CN109678813A

CN109678813A - Indoles amine -2,3- dioxygenase inhibitor salt and preparation method thereof

Info

Publication number: CN109678813A
Application number: CN201710971186.9A
Authority: CN
Inventors: 王召印; 胡新波; 郭巍
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS; Innovent Biologics Suzhou Co Ltd
Priority date: 2017-10-18
Filing date: 2017-10-18
Publication date: 2019-04-26
Also published as: CN111194309A; WO2019076324A1

Abstract

The present invention relates to indoles amine -2,3- dioxygenase inhibitor salt and preparation method thereof.In particular it relates to the salt of compound of formula I and its a variety of amorphous substances and polymorph, wherein the definition of each group is as noted in the discussion.The salt stable structure, with good photostability, thermal stability, non-hygroscopic and pharmacokinetic property, solubility property is good, purity and bioavilability significantly improve, particularly suitable for developing and producing the IDO enzyme inhibitor of high quality, the dosage form of such IDO inhibitor is optimized and exploitation has important value.

Description

Indoles amine -2,3- dioxygenase inhibitor salt and preparation method thereof

Technical field

The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of indoles amine -2,3- dioxygenase inhibitor salt and Preparation method.

Background technique

Indoles amine -2,3- dioxygenase (Indoleamine-2,3-dioxygenase, IDO) inhibitor is a kind of tumour The drug of immunization therapy.Patent application CN105481789A and CN disclose one kind and contain sulphoxide imine and 1,2,5- oxadiazoles knot The IDO inhibitor of structure, shown in structure such as formula (I).

R¹For C₁-C₁₀Alkyl, C₃-C₁₂Naphthenic base, C₆-C₂₀Aryl or 3-14 unit's heteroaryl；

R²For H, C₆-C₂₀Aryl, 3-14 unit's heteroaryl, C₁-C₁₂Alkyl or C₃-C₁₂Naphthenic base；

R³And R⁴Respectively stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl；Or R³And R⁴Three are collectively formed to octatomic ring Or three to eight circle heterocyclic rings, wherein hetero atom is sulphur, oxygen, NH or NR^h；

Ar is substituted or unsubstituted phenyl ring, five yuan or six membered heteroaryl, and the substitution refers to the one or more on Ar Hydrogen atom is optionally substituted by halogen；The integer that n is 2 to 8；

R^hIt is selected from the group: C₁-C₁₀Alkyl, C₃-C₁₂Naphthenic base, C₆-C₂₀Aryl or 3-14 unit's heteroaryl；

Wherein, the salt is selected from the group: hydrochloride, hydrobromate, toluenesulfonate, benzene sulfonate, mesylate, Phosphate or sulfate；

Unless stated otherwise, the substitution refers to that one or more hydrogen atoms on group are taken by substituent group selected from the group below Generation: halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, hydroxyl, amino, nitro, aldehyde radical ,-CF₃,-CN or-SF₅。

The specific salt form of drug is different, may will affect its solubility, absorbability, stability, crystallinity, biological utilisation Degree, and then the clinical efficacy of drug, pharmaceutical dosage form selection, safety, production technology and packaging may be influenced to a certain extent. It is studied currently without the salt to compound of formula I, does not develop the salt and its polymorph and amorphous of compound of formula I still Object.

Therefore, this field needs a variety of salt form and crystal form of research and development compound of formula I, further to improve its crystallinity, steady Qualitative, hygroscopicity and technology stability, so that it be promoted to produce and apply.

Summary of the invention

The purpose of the present invention is to provide a variety of salt form and crystal form of IDO inhibitor, further to improve its crystallinity, steady Qualitative, hygroscopicity and technology stability, so that it be promoted to produce and apply.

Another object of the present invention provides the preparation method and application of a variety of salt form of IDO inhibitor.

The first aspect of the present invention provides a kind of compound of formula I or the salt of its optical isomer:

In formula,

Ar is substituted or unsubstituted phenyl ring, five yuan or six membered heteroaryl, and the substitution refers to the one or more on Ar Hydrogen atom is optionally substituted by halogen；

The integer that n is 2 to 8；

In another preferred example, the compound of formula I is selected from following I-1, I-2 or I-3:

Wherein, Ar, R³And R⁴Definition as described in first aspect present invention.

In another preferred example, the compound of formula I is selected from the group:

In another preferred example, the compound of formula I is

In another preferred example, the salt is selected from the group:

In another preferred example, the salt is amorphous substance or crystal.

In another preferred example, the X-ray powder diffraction pattern of the amorphous substance is basic such as figure institute selected from the group below table Sign: Fig. 1-2, Fig. 2-2, Fig. 4-2, Fig. 5-2, Figure 10-2 or Figure 11-2.

In another preferred example, the infrared spectrum of the amorphous substance is basic as figure selected from the group below characterizes: Fig. 1-1, Fig. 2-1, Fig. 4-1, Fig. 5-1, Figure 10-1 or Figure 11-1.

In another preferred example, the crystal form of the crystal is selected from the group: crystal form 3, crystal form 6, crystal form 7, crystal form 8, crystal form 9, Crystal form 12, crystal form 13 or crystal form 14.

In another preferred example, the X-ray powder diffraction pattern of the crystal form N has including 3 or 3 or more and is selected from The characteristic peak of the value of 2 θ ± 0.2 ° shown in corresponding table N-1, wherein N is 3,6,7,8,9,12,13 or 14.

In another preferred example, the X-ray powder diffraction pattern of the crystal form N, which further comprises 3 or 3 or more, has The characteristic peak of the value of 2 θ ± 0.2 ° shown in the corresponding table N.

In another preferred example, the X-ray powder diffraction pattern of the crystal form N is substantially as figure N-2 is characterized.

In another preferred example, the infrared spectrum of the crystal form N is characterized as schemed N-1 substantially, and wherein N is 3,6,12,13 Or 14.

