WO2019153216A1 - 取代芳基胺醇化合物及其制备方法和用途 - Google Patents

取代芳基胺醇化合物及其制备方法和用途 Download PDF

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WO2019153216A1
WO2019153216A1 PCT/CN2018/075915 CN2018075915W WO2019153216A1 WO 2019153216 A1 WO2019153216 A1 WO 2019153216A1 CN 2018075915 W CN2018075915 W CN 2018075915W WO 2019153216 A1 WO2019153216 A1 WO 2019153216A1
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group
acid
formula
compound
pharmaceutically acceptable
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PCT/CN2018/075915
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French (fr)
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赵锡龙
李银博
林秀
李�杰
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北京梅尔森医药技术开发有限公司
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Priority to PCT/CN2018/075915 priority Critical patent/WO2019153216A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the technical field of medicine and relates to a substituted arylamine alcohol compound, a preparation method thereof and use thereof.
  • Hemangioma and vascular malformation are two manifestations of vascular disease. The essential difference between the two is that hemangioma has abnormal proliferation of vascular endothelial cells, but vascular malformation does not.
  • ISSVA The International Society for the Study of Vascular Anomalies (ISSVA) classifies hemangiomas into benign, locally invasive (intersection) and malignant, the most common infantile hemangiomas ( Infantile hemangioma, IH) is a benign hemangioma.
  • ISSVA classifies simple vascular malformations into five major categories: capillary malformation (CM), lymphatic malformation (LM), venous malformation (VM), arteriovenous malformation (AVM), and arteriovenous fistula (AVF).
  • CMTC congenital skin marble-like telangiectasia
  • CMTC congenital skin marble-like telangiectasia
  • Infantile hemangioma is a congenital benign tumor derived from vascular endothelial cells. Infants and hemangioma usually appear around 1 week after birth, and the ratio of male to female is about 1:3. In the child, the hemangioma is in the proliferative phase within 1 year old, and gradually disappears after 1 year old. Most hemangioma can gradually disappear after several years. However, half of the children will have residual skin and subcutaneous tissue degeneration, including scars, atrophy, hypopigmentation, telangiectasia and sagging skin, affecting the appearance to varying degrees.
  • a small number of infantile hemangioma grows rapidly in the proliferative phase. If it is not actively treated, it may be accompanied by various complications such as ulcer, hemorrhage, infection or dysfunction (sight, hearing, breathing, swallowing, etc.), and even serious life-threatening.
  • hemangiomas The etiology and pathogenesis of hemangiomas are not fully understood at present, and are currently considered to be closely related to "angiogenesis” and “angiogenesis” (Vasculogenesis), and the latter has been considered to play a major role in recent years. Histopathological studies of hemangiomas showed that a variety of endothelial cytokines, angiogenic factors, growth factors, vascular endothelial cell receptor family (VEGF-R), bone marrow markers, etc.
  • VEGF-R vascular endothelial cell receptor family
  • hemangiomas were highly expressed in proliferative hemangiomas; In the resected hemangioma tissues, the apoptosis of endothelial cells is accelerated, and the levels of mast cells and tissue inhibitor of metalloproteinase (TIMP) are up-regulated. Therefore, it is believed that the formation of hemangiomas may be due to changes in the local microenvironment and abnormalities in endothelial cell self-transformation, resulting in abnormal proliferation of vascular endothelial cells.
  • TIMP tissue inhibitor of metalloproteinase
  • Vascular malformation is a congenital malformation of blood vessels or lymphatic vessels. It occurs due to abnormalities in the process of Vasculogenesis during embryonic development, resulting in abnormalities in vascular structure, which are present at birth, but sometimes not obvious. It gradually became apparent after birth. The incidence of vascular malformation is equal in men and women, does not self-resolved, and grows in proportion to the growth and development of the patient. Capillary malformation, also known as Port-wine stains (PWS) or port wine stains, can also be combined with different vascular malformations. Modern science has confirmed that both capillary malformations and Venous malformation (VM) are associated with specific gene mutations in humans.
  • PWS Port-wine stains
  • VM Venous malformation
  • CM capillary malformation
  • port wine stain is a congenital skin telangiectasia malformation
  • the incidence rate is 0.3% to 0.5%, often occurs at birth, occurs in Head, face, neck, can also affect the limbs and trunk. It appears as a erythema with a clear and irregular edge, which is faded or not completely faded.
  • the color of the lesion gradually deepens and thickens, and nodular hyperplasia occurs.
  • Some severe lesions may be accompanied by soft tissue, even the proliferation of bone tissue, leading to increased deformation of the affected part, which seriously affects the quality of life of patients.
  • the existing medical treatments for hemangioma and vascular malformation are: palliative therapy, surgery, radionuclide application, freezing, electrocautery, pulsed dye laser (FPDL), photodynamic therapy (PDT), topical drugs. Treatment, systemic medication, etc.
  • these treatment methods have the disadvantages of damaging the skin tissue, possibly leaving scars, and poor patient tolerance.
  • Some methods have poor curative effect, repeated illness, and low cure rate, so it is difficult to be accepted by patients.
  • Another object of the present invention is to provide a process for the preparation of the substituted arylamine alcohol compound.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising the substituted arylamine alcohol compound of the present invention.
  • a further object of the invention is to provide the use of said substituted arylamine alcohol compounds.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • Ar is an aryl group, a heteroaryl group, or an aryl or heteroaryl group substituted by one or more C 1 -C 6 alkyl groups, a halogen, a hydroxyl group, an amine group, a fluorenyl group, an aryl group, a heterocyclic group;
  • X is O, NH or S
  • R is a C 1 -C 4 fatty alkyl group or a C 1 -C 4 fatty alkyl group substituted by a halogen or a phenyl group;
  • Ar can be phenyl, naphthyl, heteroaryl, or one or more C 1 -C 6 alkyl, halogen, hydroxy, amine, thiol, non-aromatic a heterocyclic group-substituted phenyl, naphthyl or heteroaryl; preferably, Ar is phenyl, 4-chlorophenyl, 2,4-difluorophenyl, 1H-indenyl, 1-naphthyl , 2-furyl, 5-methyl-2-furyl, 2-thienyl, 1-imidazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, 2-quinolyl, thiazolyl, Thiadiazolyl or 3-(4-morpholin-1,2,5-thiadiazole).
  • R can be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, 4-phenyl-2-butyl , chloromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, fluoroethyl, 1-chloropropyl, chloroisopropyl, 1-chlorobutyl, 2-chlorobutyl, fluorine Butyl or chloro-tert-butyl.
  • Preferred compounds of the compounds of formula (I) according to the invention may also be as shown in the following table:
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon radical containing a specific number of carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • aryl refers to a carbocyclic aromatic moiety (eg, phenyl or naphthyl) containing a specific number of carbon atoms, preferably 6-10 carbon atoms.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl and the like.
  • aryl also includes every possible positional isomer of an arene group, such as 1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, and the like.
  • heterocycle means a 5 to 7 membered monocyclic heterocyclic ring or an 8 to 10 membered bicyclic heterocyclic ring system in which either ring is saturated or partially It is saturated or unsaturated, and if it is a single ring, it may optionally be benzofused.
  • Each heterocycle consists of one or more carbon atoms and one to four heteroatoms selected from the group consisting of nitrogen (N), oxygen (O) and sulfur (S), and wherein the nitrogen and sulfur heteroatoms can optionally be Oxidation, the nitrogen atom may optionally be quaternized and include any bicyclic group wherein any of the heterocycles defined above may be fused to a benzene ring.
  • N nitrogen
  • O oxygen
  • S sulfur
  • the nitrogen atom may optionally be quaternized and include any bicyclic group wherein any of the heterocycles defined above may be fused to a benzene ring.
  • Heteroaromatic or “heteroaryl” is included within the above heterocyclic ring, and broadly refers to a heterocyclic ring wherein the ring system is an aromatic monocyclic or polycyclic atomic group having 5 to 20 carbon atoms, preferably 5 to 10 carbons. An atom in which one or more of the ring carbons are each substituted with a hetero atom (eg, N, O, S, and P).
  • Preferred heteroaryl groups include 5-6 membered monocyclic heteroaryl groups and 8-10 membered bicyclic heteroaryl groups.
  • heterocycle groups in which a non-aromatic ring containing a hetero atom is fused to one or more aromatic rings.
  • heterocycle also include every possible positional isomer of a heterocyclyl group, for example 1-dihydroindenyl, 2-di Hydroquinone, 3-dihydroindenyl.
  • heterocyclic ring examples include: imidazolyl, quinolyl, isoquinolyl, indolyl, pyridyl, pyrrolyl, pyrazolyl, piperidinyl, pyranyl, morpholinyl, furyl, thienyl, Thiazolyl, benzofuranyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazolyl, thienyl, tetrahydrothiophenyl, dihydropyranyl and the like.
  • heteroatom refers to nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen, such as N(O) ⁇ N + -O - ⁇ , and any oxidized form of sulfur, such as S(O) and S(O). 2 ) and any quaternized form of basic nitrogen.
  • the structures described herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations of each asymmetric center.
  • racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers of the present compounds are expressly included within the scope of the invention. While specific stereochemical configurations can be used to describe the particular compounds exemplified herein, compounds having any relative stereochemistry at any given chiral center, or mixtures thereof, are foreseen.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • a compound having the structure to replace hydrogen with hydrazine or hydrazine or to replace carbon with 13 C- or 14 C-enriched carbon.
  • the pharmaceutically acceptable salt is a compound of formula (I) with a pharmaceutically acceptable inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, high chloride Acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, C a salt formed by one or more of a diacid and benzenesulfonic acid; other acids, such as oxalic acid, although not in themselves pharmaceutically acceptable, may be obtained by obtaining a compound of the invention or a pharmaceutically acceptable acid addition salt thereof Used in the preparation of salts for use as intermediates.
  • a pharmaceutically acceptable inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,
  • the pharmaceutically acceptable salt also includes a salt of a compound of formula (I) with a suitable pharmaceutically acceptable base, such as a sodium salt, a potassium salt, a calcium salt, magnesium Salt, zinc salt, choline salt, ammonium salt, quaternary ammonium salt or other organic amine salt.
  • a suitable pharmaceutically acceptable base such as a sodium salt, a potassium salt, a calcium salt, magnesium Salt, zinc salt, choline salt, ammonium salt, quaternary ammonium salt or other organic amine salt.
  • Salts of the compounds of the invention can be prepared by methods known to those skilled in the art.
  • the compound of the present invention can be treated with a suitable base or acid in a suitable solvent to provide the corresponding salt.
  • the present invention provides a process for the preparation of a compound of formula (I), wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared according to the following reaction scheme:
  • Ar is an aryl group, a heteroaryl group, or an aryl or heteroaryl group substituted by one or more C 1 -C 6 alkyl groups, a halogen, a hydroxyl group, an amine group, a fluorenyl group, an aryl group, a heterocyclic group;
  • X is O, NH or S
  • X 1 is Cl, Br or I
  • R is a C 1 -C 4 fatty alkyl group or a C 1 -C 4 fatty alkyl group substituted by a halogen or a phenyl group;
  • B represents an inorganic or organic acid or a base.
  • the method for preparing the compound of the formula (I) or a pharmaceutically acceptable salt thereof according to the present invention may comprise the following steps:
  • the compound of the formula (I) obtained in the step 2) is formed into a pharmaceutically acceptable salt with an inorganic or organic acid or a base.
  • a reactive group other than XH when a reactive group other than XH is present on the Ar group, for example, a reactive group such as a hydroxyl group, an amine group, or a thiol group, then in the step 1) previously comprising the step of protecting the reactive group such as a hydroxyl group, an amine group or a thiol group other than XH on the Ar group with a protecting group, and further comprising after step 2) The step of removing the protecting group.
  • a reactive group other than XH for example, a reactive group such as a hydroxyl group, an amine group, or a thiol group
  • the group protecting the reactive group such as a hydroxyl group, an amine group, or a thiol group other than XH on the Ar group is selected from the group consisting of: benzyloxycarbonyl (Cbz) , tert-butoxycarbonyl (Boc), pentamethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyloxycarbonyl (Teoc), methoxycarbonyl, phthaloyl (Pht), pair Tosyl (Tos), trifluoroacetyl (Ffa), benzoyl (Bz), trityl (Trt), p-methoxybenzyl (PMB) or benzyl (Bn).
  • the method of deprotecting a group to give a target compound can employ methods known to those skilled in the art, such as catalytic hydrogenolysis (eg, Pd/H 2 or sodium borohydride). , acid hydrolysis cracking (such as hydrobromic acid, trimethyliodosilane, trifluoroacetic acid, or ethyl acetate), sodium or lithium / liquid ammonia reduction, tetrakistriphenylphosphine palladium (Pd (PPh 3 ) 4 ) , tetraethylammonium fluoride (TEAF), or tetramethylammonium fluoride (TMAF).
  • catalytic hydrogenolysis eg, Pd/H 2 or sodium borohydride
  • acid hydrolysis cracking such as hydrobromic acid, trimethyliodosilane, trifluoroacetic acid, or ethyl acetate
  • sodium or lithium / liquid ammonia reduction such as tetrakistri
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically Acceptable excipients.
  • the pharmaceutical composition may further comprise an active ingredient other than the compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may be an oral drug, an injection, a drug for oral administration or sublingual administration, a drug for topical transdermal administration, or a semi-solid preparation for topical use. Or a drug administered in the lumen.
  • the pharmaceutical composition may be a tablet, a capsule, a granule, a pill, a powder, an oral solution, an oral suspension, an oral emulsion, an effervescent, an ointment, a cream, a gel, a sputum.
  • Agent paint, film, patch, patch, spray, aerosol, topical solution, topical foam, suppository or enema.
  • the administration of the compound provided by the present invention can also be used for the treatment of hemangiomas and vascular malformations, in view of factors such as improving the bioavailability of the drug, reducing unnecessary adverse reactions or side effects, and people's medication habits,
  • the compounds provided by the present invention are more suitable for use in the therapeutic field in the form of pharmaceutical compositions.
  • a binder for example, polyvinylpyrrolidone, gelatin, hydroxypropylmethylcellulose
  • a lubricant for example, magnesium stearate
  • an inert diluent may be used.
  • silica silica
  • disintegrants e.g., starch, crosslinked polyvinylpyrrolidone, croscarmellose sodium
  • the pharmaceutical composition when the pharmaceutical composition is a drug for oral administration or sublingual administration, sucrose, maltose, acacia, tragacanth, gelatin, glycerin or the like, or other pharmaceutically acceptable excipients may be used. .
  • the active composition when the pharmaceutical composition is a drug to be administered through a lumen, such as a suppository, the active composition can be conveniently mixed with a softened or melted base, then cooled, and molded in a mold.
  • a commonly used suppository base may be selected from the group consisting of semi-synthetic fatty acid glycerides, cocoa butter, polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid esters, hydrogenated vegetable oils, glycerin gelatin, poloxamers, polyethylene glycols. Classes, etc.
  • Other components such as a pharmaceutically acceptable excipient or a bacteriostatic agent such as a surfactant, a diluent, and a lubricant may be added as needed.
  • the pharmaceutical composition and the appropriate adjuvant when the pharmaceutical composition is an injection, can be dissolved or dispersed in water, oil or other pharmaceutically acceptable medium to prepare a sterile injection, sterile for injection. Powder, concentrated solution for sterile injection, etc.
  • the main excipient component forming the gelling agent may be selected from the group consisting of carbomer, hypromellose, methylcellulose, polyethylene glycol, carboxymethyl Cellulose, sodium hyaluronate, or other pharmaceutically acceptable excipients.
  • the main excipient component constituting the cream oil phase may be selected from the group consisting of liquid paraffin, stearic acid, oleic acid, petrolatum, beeswax, glyceryl stearate, and sixteen Octaol, methyl silicone oil, etc.;
  • the emulsifier component constituting the cream may be selected from sodium lauryl sulfate, sodium stearate, polyoxyethylene hydrogenated castor oil, Tween polymer, carbomer, or other pharmacy Acceptable excipients.
  • the pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable ingredients such as a transdermal absorption enhancer, in view of the type of pharmaceutical preparation of the pharmaceutical composition.
  • pharmaceutically acceptable ingredients such as a transdermal absorption enhancer, in view of the type of pharmaceutical preparation of the pharmaceutical composition.
  • the transdermal absorption enhancer may be selected from the group consisting of azone, dimethyl sulfoxide, mercaptomethyl sulfoxide, sodium lauryl sulfate, sodium tetradecyl sulfate, and hexadecyl trimethyl Ammonium chloride, Tween polymer, Span polymer, ethanol, propylene glycol, glycerin, polyethylene glycol, urea, allantoin, menthol, menthol, limonene, borneol, oleic acid, lauric acid, Squalane, eucalyptus oil, wintergreen oil, clove oil, fennel oil, cinnamon oil, turpentine, cocoa butter, or a mixture of two or more of the above.
  • the flavoring agent may be selected from the group consisting of sucrose, monosaccharide syrup, stevioside, sucralose, sodium saccharin, glycerin, sorbitol, mannitol, aspartame, peppermint oil, citric acid, natural flavors. , artificial flavor, or a mixture of two or more of the above.
  • the preservative may be selected from the group consisting of methylparaben, hydroxyethyl ester, hydroxypropyl propyl ester, hydroxyphenyl butyl acrylate, potassium sorbate, sodium benzoate, calcium propionate, sodium dehydroacetate, sodium lactate, Benzyl alcohol, phenylethyl alcohol, chlorobutanol, chlorhexidine, ethanol, or a mixture of two or more of the above.
  • the pigment may be selected from inorganic pigments such as titanium dioxide, iron oxide red, iron oxide yellow, and iron oxide black, and may also be selected from organic pigments such as chlorophyll, carotene, lycopene, and carmine, or both. And a mixture of two or more kinds.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in the treatment of hemangiomas and/or veins Use in tube malformation drugs.
