CN110467596A

CN110467596A - The crystal of tetralyl urea derivative

Info

Publication number: CN110467596A
Application number: CN201810448130.XA
Authority: CN
Inventors: 刘娟
Original assignee: Mochida Co Ltd
Current assignee: Mochida Co Ltd; Mochida Pharmaceutical Co Ltd
Priority date: 2018-05-11
Filing date: 2018-05-11
Publication date: 2019-11-19
Also published as: WO2019215937A1

Abstract

[project] offer 1- ((1R useful for the crystal as pharmaceuticals raw medicine, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea various crystal.[solution] present invention provide the 1- ((1R with excellent TrkA inhibiting effect, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) the various crystal of -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea, the drug comprising the crystal and pharmaceutical composition and the crystal manufacturing method.

Description

The crystal of tetralyl urea derivative

Technical field

The present invention relates to tropomyosin receptor kinase A (TrkA) inhibiting effect and as pain etc. prevention and/or Therapeutic agent and one of useful tetralyl urea derivative, i.e. 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- four Hydrogen naphthalene -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea (also being denoted as sometimes below Close object (1)) novel crystal form (VII type crystal, VIII type crystal, IX type crystal, X-type crystal, XI type crystal and XII type are brilliant Body), the manufacturing method of these crystal and the pharmaceutical composition containing the crystal.

Background technique

Tropomyosin receptor kinase (Tropomyosin receptor kinase:Trk) is that have and nerve extracellular Binding structural domain that nutrient (NT) combines and in the receptor type tyrosine kinase of the NT intracellular for having kinase domain, can be with It is classified as the TrkA of the receptor as neural growth factor (NGF), as brain-derived neurotrophic factor (BDNF) and NT-4/5 Receptor TrkB and the receptor as NT-3 TrkC.It was reported that the high expression in nerve fiber of these Trk receptors, participates in The differentiation of nerve cell, maintenance, signal transduction (non-patent literature 1).

NGF is known in companions such as such as arthritis, pancreatitis, cystitis, chronic cephalalgia, diabetic neuropathy, cancers Rise with concentration in the disease of pain, in addition, it was reported that, by the way that NGF is administered to people, rat, it can also induce pain (non-patent text It offers 2).Further, it is also known that show congenital absence of pain (non-patent literature because people's function of NGF, TrkA lose form variation 3), pain symptom disappears (non-patent literature 4,5) in the mouse for knocking out NGF, TrkA, it is understood that in vivo, The expression of NGF/TrkA passage depth participation pain.

The inhibitor of NGF/TrkA access, i.e. anti-ngf antibodies, anti-TrkA antibody, low molecule Trk inhibitor etc. are tried in clinic It tests, show that diversified pain symptom can be improved in nonclinical test.Report to such as Accompanying Deformation arthritis, The pain of chronic back pain disease, rheumatic arthritis, fracture, interstitial cystitis and chronic pancreatitis etc., neurological pain, The pain such as Cancerous pain, complex regional pain syndrome, migraine are effective (non-patent literatures 2,6 ~ 9).

It is known that the Trk receptor comprising TrkA is because of the variation etc. including superfluous expression, activation and Gene Fusion, ginseng With include neuroblastoma, oophoroma, colorectal cancer, melanoma, head-neck carcinoma, gastric cancer, lung cancer, breast cancer, at neuroglia Cell plastid tumor, astrocytoma, medulloblastoma, cholangiocellular carcinoma, secretory breast cancer, salivary-gland carcinoma, prostate cancer, pancreas Diversified cancer including cancer, Papillary thyroid carcinoma and Cheng Ren Gu Marrow leukaemia etc., Trk inhibitor in clinical test and In nonclinical test, show to inhibit tumor proliferation (non-patent literature 10 ~ 14).

In addition, TrkA receptor is also in the inflammatory cells such as mast cell, eosinophil, monocyte, macrophage, T Expressed in the immunocompetent cells such as cell, B cell and the axoneure including cholinergic nerve etc., asthma, Rhinitis, atopical dermatitis, ulcerative colitis, Crohn's disease, psoriasis, multiple sclerosis, systemic loupus erythematosus, In the diseases such as stages alzheimer's disease, the participation (non-patent literature 15 ~ 21) of NGF/TrkA access reported.

From these reasons, researching and developing, there is the medicament of TrkA inhibitory activity to be possibly able to be applied to pain, cancer, inflammation The treatment of disease property disease, anaphylactia, autoimmune disease etc. can expect therapeutic agent and/or prevention as new type Agent.

The derivative for showing TrkA inhibiting effect with urea structure is disclosed in WO2015/175788 separate edition (patent Document 1), WO2015/039333 separate edition (patent document 2), WO2014/078378 separate edition (patent document 3) and In WO2014/078325 separate edition (patent document 4) etc..However, there is no have conduct in derivative disclosed in these The compound of the tetralyl structure of characteristic structure of the invention does not have for the compound for having tetralyl structure It is open also there is no suggestion that.

In addition, disclosing showing with tetralyl structure in WO2014/078454 separate edition (patent document 5) The derivative of TrkA inhibiting effect, but the derivative recorded in patent document 5 is the urea derivative with pyrazole ring, is not disclosed The compound of the present invention (1).

Existing technical literature

Patent document

Patent document 1:WO2015/175788 separate edition

Patent document 2:WO2015/039333 separate edition

Patent document 3:WO2014/078378 separate edition

Patent document 4:WO2014/078325 separate edition

Patent document 5:WO2014/078454 separate edition

Non-patent literature

Non-patent literature 1:Current Opinion in Neurobiology, volume 11, the 272-280 pages, 2001 years

Non-patent literature 2:Journal of Pain Research, volume 9, the 373-383 pages, 2016 years

Non-patent literature 3:Journal of Neurochemistry, volume 124, the 276-289 pages, 2013 years

Non-patent literature 4:Cell, volume 76, the 1001-1011 pages, 1994 years

Non-patent literature 5:The FASEB Journal, volume 8, the 738-744 pages, 1994 years

Non-patent literature 6:Arthritis Research & Therapy, volume 18, page 97,2016

Non-patent literature 7:Journal of Orthopaedic Research, volume 33, the 1235-1241 pages, 2015 years

Non-patent literature 8:Pain, volume 138, the 47-60 pages, 2008 years

Non-patent literature 9:The Journal of Neuroscience, volume 27, the 8190-8201 pages, 2007 years

Non-patent literature 10:Biochimica et Biophysica Acta, volume 1866, the 37-50 pages, 2016 years

Non-patent literature 11:Cancer discovery, volume 5, the 25-34 pages, 2015 years

Non-patent literature 12:Clinical & Translational Oncology, volume 18, the 599-607 pages, 2016 years

Non-patent literature 13:Journal of Proteome Research, volume 7, the 1932-1944 pages, 2008 years

Non-patent literature 14:Nature Reviews Cancer, volume 3, the 203-216 pages, 2003 years

Non-patent literature 15:Jorunal of Alzheimer ' s Disease, volume 40, the 605-617 pages, 2014 years

Non-patent literature 16:Expert review of Respiratory Medicine, volume 4, the 395-411 pages, 2010

Non-patent literature 17:Current Opinin in Pulmonary Medicine, volume 7, the 1-7 pages, 2001 years

Non-patent literature 18:Gut, volume 46, the 670-678 pages, 2000 years

Non-patent literature 19:Acta Dermato-Venereologica, volume 95,542-548,2015

Non-patent literature 20:Cytokine, volume 20, the 136-139 pages, 2002 years

Non-patent literature 21:Progress in Brain Research, volume 146, the 415-432 pages, 2004 years.

Summary of the invention

Subject to be solved by the invention

It is an object of the present invention to for tropomyosin receptor kinase A (TrkA) inhibiting effect and pre- as pain etc. The useful compounds (1) such as anti-and/or therapeutic agent, provide the crystal for being suitable for pharmaceuticals raw medicine.In addition, by providing above-mentionedization The crystal for closing object (1), is capable of providing excellent pharmaceutical composition.

" many types of " refers to substance, and there are crystal form of more than two kinds (crystal structures).In addition, the different crystal forms of predetermined substance are claimed For " polytype "." many types of " is in general, by making three-dimensional conformation or by between different molecular or intramolecular interaction The influence of (especially hydrogen bond) and be reflected as the different atoms configurations in the lattice of various polytypes.On the other hand, with substance Shape all in all be referred to as " form " or " crystal habit ", it is unrelated with internal structure, show as the external shape of crystal Shape and there are surfaces.Crystal is according to (such as the presence of the speed of growth, stirring means (speed, temperature) and impurity of various conditions Deng) and various crystal habits are shown sometimes.

Substance it is various " many types of " due to that may have different lattice energies, in the solid state, it is many types of sometimes The property (such as shape, density, fusing point, color, stability, dissolubility, solution rate etc.) of different physics is shown.Said physical Property is also sometimes to specific many types of stability, dissolubility and biological utilisation energy used in drug or pharmaceutical composition etc. Power (body absorption effect, effect of medicament etc.) and keeping service life, formulation properties and the processing characteristics of pharmaceuticals etc. cause It influences.According to many types of and body absorption speed it is different in terms of, compared with activity inherently, can induce it is high or Low bioactivity.

The crystal of pharmaceuticals is many types of since there are a variety of many types of, in the crystal form of the pharmaceuticals manufacturing processes or guarantor During pipe, it is also possible to mean that a certain crystal form variation is changed " many types of conversion of other crystal forms, i.e. crystal structure (or also referred to as crystalline transformation) ".In addition, specific many types of when showing the higher thermodynamic stability compared with other are many types of, production When preparation with this other it is many types of compared with may should more select this specific many types of sometimes, therefore confirm thermodynamic stability to select Select one of more favorable many types of and project.

The means used to solve the problem

The inventors of the present invention in order to solve the above problems and further investigate as a result, it has been found that, compound (1) is tied according to various solvents Crystallization, there are 6 kinds of crystal habits of compound (1), (the 6 kinds of crystal habits (crystal form) recorded in this specification are in this theory for discovery It is known as VII type crystal, VIII type crystal, IX type crystal, X-type crystal, XI type crystal and XII type crystal later in bright book, Further, it VII type crystal is also expressed as FormVII, VIII type crystal is sometimes expressed as FormVIII, IX crystal to be expressed as FormIX, X-type crystal are expressed as FormX, XI type crystal and are expressed as FormXI and XII type crystal being expressed as FormXII).This Outside, it was found that these VII type crystal, VIII type crystal, IX type crystal, X-type crystal, XI type crystal and XII type crystal it is new Manufacturing method.

Further, crystal habit (VII type crystal, VIII type crystal, the IX type crystalline substance of 6 types of the compound (1) are found Body, X-type crystal, XI type crystal and XII type crystal) respectively there is visibly different physical property, it can expect as pharmaceuticals Raw material, so as to complete the present invention.

The compound of the present invention (1) no matter VII type crystal, VIII crystal, IX type crystal, X-type crystal, XI type crystal and How is the crystal form of XII type crystal, is the compound with tropomyosin receptor kinase A (TrkA) inhibiting effect, and having improves The effect for the disease (such as pain etc.) that TrkA is participated in.

No matter VII type crystal, VIII crystal, IX type crystal, X-type crystal, XI type crystal and XII type crystal crystal form such as What, can expect the disease participated in as TrkA, example as the pharmaceutical composition of effective component containing the compound of the present invention (1) Such as selected from pain, cancer, inflammation/diseases associated with inflammation, anaphylactia, skin disease, neurodegenerative disease, infectious disease, dry synthesis The prophylactic and/or therapeutic agent of at least one of sign, endometrium disease, nephrosis and osteoporosis disease.

Invention effect

The VII type crystal, VIII crystal, IX type crystal, X-type crystal, XI type crystal and XII type crystalline substance of the compound of the present invention (1) Body is the compound with TrkA inhibiting effect, it is possible to understand that as pharmaceuticals is useful.

The VII type crystal, VIII crystal, IX type crystal, X-type crystal, XI type crystal and XII of the compound of the present invention (1) Type crystal can be expected can be sufficiently as pharmaceuticals raw material.

The VII type crystal, VIII crystal, IX type crystal, X-type crystal, XI type crystal and XII of the compound of the present invention (1) Type crystal can provide excellent pharmaceutical composition.

Detailed description of the invention

Fig. 1 is the powder X-ray diffraction pattern of the type III crystal of the compound (1) of (embodiment 2).

Fig. 2 is the powder X-ray diffraction pattern of the V-type crystal of the compound (1) of (embodiment 3).

Fig. 3 is the powder X-ray diffraction pattern of the VII type crystal of the compound (1) of (embodiment 4).

Fig. 4 is the DSC&TGA modal data of the VII type crystal of the compound (1) of (embodiment 4).

Fig. 5 is the powder X-ray diffraction pattern of the VIII type crystal of the compound (1) of (embodiment 5).

Fig. 6 is the DSC&TGA modal data of the VIII type crystal of the compound (1) of (embodiment 5).

Fig. 7 is the powder X-ray diffraction pattern of the IX type crystal of the compound (1) of (embodiment 6).

Fig. 8 is the DSC&TGA modal data of the IX type crystal of the compound (1) of (embodiment 6).

Fig. 9 is the powder X-ray diffraction pattern of the X-type crystal of the compound (1) of (embodiment 7).

Figure 10 is the DSC&TGA modal data of the X-type crystal of the compound (1) of (embodiment 7).

Figure 11 is the powder X-ray diffraction pattern of the XI type crystal of the compound (1) of (embodiment 8).

Figure 12 is the DSC&TGA modal data of the XI type crystal of the compound (1) of (embodiment 8).

Figure 13 is the powder X-ray diffraction pattern of the XII type crystal of the compound (1) of (embodiment 9).

Figure 14 is the DSC&TGA modal data of the XII type crystal of the compound (1) of (embodiment 9).

Figure 15 is the powder X-ray diffraction pattern of the I type crystal of the compound (1) of (embodiment 10).

Figure 16 is the powder X-ray diffraction pattern of the VI type crystal of the compound (1) of (embodiment 11).

Specific embodiment

The present invention relates to 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea (compound (1)) VII type crystal, VIII type crystal, IX Type crystal, X-type crystal, XI type crystal and XII type crystal, the manufacturing method of the crystal and the pharmaceutical composition containing the crystal.

The present invention includes following manner [1] ~ [55].

Here, the crystal referred in mode [1] ~ mode [55] is known as " 1- of the invention sometimes in this specification ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- Base) -2- phenylpyridine -3- base) urea crystal ", " crystal of compound (1) " or " crystal of the invention ".

Sometimes crystal described in any one of mode [1] ~ mode [5] is known as " VII type crystal of the invention ".

Sometimes crystal described in any one of mode [6] ~ mode [10] is known as " VIII type crystal of the invention ".

Sometimes crystal described in any one of mode [11] ~ mode [15] is known as " IX type crystal of the invention ".

Sometimes crystal described in any one of mode [16] ~ mode [20] is known as " X-type crystal of the invention ".

Sometimes crystal described in any one of mode [21] ~ mode [25] is known as " XI type crystal of the invention ".

Sometimes crystal described in any one of mode [26] ~ mode [30] is known as " XII type crystal of the invention ".

[1] the 1st mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VII type crystal, as passing through powder X-ray The angle of diffraction (2 θ) that x ray diffraction obtains, at least 4.9 ± 0.2,5.4 ± 0.2,7.6 ± 0.2,8.0 ± 0.2,9.0 ± 0.2, There is characteristic peak at 10.3 ± 0.2,12.4 ± 0.2,14.7 ± 0.2,21.5 ± 0.2 and 23.7 ± 0.2 (°).

