CN101321738A - Spirocyclic derivatives - Google Patents

Spirocyclic derivatives Download PDF

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CN101321738A
CN101321738A CNA200680045333XA CN200680045333A CN101321738A CN 101321738 A CN101321738 A CN 101321738A CN A200680045333X A CNA200680045333X A CN A200680045333XA CN 200680045333 A CN200680045333 A CN 200680045333A CN 101321738 A CN101321738 A CN 101321738A
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compound
pain
volution
quinazoline
preparation
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大卫·詹姆斯·若森
奈杰尔·艾伦·斯温
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Pfizer Ltd
Pfizer Inc
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Abstract

The invention provides compounds of formula (I): (I) wherein: m is 0, 1 or 2; X is O, S or N-CN; R is F, Cl or CN; A is a C3-6 cycloalkylene group optionally substituted with a C1-4 alkyl group; and B is a single bond or a C1-2 alkylene group; or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. The compounds are PDE7 inhibitors and have a number of therapeutic applications, particularly in the treatment of pain, especially neuropathic pain.

Description

Spirocyclic derivatives
Technical field
The present invention relates to a kind of Spirocyclic derivatives, also related to the method that is used to prepare described derivative, the intermediate that uses in the preparation of described derivative contains the purposes of the composition and the described derivative of described derivative.
Spirocyclic derivatives of the present invention is the PDE7 inhibitor, has multiple treatment using value, specifically is applied to treat pain, especially treats neuropathic pain.
Background technology
Phosphodiesterase (PDE) is a class of enzymes, and it is by being hydrolyzed into corresponding non-activity 5 '-monophosphic acid nucleotide with second messenger molecule cAMP and cGMP, thereby the process of regulating its physiology level influences various cell signal processes.Second messenger cAMP and cGMP bear the responsibility of regulating various cell internal procedures.Have at least 11 PDE families, wherein some (PDE3,4,7,8) have the cAMP specificity, and other (PDE 5,6,9) have the cGMP specificity.
PDE7 is a kind of in the PDE family, and it comprises PDE7 A and two subspecies of B.The mRNA of PDE7 is expressed in known in the pathogeny of several deficiency disorders (such as T-cell related disorder disease) the important polytype tissue and cell.Particularly, PDE7A and splice variant thereof (splicevariant) are raised (L.Li in active T-cell, C.Yee and J.A.Beavo, Science (1999), 283,848-851), in the B-lymphocyte, raised (R.Lee, S.Wolda, E.Moon, J.Esselstyn, C.Hertel and A.Lerner, Cell.Signal (2002), 14,277-284), in autoimmune disorders, raised (L.Li etc., as above) and in airway disorders, raise (S.J.Smith etc., Am.J.Physiol.Lung.Cell.Mol.Physiol. (2003), 284, L279-L289).Therefore, the selective depressant that reckons with PDE 7 has as immunosuppressor and treatment breathes the widespread use (N.A.Glavas of illness (for example chronic obstructive pulmonary disease and asthma), C.Ostenson, J.B.Schaefer, V.Vasta and J.A.Beavo.PNAS (2001), 98,6319-6324).
To studies show that of rat, PDE 7A mRNA is found the neuronal cell group that is distributed in widely in the rat brain and non-neuronal cell group in the two.Maximum concentration comes across olfactory bulb, olfactory tubercle, hippocampus, cerebellum, HM, pineal gland, brain stem area postrema and choroid plexus.In other non-cerebral tissue, also detect PDE 7A mRNA at large.These results are consistent with the cAMP Signal Regulation that PDE 7A participates in numerous brain functions, and hint PDE 7A is to influential (the X.Mir ó of memory, dysthymia disorders and vomiting, S.P é rez-Torres, J.M.Palacios, P.Puigdomenech, G.Mengod, Synapse (2001), 40,201-214).Also hinted with the AlzheimerShi disease-related (S.P é rez Torres etc., Experimental Neurology, (2003) 182,322-334).In addition, (R.Lee etc., Cell Signalling (2002) 14, and is 277-284) relevant with giving birth to disease (WO01/83772) and leukemia also to have hinted PDE 7.
From yeast (T.Michaeli etc., J.Biol.Chem. (1993) 268,12925-12932), human (P.Han, Z.Xiaoyan and M.Tamar, J.Biol.Chem. (1997) 272,16152-16157) and mouse (T.Bloom and J.A.Beavo, Proc.Natl.Acad.Sci.USA (1996), 93, isolated PDE7A 14188-14192), and in human T-lymphocyte, found PDE 7A concentration rise (M.Ichimura and H.Kase.Biochem.Biophys.Res.Commun. (1993), 193,985-990).
PDE7B belongs to second kind in the PDE7 family, and itself and PDE7A are shared in the amino acid identity (the N end regions is a regulation domain, contains the conservative phosphorylation site of PDE family) of 70% in the C end catalysis region.PDE7B has the cAMP specificity, and from mouse (preserving number-AJ251858) and human (clone (C.Gardner, N.Robas the resource of preserving number-AJ251860), D.Cawkill and M.Fidock, Biochem.Biophys.Res.Commun. (2000), 272,186-192).Shown in various tissues and expressed: brain caudatum, shell and occipital lobe; The periphery is expressed in heart, ovary and pituitary body, kidney, liver and small intestine and the thymus gland; Be expressed in addition in skeletal muscle, colon, bladder, uterus, prostate gland, stomach, suprarenal gland and the Tiroidina.Also show PDE7B to several general PDE inhibitor distinct (J.M.Hetman, S.H.Soderling, N.A.Glavas and J.A.Beavo, PNAS (2000), 97,472-476).Thereby many standard P DE inhibitor can not suppress PDE7B specifically such as Zaprinast (zaprinast), rolipram (rolipram) and Milrinone (milrinone).
The purposes of the inhibitor of known PDE7 in treating various and PDE7 relative disease.For example, WO02/074754 has described following formula: compound:
Figure A20068004533300071
And the treatment with PDE7 related disorder disease in purposes, described deficiency disorder all in this way with T cell associated diseases, autoimmune disorders, osteoarthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, asthma, cancer, acquired immune deficiency syndrome (AIDS), transformation reactions or inflammatory bowel.
WO2004/026818 has described following formula: compound:
Figure A20068004533300072
And the purposes in treatment and PDE-7 related disorder disease.
WO2006/092691 has described the purposes of PDE7 inhibitor in the treatment neuropathic pain.
We surprisingly find, dropping on WO02/074754 summarizes in the open scope, but concrete compounds that discloses or give an example with comparing near compound of enumerating among the WO02/074754, has beyond thought, outstanding pharmacokinetic property in the document.The expection of these compounds have reduce from intravital clearance rate, and these compounds have every day once the situation of taking be issued to the potentiality of result of treatment.
Summary of the invention
The invention provides formula (I) compound:
Figure A20068004533300073
(I)
Wherein,
M is 0,1 or 2;
X is O, S or N-CN;
R is F, Cl or CN;
A is C 3-6Cycloalkylidene, optional by C 1-4Alkyl replaces; And
B is singly-bound or C 1-2Alkylidene group;
Pharmaceutically-acceptable salts, solvate, polymorphic form or the prodrug of described compound perhaps are provided.
Description of drawings
Fig. 1 is concentration/time diagram, and it illustrates behind intravenously administrable 1mg/kg, the compound (compd A) of the embodiment 75 of embodiments of the invention 1 and 2 compound and WO02/074754 through the standardized average pharmacokinetics figure of dosage.
Fig. 2 represents the powder x-ray diffraction figure (PXRD) of the acetic acid solvent thing of (A) that measure and mimic (B) embodiment 2 compounds.
Fig. 3 is in the heat-processed of utilizing thermogravimetric analysis (TGA), the mass loss figure of the acetic acid solvent thing of embodiment 2 compounds (shown 15.05% mass loss equals 1 molar equivalent acetate).
Fig. 4 represent through the non-solvent form of the embodiment of silicon doping 2 compounds (asolvate form) (A crystal formation) (A), the acetic acid solvent thing of above-claimed cpd before TGA analyzes (B) and after the TGA analysis PXRD pattern of (C).
Fig. 5 represents the PXRD pattern without solvation crystallized form (A crystal formation) of embodiment 2 compounds, relatively the silicon standard correction.
Fig. 6 is differential scanning calorimetric (DSC) curve without solvation crystallized form (A crystal formation) of embodiment 2 compounds.
The non-solvent crystallized form (A) that Fig. 7 represents embodiment 2 compounds with and the PXRD figure of the solvate (F) of the solvate (E) of the solvate (D) of the solvate (C) of the solvate (B) of N,N-DIMETHYLACETAMIDE (DMAC), pyridine, tetrahydrofuran (THF) (THF), dimethyl sulfoxide (DMSO) (DMSO) and acetate.
Fig. 8 is the TGA curve of the pyridine solvent thing of embodiment 2 compounds, and the ratio that shown 17.3% mass loss is equivalent to solvent and compound is 1: 1.
Fig. 9 is the TGA curve of the tetrahydrofuran solvate of embodiment 2 compounds, and the ratio that 14.7% total mass loss is equivalent to compound and THF solvent is 1: 1 (the progressively character of the solvent loss in heat-processed can show in the middle of the existence of half-THF solvate forms).
Figure 10 is the TGA curve of the dimethylacetamide solvent thing of embodiment 2 compounds, and the ratio that 33.0% total mass loss is equivalent to solvent and compound is 2: 1.
Figure 11 represents the PXRD pattern of pyridine solvent thing (A), the pyridine solvent thing (B) behind the TGA and the A crystal formation (C) of embodiment 2 compounds.
Figure 12 represents the PXRD pattern of tetrahydrofuran solvate (A), the THF solvate (B) behind the TGA and the A crystal formation (C) of embodiment 2 compounds.
Figure 13 represents the PXRD pattern of dimethylacetamide solvent thing (A), the dimethylacetamide solvent thing (B) behind the TGA and the A crystal formation (C) of embodiment 2 compounds.
Figure 14 represents the PXRD pattern of dimethyl sulfoxide solvent thing (A), the DMSO solvate (B) after the vacuum-drying and the A crystal formation (C) of embodiment 2 compounds.
Embodiment
In the context of the present invention, term " alkylidene group " expression has the divalent saturated hydrocarbon chain of 1 or 2 carbon atom.The example of alkylidene group comprises methylene radical, ethylidene and methyl methylene radical, wherein preferred methylene radical.
Term " cycloalkylidene " expression has the divalence saturated carbon ring of 3 to 6 carbon atoms.The example of cycloalkylidene comprises that cyclopropylidene (for example, 1,1-cyclopropylidene and cis and trans 1,2-cyclopropylidene), inferior cyclobutyl (for example, 1, the inferior cyclobutyl of 1-, cis and trans 1, the inferior cyclobutyl of 2-and cis and trans 1, the inferior cyclobutyl of 3-), cyclopentylidene (for example, 1,1-cyclopentylidene, cis and trans 1,2-cyclopentylidene and cis and trans 1, the 3-cyclopentylidene) and cyclohexylidene (for example, 1, the 1-cyclohexylidene, cis and trans 1,2-cyclohexylidene, cis and trans 1,3-cyclohexylidene and cis and trans 1,4-cyclohexylidene).Preferred examples comprises inferior cyclobutyl and cyclohexylidene, more preferably inferior cyclobutyl, even more preferably 1, and the inferior cyclobutyl of 3-, most preferably trans 1, the inferior cyclobutyl of 3-.
Term " alkyl " expression contains monovalence, straight chain or the branching saturated hydrocarbon chain of 1 to 4 carbon atom.The example of alkyl comprises, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Preferred examples comprises methyl and ethyl, especially preferable methyl.
Cycloalkylidene is optional by C 1-4Alkyl replaces.Preferably, alkyl substituent if exist, is methyl or ethyl, more preferably methyl.Alkyl substituent if exist, can be positioned on any position on the ring, but is preferably placed at 1-position (that is, position) identical with hydroxy-acid group.
Preferably, m is 1 or 2, more preferably 1.
Preferably, X is O or N-CN, more preferably O.
Preferably, R is F or Cl, more preferably Cl.
Preferably, A is inferior cyclobutyl or cyclohexylidene, and this group is optional by methyl substituted.More preferably, A is inferior cyclobutyl.Even more preferably, A is 1, and the inferior cyclobutyl of 3-especially is an anti-form-1, the inferior cyclobutyl of 3-.
Preferably, B is singly-bound or methylene radical.More preferably, B is a singly-bound.
The particularly preferred compound of the present invention comprises following compound, and in these compounds, each variable in the formula (I) is selected from for the suitable and/or preferred group of each variable.The present invention even preferred compound comprise following compound, and in these compounds, each variable in the formula (I) is selected from for each variable more preferably or even preferred group.
Especially be preferably as follows compound:
Cis-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
3-[(8 '-fluoro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen methyl] cyclobutane-carboxylic acid;
Trans-3-[(8 '-cyano group-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
1-[(8 '-fluoro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen methyl] cyclobutane-carboxylic acid;
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [suberyl-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [pentamethylene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
And pharmaceutically-acceptable salts, solvate and prodrug.
Especially be preferably as follows compound:
Cis-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
And pharmaceutically-acceptable salts, solvated compounds, polymorphic form and prodrug.
Most preferably compound trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid and pharmaceutically-acceptable salts, solvate, polymorphic form and prodrug, be specially non-solvent crystallized form as described below (A crystal formation) and acetic acid solvent thing as described below.
In one embodiment, the present invention includes the compound trans-3-[(8 '-chloro-2 of non-solvent crystallized form (A crystal formation) '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid, it is characterized in that, when adopting CuK α radiation (wavelength=1.5406
Figure A20068004533300111
) when measuring, have following powder x-ray diffraction peak (2 θ, in ° ± 0.1 °): 6.3,17.8,21.5,22.1,22.4,26.3.
In another embodiment, the present invention includes the compound trans-3-[(8 '-chloro-2 of acetic acid solvent thing form '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid, it is characterized in that, when adopting CuK α radiation (wavelength=1.5406
Figure A20068004533300112
) when measuring, have following powder x-ray diffraction peak (2 θ, in ° ± 0.1 °): 8.3,10.8,16.6,17.1,19.5,20.5,23.7.
The present invention further comprises a kind of pharmaceutical compositions, and described composition is included in the wide region or (I) compound of the formula in preferable range or its pharmaceutically-acceptable salts, solvate, polymorphic form or prodrug and comprise pharmaceutically acceptable supporting agent or thinner.
The present invention further comprises formula (I) compound or its pharmaceutically-acceptable salts, solvate, polymorphic form or the prodrug in wide region or in preferable range as medicine.
The present invention further is included in the wide region or (I) compound of the formula in preferable range or its pharmaceutically-acceptable salts, solvate, polymorphic form or prodrug are used for the treatment of purposes in the medicine of following disease or illness in manufacturing, and described disease or treatment of conditions are relevant with the PDE7 inhibitor.
The present invention further comprises the method for following disease of treatment or illness, described disease or treatment of conditions are relevant with the PDE7 inhibitor, described method comprises, bestows formula (I) compound or its pharmaceutically-acceptable salts, solvate, polymorphic form or the prodrug in wide region or in preferable range of significant quantity.
Formula (I) compound is the PDE7 inhibitor, can be used for treating various deficiency disorders.Be preferred for treating pain, specifically treat neuropathic pain.
Physiological pain is the important protection mechanism that is designed to warn from the potential noxious stimulation of outside atmosphere.This system is by one group of specific main Sensory neurone running, and by destructive stimulus through peripheral sensing mechanism activated (referring to Millan, Prog.Neurobio., (1999) 57,1-164).These Sensory fibres are called as nociceptor, show as the low minor diameter aixs cylinder of conduction of velocity.Nociceptor is encoded to intensity, time length and the character of destructive stimulus, and arrives the epispinal position that stimulates through the projection coding of topology tissue by it.Nociceptor is present on the nerve fiber that pain reaction is arranged, and described nerve fiber has two types: A-δ fiber (myelinated fibre) and C fiber (unmyelinated nerve fiber).After the complex process in the dorsal horn, the activity that the nociceptor input is produced directly or via the brain stem relay nucleus is passed to ventral thalamus, is passed to cortex then, produces the pain sensation on cortex.
Pain generally can be divided into acute pain or chronic pain.The acute pain outbreak is unexpected and the time length is short (being generally for 12 weeks or shorter).Its specific reasons common and such as particular injury is relevant, and usually violent and serious.It is a kind of may be in the pain that takes place by operation, dental treatment, after pulling or sprain the particular injury that causes.Acute pain generally can not cause any lasting physiological response.On the contrary, chronic pain is long-term pain, and general continuing surpasses 3 months and cause tangible physiology and emotional problem.The common example of chronic pain is neuropathic pain (for example the diabetic neuropathy of pain, neuropathic pain after the bleb), carpal tunnel syndrome, backache, headache, cancer pain, arthritis ache and chronic post-operative pain.
When body tissue being produced substantive damage (because disease or wound), nociceptor activates characteristic and is changed, near damage is peripheral, local and be formed centrally the sensitizing range in the nociceptor terminated.These effects cause pain perception to strengthen.For acute pain, these mechanism help promoting the protection behavior, and this can make repair process to carry out better.And in case damage is fully recovered, it is normal that susceptibility is expected to recover usually.Yet for many chronic pain states, hypersensitive time length is much larger than agglutination, and normally since nervous system injury cause.This damage usually causes the unusual (Woolf﹠amp of the sensing nerve fiber relevant with maladjustment and abnormal movement; Salter, Science, (2000) 288:1765-1768).
Do not accommodate unusual susceptibility if exist in patient's symptom, clinical pain then occurs.The patient often originates and mixes and have various pain syndromes.Such syndrome comprises: 1) spontaneous pain can be numbness, cusalgia or shouting pain; 2) pain (hyperpathia) that excites of Kua Da destructive stimulus; 3) pain of normal non-noxious stimulation generation (unusual pain-Meyer etc., 1994 Textbookof Pain 13-44).Can have similar symptom although suffer from various forms of acute and patients chronic pain, implicit mechanism is discrepant, thereby the different treatment plan of needs.Therefore, according to the difference on the physiopathology, pain also can be divided into many different subtypes, comprises nociceptive pain, inflammatory pain, neuropathic pain.
Nociceptive pain is to cause by tissue injury or by the severe irritation that may cause damage.Pain is imported into and is to be activated in the stimulation transduction of damage position by the injury transmitter, and on its terminal horizontal the neurone in the spinal cord is activated.This is passed to the brain (Meyer etc., 1994 Textbook of Pain 13-44) of perception pain by the backbone passage then.The activation of nociceptor has activated two class afferent neurofibers.The fast transmission and to violent and pierce through pain and make and replying of marrow A-δ fiber is arranged, and do not have marrow C fiber with than the jogging speed transmission and pass on secret anguish.Moderate to violent acute injury susceptibility pain is the principal character by the following pain that causes: central nervous system injury, pull/sprain, pain, renal colic, cancer pain and backache after burn, myocardial infarction and acute critical pancreatitis, postoperative pain (pain after the surgical operation of any kind), the wound.Cancer pain can be a chronic pain, such as with tumour ache related (for example ostalgia, headache and face ache, visceral pain), perhaps relevant pain (for example pain syndrome after syndrome, the chronic surgical operation, radiation back syndrome after the chemotherapy) with cancer therapy.Cancer pain can also be replied chemotherapy, immunotherapy, hormonotherapy or radiotherapy and be produced.Backache may be broken or small joints in lumbar spine is unusual, the sacrum osteoarthrosis is unusual, the other muscle of vertebra is unusual or posterior longitudinal ligament causes unusually by prolapse of lumbar intervertebral disc or lumber ertebral disc.Backache can be eliminated naturally, but in some patients, if backache continued more than 12 weeks, then it becomes the chronic disease that can especially make people's weakness.
Neuropathic pain is defined as the pain that caused or caused by neural main infringement or dysfunction at present.Nerve injury can be caused by wound and disease, so term " neuropathic pain " comprises the numerous disease with Different Kinds of Pathogens.These diseases include but not limited to, pain and pain, thyroprivia, uremia, multiple sclerosis, Spinal injury, Parkinson's disease, epilepsy or the vitamin deficiency relevant with chronic alcoholism after neuropathic pain, trigeminal neuralgia, backache, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, the maincenter apoplexy after peripheral neurophaty, diabetic neuropathy, the bleb.Neuropathic pain is not owing to have a provide protection, thereby is ill.It occurs after initial reason has just disappeared usually, generally lasts for several years, and has greatly reduced patient's quality of life (Woolf and Mannion, Lancet (1999) 353:1959-1964).Neuropathic pain syndrome is difficult to treatment, and reason is that they are of a great variety, even also there are differences (Woolf﹠amp suffering between the patient of same disease; Decosterd, Pain Supp., (1999) 6:S141-S147; Woolf and Mannion, Lancet (1999) 353:1959-1964).Neuropathic pain comprises spontaneous pain, can be continuity or pain sudden and that excite unusually, for example hyperpathia (susceptibility to destructive stimulus improves) and allodynia (to normal non-noxious stimulation sensitivity).