  • the invention provides a method of treating a hemangioma and/or a vascular malformation, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to the invention or a pharmaceutical thereof An acceptable salt, or a pharmaceutical composition of the invention.
  • the hemangiomas and/or vascular malformations are selected from the group consisting of capillary malformations, lymphatic malformations, venous malformations, arteriovenous malformations, infantile hemangiomas, pyogenic granulomas (also known as lobulated capillary hemangioma), Congenital skin marble-like telangiectasia (CMTC) or wine stain (also known as port wine stain).
  • CMTC Congenital skin marble-like telangiectasia
  • wine stain also known as port wine stain
  • the round bottom flask was charged with 150 g of t-butanol, 13 g of sodium t-butoxide, 20 g of 1-tert-butoxycarbonyl-3-hydroxy-1H-indole (II-1) and 17 g of epichlorohydrin, and reacted at 65 ° C. hour. After concentration under reduced pressure, 500 g of dichloromethane and 100 g of water were added to the concentrate, and the organic layer was separated and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 1-t-butoxycarbonyl-3-(1,2- ring. 20.5 g of oxypropenyloxy-1H-indole (III-1) as a white solid, yield 82.7%, HPLC purity 96.7%.
  • the synthesis method is the same as the synthesis of 1-[(1H-3-indolyl)oxy]-3-(4-phenyl-2-butylamino)-2-propanol (I-4), using 1- tert-Butoxycarbonyl-3-(1,2-epoxypropenyl)amino-amine-1H-indole (III-2) as a starting material to give 1-[(1H-3-indolyl)amino]-3 -(4-Phenyl-2-butylamino)-2-propanol (I-5) 3.2 g, as a white solid, yield 66.5%, HPLC purity 97.3%.
  • Oil phase 50.0 g of liquid paraffin, 200 g of stearic acid, and 100 g of glyceryl monostearate were mixed and heated to about 80 ° C for use.
  • Aqueous phase Another 150 g of glycerin and 5.0 g of sodium hydroxide were dissolved in water and heated together to an aqueous solution of about 80 °C.
  • Emulsification The aqueous phase was added to the oil phase while stirring, and the mixture was stirred at 80 ° C for 30 minutes.
  • Preparation of the substrate take 2.0 g of carbomer, add 100 g of water, stir, add 10% sodium hydroxide solution to adjust the pH to 8.0-9.0, add 1.5 g of Tween 80, 5.0 g of stearic acid and 20 g of glycerin. Stir well.
  • a transdermal patch the drug is quantitatively applied to a controlled release film, covered with a backing layer, heat-sealed, cut by size, packaged, and obtained.
  • Pretreatment The original and auxiliary materials were passed through a 100 mesh sieve, and povidone K30 was made into a 5% ethanol solution for use.
  • the granules are uniformly mixed with croscarmellose sodium, microcrystalline cellulose, micronized silica gel, and magnesium stearate.
  • the Lachen chicken cockscomb is a natural model of wine stains (PWS).
  • the dermis has a large number of dilated capillaries in the superficial dermis, which has more similarities with the pathological manifestations of wine stains. Therefore, a healthy male Laiheng chicken cockscomb was selected as a pathological model of wine stains, and a variety of substituted arylamine alcohol compound creams were prepared according to the method of Example 12, and preliminary pharmacodynamic studies were carried out.
  • the experimental animals were grouped according to a completely randomized grouping method, with 8 rats in each group: blank control group (not administered), matrix control group (administered with drug-free cream base) and pharmaceutical composition group (different doses respectively)
  • blank control group not administered
  • matrix control group administered with drug-free cream base
  • pharmaceutical composition group different doses respectively
  • a substituted arylamine alcohol compound of the invention A substituted arylamine alcohol compound of the invention.
  • the blank control group was not treated at all, and the matrix control group and the pharmaceutical composition group were respectively applied with a substrate (not added with a drug) or a cream prepared according to the method of Example 12 in a 2 cm ⁇ 1 cm area on both sides of the crown surface. 3 times for 30 days.