[2] the 2nd mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VII type crystal, by shown in Fig. 3 X-ray diffractogram of powder and characteristic feature, and in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction allow ± 0.2 Error.

[3] the 3rd mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VII type crystal, spread out in X-ray powder It hits, there is the angle of diffraction (2 θ) and relative intensity (%) shown in table 4.

[4] the 4th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VII type crystal, by shown in Fig. 4 Differential scanning calorimetric analysis (DSC) & thermogravimetric analysis (TGA) spectral characterization feature；Preferably foregoing manner [1] is to mode [3] In 1 mode or multiple modes described in VII type crystal, wherein pass through DSC&TGA spectral characterization feature shown in Fig. 4.

[5] the 5th mode of the invention is described in 1 mode or multiple modes of the foregoing manner [1] into mode [4] VII type crystal, which is characterized in that the extrapolated melting point initial temperature that differential scanning calorimetry measures (DSC measurement) is 146 DEG C.

[6] the 6th mode 1- of the invention ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) - The VIII crystal of 3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea, as passing through X-ray powder The angle of diffraction (2 θ) that diffraction obtains, at least 5.3 ± 0.2,6.9 ± 0.2,10.5 ± 0.2,13.9 ± 0.2,15.7 ± 0.2, There is characteristic peak at 17.0 ± 0.2,18.2 ± 0.2,18.8 ± 0.2,20.9 ± 0.2 and 21.4 ± 0.2 (°).

[7] the 7th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VIII crystal, by shown in Fig. 5 X-ray diffractogram of powder characteristic feature, and allow ± 0.2 in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction Error.

[8] the 8th mode 1- of the invention ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) - The VIII type crystal of 3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea, in powder x-ray diffraction In, there is the angle of diffraction (2 θ) and relative intensity (%) shown in table 5.

[9] the 9th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VIII type crystal, pass through Fig. 6 institute The DSC&TGA spectral characterization feature shown；Preferably described in 1 mode or multiple modes of the foregoing manner [6] into mode [8] VIII type crystal, wherein pass through DSC&TGA spectral characterization feature shown in fig. 6.

[10] the 10th mode of the invention is described in 1 mode or multiple modes of the foregoing manner [6] into mode [9] VIII type crystal, which is characterized in that the extrapolated melting point initial temperature that differential scanning calorimetry measures (DSC measurement) is 143 DEG C.

[11] the 11st mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea IX type crystal, as passing through powder X-ray The angle of diffraction (2 θ) that x ray diffraction obtains, at least 5.0 ± 0.2,6.8 ± 0.2,10.5 ± 0.2,14.9 ± 0.2,15.5 ± 0.2, there is at 17.5 ± 0.2,19.7 ± 0.2,20.4 ± 0.2,21.1 ± 0.2 and 24.4 ± 0.2 (°) characteristic peak.

[12] the 12nd mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea IX crystal, by shown in Fig. 7 X-ray diffractogram of powder characteristic feature, and allow ± 0.2 mistake in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction Difference.

[13] the 13rd mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea IX type crystal, spread out in X-ray powder It hits, there is the angle of diffraction (2 θ) and relative intensity (%) shown in table 6.

[14] the 14th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea IX type crystal, by shown in Fig. 8 DSC&TGA spectral characterization feature；Preferably described in 1 mode or multiple modes of the foregoing manner [11] into mode [13] IX type crystal, wherein pass through DSC&TGA spectral characterization feature shown in Fig. 8.

[15] the 15th mode of the invention is described in 1 mode or multiple modes of the foregoing manner [11] into mode [14] IX type crystal, which is characterized in that differential scanning calorimetry measure (DSC measurement) extrapolated melting point initial temperature be 127 DEG C.

[16] the 16th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea X-type crystal, penetrated as by powder X-ray The angle of diffraction (2 θ) that line diffraction obtains, at least 5.2 ± 0.2,6.9 ± 0.2,10.3 ± 0.2,13.6 ± 0.2,15.5 ± 0.2, There is characteristic peak at 18.0 ± 0.2,20.2 ± 0.2,20.7 ± 0.2,21.2 ± 0.2 and 29.0 ± 0.2 (°).

[17] the 17th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea X crystal, pass through powder shown in Fig. 9 Last X-ray diffractogram characteristic feature, and allow ± 0.2 error in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction.

[18] the 18th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea X-type crystal, in powder x-ray diffraction In, there is the angle of diffraction (2 θ) and relative intensity (%) shown in table 7.

[19] the 19th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea X-type crystal, by shown in Figure 10 DSC&TGA spectral characterization feature；Preferably described in 1 mode or multiple modes of the foregoing manner [16] into mode [18] X-type crystal, wherein pass through DSC&TGA spectral characterization feature shown in Fig. 10.

[20] the 20th mode of the invention is described in 1 mode or multiple modes of the foregoing manner [16] into mode [19] X-type crystal, which is characterized in that differential scanning calorimetry measure (DSC measurement) extrapolated melting point initial temperature be 141 DEG C.

[21] the 21st mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XI type crystal, as passing through powder X-ray The angle of diffraction (2 θ) that x ray diffraction obtains, at least 5.1 ± 0.2,6.8 ± 0.2,10.1 ± 0.2,10.5 ± 0.2,13.4 ± 0.2, there is at 15.1 ± 0.2,17.7 ± 0.2,19.8 ± 0.2,20.7 ± 0.2 and 22.7 ± 0.2 (°) characteristic peak.

[22] the 22nd mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XI crystal, by shown in Figure 11 X-ray diffractogram of powder characteristic feature, and allow ± 0.2 mistake in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction Difference.

[23] the 23rd mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XI type crystal, spread out in X-ray powder It hits, there is the angle of diffraction (2 θ) and relative intensity (%) shown in table 8.

[24] the 24th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XI type crystal, by shown in Figure 12 DSC&TGA spectral characterization feature；Preferably described in 1 mode or multiple modes of the foregoing manner [21] into mode [23] XI type crystal, wherein pass through DSC&TGA spectral characterization feature shown in Figure 12.

[25] the 25th mode of the invention is described in 1 mode or multiple modes of the foregoing manner [21] into mode [24] XI type crystal, which is characterized in that differential scanning calorimetry measure (DSC measurement) extrapolated melting point initial temperature be 126 DEG C.

[26] the 26th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XII type crystal, as passing through powder X-ray The angle of diffraction (2 θ) that x ray diffraction obtains, at least 4.9 ± 0.2,6.7 ± 0.2,9.9 ± 0.2,10.4 ± 0.2,13.1 ± 0.2, there is at 14.8 ± 0.2,15.4 ± 0.2,19.5 ± 0.2,20.3 ± 0.2 and 24.2 ± 0.2 (°) characteristic peak.

[27] the 27th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XII crystal, by shown in Figure 13 X-ray diffractogram of powder characteristic feature, and allow ± 0.2 in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction Error.

[28] the 28th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XII type crystal, spread out in X-ray powder It hits, there is the angle of diffraction (2 θ) and relative intensity (%) shown in table 9.

[29] the 29th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XII type crystal, pass through Figure 14 institute The DSC&TGA spectral characterization feature shown；Preferably described in 1 mode or multiple modes of the foregoing manner [21] into mode [23] XII type crystal, wherein pass through DSC&TGA spectral characterization feature shown in Figure 14.

[30] the 30th mode of the invention is described in 1 mode or multiple modes of the foregoing manner [26] into mode [29] XII type crystal, which is characterized in that differential scanning calorimetry measure (DSC measurement) extrapolated melting point initial temperature be 119 DEG C.

[31] the 31st mode of the invention is described in 1 mode or multiple modes of the foregoing manner [1] into mode [5] 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- Base) -2- phenylpyridine -3- base) urea VII type crystal manufacturing method, be 1 side of foregoing manner [1] into mode [5] The manufacturing method of VII type crystal described in formula or multiple modes, which comprises by 1- ((1R, 2R) -2- hydroxyl -4,4- bis- Methyl-1,2,3,4- naphthane -1- base) (the change of -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea Closing object (1)) raw material is suspended in the step in the acetonitrile as crystallization solvent；Acquired solution is stood at room temperature (such as 12 Hour ~ 7 days, preferably 1 ~ 4 day, more preferably 2 ~ 3 days, further preferably 3 days) the step of.

Compound (1) raw material used in crystallization in [31-1] foregoing manner [31] is preferably the V-type of compound (1) Crystal.

In manufacturing method described in [31-2] foregoing manner [31] or [31-1], it is preferred that be dissolved completely in acetonitrile Afterwards, by (1) slowly distillation removal solvent or (2) under cooling (such as in -20 DEG C of refrigerator) stand or (3) in second Ultrasound (such as 1 ~ 10 minute, preferably 3 ~ 7 minutes, more preferably ± 1 minute 5 minutes), keeps solid evenly dispersed and obtains in nitrile Made its precipitation for the oscillation of gained suspension stirring 7 ~ 14 days to suspension.

[32] the 32nd mode of the invention is described in 1 mode or multiple modes of the foregoing manner [6] into mode [10] 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine - 5- yl) -2- phenylpyridine -3- base) urea VIII type crystal manufacturing method, be foregoing manner [6] into mode [10] 1 The manufacturing method of VIII type crystal described in a mode or multiple modes, which comprises by 1- ((1R, 2R) -2- hydroxyl - 4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- Base) urea (compound (1)) raw material is suspended in the step in the methylene chloride as crystallization solvent；Gained mixed solution is being stirred Heating (boiling point of aforementioned solvents temperature below, such as 25 ~ 40 DEG C, preferably 27 ~ 35 DEG C, more preferably 30 DEG C while mixing ± 2 DEG C) thus the step of making it dissolve (such as 0.1 ~ 12 hour, preferably 20 minutes ~ 6 hours, more preferably 30 minutes ~ 60 Minute)；With, thereafter, by the solution of heated stirring such as -30 DEG C ~ room temperature, preferably -25 ~ -10 DEG C, more preferably -20 Cooling and standings (such as 1 ~ 8 hour, preferably 2 ~ 6 hours, more preferably 4 ~ 5 hours) are at DEG C ± 5 DEG C to obtain the step of crystal Suddenly.

Compound (1) raw material is preferably V-type crystal used in crystallization in [32-1] foregoing manner [32].

In manufacturing method described in [32-2] foregoing manner [32] or [32-1], it is preferred that be dissolved completely in dichloromethane After in alkane, by (1), slowly distillation removes solvent or (2) standing or (3) under cooling (such as in -20 DEG C of refrigerator) Ultrasound (such as 1 ~ 10 minute, preferably 3 ~ 7 minutes, more preferably ± 1 minute 5 minutes) in methylene chloride, keeps solid uniform Disperse to obtain suspension, by the oscillation of gained suspension stirring 7 ~ 14 days, makes its precipitation.

[33] the 33rd mode of the invention is described in 1 mode or multiple modes of the foregoing manner [11] into mode [15] 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine - 5- yl) -2- phenylpyridine -3- base) urea IX type crystal manufacturing method, be foregoing manner [11] into mode [15] 1 The manufacturing method of IX type crystal described in a mode or multiple modes, which comprises by 1- (hydroxyl -4 (1R, 2R) -2-, 4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) Urea (compound (1)) raw material is suspended in the step in the isopropyl acetate as crystallization solvent；Gained mixed solution is being stirred Heating (boiling point of aforementioned solvents temperature below, such as 30 ~ 89 DEG C, preferably 40 ~ 80 DEG C, more preferably 50 ~ 70 while mixing DEG C) thus the step of making it dissolve (such as 0.1 ~ 12 hour, preferably 20 minutes ~ 6 hours, more preferably 30 minutes ~ 60 points Clock)；With, thereafter, by the solution of heated stirring such as -30 DEG C ~ room temperature, preferably -25 ~ -10 DEG C, more preferably -20 DEG C Cooling and standings (such as 1 ~ 48 hour, preferably 2 ~ 24 hours, more preferably 5 ~ 18 hours) are at ± 5 DEG C to obtain the step of crystal Suddenly.

Compound (1) raw material is preferably V-type crystal used in crystallization in [33-1] foregoing manner [33].

In manufacturing method described in [33-2] foregoing manner [33] or [33-1], it is preferred that it is different to be dissolved completely in acetic acid After in propyl ester, by (1) slowly distillation removal solvent or (2) under cooling (such as in -20 DEG C of refrigerator) stand or (3) ultrasound (such as 1 ~ 10 minute, preferably 3 ~ 7 minutes, more preferably ± 1 minute 5 minutes) in isopropyl acetate, makes solid It is evenly dispersed and obtain suspension, by the oscillation of gained suspension stirring 7 ~ 14 days, make its precipitation.

[34] the 34th mode of the invention is described in 1 mode or multiple modes of the foregoing manner [16] into mode [20] 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine - 5- yl) -2- phenylpyridine -3- base) urea X-type crystal manufacturing method, be foregoing manner [16] 1 into mode [20] The manufacturing method of X-type crystal described in mode or multiple modes, which comprises by 1- ((1R, 2R) -2- hydroxyl -4,4- bis- Methyl-1,2,3,4- naphthane -1- base) (the change of -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea Closing object (1)) raw material is suspended in the step in the toluene as crystallization solvent；By any earthquake at room temperature of gained aaerosol solution Stirring (such as 1 ~ 30 day, preferably 3 ~ 20 days, more preferably 7 ~ 15 days, further preferably ± 1 day 14 days) while swinging Step.

Compound (1) raw material is preferably V-type crystal used in crystallization in [34-1] foregoing manner [34].

In manufacturing method described in [34-2] foregoing manner [34] or [34-1], it is preferred that be dissolved completely in toluene Afterwards, by (1) slowly distillation removal solvent or (2) under cooling (such as in -20 DEG C of refrigerator) stand or (3) in first Ultrasound (such as 1 ~ 10 minute, preferably 2 ~ 5 minutes, more preferably ± 1 minute 2 minutes), keeps solid evenly dispersed and obtains in benzene Made its precipitation for the oscillation of gained suspension stirring 7 ~ 14 days to suspension.

[35] the 35th mode of the invention is described in 1 mode or multiple modes of the foregoing manner [21] into mode [25] 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine - 5- yl) -2- phenylpyridine -3- base) urea XI type crystal manufacturing method, be foregoing manner [21] into mode [25] 1 The manufacturing method of XI type crystal described in a mode or multiple modes, which comprises by 1- (hydroxyl -4 (1R, 2R) -2-, 4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) Urea (compound (1)) raw material is suspended in the step in the methyl tertiary butyl ether(MTBE) (MTBE) as crystallization solvent；Gained is suspended Stirring while solution arbitrarily shakes at room temperature (such as 1 ~ 30 day, preferably 3 ~ 20 days, more preferably 7 ~ 15 days, into one Step preferably ± 1 day 14 days) the step of.

Compound (1) raw material is preferably V-type crystal used in crystallization in [35-1] foregoing manner [35].

In manufacturing method described in [35-2] foregoing manner [35] or [35-1], it is preferred that be dissolved completely in methyl- tert After in butyl ether (MTBE), by (1), slowly distillation removal solvent or (2) are under cooling (such as in -20 DEG C of refrigerator) quiet Set or (3) in methyl tertiary butyl ether(MTBE) (MTBE) ultrasound (such as 1 ~ 10 minute, preferably 2 ~ 5 minutes, more preferably 2 minutes ± 1 minute), keep solid evenly dispersed and obtain suspension, by the oscillation of gained suspension stirring 7 ~ 14 days, makes its precipitation.