In another preferred example, the infrared spectrum of the salt is basic as figure selected from the group below characterizes: Fig. 1-1, Fig. 2-1, Fig. 3-1, Fig. 4-1, Fig. 5-1, Fig. 6-1, Figure 10-1, Figure 11-1, Figure 12-1, Figure 13-1 or Figure 14-1.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 3 has including 3 or 3 or more and is selected from down The characteristic peak of 2 θ ± 0.2 ° value in table 3-1:

Table 3-1

2θ(°)
	16.5
18.4
	19.7
21.9
	23.3
25.0
	27.4

In another preferred example, the X-ray powder diffraction pattern of the crystal form 3, which further comprises 3 or 3 or more, has The characteristic peak of 2 θ ± 0.2 ° value in table 3.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 3 is basic as Fig. 3-2 is characterized.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 6 has including 3 or 3 or more and is selected from The characteristic peak of 2 θ ± 0.2 ° value in the following table 6-1:

Table 6-1

2θ(°)
	6.5
13.0
	18.7
19.5
	21.7
26.1
	26.4
27.0
	27.2
39.6

In another preferred example, the X-ray powder diffraction pattern of the crystal form 6, which further comprises 3 or 3 or more, has The characteristic peak of 2 θ ± 0.2 ° value in table 6.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 6 is basic as Fig. 6-2 is characterized.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 7 has including 3 or 3 or more and is selected from down The characteristic peak of 2 θ ± 0.2 ° value in table 7-1:

Table 7-1

In another preferred example, the X-ray powder diffraction pattern of the crystal form 7, which further comprises 3 or 3 or more, has The characteristic peak of 2 θ ± 0.2 ° value in table 7.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 7 is basic as Fig. 7 is characterized.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 8 has including 3 or 3 or more and is selected from down The characteristic peak of 2 θ ± 0.2 ° value in table 8-1:

Table 8-1

2θ(°)
	6.4
12.9
	15.9
18.9
	19.5
19.7
	21.6
26.0
	26.3
27.1

In another preferred example, the X-ray powder diffraction pattern of the crystal form 8, which further comprises 3 or 3 or more, has The characteristic peak of 2 θ ± 0.2 ° value in table 8.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 8 is basic as Fig. 8 is characterized.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 9 has including 3 or 3 or more and is selected from The characteristic peak of 2 θ ± 0.2 ° value in the following table 9-1:

Table 9-1

2θ(°)
	13.0
16.0
	16.2
18.6
	18.9
21.0
	21.6
26.3
	27.2
31.7

In another preferred example, the X-ray powder diffraction pattern of the crystal form 9, which further comprises 3 or 3 or more, has The characteristic peak of 2 θ ± 0.2 ° value in table 9.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 9 is basic as Fig. 9 is characterized.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 12 has including 3 or 3 or more and is selected from The characteristic peak of 2 θ ± 0.2 ° value in the following table 12-1:

Table 12-1

2θ(°)
	18.4
18.8
	21.6
24.0
	24.4
24.8
	27.8

In another preferred example, the X-ray powder diffraction pattern of the crystal form 12 further comprises 3 or 3 or more and has There is the characteristic peak of the 2 θ ± 0.2 ° values in table 12.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 12 is basic as Figure 12-2 is characterized.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 13 has including 3 or 3 or more and is selected from The characteristic peak of 2 θ ± 0.2 ° value in the following table 13-1:

Table 13-1

2θ(°)
	15.1
18.3
	18.9
21.5
	24.0
24.4
	24.8
27.8

In another preferred example, the X-ray powder diffraction pattern of the crystal form 13 further comprises 3 or 3 or more and has There is the characteristic peak of the 2 θ ± 0.2 ° values in table 13.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 13 is basic as Figure 13-2 is characterized.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 14 further comprises 3 or 3 or more and has There is the characteristic peak of the 2 θ ± 0.2 ° values in the following table 14-1:

Table 14-1

In another preferred example, the X-ray powder diffraction pattern of the crystal form 14 includes 3 or 3 or more selected from table 14 In 2 θ ± 0.2 ° value.

In another preferred example, the X-ray powder diffraction pattern of the crystal form 14 is basic as Figure 14-2 is characterized.

The second aspect of the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes:

(a) salt as described in first aspect present invention, and (b) pharmaceutically acceptable carrier.

In another preferred example, the salt is crystal or amorphous substance or its optical isomer or its solvate.

In another preferred example, described pharmaceutical composition further includes other anti-tumor drugs.

In another preferred example, other anti-tumor drugs are the immunotherapy medicaments (such as target therapeutic agent) of cancer Or chemotherapeutics.

In another preferred example, other anti-tumor drugs are selected from the group: PD-1 antibody, CTLA-4 antibody, PD-L1 are anti- Body, PD-L2 antibody, other chemotherapeutics, or combinations thereof.

The third aspect of the present invention provides salt as described in the first aspect of the invention or as described in respect of the second aspect of the invention Pharmaceutical composition purposes, be used for:

(i) indoles amine -2,3- dioxygenase inhibitor is prepared；

(ii) drug for the disease that preparation prevention and/or treatment indoles amine -2,3- dioxygenase mediate；

(iii) tumor is prepared；Or

(iv) anti-inflammatory drug is prepared.

In another preferred example, the disease that indoles amine -2,3- dioxygenase mediates is the tryptophan metabolism that IDO is mediated The disease of the pathological characteristics of approach.

In another preferred example, the disease that indoles amine -2,3- dioxygenase mediates be cancer, neurological disease, Eye illness, mental handicape, depression, anxiety disorder, Alzheimer disease and/or autoimmune disease.

In another preferred example, the cancer includes but is not limited to: colon cancer, breast cancer, gastric cancer, lung cancer, colorectal cancer, pancreas Gland cancer, oophoroma, prostate cancer, kidney, liver cancer, the cancer of the brain, melanoma, Huppert's disease, chronic granulocytic leukemia, Neoplastic hematologic disorder, lympha tumour, including the metastasis in other tissues or organ far from tumour original site.

The fourth aspect of the present invention provides a kind of preparation method of salt as described in the first aspect of the invention, including step It is rapid: by compound shown in Formulas I and acid at salt in atent solvent, or by the salt of compound shown in Formulas I or its solvate lazy It is recrystallized in property solvent, to obtain salt as described in the first aspect of the invention；

Wherein, the acid is hydrochloric acid, hydrobromic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, methanesulfonic acid, phosphoric acid or sulfuric acid.

In another preferred example, the compound of formula I is Formulas I -1, I-2 or I-3 compound.In another preferred example, institute Stating compound of formula I is compound A or B.

In another preferred example, the atent solvent includes water, ethers, alcohols, ketone, nitrile, esters, cyclic ethers class, rouge Fat hydro carbons, or combinations thereof.

In another preferred example, the atent solvent is selected from the group: ether, t-butyl methyl ether, ethyl acetate, ethyl alcohol, second Nitrile, or combinations thereof.

In another preferred example, the method includes the steps: compound of formula I is dissolved in atent solvent, described in addition Acid obtains salt described in first aspect present invention.