  • the relevant indicators were observed and measured every 3 days during the administration, and photographed under the same conditions until the end of the experiment.
  • the cockscomb tissue was removed and pathological sections were made for histopathological observation (HE staining).
  • the curative effect was divided into four levels.
  • the efficacy of each level was scored and expressed by the Efficacy Integrate Index (EII).
  • the effect is defined as grade I, indicating cure, indicating that the color of the cockscomb is very significant, the thickness is significantly thinner, close to the hardness of normal skin, and the microvessels are significantly reduced;
  • the curative effect was defined as grade II, indicating significant effect, indicating that the crown color disappeared significantly, the thickness was significantly thinner, the cockscomb was significantly softer, and the microvessels were significantly reduced;
  • the curative effect is defined as grade III, indicating that it is effective, indicating that the crown color is regressed obviously, the thickness is thinned, the cockscomb is obviously soft, and the microvessels are reduced;
  • the effect was defined as grade IV, indicating no effect, indicating that the color of the crown color was not obvious or almost unchanged, the thickness was slightly thinner or unchanged, the crown of the chicken was slightly soft or unchanged, and the microvessels were slightly reduced or unchanged.
  • the substituted arylamine alcohol compounds (e.g., I-1 to I-8) of the present invention and pharmaceutically acceptable salts thereof (e.g., IV-8) are preferred for hemangiomas and/or vascular malformations.
  • the 4-phenyl-2-butylamine group is substituted with a substituent with a large steric hindrance, especially when X is an oxygen atom (I-4), and the activity is optimal, and one of them can reach Cure standard requirements.
  • the medicinal salt of such compounds has a stronger therapeutic effect than the prototype compound (for example, the effective rate of IV-8 is 62.5% at a content of 0.5%, compared to I-8 The effective rate was 50.0%), and the therapeutic effect increased to some extent with the increase of the concentration, and the effective rate was increased from 50.0% (IV-8, 0.25%) to 75.0% (IV-8, 1.0%).

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Abstract

本发明涉及式（I）的化合物或其药学上可接受的盐，其中：Ar是芳基，杂芳基，或者被一个或多个C1-C6烷基、卤素、羟基、胺基、巯基、芳基、杂环基取代的芳基或杂芳基；X是O、NH或者S；R是C1-C4脂肪烷基，或被卤素或苯基取代的C1-C4脂肪烷基；和n＝1-3。本发明还提供了式（I）的化合物或其药学上可接受的盐的制备方法和用途。本发明的化合物可用于血管瘤和/或脉管畸形的治疗。

Description

取代芳基胺醇化合物及其制备方法和用途 技术领域
本发明属于医药技术领域，涉及取代芳基胺醇化合物及其制备方法和用途。
背景技术
血管瘤和脉管畸形是脉管性疾病的两种表现形式，两者的本质差别在于血管瘤存在血管内皮细胞的异常增殖，而脉管畸形则无此现象。
国际血管瘤和脉管畸形研究学会(The International Society for the Study of Vascular Anomalies，ISSVA)将血管瘤分为良性、局部侵袭性(交界性)及恶性三大类，最常见的婴幼儿血管瘤(Infantile hemangioma，IH)即属于良性血管瘤。ISSVA将单纯性血管畸形分为毛细血管畸形(CM)、淋巴管畸形(LM)、静脉畸形(VM)、动静脉畸形(AVM)和动静脉瘘(AVF)五大类，临床常见的葡萄酒色斑(又名鲜红斑痣)和先天性皮肤大理石样毛细血管扩张症(CMTC)即属于毛细血管畸形(CM)。
婴幼儿血管瘤(Infantile hemangioma，IH)是来源于血管内皮细胞的先天性良性肿瘤。婴幼儿血管瘤一般出生后1周左右出现，男女发病比例约为1：3。在患儿1岁以内血管瘤处于增殖期，1岁左右逐渐进入消退期，大多数血管瘤最终可在数年后逐渐消退。但半数患儿消退后会残存皮肤及皮下组织退行性改变，包括瘢痕、萎缩、色素减退、毛细血管扩张和皮肤松弛，不同程度地影响美观。
婴幼儿血管瘤自行消退的过程漫长，加之好发于头面颈部，外观畸形影响患儿早期身心发育，并且消退后可造成瘢痕等美观问题或畸形，难以消除，成为带给患儿及家属较大心理压力的一类疾病。
少数婴幼儿血管瘤增殖期生长迅速，如不积极处理，可伴发溃疡、出血、感染或功能障碍(视力、听力、呼吸、吞咽等)等各种并发症，严重者甚至危及生命。
血管瘤的病因与发病机制目前尚未完全明确，目前主要认为与“血管新生”(Angiogenesis)和“血管生成”(Vasculogenesis)密切相关，且近年认为后者起主要作用。血管瘤的组织病理学研究显示，增殖期血管瘤组织中，多种内皮细胞因子、成血管因子、生长因子、血管内皮细胞受体家族(VEGF-R)、骨髓标志物等均高表达；而在消退期血管瘤组织中，内皮细 胞凋亡加速、肥大细胞(Mast cell)以及金属蛋白酶组织抑制因子(Tissue inhibitor of metalloproteinase 1，TIMP)等水平上调。因此，认为血管瘤的形成可能是由于局部微环境的变化以及内皮细胞自身转化的异常，从而导致血管内皮细胞的异常增殖。
脉管畸形则是血管或淋巴管的先天性发育畸形，其发生是由于胚胎发育时期“血管生成”(Vasculogenesis)过程的异常，从而导致血管结构的异常，出生时即有，但有时并不明显，出生后逐渐明显。脉管畸形的男女发病率相等，不会自行消退，随患者的生长发育等比例生长。毛细血管畸形(Capillary malformation)，也称为葡萄酒色斑(Port-wine stains，PWS)或鲜红斑痣，毛细血管畸形也可合并不同的血管畸形。现代科学已证实，毛细血管畸形和静脉畸形(Venous malformation，VM)均与人体特定基因突变有关。
葡萄酒色斑(PWS)为最常见的毛细血管畸形(CM)，又名鲜红斑痣，系先天性皮肤毛细血管扩张畸形，发病率为0.3％～0.5％，常在出生时出现，好发于头、面、颈部，也可累及四肢和躯干。表现为边缘清楚而不规则的红斑，压之褪色或不完全褪色。随着年龄的增长，病灶颜色逐渐加深、增厚，并出现结节样增生。部分严重的病变可伴有软组织，甚至骨组织的增生，导致患部增大变形等，严重影响患者的生活质量。
血管瘤和脉管畸形在医学上现有的治疗方法主要有：姑息疗法、外科手术、放射性核素贴敷、冷冻、电灼、脉冲染料激光(FPDL)、光动力治疗(PDT)、局部药物治疗、全身药物治疗等。但这些治疗方法均存在损伤皮肤组织、可能遗留瘢痕，患者耐受性差的缺点，有的方法疗效较差、病情反复，治愈率低，因而难于被患者所接受。
因此，仍然需要研究和开发新的、可有效治疗血管瘤和/或脉管畸形的药物。