[36] the 36th mode of the invention is described in 1 mode or multiple modes of the foregoing manner [26] into mode [30] 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine - 5- yl) -2- phenylpyridine -3- base) urea XII type crystal manufacturing method, be foregoing manner [26] into mode [30] 1 The manufacturing method of XII type crystal described in a mode or multiple modes, which comprises by 1- (hydroxyl -4 (1R, 2R) -2-, 4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) Urea (compound (1)) raw material is suspended in the step in the Di Iso Propyl Ether as crystallization solvent；By gained aaerosol solution in room While arbitrarily concussion under temperature stirring (such as 1 ~ 30 day, preferably 3 ~ 20 days, more preferably 7 ~ 15 days, further preferably ± 1 day 14 days) the step of.

Compound (1) raw material is preferably V-type crystal used in crystallization in [36-1] foregoing manner [36].

In manufacturing method described in [36-2] foregoing manner [36] or [36-1], it is preferred that be dissolved completely in diisopropyl After in base ether, by (1) slowly distillation removal solvent or (2) under cooling (such as in -20 DEG C of refrigerator) stand or (3) ultrasound (such as 1 ~ 10 minute, preferably 2 ~ 5 minutes, more preferably ± 1 minute 2 minutes) in Di Iso Propyl Ether, makes solid It is evenly dispersed and obtain suspension, by the oscillation of gained suspension stirring 7 ~ 14 days, make its precipitation.

[37] the 37th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea I type crystal manufacturing method, be The manufacturing method of the I type crystal of compound (1), which comprises by 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2, 3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea (compound (1)) Raw material is suspended in the step in the methanol as crystallization solvent；By the heating stirring (boiling of crystallization solvent of gained mixed solution Point temperature below, such as 30 ~ 64 DEG C, preferably 40 ~ 60 DEG C, more preferably 50 DEG C ± 5 DEG C, 0.1 ~ 24 hour, preferably 1 ~ 12 hours, more preferably ± 30 minutes 2 hours or so) the step of；With, stirred while arbitrarily concussion at room temperature (such as 12 hours ~ 15 days, preferably 1 ~ 10 day, more preferably 2 ~ 5 days, further preferably ± 1 day 3 days) the step of.

Compound (1) raw material is preferably V-type crystal used in crystallization in [37-1] foregoing manner [37].

In manufacturing method described in [37-2] foregoing manner [37] or [37-1], it is preferred that after being suspended in methanol, In It is stirred 1 ~ 3 hour at 40 ~ 60 DEG C, is stirred at room temperature thereafter 2 ~ 4 days, makes its precipitation.

[38] the 38th mode of the invention is 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VI type crystal manufacturing method, be The manufacturing method of the VI type crystal of compound (1), which comprises by 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1, 2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea (compound (1)) raw material is suspended in the step in the ethyl alcohol as crystallization solvent；Gained aaerosol solution is arbitrarily shaken at room temperature The step of stirring (such as 1 ~ 30 day, preferably 3 ~ 20 days, more preferably 7 ~ 15 days, further preferably ± 1 day 14 days) simultaneously.

Compound (1) raw material is preferably V-type crystal used in crystallization in [38-1] foregoing manner [38].

In manufacturing method described in [38-2] foregoing manner [38] or [38-1], it is preferred that after being suspended in ethyl alcohol, surpass Sound (such as 1 ~ 10 minute, preferably 2 ~ 5 minutes, more preferably ± 1 minute 2 minutes) is outstanding to this to keep solid evenly dispersed Floating solution, is stirred at room temperature 7 ~ 14 days using vibrating machine, makes its precipitation.

[39] the 39th mode of the invention is pharmaceutical composition, which is characterized in that contains foregoing manner [1] to mode [30] and crystal described in 1 mode or multiple modes of the mode [37] into mode [38] is as effective component.

[40] the 40th mode of the invention is pharmaceutical composition, is for treating selected from pain (Accompanying Deformation joint Inflammation, rheumatic arthritis, fracture, interstitial cystitis, chronic pancreatitis, prostatitic pain, chronic back pain, diabetic keratopathy Nociceptive pain representated by peripheral neuralgia, postoperative pain, pelycalgia, Cancerous pain etc., neurological pain, The pain such as Acute Pain, chronic ache or inflammatory pain), cancer, inflammation/diseases associated with inflammation, anaphylactia, skin disease, At least one of neurodegenerative disease, infectious disease, Sjogren syndrome, endometrium disease, nephrosis and osteoporosis etc. disease Drug contains for treating aforementioned diseases a effective amount of foregoing manner [1] to mode [30] and mode [37] to mode [38] crystal described in 1 mode or multiple modes in is as effective component.

In this specification, in case of no particular description, such " treatment " refers to healing, delays in " treatment disease " Solution or the progress or one or more " diseases " for inhibiting " disease ".

In this specification, " prevention " refers to the state according to patient, prevent " disease " morbidity or with " disease " phase The morbidity for any symptom closed.It further include the prevention of " disease " and the severe for mitigating " disease " or its any symptom before the onset Degree.

[41] the 41st mode of the invention is pharmaceutical composition, is for treating described in the 40th mode of the invention extremely A kind of pharmaceutical composition of few disease contains for inhibiting TrkA a effective amount of foregoing manner [1] to mode [30] and just Crystal described in 1 mode or multiple modes of the formula [37] into mode [38] is as effective component.

[42] the 42nd mode of the invention is pharmaceutical composition, contain as TrkA inhibitor foregoing manner [1] extremely Crystal described in 1 mode or multiple modes of mode [30] and mode [37] into mode [38] is as effective component.

[43] the 43rd mode of the invention is prevention and/or the therapeutic agent for the disease that TrkA is participated in, which is characterized in that is contained Crystal conduct described in foregoing manner [1] to 1 mode or multiple modes into mode [38] of mode [30] and mode [37] Effective component.

As " TrkA participate in disease ", it can be cited for example that pain (Accompanying Deformation arthritis, rheumatic arthritis, Fracture, interstitial cystitis, chronic pancreatitis, prostatitic pain, chronic back pain, diabetic peripheral pain, it is postoperative Nociceptive pain representated by pain, pelycalgia, Cancerous pain etc., neurological pain, Acute Pain, chronic pain Bitterly or the pain such as inflammatory pain), cancer, inflammation/diseases associated with inflammation, anaphylactia, skin disease, neurodegenerative disease, infection Disease, Sjogren syndrome, endometrium disease, nephrosis and osteoporosis etc., but it is not limited to these.

43-1 mode [43-1] of the invention is foregoing manner [1] to mode [30] and mode [37] to mode [38] In 1 mode or multiple modes described in crystal, be used to prevent and/or treat TrkA participation disease.

" pain " is the feature of many wounds and morbid state.Cause essence via disease or wound in bodily tissue Property damage when, nociceptor activation feature change, this leads to the allergy in damage location and similar normal tissue Property.As specific pain, osteo-arthritic pain, arthralgia, nerve can be enumerated because of property pain, postoperative pain, pain in the loins and sugar Urinate characteristic of disease neuropathy, pain in art, Cancerous pain, chemotherapy induction pain, headache (including cluster headache, tonicity head Bitterly, migraine), trigeminal neuralgia, herpes zoster pain, postherpetic neuralgia, carpal tunnel syndrome, inflammatory pain, be originated from The pain of rheumatic arthritis, the pain of interstitial cystitis, splanchnodynia, the pain from kidney stone, is originated from gallbladder knot at colitis Pain, sore-throat, fibromyalgia, chronic pain syndrome, thalamic pain syndrome, the pain from stroke, phantom limb of stone Bitterly, sunburn, nerve root injury, composite local pain syndrome, HIV sensibility neurological disorder, nervous centralis pain syndrome, multiple Property sclerosis pain, Parkinson's disease pain, Ji Marrow injury pain, physical pain, toothache, the pain from bone conversion, be originated from uterus The pain of inner membrance disease, the pain from fibroid, nociceptive pain, hyperalgia and side head lower jaw osteoarthrosis pain etc., But it is not limited to these.

" Acute Pain " according to the definition of International Society of Pain, due to the damage in disease, inflammation or tissue.This kind The pain of class in general, such as after wound or operation happens suddenly, may be with anxiety disorder or pressure, during being defined in centainly With severe degree.According to circumstances, Acute Pain may chronicity.

" chronic ache " is widely considered as indicating disease itself according to the definition of International Society of Pain.

Chronic ache is according to environment and psychology factor, it is possible to further deteriorate.Chronic ache passes through 3 in general A month or more, longer period is continuously passed through compared with Acute Pain, there are tolerances to almost all of medical treatment.It is chronic Pain causes critical problem for patients, therefore, can cause critical problem in most cases.In chronic ache, including Cancerous pain (pain generated as tumour), splanchnodynia (such as internal organ as caused by the transfer in cancer of pancreas and/or abdomen Bitterly), somatalgia is (such as by the conversion in osteocarcinoma, bone, postoperative pain, sarcoma, the cancer of connective tissue, the cancer of bone tissue, bone One or more among the cancer of the hematopoietic cell of Marrow, Duo hair Xing Gu Marrow tumor, leukaemia, primary or secondary bone cancer cause Somatalgia).

" inflammatory pain " refers to the pain generated by inflammation.Inflammatory pain in most cases, show as relative to Mechanical stimulus and increased sensitivity (mechanical hyperalgesia or tenderness).For example, inflammatory pain is by the shape in following State causes: scald, sunburn, arthritis, colitis, carditis, dermatitis, myositis, neuritis, catarrh, urethritis, bladder Inflammation, gastritis, pneumonia and collagen vascular disease etc..

" neurological pain " refers to by the pain of state or the situation generation of generation neurotrosis." neurological disorder " is Refer to the course of disease for generating the damage in nerve." cusalgia " is the state of the chronic ache after injury of digital nerve." paralgesia " refers to There is the state for reacting to make one to feel pain to usually painless stimulation, such as gentle touchdown.

" neurological pain " is by for example selected from cusalgia, diabetes, collagen vascular disease, trigeminal neuralgia, Ji Marrow damage Wound, brain-stem injury, thalamic pain syndrome, complex regional pain syndrome i type/reflex sympathetic malnutrition, method Syndrome, small fiber nerve disease, cancer, cancer chemotherapy, chronic alcoholism, cerebral apoplexy, abscess, Tuo Marrow disease, virus in cloth Caused by state in infection, antiviral therapy, AIDS and AIDS therapy etc..

" neurological pain " is by the effect for example in wound, operation, amputation, toxin and chemotherapy etc. Caused by factor.

" nociceptive pain " is induced by being possible to cause the intense stimulus of tissue damage or damage.The pain sensation to Disposition nerve fibre is activated because of the conduction of the stimulation carried out by the nociceptor at damage location, in its extreme positions Shi Ji Marrow is sensitization plays.Its brain for being then conveyed to perception pain upwards along medullary pathways.It, will in the activation of nociceptor The centrality nerve fibre of 2 seed types activates.The A- δ fiber of You Marrow conducts rapidly, undertakes sensation of pain as sharp shouting pain, The fiber C of another aspect , Wu Marrow are conducted with slower speed, convey pain as dull pain.In the isocratic acute wound to severe Evil sensitivity pain is the pain as caused by contusion/strain, postoperative pain (pain of any type of surgical site infections), wound Afterwards pain, burn, the obvious characteristic of myocardial infarction, acute pancreatitis and renal colic, but be not limited to these.In general, cancer Disease Associated Acute pain syndrome is also treated due to chemotherapy toxicity, immunotherapy, hormonotherapy and radiotherapy etc. On interaction.

In the isocratic acute nociception pain to severe be Cancerous pain (such as ostalgia, headache and face pain, it is interior Dirty pain) or with cancer therapy symptom (such as after chemotherapy after syndrome, chronic post-surgical pain syndrome, irradiation it is comprehensive Sign) in be likely to occur Cancerous pain, close sometimes due to abjection property or breaking property interverbebral disc or lumbar zygapophyseal joint, celestial intestines The obvious characteristic of the abnormal back pain of muscle or posterior longitudinal ligament by section, backbone, but it is not limited to these.

Physiology for " cancer " refers to or indicate typical in mammal characterized by unordered cell Proliferation State.As the concrete example of " cancer ", neuroblastoma, oophoroma, carcinoma of uterine body, glioblastoma multiforme cell can be enumerated Tumor, cervix cancer, cancer of pancreas, colon and rectum carcinoma, prostate cancer, melanoma, Gu Marrow tumor, thyroid cancer, lung cancer (cellule Lung cancer, non-small cell lung cancer), brain tumor, cancer of the esophagus, kidney, osteoma and leukemia it is (Man Gu Marrow leukaemia, acute thin at lymph Born of the same parents' property leukaemia, Philadelphia Chromosome Positive acute lymphoblastic leukemia (Ph+ALL), Ji Gu Marrow leukaemia (AML) and chronic lymphatic leukemia (CML)), dermoid cancer, glioma, human primary gastrointestinal cancers, oophoroma, liver cancer, Gastric cancer, bladder cancer, hepatoma, breast cancer, head-neck carcinoma, germinoma, pediatric sarcomas, paranasal sinus natural killer cells, Duo hair Xing Gu Marrow tumor etc., but it is not limited to these.

As the concrete example of " inflammation/diseases associated with inflammation ", it is comprehensive that interstitial cystitis (IC), bladder pain can be enumerated Levy (PBS), the urinary incontinence, inflammatory cystitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatism joint Inflammation, arthroncus, asthma, atopical dermatitis, psoriasis, psoriasis arthropathica and systemic loupus erythematosus etc., but it is unlimited Due to these.

As the concrete example of " anaphylactia ", asthma, atopical dermatitis and rhinitis etc. can be enumerated, but is not limited In these.

As the concrete example of " skin disease ", pruritus (including systemic cutaneous pruritus, limitation skin scabies can be enumerated Itch disease and Diffuse Cutaneous pruritus) etc., but it is not limited to these.

As the concrete example of " nephrosis ", nephrosis, renal fibrosis disease and chronic kidney disease etc. can be enumerated, but It is not limited to these.

As the concrete example of " certain specific infectious diseases ", Trypanosoma cruzi infection disease etc. can be enumerated, but be not limited to these.

As the concrete example of " neurodegenerative disease ", multiple sclerosis, Parkinson's disease and stages alzheimer's disease can be enumerated Deng, but it is not limited to these.

[44] the 44th mode of the invention is the therapeutic agent for the disease that TrkA is participated in, which is characterized in that contains foregoing manner [1] crystal described in 1 mode to mode [30] and mode [37] into mode [38] is as effective component.

[45] the 45th mode of the invention is that pain is (Accompanying Deformation arthritis, rheumatic arthritis, fracture, chromic fibrous Cystitis, chronic pancreatitis, prostatitic pain, chronic back pain, diabetic peripheral pain, postoperative pain, pelycalgia, Nociceptive pain representated by Cancerous pain etc., neurological pain, Acute Pain, chronic ache or inflammatory The pain such as pain), cancer, inflammation/diseases associated with inflammation, anaphylactia, skin disease, neurodegenerative disease, infectious disease, dry synthesis Preventions and/or the therapeutic agents such as sign, endometrium disease, nephrosis and osteoporosis, which is characterized in that extremely containing foregoing manner [1] Crystal described in 1 mode of mode [30] and mode [37] into mode [38] is as effective component.