Inflammatory process is that the existence to tissue injury or foreign matter responds and the biochemistry and the cell incident of a series of complexity of exciting can cause swelling and pain (Levine and Taiwo 1994:Textbookof Pain 45-56).Arthritis pain is modal inflammatory pain.Similar rheumatism is a kind of chronic inflammatory diseases common in the developed country, and rheumatoid arthritis is to cause disabled common cause.The accurate cause of disease of rheumatoid arthritis is unknown, and the two all is important (Grennan﹠amp but present hypothesis is thought inherited genetic factors and microbiological factor; Jayson, 1994 Textbook of Pain 397-407).Estimate, have 1,600 ten thousand Americans to suffer from symptomatic osteoarthritis (OA) or degenerative joint disease approximately, wherein the Most patients age surpasses 60 years old, and along with aging population, this digital expectation will increase to 4,000 ten thousand, make it to become serious public health problem (Houge﹠amp; Mersfelder, AnnPharmacother., (2002) 36:679-686; McCarthy etc., 1994, Textbook of Pain, 387-395).Most of osteoarthritis patient is owing to the pain of being followed is sought medicine help.Sacroiliitis has remarkably influenced to social mentality and body function, and is to cause disabled first cause in living from now on.Ankylosing spondylitis also is the arthritic rheumatosis that causes backbone and sacrum joint.It can be from the backache of the intermittent attack of lifelong generation to the severe chronic disease of attacking backbone, peripheral joint and other body member.
The inflammatory pain of another kind of type is the visceral pain that comprises the pain relevant with inflammatory bowel disease (IBD).Visceral pain is the pain relevant with internal organ, and wherein internal organ comprise the organ in abdominal cavity.These organs comprise sexual organ, spleen and part Digestive tract.The pain relevant with internal organ can be divided into digestive viscera pain and non-digestive viscera pain.The common stomach that causes pain (GI) disease comprises functional type intestinal disease (FBD) and inflammatory bowel disease (IBD).These GI diseases comprise a large amount of morbid states that only are subjected to appropriateness control at present, for FBD, comprise gastroesophageal reflux disease, maldigestion, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS); For IBD, comprise Crohn disease, ileitis and ulcerative colitis, these all cause visceral pain regularly.The visceral pain of other type comprises pain and the pelycalgia relevant with dysmenorrhoea, urocystitis and pancreatitis.
The pain that should be noted that some types comprises multiple cause of disease, therefore can be classified into a more than field, and for example backache and cancer pain have nociceptive pain and these two kinds of compositions of neuropathic pain.
The pain of other type comprises:
The pain that-flesh-skeletal diseases causes comprises, myalgia, fibromyalgia, spondylitis, seronegativity (non-rheumatic) joint disease, non-rheumatic arthritis, dystrophin disease, glycogenolysis, polymyositis, pyomyositis;
-heart and blood vessel pain comprise the pain that is caused by stenocardia, myocardial infarction, mitral stenosis, pericarditis, Raynaud phenomenon, seleredema (scleredoma), skeletal muscle ischemic;
-headache is such as migraine (comprising migraine without aura, absence of aura migraine), cluster headache, tension headache, mixed type headache, the headache relevant with vascular disease; And
-actinal surface pain comprises toothache, bright mouthful syndrome and temporomandibular joint sarolemma pain.
Formula of the present invention (I) compound also can be used for treating the illness except that pain.Particularly, formula of the present invention (I) compound can be used for treatment and T-cell associated diseases, autoimmune disorders, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, asthma, cancer, acquired immune deficiency syndrome (AIDS) (AIDS), transformation reactions or inflammatory bowel.
The present invention further is included in the wide region or (I) compound of the formula in preferable range or its pharmaceutically-acceptable salts, solvate or prodrug are used for the treatment of purposes in the medicine of following disease or illness in manufacturing, described disease or illness be selected from pain (especially neuropathic pain), with T-cell associated diseases, autoimmune disorders, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, asthma, cancer, acquired immune deficiency syndrome (AIDS) (AIDS), transformation reactions or inflammatory bowel.
The present invention further comprises the method for following disease of treatment or illness, described disease or illness be selected from pain (especially neuropathic pain), with T-cell associated diseases, autoimmune disorders, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, asthma, cancer, acquired immune deficiency syndrome (AIDS) (AIDS), transformation reactions or inflammatory bowel, described method comprises, bestows formula (I) compound or its pharmaceutically-acceptable salts, solvate or the prodrug in wide region or in preferable range of significant quantity.
The pharmaceutically-acceptable salts of formula (I) compound comprises its acid salt and its alkali salt.
Suitable acid salt is formed by the acid that forms non-toxic salt.Example comprises, acetate, adipate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, hydrosulfate/vitriol, borate, camsilate, Citrate trianion, sucdrol salt (cyclamate), ethanedisulphonate, esilate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/muriate, hydrobromate/bromide, hydriodate/iodide, isethionate, lactic acid salt, malate, maleate, malonate, mesylate, Methylsulfate, naphthoate, the 2-naphthalenesulfonate, nicotinate, nitrate, Orotate, oxalate, palmitate, embonate (pamoate), phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, pyroglutamate, sugar lime, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and hydroxyl formate (xinofoate).
Suitable alkali salt is formed by the alkali that forms non-toxic salt.Example comprises aluminium salt, arginic acid salt, benzyl star salt (benzathine), calcium salt, choline salt, diethyl amine salt, glycol amine salt, Glycinates, lysine salt, magnesium salts, meglumine salt, (second) pure amine salt (olamine), sylvite, sodium salt, tromethamine salt and zinc salt.
Can also form half salt of bronsted lowry acids and bases bronsted lowry, for example Hemisulphate and half calcium salt.
For the summary of acceptable acid addition salts, referring to Stahl and Wermuth Handbook of Pharmaceutical Salts:Properties, Selection, and Use(Wiley-VCH, 2002).
The pharmaceutically-acceptable salts of formula (I) compound can prepare by in following three kinds of methods one or more:
(i) with the acid or the alkali reaction of formula (I) compound and expectation;
(ii) from the suitable precursors of formula (I) compound, remove acid labile or alkali unstable blocking group or utilize desired acid or alkali to make suitable ring-type presoma (for example lactone or lactan) open loop; Or
(iii) by with suitable acid or alkali reacts or make a kind of salt of formula (I) compound change into another kind by suitable ion exchange column.
Above-mentioned three kinds of reactions are implemented in solution usually.Can collect or reclaim with gained salt precipitation and by filtering by evaporating solvent.The degree of ionization of gained salt can variation between ionization extremely almost is ionized fully.
Compound of the present invention can exist with the successive solid-state form, and described form comprises unformed fully to crystallization fully.Term " unformed " refers to following state, and under this state, material lacks long-range order on molecular level, and according to temperature, can present the physical properties of solid or liquid.Common this material does not have specific X-ray diffraction pattern, though and have solid property, this material more formally is called as liquid.During heating, the variation from the solid property to the liquid property takes place, this is characterized by the change of state that is generally secondary (" gamma transition ").Term " crystal " refers to following solid phase, this solid mutually in, material has regular orderly internal structure on molecular level, and has each definite peak and determine the X-ray diffraction pattern.When this material of abundant heating, it also presents liquid property, but is the phase change (fusing point) that is generally one-level by solid to the variation of liquid.
Compound of the present invention can also exist with non-solvent form and solvation form.A kind of molecular complex described in used herein term " solvate ", and this mixture comprises compound of the present invention and one or more pharmaceutically acceptable solvent molecule, for example ethanol.When described solvent is water, use term " hydrate ".The present invention includes non-solvent compound and all solvate forms.
The categorizing system of current received organic hydrate has defined separation site hydrate, channel water compound or metal-ion hydrous water compound, referring to K.R.Morris's Polymorphism in Pharmaceutical Solids(Ed.H.G.Brittain, Marcel Dekker, 1995).Separating the site hydrate is following hydrate, in this hydrate, by getting involved organic molecule water molecules is separated and not directly contact.In the channel water compound, water molecules is arranged in the lattice passage, and in this passage, water molecules is adjacent with other water molecules.In metal-ion hydrous water compound, water molecules is bonded on the metal ion.
When solvent or water were combined closely, title complex had definite stoichiometric relation, and irrelevant with humidity.Yet, when solvent or water by weak in conjunction with the time (as passage solvate and hygroscopic compound), water/solvent depends on humidity and drying conditions.In this case, there is not stoichiometric relation usually.
After this, when mentioning formula (I) compound, all comprise its salt and solvated compounds with and the solvate of salt.
Compound of the present invention comprises formula (I) compound of preamble definition, and described formula (I) compound comprises all polymorphic forms of after this defined described formula (I) compound and crystal habit, prodrug and isomer (comprising optical isomer, geometrical isomer and tautomer) and through isotope-labeled formula (I) compound.
As indicated, the what is called " prodrug " of formula (I) compound is also included within the scope of the present invention.Thereby when some derivative of formula (I) compound that itself may have or not have pharmacological activity is hardly bestowed in the body or after on the body, it can for example change into by hydrolytic scission has expectation active formula (I) compound.This derivative is called as " prodrug ".Can reference about the more information that prodrug uses Pro-drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series (T.Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed.E.B.Roche, AmericanPharmaceutical Association).
For example H.Mundgarrd's Design of ProdrugsDescribed in (Elsevier, 1985), adopt some group well known by persons skilled in the art to substitute the suitable functional group that exists in formula (I) compound and can prepare prodrug of the present invention as " precursor group ".
Formula of the present invention (I) compound comprises carboxylic acid functional (COOH).Therefore, the suitable precursor medicine comprises its ester, and wherein, the hydrogen in the carboxylic acid functional of formula (I) compound is substituted by the ester residue.Term " ester residue " means ester group, and this ester group can decompose in vivo and forms formula (I) compound or its salt with free carboxylic acid groups by biological method (such as hydrolysis).
Can come in the following way to determine whether compound is prodrug: give laboratory animal such as rat or mouse with described compound by intravenous injection, then the body fluid of animal is studied, to determine whether the formula that to detect (I) compound or its pharmaceutically-acceptable salts.
The preferred embodiment of ester residue comprises:
C 1-20Alkyl, can be the straight or branched alkyl, such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl, especially be C 1-12Alkyl is preferably C 1-8Alkyl, more preferably C 1-6Alkyl most preferably is C 1-4Alkyl defines and enumerates those groups such as preamble;
C 1-10Haloalkyl (be defined as by one or more halogen atoms, preferably by the fluorine or chlorine atom, the more preferably alkyl that is replaced by fluorine atom), be preferably C 1-8Haloalkyl, more preferably C 1-6The chloro alkyl most preferably is C 1-4Haloalkyl, such as one, two or trifluoromethyl, one, two or trichloromethyl, brooethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, 2-chloroethyl, 2,2-Dichloroethyl, 2,2,2-three chloroethyls, perfluor ethyl, perfluoro propyl and perfluoro butyl;
C 1-10Hydroxyalkyl (is defined as being preferably C by hydroxyl (OH) alkyl of Qu Daiing) 1-8Hydroxyalkyl, more preferably C 1-6Hydroxyalkyl most preferably is C 1-4Hydroxyalkyl, such as methylol, 1-or 2-hydroxyethyl, 1-, 2-or 3-hydroxypropyl, 1-, 2-, 3-or 4-hydroxyl butyl;
(C 1-10Alkoxyl group) C 1-10Alkyl (being defined as the alkyl that alkoxy replaces) is preferably (C 1-6Alkoxyl group) C 1-6Alkyl, more preferably (C 1-4Alkoxyl group) C 1-4Alkyl most preferably is (C 1-4Alkoxyl group) methyl, such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxyl methyl, propoxy-methyl, isopropoxy methyl, butoxymethyl and tert.-butoxy methyl;
Through C 1-6Oxyalkylated (C 1-6Alkoxyl group) methyl is such as 2-methoxy ethoxy methyl;
Halo (C 1-6Alkoxyl group) methyl, such as 2,2,2-trichlorine ethoxyl methyl and two (2-chloroethoxy) methyl;
C 3-8Cycloalkyl is such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group;
Aralkyl is for example by 1 to 3 C 6-14The C that aryl replaces 1-6Alkyl (wherein said aryl moiety is selected from phenyl, naphthyl, anthryl and phenanthryl) is such as benzyl, Alpha-Naphthyl methyl, betanaphthyl methyl, diphenyl methyl, trityl group, Alpha-Naphthyl diphenyl methyl and 9-anthryl methyl; With by 1 to 3 substituted C 6-14The C that aryl replaces 1-6Alkyl, one or more in the wherein said aryl by one or more (preferred 1 to 3, more preferably only 1) C 1-6Alkyl, C 1-6Alkoxyl group, nitro, halogen or cyano group substituting group replace, such as 4-methyl-benzyl, 2,4,6-trimethyl benzyl, 3,4,5-trimethyl benzyl, 4-methoxy-benzyl, 4-p-methoxy-phenyl diphenyl methyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-benzyl chloride base, 4-bromobenzyl and 4-cyano group benzyl, especially benzyl;
THP trtrahydropyranyl or tetrahydro thiapyran base, wherein, optional halogen and the C of being selected from of described THP trtrahydropyranyl or tetrahydro thiapyran base 1-6The substituting group of alkoxyl group replaces, such as tetrahydropyrans-2-base, 3-bromine tetrahydropyrans-2-base, 4-methoxyl group-tetrahydropyran-4-base, tetrahydric thiapyran-2-base and 4-methoxyl group-tetrahydropyran-4-base;
Tetrahydrofuran base or tetrahydro-thienyl, wherein, optional halogen and the C of being selected from of described tetrahydrofuran base or tetrahydro-thienyl 1-6The substituting group of alkoxyl group replaces, such as tetrahydrofuran (THF)-2-base and tetramethylene sulfide-2-base;
C 2-10Alkenyl is such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonene base and decene base; With
C 2-10Alkynyl group is such as ethynyl, proyl, butynyl, pentynyl, hexin base, heptyne base, octyne base, n-heptylacetylene base and decynyl.
Other embodiment that substitutes group among the embodiment of previous embodiment and other type prodrug can be referring to above-mentioned reference.
And some compound of formula (I) itself can be used as the prodrug of other formula (I) compound.
Formula (I) compound that contains one or more unsymmetrical carbons can exist with the form of two or more steric isomers.Because formula (I) compound comprises cycloalkenyl group, so work as CO 2When H and B group are not on the same carbon atom, can there be the cis/trans isomer.Under the situation that constitutional isomer can transform mutually via low energy barrier, tautomer (" tautomerism ") may appear.In containing formula (I) compound of ring-type urea groups, sulfo-urea groups or cyano group guanidine radicals, there is the proton tautomerism phenomenon, containing the compound of aromatic group, there is so-called valency tautomerism.Can there be the isomery of more than one types in a kind of compound.
All steric isomers, diastereomer (especially cis/trans isomer) and the tautomer that comprise formula (I) compound within the scope of the invention comprise the compound with more than one type isomerys and the mixture of one or more compounds.Also comprise acid salt or alkali salt, wherein, described gegenion has optical activity, for example d-lactic acid salt or l-lysine salt, or be racemic mixture, for example dl-tartrate or dl-arginic acid salt.
Can separate cis/trans isomer, for example chromatography and fractionation crystallization by well known to a person skilled in the art routine techniques.
The routine techniques that is used to prepare/separate single enantiomer comprises, it is synthetic to carry out chirality by the pure presoma of suitable optical, or utilizes chirality high pressure liquid chromatography (HPLC), and racemic modification (or racemic modification of salt or derivative) is split.
Perhaps, racemic modification (perhaps racemize presoma) can react with suitable optically active compound, described optically active compound for example is an alcohol, perhaps comprises under the situation of acidity or basic group at formula (I) compound, and for example be such as 1-phenyl ethyl amine or tartaric alkali or acid.Can be by chromatography and/or by the separating obtained diastereo-isomerism mixture of fractionation crystallization, and a kind of in the anisomeria or the two are changed into corresponding pure enantiomer by technology well known by persons skilled in the art.
Can utilize chromatography (being generally HPLC) to obtain the chipal compounds of the present invention (and chirality presoma) of enantiomerism enriched form in having the asymmetric resin of following moving phase, described moving phase is made up of the hydrocarbon (being generally heptane or hexane) of the alkylamine (being generally 0.1% diethylamine) of Virahol that contains 0 to 50 volume % (being generally 2% to 20%) and 0 to 5 volume %.Concentrate eluant obtains the mixture of enrichment.
When any racemic modification crystallization, can obtain two kinds of dissimilar crystal.First type is, aforesaid racemic compound (true racemic modification), and the crystal of the homogeneous form that wherein obtains contains two kinds of enantiomers of equimolar amount.Second type is, racemic mixture or aggregation wherein, obtain the crystal of two kinds of forms of equimolar amount, and every kind of crystal comprises single enantiomer.
Although two kinds of crystallized forms that exist in the racemic mixture have identical physical properties, compare them with true racemic modification and have different physical propertiess.Can the separation of racemic mixture by routine techniques well known by persons skilled in the art, described technology is for example referring to E.L.Eliel and S.H.Wilen Stereochemistry of Organic Compounds(Wiley, 1994).
Compound of the present invention comprises that all are pharmaceutically acceptable through isotope-labeled formula (I) compound, and wherein, the atom that one or more atoms are occupied the majority by atomicity and occurring in nature is identical but atoms that atomic mass or total mass number are different substitute.
Be suitable for being included in the isotropic substance that isotopic example in the The compounds of this invention comprises hydrogen, such as 2H and 3H; The isotropic substance of carbon, such as 11C, 13C and 14C; The isotropic substance of chlorine, such as 36Cl; The isotropic substance of fluorine, such as 18F; The isotropic substance of iodine, such as 123I and 125I; The isotropic substance of nitrogen, such as 13N and 15N; The isotropic substance of oxygen, such as 15O, 17O and 18O; The isotropic substance of phosphorus, such as 32The isotropic substance of P and sulphur, such as 35S.
Some is through isotope-labeled formula (I) compound, and for example those comprise the compound of radioactive isotope, can be used for medicine and/or the research of substrate tissue distribution.Consider the radioactive isotope tritium (promptly 3H) and carbon-14 (promptly 14C) be easy to add, and be easy to survey, it is specially adapted to above-mentioned purpose.
With heavier isotropic substance (promptly such as deuterium 2H) replace, owing to have higher metabolic stability, for example the transformation period prolongs or the reduction of dosage demand in the body, thus can obtain some treatment advantage, therefore in some cases can be preferred.
Use the positron radiation isotropic substance such as 11C, 18F, 15O and 13N replaces, and can be used in the research of positron radiation distributed image to study the occupy-place rate of substrate acceptor.
Can prepare by well known to a person skilled in the art routine techniques through isotope-labeled formula (I) compound, or prepare by the suitable reagent of similar method utilization described in appended embodiment and the method for making through the alternative previous used un-marked of isotope-labeled reagent.
Pharmaceutically acceptable solvent according to the present invention comprises the following solvent that can be replaced by isotropic substance, for example D 2O, d 6-acetone, d 6-DMSO.
Previous defined formula (I) midbody compound and all salt, solvate and title complex and be also included within the scope of the present invention for all solvates and the title complex of the previous defined salt of formula (I) compound.The present invention includes the polymorphic form and the crystal habit thereof of aforementioned substances.
When preparation formula of the present invention (I) compound, the form of capable conventional selecting type (I) compound of those skilled in the art, thus selected formula (I) compound provides optimum assemblage characteristic for purpose of the present invention.Described feature comprises, the productive rate of fusing point, solvability, processibility, intermediate and the complexity of purified product in sepn process.
In order to select to be best suited for the formulation and the route of administration of therapeutic goal illness, should assess the bio-pharmaceuticals character of formula (I) compound, such as solvability and stability of solution (stability in the pH scope), perviousness etc.
The compound of the present invention that is intended to be used for pharmaceutical applications can be bestowed with the form of crystal or unformed product.Can obtain for example compound of solid plug (solid plug), powder or form membrane by method such as precipitation, crystallization, freeze-drying, spraying drying or evaporation drying.Microwave drying or radio-frequency seasoning can be used for above-mentioned purpose.
Compound of the present invention can bestow separately or with one or more other compound of the present invention or with one or more other medicines (or its arbitrary combination) administered in combination.Generally speaking, they combine with the form of preparation with one or more pharmaceutically acceptable vehicle and bestow.Used herein term " vehicle " is used to describe any composition except that The compounds of this invention.Being chosen in of vehicle depended on following factor to a great extent, and such as specific mode of administration, vehicle is to solvability and the influence of stability and the character of formulation.
Pharmaceutical compositions that is applicable to the conveying The compounds of this invention and preparation method thereof is understood for a person skilled in the art.Above-mentioned composition and preparation method thereof for example can referring to Remington ' s Pharmaceutical SciencesThe 19th edition, (Mack Publishing Company, 1995).
Oral
Compound of the present invention can be oral.Swallow oral can comprising, thereby described compound enters gi tract; And/or through the cheek administration, through tongue administration or sublingual administration, thereby described compound directly enters blood flow by mouth.
Be applicable to that oral preparation comprises solid, semisolid and liquid system, such as tablet, soft or the hard capsules that contains multiple or nano particle, liquid or powder, lozenge (comprise be filled with liquid), chewable tablet, gel, the fast-dispersing type, film, the agent of ovum shape, spraying and cheek are with/docile and obedient the patch of using of mucous membrane.
Liquid formulations comprises suspension, solution, syrup and elixir.This preparation can be used as weighting agent soft or hard capsules (for example being made by gelatin or Vltra tears), and generally include supporting agent, for example water, ethanol, polyoxyethylene glycol, propylene glycol, methylcellulose gum or suitable oil, and comprise one or more emulsifying agents and/or suspension agent.Liquid formulations also can by will be for example solid in the sachet modulate again and prepare.
Compound of the present invention can also use with quick dissolving, rapidly disintegrating dosage form, such as at the Expert of Liang and Chen Opinion in Therapeutic Patents, 11(6), those formulations described in the 981-986 (2001).
For tablet form, to decide according to dosage, medicine can account for 1 weight % to 80 weight % of formulation, accounts for 5 weight % to 60 weight % usually.Except medicine, tablet contains disintegrating agent usually.Hydroxypropylcellulose, starch, pregelatinized Starch and sodium alginate that the example of disintegrating agent comprises Explotab, Xylo-Mucine, calcium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose pyce, polyvinylpolypyrrolidone, Polyvinylpyrolidone (PVP), methylcellulose gum, Microcrystalline Cellulose, replaces through low alkyl group.Generally speaking, the content of disintegrating agent accounts for 1 weight % to 25 weight % of formulation, preferably accounts for 5 weight % to 20 weight %.