The fifth aspect of the present invention provides a kind of disease prevented and/or treatment indoles amine -2,3- dioxygenase mediates Method, including giving salt as described in the first aspect of the invention or pharmaceutical composition as described in respect of the second aspect of the invention to patient The step of object.

In another preferred example, the disease that indoles amine -2,3- dioxygenase mediates is cancer, and the method is further Include the step of additional anticancer agent (also referred to as anti-tumor drug, the anti-tumor drug are as described above) is applied to patient.

It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.

Detailed description of the invention

Fig. 1-1 shows the infrared spectrum of amorphous substance 1；Fig. 1-2 shows the X-ray powder diffraction figure of amorphous substance 1.

Fig. 2-1 shows the infrared spectrum of amorphous substance 2；Fig. 2-2 shows the X-ray powder diffraction figure of amorphous substance 2.

Fig. 3-1 shows the infrared spectrum of crystal form 3；Fig. 3-2 shows the X-ray powder diffraction figure of crystal form 3.

Fig. 4-1 shows the infrared spectrum of amorphous substance 4；Fig. 4-2 shows the X-ray powder diffraction figure of amorphous substance 4.

Fig. 5-1 shows the infrared spectrum of amorphous substance 5；Fig. 5-2 shows the X-ray powder diffraction figure of amorphous substance 5.

Fig. 6-1 shows the infrared spectrum of crystal form 6；Fig. 6-2 shows the X-ray powder diffraction figure of crystal form 6.

Fig. 7 shows the X-ray powder diffraction figure of crystal form 7.

Fig. 8 shows the X-ray powder diffraction figure of crystal form 8.

Fig. 9 shows the X-ray powder diffraction figure of crystal form 9.

Figure 10-1 shows the infrared spectrum of amorphous substance 10；Figure 10-2 shows that the x-ray powder of amorphous substance 10 spreads out Penetrate figure.

Figure 11-1 shows the infrared spectrum of amorphous substance 11；Figure 11-2 shows that the x-ray powder of amorphous substance 11 spreads out Penetrate figure.

Figure 12-1 shows the infrared spectrum of crystal form 12；Figure 12-2 shows the X-ray powder diffraction figure of crystal form 12.

Figure 13-1 shows the infrared spectrum of crystal form 13；Figure 13-2 shows the X-ray powder diffraction figure of crystal form 13.

Figure 14-1 shows the infrared spectrum of crystal form 14；Figure 14-2 shows the X-ray powder diffraction figure of crystal form 14.

Specific embodiment

The present inventor passes through long-term in-depth study, it has unexpectedly been found that the salt of compound of formula I and its a variety of amorphous Object and polymorph, salt (including the amorphous substance and polymorph) stable structure have good photostability, thermostabilization Property, non-hygroscopic and pharmacokinetic property, solubility property are good, and purity and bioavilability significantly improve, and can efficiently press down IDO enzyme processed, particularly suitable for developing and producing the IDO enzyme inhibitor of high quality, to the optimization of the dosage form of such IDO inhibitor and Exploitation has important value.On this basis, inventor completes the present invention.

Definition

Unless otherwise defined, otherwise whole technologies used herein and scientific term all have such as fields of the present invention The normally understood identical meanings of those of ordinary skill.

As used herein, in use, term " about " means that the value can be from enumerating in mentioning the numerical value specifically enumerated Value changes not more than 1%.For example, as used herein, statement " about 100 " include 99 and 101 and between whole values (for example, 99.1,99.2,99.3,99.4 etc.).

As used herein, term " containing " or " including (including) " can be open, semi-enclosed and enclosed.It changes Yan Zhi, the term also include " substantially by ... constitute " or " by ... constitute ".

As used herein, term " n or n or more 2 θ values selected from the group below " refers to including n and any just whole greater than n Number (such as n, n+1 ...), wherein upper limit Nup is the number of all 2 θ peak values in the group.Such as " 3 or 3 or more " are not only Including 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 ... each positive integer of upper limit Nup, also Including the ranges such as " 4 or 4 or more ", " 5 or 5 or more ", " 6 or 6 or more ".

Term " alkyl " refers to monovalence radical of saturated aliphatic alkyl, has 1 to 12 (preferably 1 to 10) a carbon atom, including straight Chain and branched hydrocarbyl, such as methyl (i.e. CH₃), ethyl (i.e. CH₃CH₂), n-propyl (i.e. CH₃CH₂CH₂), isopropyl (i.e. (CH₃)₂CH-), normal-butyl (i.e. CH₃CH₂CH₂CH₂), isobutyl group (i.e. (CH₃)₂CHCH₂), sec-butyl (i.e. (CH₃)(CH₃CH₂)CH-)、 Tert-butyl (i.e. (CH₃)₃C-), n-pentyl (i.e. CH₃CH₂CH₂CH₂CH₂), neopentyl (i.e. (CH₃)₃CCH₂-)。

As used herein, term " aryl " refers to the monovalent aromatic carbocyclic base of 6 to 20 (preferable 6-14) carbon atoms Group, it has monocycle (such as phenyl) or condensed ring (such as naphthalene or anthryl), if tie point is in aromatic carbon original, condensed ring may right and wrong (such as 2- benzoxazolone, 2H-1,4- benzoxazine -3 (4H) -one -7- base etc.) of armaticity.Preferred aryl include phenyl and Naphthalene.

As used herein, term " naphthenic base " refer to it is with 3 to 12 (preferably 3 to 10) a carbon atoms, have monocycle Or the cyclic alkyl of polycyclic (including fused system, bridged-ring system and spiro ring system).In fused ring system, one or more rings can To be naphthenic base, heterocycle, aryl or heteroaryl, as long as connection site is the ring by naphthenic base.The example of suitable naphthenic base Son includes: for example, adamantyl, cyclopropyl, cyclobutyl, cyclopenta and cyclooctyl.

As used herein, term " halogenated " or " halogen " refer to fluorine, chlorine, bromine and iodine.

As used herein, term " heteroaryl " is with 1 to 10 carbon atom and 1 to 4 in finger ring selected from oxygen, nitrogen and sulphur Heteroatomic aromatic group, such heteroaryl can be (such as pyridyl group or furyl) or condensed ring (such as indolizine base of monocycle (indolizinyl) or benzothienyl), wherein the condensed ring can be it is nonaromatic and/or containing a hetero atom, As long as tie point is the atom by armaticity heteroaryl.In one embodiment, the annular atom nitrogen of heteroaryl and/or sulphur is optionally It is oxidized to N- oxide (N-O), sulfinyl or sulfonyl.Preferably heteroaryl include pyridyl group, pyrrole radicals, indyl, Thienyl and furyl.In one embodiment, heteroaryl refers to 3-14 unit's heteroaryl, it is therefore preferable to 5-12 unit's heteroaryl.