发明内容
因此，针对现有技术中存在的上述问题和缺陷，本发明的一个目的是提供一种用于血管瘤和/或脉管畸形的治疗的取代芳基胺醇化合物。
本发明的另一个目的是提供所述取代芳基胺醇化合物的制备方法。
本发明的又一个目的是提供包含本发明的取代芳基胺醇化合物的药物组合物。
本发明的再一个目的是提供所述取代芳基胺醇化合物的用途。
本发明的目的是通过以下技术方案来实现的。
一方面，本发明提供式(I)所示的化合物或其药学上可接受的盐，
Figure PCTCN2018075915-appb-000001
其中：
Ar是芳基，杂芳基，或者被一个或多个C 1-C 6烷基、卤素、羟基、胺基、巯基、芳基、杂环基取代的芳基或杂芳基；
X是O、NH或者S；
R是C 1-C 4脂肪烷基，或被卤素或苯基取代的C 1-C 4脂肪烷基；以及
n＝1-3，优选n＝1。
在本发明的某些实施方案中，其中，Ar可以是苯基，萘基，杂芳基，或者被一个或多个C 1-C 6烷基、卤素、羟基、胺基、巯基、非芳香杂环基取代的苯基、萘基或杂芳基；优选地，Ar是苯基、4-氯代苯基、2,4-二氟代苯基、1H-吲哚基、1-萘基、2-呋喃基、5-甲基-2-呋喃基、2-噻吩基、1-咪唑基、2-咪唑基、2-吡啶基、3-吡啶基、2-喹啉基、噻唑基、噻二唑基或3-(4-吗啉-1,2,5-噻二唑)基。
在本发明的某些实施方案中，其中，R可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基、仲丁基、4-苯基-2-丁基、氯甲基、氟甲基、1-氯乙基、2-氯乙基、氟乙基、1-氯丙基、氯代异丙基、1-氯丁基、2-氯丁基、氟丁基或氯代叔丁基。
在本发明的某些实施方案中，其中所述的式(I)所示的化合物选自：
1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)-2-丙醇；
1-[(1H-3-吲哚基)胺基]-3-(叔丁基胺基)-2-丙醇；
1-[(1H-3-吲哚基)硫基]-3-(叔丁基胺基)-2-丙醇；
1-[(1H-3-吲哚基)氧基]-3-(4-苯基-2-丁基胺基)-2-丙醇；
1-[(1H-3-吲哚基)胺基]-3-(4-苯基-2-丁基胺基)-2-丙醇；
1-[(1H-3-吲哚基)硫基]-3-(4-苯基-2-丁基胺基)-2-丙醇；
1-[(1-萘基)氧基]-3-(异丙基胺基)-2-丙醇；或
(S)-1-(叔丁基氨基)-3-[(4-吗啉基-1,2,5-噻二唑-3-基)氧]-2-丙醇。
本发明所述的式(I)的化合物中的优选化合物还可以如下表所示：
Figure PCTCN2018075915-appb-000002
在本发明中，单独或与任何其它术语组合使用的术语“烷基”是指含有具体数目碳原子的直链或支链饱和脂肪烃原子团。烷基的例子包括但不局限于：甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基等。
单独或与任何其它术语组合使用的术语“芳基”是指含有具体数目碳原子，优选6-10个碳原子的碳环芳香部分(例如苯基或萘基)。芳基的例子包括但不局限于：苯基，萘基，四氢萘基等。除非另有陈述，否则，术语“芳基”还包括芳烃基团的每个可能的位置异构体，例如1-萘基，2-萘基，5-四氢萘基等。
本文使用的术语“杂环”、“杂环的”和“杂环基”指的是5至7元单环杂环或8至10元双环杂环系统，其中任一环是饱和的、部分饱和的或不饱和的，并且如果是单环的话，其可以任选为苯并稠合的。每个杂环由一个或多个碳原子和一个至四个杂原子组成，杂原子选自氮(N)、氧(O)和硫(S)，且其中氮和硫杂原子可以任选被氧化，氮原子可以任选地被季铵化，并且包括任一双环基团，其中任何上述定义的杂环可以与苯环稠合。当杂环具有取代基时，应该理解，该取代基可以与环中的任何原子连接，无论杂原子或碳原子，条件是得到稳定的化学结构。“杂芳香”或“杂芳基”包括在上述杂环之内，并且泛指其中环系是含有5至20个碳原子的芳香单环或多环原子团的杂环，优选5至10个碳原子，其中一个或多个环碳 各自被杂原子(例如N、O、S和P)取代。优选的杂芳基包括5-6元单环杂芳基和8-10元双环杂芳基。还包括在术语“杂环”、“杂环的”或“杂环基”范围内的是其中含有杂原子的非芳香环与一个或多个芳香环稠合的基团。除非另有陈述，否则术语“杂环”、“杂环的”或“杂环基”还包括杂环基的每个可能的位置异构体，例如1-二氢吲哚基、2-二氢吲哚基、3-二氢吲哚基。杂环的例子包括：咪唑基，喹啉基，异喹啉基，吲哚基，吡啶基，吡咯基，吡唑基，哌啶基，吡喃基，吗啉基，呋喃基，噻吩基，噻唑基，苯并呋喃基，四氢吡喃基，四氢呋喃基，噻唑基，噻二唑基，噻吩基，四氢噻吩基，二氢吡喃基等。
术语“杂原子”是指氮、氧或硫，并且包括氮的任何氧化形式，例如N(O){N +-O -}，和硫的任何氧化形式，例如S(O)和S(O) 2，和任何碱性氮的季铵化形式。
在本发明中，取代基或变量的组合是容许的，只要这种组合可形成稳定或化学上可行的化合物即可。
除非另有说明，否则本文所描述的结构还意在包括该结构的所有立体化学形式，即每个不对称中心的R和S构型。因此，本化合物的外消旋体和外消旋混合物、单一对映体、非对映体混合物和单一非对映异构体明确地包括在本发明范围内。尽管可以用具体立体化学构型来描述本文举例说明的具体化合物，但在任何给定手性中心具有任一种相对立体化学的化合物或其混合物都是可以预见的。
除非另有说明，否则本文所描述的结构还意味着包括仅仅在存在一个或多个同位素富集的原子方面有差别的化合物。例如，具有所述结构的化合物，只是用氘或氚替代氢、或用 13C-或 14C-富集的碳替代碳，也在本发明的范围内。
对本领域技术人员显而易见的是，某些本发明的化合物可以存在交替互变异构形式。本化合物的所有这种互变异构形式都在本发明的范围之内。除非另有陈述，否则任何一种互变异构体的表述意味着包括另一个互变异构体。
在本发明的某些实施方案中，其中所述药学上可接受的盐为式(I)的化合物与可药用的无机酸或有机酸，如盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、乙磺酸、甲酸、苯甲酸、丙二酸和苯磺酸中的一种或多种所形成的盐；其它酸，例如草酸，尽管其本身不是 可药用的，但可以在获得本发明化合物或其可药用酸加成盐的过程中用于制备用作中间体的盐。
在本发明的某些实施方案中，其中所述药学上可接受的盐也包括式(I)的化合物与合适的可药用碱所形成的盐，如钠盐、钾盐、钙盐、镁盐、锌盐、胆碱盐、铵盐、季铵盐或其它有机胺盐。
本发明化合物的盐可以用本领域技术人员已知的方法制备。例如，在合适的溶剂中用合适的碱或酸处理本发明的化合物，可以得到相应的盐。
另一方面，本发明提供式(I)所述的化合物的制备方法，式(I)所述的化合物或其药学上可接受的盐可以按照如下反应过程进行制备：
Figure PCTCN2018075915-appb-000003
其中：
Ar是芳基，杂芳基，或者被一个或多个C 1-C 6烷基、卤素、羟基、胺基、巯基、芳基、杂环基取代的芳基或杂芳基；
X是O、NH或者S；
X 1是Cl、Br或者I；
R是C 1-C 4脂肪烷基，或被卤素或苯基取代的C 1-C 4脂肪烷基；以及
n＝1-3，优选n＝1；
B代表无机或有机酸、碱。
本发明所述的式(I)的化合物或其药学上可接受的盐的制备方法，可以包括以下步骤：
1)使式(II)所示的化合物与环氧卤代烃发生烃化反应得到式(III)所示的环氧烷取代的中间体；
2)将步骤1)得到的式(III)所示的环氧烷取代的中间体与RNH 2进行胺化反应得到式(I)所示的化合物；
3)任选地，将步骤2)得到的式(I)所示的化合物与无机或有机酸、碱形成药学上可接受的盐。
在本发明的某些实施方案中，在Ar-XH中，当Ar基团上存在除了XH之外的活性基团时，例如：羟基、胺基、或巯基等活性基团时，则在步骤1)之前还包括将所述Ar基团上的除XH之外的其余的羟基、胺基、或巯基等活性基团用保护基团进行基团保护的步骤，并且在步骤2)之后还包括脱去所述保护基团的步骤。
在本发明的某些实施方案中，其中所述的对Ar基团上除了XH之外的羟基、胺基、或巯基等活性基团进行基团保护的物质选自:苄氧羰基(Cbz)、叔丁氧羰基(Boc)、五甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Ffa)、苯甲酰基(Bz)、三苯甲基(Trt)、对甲氧苄基(PMB)或苄基(Bn)。
在本发明的某些实施方案中，其中所述脱去保护基团得到目标化合物的方法可采用本领域技术人员已知的方法，如：催化氢解(如Pd/H 2或硼氢化钠)、酸解裂解(如氢溴酸、三甲基碘硅烷、三氟乙酸、或氯化氢乙酸乙酯溶液)、钠或者锂/液氨还原、四三苯基膦钯(Pd(PPh 3) 4)、四乙基氟化铵(TEAF)、或四甲基氟化铵(TMAF)。
又一方面，本发明提供了一种药物组合物，其包含治疗有效量的本发明所述的式(I)所示的化合物或其药学上可接受的盐，以及一种或多种药学上可接受的辅料。其中，所述药物组合物还可以包含除式(I)所示的化合物或其药学上可接受的盐以外的活性成分。
在本发明的某些实施方案中，其中，所述药物组合物可以是口服药物、注射剂、用于口腔给药或舌下给药途径的药物、局部经皮给药的药物、外用半固体制剂或腔道给药的药物。
优选地，所述药物组合物可以为片剂、胶囊剂、颗粒剂、丸剂、散剂、口服溶液剂、口服混悬剂、口服乳剂、泡腾剂、软膏剂、乳膏剂、凝胶剂、搽剂、涂剂、涂膜剂、贴剂、贴膏剂、喷雾剂、气雾剂、外用溶液剂、外用泡沫剂、栓剂或灌肠剂。
尽管直接给予本发明提供的化合物同样可以起到治疗血管瘤和脉管畸形的治疗效果，但考虑到提高药物的生物利用度、减少不必要的不良反应或副作用，以及人们的用药习惯等因素，本发明提供的化合物更适合以药物组合物的形式用于治疗领域。