Tackiness agent is normally used for giving tablet formulation product cohesion matter.Suitable binder comprises Microcrystalline Cellulose, gelatin, sugar, polyoxyethylene glycol, natural and synthetic gum, Polyvinylpyrolidone (PVP), pregelatinized Starch, hydroxypropylcellulose and Vltra tears.Tablet can also comprise thinner, such as lactose (Lactose hydrate, a spray-dried Lactose hydrate, unformed lactose etc.), N.F,USP MANNITOL, Xylitol, glucose, sucrose, sorbyl alcohol, Microcrystalline Cellulose, starch, dicalcium phosphate dihydrate.
The also optional tensio-active agent that comprises of tablet is such as Sodium Lauryl Sulphate BP/USP and Spheron MD 30/70 (polysorbate 80); And the optional antiseize paste that comprises is such as silicon-dioxide and talcum.Tensio-active agent when existing, can account for 0.2 weight % to 5 weight % of tablet, and antiseize paste can account for 0.2 weight % to 1 weight % of tablet.
Tablet also comprises lubricant usually, such as the mixture of Magnesium Stearate, calcium stearate, Zinic stearas, sodium stearyl fumarate and Magnesium Stearate and sodium lauryl sulphate.Lubricant accounts for 0.25 weight % to 10 weight % of tablet usually, preferably accounts for 0.5 weight % to 3 weight %.
Other composition can comprise antioxidant, tinting material, seasonings, sanitas, odor mask.
Exemplary tablet comprises about at the most 80% medicine, and about 10 weight % are to the tackiness agent of about 90 weight %, and about 0 weight % is to the thinner of about 85 weight %, the lubricant of about 2 weight % to the disintegrating agent of about 10 weight % and about 0.25 weight % to about 10 weight %.
Directly film-making or form tablet of tablet mixture by roller compacting.Tablet blend or part blend can carry out wet granulation, non-slurry pelletizing, melt pelletization before film-making, fusion is freezed or extrude.Final preparation can comprise one or more layers, and can be by dressing or not coated; Even can incapsulate.
At H.Lieberman and L.Lachman Pharmaceutical Dosage Forms: Tablets, Vol.1 has discussed the tablet formulation product in (Marcel Dekker, New York, 1980).
Human or for animals consume oral film be generally softish can water-soluble or water swellable thin-film dosage form, this formulation can be dissolved fast or be adhered to mucous membrane, and generally includes formula (I) compound, film-forming polymer, tackiness agent, solvent, wetting agent, softening agent, stablizer or emulsifying agent, viscosity modifier and solvent.Some components in the preparation can have more than one function.
Formula (I) compound can for can be water-soluble or can not be water-soluble.But water soluble compounds accounts for 1 weight % to 80 weight % of solute usually, more common 20 weight % to the 50 weight % that account for.The low-solubility compound can account for the larger proportion of composition, accounts for the 88 weight % at the most of solute usually.Perhaps, formula (I) compound can be granose bead formulation.
Film-forming polymer can be selected from natural polysaccharide, protein or synthetic water gel, and common content is in the scope of 0.01 to 99 weight %, and is more common in the scope of 30 to 80 weight %.
Other composition can comprise antioxidant, tinting material, seasonings and flavor potentiator, sanitas, saliva stimulant, refrigerant, cosolvent (comprising oil), softener, weighting agent, defoamer, tensio-active agent and odor mask.
Usually prepare by the following method according to film of the present invention: will be coated in the water-based thin film evaporation drying on peelable support base material or the cardboard.This process can be generally the applicator moisture eliminator of combination in drying oven or passage, or is undertaken by freeze-drying or vacuum-drying.
The oral administration solid preparation can be formulated into and discharge at once and/or modify release.Modify release formulations and comprise that delay discharges, continues release, pulsation release, sustained release, target release and program and discharges.
US patent 6,106,864 has been described the modification release formulations that is applicable to the object of the invention.The release tech that other is suitable can be referring to Verma's etc. such as the details of high energy dispersion and infiltration, coated granule Pharmaceutical Technology On-line, 25 (2), 1-14 (2001).The use Chewing gum has been described to realize sustained release among the WO00/35298.
Parenteral admin
Compound of the present invention can directly be bestowed in the blood flow, in the muscle or among the internal.The suitable mode of parenteral admin comprises, administration and subcutaneous administration in administration in administration in administration in intravenously administrable, artery administration, intraperitoneal administration, intrathecal drug delivery, the ventricle, the urethra, the breastbone, encephalic administration, intramuscular administration, the synovial membrane.The appropriate device that is used for parenteral admin comprises syringe needle (comprising miniature syringe needle) syringe, needleless injector and infusion techn.
The parenteral preparation is generally the aqueous solution, can comprise vehicle, such as salt, carbohydrate and buffer reagent (preferred pH is 3 to 9), but for some application, described parenteral preparation is more suitable for being mixed with aseptic non-aqueous solution, or is mixed with dried forms and is used in combination with suitable medium such as sterile pyrogen-free water.
For example preparing the parenteral preparation by freeze-drying under aseptic condition can finish by well known to a person skilled in the art the standard pharmaceutical technology.
Can strengthen reagent such as mixing solvability by using suitable compounding process, improve the solvability of formula used in the preparation of parenteral solution (I) compound.
The preparation that is used for parenteral admin can be formulated into and discharge at once and/or modify release.Modify release formulations and comprise that delay discharges, continues release, pulsation release, sustained release, target release and program and discharges.Therefore, compound of the present invention can be formulated into suspension or be mixed with solid, semisolid or thixotropic liquid and be used for administration with the form of implanting the storehouse, discharges thereby active compound is modified.The example of this preparation comprises, through the support of medicine coating and semi-solid and comprise poly-(d-lactic acid-copolymerization oxyacetic acid) (PGLA) suspension of microballoon that loads medicine.
Topical
The all right topical of compound of the present invention, intradermal administration or percutaneous dosing are to skin or mucous membrane.The typical preparation that is used for above-mentioned purpose comprises gel, hydrogel, washing lotion, solution, emulsifiable paste, ointment, face powder, dressing, foam, film, skin patch, diaphragm (wafer), implant, sponge, fiber, bandage and microemulsion.Can also use liposome.Typical supporting agent comprises alcohol, water, mineral oil, whiteruss, white paraffin, glycerine, polyoxyethylene glycol and propylene glycol.Can mix penetration enhancers, referring to the J.Pharm.Sci. of for example Finnin and Morgan, 88(10), 955-958 (in October, 1999).
Other method of topical comprises by electroporation, ionophoresis, ultrasonic wave importing and micropin injection or Needleless injection carries (for example, Powderject TM, Bioject TMDeng).
The preparation that is used for topical can be formulated into and discharge at once and/or modify release.Modify release formulations and comprise that delay discharges, continues release, pulsation release, sustained release, target release and program and discharges.
Suction/intranasal administration
Compound of the present invention can also be by in the nose or inhalation, usually with dry powder form (separately, mixture for example mixes thing with doing of lactose, or as the blended component particles, for example mixes with phosphatide (such as Yelkin TTS)) by the Diskus administration; With container, pump, injector, atomizer (preferably utilize electric hydaulic generate the atomizer of fine mist) or the aerosolizer administration of aerosol spray form, can use or not use suitable propelling agent, such as 1,1 by pressurization, 2,2-Tetrafluoroethane or 1,1,1,2,3,3, the 3-heptafluoro-propane; Or with the nasal drop form administration.For using in the nose, powder can comprise biological adhesive, such as chitosan or cyclodextrin.
Container, pump, injector, atomizer or the aerosolizer of pressurization comprises the solution or the suspension of The compounds of this invention, described solution or suspension comprise, for example ethanol, aqueous ethanolic solution or suitable other be used to disperse, dissolve or prolong reagent that actives discharges, as the propelling agent and the optional tensio-active agent of solvent, such as sorbitan trioleate, oleic acid ester or lact-acid oligomer.
Before in dry powder or suspension preparation, using, the medicine particulate is changed into the size (usually less than 5 microns) that is suitable for by the suction conveying.This can realize by any suitable breaking method, processes to form nano particle, high pressure homogenize or spraying drying such as spiral spray grinding, liquid bed jet grinding, supercutical fluid.
The capsule that in sucker or insufflator, uses (for example making), cover bubble (blisters) and cartridge case by gelatin or Vltra tears can be formulated into the powdered mixture that contains The compounds of this invention, suitable powder matrix (such as lactose or starch) and properties modifier (such as, l-leucine, N.F,USP MANNITOL or Magnesium Stearate).Lactose can or be the monohydrate form for anhydrous form, is preferably the monohydrate form.Other suitable vehicle comprises, glucosides, glucose, maltose, Sorbitol Powder, Xylitol, fructose, sucrose and trehalose.
The suitable solution preparation that use utilizes electric hydaulic to generate fine mist in aerosolizer can comprise the compound of the present invention of 1 μ g to 20mg when each the actuating, and the actuating volume can change between 1 μ l to 100 μ l.Typical preparation can comprise formula (I) compound, propylene glycol, aqua sterilisa, ethanol and sodium-chlor.Other solvent that can be used for alternative propylene glycol comprises glycerol and polyoxyethylene glycol.
Suitable flavouring agent, such as menthol and left-handed menthol, perhaps sweeting agent such as asccharin or soluble saccharin, can add in those preparations of the present invention in order to suction/intranasal administration.
Be used to suck/preparation of intranasal administration can be formulated into discharge at once and/or for example PGLA modify and discharge.The preparation of modifying release comprises delay release, the lasting release that discharges, pulses, sustained release, target release and program release.
Internal rectum/intravaginal administration
Compound of the present invention can for example carry out internal rectum or intravaginal administration with the form of suppository, vaginal suppository or enema.Theobroma oil is traditional suppository base, but also can use suitable various substitutes.
The preparation that is used for internal rectum/intravaginal administration can be formulated into and discharge at once and/or modify release.The preparation of modifying release comprises delay release, the lasting release that discharges, pulses, sustained release, target release and program release.
Eye/ear's administration
Compound of the present invention can also directly be administered into ear or eyes, usually with micronized hanging drop or waits ooze, the form of solution in the Sterile Saline of PH adjustment.Other preparation that is suitable for eye and ear's administration comprises ointment, gel, biodegradable (for example can absorb gel sponge, collagen) and not biodegradable (for example silica gel) implant, diaphragm, eyeglass and microparticle system or vesicle system, such as vesicle (niosomes) or liposome.Polymkeric substance such as cross linked polyacrylate, polyvinyl alcohol, hyaluronic acid acid, cellulose polymer compound (for example Vltra tears, Natvosol or methylcellulose gum) or mixed polysaccharide polymkeric substance (for example gelan natural gum) can mix with the sanitas such as benzalkonium chloride.Above-mentioned preparation also can be carried by ionophoresis.
The preparation that is used for eye/ear's administration can be formulated into and discharge at once and/or modify release.The preparation of modifying release comprises delay release, the lasting release that discharges, pulses, sustained release, target release and program release.
Other technology
Compound of the present invention can with the soluble large molecule entity, such as cyclodextrin and suitable derivative thereof or contain the polymkeric substance of polyoxyethylene glycol, combination, thus its solvability, dissolution rate, taste masking, bioavailability and/or stability improved, thus use with any above-mentioned administering mode.
For example find that medicine-cyclodextrin title complex can be used for most of formulations and route of administration usually.Can use inclusion complex and non-inclusion complex.Directly the another kind of method that cooperates with medicine is that cyclodextrin can be used as adjuvant, promptly as supporting agent, thinner or solubilizing agent.Be most commonly used to these purposes be α-, β-and γ-cyclodextrin, the example can be referring to WO 91/11172, WO 94/02518 and WO 98/55148.
Tool kit
Owing to for example wishing to bestow the active compound of combination in order to treat specified disease or illness, so can be to be suitable for bestowing simultaneously the tool kit form of composition, with two or more pharmaceutical compositions (in the described composition at least a comprise compound of the present invention) combination easily, above-mentioned situation also falls within the scope of the invention.
Therefore, tool kit of the present invention comprises two or more independent pharmaceutical compositions (in the described composition at least a comprise compound of the present invention), and the device that is used for preserving separately described composition, such as container, the bottle that separates or the tinfoil bag that separates.The example of above-mentioned tool kit is the common Blister Package that is used for package troche, capsule etc.
Tool kit of the present invention is specially adapted to bestow different dosage form (for example oral and parenteral dosage forms), and being applicable to takes medicine with difference at interval bestows independent various compositions, or is applicable to each other the quantitatively independent various compositions of titration.In order to help compliance, tool kit generally includes the explanation of taking medicine, and can provide so-called memory auxiliary.
Formulation
For bestowing human patients, in the scope of 10mg to 1000mg, this depends on the pattern of administration to total per daily dose of The compounds of this invention certainly usually.For example, the total per daily dose of oral requirement is 10mg to 1000mg, and vein dosage can be 10mg to 1000mg.Total per daily dose can be bestowed for single dose or multidose form, and also can according to doctor's advice drop on this paper beyond the given scope.
Above-mentioned dosage is based on the general adult of the about 60kg to 70kg of body weight.The doctor can determine easily that body weight drops on above-mentioned scope patient's (such as baby and old man) in addition dosage.
For fear of doubt, " treatment " that this paper mentions comprises therapeutic treatment, the property alleviated treatment and prophylactic treatment.
All formulas (I) compound can prepare by the process described in the general method as described below, perhaps prepares by the ad hoc approach described in embodiment part and the method for making part, perhaps is out of shape by the routine of aforesaid method to prepare.Except any novel intermediate, the present invention also contained those methods of being used for preparation formula (I) compound any one or multiple.
General method
Use following shortenings:
The DMF=dimethyl formamide
The DMSO=dimethyl sulfoxide (DMSO)
TEMPO=2,2,6,6-tetramethyl piperidine N-oxide compound
The THF=tetrahydrofuran (THF)
The DCM=methylene dichloride
Formula (I) compound can be prepared shown in following route 1 (Scheme 1).
Figure A20068004533300301
In the route 1; P representation hydroxy blocking group, its suitable case description be in T.W.Greene and P.Wuts " Protective Groups in Organic Synthesis " Wiley and Sons, in 1991; the leavings group that the LG representative is suitable is such as halogen, (C 1-6Alkyl) sulfonyloxy (for example sulfonyloxy methyl oxygen base), (C 1-6Haloalkyl) sulfonyloxy (for example trifluoromethane sulfonyloxy) or phenylsulfonyloxy or tosyloxy (for example tolysulfonyl oxygen base).Preferably, P is a benzyl, and LG is a tolysulfonyl oxygen base.
Step (a): with compound (II) and the suitable reagent that hydroxyl can be changed into leavings group; be generally sulfonylation agent (for example methane sulfonyl chloride or Tosyl chloride); in the presence of alkali (for example triethylamine or pyridine); in suitable solvent (for example pyridine or methylene dichloride); 0 ℃ to room temperature, react 15 minutes to 24 hours can preparation formula (III) compound.
Preferred condition is: 1 equivalent compound (II) in methylene dichloride, and 1.2 equivalent Tosyl chlorides, 2 equivalent pyridines, at room temperature, 18 hours.
Step (b): with compound (III) and formula (VI) oxy-compound, in suitable solvent (for example DMF, DMSO), at suitable alkali (Cs 2CO 3, K 2CO 3) existence under, can be selected under the existence of crown ether (for example 18-hat-6), whole night can preparation formula (IV) compound 50 to 120 ℃ of following reactions.
Preferred condition is: 1 equivalent compound (IV), 1.1 equivalent compounds (III), 1.2 equivalent Cs 2CO 3, in DMF, 80 ℃ were reacted 24 hours down.
WO02/074754 has carried out general description to formula (VI) compound.As Bioorg.Med.Chem.Lett., (2004), 14 (18), described in the 4627-32 or following route 5 summarize, can prepare concrete formula (VI) compound, wherein X is O, m is 1, R is Cl.
Step (c): formula (IV) compound can be by coming deprotection with the reaction of deprotecting regent in suitable solvent, thereby generate the formula V compound." Protective Groups in OrganicSynthesis " (referring to the same) described suitable reagent and method.When P was benzyl, the example of suitable agent comprised boron trichloride or iron(ic) chloride (III).
Preferred condition is: the compound (IV) of 1 equivalent in methylene dichloride, 4 equivalent BCl 3, at room temperature reacted 18 hours.
Step (d): can utilize oxidising agent that the formula V compound is carried out oxidation in suitable solvent and come preparation formula (I) compound.Typical reagent and condition comprise, play the chromium trioxide and the Periodic acid (H of katalysis 5IO 6) in such as the solvent of acetonitrile in room temperature to 50 ℃ reaction 18 to 36 hours down, perhaps NaOCl adds NaClO 2In such as the solvent of acetonitrile, to room temperature, reacting 18 to 36 hours in the presence of the TEMPO that plays katalysis at 0 ℃.
Preferred condition is: 1 equivalent compound (V), 2.5 equivalent Periodic acid, 0.02 equivalent CrO 3, in 0.75% water-based acetonitrile, under 0 ℃, oxidation 24 hours.
Also can be shown in route 2 (Sheme 2), by with two steps process oxidation formula V compound, come preparation formula (I) compound via the aldehyde of formula (VII).
Figure A20068004533300321
Step (a): pure (V) arrives the common following enforcement of oxidation of aldehyde (VII): use the TEMPO of a NaOCl and a katalysis to react 2 to 18 hours to room temperature at 0 ℃ in the suitable solvent of for example acetonitrile, acetone, perhaps utilize sulphur trioxide-pyridine complex and DMSO to react 2 to 18 hours to room temperature at 0 ℃ in such as the solvent of THF.
Step (b): aldehyde (VII) arrives the common following enforcement of further oxidation of acid (I): use NaClO 2In the presence of potassiumphosphate, in such as the solvent of the water-based trimethyl carbinol, to room temperature, reacted 2 to 18 hours, perhaps utilize the TEMPO of a trichloroisocyanuric acid and a katalysis in the suitable solvent of for example acetone or acetonitrile, to room temperature, to react 2 to 18 hours at 0 ℃ at 0 ℃.
Formula (II) compound is known by document.For example, as J.Chem.Soc., Perkin Trans.1, (1995), and 18,2281-7 is described, can preparation formula (II) compound, wherein A is a cis-1, the inferior cyclobutyl of 3-, B is a singly-bound.
Perhaps, shown in route 3 (Scheme 3), can be by formula (VIII) or compound (IX) by standard method preparation formula (Ib) compound, this compound is cis-or anti-form-1 for A wherein, the inferior cyclobutyl of 3-, B is single bonded formula (I) compound.By cis-compound (II) and (X) utilize and Synthesis, (1981), 1 described similar Mitsunobu chemical reaction can obtain trans-compound (II) and (X) respectively by upset.
Figure A20068004533300331
In the route 3, R aBe the ester residue, its suitable example for reference to previous prodrug described those and description (for example, (C is arranged in " Protective Groups in Organic Synthesis " (referring to the same) 1-6) alkyl, benzyl or (+) or (-)-menthyl), LG is a leavings group, such as halogen, (C 1-6Alkyl) sulfonyloxy (for example sulfonyloxy methyl oxygen base), (C 1-6Haloalkyl) sulfonyloxy (for example trifluoromethane sulfonyloxy) or phenylsulfonyloxy or tosyloxy (for example tolysulfonyl oxygen base).
Step (a): can pass through compound (VIII) and suitable formula R aOH alcohol (for example, methyl alcohol, the trimethyl carbinol, benzylalcohol or (-) menthol) react preparation formula (IX) compound, the suitable example of described condition to be described in " Protective Groups in OrganicSynthesis " (referring to the same) under various conditions.
Preferred condition is: 1 equivalent compound (VIII), and 1.1 equivalents 1,1 '-carbonyl dimidazoles in ethyl acetate, refluxed 1 hour, then with 1 equivalent R aOH at room temperature reacted 4 hours.
Step (b): compound (IX) can followingly be implemented to the reduction of alcohol (X): utilize the suitable original reagent of going back, for example sodium borohydride or L-Selectride
Figure A20068004533300332
, in suitable solvent such as THF.
Preferred condition is: 1 equivalent compound (IX), 0.5 equivalent NaBH 4, the THF at 20: 1: in the methyl alcohol, 0 ℃ of following reductase 12 0 minute.
Step (c): can utilize and route 1, similar agents described in the step (a) and condition preparation formula (XI) compound by compound (X).
Preferred condition is: 1 equivalent compound (X), and 1.05 equivalent Tosyl chlorides, in pyridine, 0 ℃ to room temperature.
Step (d): can be by compound (XI) and formula (VI) oxy-compound utilization and route 1, similar agents described in the step (b) and condition preparation formula (Ia) compound.
Preferred condition is: 1.2 equivalent compounds (XI), 1.0 equivalent compounds (VI), 1.5 equivalent Cs 2CO 3, in DMF, 80 ℃ were reacted 18 hours down.
Step (e): formula (Ia) compound can hydrolysis obtain formula (Ib) compound.This reaction can be finished under various conditions, and the suitable example of described reaction is described in " Protective Groups inOrganic Synthesis " (referring to the same).Preferred condition is: compound (Ia), 2 equivalent NaOH are at 1: 1 ethanol: in the water, 60 ℃ of following hydrolysis 2 hours.
J.Org.Chem., (1981), 53,3841-43 has described compound (VIII), J.Org.Chem., (1994), and 59,2132-34 has described formula (IX) compound, wherein R aBe methyl.
Figure A20068004533300341
Shown in route 4 (Scheme 4), can preparation formula (Id) compound, this compound is formula (I) compound of methylene radical for B wherein.