As used herein, term " substituted heteroaryl " refers to is taken by 1 to 5, preferably 1 to 3, more preferable 1 to 2 Heteroaryl replaced Dai Ji, the substituent group are selected from and identical substituent group defined in substituted aryl.

As used herein, term " heterocycle " or " heterocycle " or " Heterocyclylalkyl " or " heterocycle " refer to saturation, part Saturated or unsaturated group (but not being armaticity) has monocycle or condensed ring (including bridged-ring system and spiro ring system, ring Inside there is 1 to 10 carbon atom and 1 to 4 hetero atom selected from nitrogen, sulphur or oxygen, in fused ring system, one or more rings can To be naphthenic base, aryl or heteroaryl, as long as tie point passes through nonaro-maticity ring.In one embodiment, the nitrogen of heterocyclic group is former Son and/or sulphur atom are optionally oxidized, to provide N- oxide, sulfinyl and sulfonyl moieties.

As used herein, term " substituted heterocycle " or " substituted Heterocyclylalkyl " or " substituted heterocycle " refer to by 1 to 5 (such as 1 to 3) heterocyclic group replaced a substituent group, replace base phase defined in the substituent group and substituted naphthenic base Together.

As used herein, term " stereoisomer " refers to the different compound of the chirality of one or more Stereocenters. Stereoisomer includes enantiomter and diastereoisomer.

As used herein, term " tautomer " refers to the alternative form of the different compound in proton position, such as enol- The tautomeric form of ketone and imine-enamine tautomers or heteroaryl, the heteroaryl include with the part-NH- of ring and Ring=N- part connection annular atom, such as pyrazoles, imidazoles, benzimidazole, triazole and tetrazolium.

" prodrug " refers to any derivative of embodiment compound, when being applied to subject, can directly or The compound or its active metabolite or residue of ground connection offer embodiment.Particularly preferred derivative and prodrug are those, when When being applied to subject, the bioavilability of embodiment compound is improved (as the compound of oral administration is easier to be absorbed Into blood) or relative to parent species improve parent compound to biology compartment (such as brain or lymphatic system) transport derivative Object and prodrug.Prodrug includes the esters form of the compounds of this invention.

Compound of formula I and its salt

In formula,

R¹、R²、R³、R⁴It is defined as described above with Ar.

Patent application CN105481789A describes a kind of containing sulphoxide imine and the IDO of 1,2,5- oxadiazoles structure inhibition Agent formula (I) compound and preparation method thereof and activity test, all the contents of the application are incorporated herein by reference.

The salt of heretofore described compound of formula I is selected from the group: hydrochloride, hydrobromate, toluenesulfonate, benzene sulphur Hydrochlorate, mesylate, phosphate or sulfate.

In another preferred example, the compound of formula I is Formulas I -1, I-2 or I-3 compound.

In another preferred example, the compound of formula I is S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine (compound A).

In another preferred example, the compound of formula I is R- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine (compound B).

Preferred salt of the invention includes (but being not limited to): compound A1, compound A2, compound A-13, compound A4, Compound A-45, compound A6, compound B-11, compound B2, compound B3, compound B4 or compound B5.

Polymorph

It is exactly to exist in the form of crystallization that solid, which is not in the form of unbodied,.In the case where crystal form, molecule is fixed In three-dimensional lattice case.When compound is crystallized out from solution or slurries, the space lattice that it can be different is arranged Crystallization (this property is referred to as " polymorphism "), forms the crystal with different crystal forms, this various crystal form Referred to as " polymorph ".The different polymorphs of given substance can in terms of one or more physical attributes (such as solubility and Rate of dissolution, true specific gravity, crystalline form, accumulation mode, mobility and/or solid-state stability) it is different from each other.

The polymorphic forms of compound can show different fusing points, hygroscopicity, stability, solubility, biological utilisation Degree and mobility etc., and these are an important factor for influencing druggability.

As used herein, term " polymorph of the invention " includes the polymorph of the salt of compound of formula I.

Preferred polymorph of the present invention includes (but being not limited to): formula A3 compound polymorph 3, formula A6 compound is more Crystal form object 6,7,8,9, formula B3 compound polymorph 12, formula B4 compound polymorph 13 or formula B5 compound polymorph 14。

Amorphous substance

The amorphous substance of the salt of compound of formula I provided by the invention, has that solubility is big, is easily absorbed by the human body, oral life The advantages that object utilization rate is high.The amorphous substance of the salt of compound of formula I can be by being dissolved in suitable solvent for the salt of compound of formula I In, it is obtained by the methods of being freeze-dried, being spray-dried.

Preferred amorphous substance of the present invention includes (but being not limited to): formula A1 compound amorphous substance 1, formula A2 compound without Amorphous substance 2, formula A4 compound amorphous substance 4, formula A5 compound amorphous substance 5, formula B1 compound amorphous substance 10 or formula B2ization Close object amorphous substance 11.

Solvate

In compound or drug molecule and solvent molecule contact process, external condition and interior condition factor cause solvent point The situation that son forms eutectic with compound molecule and remains in solid matter is difficult to avoid that.It is formed after drug and solvent crystallization Substance is referred to as solvate (solvate).Be easy with organic compound formed solvate solvent type be water, methanol, benzene, Ethyl alcohol etc..

Hydrate is a kind of special solvate.In pharmaceuticals industry, no matter the synthesis of bulk pharmaceutical chemicals, pharmaceutical preparation, In medicine storage and pharmaceutical activity evaluation, hydrate all has the value individually discussed because of its particularity.

Crystallization

It can be by working solution, so that the solubility limit of compound of interest is exceeded, to complete production scale Crystallization.This can be completed by a variety of methods, for example, dissolved compound at relatively high temperature, then cools down solution To saturation limit.Or by boiling, atmospheric evaporation, vacuum drying or by some other methods reduce liquid bulk Product.It can be come by the way that anti-solvent or compound is added in the mixture of solvent or such solvent wherein with low solubility Reduce the solubility of compound of interest.Another optional method is to adjust pH value to reduce solubility.Related crystallization aspect It is described in detail and refers to Crystallization, the third edition, J W Mullens, Butterworth-Heineman Ltd., 1993,ISBN 0750611294。

If it is expected that the formation of salt with crystallization occur simultaneously, if salt is smaller than dissolution of raw material degree in reaction medium, Acid or alkali appropriate, which is added, can lead to the direct crystallization of required salt.Equally, smaller than reactant solubility in finally desired form Medium in, the completion of synthetic reaction can make final product direct crystallization.