Preferably pain (Accompanying Deformation arthritis, rheumatic arthritis, fracture, interstitial cystitis, chronic pancreas The institutes such as scorching, prostatitic pain, chronic back pain, diabetic peripheral pain, postoperative pain, pelycalgia, Cancerous pain The pain such as nociceptive pain, neurological pain, Acute Pain, chronic ache or the inflammatory pain of representative) it is pre- Anti- and/or therapeutic agent, which is characterized in that containing foregoing manner [1] to mode [30] and mode [37] into mode [38] 1 Crystal described in a mode is as effective component.

45-1 mode [45-1] of the invention is foregoing manner [1] to mode [30] and mode [37] to mode [38] In 1 mode described in crystal, be used to prevent and/or treat pain (Accompanying Deformation arthritis, rheumatic arthritis, Fracture, interstitial cystitis, chronic pancreatitis, prostatitic pain, chronic back pain, diabetic peripheral pain, it is postoperative Nociceptive pain representated by pain, pelycalgia, Cancerous pain etc., neurological pain, Acute Pain, chronic pain Bitterly or the pain such as inflammatory pain), cancer, inflammation/diseases associated with inflammation, anaphylactia, skin disease, neurodegenerative disease, infection Disease, Sjogren syndrome, endometrium disease, nephrosis and osteoporosis etc..

Preferably crystalline substance described in foregoing manner [1] to 1 mode into mode [38] of mode [30] and mode [37] It is (Accompanying Deformation arthritis, rheumatic arthritis, fracture, interstitial cystitis, slow to be used to prevent and/or treat pain for body Property pancreatitis, prostatitic pain, chronic back pain, diabetic peripheral pain, postoperative pain, pelycalgia, cancer pain The pains such as nociceptive pain, neurological pain, Acute Pain, chronic ache or inflammatory pain representated by pain etc. Bitterly).

[46] the 46th mode of the invention is selected from least one of disease described in the 42nd mode of the invention disease Therapeutic agent, crystalline substance described in 1 mode containing foregoing manner [1] to mode [30] and mode [37] into mode [38] Body is as effective component.

In [46-1] foregoing manner [48], the preferably therapeutic agent of the disease of pain contains foregoing manner [1] to mode [30] and crystal described in 1 mode of the mode [37] into mode [38] is as effective component.

[47] the 47th mode of the invention is TrkA inhibitor, and it includes foregoing manners [1] to mode [30] and mode [37] it one or more of crystal described in 1 mode into mode [38] or is made of it.

47-1 mode [47-1] of the invention is foregoing manner [1] to mode [30] and mode [37] to mode [38] In 1 mode described in crystal, be used to inhibit TrkA.

[48] the 48th mode of the invention be foregoing manner [1] to mode [30] and mode [37] into mode [38] 1 Purposes of at least one of the crystal described in a mode as pharmaceutical composition.

48-1 mode [48-1] of the invention is foregoing manner [1] to mode [30] and mode [37] to mode [38] In 1 mode described in crystal be used to manufacture the purposes of pharmaceutical composition.

[49] the 49th mode of the invention be foregoing manner [1] to mode [30] and mode [37] into mode [38] 1 At least one of crystal described in a mode is as the purposes for inhibiting TrkA.

49-1 mode [49-1] of the invention is foregoing manner [1] to mode [30] and mode [37] to mode [38] In 1 mode described in crystal be used to manufacture the purposes of TrkA inhibitor.

[50] the 50th mode of the invention be foregoing manner [1] to mode [30] and mode [37] into mode [38] 1 Purposes of the crystal described in a mode in the manufacture of pharmaceutical composition.

[51] the 51st mode of the invention be foregoing manner [1] to mode [30] and mode [37] into mode [38] 1 Purposes of the crystal described in a mode in the manufacture of TrkA inhibitor.

[52] the 52nd mode of the invention is method, is treatment selected from pain (Accompanying Deformation arthritis, rheumatic pass Save inflammation, fracture, interstitial cystitis, chronic pancreatitis, prostatitic pain, chronic back pain, diabetic peripheral bitterly, It is nociceptive pain representated by postoperative pain, pelycalgia, Cancerous pain etc., neurological pain, Acute Pain, slow Property pain or inflammatory pain etc. pain), cancer, inflammation/diseases associated with inflammation, anaphylactia, skin disease, neurodegenerative disease, Infectious disease, Sjogren syndrome, endometrium disease, nephrosis and the disease in osteoporosis method comprising: by foregoing manner [1] at least one of crystal described in 1 mode to mode [30] and mode [37] into mode [38] is to needing to treat The object of aforementioned diseases is administered.

Preferably method, for treatment pain (Accompanying Deformation arthritis, rheumatic arthritis, fracture, chromic fibrous bladder Inflammation, chronic pancreatitis, prostatitic pain, chronic back pain, diabetic peripheral pain, postoperative pain, pelycalgia, cancer Nociceptive pain, neurological pain, Acute Pain, chronic ache or inflammatory pain representated by property pain etc. Etc. pain) method comprising: by 1 mode of foregoing manner [1] to mode [30] and mode [37] into mode [38] The object for needing to treat aforementioned diseases is administered at least one of described crystal；More preferably treat pain (Accompanying Deformation Property arthritis, rheumatic arthritis, fracture, interstitial cystitis, chronic pancreatitis, prostatitic pain, chronic back pain, sugar Urinate nociceptive pain, neurological disorder representated by characteristic of disease peripheral neuralgia, postoperative pain, pelycalgia, Cancerous pain etc. The pain such as property pain, Acute Pain, chronic ache or inflammatory pain) method.

Here, " object " refers to other than people, it further include that dog, cat, rat, mouse, monkey, ox, horse, pig, sheep etc. are inhuman Mammal.

In this specification, in case of no particular description, in " treatment of disease " such " treatment " refer to healing, Alleviate or inhibit the progress or one or more " diseases " of " disease ".

[53] the 53rd mode of the invention is method, is treated in disease described in the 40th mode of the invention The method of at least one disease comprising: will for treating aforementioned diseases a effective amount of foregoing manner [1] to mode [30], The object for needing to treat aforementioned diseases is administered with crystal described in 1 mode of the mode [37] into mode [38].

[54] the 54th mode of the invention is method, is treated in disease described in the 40th mode of the invention The method of at least one disease comprising: will for inhibiting TrkA a effective amount of foregoing manner [1] to mode [30] and side The object for needing to treat aforementioned diseases is administered in crystal described in 1 mode of the formula [37] into mode [38].

[55] the 55th mode of the invention is side described in prevention and/or therapeutic agent described in mode [43] or mode [52] Method, wherein aforementioned diseases are selected from osteo-arthritic pain, arthralgia, nerve because of property pain, postoperative pain, pain in the loins and diabetic keratopathy Pain in neuropathy, art, Cancerous pain, chemotherapy induction pain, headache (including cluster headache, tension headache, inclined head Bitterly), trigeminal neuralgia, herpes zoster pain, postherpetic neuralgia, carpal tunnel syndrome, inflammatory pain, be originated from rheumatic close Save scorching pain, colitis, the pain of interstitial cystitis, splanchnodynia, the pain from kidney stone, the pain from gall stone Bitterly, sore-throat, fibromyalgia, chronic pain syndrome, thalamic pain syndrome, the pain from stroke, phantom limb pain, solarization It is wound, nerve root injury, composite local pain syndrome, HIV sensibility neurological disorder, nervous centralis pain syndrome, multiple hard Change disease pain, Parkinson's disease pain, Ji Marrow injury pain, physical pain, toothache, the pain from bone conversion, be originated from endometrium The pain of disease, the pain from fibroid, nociceptive pain, hyperalgia, side head lower jaw osteoarthrosis pain, at neural thin Born of the same parents' tumor, oophoroma, carcinoma of uterine body, glioblastoma multiforme, cervix cancer, cancer of pancreas, colon and rectum carcinoma, prostate Cancer, melanoma, Gu Marrow tumor, thyroid cancer, lung cancer (Small Cell Lung Cancer, non-small cell lung cancer), brain tumor, cancer of the esophagus, kidney, osteoma With leukemia (Man Gu Marrow leukaemia, acute lymphoblastic leukemia, Philadelphia Chromosome Positive Acute Lymphoblastic Leukaemia (Ph+ALL), Ji Gu Marrow leukaemia (AML) and chronic lymphatic leukemia (CML)), dermoid cancer, Glioma, human primary gastrointestinal cancers, oophoroma, liver cancer, gastric cancer, bladder cancer, hepatoma, breast cancer, head-neck carcinoma, reproduction cell are swollen Tumor, pediatric sarcomas, paranasal sinus natural killer cells, Duo hair Xing Gu Marrow tumor, interstitial cystitis (IC), bladder pain syndrome (PBS), the urinary incontinence, inflammatory cystitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic red yabbi It is sore, rheumatic arthritis, arthroncus, asthma, atopical dermatitis, psoriasis, psoriasis arthropathica, rhinitis, systemic Cutaneous pruritus, limitation cutaneous pruritus, Diffuse Cutaneous pruritus, multiple sclerosis, Parkinson's disease and alzheimer Disease, Trypanosoma cruzi infection disease, Sjogren syndrome, endometrium disease, nephrosis, renal fibrosis disease and chronic kidney disease and bone Matter osteoporosis.

Crystal described in mode [1] of the present invention to 1 mode into mode [38] of mode [30] and mode [37] TrkA inhibiting effect can by proper choice of method, for example (source of people TrkA is combined to be inhibited to make aftermentioned pharmacological experimental example 1 With) measure.

Crystal described in mode [1] of the present invention to 1 mode into mode [38] of mode [30] and mode [37] is in medicine It manages in experimental example 1 (people's TrkA combination inhibiting effect), there is excellent TrkA inhibitory activity.

Hereinafter, the present invention will be described in detail.

1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first in the present invention Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea crystal in, any crystal form may each be deuterated body.

Analysis method in this specification, as gained crystal, it is however generally that carry out crystal analysis by X-ray diffraction Method.Further, as the method for determining crystal orientation, mechanical means or optical means (such as FT- Raman can also be enumerated Spectrum, Solid NMR Spectroscopy) etc..In addition, heat analysis (differential scanning calorimetry measurement, the Differential Scanning of crystal Calorimetry (DSC)), infrared absorption spectrum (IR) analysis (KBr method, solwution method) etc. can also measure according to usual way.

The peak of the spectrum obtained by above-mentioned analysis method necessarily leads to certain evaluated error at it in nature.The peak of spectrum Numerical value also includes the error range in crystal of the invention.

For example, the various sample of specific crystal form shares the angle of diffraction (2 θ) phase in the angle of diffraction (2 θ) of powder x-ray diffraction Same main peaks, but about secondary peaks, difference may be generated in powder X-ray diffraction pattern.The diffraction of powder x-ray diffraction In angle (2 θ), the error of " ± 0.2 " or " ± 0.1 " is meant to be admissible.In general, spreading out in powder x-ray diffraction In firing angle degree (2 θ), error may be generated in the range of ± 0.2 °.Therefore, in the present invention, claim " (about) angle of diffraction (2 θ) X ° " when, in addition to the specific record the case where other than, refer to " angle of diffraction (2 θ) ((X-0.2) ~ (X+0.2)) ° ".In the present invention, no The only crystal completely the same including the angle of diffraction in powder x-ray diffraction further includes the error for being ± 0.2 ° in angle of diffraction Consistent crystal in range.

In the angle of diffraction (2 θ) of powder x-ray diffraction in this specification, " characteristic peak " refers to be arranged in such as 2 ~ table of table 10 The peak (error for allowing ± 0.2) of maximum absorption is shown at the angle of diffraction (2 θ) of act value.In addition, for relative to X-ray powder The relative intensity (%) of each angle of diffraction (2 θ) of diffraction, the intensity of the X-ray at each peak sometimes according to crystal size and Orientation and become Change, does not observe sometimes, it is thus possible to be changed according to determination condition.

In this specification, the phenomenon that crystal structure changes when crystalline transformation refers to more than a certain temperature or pressure.

As " crystalline transformation method ", method commonly known per se can be enumerated, such as crystallized from solution (such as be concentrated Method, slow cooling method, reaction method (diffusion method, electrolysis method), hydrothermal growth process, melting agent method etc.), (example is crystallized from steam Such as evaporating method (sealed-tube method, air-flow method), gas-phase reaction method, chemical delivery method), crystallization (such as the normal freezing from molten mass Method (czochralski method, temperature gradient method, Bridgman method), zone melting method (zone-leveled method, float-zone method), special growth method (VLS Method, liquid phase epitaxial process)), evaporation (after crystal is dissolved in solvent and is filtered, in atmospheric conditions evaporate solvent side Method), slurry method (adds crystal into solvent in a manner of remaining excess solids and is made suspension, in atmospheric temperature or add After heat or cooling lower stirring, method that solid is collected by filtration), be dried under reduced pressure, grind, crushing, pressurizeing.

Crystal, particularly VII type crystal, VIII type crystal, IX type crystal, the X-type of compound (1) in the present invention are brilliant The chemical purity of body, XI type crystal or XII type crystal is, for example, about 95% ~ 100%, is preferably from about 97% ~ 100%, is further preferred It is about 99% ~ 100%.

[1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- first Yl pyrimidines -5- base) -2- phenylpyridine -3- base) urea (compound (1)) manufacturing method]

Compound (1) can be manufactured by the method for the embodiment of the present application 1.Herein so-called compound (1) refer to no matter crystal form How and with following structural formula (1) compound.

The structural formula of compound (1) is as follows.

。

[manufacturing method of each crystal of compound (1)]

I type crystal, type III crystal, V-type crystal, VII type crystal, VIII type crystal, IX type crystal, the X-type of compound (1) are brilliant Above-mentioned well known " crystalline transformation method " can be used to manufacture in body, XI type crystal and XII type crystal, but in order to which each crystal shape is made State, it is important that selective freezing solvent.Specifically, it is preferable that the following such solvents of selection.

Table A

[agent is applied in combination with what crystal of the invention or its pharmaceutical composition were applied in combination]

Crystal of the invention or its pharmaceutical composition can also by the conventional method and other drugs that are carried out at medical scene or Person's pharmaceutical agent combinations use.As the drug that can cooperate or be applied in combination with crystal of the invention, it can be cited for example that (A) pain Medicine, (B) are easy medicine of disease of concurrent pain etc..

Therefore, another way according to the present invention, provides pharmaceutical composition, contains: the crystal of compound (1) and (A) therapeutic agent for pain or (B) are easy in the other drugs such as preventive medicine and/or the medicine of the disease of concurrent pain or medicament 1 kind or more.

According to the present invention and another way, provides pharmaceutical composition, contains and holds with (A) therapeutic agent for pain or (B) Shown in the above-mentioned formula (1) that other drugs or the pharmaceutical agent combinations such as the preventive medicine and/or medicine of the disease of easily concurrent pain use At least one of its admissible salt or its solvate are used as effective component on compound or pharmaceutics.

As the drug of aforementioned (A), it may be exemplified out such as following substances.