In the route 4, R aBe the ester residue, its suitable example be with reference to previous prodrug described those and in " Protective Groups in Organic Synthesis " (referring to the same), description (for example, (C is arranged 1-6) alkyl or benzyl), LG is a leavings group, such as halogen or (C 1-6Alkyl) sulfonyloxy (for example sulfonyloxy methyl oxygen base), (C 1-6Haloalkyl) sulfonyloxy (for example trifluoromethane sulfonyloxy) or phenylsulfonyloxy or tosyloxy (for example tolysulfonyl oxygen base).Preferably, R aBe benzyl, LG is a tolysulfonyl oxygen base.Be available commercially formula (XII) compound.
Step (a): formula (XIII) compound can be by being prepared as follows: with the hydrolysis under acidity or alkaline condition of formula (XII) compound, for example aqueous sodium hydroxide solution and suitable cosolvent, such as methyl alcohol, ethanol or 1,4-dioxy hydridization hexane, perhaps aqueous hydrochloric acid or aqueous sulfuric acid and optional suitable cosolvent, such as ethanol or 1,4-dioxy hydridization hexane.
Preferred condition is: 1 equivalent compound (XII), 4 equivalent NaOH are at 1: 1 ethanol: refluxed 2.5 hours in the water.
Step (b): can through type (XIII) compound and suitable formula R aOH alcohol (for example methyl alcohol, the trimethyl carbinol, benzylalcohol) reacts under various conditions and comes preparation formula (XIV) compound, the suitable example of described condition to be described in " Protective Groups in Organic Synthesis " (referring to the same).Preferred condition is: 1 equivalent compound (XIII), 1.1 equivalents 1,1 '-carbonyl dimidazoles reacted in ethyl acetate about 1 hour, at room temperature reacted 18 hours with 1.2 equivalent benzylalcohols then.
Step (c): with formula (XIV) compound adopt hydrogen boronation reagent (hydroboratingagent) such as borine-dimethylsulphide, catecholborane or 9-boron dicyclo [3.3.1] nonane (9-BBN) suitable solvent such as THF in, handle to room temperature at 0 ℃, then adopt oxygenant such as hydrogen peroxide, Sodium peroxoborate or Trimethylamine-N-oxide compound at room temperature to 60 ℃ following in-situ oxidation, can preparation formula (XV) compound.
Preferred condition is: 1 equivalent compound (XIV), 0.5 equivalent borine-dimethylsulphide in THF, was at room temperature handled 1 hour, then heated 1 hour down by 1.2 equivalent Sodium peroxoborate oxidations and at 60 ℃.
Step (d): by formula (XV) compound utilization and route 1, described similar agents of step (a) and condition preparation formula (XVI) compound.
Preferred condition is: 1 equivalent compound (XV), 1.3 equivalent Tosyl chlorides, 2.6 equivalent pyridines, in DCM, at 0 ℃ to room temperature.
Step (e): by formula (XVI) compound and formula (VI) oxy-compound utilization and route 1, described similar agents of step (b) and condition preparation formula (Ic) compound.Preferred condition is: 1.2 equivalent compounds (XVI), 1.0 equivalent compounds (VI), 1.5 equivalent Cs 2CO 3, in DMF, reacted 18 hours down at 80 ℃.
Step (f): formula (Ic) compound can hydrolysis obtain formula (Ib) compound.This reaction can be finished under various conditions, and the suitable example of described reaction is described in " Protective Groups inOrganic Synthesis " (referring to the same).Preferred condition is: compound (Ia), 2 equivalent NaOH are at 1: 1 ethanol: in the water, 60 ℃ of following hydrolysis 2 hours.
WO02/074754 has carried out general description to formula (VI) compound.As Bioorg.Med.Chem.Lett., (2004), 14 (18), described in the 4627-32 or following route 5 (Scheme5) summarize, can prepare concrete formula (VIa) compound, this compound is formula (VI) compound of O or S for X wherein.
Figure A20068004533300371
In the route 5, R bBe (C 1-6) alkyl or benzyl.
Step (a): aniline (XVII) and Zassol or potassium or sulfocyanic acid sodium or potassium, at suitable solvent or solvent mixture for example methylene dichloride or acetate: in the water, in the presence of acid such as toxilic acid or acetate, react, can preparation formula (XVIII) compound.Perhaps,, in solvent, react, then adopt the water in-situ hydrolysis such as methylene dichloride by aniline (XVII) and trimethylsilyl isocyanate or thiocyanide, can preparation formula (XVIII) compound.
When X was O, preferred condition was: at acetate: 1 equivalent compound (XVII) in the water (9: 1), then drip 1.2 equivalent potassium cyanates in water, and remain on 40 ℃ following 1 hour.
Step (b): formula (XVIII) and suitable ketone, such as polyphosphoric acid or the Eaton reagent (7.5%P in methanesulfonic 2O 5) the existence of dehydrated reagent under, under 50 to 100 ℃, react, can preparation formula (XIX) compound.
Preferred condition is: 1 equivalent compound (XVIII), Eaton reagent (30g/g) under 60 ℃, then adds 2 equivalent ketone, and heats 1 hour down at 80 ℃.
Step (c): formula (XIX) compound with at room temperature react in suitable solvent such as the Lewis acid of boron tribromide such as methylene dichloride, perhaps with strong acid at high temperature, for example with Hydrogen bromide under 110 ℃, react, can preparation formula (VIa) compound.
Preferred condition is: 1 equivalent compound (XIX), the aqueous solution of hydrogen bromide of 20 equivalents 48% in acetate, reacted 4 days down at 110 ℃.
Formula (I) PDE7 inhibitor can make up effectively with other pharmaceutically active compound or with two or more other pharmaceutically active compounds, particularly when treatment pain.For example, as defined above the PDE7 inhibitor of formula (I) or its pharmaceutically-acceptable salts, solvate or prodrug can be selected from one or more following reagent and take simultaneously, successively take or take respectively:
Opium anodyne, for example morphine (morphine), heroine (heroin), hydromorphone (hydromorphone), oxymorphone (oxymorphone), levo-dromoran (levorphanol), Lorfan (levallorphan), methadone (methadone), Pethidine (meperidine), sweet smell is slave (fentanyl) too, Cocaine (cocaine), morphine monomethyl ether (codeine), paracodin (dihydrocodeine), hydroxyl hydrogen is examined ketone (oxycodone), ketone (hydrocodone) is examined in hydrogenation, the third oxygen sweet smell (propoxyphene), Nalmefene (nalmefene), nalorphine (nalorphine), Narlan (naloxone), TREXUPONT (naltrexone), testosterone (buprenorphine), Bu Tuonuofei (butorphanol), nalbuphine (nalbuphine) or pentazocine (pentazocine);
Non-steroid antiinflammatory drug (NSAID), for example acetylsalicylic acid (aspirin), Diclofenac sodium (diclofenac), diflusinal, R-ETODOLAC (etodolac), put forth energy Bu Fen (fenbufen), Lip river, Fino sweet smell (fenoprofen), flufenisal (flufenisal), flurbiprofen (flurbiprofen), Ibuprofen BP/EP (ibuprofen), indomethacin (indomethacin), Ketoprofen BP 93 (ketoprofen), ketorolac (ketorolac), meclofenamic acid (meclofenamic acid), mefenamic acid (mefenamic acid), meloxicam (meloxicam), nabumetone (nabumetone), Naproxen Base (naproxen), nimesulide (nimesulide), nitroflurbiprofen, Olsalazine (olsalazine), Taisho) (oxaprozin), phenylbutazone (phenylbutazone), piroxicam (piroxicam), sulfasalazine (sulfasalazine), sulindac (sulindac), Tuo Maiting (tolmetin) or zomepirac (zomepirac);
The barbiturate(s) tranquilizer, for example Amobarbital (amobarbital), somnifen (aprobarbital), Secbutabarbital (butabarbital), butalbital (butabital), prominal (mephobarbital), metharbital (metharbital), U.S.A contract than appropriate (methohexital), Sodital (pentobarbital), phenylethyl barbituric acid (phenobartital), secobarbital (secobarbital), Talbutal (talbutal), theamylal or thiopental (thiopental);
Benzodiazepine with sedative effect, for example chlorine phenodiazine Zhuo (chlordiazepoxide), chlordiazepoxide (clorazepate), diazepam (diazepam), flurazepam (flurazepam), lorazepam (lorazepam), oxazepam (oxazepam), temazepam (temazepam) or triazolam (triazolam);
H1 antagonist with sedative effect, for example diphenhydramine (diphenhydramine), than Lamine (pyrilamine), promethazine (promethazine), chlorphenamine (chlorpheniramine) or Chlorcyclizine (chlorcyclizine);
Tranquilizer is such as glutethimide (glutethimide), first propylamine ester (meprobamate), turzolon (methaqualone) or Dichloralphenazone (dichloralphenazone);
Skeletal muscle relaxant, for example baclofen (baclofen), Cali general many (carisoprodol), chlorzoxazone (chlorzoxazone), cyclobenzaprine (cyclobenzaprine), methocarbamol (methocarbamol) or orphrenadine;
Nmda receptor antagonist, for example right perhydrophenanthrene (dextrorphan) ((+)-3-hydroxy-n-methyl is muttered) of dextro-methorphan (dextromethorphan) ((+)-3-hydroxy-n-methyl is muttered) or its metabolite, Ketamine (ketamine), Memantine hydrochloride (memantine), pyrroles's third quinoline, quinine, cis-4-(phosphoryl methyl)-2 piperidine carboxylic acid, 1-tert-butyl-4,4-diphenylpiperidine (budipine), EN-3231 (MorphiDex
Figure A20068004533300391
The formulated in combination product of morphine and dextro-methorphan), topiramate (topiramate), neramexane or perzinfotel, comprise the NR2B antagonist, ifenprodil (ifenprodil), Qu Suoluo ground (traxoprodil) or (-)-(R)-6-{2-[4-(3-fluoro phenyl)-4-hydroxyl-piperidino for example]-1-hydroxyethyl-3,4-dihydro-2 (1H)-quinolinone;
α-suprarenin, for example Doxazosin (doxazosin), tamsulosin (tamsulosin), clonidine catapresan (clonidine), guanfacine (guanfacine), dexmetatomidine, modafinil (modafinil) or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridyl) quinazoline;
Tricyclic antidepressants, for example Desipramine (desipramine), imipramine (imipramine), amitriptyline (amitriptyline) or bent first are for woods (nortriptyline);
Spasmolytic, for example carbadipimidine (carbamazepine), lamotrigine (lamotrigine), topiramate (topiratmate) or valproic acid ester (valproate);
Tachykinin (NK) antagonist, be specially NK-3, NK-2 or NK-1 antagonist, (α R for example, 9R)-7-[3,5-two (trifluoromethyl) benzyl]-8,9,10,11-tetrahydrochysene-9-methyl-5-(4-aminomethyl phenyl)-7H-[1,4] two azocines [2,1-g] [1,7]-naphthyridine-6-13-diketone (TAK-637) also, 5-[[(2R, 3S)-2-[(1R)-1-[3,5-two (trifluoromethyl) phenyl] oxyethyl group-3-(4-fluorophenyl)-4-morpholinyl]-methyl isophthalic acid, 2-dihydro-3H-1,2,4-triazole-3-ketone (MK-869), aprepitant (aprepitant), draw Napitane (lanepitant), reach pyrrole smooth (dapitant) or 3-[[2-methoxyl group-5-(trifluoromethoxy) phenyl]-methylamino-]-the 2-Phenylpiperidine (2S, 3S);
Muscarinic type antagonist, for example Oxybutynin (oxybutynin), tolterodine (tolterodine), propiverine (propiverine), tropsium muriate, darifenacin (darifenacin), Solifenacin (solifenacin), temiverine (temiverine) and Ipratropium Bromured (ipratropium);
The COX-2 selective depressant, for example match comes former times cloth (celecoxib), rofecoxib (rofecoxib), Parecoxib (parecoxib), penta ground former times cloth (valdecoxib), SC 59046 (deracoxib), relies on former times cloth (etoricoxib) or Luo Mei former times cloth (lumiracoxib);
The coal tar pain killer is specially Paracetamol (paracetamol);
Tranquilizer is such as droperidol (droperidol), chlorpromazine (chlorpromazine), halogen is than alcohol (haloperidol), trilafon (perphenazine), thioridazine (thioridazine), mesoridazine (mesoridazine), trifluoperazine (trifluoperazine), fluphenazine (fluphenazine), leoponex (clozapine), olanzapine (olanzapine), risperidone (risperidone), Ziprasidone (ziprasidone), Quetiapine (quetiapine), Sertindole (sertindole), Aripiprazole (aripiprazole), rope naphthalene piperazine azoles (sonepiprazole), blonanserin (blonanserin), Zomaril (iloperidone), Perospirone (perospirone), raclopride (raclopride), zotepine (zotepine), bifeprunox, asenapine, lurasidone, amisulpride (amisulpride), balaperidone, palindore, eplivanserin (eplivanserin), oxamniquine (osanetant), Rimonabant (rimonabant), meclinertant, Miraxion Or sarizotan (sarizotan);
Capsaicin receptor agonist (for example resinferatoxin) or antagonist (for example capsazepine);
Beta-adrenaline is such as Proprasylyte (propranolol);
Local anesthetic is such as mexiletine (mexiletine);
Corticosteroid is such as dexamethasone (dexamethasone);
5-HT receptor stimulant or antagonist are specially 5-HT 1B/1DAgonist is such as complying with Qu Tan (eletriptan), sulphur Ma Qutan (sumatriptan), naratriptan (naratriptan), Zomitriptan (zolmitriptan) or risatriptan (rizatriptan);
5-HT 2AReceptor antagonist is such as R (+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenyl ethyl)]-4-piperidine carbinols (MDL-100907);
Cholinomimetic function (nicotine function) pain killer is such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridyl)-3-butene-1-amine (RJR-2403), (R)-5-(2-azetidin ylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
·Tramadol
Figure A20068004533300412
The PDEV inhibitor, such as 5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (Virga (sildenafil)), (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl)-pyrazolo [2 ', 1 ': 6,1]-pyrido [3,4-b] indoles-1,4-diketone (IC-351 or Tadalafei (tadalafil)), 2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-base-1-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil (vardenafil)), 5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 5-(5-ethanoyl-2-propoxy--3-pyridyl)-3-ethyl-2-(1-sec.-propyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 4-[(3-chloro-4-methoxy-benzyl) amino]-2-[(2S)-2-(methylol) tetramethyleneimine-1-yl]-N-(pyrimidine-2-base methyl) pyrimidine-5-carboxylic acid amides, 3-(1-methyl-7-oxo-3-propyl group-6, the 7-dihydro-1 h-pyrazole is [4,3-d] pyrimidine-5-yl also)-N-[2-(1-methylpyrrolidin-2-yl) ethyl]-4-propoxy-benzsulfamide;
Alpha-2-delta ligand, such as, gabapentin (gabapentin), lyrica (pregabalin), 3-methyl gabapentin, (1 α, 3 α, 5 α) (3-amino-methyl-dicyclo [3.2.0] heptan-3-yl)-acetate, (3S, 5R)-3-amino methyl-5-methyl-enanthic acid, (3S, 5R)-3-amino-5-methyl-enanthic acid, (3S, 5R)-and 3-amino-5-methyl-sad, (2S, 4S)-4-(3-chlorophenoxy) proline(Pro), (2S, 4S)-4-(3-luorobenzyl)-proline(Pro), [(1R, 5R, 6S)-and 6-(ammonia first methyl) dicyclo [3.2.0] heptan-6-yl] acetate, 3-(1-amino methyl-cyclohexyl methyl)-4H-[1,2,4] oxadiazole-5-ketone, C-[1-(1H-tetrazolium-5-ylmethyl)-suberyl]-methylamine, (3S, 4S)-(1-amino methyl-3,4-dimethyl-cyclopentyl)-acetate, (3S, 5R)-and 3-amino methyl-5-methyl-sad, (3S, 5R)-3-amino-5-methyl-n-nonanoic acid, (3S, 5R)-3-amino-5-methyl-sad, (3R, 4R, 5R)-and 3-amino-4,5-dimethyl-enanthic acid and (3R, 4R, 5R)-and 3-amino-4,5-dimethyl-sad;
Cannabinoids;
Metabotropic glutamate hypotype 1 acceptor (mGluR1) antagonist;
The thrombotonin reuptake inhibitors, such as Sertraline (sertraline), Sertraline metabolite demethyl house district woods, fluoxetine (fluoxetine), remove fluoxetine (norfluoxetine) (fluoxetine demethyl metabolite), fluvoxamine (fluvoxamine), paroxetine (paroxetine), citalopram (citalopram), citalopram metabolite demethyl citalopram, according to Pulan (escitalopram), ground, d, the 1-S-768 (d, 1-fenfluramine), Phenazopyridine (femoxetine), ifoxetine (ifoxetine), cyano group dothiepin (cyanodothiepin), lividomycin (litoxetine), Da Moxiting (dapoxetine), Buddhist nun's method oxazolone (nefazodone), Sinitrodil (cericlamine) and trazodone (trazodone);
Norepinephrine (nor-epinephrine) reuptake inhibitors, such as, maprotiline (maprotiline), Tymelvt (lofepramine), mirtazapine (mirtazepine), Ou Pu are for woods (oxaprotiline), fezolamine (fezolamine), tomoxetine (tomoxetine), Mi Sailin (mianserin), Bupropion (buproprion), bupropion metabolites hydroxyl Bupropion, nomefensine (nomifensine) and viloxazine (viloxazine) (Vivalan
Figure A20068004533300431
), selectivity noradrenalin reuptake inhibitors especially, such as, Reboxetine is specially, (S, S)-Reboxetine;
The dual reuptake inhibitors of thrombotonin-noradrenalin is such as dimension Effexor (venlafaxine), dimension Effexor metabolite O-demethyl dimension Effexor, clomipramine (clomipramine), clomipramine metabolite demethyl clomipramine, duloxetine (duloxetine), Midalcipran (milnacipran) and Mi Paming (imipramine);
Inducibility nitric oxide synthase (iNOS) inhibitor, such as S-[2-[(1-imino-ethyl) amino] ethyl]-the L-homocysteine, S-[2-[(1-imino-ethyl)-and amino] ethyl]-4,4-dioxo-L-halfcystine, S-[2-[(1-imino-ethyl) amino] ethyl]-2-methyl-L-halfcystine, (2S, 5Z)-and 2-amino-2-methyl-7-[(1-imino-ethyl) amino]-the 5-heptenoic acid, 2-[[(1R, 3S)-and 3-amino-4-hydroxy-1-(5-thiazolyl)-butyl] sulfenyl]-5-chloro-3-pyridine carbonitrile, 2-[[(1R, 3S)-and 3-amino-4-hydroxy-1-(5-thiazolyl) butyl] sulphur]-the 4-chlorobenzonitrile, (2S, 4R)-and 2-amino-4-[[2-chloro-5-(trifluoromethyl) phenyl] sulfenyl]-5-thiazole butanols, 2-[[(1R, 3S)-and 3-amino-4-hydroxy-1-(5-thiazolyl) butyl] sulfenyl]-6-(trifluoromethyl)-3 pyridine carbonitrile, 2-[[(1R, 3S)-3-amino-4-hydroxy-1-(5-thiazolyl) butyl] sulfenyl]-the 5-chlorobenzonitrile, N-[4-[2-(3-benzyl chloride base amino) ethyl] phenyl] thiophene-2-carbonamidine or GE disulphide;
Acetylcholinesterase depressant, such as, many naphthalenes piperazine neat (donepezil);
PGE 2Hypotype 4 (EP4) antagonist, such as, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridine-1-yl) phenyl] ethyl } amino)-carbonyl]-4-methyl benzenesulfonamide or 4-[(1S)-1-({ [5-chloro-2-(3-fluorophenoxy) pyridin-3-yl] carbonyl } amino) ethyl] phenylformic acid;
The leukotrienes B4 antagonist, such as, 1-(3-biphenyl-4-ylmethyl-4-hydroxyl-Se alkane-7-yl)-Cyclopentane carboxylic acid (CP-105696), 5-[2-(2-propyloic)-3-[6-(4-p-methoxy-phenyl)-5E-hexenyl] the phenoxy base]-valeric acid (ONO-4057) or DPC-11870;
5-fat methoxy enzyme inhibitors, such as, stay ketone (zileuton), 6-[(3-fluoro-5-[4-methoxyl group-3 together, 4,5,6-tetrahydrochysene-2H-pyrans-4-yl]) phenoxy group-methyl]-1-methyl-2-quinolinone (ZD-2138) or 2,3,5-trimethylammonium-6-(3-pyridylmethyl)-1,4-benzoquinones (CV-6504);
Sodium channel inhibitor is such as lignocaine (lidocaine);
The 5-HT3 antagonist is such as ondansetron (ondansetron);
And pharmaceutically can receive salt and solvate.
Can use following testing program to measure the ability that formula (I) compound suppresses PDE7.
PDE7A and PDE7B enzyme catalysis 3 ', 5 '-ring-type adenosine Monophosphate (cAMP) are hydrolyzed into 5 ' adenylic acid ester (5 ' AMP).In porous plate second month in a season, with the PDE enzyme, [ 3H]-cAMP and test compounds at room temperature cultivate.Stop described cultivation by adding the commercially available yttrium silicate flicker that contains zinc sulfate near analyzing (SPA) pearl.The linear nucleosides of the preferred bonding of yttrium silicate pearl, thereby the product of enzyme reaction [ 3H]-5 ' AMP is bonded on the pearl, thus the generation optical signal, this optical signal is surveyed by scintillometer.The semaphore that is produced is directly related to formed product amount, thereby relevant with the activity of enzyme.When single culture enzyme and substrate, obtain peak signal.Measure background signal by the hole of not containing enzyme, perhaps measure background signal by the hole of the known PDE7A/B inhibitor that contains ultrahigh concentration.Enzyme to every batch of purifying carries out quality control, and before the research, measures its K by dynamics research in the research of compound inhibition m, V MaxAnd specific activity (specific activity).Calculate the restraining effect of test compounds with respect to peak response and background response to enzyme.Utilize these data, calculate inhibition % number with respect to gained greatest measure and minimum value.