The optimization of crystallization may include that the crystal of required form is used to be inoculated in crystallization medium as crystal seed.In addition, many knots Crystal method uses the combination of above-mentioned strategy.A kind of mode be by the dissolution of interested compound in a solvent, then by controlled The anti-solvent of proper volume is added in mode, so that system is just under saturated level.At this point, the crystal seed of required form can be added (and the integrality for keeping crystal seed), by the way that system is cooling to complete to crystallize.

As used herein, term " room temperature " refers generally to 4-30 DEG C, preferably refers to 20 ± 5 DEG C.

Pharmaceutical composition

The present invention also provides a kind of pharmaceutical compositions, it includes the active constituent and medicine within the scope of safe and effective amount Acceptable carrier on.

" active constituent " of the present invention refers to compound of Formula I of the present invention or its pharmaceutically acceptable Salt, its stereoisomer or its tautomer or its prodrug.In another preferred example, " active constituent " of the invention refers to Formulas I Close the salt of object, including its polymorph and amorphous substance.

" active constituent " of the present invention and pharmaceutical composition can be used as IDO inhibitor.In another preferred example, it is used for The drug of preparation prevention and/or treatment tumour.In another preferred example, it is used to prepare prevention and/or treats the disease that IDO is mediated Drug.

" safe and effective amount " refers to: the amount of active constituent is enough to be obviously improved the state of an illness, and is unlikely to generate serious pair Effect.In general, pharmaceutical composition contains 1-2000mg active constituent/agent, more preferably, contain 10-200mg active constituent/agent.Compared with Goodly, it is described it is " one " be a tablet.

" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or gelatinous mass, They are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as composition Middle each component energy and active constituent of the invention and they between mutually admix, and significantly reduce the drug effect of active constituent.

The compound of the preferred embodiment of the present invention can be used as the administration of independent active agents, can also with it is one or more its The reagent that it is used for treating cancer is applied in combination.The compound of the preferred embodiment of the present invention and known therapeutic agent and anticancer agent group Close using be also it is effective, the combination of the compound and other anticancer agents or chemotherapeutics that are currently known preferred embodiment range it It is interior.The example of this kind of medicament can be found in " cancer theory and practice oncology " (Cancer Principles and Practice Of Oncology), V.T.Devita and S.Hellman (editor), the 6th edition (on 2 15th, 2001), Lippincott Williams&Wilkins publishing house.Special nature and related cancer based on drug, those of ordinary skill in the art's energy Enough distinguish effective pharmaceutical agent combinations.This anticancer agent is including but not limited to as follows: estrogenic agents, androgen receptor Regulator, retinoid receptor modulators, cytotoxicity/cytostatic agent, antiproliferative, prenyl protein transferase Inhibitor, HMG-CoA reductase inhibitor and other angiogenesis inhibitors, cell Proliferation and survival signaling inhibitor, apoptosis Inducer and the interference reagent of cell cycle checkpoint (cell cycle checkpoint), CTLA4 antibody, PD-1 antibody, PD-L1 antibody etc..It is also effective when the compound of preferred embodiment is administered simultaneously with radiotherapy.

Generally, it is preferred to the compound of embodiment by with therapeutically effective amount, pass through any one of the medicament with similar effect The acceptable mode application of kind.The actual amount of the compound (i.e. active constituent) of preferred embodiment is determining according to Multiple factors, As the severity of disease to be treated, the age of patient and relative health, the effect for being used compound, application path And form and other factors.The drug can be applied repeatedly for one day, it is preferable that once or twice daily.All of these factors taken together is all Within the scope of the attending physician the considerations of.

The purpose of preferred embodiment, treatment effective dose usually can be to patient's one-time use or by several times application it is every Total daily dose, for example, about 0.001 to about 1000 mg kg of body weight daily, it is preferable that daily about 1.0 to about 30 milligrams/thousand Gram weight.Units dosage composition (Dosage unit composition) may include its dosage factor to form daily dosage. The selection of dosage form depends on various factors, such as the bioavilability of mode of administration and drug substance.Generally, it is preferred to embodiment Compound, which can be used as pharmaceutical composition and pass through any one following route, to be administered: oral, Formulations for systemic administration is (such as transdermal, intranasal or logical Cross suppository) or parenteral administration (such as intramuscular, intravenously or subcutaneously).Preferably administration mode is oral, can be according to bitter degree tune Save convenient daily dose.The form that composition can be taken be tablet, pill, capsule, semisolid, pulvis, sustained release preparation, solution, Suspension, elixir, aerosol or any other composition appropriate.Another side of preferred application preferred embodiment compound Formula is sucking.This be it is a kind of by therapeutic agent be shipped directly to respiratory tract effective ways (referring to, such as U.S. Patent number 5,607, 915)。

Suitable pharmaceutically acceptable carrier or excipient include: that such as inorganic agent and drug transport modifying agent and promotion Agent, such as calcium phosphate, magnesium stearate, talcum, monosaccharide, disaccharides, starch, gelatin, cellulose, sodium carboxymethylcellulose pyce, carboxymethyl are fine Tie up element, glucose, hydroxypropyl-B- cyclodextrin, polyvinylpyrrolidone, low melt wax, ion exchange resin etc. and its any two Kind or a variety of combinations.Liquid and semisolid excipient can be selected from glycerol, propylene glycol, water, ethyl alcohol and various oil, including stone Oil, animal oil, vegetable oil or synthesis source, such as peanut oil, soya-bean oil, mineral oil, sesame oil.Preferred liquid-carrier, especially It is the carrier for Injectable solution, including water, salt water, glucose aqueous solution and ethylene glycol.Other suitable pharmaceutically may be used The excipient of receiving is in " Remington pharmaceutical science " (Remington ' s Pharmaceutical Sciences), Mack Pub.Co., New Jersey (1991) are described, and are totally incorporated herein by reference.

