CN1285828A - Imidazoylalkyl substituted with a five, six or seven membered heterocyclic ring containing one nitrogen atom - Google Patents

Abstract

Disclosed are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof. Also disclosed are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a Compound of Formula (I). Further disclosed is a method of treating allergy (for example asthma), inflammation, hypotension, raised intraocular pressure (such as glaucoma) i.e., a method of lowering intraocular pressure, sleeping disorders, states of hyper and hypo motility and acidic secretion of the gastrointestinal tract, hypo and hyperactivity of the central nervous system (for example, agitation and depression) and other CNS disorders (such as Alzheimer's, Schizophrenia, obesity and migraine) comprising administering an effective amount of a compound of Formula (I) to a patient in need of such treatment. Also disclosed are methods for treatment of upper airway allergic responses comprising administering a compound, or salt or solvate thereof, of Formula (I) in combination or admixture with a histamine H1 receptor antagonist.

Description

The imidazolyl alkyl that is contained five, six or the seven membered heterocyclic replacement of a nitrogen-atoms

Background

H ₃Acceptor site it is known to the person skilled in the art that and be that their institute is interested at present that for example referring to West, people such as Jr. are " with H in the mouse brain ₃Histamine Receptors bonded (R)-α-[ ³H] the second power kinetics of methylhistamine ", " neurochemistry " (Journal ofNeuochemistry), the 55th volume the 5th phase 1612-1616 page or leaf, 1990; West, people such as Jr. " two kinds of H ₃The evaluation of-Histamine Receptors hypotype ", " molecular medicine " (MolecularPharmacology), 38:610-613; With people " H in the cavy such as Korte ₃The N of Histamine Receptors ^aThe sign of-methylhistamine and tissue distribution ", " biological chemistry and biophysical studies communication " (Biochemical and Biophysical Research Communications), the 168th volume the 3rd phase 979-986 page or leaf.

People such as Arrang disclose a kind of pharmaceutical composition that contains the following formula histamine derivatives in US4767778 (on August 30th, 1988 is open): R wherein ₁, R ₂And R ₄Represent hydrogen or methyl separately, perhaps R ₁And R ₂Represent methylene radical together, and R ₃Be hydrogen, methyl or carboxyl, condition is R ₁, R ₂, R ₃And R ₄Be not methyl simultaneously.Now disclose this derivative and be equivalent to H in the mouse brain ₃The complete agonist of acceptor, and produce and to be equal to histamine institute inductive and to discharge maximum restraining effect (about 60%).Histamine derivatives is also disclosed by optionally stimulating H ₃Acceptor suppresses the release of histamine consumingly and synthesizes.Therefore according to people's such as Arrang discovery, this derivative be it seems the transmission that can reduce histamine in digestive tube and neural, cardiovascular and the immunity system.People such as Arrang disclose this derivative and can treat as the medicine with sedation effect, sleep conditioning agent, anticonvulsive agent, hypothalmic-hypophyseal secretion conditioning agent, antidepressive and brain circulation conditioning agent.According to people's such as Arrang discovery, being expected at the inhibition that the inflammation courier discharges under the various allergy symptoms (for example asthma) is because the H of lung ₃The stimulation of acceptor causes.Also disclose the release that suppresses the stomach histamine and may produce secretion inhibitor and antiulcer effect.According to people's such as Arrang research, immune response courier's release changes may regulate immune response.

The Derwent summary 86-273706/42 of EP0197840 discloses the imdazole derivatives shown in the following formula: R wherein ₁Be H, methyl or ethyl; R is H or R ₂R ₂Be 1-6C alkyl, piperonyl, 3-(benzimidazolone-1-yl) propyl group ,-CZ-NHR ₅Or group (ⅰ):

Wherein n is 0-3; X is key, O, S, NH, CO, CH=CH or a group (ⅱ):

R ₃Be H, methyl, halogen, CN, CF ₃Or COR ₄R ₄Be 1-6C alkyl, 3-6C cycloalkyl or phenyl (can be replaced arbitrarily) by methyl or F; Z is O, S, NH, N-methyl or N-CN; And R ₅Be 1-8C alkyl, 3-6C cycloalkyl (can be replaced arbitrarily), 3-6C cycloalkyl (1-3C) alkyl by phenyl, phenyl (can be by methyl, halogen or CF ₃Replacement arbitrarily), phenyl (1-3C) alkyl, naphthyl, golden steel alkyl or p-toluenesulfonyl.Disclosing these compounds is antipsychotic medicines.Also disclosing these compounds can the antagonism histamine H ₃Acceptor also improves the renewal speed of brain histamine.

2-or 4-(2-(1H-imidazoles-1-yl) ethyl) piperidine compounds are disclosed among the Derwent summary 90-184730/24 of US4925851 as suppressing lymphoma, sarcoma, myelomatosis and leukemic antineoplastic agent.This compound has following general formula: Wherein R is-CH ₂(CH ₂) _m-Me ,-CO-(CH ₂) _m-Me or-CO-CMe ₂-R ₂M is 2-18; R ₂Be H or methyl; R ₁Be-(CH ₂) _n-R ₃N is 0-13; R ₃Be H, sec.-propyl or the tertiary butyl; Indefinite group is in 2-or 4-position; Condition is (1) R ₁Middle the total number of carbon atoms is no more than 13; (2) R and R ₁Middle the total number of carbon atoms is no more than 25.