(A1) Opioid receptor agonist；(A2) woods system analgesic-antipyretic；(A3) non-woods system analgesic-antipyretic；(A4) non- Steroidal sex anti-inflammatory agent (NSAIDs)；(A5) COX-2 selective depression medicine；(A6) peripheral neurological pain fiber Myalgia pain disease medicine；(A7) inhibition of decline property pain is medicine；

In addition, being also diverted to following drugs of nerve prescription due to property pain:

(A8) antiepileptic；(A9) antidepressants；(A10) antiarrhythmics；(A11) nmda receptor antagonistic；(A12) double phosphines Hydrochlorate；(A13) vanilloid receptor excitomotor；(A14) modulators of ion channels；(A15) fatty acid amide hydrolase (FAAH) Inhibitory activity compound；(A16) barbiturate sedative；(A17) has contrastimulant benzene phenodiazine；(A18) H1 antagonism Medicine；(A19) 5-HT receptor agonism medicine or antagonistic；(A20) 1 type Microsomal prostaglandin E synzyme (mPGES-1) depressant； (A21) leukotriene B4 antagonistic；(A22) α 2- 2-delta ligand；(A23) Metabolism regulation type glutamic acid hypotype 1 receptor (mGluR1) antagonism Medicine；(A24) prostaglandin E2 hypotype 4 (EP4) antagonistic.

In addition, the drug as aforementioned (B), may be exemplified out such as following substances.

(B1) medicine for treating diabetes ((i) PPAR γ make medication (excitomotor, depressant), (ii) insulin secretion promote medicine, (iii) intermediate acting insulins useful secernent, (iv) α glucosidase inhibitor, (v) insulin resistance improve medicine [it is specific and Speech (a) PPAR γ makees medication, (b) PTP-1B depressant, (c) DPP-4 depressant, (d) GLP-1 and GLP-1 excitomotor, (e) 11 β-HSD depressant etc., (f) GPR40 excitomotor, (g) GPR119 excitomotor, (h) GPR120 excitomotor], (vi) hepatic glycogen regeneration Inhibitor, the agent of (vii) biguanides,

(viii) insulin or insulin derivates, 2 antagonistic of (ix) α, (x) SGLT2 inhibitor；

(B2) antiadipositas drug ((i) β3-adrenoceptors excitomotor, (ii) CB-1 receptor antagonist, (iii) neuropeptide tyrosine (NPY) Receptor antagonist,

(iv) depressant, (v) lipase inhibitors, (vi) Peptide YY (PYY) receptor antagonist etc. are fed)；

(B3) cholesterol reduce the hyperlipidemias medicine such as medicine ((i) omega-3 fatty acid class, (ii) HMG-CoA reductase inhibitor, (iii) HMG-CoA synthetase inhibitors, (iv) cholesterol absorption inhibitor, (v) acyl group-CoA cholesterol acyltransferase (ACAT) inhibitor, (vi) CETP inhibitor, (vii) inhibitor for squalene synthetic enzyme, (viii) antioxidant, (ix) PPAR α Excitomotor, (x) PPAR δ excitomotor, (xi) LXR excitomotor, (xii) FXR excitomotor, (xiii) MTTP inhibitor,

(xiv) squalene epoxidase inhibitor etc.)；

(B4) depressor ((i) diuretics, (ii) calcium receptor antagonist, (iii) angiotensin converting enzyme inhibitor (ACEI), (iv) angiotensin receptor antagonist (ARB), (v) direct renin inhibitor, (vi) alpha receptor blocking medicine, (vii) beta receptor Blocking agent,

(viii)α₁β blocking agent)；

(B5) improve state of an illness antirheumatic drug (DMARDs)；

(B6) antibacterial agent medicine；(B7) sex hormone or derivatives thereof；(B8) parathormone (PTH)；(B9)GABA_BReceptor swashs Dynamic medicine；(B10) alclometasone diproionate；(B11) α adrenaline makees medication；(B12) 2 adrenergic receptor agonists of α；

(B13) sedative；(B14) skeletal muscle relaxant；(B15) antispasmodic；(B16) tachykinin (NK) antagonistic (NK-3, NK-2 or NK-1 antagonistic)；(B17) muscarinic antagonistic；(B18) coal tar (coal tar) antalgesic；(B19) nerve resistance Off-drug；

(B20) T2A receptor antagonist；(B21) 5-HT3 antagonistic；(B22) choline functionality (nicotine) antalgesic；(B23) PDEV depressant；(B24) nitric oxide synthetase (iNOS) depressant；(B25) acetyl cholinesterase enzyme inhibitor；(B26)5- Lipoxygenase depressant；(B27) anti-TNF treatment；(B28) metabolic antagonist and antifol；

(B29) targetingization kinase inhibitor；

(B30) Anticonvulsants；(B31) calcitonin gene related peptide receptor (CGRP) antagonistic；(B32) tyrosine kinase targets Change medicine；(B33) Ras-Raf-MEK-ERK pathway inhibitor；(B34) PI3K-Akt-mTOR-S6K pathway inhibitor；

(B34) apoptosis regulating factors and signal transduction pathway inhibitor；(B35) cell disorders chemotherapeutic agent；

(B36) angiogenesis targeted chemotherapy method medicine；(B37) targeting medicament is immunized；(B38) NGF targets metaplasia object pharmaceuticals； (B39) has activity to TrkA access other than the compound of formula (1) of the invention including broad sense Trk inhibitor Medicament.

To aforementioned diseases, by by existing medicine group as the crystal of the compound of the present invention (1) and above-mentioned (A) and (B) It closes and uses, can reduce the dosage of existing medicine, can reduce the side effect of existing medicine.Certainly, made using the combination of the drug The drug for being not limited to aforementioned diseases with method, and being applied in combination is not limited to the compound of aforementioned illustration.

Medicine group will be applied in combination as the crystal of the compound of the present invention (1) and above-mentioned (A) and (B) that is applied in combination It closes in use, can be the preparation (or comprising respective kit) of difference, is also possible to mixture.In addition, in preparation respectively Both in, can take simultaneously, it can also be administered with staggering time.

The crystal of the compound of the present invention (1) can by it is single or multiple administration any one of, be administered alone or with Pharmaceutically admissible carrier combination medicine-feeding.In pharmaceutical carrier appropriate, including not active solid diluent or filler, sterilizing Aqueous solution and various organic solvents.The pharmaceutical composition being consequently formed then can be easily with tablet, pulvis, pastille, liquid The diversified administration form administration such as modulator, syrup, injection.These pharmaceutical compositions can according to circumstances contain perfume Taste agent, bonding agent, excipient etc. add ingredient.Therefore, the crystal of the compound of the present invention (1) can be suitable for passing through through Mouth, oral cavity, nasal cavity, non-oral (such as intravenous, intramuscular or subcutaneous), percutaneous (such as patch) or rectally use, Or using the administration form suck or injected (insufflations) and be administered come formulation.

[compounding agent/combination agent administration form is applied in combination]

The crystal of the compound of the present invention (1) and above-mentioned (A) and (B) such administration form that drug is applied in combination be not special It limits, as long as pharmaceutical composition is applied in combination with this in the crystal of the compound of the present invention (1) in administration.As such Form is administered, can be used for example:

(1) by the compound of the present invention (1) crystal and be applied in combination drug it is formulation simultaneously obtained from single formulation into Row administration；

(2) by the compound of the present invention (1) crystal be applied in combination drug difference it is formulation obtained from 2 kinds of preparations with phase It is administered simultaneously with administration access；

(3) by the compound of the present invention (1) crystal be applied in combination drug difference it is formulation obtained from 2 kinds of preparations with phase The time is separated with administration access to be poorly administered；

(4) by the compound of the present invention (1) crystal and be applied in combination drug difference it is formulation obtained from 2 kinds of preparations with not It is administered simultaneously with administration access；

(5) by the compound of the present invention (1) crystal and be applied in combination drug difference it is formulation obtained from 2 kinds of preparations with not With administration access be separated with the time be poorly administered (such as by the compound of the present invention (1) crystal → drug is applied in combination Sequence is administered or is administered in the opposite order) etc..Hereinafter, these administration forms are totally referred to as of the invention Agent is applied in combination.

It is administered of the invention when agent is applied in combination, be applied in combination as above-mentioned (A) and (B) being administered in the phase same time The compound of the present invention can also be administered after drug is applied in combination in administration in the crystal of drug and the compound of the present invention (1) (1) crystal can also be administered after the crystal of administration the compound of the present invention (1) and drug is applied in combination.It is separated with the time difference When ground is administered, time difference difference according to given the effective elements of the medicine, dosage form and medication, for example, first administration combination When using drug, it can enumerate after drug is applied in combination in administration within 1 minute ~ 3 days, preferably within 10 minutes ~ 1 day, more The method of the crystal of the compound of the present invention (1) is administered within preferably 15 minutes ~ 1 hour.The compound of the present invention is first administered (1) it when crystal, can enumerate after the crystal of administration the compound of the present invention (1) within 1 minute ~ 1 day, preferably 10 minutes Within ~ 6 hours, the method that drug is applied in combination more preferably is administered within 15 minutes ~ 1 hour.

As long as the dosage side effect that drug is applied in combination does not become problem, any amount can also be set, it can be to face The dosage used on bed is suitably selected as benchmark.In addition, the crystal of the compounds of this invention (1) and the cooperation that drug is applied in combination Than can suitably be selected according to administration object, administration access, object disease, symptom, combination etc..The compound of the present invention (1) Crystal and pharmaceutical composition is applied in combination in use, the amount of mutual medicament is considered that the opposite effect of these medicaments and It is reduced in the range of safety.

For example, relative to 1 mass parts of crystal of the compounds of this invention (1), using 0.01 ~ 100 matter when administration object is people Drug is applied in combination in amount part, preferably 0.1 ~ 90 mass parts, more preferably 1 ~ 80 mass parts.

The toxicity that agent is applied in combination of the invention is low, for example, can by the compound of the present invention (1) or (and) said combination It mixes that pharmaceutical composition, such as tablet is made with pharmacologically admissible carrier according to known methods using drug (including sugar coated tablet, film coating piece), powder, granule, capsule (including soft capsule), liquor, injection, suppository, sustained release agent Deng they can be safely administered in a manner of oral or para-oral (such as local, rectum, vein etc.).

The pharmacologically admissible carrier that can be used in the manufacture of agent is applied in combination as of the invention, can be used Substance identical with substance used in the pharmaceutical composition of aforementioned present invention.

The crystal of the compound of the present invention (1) being applied in combination in agent of the invention and the match ratio that drug is applied in combination can Suitably to be selected according to administration object, administration access, disease etc..

Two or more can be applied in combination using drug in said combination in the proper ratio.

Be applied in combination drug dosage can the dosage clinically to use suitably selected as benchmark.In addition, this hair The crystal of bright compound (1) be applied in combination drug match ratio can according to administration object, administration access, object disease, Symptom, combination etc. and suitably select.For example, when administration object is people, 1 mass of crystal relative to the compound of the present invention (1) Part, drug is applied in combination using 0.01 ~ 100 mass parts.

For example, the content of the crystal of the compound of the present invention (1) being applied in combination in agent of the invention according to preparation to Medicine form and it is different, be generally the range of about 0.01 ~ 99.9 mass % relative to usual preparation, be preferably from about 0.1 ~ 50 mass % The range of range, more preferably about 0.5 ~ 20 mass % or so.It should be noted that the upper limit value and lower limit of these numberical ranges Value can in any combination respective value and form numberical range.

The content that drug is applied in combination being applied in combination in agent of the invention is different according to the administration form of preparation, usually Relative to preparation be generally about 0.01 ~ 99.9 mass % range, be preferably from about 0.1 ~ about 50 mass % range, further preferably It is the range of about 0.5 ~ about 20 mass %.It should be noted that the upper limit value and lower limit value of these numberical ranges can in any combination respectively Value and form numberical range.

The content of the additives such as the carrier being applied in combination in agent of the invention is different according to the administration form of preparation, usually The range of about 1 ~ 99.99 mass % is generally relative to preparation, is preferably from about the range of 10 ~ about 90 mass %.It should be noted that these The upper limit value and lower limit value of numberical range can in any combination respective value and form numberical range.

By the crystal of the compound of the present invention (1) and be applied in combination drug it is respectively formulation when, or it is identical Content.

As described above, dosage changes under various conditions, therefore sometimes with the amount less than above-mentioned dosage with regard to abundant, In addition, also sometimes for overruning being administered.

[pharmaceutical composition of crystal of the invention]

The pharmaceutical composition of crystal of the invention includes 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- of the invention Naphthane -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea crystal, and pharmaceutically Admissible additive is combined and is made.It more specifically, can be by excipient (such as glucose, lactose (monohydrate, spray Mist dries monohydrate, anhydrous etc.), sucrose, white sugar, mannitol, mannitol, xylitol, D-sorbite, avicel cellulose, Microcrystalline cellulose, silicic acid, starch, cornstarch, potato starch and dicalcium phosphate dihydrate etc.), bonding agent it is [such as fine Tie up plain class (hydroxy propyl cellulose (HPC), HYDROXY PROPYL METHYLCELLULOSE (HPMC)), avicel cellulose, microcrystalline cellulose, bright (cornstarch, potato are formed sediment for glue, carbohydrate (lactose, mannitol, white sugar, D-sorbite, antierythrite, xylitol), starch Powder), it is alphalysed starch, glucan, polyvinylpyrrolidone (PVP), polyethylene glycol (Macrogol), polyvinyl alcohol (PVA), poly- Ethylene glycol, natural rubber and synthetic rubber etc.], lubricant (such as magnesium stearate, calcium stearate, zinc stearate, stearyl richness horse Sour sodium, the mixture of magnesium stearate and NaLS, talcum, carboxymethyl cellulose etc.), [such as starch is (beautiful for disintegrating agent Rice starch, potato starch, starch, alphalysed starch), sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethylcellulose, crosslinking Sodium carboxymethylcellulose, crospovidone, Explotab, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinyl Hydroxy propyl cellulose and mosanom etc. that pyrrolidones, methylcellulose, microcrystalline cellulose, low alkyl group replace], surface Activating agent (NaLS and polysorbate80 etc.), flow improver additive (silica and talcum etc.), filming agent [such as (hydroxy propyl cellulose (HPC), HYDROXY PROPYL METHYLCELLULOSE (HPMC), amino alkyl methacrylate are total for cellulose family Polymers E, Eudragit L100D55], plasticizer (such as triethyl citrate, polyethylene glycol), smoke agent for shielding (such as aoxidize Titanium), colorant, flavouring agent, preservative (such as benzalkonium chloride, p-hydroxybenzoate), isotonic agent (such as glycerine, chlorine Change sodium, calcium chloride, mannitol, glucose), pH adjusting agent (such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphorus The buffers such as acid buffer), stabilization agent (such as sugar, sugar alcohol, xanthan gum), dispersing agent, antioxidant (such as ascorbic acid, Butylated hydroxy anisole (BHA), propylgallate, dl- alpha-tocopherol), buffer, preservative agent (such as nipalgin, benzene first Alcohol, benzalkonium chloride), aromatic (such as vanillic aldehyde, l-menthol, attar of rose), cosolvent (such as polyethylene glycol hydrogenated castor-oil plant Oil, polysorbate80, polyethylene glycol, Phospholipids cholesterol, triethanolamine), sorbefacient (such as sodium glycollate, according to ground Sour sodium, sodium caprate, acylcarnitines class, limonene), it is gelating agent, suspension agent or emulsifier, conventional use of appropriate The crystal of the type of additive or solvent and the compound of the present invention (1) is appropriately combined to which various dosage forms be made.

As various dosage forms, it can be cited for example that tablet, capsule, granule, powder, pill, aerosol agent, sucking Agent, ointment, patch, suppository, injection, containing tablet, liquor, spirits, suspension, extract, elixir etc..In addition, this hair Bright pharmaceutical composition can be for example, by oral, subcutaneous administration, intramuscular adminstration, intranasal administration, percutaneous dosing, intravenous Administration, intraarterial delivery, nerve around administration, epidural administration, Subdural space intracavitary administration, intracerebroventricular administration, drop rectum with drug, Sucking etc. and to patient be administered.Pharmaceutical composition of the invention is preferably adapted to oral administration.