As used herein, term " pharmaceutically acceptable salt " refers to the non-toxic acid or alkaline-earth metal of compound of Formula I Salt.These salt can be made in situ when being finally recovered and purifying compound of Formula I or respectively by suitable organic or inorganic acid or Alkali is reacted with alkalinity or acidic functionality to be made.Representative salt includes, but are not limited to: acetate, adipate, alginates, Citrate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphor hydrochlorate, camsilate, two Gluconate, cyclopentane propionate, lauryl sulfate, esilate, flucoheptanoate, glycerophosphate, hemisulfic acid Salt, enanthate, caproate, fumarate, hydrochloride, hydrobromate, hydriodate, 2- isethionate, lactate, Malaysia Hydrochlorate, mesylate, nicotinate, 2- naphthyl sulphonic acids salt, oxalates, embonate, pectate, rhodanate, 3- phenyl Propionate, picrate, Pivalate, propionate, succinate, sulfate, tartrate, rhodanate, p-methyl benzenesulfonic acid Salt and undecanoate.In addition, nitrogenous basic group can be by following reagent quaternization: alkyl halide, such as methyl, second Base, propyl, the chloride of butyl, bromide and iodide；Dialkyl sulfate, such as dimethyl, diethyl, dibutyl and diamyl Base sulfuric ester；The chloride, bromide and iodide of long chain halide such as decyl, lauryl, myristyl and stearyl；Aralkyl Base halide such as benzyl and phenylethyl bromide etc..Thus water-soluble or oil-soluble or dispersible product are obtained.It can be used for shape Example at the acid of pharmaceutically acceptable acid-addition salts include as hydrochloric acid, sulfuric acid, phosphoric acid inorganic acid, and such as oxalic acid, Malaysia Acid, methanesulfonic acid, succinic acid, citric acid organic acid.Base addition salts can be in situ when being finally recovered and purifying compounds of formula I Be made or make carboxylic moiety respectively with suitable alkali (hydroxide of such as pharmaceutically acceptable metal cation, carbonate or Bicarbonate) or ammonia or organic primary, secondary or tertiary amine reaction be made.Pharmaceutically acceptable salt includes, but are not limited to based on alkali The cation of metal and alkaline-earth metal, such as the salt and nontoxic ammonium, quaternary ammonium and amine cation of sodium, lithium, potassium, calcium, magnesium, aluminium, Include, but are not limited to: ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethamine etc..Other representatives The organic amine for being used to form base addition salts of property includes diethylamine, ethylenediamine, ethanol amine, diethanol amine, piperazine etc..

Main advantages of the present invention are:

(1) salt (including amorphous substance and polymorph) stable structure of formula Compound I has good light steady Qualitative, thermal stability, non-hygroscopic and pharmacokinetic property, solubility property is good, and purity and bioavilability significantly improve, IDO enzyme can efficiently be inhibited, particularly suitable for developing and producing the IDO enzyme inhibitor of high quality.

(2) salt (including amorphous substance and polymorph) preparation method of formula Compound I is simple, quick, mild, Operation is simple, low in cost, and process stabilizing, favorable reproducibility, yield is higher, is suitble to industry amplification quantity production.

(3) salt of formula Compound I has antitumor, neurodegenerative disease (Alzheimer disease), anti-inflammatory etc. A variety of pharmacological activity.

Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.

Experimental material used in following embodiment and reagent can obtain unless otherwise instructed from commercially available channel.Room temperature or Room temperature refers to 4 DEG C -30 DEG C, preferably 15-25 DEG C.

X-ray powder diffraction

The method for measuring the X-ray powder diffraction of crystal is well known in the art.

X-ray powder diffraction figure of the present invention is in PANalytical X ' Pert Powder X-ray powder diffraction It is acquired on instrument.

The method parameter of X-ray powder diffraction of the present invention is as follows:

X ray reflection parameter: Cu, K α

Kα1: 1.540598；Kα2: 1.544426

1 intensity of K α 2/K α: 0.50

Voltage: 40 volt (kV)

Electric current: 40 milliamperes (mA)

Scanning range: 3.0 to 40.0 degree

Embodiment 1

S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine (compound A) hydrochloride

Compound A (200mg, 0.475mmol) is dissolved in 2mL ether, and HCl solution (0.14mL, 4M1,4- is then added dropwise Dioxane solution), it is stirred overnight, solid is precipitated and is collected by filtration, dry after being washed with a small amount of ether, obtained solid is S- (Z)- Nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- Amitraz hydrochloride amorphous substance 1 (175mg).Fusing point: 108.8-111.0 DEG C.Infrared spectrum is substantially as Figure 1-1.

The XRD diffracting spectrum of gained amorphous substance 1 is substantially as shown in Figs. 1-2, and diffraction angular data is substantially as shown in table 1 below.

Table 1

Embodiment 2

S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine mesylate

Compound A (100mg) is dissolved in 2mL ether, and methanesulfonic acid (24mg) then is added dropwise, is stirred overnight, and solid is precipitated It is collected by filtration, dry after being washed with a small amount of ether, obtained solid is S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine mesylate amorphous substance 2 (60mg).It is molten Point: 98.7-101.7 DEG C.Infrared spectrum is basic as shown in Fig. 2-1.

The XRD diffracting spectrum of gained amorphous substance 2 is basic as shown in Fig. 2-2, and diffraction angular data is substantially as shown in table 2 below.

Table 2

Embodiment 3

S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine benzene sulfonate crystal form 3

Compound A (100mg) is dissolved in 2mL ether, and benzene sulfonic acid (39.5mg) then is added dropwise, is stirred overnight, and is precipitated solid Body is collected by filtration, dry after being washed with a small amount of ether, and obtained solid is S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine benzene sulfonate crystal form 3 (125mg).Fusing point: 170.0-172.1℃.Infrared spectrum is substantially as shown in figure 3-1.

Substantially as shown in figure 3-2, diffraction angular data is substantially as shown in table 3 below for the XRD diffracting spectrum of gained crystal form 3.

Table 3

Embodiment 4

S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- formamidine sulphinic acid salt

Compound A (100mg) is dissolved in 2mL ether, and sulfuric acid acid (45mg) is then added dropwise, is stirred overnight, and solid is precipitated It is collected by filtration, dry after being washed with a small amount of ether, obtained solid is S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- formamidine sulphinic acid salt amorphous substance 4 (90mg).It is molten Point: 88.9-90.0 DEG C.Infrared spectrum is basic as shown in Fig. 4-1.