The preparation of working solution
Prepare 1000mL stand-by buffer liquid by composition as shown in table 1 below:
Table 1
Figure A20068004533300441
At room temperature, stand-by buffer liquid is adjusted to pH 7.4, the strainer by 0.2 μ m filters then.From preparation, stand-by buffer liquid was stablized 1 month under 4 ℃.
Testing the same day, bovine serum albumin (BSA derives from Sigma) is added in the volume required damping fluid, is 0.00625% thereby make the ultimate density of BSA.This reaches by being prepared as follows 10% BSA stock solution.
The preparation of 10%BSA stock solution
1g BSA is dissolved in the 10mL pure water, by be inverted mixing, guaranteeing evenly, and the aliquots containig of 100 μ l volumes is placed the test tube of suitable mark.This 10%BSA solution was stablized down 6 months at the most at-20 ℃.
From storage, take out the aliquots containig of 10%BSA stock solution, and it at room temperature thawed before use, be used to prepare the BSA working solution then as shown in the following Table 2:
The preparation of 10mL BSA analytical work damping fluid
Table 2
Reagent Volume Final BSA concentration
1x damping fluid stock solution 9.99ml
The 10%BSA stock solution 6.25μl 0.00625％
The preparation of n-compound and control compound
Compound 5 '-carboxyl propoxy--8 '-chloro-volution [hexanaphthene-1-4 '-(3 ', 4 '-dihydro) quinazoline]-2 ' (1 ' the H)-ketone (after this being called " compd A ") that uses embodiment 75 among the WO 02/074754 is as standard substance.
The 4mM stock solution for preparing in 100%DMSO can be stored under 4 ℃.
The volume calculation of DMSO is as follows:
Figure A20068004533300451
30 * maximum contrast is the solution of 100%DMSO.30 μ M compd As are dissolved among the 100%DMSO obtaining non-enzymatic activity, thereby obtain 30 * minimum contrast.Can add the compd A solution for preparing 5mL 30 μ M in the 4mM compd A of 37.5 μ L by 100%DMSO with 4.962mL.
Method
Testing the same day, preparing 1 * final analysis damping fluid, and it had been kept in the ice up to needs as preceding detailed description.
Dynamic analysis
For every batch of new enzyme, measure K m, and be evaluated at that acquisition～1000cpm signal is retained in enzyme amount required in the linear portion of reaction process curve simultaneously in 45 minutes.Ideally, in analytic process,＜10% available [ 3H]-the cAMP hydrolysis.
Enzyme solution
The cell lysates that utilization contains total length PDE7A and PDE7B enzyme is carried out optimization to this test.Concentration the unknown of enzyme in the cell lysates sample is so the specific activity that uses cell lysates is as measuring, guaranteeing the active identical of every hole, and regardless of the concentration/activity change of each batch.
The preparation of PDE7A/B enzyme
Prepare the PDE7 alternation enzyme, and be kept under-20 ℃, to reduce the number of times of freeze with suitable equal portions size.It is volume required that following table 3 expressions are used to prepare 9mL PDE7A/B enzyme solution.With 8000 times of PDE7A dilutions, with 10000 times of PDE7B dilutions.
Table 3
Figure A20068004533300461
Figure A20068004533300471
Before the use, the enzyme solution for preparing is kept in the ice.
The preparation of 50nM adenosine 3 ', 5 ' annular phosphate (cAMP) substrate solution
Substrate by the cAMP of un-marked and adopt tritium radiation mark cAMP ([ 3H]-cAMP) form.[ 3H]-specification of cAMP stock solution will determine used volume.
Following described utilize 1mCi/ml and 24Ci/mmol [ 3H]-the cAMP stock solution prepares the method for 9mL substrate solution (thereby being 41.66 μ M):
The K of each batch enzyme up to now mAs follows:
PDE7A-20nM PDE7B-100nM
It is 30 μ l that this test requirements document is distributed into the overall test volume with the substrate solution of 15 μ l, promptly carries out 2 * dilution in test board.Because desired final test [cAMP] concentration is～25nM, so preparation～50nM [ 3H]-cAMP.
With 10.8 μ l[ 3H]-cAMP (can derive from Amersham) mixes with 8975 μ l test damping fluid, thus preparation 9ml substrate solution.
Place the flicker bottle by sample, thereby determine the accurate concentration of cAMP three 15 μ l.Then, add 4ml Starscint
Figure A20068004533300472
(scintillation mixed solution can derive from Perkin Elmer) also counts each test tube with the dpm program on beta-counter.
Determine the concentration of radioligand by following equation:
Then, concentration divided by 2, is made and carry out 2 * dilution in test board.
6.6mg/ml the preparation of yttrium silicate PDE SPA pearl
Phosphodiesterase SPA pearl (yttrium silicate) can derive from Amersham.
According to manufacturer's recommendation, use the distilled water of 28ml or deionized water make pearl live again (～20mg/ml).The pearl of living again was stablized one month under 2 to 8 ℃.Use pearl in order to prepare test, in aseptic bi-distilled water, pearl diluted 3 times (～6.6mg/ml).Pearl may sedimentation, so need constant agitation/stirring between allotment period.
With 30 μ l～the 6.6mg/ml pearl adds in the 30 μ l testing liquids, thereby the ultimate density that obtains pearl is～0.2mg/ hole.
Requirement in diluted chemical compound and " background " boring ratio test board is strong 30 times, thereby allows other test component (14 μ l enzymes and 15 μ radioligands) dilution 1 μ l compound by 29 μ l.Thereby, be 10 μ M for final experimental concentration, the compound that compound adds in the plate is necessary for 300 μ M.4mM compound stock solution (or by powder furnishing 4mM) is provided in 100%DMSO.This requires to dilute 13.33 times in DMSO.
Testing program
Before adding reagent at once, 1 μ l test compounds is transferred in the suitable porous test board, then 14 μ l enzyme solution are added in the test board, add 15 μ l substrate solutions (be that final test volume is 30 μ l, the ultimate density of SCREENED COMPOUND is 1 μ M) then.Then, utilize the plate sealing with this plate sealing, and under room temperature on the plate wobbler, cultivated 45 minutes.
Then, add 30 μ l yttrium silicate PDE4 SPA pearls, guarantee the constant agitation pearl, thereby it is evenly distributed in the test board.Then, utilize the plate sealing agent with this plate sealing, and under room temperature on the plate wobbler, cultivated 30 minutes.Then, make the pearl sedimentation 30 minutes, and under 200g, rotated this plate 1 minute.
Then, for example use relevant programme at suitable radioactive counter, for example NXT-TopCount TM(can derive from Perkin Elmer) gone up this plate carried out reading (every hole reading duration is 30 seconds).
Utilize least-squares algorithm, data fitting is become sigmoid curve.
Utilize the Cheng-Prussof equation, with IC 50Numerical value is converted into K i
PDE according to above scheme test implementation example 1-7 compound suppresses active.Listed gained Ki numerical value in the following table 4:
Table 4
Embodiment K i PDE7A (nM) K i PDE7B (nM)
1 1.9 4.6
2 3.1 13.4
3 15.6 108
4 11.6 144
5 276 1420
6 NT 17.6
7 19.8 140
NT=does not test
The human liver cell data are summed up
People's hepatic metabolism stability of the assessment embodiment of the invention 1 to 7 compound in model as described below.The compound 5 ' of embodiment 75 among the WO 02/074754-carboxyl propoxy--8 '-chloro-volution [hexanaphthene-1-4 '-(3 ', 4 '-dihydro) quinazoline]-2 ' (1 ' H)-ketone (after this being called " compd A ") (thinking that this compound is immediate prior art) is with making comparisons.
Method
Liver cell is as vitro system, be used to monitor the metabolism of liver, because middle all liver enzymes that exist in the inclusion body in these intact cells, comprise I stage enzyme, such as Cytochrome P450 oxydase (CYPs), aldehyde oxidase and monoamine oxidase (MAOs), with II stage enzyme, such as UDP-glucuronyl transferase and commentaries on classics sulfo group enzyme.The human liver cell of cryopreservation is prepared by 5 contributors, and is suspended in Williams ' the E media.Adding 4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid (HEPES), is 50mM thereby make ultimate density, and with pH regulator to 7.4.To test substrate and be dissolved among the DMSO, and add in the liver cell, be 1 μ M thereby make concentration of substrate, and wherein the ultimate density of DMSO is lower than 0.1% in the culturing process.Test is carried out in 37 ℃ of following 96 holes or 384 orifice plates, and wherein liver cell concentration is 0.5 hundred ten thousand viable cell/mL.Took a sample at 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes, and analyze quantitatively by LC-MS/MS.Utilize following formula to calculate intrinsic clearance (apparent):
Clint ApparentL/ minute/M of=[slope/0.5M cell/mL] 1000 μ L/mL=μ cell
Measure the human liver cell metabolic stability of The compounds of this invention according to above scheme.Listed the numerical value of gained intrinsic clearance in the following table 5.
Table 5
Compound Human liver cell CLint (μ L/ minute/the M cell)
Compd A 25
Embodiment 1 ＜5
Embodiment 2 ＜5
Embodiment 3 ＜5
Embodiment 4 ＜5
Embodiment 5 ＜5
Embodiment 6 ＜5
Embodiment 7 ＜5
Data in the above table 5 show, embodiments of the invention 1 to 7 compound with compare near prior art, have evident difference between the intrinsic hepatic metabolism stability.Therefore, according to above data, can infer that the hepatic clearance of the compound of the embodiment of the invention 1 to 7 is lower, this causes these compounds to be compared with compd A, has the transformation period of improvement in the mankind.
Rat IV pharmacokinetics is summed up
The pharmacokinetic property of the assessment embodiment of the invention 1 and 2 compounds in model as described below.The compound 5 ' of embodiment 75 among the WO 02/074754-carboxyl propoxy--8 '-chloro-volution [hexanaphthene-1-4 '-(3 ', 4 '-dihydro) quinazoline]-2 ' (1 ' H)-ketone (after this being called " compd A ") (thinking that this compound is immediate prior art) is with making comparisons.
Method
Test compounds is bestowed male rat (every rat is accepted a kind of compound) with the dosage (compound of embodiment 1 is 0.08mg/kg) of 1mg/kg by tail vein.Preset time point after administration, by jugular vein sleeve pipe blood-sample withdrawal from rat of surgical operation implantation, and blood sample is centrifugal to obtain blood plasma.Plasma sample is analyzed by specific LC-MS/MS test, thus quantitative to the medicine in the blood plasma.Utilize non-chamber pharmacokinetic analysis (non-compartmentalpharmacokinetic analysis) that gained plasma concentration-time curve is detected, to understand the distribution of all cpds.The result who obtains subsequently is used to assess possible human medicine kinetic property, and is as described below.
Following table 6 and Fig. 1 show behind intravenously administrable 1mg/kg, embodiment 1 and 2 compounds and compd A through the standardized average pharmacokinetic property of dosage.
Table 6
Embodiment 1 Embodiment 2 Compd A
Cl (ml/min/kg) 1.9 0.7 7
fup 0.07 0.1 0.045
Cl u (ml/min/kg) 27 70 156
V d(ml/min/kg) 0.6 0.7 0.4
T 1/2(hour) 4 11 ＜1
In the table 6, use following shortenings:
Cl is the rat clearance rate;
T 1/2It is the transformation period;
V dIt is the volume of distribution in the rat;
Fup is a unconjugated part in the rat plasma;
Cl uBe unconjugated rat plasma clearance rate, wherein Cl u=Cl/fup.
The assessment of human medicine kinetics
Based on above-mentioned pharmacokinetic data in rat, can assess embodiment 1 and 2 and the possible human medicine dynamics data of compd A, assess as follows.
Use following relation, to observed without bonded rat plasma clearance rate (Cl behind intravenously administrable The u rat) carry out convergent-divergent, to assess unconjugated human plasma clearance rate (Cl U people):
Cl U people=Cl The u rat* (BW The people/ BW rat) 0.75
Wherein, BW The peopleAnd BW RatBe respectively people's mean body weight (70kg) and the mean body weight (0.25kg) of rat, the unit of clearance rate is ml/min.
Be converted into Cl U people, remove rate (Cl with the total serum in the evaluator The people):
Cl The people=[(Cl U people) * f Up]/B: P
Wherein, f UpBe the part of bound drug not in the blood plasma, B: P is the ratio of blood and blood plasma in the human blood.
Utilize following relation to derive the valuation of the human transformation period of each compound:
T 1/2＝[ln(2)*V d]/Cl
Wherein, T 1/2The human transformation period of be estimating, in hour, V dBe the volume of distribution in the mankind (because the physicochemical property of this series compound are assumed to 0.2L/kg) that Cl is human clearance rate.
Following table 7 is summed up for the human pharmacy kinetics of estimating.
Table 7
Compound 1 Compound 2 Compd A
CI The u rat(ml/min/kg) 27 70 156
fup 0.07 0.01 0.03
CI U people(ml/min/kg) 0.8 0.2 1.9
B∶P 0.6 0.7 0.6
The T that estimates 1/2(hour) 3 10 1
Data in the above table 6 and 7 show, the compound of embodiments of the invention 2 with compare near prior art, all there is evident difference in the human medicine kinetics of pharmacokinetics in the rat that observes and prediction.Outstanding difference finds expression in the human transformation period, and the transformation period of embodiment 2 compounds is estimated as 10 hours, and by comparison, the people that compd A may provide is about 1 hour the transformation period.
Therefore,, can infer that the pharmacokinetics of the compound of the embodiment of the invention 2 is equivalent to a times or the per daily dose of twice at present clinical according to above data.The pharmacokinetics of the compound of the embodiment of the invention 1 is equivalent to twice or triple per daily dose.This has obviously improved than immediate prior art compd A, because the transformation period of compd A can not be suitable for bestowing with above-mentioned similar fashion than weak point.
Can measure the activity of formula of the present invention (I) compound in the treatment neuropathic pain according to following testing scheme.
Animal: male Sprague Dawley rat (on average heavy 500g) is carried out stable breeding for 12 one group.All animals were maintained in 12 hours bright/dark cycles (7:00 turns on light), and food and water are appointed and got.All experiments are undertaken by the viewer that treatment is known nothing, and this experimental basis HomeOffice Animals (Scientific Procedures) Act 1986.
Chronic constriction damage (CCI) rat model of neuropathic pain
As discussed previouslyly carry out sciatic CCI (G.J.Bennett and Y.K.Xie, Pain (1988) 33,87-107).Adopt 2% isoflurane (isofluorane)/O 2Mixture is anaesthetized animal.Right rear leg is shaved hair, and wiping 1% tincture of iodine.Then, in whole section treating processes, animal is moved on the constant temperature blanket, and keeps anesthesia by nose cone in surgical procedure.Cut skin along the Thigh bone line.On biceps muscle of thigh, carry out blunt dissection, thereby make sciatic nerve be exposed to big midleg.By tweezers are inserted neural below and with nerve lightly by taking out in the thigh, thereby make about 7mm the nerve disengaging and near the sciatic nerve trident.Use tweezers below nerve, to pull out suture line, and beat a simple knot,, beat a binode then up to feeling slightly resistance.Repeat said process, up to 4 bandages (4-0 silk thread) around nerve, every bandage be spaced apart about 1mm.Sew up each layer otch, and adopt local antibiotic that wound is handled.
By streptozotocin (STZ) inductive rat diabetes neuropathy
Carry out independent peritoneal injection by the streptozotocin (50mg/kg) that will newly be dissolved in 0.9% Sterile Saline, thereby induce diabetes.The injection streptozotocin is induced in 3 weeks and reproducible mechanical allodynia (mechanical allodynia) occurred, continued for 7 weeks at least (S.R.Chen andH.L.Pan.J.Neurophysiol. (2002), 87,2726-2733).
Assessment of static and dynamic pain are unusual
Static pain is unusual
Before the assessment allodynia, make animal custom metal wire bottom test-cage.(Illinois USA) comes the assessment of static allodynia for Stoelting, Wood Dale to apply Von Frey hair with the power (0.6,1,1.4,2,4,6,8,10,15 and 26 gram) that increases gradually to the toe face of hind paw.Every Von Frey hair is applied on the sole 6 seconds at the most, or up to the withdrawal reaction occurring.In case determine that Von Frey hair is had the withdrawal reaction, begin by silk thread so than the low one-level of appearance withdrawal, order adopts has all the other silk threads that reduce power gradually, again sole is tested, up to no longer appearance withdrawal.Lifting sole and the maximum, force that induces reaction are 26g, and therefore, this power is represented cut-out point.By this way, two hind paws of every animal are tested.The minimum force that induces reaction is registered as sole withdrawal starting value (PWT), in gram.If animal responds to 4g or the stimulation below the 4g (is not have influence for the rat that is used to first test), be defined as so static pain unusual (Pain (1999) such as M.J.Field, 83,303-11).
Dynamically pain is unusual
Dynamic abnormal pain is by assessing for the sole plane of knocking rear solid end lightly with cotton rod.For fear of the common motor activity of record, in the sluggish rat that adapts to fully, carry out this process carefully.Carry out at least twice test at each time point, its mean value is represented pawl withdrawal latent period (PWL).If not reaction in 15 seconds, then this process is terminated, and this withdrawal time is assigned to animal.Pain withdrawal reaction is attended by the pawl or lick the pawl behavior of contracting repeatedly usually.If animal is reacted beginning to knock in back 8 seconds cotton rod stimulated, then be considered to exist dynamic abnormal pain (Field et al, 1999).
Embodiment
In all embodiments, 1H nucleus magnetic resonance (NMR) spectrogram conforms to the structure of expection.Characterization displacement study (δ) represents with per 1,000,000 (ppm) of part that from the downfield of tetramethylsilane it uses conventional shortenings to represent main each peak: for example, s, unimodal; D, bimodal; T, three peaks; Q, four peaks; M, multimodal; Br, broad peak.Utilize electrospray ionization mass spectrometry (ES or ESI) or atmospheric chemical ionization mass spectrum (APCI) record mass spectrum (m/z).The abbreviation of common solvent is as follows: CDCl 3, deuterochloroform; D 6-DMSO, hexadeuterated dimethyl sulfoxide.
The monocrystalline x-ray diffraction experiment
Utilize Bruker SMART APEX Single Crystal X-Ray diffractometer and Mo K α radiation at room temperature to measure the crystalline structure of the acetic acid solvent thing of embodiment 2 compounds by the monocrystalline X-ray diffraction.Intensity is utilized SMART v5.622 (contrast) and SAINT v6.02 (integration) software (BrukerAXS Inc., Madison, Wisconsin, USA, 1994) by number system row exposure carrying out integration, wherein each exposure covers 0.3 ° (in ω), and exposure time is 60 seconds, and all data set surpasses hemisphere.(SADABS is used for the program of convergent-divergent and correcting area detector data, G.M.Sheldrick, University of to utilize the multiple scanning method
Figure A20068004533300551
1997, based on the method for R.H.Blessing, Acta Cryst.1995, A51 33-38) proofreaies and correct absorption data.
Utilize SHELXS-97 (crystallographic structural analysis program, G.M.Sheldrick, University of
Figure A20068004533300552
Germany, 1997, distribution 97-2) successfully resolved crystalline structure by the direct method in spacer C2/c, and utilize SHELXL-97 (crystalline structure refinement program, G.M.Sheldrick, University of
Figure A20068004533300553
Germany, 1997, distribution 97-2) by method of least squares above-mentioned crystalline structure is carried out refinement.Crystalline structure refinement program shows, has the molecule and the molecular acid of embodiment 2 compounds in asymmetric cell.Therefore, this structure is defined as the acetic acid solvent thing of 1: 1 embodiment 2 compounds.
By embodiment 2, the crystalline structure of step (b) (acetic acid solvent thing) calculates powder X-ray-ray and spreads out Penetrate pattern
Utilize Accelrys MS Modelling TM" the Reflex Powder Diffraction " module of [version 3 .0] is calculated 2 θ angles and relative intensity (seeing table 8) by the single crystal structure of the acetic acid solvent thing of embodiment 2 compounds.Relevant analog parameter is:
Wavelength=1.5406
Figure A20068004533300554
(Cu K α)
Polarization factor=0.5
Pseudo-Voigt figure (U=0.01, V=-0.001, W=0.002)
The pattern that calculates is represented the pure phase pattern of the acetic acid solvent thing of embodiment 2 compounds, because this pattern is obtained by single crystal structure.Compared test pattern among Fig. 2 and calculated pattern, and confirmed that body represented by single crystal structure.Difference small between the peak intensity can be owing to the preferred orientation effect of measuring pattern.
Powder x-ray diffraction
Utilize the x-ray diffractogram of powder case of the D4 powder x-ray diffraction mensuration embodiment 2 compound non-solvent crystallized forms (A crystal formation) of Bruker-AXS Ltd., described diffractometer is equipped with automatic sampler, θ-θ protractor, automatic beam splitting crack (divergence slit) and PSD Vantec-1 detector.Thereby the prepared sample that is used to analyze begins to measure accurate peak position with silicon doping, subsequently sample is installed on the low background silicon wafer sample platform.Make the sample rotation, adopt copper K-α simultaneously 1X-ray (wavelength=1.5406
Figure A20068004533300561
) carry out radiation, wherein X-ray tube is operated under 40kV/30mA.Employing is analyzed with the protractor of continuous mode operation, and this continuous mode is set to: the step-length with 0.018 ° in 2 ° to 55 ° 2 θ scopes was counted in 0.2 second.On this diffractometer, also collect utilize identical parameters through the PXRD of vacuum drying solvate sample pattern, but these samples not with silicon doping.