On June 24th, 1993, disclosed WO93/12107 disclosed following formula: compound: Or acceptable salt or solvate on its pharmacology, wherein:

(A) m is selected from 1 and 2 integer;

(B) n and p are integers, are selected from 0,1,2,3 and 4 respectively separately, make that n and p sum are 4, and T is 6 yuan of rings;

(C) R ³And R ⁴Be connected with identical or different carbon atom in the T ring separately respectively, make and have only a R in the T ring ³Group and a R ⁴Group, and R ¹, R ², R ³And R ⁴Be selected from separately respectively:

(1)H；

(2) C ₁-C ₆Alkyl; With

(3)-(CH ₂) _q-R ⁶, wherein q is the integer of 1-7, R ⁶Be selected from phenyl, replacement phenyl ,-OR ⁷,-C (O) OR ⁷,-C (O) R ⁷,-O (C) OR ⁷,-C (O) NR ⁷R ⁸, CN and-SR ⁷, R wherein ⁷And R ⁸Being defined as follows, the substituting group in the phenyl of described replacement is selected from respectively-OH ,-O-(C ₁-C ₆) alkyl, halogen, C ₁-C ₆Alkyl ,-CF ₃,-CN and-NO ₂, the phenyl of wherein said replacement contains 1-3 substituting group;

(D) R ⁵Be selected from:

(1)H；

(2) C ₁-C ₂₀Alkyl;

(3) C ₃-C ₆Cycloalkyl;

(4)-C (O) OR ⁷R wherein ^{7 '}With the R that defines below ⁷Identical, be R ^{7 '}Not H;

(5)-C(O)R ⁷；

(6)-C(O)NR ⁷R ⁸；

(7) allyl group;

(8) propargyl; With

(9)-(CH ₂) _q-R ⁶, wherein q and R ⁶Define the same, when q equals 1, R ⁶Not OH or SH;

(E) R ⁷And R ⁸Be selected from H, C respectively separately ₁-C ₆Alkyl and C ₃-C ₆Cycloalkyl;

(F) dotted line (---) expression when m be 1, n is not 0, p is not 0 o'clock two key that can exist arbitrarily, and if described couple of key existence, then R ²Do not exist; And

(G) when m is 2, for each m, each R ¹Be identical or different substituting group, each R ²Be identical or different substituting group, R ¹And/or R ²In at least two substituting groups are H.

The application that what is claimed is this compounds for treating transformation reactions and other disorders of the two pieces of documents in back.

EP0428434A2 and WO96/29315 and WO95/06037 have described chemical compound lot, and what is claimed is them as H ₃The application of acceptor (antagonist) agonist.Above-mentioned document has also comprised the summary relevant with this chemical field.

The U. S. application 08/909319 of the U. S. application 08/689951 of application on August 16th, 1996 and application on August 14th, 1997 discloses and has used at least a histamine H ₁Receptor antagonist and at least a histamine H ₃Receptor antagonist combines and treats the composition of rhinallergosis.

Consider that this area is for influencing H ₃The interest of the compound of acceptor is to H ₃Acceptor has the active new compound of antagonism to make rather well received contribution to this area.The present invention has H by providing just ₃Resist active new compound and made such contribution.

Summary of the invention

The present invention relates to formula I compound

Or acceptable salt or solvate on its pharmacology, wherein:

X is the alkenyl or alkynyl that contains the straight chained alkyl of 1-7 carbon atom or contain 2-4 carbon atom; Wherein said alkyl or alkenyl can be by 2 at the most (promptly 1 or 2) R ⁷Group replaces arbitrarily;

N is 0,1 or 2,

M and p are 0-4;

When m was 0-4, Y represented-SO ₂-;-CS-;-CO-;-CONR ⁵-;-CO (CH ₂) _wO-(wherein w is 1-4);-COO-;-CON (OR ⁵)-;-C (NR ⁵) NR ⁵-;-SO ₂NR ⁵-or-CSNR ⁵-;

When m was 2-4, Y represented above-mentioned all groups, and in addition, when m was 0-4, Y represented-CHOR ⁵-;-O-;-NR ⁵CONR ⁵-;-NR ⁵CO-;-MR ⁵-;-OCONR ⁵-;-NR ⁵C (NR ⁵) NR ⁵-;-NR ⁵CSNR ⁵-;-NR ⁵CS-or-NR ⁵SO ₂-;-NR ⁵C (O) O-; Or-CSNR ⁵-;

Each R ⁵Independent expression hydrogen, alkyl or benzyl;