Pharmaceutical composition of the invention can orally be administered.Oral administration in such a way that compound enters gastrointestinal tract, from It is for oral use and swallow, or it is also possible to oral administration or sublingual administration that compound enters direct blood flow from mouth.As suitable In the preparation of oral administration, tablet can be enumerated；Capsule containing microparticle, liquid or powder；Pastille (includes liquid inside Body), masticatory (chewable tablets)；More particles and nano particle agent；Gelling agent, solid solution, liposome, film (adhere to comprising mucous membrane Agent), vaginal suppository, the solid pharmaceutical preparations and liquid preparation etc. such as spray.

As liquid preparation, suspension, liquor, syrup and elixir etc. can be enumerated.Said preparation can be with soft or hard The form of the filler of the capsule of matter uses, specifically, including carrier (such as water, ethyl alcohol, polyethylene glycol, propylene glycol, first Base cellulose or oil appropriate etc.) and one or more emulsifiers and/or suspension agent.Liquid preparation can also be by by solid The reconstruct of body, such as electuary (sache, サシェ, the packet or packaging of granule) and prepare.

Pharmaceutical composition of the invention can in blood flow, in muscle or in internal organ by include using conduit skill and technique or Injection (infusion) including injection and be directly administered.As injection, intravenous administration, intraarterial delivery, abdomen can be enumerated Intracavitary administration, Marrow intracavitary administration, intracerebroventricular administration, administration in urethra, administration in breastbone, administration in skull, intramuscular adminstration and Subcutaneous administration etc..In injection, the devices such as needle injection, needleless injector are used.In the direct administration carried out by injection, also wrap Include the pharmacy skill and technique such as the preparation by the injection preparation of freeze-dried progress.

Injection preparation can be by adding preservative agent conduct in such as ampoule (ampoule) or multiple dosing container Unit is administered form and provides.These preparations can take suspension, liquor or emulsion in oiliness or aqueous medium etc. to be administered Form can contain the preparations agents such as suspension agent, stabilization agent, and/or dispersing agent.Alternatively, active constituent is using preceding Can be for by medium appropriate, for example sterilizing pyrogen water removal reconstruct powder morphology.

When needing product solution, product solution can be with to generating the intensity to necessary to patient is oral or non-oral administration Solution for full amount, manufactured and being dissolved in individual inclusion complex in water (or other aqueous mediums).This A little compounds can preparation turn to dispersion administration form (fddf) rapidly, be designed to release active constituent in oral cavity.This A little preparations use the matrix based on rapidly dissolubility gelatin and formulation in most cases.These administration forms are known , it can be used in delivering extensive drug.Almost all of rapid dispersion administration form is using gelatin as carrier or structure shape At agent.For typical case, gelatin is used to prevent damaged abundant intensity when administration form is assigned and being taken out from the package, but once into In entrance, then gelatin can be such that the administration form decomposes immediately.Alternatively, identical effect in order to obtain, can be used various shallow lakes Powder.

Pharmaceutical composition of the invention can to skin or mucous membrane, i.e. percutaneously (dermally or transdermally) Local administration.As these typical preparations, gelling agent can be enumerated, hydrogel adhesive, lotion, liquor, creme, ointment, dissipated Agent, bandage agent, foaming agent, film, skin plaster agent, thin slice (wafer) agent, implant, sponginum, fiber agent, wound patch And microemulsion.Liposome can also be used.

Pharmaceutical composition of the invention can by such as suppository, vaginal suppository or bowel lavage etc. be administered in the form of and rectally Or Via vagina be administered.As suppository base, can be used such as cocoa butter or other glyceride, so that preparation turns to suppository Or stop the rectal compositions such as bowel lavage.

Pharmaceutical composition of the invention can also be with the outstanding of the micropowder in the sterile saline through pH adjustment of isotonicty The administration form of the point drops of supernatant liquid or solution is directly administered to eye or ear.As be suitable for E & E administration other preparations, Ointment, Biodegradable (such as absorbability gel sponge, collagen) and abiotic decomposability (such as silicone) can be enumerated to plant Enter agent, eye disc, eyeglass (lens) agent and the fine granules or utricle agent etc. such as vesicle (niosome) or liposome.

Pharmaceutical composition of the invention is interior by nasal cavity or sucks, additionally it is possible to the administration shape as such as solution or suspension State is given as the administration form of the dried powder from dried powder injector (impeller) or as aerosol spray Medicine.In the administration form of solution or suspension, using by patient's extruding or the pump spraying container by pumping out.Aerosol spray In mist, using use the pressurizing vessel of appropriate stock solution or other gases (or not using) appropriate, pump, injector (spray), Atomizer (atomizer) or sprayer (nebulizer) etc..In the case where dried powder injector and aerosol, dosage unit It determines according to pre-filled capsule, pack (blister) or bag or according to by the system to coyote hole using quality determination supply It is fixed.It is constituted for unit according to the present invention is typical a certain amount of, i.e. containing 1 ~ 5000 μ g of compound or salt to be administered " secondary (puff) ".The range for being 1 μ g ~ 20mg for total dosage was typical in 1 day with single-dose or can split administration.

In the administration to human patient, the total dosage in 1 day of the crystal of the compound of the present invention (1) according to medication and It determines, range, the range of more preferably 0.1mg ~ 50mg of the range, preferably 0.01mg ~ 100mg that are 0.005mg ~ 200mg. Total dosage can be administered with single dosage or fractionation dosage within 1 day.These dosages are based on the body with about 65kg ~ 70kg Weight average human patient and calculate.Doctor can separately determine the object that the weight such as children and old man are deviateed with aforementioned range Dosage.

Above-mentioned treatment with the dosage being administered on the way according to used compound or salt, administration mode, desired treatment, With the symptom of adaptation and use diversified dosage.The dosage expectation of pharmaceutical composition of the invention is in view of patient's It is set on the basis of age, weight, the type of disease, degree, administration access etc., when oral administration, can be usually 0.05 ~ In the range of 100mg/kg/ days, preferably 0.1 ~ 10mg/kg/ days.In addition, in para-oral situation, according to administration access And there is very big difference, but can be usually in the range of 0.005 ~ 10mg/kg/ days, preferably 0.01 ~ 1mg/kg/ days.It can be with It is 1 day 1 time administration (single-dose) to being divided into multiple dosing (split administration).It should be noted that the upper limit value of these numberical ranges With lower limit value can in any combination respective value and form numberical range.

[pharmacological experimental example]

Hereinafter, enumerating experimental example illustrates the present invention, but the present invention not due to these by any restriction.Following pharmacology are implemented Example 1 to 4 provides the method tested the validity of crystal of the invention.It should be noted that claiming " test-compound in following (1) " when, refer to the crystal habit including test-compound (1).

(pharmacological experimental example 1): to the combination activity rating of people's TrkA protein

Use TrkA LanthaScreen (registered trademark) Eu Kinase Binding Assay (ThermoFisher SCIENTIFIC it) measures.On 384 orifice plates (Corning), add 2.5 μ L use kinase buffer liquid (Kinase buffer, ThermoFisher SCIENTIFIC) diluted each concentration test-compound (1) solution and 2.5 μ L 15nM TrkA enzyme (ThermoFisher SCIENTIFIC).Further, the anti-His labelled antibody (Eu-anti-His of 3nM Eu- of 5 μ L is added Tag antibody, ThermoFisher SCIENTIFIC), 30nM Kinase (registered trademark) Tracer 236 of 5 μ L (ThermoFisher SCIENTIFIC) reacts 60 minutes at room temperature.After reaction, with EnVision 2100 (PerkinElmer) fluorescence intensity (launch wavelength 615nm) and TR-FRET of the europium of the excitation wavelength based on 340nm are measured (launch wavelength 665nm), to calculate its binding capacity of fluorescence ratio as test-compound (1) and TrkA enzyme.Will substitution by The fluorescence ratio for trying compound (1) and being added to the hole of solvent is denoted as 0%, and the fluorescence ratio for being not added with the hole of TrkA protein is denoted as 100%, to calculate the inhibitory activity (IC of each test-compound₅₀Value).

Test-compound (1), i.e. 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- The TrkA inhibitory activity of each crystal of (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea can pass through IC₅₀Value evaluation.By IC₅₀Value is that 50nmol/L compound below is denoted as A (activity is very high), by IC₅₀Value is greater than 50nmol/L And it is denoted as B (activity is high) for 1000nmol/L compound below, by IC₅₀It is (living that compound of the value greater than 1000nmol/L is denoted as C Property is low), it is shown in table 1.

Table 1

。

(pharmacological experimental example 2): the inhibitory activity evaluation of user's TrkA expression cell

The inhibitory activity to TrkA kinases in cell line is to use the CHO-K1 cell for making one TrkA and stablizing expression The ligand of (CellSenser (registered trademark) TrkA-NFAT-bla CHO-K1 cell, ThermoFisher SCIENTIFIC) The rising of calcium concentration is implemented as index in dependent cell.

In the previous day of measurement, by cell be suspended in comprising measurement culture medium (0.5% inactivation through the FBS that dialyses (ThermoFisher SCIENTIFIC), NEAA (ThermoFisher SCIENTIFIC), 1mM Sodium Pyruvate (ThermoFisher SCIENTIFIC)) 1 Reduced Serum Medium of Opti-MEM (registered trademark) In (ThermoFisher SCIENTIFIC), with 4.0 × 10⁴Cell/100 holes μ L/ density, is inoculated in 96 hole dianegatives (Greiner) in.The same day is measured, sample-loading buffer (the FLIPR Calcium assay of the probenecid containing 2.5mM of 100 μ L is added Kit, FLIPR calcium measure kit, Molecular Devices, LLC.), in 37 DEG C, 5%CO₂Under conditions of cultivate 1 hour. The test-compound (1) for adding the 20mM HEPES/HBSS beforehand dilution containing 0.1%BSA (DMSO final concentration: 0.1%), is installed In in intracellular calcium concentration measurement system (FDSS7000, creek pine ホトニ Network ス).It adds test-compound (1) after five minutes, adds Add NGF- β (Sigma-Aldrich Japan) (final concentration: 30ng/mL), measures intracellular calcium concentration as fluorescence signal.It will The fluorescence signal for substituting test-compound (1) and being added to the hole of solvent is denoted as 0%, will be not added with the fluorescence signal in the hole of NGF- β It is denoted as 100%, calculates the inhibitory activity (IC of each test-compound₅₀Value).

(pharmacological experimental example 3): the inhibiting effect hyperfunction to the blood vessel permeability of rat NGF induction

Evaluate the inhibitory activity to TrkA in (In vivo) in vivo.To the male Sprague-Dawley rat of back shaving (CD (SD) IGS rat, Charles River Japan), the test-compound (1) that oral administration is dissolved or suspended using solvent (administration capacity: 5mL/kg).To solvent control group oral administration solvent.After administration 1 ~ 24 hour, under isoflurane anesthesia, tail is quiet Administration 1% evans blue (Nacalai Tesque) (administration capacity: 3mL/kg) in arteries and veins, the thereafter intradermal administration at back 2 at once With NGF (mouse 2.5s, Alomone) solution of the diluted 300ng/mL of physiological saline liquid, furthermore at back 2, intradermal administration is raw Manage salt solution (administration capacity: at 50 μ L/).Intradermal administration after ten minutes, cuts the medicine-feeding part (at 4) of skin of back, by this Skin samples shift each 1 sample into each hole of 24 orifice plates (day meter production institute).First is added respectively with the hole 1.5mL/ into plate After amide (and Wako Pure Chemical Industries) and capping, cultivated overnight at 37 DEG C.The extracting solution of the formamide of 200 μ L is transferred to 96 holes Plate (nunc) uses the evans blue extracted in SpectraMax (Molecular Devices, LLC.) measurement formamide Absorbance (wavelength: 620nm).

Meanwhile the absorbance of the also measurement diluted evans blue standard sample of formamide, make standard curve.According to this The absorbance of standard curve and each sample calculates the evans blue concentration of each sample.

From the 4 of same individual acquisition among skin samples, the average value at NGF has been administered 2 is subtracted, life has been administered Value obtained from average value at the 2 of reason salt solution is denoted as the value of the individual.The hyperfunction inhibition of blood vessel permeability of rat NGF induction The evans blue concentration of solvent control group is denoted as 0% and calculated by rate.

(pharmacological experimental example 4): to the analgesic activity of complete Freund's adjuvant (CFA) guidance model rat

Using CFA guidance model rat, the analgesic activity of test-compound (1) is evaluated.

(1) production of CFA guidance model rat

By CFA (Sigma-Aldrich Japan) and physiological saline liquid, respectively equally mixing is to prepare lotion, in isoflurane Under anesthesia, 100 μ L are administered using 26G injection needle to Rat Right limb vola.100 μ L of physiological saline liquid is administered to Normal group.

(2) administration of test-compound (1), anti-ngf antibodies

Test-compound (1) is dissolved with 0.5% methylcellulose (and Wako Pure Chemical Industries) or suspends (administration capacity: 5mL/kg). The solution of 2mL/kg will be prepared as the anti-ngf antibodies physiological saline liquid dissolved dilution of positive control.Testedization Close object (1) administration group 1 day 2 times, 7 days oral administrations repeatedly from the day of administration CFA.Anti-ngf antibodies and CFA are administered on the same day Intraperitoneal administration.

The measurement of (3) 50% threshold values (g)

Implement measurement after administration CFA7 days.After determination of the environment makes animal adaptation 1 hour or more, according to Dixon up-down method (Journal of Neuroscience Methods, volume 53, the 55-63 pages, 1994) uses von Frey filament to pierce Swash vola, 50% threshold value (g) is calculated by following formula.It should be noted that measurement is implemented under blind examination.

50% threshold value (g)=(10^ [Xf+k δ]/10000)

Xf: the value of the filament finally used

K: tabulated value (tabular value)

δ: average (=0.224) of the difference between used filament

According to the above results, the compound of the present invention (1) is shown with excellent TrkA inhibiting effect.In addition, according to rat Pharmacological experimental example 3 and 4 as a result, any exception is not observed in safety testing, hypotoxicity of the invention is shown.

Therefore, the compound of the present invention (1) is used as TrkA inhibitor, can expect the disease participated in for TrkA, ache Bitterly (Accompanying Deformation arthritis, rheumatic arthritis, fracture, interstitial cystitis, chronic pancreatitis, prostatitic pain, The pain of nociception representated by chronic back pain, diabetic peripheral pain, postoperative pain, pelycalgia, Cancerous pain etc. Bitterly, the pain such as neurological pain, Acute Pain, chronic ache or inflammatory pain), cancer, inflammation/diseases associated with inflammation, Anaphylactia, skin disease, neurodegenerative disease, infectious disease, Sjogren syndrome, endometrium disease, nephrosis and osteoporosis etc. The prophylactic and/or therapeutic agent of disease.As the purposes of these prophylactics and/or therapeutic agent independent of crystal form, therefore this hair The VII type crystal of bright compound (1), VIII crystal, IX type crystal, X-type crystal, XI type crystal and XII type crystal are also the same Ground can expect the purposes of prophylactic and/or therapeutic agent as above-mentioned disease.

The VII type crystal, VIII crystal, IX type crystal, X-type crystal, XI type crystal and XII of the compound of the present invention (1) Type crystal can be expected to show promising prevention or therapeutic effect to the various diseases of the disease participated in as TrkA.