根据本发明，当所述药物组合物是片剂时，可选用粘合剂(例如聚乙烯吡咯烷酮、明胶、羟基丙基甲基纤维素)、润滑剂(例如硬脂酸镁)、惰 性稀释剂(例如二氧化硅)、崩解剂(例如淀粉、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠)及其它药学上可接受的辅料。
根据本发明，当所述药物组合物是通过口腔给药或舌下给药途径的药物时，可选用蔗糖、麦芽糖、阿拉伯胶、黄芪胶、明胶、甘油等，或其它药学上可接受的辅料。
根据本发明，当所述药物组合物是通过腔道给药的药物，如栓剂时，可方便地将活性组合物与软化或融化的基质混合，而后冷却，并在模型中成型而制得。常用的栓剂基质可选自半合成脂肪酸甘油酯、可可豆脂、聚氧乙烯硬脂酸酯、聚氧乙烯山梨聚糖脂肪酸酯、氢化植物油、甘油明胶、泊洛沙姆、聚乙二醇类等。根据需要，还可加入表面活性剂、稀释剂、润滑剂等药学上可接受的辅料或抑菌剂等其它成分。
根据本发明，当所述药物组合物是注射剂时，可将药物组合物与适宜的辅料溶解或分散于水、油或其它药学上可接受的介质中制成无菌注射液、注射用无菌粉末、无菌注射用浓溶液等。
根据本发明，当所述药物组合物是凝胶剂时，形成凝胶剂的主要辅料成分可选自卡波姆、羟丙甲纤维素、甲基纤维素、聚乙二醇、羧甲基纤维素、透明质酸钠，或其它药学上可接受的辅料。
根据本发明，当所述药物组合物是乳膏剂时，组成乳膏剂油相的主要辅料成分可选自液体石蜡、硬脂酸、油酸、凡士林、蜂蜡、甘油硬脂酸脂、十六十八醇、甲基硅油等；组成乳膏剂的乳化剂成分可选自十二烷基硫酸钠、硬脂酸钠、聚氧乙烯氢化蓖麻油、吐温类聚合物、卡波姆，或其它药学上可接受的辅料。
应该理解，除了具体提到的上述组分之外，考虑到所述药物组合物的药物制剂类型，本发明的药物组合物还可以包含药学上其它可以接受的成分，例如透皮吸收促进剂、矫味剂、防腐剂、抑菌剂、色素等。
根据本发明，所述的透皮吸收促进剂可选自氮酮、二甲亚砜、癸基甲基亚砜、十二烷基硫酸钠、十四烷基硫酸钠、十六烷基三甲基氯化铵、吐温类聚合物、司盘类聚合物、乙醇、丙二醇、甘油、聚乙二醇、尿素、尿囊素、薄荷脑、薄荷醇、柠檬烯、冰片、油酸、月桂酸、鲨烷、桉叶油、冬青油、丁香油、藏茴香油、肉桂油、松节油、可可脂，或上述两种及两种以上的混合物。
根据本发明，所述的矫味剂可选自蔗糖、单糖浆、甜菊苷、三氯蔗糖、糖精钠、甘油、山梨醇、甘露醇、阿斯巴甜、薄荷油、枸橼酸、天然香精、 人造香精，或上述两种及两种以上的混合物。
根据本发明，所述的防腐剂可选自羟苯甲酯、羟苯乙酯、羟苯丙酯、羟苯丁酯、山梨酸钾、苯甲酸钠、丙酸钙、脱氢乙酸钠、乳酸钠、苯甲醇、苯乙醇、三氯叔丁醇、氯己定、乙醇，或上述两种及两种以上的混合物。
根据本发明，所述的色素可选自二氧化钛、氧化铁红、氧化铁黄、氧化铁黑等无机色素，也可选自叶绿素、胡萝卜素、番茄红素、胭脂红等有机色素，或上述两种及两种以上的混合物。
再一方面，本发明提供了本发明所述的式(I)所示的化合物或其药学上可接受的盐、或本发明所述的药物组合物在制备用于治疗血管瘤和/或脉管畸形的药物中的用途。
又一方面，本发明提供了一种治疗血管瘤和/或脉管畸形的方法，该方法包括：向有需要的对象给予治疗有效量的本发明所述的式(I)的化合物或其药学上可接受的盐、或本发明所述的药物组合物。
优选地，所述血管瘤和/或脉管畸形选自毛细血管畸形、淋巴管畸形、静脉畸形、动静脉畸形、婴幼儿血管瘤、化脓性肉芽肿(又名分叶状毛细血管瘤)、先天性皮肤大理石样毛细血管扩张症(CMTC)或葡萄酒色斑(又名鲜红斑痣)。
通过大量的实验研究，本发明的发明人惊讶地发现了本发明所述的取代芳基胺醇类化合物在治疗血管瘤和脉管畸形疾病中的惊人疗效，而且其疗效远远超过了现有的局部药物疗法或全身药物治疗法，从而提供了一种更有效的、全新的血管瘤和脉管畸形的治疗药物。
此外，相比现有的用于治疗血管瘤或脉管畸形的姑息疗法、外科手术、放射性核素贴敷、冷冻、电灼、脉冲染料激光(FPDL)、光动力治疗(PDT)等方法，采用本发明所述的取代芳基胺醇类化合物治疗血管瘤或脉管畸形还成功地避免了现有的这些治疗方法中存在的损伤皮肤组织、可能遗留瘢痕，患者耐受性差的缺点。
具体实施方式
下面详细描述本发明的实施例，下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
另外，如果没有明确说明，在下面的实施例中所采用的所有试剂均为市场上可以购得的，或者可以按照本文或已知的方法合成的，对于没有列出的反应条件，也均为本领域技术人员可以获得的。
实施例1
1-叔丁氧羰基-3-(1,2-环氧丙烷)基氧基-1H-吲哚(III-1)的制备
Figure PCTCN2018075915-appb-000004
取圆底烧瓶，分别加入叔丁醇150g、叔丁醇钠13g、1-叔丁氧羰基-3-羟基-1H-吲哚(II-1)20g和环氧氯丙烷17g，65℃反应8小时。减压浓缩，向浓缩物中加入二氯甲烷500g和水100g，分出有机层，减压浓缩，剩余物用乙醇重结晶一次，得到1-叔丁氧羰基-3-(1,2-环氧丙烷)基氧基-1H-吲哚(III-1)20.5g，为白色固体，收率82.7％，HPLC纯度96.7％。
1H NMR(600MHz,DMSO-d 6):8.02-8.16(m,2H,Ar-H),7.52(s,1H,Ar-H),6.95-7.17(dd,2H,Ar-H),3.92-4.03(m,2H,OCH 2CH),3.52(m,1H，CHCH 2O),2.57–2.71(m,2H,CH 2CHCH 2O),1.62(s,9H,C(CH 3) 3)。
实施例2
1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)-2-丙醇(I-1)的制备
Figure PCTCN2018075915-appb-000005
取圆底烧瓶，分别加入二氯甲烷400g、1-叔丁氧羰基-3-(1,2-环氧丙烷)基氧基-1H-吲哚(III-1)10g和叔丁胺8.0g，搅拌滴加三乙胺12g，于20-30℃反应5小时。加入水150g，分取有机层，无水硫酸钠干燥，减压浓缩。向浓缩物中加入二氯甲烷300g，三氟乙酸5.0g，于20-30℃反应12小时。加水120g，分取有机层，无水硫酸钠干燥，减压浓缩，剩余物用乙酸乙酯/正己烷重结晶一次，得到1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)2-丙醇(I-1)6.9g，为白色固体，收率80.6％，HPLC纯度98.6％。
1H NMR(600MHz,DMSO-d 6):11.03(br s,1H,Ar-NH),7.19-7.20(m, 1H,Ar-H),6.95-6.99(m,2H,Ar-H),6.42-6.47(dd,2H,Ar-H),4.95(br s,1H,CHOH),3.97-4.03(m,2H,OCH 2CH),3.92(m,1H，CHCH 2N),2.58–2.76(m,2H,CHCH 2N),1.59(br s,1H,NHC(CH 3) 3),0.98(s,9H,C(CH 3) 3)。
实施例3
1-[(1H-3-吲哚基)氧基]-3-(4-苯基-2-丁基胺基)-2-丙醇(I-4)的制备
Figure PCTCN2018075915-appb-000006
取圆底烧瓶，分别加入二氯甲烷300g、1-叔丁氧羰基-3-(1,2-环氧丙烷)基氧基-1H-吲哚(III-1)10g和1-甲基-3-苯基丙胺8g，搅拌滴加三乙胺10g，于20-30℃反应5小时。加入水150g，分取有机层，无水硫酸钠干燥，减压浓缩。向浓缩物中加入二氯甲烷300g，三氟乙酸5.0g，于20-30℃反应12小时。加水120g，分取有机层，无水硫酸钠干燥，减压浓缩，剩余物用乙酸乙酯/正己烷重结晶一次，得到1-[(1H-3-吲哚基)氧基]-3-(4-苯基-2-丁基胺基)-2-丙醇(I-4)10.5g，为白色固体，收率78.4％，HPLC纯度98.3％。
1H NMR(600MHz,DMSO-d 6):11.01(br s,1H,Ar-NH),7.19-7.20(m,1H,Ar-H),6.95-6.99(m,2H,Ar-H),6.74-6.77(m,5H,Ar-H),6.42-6.47(dd,2H,Ar-H),4.94(br s,1H,CHOH),3.97-4.03(m,2H,OCH 2CH),3.92-3.98(m,1H,OCH 2CH),2.73-2.76(m,1H,CHCH 2N),2.58–2.66(m,4H,CH 2CHN,CH 2CH 2CH,CHCH 2N),1.76–1.79(m,2H,CH 2CHN),1.55(br s,1H,NHCHCH 3),0.98(d,3H,CHCH 3)。
实施例4
1-[(1H-3-吲哚基)胺基]-3-(叔丁基胺基)-2-丙醇(I-2)的制备
Figure PCTCN2018075915-appb-000007
参考1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)2-丙醇(I-1)的合成方法，制得1-[(1H-3-吲哚基)胺基]-3-(叔丁基胺基)-2-丙醇(I-2)4.8g，为白色固体，收率76.8％，HPLC纯度98.3％。
1H NMR(600MHz,DMSO-d 6):11.13(br s,1H,Ar-NH),9.63(br s,1H,NHCH 2CHNH),7.20-7.22(m,1H,Ar-H),6.95-6.99(m,2H,Ar-H),6.42-6.47(dd,2H,Ar-H),4.97(br s,1H,CHOH),3.63(m,1H，CHCH 2N),3.36-3.44(m,2H,ArNCH 2CH),2.58–2.76(m,2H,CHCH 2N),1.73(br s,1H,NHC(CH 3) 3),0.99(s,9H,C(CH 3) 3)。
实施例5
1-[(1H-3-吲哚基)硫基]-3-(叔丁基胺基)-2-丙醇(I-3)的制备
Figure PCTCN2018075915-appb-000008