Substantially as shown in the Fig. 4-2, diffraction angular data is substantially as shown in table 4 below for the XRD diffracting spectrum of gained amorphous substance 4.

Table 4

Embodiment 5

S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine Hemisulphate

Compound A (100mg) is dissolved in 2mL ether, and sulfuric acid acid (23mg) is then added dropwise, is stirred overnight, and solid is precipitated It is collected by filtration, dry after being washed with a small amount of ether, obtained solid is S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine Hemisulphate amorphous substance 5 (90mg).It is molten Point: 133.1-135.0 DEG C.Infrared spectrum is substantially as shown in fig. 5-1.

The XRD diffracting spectrum of gained amorphous substance 5 is basic as shown in Fig. 5-2.

Embodiment 6

S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate crystal form 6

Compound A (200mg) is dissolved in 2mL ether, and then p-methyl benzenesulfonic acid (90mg, hydrate), is stirred overnight, Solid is precipitated to be collected by filtration, dry after being washed with a small amount of ether, obtained solid is S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl Base -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate crystal form 6 (217mg).Fusing point: 127.8-129.0 DEG C.Infrared spectrum is substantially as in Figure 6-1.

Substantially as in fig. 6-2, diffraction angular data is substantially as shown in table 6 below for the XRD diffracting spectrum of gained crystal form 6.

Table 6

Embodiment 7

S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate crystal form 7

Compound A (100mg) is dissolved in 3mL ethyl acetate, and then p-methyl benzenesulfonic acid (49.6mg, hydrate), is stirred It mixes overnight, reaction solution is concentrated under reduced pressure into 2.5mL, is then slowly added into a small amount of n-hexane until solid precipitation, it is small to continue stirring 2 When, solid is collected by filtration, and dry after being washed with a small amount of n-hexane, obtained solid is S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '- Hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate crystal form 7 (100mg).Fusing point: 127.0-129.0 DEG C

The XRD diffracting spectrum of gained crystal form 7 is basic as shown in fig. 7, diffraction angular data is substantially as shown in table 7 below.

Table 7

Embodiment 8

S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate crystal form 8

Compound A (100mg) is dissolved in 3mL ethyl alcohol, and then p-methyl benzenesulfonic acid (49.6mg, hydrate), stirred Night, reaction solution are concentrated under reduced pressure into 2.5mL, are then slowly added into a small amount of n-hexane until solid precipitation, continue stirring 2 hours, Gu Body is collected by filtration, dry after being washed with a small amount of n-hexane, and obtained solid is S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl- 4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate crystal form 8 (90mg).Fusing point: 127.-128.9 DEG C.

The XRD diffracting spectrum of gained crystal form 8 is basic as shown in figure 8, diffraction angular data is substantially as shown in table 8 below.

Table 8

Embodiment 9

S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate crystal form 9

Compound A (10g) is suspended in 150mL methyl tertiary butyl ether(MTBE), and p-methyl benzenesulfonic acid (4.5g, hydration is then added dropwise Object) methyl tertiary butyl ether(MTBE) (50mL) solution, be stirred overnight, solid is collected by filtration, with a small amount of methyl tertiary butyl ether(MTBE) (10mL), institute Obtaining solid is S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - 1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate crystal form 9 (11.5g).Fusing point: 126-129 DEG C.LCMS (liquid chromatogram-matter Spectrum): 420.9 ([M+1]⁺)。

Nuclear magnetic resonance data is as follows:

¹H NMR(400MHz,CD₃OD): δ 7.73 (d, 2H, J=8.4Hz), 7.25 (d, 2H, J=8.0Hz), 7.14- 7.16(m,1H),7.05-7.09(m,1H),6.86-6.90(m,1H),4.10-4.24(m,2H),3.98-4.00(m,2H), 3.69(s,3H),2.39(s,3H).

The XRD diffracting spectrum of gained crystal form 9 is basic as shown in figure 9, diffraction angular data is substantially as shown in table 9 below.

Table 9

Embodiment 10

R- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine (compound B) hydrochloride

Compound B (43mg) is dissolved in 2mL ether, and HCl solution (0.05mL, 4M Isosorbide-5-Nitrae-dioxane is then added dropwise Solution), it is stirred overnight, solid is precipitated and is collected by filtration, dry after being washed with a small amount of ether, obtained solid is that R- (Z)-(3- is bromo- for nitrogen- 4- fluorophenyl)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine hydrochloric acid Salt amorphous substance 10 (35mg).Fusing point: 108.0-111.0 DEG C.Infrared spectrum is basic as shown in Figure 10-1.

The XRD diffracting spectrum of gained amorphous substance 10 is basic as shown in Figure 10-2, and diffraction angular data is basic such as the following table 10 institute Show.

Table 10

Embodiment 11

R- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- formamidine sulphinic acid salt

Compound B (100mg) is dissolved in 2mL ether, and sulfuric acid acid (45mg) is then added dropwise, is stirred overnight, and solid is precipitated It is collected by filtration, dry after being washed with a small amount of ether, obtained solid is R- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- formamidine sulphinic acid salt amorphous substance 11 (90mg).It is molten Point: 85.1-87.0 DEG C.Infrared spectrum is basic as shown in Figure 11-1.

The XRD diffracting spectrum of gained amorphous substance 11 is basic as shown in Figure 11-2, and diffraction angular data is basic such as the following table 11 institute Show.

Table 11

Embodiment 12

R- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine Hemisulphate (crystal form 12)

Embodiment 12 is by being made crystal form 12 using method same as Example 5 using compound B as raw material.Fusing point: 133.1-135.0℃.Infrared spectrum is basic as shown in Figure 12-1.

Substantially as shown in fig. 12-2, diffraction angular data is substantially as shown in table 12 below for the XRD diffracting spectrum of gained crystal form 12.

Table 12

Embodiment 13

R- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine mesylate

Compound B (43mg) is dissolved in 2mL ether, and methanesulfonic acid (10mg) then is added dropwise, is stirred overnight, and solid mistake is precipitated Filter is collected, dry after being washed with a small amount of ether, and obtained solid is R- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine Mesylate Form 13 (35mg).Fusing point: 99.0-101.5℃.Infrared spectrum is basic as shown in Figure 13-1.

The XRD diffracting spectrum of gained crystal form 13 is basic as shown in Figure 13-2, and diffraction angular data is substantially as shown in table 13 below.