It should be noted that all literature and publications recorded in this specification are regardless of its purpose, with the side of reference Formula is integrally incorporated in this specification.

Embodiment

Then, in order to which present invention be described in more detail and enumerates embodiment, test example, but these examples are simple realities It applies, does not limit the present invention, furthermore, it is possible to be changed in the range of not departing from the scope of the present invention.

In the measurement of nuclear magnetic resoance spectrum (NMR), JEOL JNM-ECX400 FT-NMR (Japan Electronics), JEOL are used JNM-ECX300 FT-NMR (Japan Electronics), Bruker Avance III 400MHz NMR (Bruker Corporation). Liquid chromatography-mass spectrography (LC-Mass) is measured by following methods.[UPLC] [method A] uses Waters AQUITY UPLC system System and CAPCELL Pak column (2.0mm × 50mm, 3 μm) (Shiseido), use methanol: 0.05% trifluoroacetic acid aqueous solution=5:95 The mobile phase and gradient condition of (0 minute) ~ 95:5 (1.0 minutes) ~ 95:5 (1.6 minutes) ~ 5:95 (2.0 minutes).

[LCMS] [method B] uses Waters FractionLynx MS system (Waters) and SunFire column (4.6mm × 5cm, 5 μm) (Waters), use acetonitrile: 0.05% acetic acid aqueous solution=10:90 (0 minute) ~ 100:0 (5.0 minutes) ~ 100:0 (6.0 minutes) ~ 10:90 (7.0 minutes) or [method C] acetonitrile: 0.05% trifluoroacetic acid aqueous solution=10:90 (0 minute) ~ 100:0 The mobile phase and gradient condition of (5.0 minutes) ~ 100:0 (6.0 minutes) ~ 10:90 (7.0 minutes).In separation and Extraction system, according to Compound and use the gradient condition that suitably changes.It is used using the optical resolution of supercritical fluid liquid chromatogram (SFC) Waters SFC Prep15 System, SFC80q System and corresponding chiral column are implemented.Optical purity analysis uses Waters SFC UPC2 and corresponding chiral column are implemented.LC-Mass uses the mass spectrum using ESI (electro-spray ionization) (MS-ESI)。

¹In H-NMR data, in the pattern of NMR signal, s refers to that singlet state, d refer to doublet, and t refers to triplet, q Referring to quartet, m refers to multiplet, and br refers to that broad peak, J refer to coupling constant, and Hz refers to that hertz, CDCl3 refer to deuterated chloroform, DMSO-D6 refers to that deuterated dimethyl sulfoxide, CD3OD refer to deuterated methanol.¹In H-NMR data, for hydroxyl (OH), amino (NH₂), the proton of carboxyl (COOH) etc. due to being wide band and the signal that can not be confirmed, do not recorded in data.

In MS-ESI data in aftermentioned table, M refers to molecular weight, [M+H]⁺Refer to molecular ion peak.In addition, A in table, B, C refers respectively to " UPLC [method A] ", " LCMS [method B] ", " LCMS [method C] ".In addition, MS-ESI refers to using ESI's Mass spectrum.

" room temperature " in this specification indicates to be usually 1 DEG C to 30 DEG C of temperature (Japanese Pharmacopoeia regulation), is preferably 20 DEG C ± 15 DEG C (JIS Z 8703), more preferably 15 ~ 25 DEG C." room temperature " in the present embodiment indicates 20 DEG C.

In the crystallization of embodiment, using commercially available solvent without purification.

Powder x-ray diffraction analysis uses D8 Discover (the Bruker Corporation company with GADDS CS System), pass through Bragg-Brentano method (x-ray source: 40kV, 40mA, wavelength: 1.5418 (angstroms) (CuKalpha), camera Length: 250mm, temperature: room temperature, the position Phi: 0 degree, exposure time: 2 minutes, Theta1:7 degree, Theta2:7 degree) it measures.

Alternatively, powder x-ray diffraction analysis uses D8 Advance (Bruker Corporation corporation), pass through Bragg-Brentano method (x-ray source: 40kV, 40mA, wavelength: 1.54056 (angstroms) (CuKalpha), temperature: room temperature) is surveyed It is fixed.

Differential scanning calorimetric analysis (DSC) uses differential scanning calorimetry (DSC) DSC1000 (TA Instruments system), to rise Warm speed is the range of 10 DEG C per minute measurement room temperatures to 300 DEG C.Thermogravimetric analysis (TGA) uses thermogravimetric measurement device TGA500 (TA Instruments system), under the nitrogen atmosphere of 60mL per minute, with heating rate be 10 DEG C of measurements room temperature per minute extremely 300 DEG C of range.

Here, extrapolated melting point initial temperature refers to the lifting temperature at the fusing point peak of the compound.For example, (VII type is brilliant by Fig. 4 The DSC modal data of body) in, 155.44 DEG C are fusing point peak, lift temperature and are determined as 145.88 DEG C, i.e. extrapolated melting point initial temperature It is determined as 146 DEG C.

The extrapolated melting point initial temperature of each crystal habit is value as described below.

Table B

。

(embodiment 1) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl - 6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea (1=compound of embodiment (1)) synthesis:

The synthesis of < step 1 > 5- methyl -2- phenylpyridine -3- amine (embodiment 1-1):

By the chloro- 5- methyl -3- pyridine amine of commercially available 2- (CAS 34552-13-1) (1.0 g), phenylboric acid (0.86g) and four (triphenyl) phosphine palladium (0.81g) is added to ethyl alcohol (15mL), toluene (35mL) and 2 centinormal 1 wet chemicals The in the mixed solvent of (11mL) stirs 18 hours under nitrogen atmosphere, at 100 DEG C.After placing cooling, added to gained reaction solution Ethyl acetate and water simultaneously distribute, dry with sodium sulphate by organic layer saturated common salt water washing.By the lower distillation removal solvent of decompression Obtained from residue with silica gel column chromatography (mobile phase: heptane/ethyl acetate=70:30 ~ 65:35 ~ 60:40) purify, with colourless solid The form of body obtains title compound (1.2g).

The synthesis of the bromo- 5- methyl -2- phenylpyridine -3- amine (embodiment 1-2) of < step 2 > 6-:

It is added to N-Methyl pyrrolidone (2.0mL) solution of compound (0.19g) obtained in (embodiment 1) < step 1 > N- bromo-succinimide (0.21g) is stirred at room temperature 2 hours.Water (2.0mL) is added to gained reaction solution, uses tert-butyl Methyl ether is extracted twice, and organic layer is washed with water.By residue silica gel column chromatography obtained from the lower distillation removal solvent of decompression (stationary phase: amino-silica gel, mobile phase: heptane/ethyl acetate=90:10 ~ 30:10) purification, is obtained in the form of brown solid Title compound (0.20g).

The conjunction of < step 3 > 5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- amine (embodiment 1-3) At:

To the 1,2- dimethoxy-ethane (10mL) and water of compound (0.40g) obtained in (embodiment 1) < step 2 > The mixed solution of (2.0mL), addition 2- methyl -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan alkane -2- base) are phonetic Pyridine (0.44 g), cesium carbonate (1.5g) and dichloro [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride dichloromethane adduct (0.12g) is stirred 4 hours at 80 DEG C.After placing cooling, water is added to gained reaction solution.By insoluble matter Celite pad mistake Filter separation, is washed with ethyl acetate, organic layer is separated from filtrate, successively washed with water, saturated salt solution, dry with sodium sulphate It is dry.It will (the stationary phase: amino-silica gel, flowing of the residue silica gel column chromatography as obtained from distilling removal solvent under reduced pressure Phase: heptane/ethyl acetate=100:0 ~ 50:50) purification, obtain title compound (0.31g).

< step 4 > (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) carbamic acid 2,2,2- The synthesis of trichloro ethyl ester (embodiment 1-4):

To 1,2- dichloroethanes (100mL) solution of compound (0.30g) obtained in (embodiment 1) < step 3 >, in room temperature 2,2,2- trichloro ethyl ester (0.36mL) of lower addition pyridine (0.22mL) and chloro-carbonic acid stirs 1 hour at the same temperature.To gained Reaction solution adds sodium bicarbonate aqueous solution, is extracted with ethyl acetate, organic layer water, saturated salt solution are successively washed, sulphur is used Sour sodium is dry.By residue silica gel column chromatography (stationary phase: amino-silica gel, flowing obtained from the lower distillation removal solvent of decompression Phase: heptane/ethyl acetate=2:1) purification, title compound (0.41g) is obtained as a white solid.

The synthesis of < step 5 > 4,4- dimethyl -1,2,3,4- naphthane -1- alcohol (embodiment 1-5):

To the methanol (10mL) of commercially available 4,4- dimethyl -3,4- dihydronaphthalene -1 (2H) -one (CAS 2979-69-3) (1.0g) Solution adds sodium borohydride (0.24g) in two times, is stirred at room temperature 1 hour in the case where ice water is cooling.Decompression is lower to remove methanol, To 1 centinormal 1 sodium hydrate aqueous solution (30mL) of residue obtained addition and ethyl acetate (40mL), it is allocated.It will be organic Layer is washed with saturated salt solution (25mL), after sodium sulphate drying, is concentrated under reduced pressure, is thus obtained in the form of light yellow oil Title compound (1.0g).

The synthesis of < step 6 > 1,1- dimethyl -1,2- dihydronaphthalene (embodiment 1-6):

By the toluene of compound (1.0g) and p-methyl benzenesulfonic acid monohydrate (0.05g) obtained in (embodiment 1) < step 5 > (10mL) solution stirs 1.5 hours at 90 DEG C.After placing cooling at room temperature, ethyl acetate (40mL) and unsaturated carbonate are added Hydrogen sodium water solution (30mL), and be allocated.Organic layer saturated common salt water washing is concentrated under reduced pressure after sodium sulphate drying, Thus title compound (0.86g) is obtained in the form of yellow oil.

The conjunction of < step 7 > 3,3- dimethyl -1a, 2,3,7b- tetrahydro naphtho- [1,2-b] oxireme (embodiment 1-7) At:

It is outstanding to the acetone (0.60mL) of compound (30mg) obtained in (embodiment 1) < step 6 > and sodium bicarbonate (80 mg) Supernatant liquid adds permonosulphuric acid potassium (0.15g) aqueous solution (0.60mL) under ice-cooling.Gained reaction solution is stirred at the same temperature After mixing 1 hour, it is stirred at room temperature 16 hours.Thereafter, ethyl acetate and saturated sodium bicarbonate aqueous solution are added to reaction solution, and It is allocated.Organic layer sodium thiosulfate solution, saturated salt solution are successively washed, it is dry with sodium sulphate.It will be under decompression Residue obtained from distillation removal solvent is purified with silica gel column chromatography (mobile phase: heptane/ethyl acetate=100:0 ~ 90:10), with The form of colorless oil obtains title compound (24 mg).

< step 8 > racemic-(1RS, 2RS) -1- amino -4,4- dimethyl -1,2,3,4- naphthane -2- alcohol (is implemented Example 1-8) synthesis:

Into ethyl alcohol (0.070mL) solution of compound (30mg) obtained in (embodiment 1) < step 7 >, 25% ammonium hydroxide is added (1.0mL).Gained reaction solution is stirred 1 hour in seal pipe, at 90 DEG C.After placing cooling, leaching adds water to reaction solution And the solid being precipitated, it is dried under reduced pressure, thus obtains title compound (14mg).

< step 9 > (1R, 2R) -1- amino -4,4- dimethyl -1,2,3,4- naphthane -2- alcohol (2S, 3S) -2,3- The synthesis of dyhydrobutanedioic acid salt monohydrate (embodiment 1-9):

To the acetonitrile (74mL) of compound (3.4g) obtained in (embodiment 1) < step 8 > and the mixed solution of water (19mL), Add D- (-)-tartaric acid (2.7g) at room temperature.Gained reaction solution is stirred 5 minutes at 100 DEG C, placement is cooled to room temperature Afterwards, 2 hours are stood at the same temperature.The crystal that leaching is precipitated, in the mixed solvent of the acetonitrile-water (4:1) pre-cooled Middle washing crystal, is dried under reduced pressure, and thus obtains product (2.0g).Acetonitrile-water (4:1) (25mL) is added to the product, In It is stirred 10 minutes at 100 DEG C, after placement is cooled to room temperature, stands 1 hour at the same temperature and recrystallized.Leaching is precipitated Crystal, the acetonitrile-water (4:1) pre-cooled in the mixed solvent wash crystal, be dried under reduced pressure, thus with colourless solid The form of body obtains title compound (1.4g).

< step 10 > 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea (1=compound of embodiment (1)) synthesis:

To N-Methyl pyrrolidone (0.50mL) solution of compound (0.10g) obtained in (embodiment 1) < step 4 >, add Add compound (76mg) obtained in (embodiment 1) < step 9 > and triethylamine (0.093mL), stirs 18.5 at 40 DEG C Hour.Water (3.0mL) is added to gained reaction solution, the precipitating that leaching is precipitated and washing.The crude product of institute's leaching is suspended in The in the mixed solvent of heptane-isopropanol (9:1), after solidification crushes, leaching is simultaneously washed with heptane-isopropanol (9:1), and decompression is dry It is dry, thus obtain title compound (82mg).

The midbody compound of above-mentioned (embodiment 1-1) ~ (embodiment 1-9) and the final compound of (embodiment 1) Structure is as follows.The embodiment final compound of (embodiment 1) 1H-NMR data (it is unmarked: 400MHz NMR, * label: 300MHz NMR) and LC-Mass data be shown in following tables (table 11, table 12).

In addition, the 1H-NMR data of the midbody compound synthesized in each step of embodiment 1 are (unmarked: 400MHz NMR, * are marked: 300MHz NMR) and LC-Mass data are shown in following table 13, table 14.

(embodiment 2) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea type III crystal:

The compound (1) (0.76g) obtained according to the method for (embodiment 1) is set to be suspended in methyl tertiary butyl ether(MTBE) (MTBE) (11.5mL) is stirred at room temperature 29 hours.The crystal that leaching is precipitated washs crystal with MTBE, is dried under reduced pressure, thus Obtain product (0.66g).It is suspended in the product in MTBE (9.5mL), is stirred at room temperature 98 hours.The crystalline substance that leaching is precipitated Body obtains title compound (0.57g) (the type III crystal of compound (1)) as a white solid.

The measurement result of the powder x-ray diffraction of the type III crystal of gained compound (1) is shown in Fig. 1, the type III crystal Characteristic peak be shown in table 2.

Table 2

。

(embodiment 3) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea V-type crystal:

(compound (1)) type III crystal (27.0g) obtained in (embodiment 2) is set to be suspended in acetone (135mL) and normal heptane In the mixed solution of (135mL), it is stirred at room temperature 110 minutes.The crystal that leaching is precipitated, with acetone-normal heptane (1:3) Mixed solution (200mL) washs crystal, is dried under reduced pressure, and thus obtaining title compound (20.2g), (V-type of compound (1) is brilliant Body).

The measurement result of the powder x-ray diffraction of the V-type crystal of gained compound (1) is shown in Fig. 2, and the V-type crystal-type is brilliant The characteristic peak of body is shown in table 3.

Table 3

。

(embodiment 4) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VII type crystal

It is suspended in the V-type crystal (10.0mg) of compound obtained in (embodiment 3) (1) in acetonitrile (4mL), surpasses at room temperature It sound 5 minutes, makes it completely dissolved.V-type crystal is further added to the solution, prepares slightly suspended solution.By will be not molten Acquired solution, to remove, is stood 3 days, thus gradually distillation is gone with 0.45 μm of nylon membrane filtering by the crystal of solution at room temperature Except solvent.Crystal be precipitated is separated, the compound (the VII type crystal of compound (1)) of title is obtained.