参考1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)-2-丙醇(I-1)合成方法，以1-叔丁氧羰基-3-巯基-1H-吲哚(II-3)为起始原料，制得1-[(1H-3-吲哚基)硫基]-3-(叔丁基胺基)-2-丙醇(I-3)3.9g，为白色固体，收率57.9％，HPLC纯度98.7％。
1H NMR(600MHz,DMSO-d 6):11.03(br s,1H,Ar-NH),7.19-7.20(m,1H,Ar-H),6.95-6.99(m,2H,Ar-H),6.42-6.47(dd,2H,Ar-H),4.95(br s,1H,CHOH),3.93(m,1H，CHCH 2N),3.35-3.43(m,2H,SCH 2CH),2.58–2.76(m,2H,CHCH 2N),1.52(br s,1H,NHC(CH 3) 3),0.98(s,9H,C(CH 3) 3)。
实施例6
1-[(1H-3-吲哚基)胺基]-3-(4-苯基-2-丁基胺基)-2-丙醇(I-5)的制备
Figure PCTCN2018075915-appb-000009
合成方法同1-[(1H-3-吲哚基)氧基]-3-(4-苯基-2-丁基胺基)-2-丙醇(I-4)的合成，采用1-叔丁氧羰基-3-(1,2-环氧丙烷)基胺基-1H-吲哚(III-2)为原料，得到1-[(1H-3-吲哚基)胺基]-3-(4-苯基-2-丁基胺基)-2-丙醇(I-5)3.2g，为白色固体，收率66.5％，HPLC纯度97.3％。
1H NMR(600MHz,DMSO-d 6):11.06(br s,1H,Ar-NH),9.61(br s,1H,NHCH 2CHNH),7.10-7.12(m,1H,Ar-H),6.95-6.99(m,2H,Ar-H),6.74-6.77(m,5H,Ar-H),6.42-6.47(dd,2H,Ar-H),4.99(br s,1H,CHOH),3.63(m,1H,NHCH 2CH),3.36-3.44(m,2H,NHCH 2CHNH),2.73-2.76(m,1H,CHCH 2N),2.58–2.66(m,4H,CH 2CHN,CH 2CH 2CH,CHCH 2N),1.77–1.80(m,2H,CH 2CHN),1.55(br s,1H,NHCHCH 3),0.98(d,3H,CHCH 3)。
实施例7
1-[(1H-3-吲哚基)硫基]-3-(4-苯基-2-丁基胺基)-2-丙醇(I-6)的制备
Figure PCTCN2018075915-appb-000010
取圆底烧瓶，分别加入叔丁醇150g、叔丁醇钠13g、1-叔丁氧羰基-3-巯基-1H-吲哚20g(II-3)和环氧氯丙烷17g，60℃反应8小时。减压浓缩，向浓缩物中加入二氯甲烷500g和水100g，分出有机层，减压浓缩，剩余物用无水乙醇重结晶一次，得到1-叔丁氧羰基-3-(1,2-环氧丙烷)基巯基-1H-吲哚(III-3)，为类白色固体。取10g该类白色固体，投入圆底烧瓶中，加入二氯甲烷300g、1-甲基-3-苯基丙胺6.5g，搅拌滴加三乙胺10g，于20-30℃反应5小时。加入水150g，分取有机层，无水硫酸钠干燥，减压浓缩。向浓缩物中加入二氯甲烷300g，三氟乙酸5.0g，于20-30℃反应12小时。加水120g，分取有机层，无水硫酸钠干燥，减压浓缩，剩余物用苯/乙酸乙酯/正己烷重结晶一次，得到1-[(1H-3-吲哚基)硫基]-3-(4-苯基-2-丁基胺基)-2-丙醇(I-6)9.0g，为白色固体，HPLC纯度99.1％。
1H NMR(600MHz,DMSO-d 6):11.09(br s,1H,Ar-NH),7.19-7.20(m,1H,Ar-H),6.95-6.99(m,2H,Ar-H),6.74-6.77(m,5H,Ar-H),6.42-6.47(dd,2H,Ar-H),4.96(br s,1H,CHOH),3.93(m,1H,NHCH 2CH),3.35-3.43(m,2H,SCH 2CH),2.73-2.76(m,1H,CHCH 2N),2.58–2.66(m,4H,CH 2CHN, CH 2CH 2CH,CHCH 2N),1.77–1.80(m,2H,CH 2CHN),1.54(br s,1H,NHCHCH 3),0.98(d,3H,CHCH 3)。
实施例8
1-[(1-萘基)氧基]-3-(异丙基胺基)-2-丙醇盐酸盐(IV-7)的制备
Figure PCTCN2018075915-appb-000011
参考1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)-2-丙醇(I-1)合成方法，制得1-[(1-萘基)氧基]-3-(异丙基胺基)-2-丙醇(I-7)5.5g，将其溶于25g乙醇中，加入2.5g盐酸溶液，收集生成的固体，用乙醇重结晶精制一次，得1-[(1-萘基)氧基]-3-(异丙基胺基)-2-丙醇盐酸盐(IV-7)5.0g，为白色固体，收率79.7％，HPLC纯度99.1％。
1H NMR(400MHz,CDCl 3):δ9.77(br s,1H,HCl),8.66(br s,2H,NHCH(CH 3) 2),6.67-8.28(m,7H,Ar-H),5.62(s,1H,CHOH),4.86-4.88(m,1H,CHOH),4.10-4.24(m,2H,OCH 2CH),3.40–3.52(m,2H，CHCH 2N),3.27–3.32(m,1H,NHCH(CH 3) 2),1.52(d,6H,CH(CH 3) 2)。
实施例9
(S)-1-(叔丁基氨基)-3-[(4-吗啉基-1,2,5-噻二唑-3-基)氧]-2-丙醇马来酸盐(IV-8)的制备
Figure PCTCN2018075915-appb-000012
参考1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)-2-丙醇(I-1)合成方法，制得到1-(叔丁基氨基)-3-[(4-吗啉基-1,2,5-噻二唑-3-基)氧]-2-丙醇(I-8)，为浅黄色油状物，HPLC纯度94.5％。
将所得油状物溶于四氢呋喃中，加入马来酸，收集生成的固体，用乙醇重结晶精制两次，得到1-(叔丁基氨基)-3-[(4-吗啉基-1,2,5-噻二唑-3-基)氧]-2-丙醇马来酸盐(IV-8)，HPLC纯度99.8％。
1H NMR(600MHz,DMSO-d 6):δ20.1(br s,1H,COOH),8.36(br s,2H,NH 2C(CH 3) 3),6.03(s,2H,CH＝CH),5.97(s,1H,CHOH),4.38(m,2H,OCH 2CH),4.19(m,1H,CHOH),3.72(t,4H,O(CH 2CH 2) 2N),3.47(t,4H,O(CH 2CH 2) 2N),3.09–3.16(m,1H，CHCH 2N),2.82–2.92(m,1H,CHCH 2N),1.27(s,9H,C(CH 3) 3)。
实施例10
1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)-2-丙醇(I-1)凝胶剂的制备方法
(1)制备凝胶基质：取10.0g卡波姆，加入650g水，搅拌分散，加入稀氢氧化钠溶液调pH值至7.0-9.0，加入50g甘油、1.0g羟苯甲酯和0.1g羟苯丙酯，继续搅拌至均匀，得到凝胶基质。
(2)混合：称取10.0g 1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)-2-丙醇，用稀盐酸溶液溶解后加水至200g，过滤，滤液加入凝胶基质中，再投入5.0g辛酸癸酸聚乙二醇甘油酯，搅拌下用稀氢氧化钠溶液调pH值至7.0-8.0，加水至1000g。
(3)排气泡：慢速搅拌下，抽真空30分钟，除去气泡。
(4)灌装：将制成的凝胶于灌装机中灌装，灌装时控制最低装量为 20.0g/支。
实施例11
(S)-1-(叔丁基氨基)-3-[(4-吗啉基-1,2,5-噻二唑-3-基)氧]-2-丙醇马来酸盐(IV-8)凝胶剂的制备方法
(1)制备凝胶基质：取10.0g卡波姆，加入600g水，搅拌分散，加入10％氢氧化钠溶液调pH值至7.0-9.0，加入20g聚乙二醇400、75g甘油和2.5g苯甲酸钠，继续搅拌至均匀，得到凝胶基质。
(2)混合：称取5.0g 1-(叔丁基氨基)-3-[(4-吗啉基-1,2,5-噻二唑-3-基)氧]-2-丙醇马来酸盐，用100g水溶解后加入凝胶基质中，再投入20g辛酸癸酸聚乙二醇甘油酯，搅拌下用10％氢氧化钠溶液调pH值至7.5-8.5，并加水至1000g。
(3)排气泡：慢速搅拌下，抽真空30分钟，除去气泡。
(4)灌装：将制成的凝胶于灌装机中灌装，灌装时控制最低装量为20.0g/支。
实施例12
1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)-2-丙醇(I-1)乳膏剂的制备方法
(1)油相：取50.0g液体石蜡、200g硬脂酸、100g单硬脂酸甘油酯混合，加热至约80℃左右备用。
(2)水相：另取150g甘油、5.0g氢氧化钠溶于水中并一起加热至约80℃成水溶液。
(3)乳化：趁热将水相加入油相中，保持80℃搅拌30分钟。
(4)总混：将10.0g 1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)-2-丙醇和2.0g羟苯乙酯依次加入，继续搅拌30分钟。
(4)灌装：搅拌下冷却至室温，将制成的乳膏剂于灌装机中灌装，灌装时控制最低装量为20.0g/支。
实施例13
1-[(1H-3-吲哚基)硫基]-3-(4-苯基-2-丁基胺基)-2-丙醇(I-6)透皮贴剂的制备方法
(1)制备基质：取2.0g卡波姆，加入100g水，搅拌，加入10％氢氧 化钠溶液调pH值至8.0-9.0，加入1.5g吐温80、5.0g硬脂酸和20g甘油，搅拌均匀。