Table 13

Embodiment 14

R- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The preparation of 1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate

Compound B (43mg) is dissolved in 2mL ether, and then p-methyl benzenesulfonic acid (90mg, hydrate), is stirred overnight, Solid is precipitated to be collected by filtration, dry after being washed with a small amount of ether, obtained solid is R- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl Base -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) -1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate crystal form 14 (50mg).Fusing point: 127.6-129.7 DEG C.Infrared spectrum is basic as shown in Figure 14-1.

The XRD diffracting spectrum of gained crystal form 14 is basic as shown in Figure 14-2, and diffraction angular data is substantially as shown in table 14 below.

Table 14

Embodiment 15

S- (Z)-nitrogen-(the bromo- 4- fluorophenyl of 3-)-nitrogen '-hydroxyl -4- ((2- (sulphur-methyl sulfoxide imines) propyl) amino) - The oral medicine generation in mouse of 1,2,5- oxadiazoles -3- carbonamidine toluenesulfonate (compound A-p-TsOH salt, crystal form 6) Dynamics

1. dosage regimen

BALB/c mouse 6, male, weight 18-22g, stomach-filling compound A-p-TsOH salt (crystal form 6, embodiment 6), such as Shown in the following table 5:

Table 5

Gastric infusion is formulated as suspension with 0.5%HPMC, fasting 12h, free water before testing.After administration 2h it is unified into Food.

2. blood sampling time point and sample treatment:

Gastric infusion: 0.25,0.5,1.0,2.0,4.0,8.0,12 and for 24 hours after administration；

It takes blood 0.01ml in centrifuge tube through mouse femoral vein in the above setting time point, 100 μ L is added and contain The isometric mixed solution precipitating of 50nMverapamil acetonitrile methanol, is vortexed 1min, is centrifuged (15000rpm) 5min.It takes on 10 μ L Clear liquid and 30 μ L ACN (acetonitrile): H₂Sample introduction is analyzed after O=1:1 (v/v) is mixed.

3. sample test and data analysis

4. test result

Intragastric administration on mice gives the pharmacokinetic parameters that compound A is measured after 140mg/kg and 420mg/kg COMPOUNDS EXAMPLE 6 It is shown in Table 15 and table 16.

Compound A pharmacokinetic parameters are measured after 15 intragastric administration on mice 140mg/kg COMPOUNDS EXAMPLE 6 of table

The pharmacokinetics number of compound A is measured after 16 intragastric administration on mice 420mg/kg COMPOUNDS EXAMPLE 6 of table

The result shows that after 140mg/kg and 420mg/kg oral administration, the compound A in Mice Body of COMPOUNDS EXAMPLE 6 Exposed amount (AUC_0-24h) it is respectively 13151ngh/mL and 30034ngh/mL, there is apparent linear dose-relationship, from And guarantee the dose-effect relationship of drug effect in clinical test.

Embodiment 16

The solubility test of embodiment 2 and 6 compound of embodiment from free alkali cpd A in different pH buffer solutions

Test-compound (1-2mg) is respectively put into the vial of two 1.5mL, and the PBS buffering that 1mL difference pH is added is molten Liquid, sample are then placed in Eppendorf Thermomixer Confort plate shaker and shake under the revolving speed of 1100rpm 24 hours.0.2mL filtering is then taken out, with 1000 times of methanol dilution, sample is quantitatively divided filtrate with above-mentioned LC/MS method It analyses, the mean concentration of compound A is calculated by extension rate in two samples.

The solubility of 17 embodiment 2 of table and embodiment 6 from free alkali cpd A in different pH buffer solutions

Above-mentioned test data shows that embodiment 2 and 6 compound of the embodiment solubility in PBS buffer solution have significant increasing It is high.

All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims

1. the salt of a kind of compound of formula I or its optical isomer:

In formula,

R³And R⁴Respectively stand alone as hydrogen, substituted or unsubstituted C₁-C₁₀Alkyl；Or R³And R⁴Be collectively formed three to octatomic ring or three to Eight circle heterocyclic rings, wherein hetero atom is sulphur, oxygen, NH or NR^h；

Ar is substituted or unsubstituted phenyl ring, five yuan or six membered heteroaryl, and the substitution refers to the original of one or more hydrogen on Ar Son is optionally substituted by halogen；

The integer that n is 2 to 8；

Wherein, the salt is selected from the group: hydrochloride, hydrobromate, toluenesulfonate, benzene sulfonate, mesylate, phosphoric acid Salt or sulfate；

Unless stated otherwise, the substitution refers to that one or more hydrogen atoms on group are replaced by substituent group selected from the group below: Halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, hydroxyl, amino, nitro, aldehyde radical ,-CF₃,-CN or-SF₅。

2. salt as described in claim 1, which is characterized in that the compound of formula I is selected from following I-1, I-2 or I-3:

Wherein, Ar, R³And R⁴Definition as described in the appended claim 1.

3. salt as claimed in claim 2, which is characterized in that the compound of formula I is selected from the group:

4. salt as claimed in claim 2, which is characterized in that the salt is selected from the group:

5. salt as described in claim 1, which is characterized in that the salt is amorphous substance or crystal.

6. salt as claimed in claim 5, which is characterized in that the crystal form of the crystal is selected from the group: crystal form 3, crystal form 6, crystal form 7, crystal form 8, crystal form 9, crystal form 12, crystal form 13 or crystal form 14；Or

The X-ray powder diffraction pattern of the amorphous substance is basic as figure selected from the group below characterizes: Fig. 1-2, Fig. 2-2, Fig. 4- 2, Fig. 5-2, Figure 10-2 or Figure 11-2.

7. salt as claimed in claim 6, which is characterized in that the X-ray powder diffraction pattern of the crystal form N includes 3 or 3 A above characteristic peak with the 2 θ ± 0.2 ° value shown in the corresponding table N-1, wherein N be 3,6,7,8,9,12,13 or 14。

8. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes:

(a) salt as described in any in claim 1-7, and (b) pharmaceutically acceptable carrier.

9. the purposes of any salt or pharmaceutical composition according to any one of claims 8 in claim 1-7, which is characterized in that For:

(i) indoles amine -2,3- dioxygenase inhibitor is prepared；

(iii) tumor is prepared；Or

(iv) anti-inflammatory drug is prepared.

10. a kind of preparation method of such as salt of any of claims 1-7, which is characterized in that comprising steps of by Formulas I Shown compound and acid in atent solvent at salt, or by the salt of compound shown in Formulas I or its solvate in atent solvent Recrystallization, to obtain salt of any of claims 1-7；