use according to claim 22, wherein said compound is substantially enantiomerically pure. 24. Use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for a dose of the compound of at least 100 mg/day, preferably at least 200 mg/day, more preferably at least 300 mg/day, most preferably at least 400 mg/day for treatment. 25. The use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for treatment with a compound dose of a maximum dose of 6 g/day, more preferably a maximum dose of 1 g/day, most preferably a maximum dose of 600 mg/day. 26. The use according to any one of the preceding claims, wherein said pharmaceutical composition is prepared for treatment with increasing daily dosage until a predetermined daily dosage is reached, which predetermined daily dosage is maintained during further treatment. 27. The use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for treatment in three daily doses, preferably in two daily doses, more preferably in a single daily dose. 28. Use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for administration which results in plasma concentrations of 0.1 to 15 μg/ml (trough) and 5 to 18.5 μg/ml (peak), Calculated as the average of most subjects. 29. The use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for oral or intravenous administration. 30. The use according to any one of the preceding claims, wherein the pharmaceutical composition further comprises a drug for preventing, alleviating or/and treating viral infections, such as HIV infection including AIDS; cancer, such as breast cancer, prostate cancer, Agents of lung cancer, bone cancer, metastatic disease; or/and tumor progression caused by infiltration in or pressure on bone, viscera, soft tissue or nerves. 31. Use according to claim 30, wherein the pharmaceutical composition comprises a single dosage form, or comprises a separate dosage form comprising a first composition and a second composition, the first composition comprising the A compound as defined in any one of claims 1 and 3 to 23 and the second composition comprises a further active agent. 32. The use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for administration in a mammal. 33. Use according to claim 32, wherein said pharmaceutical composition is prepared for administration in humans. 34. A pharmaceutical composition comprising (a) a compound as defined in any one of claims 1 and 3 to 23, and (b) for the prevention, alleviation or/and treatment of viral infections, such as HIV infection including AIDS; cancer, such as breast cancer, prostate cancer, lung cancer, bone cancer, metastatic disease; Other active agents in tumor progression induced by infiltration within soft tissue or nerves or pressure thereon. 35. The pharmaceutical composition according to claim 34, which is in a single dosage form, or which comprises a separate dosage form comprising a first composition and a second composition, the first composition comprising claim 1 and a compound as defined in any one of 3 to 23 and the second composition comprises the other active agent (b).

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