(2)制备药物储库：取10.0g的1-[(1H-3-吲哚基)硫基]-3-(4-苯基-2-丁基胺基)-2-丙醇，加入50％甘油水溶液，搅拌均匀。
(3)混合：将(2)加入(1)中，补水至200g，充分搅拌至均匀。
(4)制备压敏胶：将聚硅氧烷压敏胶均匀涂布在乙烯-醋酸乙烯控释膜上，70℃烘干，覆盖聚四氟乙烯膜保护层。
(5)制备透皮贴剂：将药物定量加到控释膜上，盖上背衬层，热封，按尺寸剪切，包装，即得。
实施例14
1-[(1H-3-吲哚基)氧基]-3-(4-苯基-2-丁基胺基)-2-丙醇(I-4)包衣片的制备方法
(1)预处理：取原、辅料分别过100目筛，聚维酮K30制成5％乙醇溶液，备用。
(2)制粒：取1-[(1H-3-吲哚基)氧基]-3-(4-苯基-2-丁基胺基)-2-丙醇，用5％聚维酮K30乙醇溶液湿法制粒，干燥整粒。
(3)混合：将制颗粒与交联羧甲基纤维素钠、微晶纤维素、微粉硅胶、硬脂酸镁混合均匀。
(4)压片。
(5)包衣：制成薄膜衣片。
(6)铝塑包装，即得。
实施例15
实验模型的选择：
莱亨鸡鸡冠是葡萄酒色斑(PWS)的天然模型，鸡冠的真皮浅层有大量扩张的毛细血管，与葡萄酒色斑的病理表现有较多相似之处。因此，选用健康雄性莱亨鸡鸡冠为葡萄酒色斑的病理模型，按实施例12的方法制备多种取代芳基胺醇类化合物的乳膏剂，并进行初步的药效学研究。
动物来源：6个月龄健康的雄性莱亨鸡，体重约1.5～1.8kg，由中国医学科学院北京协和医学院新药安全评价研究中心提供。
动物分组：
实验动物按照完全随机分组法分组，每组8只，分别为：空白对照组 (不给药)、基质对照组(给予不含药的乳膏基质)和药物组合物组(分别给予一定剂量的本发明的取代芳基胺醇类化合物)。
实验方法：
空白对照组不予任何处理，基质对照组和药物组合物组分别于鸡冠表面双侧正中选取2cm×1cm区域涂抹按照实施例12中方法制得的基质(不加入药物)或乳膏剂，每日3次，持续30天。
给药期间每3天观察并测量一次相关指标(鸡冠颜色、厚度、软硬度)，并于相同条件下进行拍照，直至实验结束。实验结束后摘取鸡冠组织，制作病理切片，待进行病理组织学观察(HE染色)。
治疗指标和评分标准如表1所示。
表1.给药后鸡冠变化评分指标
Figure PCTCN2018075915-appb-000013
根据病变的消退程度将疗效分为四级，为方便统计分析，对各级疗效进行打分，用疗效综合指数(Efficacy Integrate Index,EII)表示。
疗效综合指数(EII)＝T×C×H×M
当192≤EII≤256时，疗效定义为I级，表示治愈，说明鸡冠色消退非常显著，厚度显著变薄，接近正常肌肤的软硬度，微血管显著减少；
当128≤EII<191时，疗效定义为II级，表示显效，说明鸡冠色消退显著，厚度明显变薄，鸡冠显著变软，微血管明显减少；
当64≤EII<128时，疗效定义为III级，表示有效，说明鸡冠色消退明显，厚度变薄，鸡冠明显变软，微血管减少；
当EII<64时，疗效定义为IV级，表示无效，说明鸡冠色消退不明显或者几乎无改变，厚度略微变薄或者无改变，鸡冠略微变软或者无改变，微血管略微减少或者无改变。
按照上述实验方法，我们分别将取代芳基胺醇类化合物I-1～I-8和IV-8按照实施例12中的配制方法，制成乳膏剂，测试药效情况，结果如表2。
表2.各给药组不同疗效的结果(n＝8)
Figure PCTCN2018075915-appb-000014
从表2中可以看出，本发明的取代芳基胺醇化合物(例如I-1～I-8)及其药用盐(例如IV-8)对血管瘤和/或脉管畸型有较好的治疗效果。其中以4-苯基-2-丁基胺基等位阻大的取代基取代时疗效较好，尤其是X是氧原子取代时(I-4)，活性最佳，其中有1例能够达到治愈标准要求。同时也可以看出这类化合物的药用盐比其原型化合物拥有更强的疗效(例如，在含量均为0.5％时，IV-8的有效率为62.5％，相比之下I-8的有效率为50.0％)，而且疗效随着浓度的升高而有一定程度的提高，有效率由50.0％(IV-8， 0.25％)提高至75.0％(IV-8，1.0％)。

Claims (11)

  1. 式(I)所示的化合物或其药学上可接受的盐，
    Figure PCTCN2018075915-appb-100001
    其中：
    Ar是芳基，杂芳基，或者被一个或多个C 1-C 6烷基、卤素、羟基、胺基、巯基、芳基、杂环基取代的芳基或杂芳基；
    X是O、NH或者S；
    R是C 1-C 4脂肪烷基，或被卤素或苯基取代的C 1-C 4脂肪烷基；以及
    n＝1-3，优选n＝1。
  2. 根据权利要求1所述的式(I)所示的化合物或其药学上可接受的盐，其中，Ar是苯基，萘基，杂芳基，或者被一个或多个C 1-C 6烷基、卤素、羟基、胺基、巯基、非芳香杂环基取代的苯基、萘基或杂芳基；
    优选地，Ar是苯基、4-氯代苯基、2,4-二氟代苯基、1H-吲哚基、1-萘基、2-呋喃基、5-甲基-2-呋喃基、2-噻吩基、1-咪唑基、2-咪唑基、2-吡啶基、3-吡啶基、2-喹啉基、噻唑基、噻二唑基或3-(4-吗啉-1,2,5-噻二唑)基。
  3. 根据权利要求1所述的式(I)所示的化合物或其药学上可接受的盐，其中，R是甲基、乙基、正丙基、异丙基、正丁基、叔丁基、仲丁基、4-苯基-2-丁基、氯甲基、氟甲基、1-氯乙基、2-氯乙基、氟乙基、1-氯丙基、氯代异丙基、1-氯丁基、2-氯丁基、氟丁基或氯代叔丁基。
  4. 根据权利要求1所述的式(I)所示的化合物或其药学上可接受的盐，其中所述的式(I)的化合物选自：
    1-[(1H-3-吲哚基)氧基]-3-(叔丁基胺基)-2-丙醇；
    1-[(1H-3-吲哚基)胺基]-3-(叔丁基胺基)-2-丙醇；
    1-[(1H-3-吲哚基)硫基]-3-(叔丁基胺基)-2-丙醇；
    1-[(1H-3-吲哚基)氧基]-3-(4-苯基-2-丁基胺基)-2-丙醇；
    1-[(1H-3-吲哚基)胺基]-3-(4-苯基-2-丁基胺基)-2-丙醇；
    1-[(1H-3-吲哚基)硫基]-3-(4-苯基-2-丁基胺基)-2-丙醇；
    1-[(1-萘基)氧基]-3-(异丙基胺基)-2-丙醇；或
    (S)-1-(叔丁基氨基)-3-[(4-吗啉基-1,2,5-噻二唑-3-基)氧]-2-丙醇。
  5. 根据权利要求1至4中任一项所述的式(I)所示的化合物或其药学上可接受的盐，其中所述药学上可接受的盐为式(I)所示的化合物与可药用的无机酸或有机酸，如盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、乙磺酸、甲酸、苯甲酸、丙二酸和苯磺酸中的一种或多种所形成的盐；或者为式(I)的化合物与合适的可药用碱所形成的盐，如钠盐、钾盐、钙盐、镁盐、锌盐、胆碱盐、铵盐、季铵盐以及其它有机胺盐。
  6. 权利要求1至5中任一项所述的式(I)的化合物或其药学上可接受的盐的制备方法，包括以下步骤：
    Figure PCTCN2018075915-appb-100002
    1)使式(II)所示的化合物与环氧卤代烃发生烃化反应得到式(III)所示的环氧烷取代的中间体；
    2)将步骤1)得到的式(III)所示的环氧烷取代的中间体与RNH 2进行胺化反应得到式(I)所示的化合物；
    3)任选地，将步骤2)得到的式(I)所示的化合物与无机或有机酸、碱形成药学上可接受的盐；
    优选地，在Ar-XH中，当Ar基团上存在除XH之外的活性基团，例如羟基、胺基、或巯基时，则在步骤1)之前还包括将所述Ar基团上除XH之外的活性基团，例如羟基、胺基、或巯基用保护基团进行基团保护的步骤，并且在步骤2)之后还包括脱去所述保护基团的步骤；
    其中，X 1为Cl、Br或者I；Ar、X、R、n的定义与权利要求1至5中Ar、X、R、n的定义相同。
  7. 一种药物组合物，其包含治疗有效量的根据权利要求1至5中任一项所述的式(I)所示的化合物或其药学上可接受的盐或根据权利要求6所述的制备方法制备的式(I)所示的化合物或其药学上可接受的盐，以及一种或多种药学上可接受的辅料；
    任选地，所述药物组合物还可以包含除式(I)所示的化合物或其药学上可接受的盐以外的活性成分。
  8. 根据权利要求7所述的药物组合物，其中，所述药物组合物是口服药物、注射剂、用于口腔给药或舌下给药途径的药物、局部经皮给药的药物、外用半固体制剂或腔道给药的药物。
  9. 根据权利要求7所述的药物组合物，其中，所述药物组合物为片剂、胶囊剂、颗粒剂、丸剂、散剂、口服溶液剂、口服混悬剂、口服乳剂、泡腾剂、软膏剂、乳膏剂、凝胶剂、搽剂、涂剂、涂膜剂、贴剂、贴膏剂、喷雾剂、气雾剂、外用溶液剂、外用泡沫剂、栓剂或灌肠剂。
  10. 权利要求1至5中任一项所述的式(I)所示的化合物或其药学上可接受的盐、根据权利要求6所述的制备方法制备的式(I)所示的化合物或其药学上可接受的盐或权利要求7至9中任一项所述的药物组合物在制备用于治疗血管瘤和/或脉管畸形的药物中的用途；
    优选地，所述血管瘤和/或脉管畸形选自毛细血管畸形、淋巴管畸形、静脉畸形、动静脉畸形、婴幼儿血管瘤、化脓性肉芽肿、先天性皮肤大理石样毛细血管扩张症(CMTC)或葡萄酒色斑。
  11. 一种治疗血管瘤和/或脉管畸形的方法，该方法包括：向有需要的对象给予治疗有效量的权利要求1至5中任一项所述的式(I)的化合物或其药学上可接受的盐、根据权利要求6所述的制备方法制备的式(I)所示的化合物或其药学上可接受的盐或权利要求7至9中任一项所述的药物组合物；
    优选地，所述血管瘤和/或脉管畸形选自毛细血管畸形、淋巴管畸形、静脉畸形、动静脉畸形、婴幼儿血管瘤、化脓性肉芽肿、先天性皮肤大理石样毛细血管扩张症(CMTC)或葡萄酒色斑。
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