The measurement result of the powder x-ray diffraction of the VII type crystal of gained compound (1) is shown in Fig. 3, the VII type crystal The characteristic peak of type crystal is shown in table 4.In addition, the DSC&TGA modal data of the VII type crystal is shown in Fig. 4.

Table 4

。

(embodiment 5) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VIII type crystal

Methylene chloride (0.5mL) is added to the V-type crystal (40.0mg) of compound obtained in (embodiment 3) (1), at 30 DEG C Heating stirring 0.5 hour, thus prepare supersaturated solution.By undissolved crystal with 0.45 μm of nylon membrane filtering to go It removes, acquired solution is stood in -20 DEG C of refrigerator to about 4.5 hours at once.The crystal being precipitated is passed through into centrifuge separation (12000rpm, 10 minutes) leaching, it is dry, thus obtain the compound (the VIII type crystal of compound (1)) of title.

The measurement result of the powder x-ray diffraction of the VIII type crystal of gained compound (1) is shown in Fig. 5, and the VIII type is brilliant The characteristic peak of bulk crystal is shown in table 5.In addition, the DSC&TGA modal data of the VIII type crystal is shown in Fig. 6.

Table 5

。

(embodiment 6) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea IX type crystal

Isopropyl acetate (0.5mL) is added to the V-type crystal (40.0mg) of compound obtained in (embodiment 3) (1), about 60 Heating stirring 0.5 hour, thus prepares supersaturated solution at DEG C.By undissolved crystal with the filtering of 0.45 μm of nylon membrane to Removal, stands 12 hours in -20 DEG C of refrigerator at once for acquired solution.The crystal being precipitated is passed through into centrifuge separation (12000rpm, 10 minutes) leaching, it is dry, thus obtain the compound (the IX type crystal of compound (1)) of title.

The measurement result of the powder x-ray diffraction of the IX type crystal of gained compound (1) is shown in Fig. 7, the IX type crystal-type The characteristic peak of crystal is shown in table 6.In addition, the DSC&TGA modal data of the IX type crystal is shown in Fig. 8.

Table 6

。

(embodiment 7) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea X-type crystal

It is suspended in the V-type crystal (20.0mg) of compound obtained in (embodiment 3) (1) in toluene (1mL), ultrasound 2 minutes To keep solid evenly dispersed.The aaerosol solution is stirred at room temperature 14 days by vibrating machine.The crystal being precipitated is passed through It is centrifugated (12000rpm, 10 minutes) leaching, it is dry, thus obtain the compound (the X-type crystal of compound (1)) of title.

The measurement result of the powder x-ray diffraction of the X-type crystal of gained compound (1) is shown in Fig. 9, and the X-type crystal-type is brilliant The characteristic peak of body is shown in table 7.In addition, the DSC&TGA modal data of the X-type crystal is shown in Figure 10.

Table 7

。

(embodiment 8) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XI type crystal

It is suspended in the V-type crystal (20.0mg) of compound obtained in (embodiment 3) (1) in MTBE (1mL), ultrasound 2 minutes To keep solid evenly dispersed.The aaerosol solution is stirred at room temperature 14 days by vibrating machine.The crystal being precipitated is passed through It is centrifugated (12000rpm, 10 minutes) leaching, it is dry, thus obtain the compound (the XI type crystal of compound (1)) of title.

The measurement result of the powder x-ray diffraction of the XI type crystal of gained compound (1) is shown in Figure 11, the XI type crystal-type The characteristic peak of crystal is shown in table 8.In addition, the DSC&TGA modal data of the XI type crystal is shown in Figure 12.

Table 8

。

(embodiment 9) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XII type crystal

It is suspended in the V-type crystal (20.0mg) of compound obtained in (embodiment 3) (1) in Di Iso Propyl Ether (1mL), ultrasound 2 minutes to keep solid evenly dispersed.The aaerosol solution is stirred at room temperature 14 days by vibrating machine.The crystal that will be precipitated It is dry by centrifuge separation (12000 rpm, 10 minutes) leaching, thus obtain compound (the XII type of compound (1) of title Crystal).

The measurement result of the powder x-ray diffraction of the XII type crystal of gained compound (1) is shown in Figure 13, the XII type crystal The characteristic peak of type crystal is shown in table 9.In addition, the DSC&TGA modal data of the XII type crystal is shown in Figure 14.

Table 9

。

(embodiment 10) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea I type crystal

Be suspended in the V-type crystal (204.7 mg) of compound obtained in (embodiment 3) (1) in methanol (1mL), 50 DEG C, It is stirred 2 hours under 200rpm.Thereafter, it is stirred at room temperature 3 days, the crystal that leaching is precipitated, is washed with methanol (400 μ l).It will Gained crystal is dried 2 hours under reduced pressure, at 40 DEG C, thus obtains the compound (the I type crystal of compound (1)) of title.

The measurement result of the powder x-ray diffraction of the I type crystal of gained compound (1) is shown in Figure 15.

(embodiment 11) 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- first Base -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VI type crystal

It is suspended in the V-type crystal (20.0mg) of compound obtained in (embodiment 3) (1) in ethyl alcohol (1mL), ultrasound 2 minutes To keep solid evenly dispersed.The aaerosol solution is stirred at room temperature 14 days by vibrating machine.The crystal being precipitated is passed through It is centrifugated (12000rpm, 10 minutes) leaching, it is dry, thus obtain the compound (the VI type crystal of compound (1)) of title.

The measurement result of the powder x-ray diffraction of the VI type crystal of gained compound (1) is shown in Figure 15, the VI type crystal-type The characteristic peak of crystal shown in table 10.

Table 10

。

The crystallization degree of crystal of (embodiment 4) of the invention to (embodiment 9) is high, and solubility is high, therefore as raw medicine It is easy to operate when manufacture pharmaceuticals, it is suitable for drug raw medicine, pharmaceutical preparation.

Table 11

。

Table 12

。

Table 13

。

Table 14

。

Industrial applicibility

Crystal of the invention can be understood as showing excellent TrkA inhibiting effect, therefore be capable of providing the clinic of pains and other diseases Upper useful prophylactic and/or therapeutic agent.

In addition, crystal of the invention is useful as the crystal of pharmaceuticals raw medicine.By providing chemical combination as described above The crystal of object (1), is capable of providing excellent pharmaceutical composition, so be useful.

More than, a variety of concrete modes of the invention are described in detail, but those skilled in the art can be specific to shown in Mode carries out various amendments and change in the range of not substantially being detached from the teachings of the present invention and advantage.Therefore, this The amendment and change of sample are also included in the claimed the spirit and scope of the present invention of all authority claim.

Claims

((2- methyl is phonetic by 5- methyl -6- by -3- by 1.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) Pyridine -5- base) -2- phenylpyridine -3- base) urea VII type crystal, as the angle of diffraction (2 θ) obtained by powder x-ray diffraction, At least 4.9 ± 0.2,5.4 ± 0.2,7.6 ± 0.2,8.0 ± 0.2,9.0 ± 0.2,10.3 ± 0.2,12.4 ± 0.2,14.7 ± 0.2, there is at 21.5 ± 0.2 and 23.7 ± 0.2 (°) characteristic peak.
((2- methyl is phonetic by 5- methyl -6- by -3- by 2.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) Pyridine -5- base) -2- phenylpyridine -3- base) urea VII type crystal, spy is characterized by x-ray diffractogram of powder shown in Fig. 3 Sign, and allow ± 0.2 error in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction.
3. VII type crystal according to claim 1 or 2, which is characterized in that differential scanning calorimetry measures (DSC measurement) Extrapolated melting point initial temperature is 146 DEG C.
4. 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- claimed in any one of claims 1 to 3 Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VII type crystal manufacturing method, It include: by 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methyl Pyrimidine -5- base) -2- phenylpyridine -3- base) urea is suspended in the step in the acetonitrile as crystallization solvent；With from acquired solution The step of obtaining crystal.
((2- methyl is phonetic by 5- methyl -6- by -3- by 5.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) Pyridine -5- base) -2- phenylpyridine -3- base) urea VIII type crystal, as the angle of diffraction (2 obtained by powder x-ray diffraction θ), at least 5.3 ± 0.2,6.9 ± 0.2,10.5 ± 0.2,13.9 ± 0.2,15.7 ± 0.2,17.0 ± 0.2,18.2 ± 0.2, There is characteristic peak at 18.8 ± 0.2,20.9 ± 0.2 and 21.4 ± 0.2 (°).
((2- methyl is phonetic by 5- methyl -6- by -3- by 6.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) Pyridine -5- base) -2- phenylpyridine -3- base) urea VIII type crystal, it is special by x-ray diffractogram of powder shown in fig. 5 characterization Sign, and allow ± 0.2 error in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction.
7. VIII type crystal according to claim 5 or 6, which is characterized in that differential scanning calorimetry measures (DSC measurement) Extrapolated melting point initial temperature is 143 DEG C.
8. ((1R, the 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- of 1- described in any one of claim 5 ~ 7 Base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea VIII type crystal manufacturing method, It include: by 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methyl Pyrimidine -5- base) -2- phenylpyridine -3- base) urea is suspended in the step in the methylene chloride as crystallization solvent；With from gained Solution obtains the step of crystal.
((2- methyl is phonetic by 5- methyl -6- by -3- by 9.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) Pyridine -5- base) -2- phenylpyridine -3- base) urea IX type crystal, as the angle of diffraction (2 θ) obtained by powder x-ray diffraction, At least 5.0 ± 0.2,6.8 ± 0.2,10.5 ± 0.2,14.9 ± 0.2,15.5 ± 0.2,17.5 ± 0.2,19.7 ± 0.2, There is characteristic peak at 20.4 ± 0.2,21.1 ± 0.2 and 24.4 ± 0.2 (°).
10.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methyl Pyrimidine -5- base) -2- phenylpyridine -3- base) urea IX type crystal, it is special by x-ray diffractogram of powder shown in Fig. 7 characterization Sign, and allow ± 0.2 error in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction.
11. IX type crystal according to claim 9 or 10, which is characterized in that differential scanning calorimetry measures (DSC measurement) Extrapolated melting point initial temperature is 127 DEG C.
12. ((1R, the 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane-of 1- described in any one of claim 9 ~ 11 1- yl) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea IX type crystal manufacturing method, It include: by 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methyl Pyrimidine -5- base) -2- phenylpyridine -3- base) urea is suspended in the step in the isopropyl acetate as crystallization solvent；With, from institute Obtain the step of solution obtains crystal.
13.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methyl Pyrimidine -5- base) -2- phenylpyridine -3- base) urea X-type crystal, as the angle of diffraction (2 θ) obtained by powder x-ray diffraction, At least 5.2 ± 0.2,6.9 ± 0.2,10.3 ± 0.2,13.6 ± 0.2,15.5 ± 0.2,18.0 ± 0.2,20.2 ± 0.2, There is characteristic peak at 20.7 ± 0.2,21.2 ± 0.2 and 29.0 ± 0.2 (°).
14.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methyl Pyrimidine -5- base) -2- phenylpyridine -3- base) urea X-type crystal, it is special by x-ray diffractogram of powder shown in Fig. 9 characterization Sign, and allow ± 0.2 error in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction.
15. X-type crystal described in 3 or 14 according to claim 1, which is characterized in that differential scanning calorimetry measures (DSC measurement) Extrapolated melting point initial temperature is 141 DEG C.
16. ((1R, the 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- tetrahydro of 1- described in any one of claim 13 ~ 15 Naphthalene -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea X-type crystal manufacturing method, Comprising: by 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- first Yl pyrimidines -5- base) -2- phenylpyridine -3- base) urea is suspended in the step in the toluene as crystallization solvent；With it is molten from gained Liquid obtains the step of crystal.
17.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methyl Pyrimidine -5- base) -2- phenylpyridine -3- base) urea XI type crystal, as the angle of diffraction (2 obtained by powder x-ray diffraction θ), at least 5.1 ± 0.2,6.8 ± 0.2,10.1 ± 0.2,10.5 ± 0.2,13.4 ± 0.2,15.1 ± 0.2,17.7 ± 0.2, There is characteristic peak at 19.8 ± 0.2,20.7 ± 0.2 and 22.7 ± 0.2 (°).
18.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methyl Pyrimidine -5- base) -2- phenylpyridine -3- base) urea XI type crystal, it is special by the characterization of x-ray diffractogram of powder shown in Figure 11 Sign, and allow ± 0.2 error in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction.
19. XI type crystal described in 7 or 18 according to claim 1, which is characterized in that differential scanning calorimetry measures (DSC measurement) Extrapolated melting point initial temperature be 126 DEG C.
20. ((1R, the 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- tetrahydro of 1- described in any one of claim 17 ~ 19 Naphthalene -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XI type crystal manufacturer Method comprising: by 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- bases) -3- (5- methyl -6- (2- Methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea is suspended in the methyl tertiary butyl ether(MTBE) (MTBE) as crystallization solvent Step；With the step of obtaining crystal from acquired solution.
21.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methyl Pyrimidine -5- base) -2- phenylpyridine -3- base) urea XII type crystal, as the angle of diffraction (2 obtained by powder x-ray diffraction θ), at least 4.9 ± 0.2,6.7 ± 0.2,9.9 ± 0.2,10.4 ± 0.2,13.1 ± 0.2,14.8 ± 0.2,15.4 ± 0.2, There is characteristic peak at 19.5 ± 0.2,20.3 ± 0.2 and 24.2 ± 0.2 (°).
22.1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- base) -3- (5- methyl -6- (2- methyl Pyrimidine -5- base) -2- phenylpyridine -3- base) urea XII type crystal, pass through the characterization of x-ray diffractogram of powder shown in Figure 13 Feature, and allow ± 0.2 error in each characteristic peak of the angle of diffraction (2 θ) of powder x-ray diffraction.
23. the XII type crystal according to claim 21 or 22, which is characterized in that differential scanning calorimetry measures (DSC measurement) Extrapolated melting point initial temperature be 119 DEG C.
24. ((1R, the 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- four of the 1- according to any one of claim 21 ~ 23 Hydrogen naphthalene -1- base) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea XII type crystal manufacture Method comprising: by 1- ((1R, 2R) -2- hydroxyl -4,4- dimethyl -1,2,3,4- naphthane -1- bases) -3- (5- methyl -6- (2- methylpyrimidine -5- base) -2- phenylpyridine -3- base) urea is suspended in the step in the Di Iso Propyl Ether as crystallization solvent； With the step of obtaining crystal from acquired solution.
25. pharmaceutical composition contains claim 1 ~ 3, claim 5 ~ 7, claim 9 ~ 11, claim 13 ~ 15, power Benefit requires crystal described in any one of 17 ~ 19 and claim 21 ~ 23 as effective component.
26. pharmaceutical composition according to claim 25 is TrkA inhibitor.
27. pharmaceutical composition according to claim 25, for selected from pain, cancer, inflammation/diseases associated with inflammation, allergy In property disease, skin disease, neurodegenerative disease, infectious disease, Sjogren syndrome, endometrium disease, nephrosis and osteoporosis extremely The prophylactic and/or therapeutic agent of a kind of few disease.
28. claim 1 ~ 3, claim 5 ~ 7, claim 9 ~ 11, claim 13 ~ 15, claim 17 ~ 19 and power Benefit require any one of 21 ~ 23 described in purposes of the crystal in the manufacture of pharmaceutical composition.