Utilize the senior powder x-ray diffraction of D8 of Bruker AXS Ltd. to write down all other x-ray diffractogram of powder cases that are installed in the sample on the flat silicon chip, described diffractometer is equipped with Goble mirror optical element, single sample platform and position sensing detection instrument (PSD).Adopt copper K-α 1X-ray (wavelength=1.5406
Figure A20068004533300562
) each sample is carried out radiation, wherein X-ray tube is operated under 40kV/40mA.The protractor that employing moves in the continuous sweep mode is analyzed, and this continuous mode is set to: the step-length with 0.014 ° in 3 ° to 35 ° 2 θ scopes was counted in 0.2 second.
Differential scanning calorimetric (DSC)
Utilize Perkin Elmer Diamond differential scanning calorimeter to carry out dsc measurement.In 50 μ l airy aluminium dishes, sample is heated to 300 ℃ by envrionment temperature with 20 ℃/minute.Flowing gas is the nitrogen of 40ml/min.
Thermogravimetric analysis (TGA)
The TGA that utilizes TA Instruments TGA2950 Hi-Res thermogravimetric analyzer to carry out solvate measures, and described mensuration is used 75cm 3The nitrogen purging gas of/min will be heated to precipitation thinner temperature (150 ℃ to 180 ℃) from envrionment temperature with the heating rate of 20 ℃/min.Then this sample being cooled to the PXRD that room temperature is used for subsequently analyzes.
Embodiment 1
Cis-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] the ring fourth The alkane carboxylic acid
Figure A20068004533300571
With Periodic acid (82mg, 0.359mmol) and chromic oxide (IV) (1.6mg, 0.016mmol) at 99.25: 0.75 acetonitriles: the solution in the water (2ml) adds the alcohol (50mg of preparation 8,0.14mmol) at 99.25: 0.75 acetonitriles: in the solution in the water (2ml), keep temperature of reaction to be lower than 5 ℃ simultaneously.Reaction mixture was at room temperature stirred 18 hours.Reaction mixture is filtered, and resistates is adopted 99.25: 0.75 acetonitriles: water, 2N hydrochloric acid: methyl alcohol (5: 1), water and methanol wash.With resistates vacuum-drying, thereby obtain white solid title compound (28mg, 0.077mmol, 55%).
1H-NMR(400MHz，D 6-DMSO)：δ1.17(m，1H)，1.40-1.65(m，5H)，1.79(m，2H)，2.16(m，2H)，2.48(m，2H)，2.72(m，3H)，4.64(m，1H)，6.43(d，1H)，7.0(s，1H)，7.21(d，1H)，7.90(s，1H)，12.26(bs，1H)。
LRMS m/z(APCI)：365[M+H] +，406[M+CH 3CN+H] +。
Embodiment 2
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] the ring fourth The alkane carboxylic acid
Method A
With chromic oxide (VI) (12mg, 0.11mmol) and Periodic acid (3.33g, 14.6mmol) solution add the alcohol of preparation 11 (2.05g 5.84mmol) in the solution in the acetonitrile that contains 0.75% water (50mol), and stir reaction mixture 96 hours down at 40 ℃.Add entry (100ml) and suspension was stirred 2 hours.The gained throw out is collected by filtering, adopted water washing, and vacuum-drying, thereby title compound (1.90g, 5.2mmol, 89%) obtained.
1H-NMR(400MHz，D 6-DMSO)：δ1.2(m，1H)，1.2(m，2H)，1.6(m，2H)，1.8(m，2H)，2.3(m，2H)，2.6(m，2H)，3.1(m，1H)，3.2(s，1H)，4.0(bs，1H)，4.8(m，1H)，6.4(d，1H)，7.0(s，1H)，7.2(d，1H)，7.9(s，1H)。
LRMS m/z(APCI)365[MH] +。
Method B
Step (a)
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] the ring fourth The alkane carboxylic acid tert-butyl ester
Figure A20068004533300582
To prepare 27, (34.1g 130mmol) is suspended among the DMF (300mL) compound of step (b), and slurries are heated to 35 ℃.Disposable adding cesium carbonate (63g, 190mmol).Be dissolved in preparation 22 compound among the DMF (90mL) and add in the reaction.To be reflected at 1 hour internal heating to 90 ℃ and keep 8 hours.Reaction is cooled to 73 ℃, and adds entry (160ml) and keep temperature to be higher than 65 ℃ simultaneously.The gained slurries are cooled to 35 ℃, follow disposable adding ethyl acetate (260mL).After being cooled to room temperature, with dope filtration, and product is adopted ethyl acetate, and (2 * 100mL) wash.With gained white solid under 60 ℃ vacuum dry 16 hours, obtain white solid title compound (44.4g, 105mmol, 82%).
1H-NMR(300MHz，CDCl 3)：δ1.3(m，1H)，1.4(m，1H)，1.5(s，9H)，1.6(m，1H)，1.7(bm，1H)，1.8(bm，2H)，1.8(bm，1H)，2.4(m，2H)，2.6(t，2H)，2.7(m，2H)3.1(m，1H)，3.2(m，1H)，4.8(m，1H)，5.5(s，1H)，6.2(d，1H)，6.9(s，1H)，7.1(d，1H)。
LC-MS (ESI): 22.6 minutes 11.8 (%) { cis-isomeride } m/z 422[MH +]; 23.1 minute 88.2 (%) { trans-isomer(ide) } m/z 422[MH +].
Step (b)
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] the ring fourth Alkane carboxylic acid acetic acid solvent thing
Figure A20068004533300591
With the product of step (a) (207g, 0.492mol) pulp and be heated to 60 ℃ in acetate (3100mL).Drip 48% Hydrogen bromide (4.93mol) and temperature is remained on 60 ℃.Solution was stirred 30 minutes down at 60 ℃.Drip water (700mL) and temperature remained on and be higher than 55 ℃.Slurries are cooled to 20 ℃ and further the stirring 30 minutes, after this with its filtration, adopt acetate: water (2000mL) and water (1000mL) wash, and drying is whole night in 60 ℃ vacuum drying oven then, obtain white solid title compound (153.6g, 73.5%) as the acetic acid solvent thing.
1H-NMR(400MHz，D 6-DMSO)：δ1.2(m，1H)，1.2(m，2H)，1.6(m，2H)，1.8(m，2H)，1.9(s，3H，CH 3COOH)，2.3(m，2H)，2.6(m，2H)，3.1(m，1H)，3.2(s，1H)，4.0(bs，1H)，4.8(m，1H)，6.4(d，1H)，7.0(s，1H)，7.2(d，1H)，7.9(s，1H)，9.9(s，1H，CH 3COOH)。
LC-MS (ESI): 18.0 minutes 1.65 (%) { cis-isomeride } m/z 365[MH +]; 18.3 minute 98.4 (%) { trans-isomer(ide) } m/z 365[MH +].
By the crystalline structure of determining by monocrystalline X-ray diffraction method as seen, find that above-mentioned acetic acid solvent thing was with stoichiometry crystallization in 1: 1.Fig. 2 shows measurement powder x-ray diffraction (PXRD) pattern (A) of above-mentioned acetic acid solvent thing and the simulation RXRD pattern (B) that is calculated by single crystal structure.This shows that the peak position of two patterns is in full accord.Any difference in the relative intensity of diffraction peak and the width can be respectively owing to preferred orientation and particle size effect.The feature 2 θ X-ray diffraction peaks of above-mentioned acetic acid solvent thing and its relative intensity are listed in as in the following table 8.
Table 8
2θ/° Intensity % 2θ/° Intensity %
8.3 58.5 20.5 36.8
10.8 18.3 21.8 18.4
16.6 52.5 22.9 12.5
17.1 22.7 23.1 12.4
17.7 14.6 23.7 100
19.2 14 24.7 21.2
19.5 24.1 26.3 10.4
By thermogravimetric analysis (TGA) as seen, find that the acetic acid solvent thing down the pyrolysis solvation takes place at about 115 ℃, wherein observe the weight loss of rapid～15% under said temperature, this loss equates with the acetate of 1 molar equivalent.Fig. 3 shows TGA figure.As seen PXRD as shown in Figure 4 schemes, and in the desolvation process, above-mentioned solvate recrystallization becomes through the A of desolvation crystalline form (describing in following steps (c)).
Step (c)
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] the ring fourth The alkane carboxylic acid
(157g, 369mmol) pulp is whole night under the room temperature in water (5200mL) with the acetic acid solvent thing of step (b).Then with dope filtration, adopt water (4 * 500mL) washings, then in 60 ℃ vacuum drying oven drying whole night, thereby obtain white solid non-solvent title compound (130g, 357mmol, 96%).
1H-NMR(400MHz，D 6-DMSO)：δ1.2(m，1H)，1.2(m，2H)，1.6(m，2H)，1.8(m，2H)，2.3(m，2H)，2.6(m，2H)，3.1(m，1H)，3.2(s，1H)，4.0(bs，1H)，4.8(m，1H)，6.4(d，1H)，7.0(s，1H)，7.2(d，1H)，7.9(s，1H)。
LRMS m/z(APCI)365[MH] +。
Find that also this compound with the crystallization of non-solvent form (A crystalline form), has the characteristic powder X-ray diffraction shown in Fig. 5 (PXRD) pattern.Feature 2 θ X-ray diffraction peaks and relative intensity thereof are listed in as in the following table 9.As illustrated in Figure 6 differential scanning calorimetry (DSC) as seen, this crystallized form has 250 ℃ fusing point.
Table 9
2θ/° Intensity % 2θ/° Intensity %
6.3 24.6 24.8 17.9
9.7 14.6 25.3 11.3
13.6 20.0 25.5 13.7
14.7 13.4 26.3 48.8
16.2 20.0 28.2 11.2
17.8 47.5 28.5 22.0
18.5 15.9 29.8 14.7
18.7 18.3 31.3 12.1
18.9 13.7 31.8 13.5
19.4 12.9 36.4 12.8
21.5 100.0 37.9 18.2
22.1 31.5 38.8 15.2
22.4 57.5 48.7 10.4
22.7 13.0
Also find of the solvate forms crystallization of the compound of embodiment 2 with N,N-DIMETHYLACETAMIDE (DMAC), pyridine, tetrahydrofuran (THF) (THF) and dimethyl sulfoxide (DMSO) (DMSO).Each above-mentioned solvate has the feature PXRD pattern shown in Fig. 7.
The TGA test shows of these solvates, pyridine and THF solvate have 1: 1 stoichiometry (Tu8 ﹠amp; 9), and the DMAC solvate has the stoichiometry (Figure 10) of 2: 1 solvent ratio compound.The frangible character of DMSO solvate means, and can not determine the stoichiometry of described solvate.
PXRD analysis revealed as shown in Figure 11,12,13 and 14, in the desolvation process, each pyridine, THF, DMAC and DMSO solvate recrystallization respectively become anhydrous crystal forms A.
Embodiment 3
3-[(8 '-fluoro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen methyl] the ring fourth The alkane carboxylic acid
Figure A20068004533300621
(a) 3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen methyl] Cyclobutane-carboxylic acid benzyl ester
Figure A20068004533300622
With 8 '-fluoro-5 '-hydroxyl-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-2 ' (3 ' H)-ketone (140mg, 0.56mmol) (as preparation as described in the WO2004/026818, intermediate c) and cesium carbonate (301mg, 0.925mmol) merge among the DMF (2mL), (220mg stirred 18 hours down at 80 ℃ 0.588mmol) at the solution of DMF (2mL), and with mixture to add the compound of preparation 15.Then, add entry (35mL), and (2 * 25mL) extract with ethyl acetate with product.The organic extract that merges is adopted the saturated brine washing, and pass through dried over mgso.Solvent evaporated obtains with～5: the title compound that 4 cis and trans-isomer(ide) mixture exist, brown jelly (204mg, 80%).
1H-NMR(400MHz，CDCl 3)：δ1.29(m，1H)，1.66(m，7H)，2.21(m，2H)，2.41(m，2H)，2.59(m，2H)，2.8&2.90(2xm，1H)，3.2(m，1H)，3.96&4.00(2xd，2H)，5.13(2xs，2H)，6.6(m，1H)，6.95(m，1H)，7.33(m，5H)。
LRMS m/z(ES)453[MH] +。
(b) 3-[(8 '-fluoro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen methyl] Cyclobutane-carboxylic acid
(200mg 0.442mmol) is dissolved in the methyl alcohol (2mL), and (2mL 4.0mmol), stirs brown emulsion 1.5 hours down at 60 ℃, then cooling to add 2M NaOH with the product of step (a).Adding 2N HCl (2mL, 4.0mmol), and with gained suspension stirring 1.5 hours.Collect emulsifiable paste shape solid by filtering, the water thorough washing, and vacuum-drying obtains title compound (136mg, 85%).
Chirality HPLC on Chiralpak AD-H (15% Virahol: 85% hexane+0.1% trifluoroacetic acid) show the isomer (retention time was respectively 13.69 minutes and 15.27 minutes) of 43: 57 ratios.
1H-NMR(400MHz，CDCl 3)：δ1.16(m，1H)，1.43(m，2H)，1.57(m，3H)，1.76(m，2H)，2.05(m，2H)，2.28(m，2H)，2.43(m，2H)，2.68(2xm，1H)，3.03(2xm，1H)，3.88&3.97(2xd，2H)，6.48(m，1H)，6.76(m，1H)，6.98(m，1H)，8.79(s，1H)，12.06(br，1H)。
LRMS m/z(ES)363[MH] +。
Embodiment 4
Trans-3-[(8 '-cyano group-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] ring The butane carboxylic acid
Figure A20068004533300631
Adopt the method for embodiment 1, by the compound of preparation 16 (101mg 0.296mmol) sets out, adopt chromic oxide (VI) (0.5mg, 0.005mmol) and Periodic acid (167mg 0.733mmmol), obtains title compound (76mg, 72%).
1H-NMR(400MHz，D 6-DMSO)：δ1.1-1.85(m，8H)，2.3-2.7(m，6H)，3.10(m，1H)，4.92(m，1H)，6.47(d，1H)，7.14(s，1H)，7.51(d，1H)，8.51(s，1H)。
LC-MS: retention time=2.49 minute (100%), LRMS (ESI) m/z 356[MH +].
Embodiment 5
1-[(8 '-fluoro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen methyl] the ring fourth The alkane carboxylic acid
Figure A20068004533300641
(a) 1-[(8 '-fluoro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen methyl] The cyclobutane-carboxylic acid methyl esters
Figure A20068004533300642
At room temperature, with cesium carbonate (234mg, 0.72mmol) adding 8 '-fluoro-5 '-hydroxyl-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-2 ' (3 ' H)-ketone (120mg, 0.48mmol) in (as preparation as described in the WO2004/026818) solution in DMF (1mL), mixture was stirred 10 minutes, add compound (172mg, 0.58mmol) solution in DMF (1mL) of preparation 18 then.With reaction mixture be heated to 80 ℃ following 18 hours, be cooled to room temperature then.Mixture is adopted ethyl acetate (20mL) and water (20mL) dilution, and organic layer is separated, water layer is extracted with ethyl acetate (20mL).With the organic layer water that merges (2 * 20mL) and salt solution (2 * 20mL) washings, dry on sal epsom, filter also vacuum-evaporation.Adopt diethyl ether (10ml) to grind light brown oil, thereby obtain light brown solid state title compound (the 140mg solvate that contains 0.3mol DMF, 0.35mmol, 73%).
1H-NMR(400MHz，D 6-DMSO)：
Figure A20068004533300643
1.16(m，1H)，1.35(m，2H)，1.49(m，3H)，1.72(m，2H)，1.90(m，1H)，2.03(m，3H)，2.26(m，2H)，2.42(m，2H)，3.60(s，3H)，4.22(s，2H)，6.52(dd，1H)，6.79(s，1H)，7.01(t，1H)，8.85(s，1H)。
(b) 1-[(8 '-fluoro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen methyl] Cyclobutane-carboxylic acid
With sodium hydroxide (28mg, 0.70mmol) add step (a) product (140mg, 0.35mmol) methanol (1: 1,2mL) in the part solution in, this is reflected at 50 ℃ stirred 24 hours down.Mixture is cooled to room temperature and further the stirring 6 days, adopts the aqueous hydrochloric acid (2mL) of 2N to handle then.Gained paste solid by filtration is collected, wash with water and vacuum-drying, thereby obtain title compound (83mg, 0.23mmol, 65%).
1H-NMR(400MHz，D 6-DMSO)：δ1.25(m，1H)，1.37(m，2H)，1.49(m，3H)，1.71(m，2H)，1.90(m，1H)，2.01(m，3H)，2.38(m，4H)，4.18(s，2H)，6.52(dd，1H)，6.71(s，1H)，7.00(dd，1H)，8.78(s，1H)，12.43(s，1H)。
LRMS m/z(ESI)377[M+H] +。
Embodiment 6
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [suberyl-1,4 '-quinazoline]-5 '-yl) oxygen] ring The butane carboxylic acid
Figure A20068004533300651
(a) trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [suberyl-1,4 '-quinazoline]-5 '-yl) Oxygen] cyclobutane carboxylate
Figure A20068004533300652
Under 80 ℃, with 3-(toluene-4-sulfonyloxy)-cis-cyclobutane carboxylate (by preparing) (123mg with method like preparation 22 compounds, 0.41mmol) solution in dimethyl formamide (1mL) adds the compound (100mg of preparation 20,0.36mmol), salt of wormwood (57mg, 0.41mmol) and 18-hat-6 (110mg, 0.41mmol) in the suspension in dimethyl formamide (3mL), and reaction mixture stirred 18 hours down at 80 ℃.Mixture is cooled to room temperature, and is extracted into ethyl acetate (2 * 20mL) twice from water (30mL).With organic layer salt solution (2 * 20mL) washings, drying on sal epsom, filtration and the vacuum-evaporation that merges.The oily resistates is evaporated once more by methyl alcohol, and adopt diethyl ether to grind, thereby obtain the solid shape title compound (75mg, 0.18mmol, 51%) of emulsifiable paste.
1H-NMR(400MHz，D 6-DMSO)：δ1.19(t，3H)，1.43-1.77(m，10H)，2.24(m，2H)，2.38(m，2H)，2.63(m，2H)，3.14(m，1H)，4.09(q，2H)，4.82(m，1H)，6.36(d，1H)，7.17(d，1H)，7.29(s，1H)，8.05(s，1H)。
LRMS m/z(ESI)407[MH] +。
(b) trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [suberyl-1,4 '-quinazoline]-5 '-yl) Oxygen] cyclobutane-carboxylic acid
(14mg, 0.35mmol) (70mg 0.17mmol) in the suspension in methyl alcohol (1mL), stirs gained suspension 2 hours down at 40 ℃ the compound of the adding step of the solution in water (1mL) (a) with sodium hydroxide.Vacuum is removed methyl alcohol, and by drip the 2N HCl aqueous solution (5mL) with the pH regulator of gained solution to～1.With the gained solid filtering and adopt Virahol (1.5mL) washing, obtain white solid title compound (25mg, 0.066mmol, 40%).
1H-NMR(400MHz，D 6-DMSO)：δ1.43-1.77(m，10H)，2.23(m，2H)，2.34(m，2H)，2.61(m，2H)，3.06(m，1H)，4.81(q，1H)，6.36(d，1H)，7.17(d，1H)，7.29(s，1H)，8.05(s，1H)，12.35(s，1H).
LRMS m/z(ESI)755[2M-H] -。
Embodiment 7
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [cyclopentyl-1,4 '-quinazoline]-5 '-yl) oxygen] ring The butane carboxylic acid
Figure A20068004533300671
(a) trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [cyclopentyl-1,4 '-quinazoline]-5 '-yl) Oxygen] the cyclobutane-carboxylic acid tert-butyl ester
Figure A20068004533300672
With cesium carbonate (559mg, 1.72mmol) add the compound (300mg of preparation 24,1.14mmol) in the part solution in DMF (3mL), and with reaction mixture be heated to 40 ℃ the reaction 10 minutes, crude compound (523mg, 1.60mmol) solution in DMF (3mL) of disposable then adding preparation 22.Reaction mixture is heated to 80 ℃ further reacted 9 hours, and make it be cooled to room temperature.Then water is added in the reaction mixture, then add ethyl acetate (5mL), and attempt collecting the gained throw out, but not success.Follow quick and complete dissolving, the reaction mixture vacuum concentration to 2ml, is added entry (5mL) with induced crystallization, and products therefrom is leached and vacuum-drying, thereby obtain title compound (310mg, 0.76mmol, 67%).The LC-MS analysis revealed remains 10% raw material phenol.This material is used in step (b), is not further purified.
LRMS m/z(ESI)407[M+H] +。
(b) trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [cyclopentyl-1,4 '-quinazoline]-5 '-yl) Oxygen] cyclobutane-carboxylic acid
Under 60 ℃, (310mg 0.76mmol) in the solution in acetate (3mL), and should react and at room temperature stir 30 minutes the product of the hydrobromic acid aqueous solution with 48% (0.5mL) adding step (a).Mixture is quenched muddy slightly by dripping water (0.1mL) up to observing.Reaction is cooled to room temperature, filters the gained throw out then, to obtain light brown solid (130mg).Carry out purifying by recrystallization in acetate (1.5mL)/water (0.1mL), thereby obtain the solid shape title compound (35mg, 0.09mmol, 9%) of canescence.
1H-NMR(400MHz，D 6-DMSO)：δ1.70(m，4H)，1.82(m，2H)，2.27(m，2H)，2.60(m，2H)，3.04(m，2H)，4.81(m，1H)，6.35(d，1H)，7.18(d，1H)，7.30(s，1H)，7.98(s，1H)，12.14(s，1H)。
LRMS(ESI)m/z 351[M+H] +。
Preparation
Preparation 1
The 3-[(benzyloxy) methyl]-2,2-dichloro cyclobutanone
Figure A20068004533300681
With zinc powder (6.54g 0.1mol) is suspended in the water (30mL), and makes the argon gas bubbling by this suspension 15 minutes, add then copper sulfate (II) (780mg, 3.1mmol).Reaction mixture was stirred 30 minutes under room temperature, argon gas.Mixture is filtered under argon gas stream, and adopt water (100mL), acetone (100mL) to wash also vacuum-drying 4 hours solid.With gained zinc/copper idol at the argon gas low suspension in diethyl ether: 1, the 2-glycol dimethyl ether (70mL: 10mL), and add the allyl group benzylic ether (4.6mL, 30mmol).In 45 minutes, drip trichoroacetic chloride (9mL, 81mmol) at diethyl ether: 1,2-glycol dimethyl ether (58mL: the solution 7mL), and with reaction mixture reflux 48 hours.Reaction mixture is passed through Celite
Figure A20068004533300682
Filter, and salt is adopted diethyl ether (3 * 70mL) washings.Again be dissolved in the hexane (150mL) with filtrate vacuum-evaporation and with resistates.Remaining solid by filtration is removed, and with filtrate by saturated sodium bicarbonate aqueous solution (2 * 100mL), salt solution (80mL) washing, dry on sal epsom, filter and vacuum-evaporation.Crude material is adopting 10 to 25% hexanes by column chromatography: purifying on the silica gel of diethyl ether wash-out.Obtain yellow oily title compound (7.03g, 27.3mmol, 91%).
1H-NMR(CDCl 3，400MHz)：δ3.11-3.21(m，2H)，3.48(m，1H)，3.70(m，1H)，3.85(m，1H)，7.35(m，5H)，4.58(s，2H)。
Preparation 2
The 3-[(benzyloxy) methyl] cyclobutanone
Figure A20068004533300691
(9.25g, (5.98g 23.08mmol) in the solution in adopting the saturated methyl alcohol (90mL) of ammonium chloride, and at room temperature stirred this reaction mixture 2 hours 142mmol) to add the dichloro cyclobutanone of preparation 1 with zinc powder.Add ammonium chloride, and will react mixed thing and at room temperature further stir 6 hours.Mixture is passed through Celite
Figure A20068004533300692
Filter, and salt is adopted diethyl ether (50mL) washing.With the filtrate vacuum concentration, and resistates distributed between diethyl ether (200mL) and water (100mL).Mixture is filtered, and organic phase is adopted water washing, dry on sal epsom, also vacuum-evaporation of filtration.Obtain yellow oily title compound (3.7g, 19.5mmol, 84%).
1H-NMR(CDCl 3，400MHz)：δ2.69(m，1H)，2.90(m，2H)，3.11(m，2H)，3.60(d，2H)，4.56(s，2H)，7.34(m，5H)。
Preparation 3
Cis-3-[(benzyloxy) methyl] cyclobutanol
In-70 ℃ of whipping process, (1.166g 6.13mmol) in the solution in tetrahydrofuran (THF), keeps temperature of reaction to be lower than-65 ℃ to the cyclobutanone of the preparation 2 that the solution (40mL) of 1M 3-sec-butyl lithium borohydride in tetrahydrofuran (THF) is added drop-wise to simultaneously.Reaction was warmed to room temperature reaction 18 hours.Adopt the saturated aqueous solution (25mL) of sodium bicarbonate that reaction mixture is quenched, reaction mixture is cooled to 5 ℃ then.The aqueous hydrogen peroxide solution (4mL) of dropping 30% keeps temperature of reaction to be lower than 10 ℃ simultaneously.Mixture is extracted in the ethyl acetate (50mL) by water, and the organic phase that merges is adopted salt solution (30mL) washing, dry on sal epsom, filter and vacuum-evaporation.Crude material is adopting 25 to 50% ethyl acetate by column chromatography: purifying on the silica gel of pentane wash-out obtains water white oil (1.05g, 5.5mmol, 89%). 1H-NMR shows cis: the ratio of trans-isomer(ide) is 15: 1.
1H-NMR(CDCl 3，400MHz)：δ1.70(m，2H)，2.10(m，1H)，2.46(m，2H)，3.45(d，2H)，4.15(q，1H)，4.52(s，2H)，7.33(m，5H)。
Preparation 4
The 4-nitrobenzoic acid is trans-the 3-[(benzyloxy) and methyl] the ring butyl ester
Under 0 ℃, with diethylazodicarboxylate (2g, 11.5mmol) drips of solution in tetrahydrofuran (THF) (5mL) is added to the cyclobutanol (1.05g of preparation 3,5.47mmol), 4-nitrobenzoic acid (1.82g, 10.9mmol) and triphenylphosphine (3.016g is 11.5mmol) in the stirred solution of tetrahydrofuran (THF) (20mL).Reaction mixture was at room temperature stirred 18 hours.With solvent vacuum-evaporation, and resistates is dissolved in the diethyl ether (30mL) again.Remaining solid by filtration is removed, and with filtrate vacuum-evaporation.Crude material by column chromatography in the ethyl acetate that adopts 1: 10 to 1: 3: purifying on the silica gel of pentane wash-out obtains water white oil (1.64g, 4.8mmol, 88%). 1H-NMR shows trans: the ratio of cis-isomeride is 15: 1.
1H-NMR(CDCl 3，400MHz)：δ2.40(m，4H)，2.67(m，1H)，3.53(d，2H)，4.57(s，2H)，5.36(q，1H)，7.37(m，5H)，8.20(d，2H)，8.29(d，2H)。
Preparation 5
Trans-the 3-[(benzyloxy) methyl] cyclobutanol
Figure A20068004533300702
With sodium hydroxide (385mg, 9.6mmol) solution in water (25mL) add preparation 4 (1.64g 4.8mmol) 1, in the solution in the 4-dioxane (35mL), and at room temperature stirred reaction mixture 30 minutes to nitro ester.(0.4mL is 7mmol) and with the mixture vacuum concentration to add acetate.The saturated aqueous solution of resistates by sodium bicarbonate is extracted in the ethyl acetate (20mL), dry on sal epsom, filter and vacuum-evaporation.Obtain yellow oily title compound (850mg, 4.4mmol, 92%).
1H-NMR(CDCl 3，400MHz)：
Figure A20068004533300703
2.08(m，2H)，2.20(m，2H)，2.47(m，1H)，3.47(d，2H)，4.39(q，1H)，4.52(s，2H)，7.34(m，5H)。
Preparation 6
Tosic acid is trans-the 3-[(benzyloxy) and methyl] the ring butyl ester
Figure A20068004533300711
Under 0 ℃, (1.18g, 6.2mmol) add the cyclobutanol of preparation 5 (850mg 4.42mmol) in the stirred solution in pyridine (5mL), and at room temperature stirred reaction mixture 18 hours in batches with Tosyl chloride.With solvent vacuum-evaporation, and resistates is dissolved in the ethyl acetate (30mL) again, adopts the saturated aqueous solution (30mL) and salt solution (30mL) washing of 2N hydrochloric acid (30mL), sodium bicarbonate, dry on sal epsom, filter also vacuum-evaporation.Crude material is by column chromatography purifying on the silica gel that adopts the methylene dichloride wash-out.Obtain the colorless oil title compound (1.53g, 4.4mmol).
1H-NMR(CDCl 3，400MHz)：δ2.15(m，2H)，2.31(m，2H)，2.44(s，3H)，2.49(m，1H)，3.4(d，2H)，4.49(s，2H)，4.93(q，1H)，7.32(m，7H)，7.75(d，2H)。
Preparation 7
5 '-(cis-3-[(benzyloxy) and methyl] cyclobutyl } oxygen)-8 '-chloro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]- 2 ' (3 ' H)-ketone
Figure A20068004533300712
With 8 '-chloro-5 '-hydroxyl-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-2 ' (3 ' H)-ketone is (as Bioorg.Med.Chem.Lett, (2004), 14 (18), the described preparation of 4627-4632) (640mg, 2.4mmol), salt of wormwood (400mg, 2.9mmol) and 18-hat-6 (767mg, 2.9mmol) in dimethyl formamide (8mL), merge, and reaction mixture is heated to 80 ℃.The tosylate of adding preparation in three batches 6 (1g, the 2.9mmol) solution in dimethyl formamide, and with mixture heating up to 80 ℃ further reaction 18 hours.Reaction mixture is distributed in ethyl acetate (100mL) and water (150mL), and pass through solid collected by filtration.To respectively be separated, and water will be adopted ethyl acetate extraction once more, and adopt the salt solution dilution, and be extracted in the ethyl acetate once more.With the organic phase vacuum concentration that merges, and adopt water and methyl alcohol to grind the resistates.The crude product that merges is adopting methylene dichloride to methylene dichloride by column chromatography: purifying on the silica gel of ethyl acetate (1: 1) wash-out obtains pale solid shape title compound (685mg, 1.156mmol, 64%).
1H-NMR(D 6-DMSO，400MHz)：δ1.1(m，1H)，1.4(m，2H)，1.6(m，3H)，1.7(m，2H)，1.8(m，2H)，2.3(m，1H)，2.5(m，4H)，3.4(s，2H)，4.4(s，2H)，4.6(m，1H)，6.4(d，1H)，7.0(s，1H)，7.2(d，1H)，7.3(m，5H)，7.8(s，1H)。
Preparation 8
8 '-chloro-5 '-{ [cis-3-(methylol) cyclobutyl] oxygen }-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-2 ' (3 ' H)- Ketone
Figure A20068004533300721
(1.8mL, (400mg is 0.9mmol) in the suspension in methylene dichloride (10mL), with reaction mixture stirred overnight at room temperature 3.6mmol) to add the benzylalcohol of preparation 7 with the 2M solution of boron trichloride-dimethylsulphide title complex in methylene dichloride.Add the saturated aqueous solution (10mL) of sodium bicarbonate and mixture was stirred 5 minutes.Add methylene dichloride and water, and collect the gained solid by filtering.Obtain white solid title compound (230mg, 0.657mmol, 73%).
1H-NMR(D 6-DMSO，400MHz)：δ.1.17(m，1H)，1.42(m，2H)，1.57(m，3H)，1.82(m，4H)，2.05(m，1H)，2.45(m，4H)，3.38(t，2H)，4.58(m，2H)，6.41(d，1H)，6.99(s，1H)，7.20(d，1H)，7.86(s，1H)。
LRMS m/z(APCI)351[MH] +。
Preparation 9
Tosic acid cis-3-[(benzyloxy) methyl] the ring butyl ester
Figure A20068004533300722
Under 5 ℃, with pyridine (14.3mL, 176mmol) and Tosyl chloride (20.2g, (17g 88.4mmol) in the stirred solution in methylene dichloride (90mL), and at room temperature stirred reaction mixture 18 hours 105.9mmol) to add the alcohol of preparation 3.Reaction mixture with methylene dichloride (50mL) dilution, is adopted saturated aqueous solution (50mL) washing of 2N hydrochloric acid (50mL), sodium bicarbonate, dry on sal epsom, filter and vacuum-evaporation.Crude material is adopting pentane by column chromatography: purifying on the silica gel of ethyl acetate (19: 1,9: 1,4: 1) wash-out.Obtain colorless oil title compound (24.8g, 71.6mmol, 81%).
1H-NMR(CDCl 3，400MHz)：δ1.95(m，2H)，2.1(m，1H)，2.35(m，2H)，2.45(s，3H)，3.4(m，2H)，4.5(s，2H)，4.7(m，1H)，7.3(m，7H)，7.8(m，2H)。
LRMS m/z(ESI)347[MH] +。
Preparation 10
5 '-(trans-the 3-[(benzyloxy) and methyl] cyclobutyl } oxygen)-8 '-chloro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]- 2 ' (3 ' H)-ketone
Figure A20068004533300731
Method A
With cesium carbonate (730mg, 2.24mmol) adding 8 '-chloro-5 '-hydroxyl-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-2 ' ((500mg 1.87mmol) in the stirred suspension in dimethyl formamide (2mL), and is heated to 80 ℃ with reaction mixture to 3 ' H)-ketone.After 5 minutes, add preparation 9 tosylate (710mg, the 2.05mmol) solution in dimethyl formamide (1mL), and with reaction mixture 80 ℃ of heating 18 hours down.With mixture from salt solution (60mL) be extracted into ethyl acetate (1 * 80mL, in 2 * 30mL), adopt salt solution (3 * 100mL) washings, dry on sal epsom, filter and vacuum-evaporation.Obtain impure slightly emulsifiable paste solid state title compound (800mg, 0.96mmol, 96%).
Method B
Under 80 ℃, with salt of wormwood (590mg, 4.27mmol) and 18-hat-6 (1.1g, 4.27mmol) add 8 '-chloro-5 '-hydroxyl-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-2 ' ((950mg is 3.56mmol) in the stirred solution in dimethyl formamide (12mL) for 3 ' H)-ketone.Reaction mixture was stirred 10 minutes, add tosylate (1.48g, 4.27mmol) solution in dimethyl formamide (3mL) of preparation 9 then.Reaction mixture was heated 24 hours down at 80 ℃.Pour mixture into water: methyl alcohol (75mL: 25mL), stirred 10 minutes, methanol wash is collected and adopted to the gained throw out by filtering.Solid is dissolved in the methylene dichloride, passes through Celite
Figure A20068004533300741
Filter, and with the vacuum-evaporation of gained filtrate, trans to obtain: cis-isomeride is 9: 1 blended title compounds (887mg, 2.0mmol, 56%).
1H-NMR(CDCl 3，400MHz).：δ1.3(m，1H)，1.5-1.9(m，9H)，2.4(m，3H)，2.6(m，2H)，3.5(d，2H)，4.6(s，2H)，4.75(m，1H)，5.85(bs，1H)，6.25(d，1H)，7.05(bs，1H)，7.1(d，1H)，7.3-7.4(m，5H)。
LRMS m/z(ESI)441[MH] +。
Preparation 11
8 '-chloro-5 '-({ trans-3-(methylol) cyclobutyl } oxygen)-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-2 ' (3 ' H)- Ketone
Figure A20068004533300742
The 2M solution of boron trichloride-dimethylsulphide title complex in methylene dichloride (15mL) is added the benzyl oxide of preparation 10, and (3.5g 7.9mmol) in the solution in methylene dichloride (80mL), at room temperature stirred reaction mixture 18 hours.Mixture is poured in the saturated aqueous solution (200mL) of sodium bicarbonate and stirred up to stopping bubbling.(1 * 200mL in 2 * 100mL), adopts salt solution (50mL) washing, and is dry on sal epsom, filters and vacuum-evaporation to methylene dichloride with mixture extraction.By the acetonitrile recrystallization, obtain trans: cis-product is 91: 9 a title compound (2.33g, 6.65mmol, 84%) with crude material.
1H-NMR(CDCl 3，400MHz)：
Figure A20068004533300751
1.3(m，1H)，1.5(m，2H)，1.8(m，5H)，2.4(m，4H)，2.6(m，3H)，3.8(d，2H)，4.8(m，1H)，5.7(bs，1H)，6.25(d，1H)，7.0(bs，1H)，7.1(d，1H)。
LRMS m/z(ESI)351[MH] +。
Preparation 12
3-methylene radical cyclobutane-carboxylic acid
Figure A20068004533300752
(17.37g is 214.7mmol) in water-soluble (20mL) and add ethanol (20mL) with potassium hydroxide.When cooling, with this solution add 3-methylene radical tetramethylene formonitrile HCN (5.0g, 53.7mmol) in, and gained solution be heated to refluxed 2.5 hours, cool off and vacuum-evaporation, obtain emulsifiable paste shape solid.With in the solid water-soluble (15mL) and in ice bath, cool off, add dense HCl to pH 1, and adopt diethyl ether (3 * 20mL) extractions.With the dry and vacuum-evaporation on sal epsom of upper strata extract, obtain light yellow liquid shape title compound (5.6g, 93%).
1H-NMR (CDCl 3, 400MHz): (m, 2H), 3.02 (m, 2H), 3.17 (m, 1H), 4.82 (m 2H) (does not see an exchangeable protons) to δ 2.95.
Preparation 13
3-methylene radical cyclobutane-carboxylic acid benzyl ester
Figure A20068004533300753
With 1, (1.59g, 9.81mmol) (1g is 8.9mmol) in the solution in ethyl acetate (5mL) to the product for preparing 12 for the suspension portion-wise addition in ethyl acetate (5mL) for 1 '-carbonyl dimidazoles.Observe slight bubbling.With this mixture stir about 1.5 hours at room temperature, add benzylalcohol (1.11mL, 10.7mmol) and continuously stirring whole night.Solution is adopted diethyl ether (20mL) dilution, and (2 * 10mL) wash, and dry also vacuum-evaporation is to colourless liquid on sal epsom, and this liquid is by 10g SiO to adopt water 2, adopt the methylene dichloride wash-out to filter purifying, obtain colorless oil title compound (1.246g, 69%).
1H-NMR(CDCl 3，400MHz)：δ2.92(m，2H)，3.02(m，2H)，3.16(m，2H)，4.80(m，2H)，5.15(s，2H)，7.36(m，5H)。
LRMS m/z(ESI)203[MH] +。
Preparation 14
3-(methylol) cyclobutane-carboxylic acid benzyl ester
(0.07mL, (300mg is 1.48mmol) in the stirred solution in THF (1mL) 0.72mmol) to adopt THF (1mL) to dilute the compound that also at room temperature is added drop-wise to preparation 13 with borine-dimethylsulphide.Colourless solution was at room temperature stirred 1 hour, add Sodium peroxoborate (145mg, 1.78mmol) solution in water (1mL) with the speed of control bubbling then.Add finish after, mixture is adopted 1,4-dioxane (1mL) dilution, and with gained solution 60 ℃ warm 1 hour down, quench and adopt ethyl acetate (10mL) extraction by adding water (5mL).Acetic acid ethyl acetate extract dry also vacuum-evaporation on sal epsom is obtained water white oil (226mg, 69%), and this water white oil former state is used for next step.
1H-NMR(CDCl 3，400MHz)：δ2.05(m，2H)，2.33(m，2H)，2.45(m，1H)，3.11(m，1H)，3.62(dd，2H)，5.13(d，2H)，7.35(m，5H)。
Preparation 15
3-(tolysulfonyl oxygen methyl) tetramethylene-1-benzyl carboxylate
At room temperature, with Tosyl chloride (309mg, 1.62mmol) drips of solution in methylene dichloride (2mL) be added to preparation 14 compound (275mg, 1.25mmol) and pyridine (0.26mL is in stirred solution 3.25mmol), and continuously stirring 3 days.This mixture (is distributed between 2 * 20mL) at methylene dichloride (20mL) and water, dichloromethane extract is dry on sal epsom, and vacuum-evaporation, obtain water white oil, this water white oil is adopting methylene dichloride to 1 by column chromatography: 1 diethyl ether: purifying on the silica gel of methylene dichloride wash-out, obtain colorless oil title compound (226mg, 48%).
1H-NMR(CDCl 3，400MHz)：δ2.02(m，2H)，2.25-2.41(m，2H)，2.44(s，3H)，2.55-2.75(m，1H)，3.07(m，1H)，4.00(2xd，2H)，5.10(d，2H)，7.34(m，7H)，7.78(m，2H)。
Preparation 16
5 '-{ [trans-3-(methylol) cyclobutyl] oxygen }-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinoline The azoles quinoline]-8 '-formonitrile HCN
Figure A20068004533300771
Successively with sodium cyanide (27.9mg, 0.57mmol) and nickelous bromide (62.3mg, 0.285mmol) add preparation 11 compound (100mg, 0.285mmol) in the suspension in N-Methyl pyrrolidone (1.5mL), and with reaction mixture in microwave reactor 200 ℃ of heating 10 minutes down.With mixture diethyl ether (2 * 20mL) and water (10mL) between distribute, the organic extract dry and vacuum concentration on sal epsom with merging obtains shallow tangerine look/red solid shape title compound (27.8mg).
1H-NMR(400MHz，CDCl 3)：δ1.4-1.85(m，9H)，2.3-2.7(m，6H)，3.73(d，2H)，4.83(m，1H)，5.60(s，1H)，6.33(d，1H)，6.98(s，1H)，7.36(d，1H)。
LC-MS: retention time=2.54 minute (100%); LRMS m/z 342[MH +].
Preparation 17
1-(methylol)-cyclobutane-carboxylic acid methyl esters
Figure A20068004533300781
At room temperature, with three tert.-butoxy aluminium lithium hydride (the 1M solution of 25.5mL in tetrahydrofuran (THF), 25.5mmol) in 10 minutes, be added drop-wise to 1,1-cyclobutane dicarboxylic acid dimethyl ester (derives from Lancaster Synthesis Ltd, UK) (2.0g is 11.6mmol) in the solution in tetrahydrofuran (THF) (20mL).Reaction mixture is heated to slowly refluxes 3 hours, be cooled to room temperature and stirred 18 hours.Gained suspension is adopted ammonium chloride saturated aqueous solution (30mL) dilution, and vigorous stirring 15 minutes, filter then.Solid is adopted diethyl ether (50mL) washing, organic layer is separated, and water layer is adopted diethyl ether (50mL) extraction.The organic extract that merges is dry on sal epsom, filter and vacuum-evaporation, obtain colorless oil title compound (1.8g).
Preparation 18
1-(tolysulfonyl oxygen methyl)-cyclobutane-carboxylic acid methyl esters
Figure A20068004533300782
With Tosyl chloride (4.2g, 22.0mmol) and pyridine (2.7mL, (1.6g 11.0mmol) in the solution in methylene dichloride (5mL), and at room temperature stirred solution 18 hours 33.0mmol) successively to add the crude compound of preparation 17 to.Then reaction mixture is adopted methylene dichloride (30mL) dilution, and adopt the 2N HCl aqueous solution (2 * 25mL) and saturated aqueous solution of sodium bicarbonate (50mL) washing, dry also vacuum-evaporation on sal epsom.Rough tangerine look oil (5g) is adopting ethyl acetate by flash chromatography: purifying on the silica gel of pentane (1: 5) wash-out obtains colorless oil title compound (1.7g, 5.7mmol, 49%).
1H-NMR(CDCl 3，400MHz)：δ1.96(m，4H)，2.40(m，2H)，2.45(s，3H)，3.62(s，3H)，4.24(s，2H)，7.35(d，2H)，7.79(d，2H)。
Preparation 19
8 ' chloro-5 '-methoxyl group-1 ' H-volution [suberyl-1,4 '-quinazoline]-2 ' (3 ' H)-ketone
Figure A20068004533300791
With 2-chloro-5-p-methoxy-phenyl urea (WO02/074754, intermediate 5) (17.9g, 89.5mmol) (60mL, 0.51mol) solution in is added drop-wise in the Tripyrophosphoric acid (213g) (notice heat release to 127 ℃) in following 20 minutes and heated 1 hour at 100 ℃ at suberone.Mixture is poured in water (3 liters) and the ethyl acetate (1 liter), stirred simultaneously.The gained solid by filtration is collected, by ethyl acetate thorough washing and dry.The exsiccant solid is dissolved in the chloroform, adopts the sodium bicarbonate aqueous solution washing, dry and vacuum concentration obtains white solid title compound (10.2g, 34mmol, 39%) on sal epsom.
Two-phase filtrate is separated, and ethyl acetate is adopted water and salt water washing mutually, dry and concentrated on sal epsom.Resistates is ground in t-butyl methyl ether, and the gained white solid is collected by filtering, adopt other t-butyl methyl ether washing and dry, obtain second section title compound (9.0g, 30.6mmol, 34%).
1H-NMR(400MHz，CDCl 3)：δ1.53-1.84(complex，10H)，2.46(m，2H)，3.81(s，3H)，5.33(br，1H)，6.46(d，1H)，7.03(br，1H)，7.18(d，1H)。
LRMS m/z 295[M+H] +。
Preparation 20
8 '-chloro-5 '-hydroxyl-1 ' H-volution [suberane-1,4 '-quinazoline]-2 ' (3 ' H)-ketone
Figure A20068004533300792
(129mL, (19.0g 64.6mmol) in the solution in methylene dichloride (500mL), and at room temperature stirred mixture 3 days 129mmol) to add the compound of preparation 19 with the 1M solution of boron tribromide in methylene dichloride.Reaction mixture being poured in water (1.5 liters) and the ethyl acetate (1 liter), white solid by filter collecting, will respectively be separated and organic phase is dry on sodium sulfate, and vacuum concentration being obtained brown solid.The white solid recrystallization in ethanol that leaches is obtained title compound (7.4g, 26.4mmol, 41%).The mother liquor and the brown solid of recrystallization are merged, and mixture is stirred in ethanol, filtering also, drying obtains second batch of product (7.0g, 25mmol, 39%).
1H-NMR(400MHz，D 6-DMSO).：δ1.38-1.78(complex，10H)，2.26(m，2H)，6.40(d，1H)，7.02(d，1H)，7.20(br，1H)，7.80(br，1H)，9.84(br，1H)。
Preparation 21
Cis-3-hydroxyl cyclobutyl carboxylic acid the tert-butyl ester
Figure A20068004533300801
Method A
With the 3-oxo cyclobutane-carboxylic acid tert-butyl ester (J.Org.Chem. (1993) 58,110) (3.10g 18.2mmol) is dissolved in tetrahydrofuran (THF): methyl alcohol (20: 1,30mL) in, and under nitrogen, be cooled to 5 ℃.Add sodium borohydride (345mg) in batches, and the gained settled solution was stirred 15 minutes down at 5 ℃, then water (135mL) and ethyl acetate (135mL) dilution by successively dripping.Aqueous phase separation is come out, and adopt ethyl acetate (2 * 25mL) washings.The organic phase that merges is adopted salt solution (20mL) washing, and dry and vacuum concentration obtains light yellow oily title compound (3.05g, 17.7mmol, 97%) on sal epsom.
1H-NMR(CDCl 3，400MHz)：δ1.46(s，9H)，2.12(m，2H)，2.55(m，3H)，4.17(m，1H)。
GC analyzes (sample is in acetonitrile): retention time 4.57 minutes (91.5% area).
Method B
(10.0g 88mmol) is dissolved in the tetrahydrofuran (THF) (20mL), and is cooled to 5 ℃ with the 3-oxo cyclobutane-carboxylic acid tert-butyl ester (J.Org.Chem. (1993) 58,110).Add in batches 4-dimethylaminopyridine (8.6g, 70mmol), follow the disposable adding trimethyl carbinol (13.0g, 176mmol).Drip N, (96mL 96mmol), maintains the temperature between 0 ℃ to 5 ℃ the 1M solution of N '-dicyclohexyl carbodiimide in methylene dichloride simultaneously.The gained slurries are warmed to room temperature, and stirred overnight.After the filtration, under 5 ℃, filtrate is added drop-wise in the 2M hydrochloric acid (50mL).Gained respectively is separated, and lower organic layer is warmed to room temperature and adopts water (50mL) and saturated aqueous solution of sodium bicarbonate (50mL) washing.Organic phase that will be lower is by distilling concentrated and carrying out exchange of solvent with tetrahydrofuran (THF).Final reaction volume is 30mL.Add methyl alcohol (6mL).Simultaneously, (1.65g 44mmol) is suspended in the tetrahydrofuran (THF) (39mL) and is cooled to 5 ℃ with sodium borohydride.The intermediate tetrahydrofuran solution is added drop-wise in the sodium borohydride slurries, maintains the temperature at simultaneously between 0 ℃ to 5 ℃.Then this being reflected at 0 to 5 ℃ stirred 2 hours down.Drip water, maintain the temperature at simultaneously between 0 ℃ to 5 ℃.Adding ethyl acetate (75mL) also will respectively be separated.The bottom water layer is warmed to room temperature, and adopts ethyl acetate (37mL) washing.The organic layer that merges is concentrated, and further successively adopt the washing of salt solution (37mL) and water (37mL).The organic layer on top is extracted out under vacuum, thereby obtained yellow oily title compound (10.1g, 58.6mmol, 67%).
1H-NMR(CDCl 3，400MHz)：δ1.46(s，9H)，2.12(m，2H)，2.55(m，3H)，4.17(m，1H)。
GC analyzes: 9.02 minutes (cis-isomeride) (87.5% areas) of retention time; 9.07 minutes (trans-isomer(ide)) (10.0% areas) of retention time
Preparation 22
3-(tolysulfonyl the oxygen)-cyclobutane-carboxylic acid tert-butyl ester
Figure A20068004533300811
Method A
(3.02g 17.35mmol) is dissolved in the pyridine (15mL), and is cooled to 0 ℃ under nitrogen with preparation 21 compound.(3.5g 18.4mmol) and with solution at room temperature stirred 72 hours disposable adding Tosyl chloride.The gained pink colour solution for vacuum concentration that will contain the white suspension thing, and between the 2N HCl aqueous solution (30mL) and ethyl acetate (30mL), distribute, and water layer is adopted ethyl acetate (15mL) washing once more.The organic layer that merges is adopted the 2N HCl aqueous solution (15mL), saturated aqueous solution of sodium bicarbonate (15mL) and salt solution (30mL) washing, and vacuum-drying concentrates, the tangerine look oily title compound (5.15g, 15.7mmol, 90%) that obtains solidifying in the process of leaving standstill.
1H-NMR(400MHz，CDCl 3).：δ1.43(s，9H)，2.32-2.57(complex，5H)，2.46(s，3H)，4.73(m，1H)，7.35(d，2H)，7.79(d，2H)。
LC-MS: cis-isomeride retention time 21.78 minutes (81%), LRMS (ESI) m/z327[MH +]; Trans-isomer(ide) retention time 22.08 minutes (7.3%), LRMS (ESI) m/z327[MH +].
Method B
(10.0g 58mmol) is dissolved in the pyridine (25mL), and is cooled to 0 ℃ under nitrogen with preparation 21 compound.(16.6g 87mmol) is dissolved in the pyridine (25mL) and dropping, maintains the temperature at simultaneously between 0 ℃ to 5 ℃ with Tosyl chloride.Then, this reaction is warmed to room temperature and stirred overnight.
This reaction mixture is condensed into solid, and in ethyl acetate (50mL) pulp.Slurries are cooled to 0 to 5 ℃, and employing 2M hydrochloric acid (75mL) washing also will respectively be separated.Lower aqueous is adopted ethyl acetate (50mL) extraction.The organic phase that merges is adopted water (50mL) and sodium hydrogen carbonate solution (50mL) washing.Organic phase is concentrated, and be cooled to 0 to 5 ℃.Drip N, and N-dimethyl ethylene diamine (3.5g, 40mmol).Reaction mixture is adopted 2M hydrochloric acid (75mL) washing.The top organic phase is adopted water (75mL) and salt solution (75mL) washing.Organic phase is concentrated into crystalline light yellow oil in the process of leaving standstill (15.5g, 47mmol, 82%).
1H-NMR(400MHz，CDCl 3).：δ1.43(s，9H)，2.32-2.57(complex，5H)，2.46(s，3H)，4.73(m，1H)，7.35(d，2H)，7.79(d，2H)。
GC analyzes: 15.98 minutes (cis-isomeride) (94.1% areas) of retention time; 15.82 minutes (trans-isomer(ide)) (5.9% areas) of retention time.
Preparation 23
8 ' chloro-5 '-methoxyl group-1 ' H-volution [cyclopentyl-1,4 '-quinazoline]-2 ' (3 ' H)-ketone
Figure A20068004533300831
Successively (440.8mL) and suberone (19.5mL with Eaton reagent (the 7.7wt% solution of phosphorus oxide (V) in methylsulphonic acid), 0.22mol) adding 2-chloro-5-p-methoxy-phenyl urea (WO02/074754, intermediate 5) (22.04g, 0.11mol), and with gained solution 85 ℃ of down heating 4 hours.Reaction is cooled to～5 ℃, and carefully adds water, to maintain the temperature between 20 ℃ to 30 ℃.Add methylene dichloride (400mL altogether) and salt solution (200mL) then, and will respectively be separated.Water is adopted methylene dichloride (2 * 100mL) washings, organic extract is merged and vacuum-evaporation, obtain dark oil, this dark oil is adopting methylene dichloride: purifying on the tripoli chromatographic column of methyl alcohol (95: 5 to 90: 10) wash-out obtains dark brown solid shape product.Adopt diethyl ether and pentane to grind this solid, collect by filtering, and drying obtains brown solid shape title compound (27.17g, 0.1mol, 92%).
1H-NMR(400MHz，CDCl 3)：δ1.7-1.8(m，6H)，2.4-2.5(m，2H)，3.7(s，3H)，5.75(br s，1H)，6.4(d，1H)，7.05(s，1H)，7.15(d，1H)。
LRMS m/z(APCI)267[M+H] +。
Preparation 24
8 ' chloro-5 '-hydroxyl-1 ' H-volution [pentamethylene-1,4 '-quinazoline]-2 ' (3 ' H)-ketone
Figure A20068004533300832
Successively with the hydrobromic acid aqueous solution of acetate (250mL) and 48% (207mL, 1.86mol) compound of disposable adding preparation 23 (25g, 0.093mol) in, and with gained solution 115 ℃ of stirrings 7 days down.Reaction mixture is cooled to 100 ℃, and drips water (207mL).With the mixture vacuum concentration, and precipitation obtains brown solid, also employing water (2 * 100mL) washings of this solid by filtration collection.Leave standstill in the process and obtain the second section product by filtrate.The product that merges by toluene (150mL) pulp and desolventize three times, is obtained gray solid under vacuum, this solid preadsorption is to tripoli, and by the employing methylene dichloride: the column chromatography purifying of methyl alcohol (98: 2 to 95: 5 to 80: 20) wash-out.With product fraction vacuum concentration, and with the grinding of gained solid employing pentane, and filtration obtains brown solid shape title compound (10g, 0.0395mol, 42%).
1H-NMR(400MHz，D 6-DMSO)：δ1.6-1.8(m，6H)，2.3-2.4(m，2H)，6.4(d，1H)，7.11(d，1H)，7.2(s，1H)，7.8(s，1H)，9.9(s，1H)。
LRMS m/z(ESI)253[M+H] +。
Preparation 25
(2-chloro-5-p-methoxy-phenyl) urea
Figure A20068004533300841
(26g 134mmol) adds in acetate (117mL) and the water (13mL) with 2-chloro-5-anisidine hydrochloride.Slurries are warmed to 30 ℃.Drip potassium cyanate (13g, 161mmol) solution in water (104mL).At 40 ℃ after following 1 hour, reaction is cooled to 20 ℃, filter and also adopt water (78mL) washing.With product whole night, obtain white solid title compound (21.8g, 81%) 60 ℃ of following vacuum-dryings.
1H-NMR(300MHz，D 6-DMSO)：d 3.71(s，3H)，6.41(s，2H)，6.53(d，1H)，7.26(d，1H)，7.85(s，1H)，7.98(s，1H)。
LC-MS (ESI): 10.9 minutes 99.4 (%), m/z 201[MH +].
Preparation 26
8 '-chloro-5 '-the methoxyl group volution [hexanaphthene-1,4 '-quinazoline]-2 ' (1 ' H)-ketone
Figure A20068004533300851
(5.0g 25mmol) adds Eaton reagent (the 7.7wt% solution of phosphorus oxide (V) in methylsulphonic acid) and forms solution in (150g), then this solution is heated to 60 ℃ with preparation 25 compound.(4.9g 50mmol), is warmed to 80 ℃ with this reaction then, and remains on this temperature following 1 hour to add pimelinketone in 10 minutes.Reaction mixture is cooled to 5 ℃ then, adds entry (150mL).Then reaction mixture is adopted methylene dichloride (100mL) extraction, and upper aqueous phase is adopted methylene dichloride (2 * 100mL) washings.The organic phase that merges is concentrated, add 2-propyl alcohol (110mL) then.With reaction mixture further concentration under barometric point, to remove remaining methylene dichloride.To react cooling, and stir 1 hour down at 5 ℃, thereby make the product crystallization.Product by filter collecting, and is adopted 2-propyl alcohol (15mL) washing, then 50 ℃ dry 18 hours down, thereby obtain white solid title compound (5.2g, 19mmol, 76%).
1H-NMR(300MHz，D 6-DMSO)：d 1.2(m，1H)，1.4(m，2H)，1.5(m，1H)，1.6(m，2H)，1.7(m，1H)，1.8(m，1H)，2.4(t，2H)，3.79(s，3H)，6.64(d，1H)，6.97(s，1H)，7.26(d，1H)，7.91(s，1H)。
LC-MS (ESI): 18.5 minutes 97.4 (%), m/z 281[MH +].
Preparation 27
8 '-chloro-5 '-the hydroxyl volution [hexanaphthene-1,4 '-quinazoline]-2 ' (1 ' H)-ketone
Figure A20068004533300852
Step (a)
8 '-chloro-5 '-the hydroxyl volution [hexanaphthene-1,4 '-quinazoline]-2 ' (1 ' H)-ketone acetic acid solvent thing
Compound (350g, 1.24mol) pulp in acetate (3500mL) with preparation 26.At room temperature, (2800mL 24.8mol) adds in the above-mentioned slurries with Hydrogen bromide (48%w/w is in water).Then these slurries are warmed to and reflux and stirred 4 days.This reaction is cooled to 100 ℃, and in 1 hour, drips water (2800mL).Slurries are cooled to 10 ℃, stirred 1 hour, filter then, water (1100mL) washing and in vacuum drying oven a dry night, thereby obtain white solid title compound (344g, 1.28mol, 103%).
1H-NMR(D 6-DMSO，300MHz).：
Figure A20068004533300861
1.2(m，1H)，1.4(m，2H)，1.5(m，1H)，1.6(m，2H)，1.7(m，1H)，1.8(m，1H)，1.9(s，3H，CH 3COOH)，2.4(t，2H)，6.45(d，1H)，6.95(s，1H)，7.1(d，1H)，7.75(s，1H)，9.9(s，1H，CH 3COOH)。
LC-MS (ESI): 14.2 minutes 99.1 (%), m/z 267[MH +].
Step (b)
8 '-chloro-5 '-the hydroxyl volution [hexanaphthene-1,4 '-quinazoline]-2 ' (1 ' H)-ketone
At room temperature, (330g is 1.24mol) acetone (730mL) pulp 6 days with the acetic acid solvent thing of step (a).Then, product by filter collecting, is adopted washing with acetone, then 60 ℃ dry 18 days down, obtain white solid non-solvent title compound (238g, 0.89mol, 72%).
1H-NMR(D 6-DMSO，300MHz)：d 1.2(m，1H)，1.4(m，2H)，1.5(m，1H)，1.6(m，2H)，1.7(m，1H)，1.8(m，1H)，2.4(t，2H)，6.45(d，1H)，6.95(s，1H)，7.1(d，1H)，7.75(s，1H)。

Claims (19)

1. formula (I) compound:
Wherein,
M is 0,1 or 2;
X is O, S or N-CN;
R is F, Cl or CN;
A is C 3-6Cycloalkylidene, optional by C 1-4Alkyl replaces; And
B is singly-bound or C 1-2Alkylidene group;
The perhaps pharmaceutically-acceptable salts of described compound, solvate, polymorphic form or prodrug.
2. compound as claimed in claim 1, wherein, m is 1.
3. as claim 1 or the described compound of claim 2, wherein, X is O.
4. as any described compound in the claim 1 to 3, wherein, R is Cl.
5. as any described compound in the claim 1 to 4, wherein, A is inferior cyclobutyl.
6. compound as claimed in claim 5, wherein, A is 1, the inferior cyclobutyl of 3-.
7. compound as claimed in claim 6, wherein, A is an anti-form-1, the inferior cyclobutyl of 3-.
8. as any described compound in the claim 1 to 7, wherein, B is a singly-bound.
9. compound, described compound is selected from:
Cis-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
3-[(8 '-fluoro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen methyl] cyclobutane-carboxylic acid;
Trans-3-[(8 '-cyano group-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
1-[(8 '-fluoro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [hexanaphthene-1,4 '-quinazoline]-5 '-yl) oxygen methyl] cyclobutane-carboxylic acid;
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [suberyl-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
Trans-3-[(8 '-chloro-2 '-oxo-2 ', 3 '-dihydro-1 ' H-volution [pentamethylene-1,4 '-quinazoline]-5 '-yl) oxygen] cyclobutane-carboxylic acid;
Or its pharmaceutically-acceptable salts, solvate, polymorphic form or prodrug.
10. pharmaceutical compositions, described composition comprises any described compound or its pharmaceutically-acceptable salts, solvate, polymorphic form or prodrug and pharmaceutically acceptable supporting agent or thinner in the claim 1 to 9.
11. as medicine as any described compound or its pharmaceutically-acceptable salts, solvate, polymorphic form or prodrug in the claim 1 to 9.
12. be used for the treatment of purposes in medicine of its treatment disease relevant or illness in manufacturing with the PDE7 inhibitor as any described compound or its pharmaceutically-acceptable salts, solvate, polymorphic form or prodrug in the claim 1 to 9.
13. purposes as claimed in claim 12, wherein, described disease or illness be selected from pain, with T-cell associated diseases, autoimmune disorders, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, asthma, cancer, acquired immune deficiency syndrome (AIDS) (AIDS), transformation reactions or inflammatory bowel.
14. purposes as claimed in claim 13, wherein, described disease or illness are pain.
15. purposes as claimed in claim 14, wherein, described pain is neuropathic pain.
16. method that is used for the treatment of disease or illness, described disease or treatment of conditions are relevant with the PDE7 inhibitor, and described method comprises any described compound or its pharmaceutically-acceptable salts, solvate, polymorphic form or prodrug in the claim 1 to 9 of bestowing significant quantity.
17. method as claimed in claim 16, wherein, described disease or illness be selected from pain, with T-cell associated diseases, autoimmune disorders, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease, asthma, cancer, acquired immune deficiency syndrome (AIDS) (AIDS), transformation reactions or inflammatory bowel.
18. method as claimed in claim 17, wherein, described disease or illness are pain.
19. method as claimed in claim 18, wherein, described pain is neuropathic pain.
CNA200680045333XA 2005-12-02 2006-11-23 Spirocyclic derivatives Pending CN101321738A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068394A (en) * 2010-04-15 2013-04-24 皇家学习促进学会/麦吉尔大学 Topical treatments for pain
CN107903161A (en) * 2017-11-23 2018-04-13 上海毕路得医药科技有限公司 A kind of synthetic method of cis 3 hydroxycyclobutyl formic acid
CN108129288A (en) * 2017-12-27 2018-06-08 上海毕得医药科技有限公司 A kind of synthetic method of trans- -3- hydroxycyclobutyls formic acid

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068394A (en) * 2010-04-15 2013-04-24 皇家学习促进学会/麦吉尔大学 Topical treatments for pain
CN107903161A (en) * 2017-11-23 2018-04-13 上海毕路得医药科技有限公司 A kind of synthetic method of cis 3 hydroxycyclobutyl formic acid
CN108129288A (en) * 2017-12-27 2018-06-08 上海毕得医药科技有限公司 A kind of synthetic method of trans- -3- hydroxycyclobutyls formic acid

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