R ⁶Contain 1-3 the first heterocycle of heteroatomic 3-7 in expression aryl, heteroaryl or the ring, wherein heteroatoms is selected from N, S and O, wherein said R ⁶Group can be replaced arbitrarily as the substituting group of giving a definition by 1-3;

When Y is-SO ₂-, R except above-mentioned group so ⁶Also the expression contain 1-7 carbon atom alkyl or-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Be selected from H, alkyl or trihalomethyl group respectively;

Each R ¹Independent is hydrogen, alkyl or trihalomethyl group;

Each R ⁷Independently be selected from hydrogen, alkyl, trihalomethyl group, phenyl or benzyl, wherein said phenyl and benzyl can be selected from alkyl, halogen, trihalomethyl group, CN, NO respectively by 1-3 ₂, OR ¹⁰Or NR ¹⁰R ¹¹Substituting group replace R wherein arbitrarily ¹⁰And R ¹¹Define the same.

The present invention also provides the pharmaceutical composition that comprises acceptable carrying agent and significant quantity formula I compound (or its salt or solvate) on the pharmacology.

The present invention also provides treatment transformation reactions (for example asthma), inflammation, cardiovascular diseases, ypotension, intraocular pressure (the glaucoma for example that raises, promptly reduce the method for intraocular pressure), dyssomnias (hypersomnia for example, lethargy, hypnolepsy and insomnia, as insomnia), gastrointestinal tract disease, the gi tract motility is crossed state strong and that motility weakens and acidic secretion is strong excessively, central nervous system disorder, nervus centralis hypo and hyperactivity (for example exciting and depressed) and other CNS disorders (Alzheimer's for example, schizophrenia, obesity and migraine) method, comprise that the patient to this treatment of needs uses the formula I compound of significant quantity, its salt or solvate.

The present invention also provides the method for treatment upper airway allergic responses, comprises formula I compound or its salt or the solvate of using significant quantity, and combination or mixing appropriate H ₁Receptor antagonist.

The detailed description of invention

Except as otherwise noted, term definition used herein is as follows:

Alkyl-expression contains the saturated hydrocarbon chain of the straight or branched of 1-6 carbon atom;

Low alkyl group (moieties that comprises lower alkoxy)-expression contains the saturated hydrocarbon chain of the straight or branched of 1-6 carbon atom, preferred 1-4 carbon atom;

Cycloalkyl-expression contains the saturated carbon ring of 3-6 carbon atom, can be selected from low alkyl group, trihalomethyl group and NR respectively by 1-3 ¹⁰R ¹¹Substituting group replace R wherein arbitrarily ¹⁰And R ¹¹Define the same;

Halogen-expression fluorine, chlorine, bromine or iodine;

Aryl-expression contains the carbon ring group of 6-14 carbon atom and at least one class phenyl ring, all commutable aromatic carbon atoms all may be as tie point on the carbon ring group, makes described carbon ring group be selected from following group separately by 1-3 and replaces arbitrarily: halogen, alkyl, hydroxyl, phenoxy group, amino, low-grade alkyl amino, two elementary alkyl amido (NR for example ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Be selected from hydrogen, low alkyl group or trihalomethyl group respectively), lower alkoxy, many halogenated lower alkoxies (OR for example ¹⁰, R wherein ¹⁰As defined above), many junior alkyl halides (for example trihalomethyl group), CN or NO ₂Preferred aryl groups comprises 1-naphthyl, 2-naphthyl and 2,3-indanyl, the phenyl of preferred especially phenyl and replacement;

Heterocycle-expression has at least one O, S and/or N atom to cut off the saturated and undersaturated non-aromatic ring organic group of carbocyclic ring structure, wherein the carbocyclic ring structure is made up of a ring or two condensed ring, each ring is 3-7 unit's ring (for example 5,6 or 7 yuan of rings), and wherein ring structure contains 2-8, preferred 3-6 carbon atom; For example 2-or 3-pyrrolidyl, 2-, 3-or 4-piperidyl, 2-or 3-piperazinyl, 2-or morpholinyl, or 2-or 3-thio-morpholinyl; Described heterocyclic group can be selected from alkyl, trihalomethyl group and NR respectively by 1-3 ¹⁰R ¹¹Group replaces arbitrarily, wherein R ¹⁰And R ¹¹Be selected from hydrogen, alkyl or trihalomethyl group respectively, described substituting group is gone up with ring and being connected of carbon atom (commutable carbon atom) will be made the substitution in ring base add up to 1-3; Contain nitrogen-atoms in the wherein said heterocycle, described nitrogen-atoms (nitrogen-atoms that can replace) can be replaced arbitrarily by low alkyl group (for example methyl), for example N-methylpyrrole alkyl;

Heteroaryl-expression have at least one O, S and/or N atom to cut off the carbocyclic ring structure and delocalized with sufficient amount so that the cyclic organic group of fragrance characters to be provided, wherein aromatic heterocycle contains 2-14, preferred 4-5 carbon atom, for example 2-, 3-or 4-pyridyl, 2-or 3-furyl, 2-or 3-thienyl, 2-, 4-or 5-thiazolyl, 2-or 4-imidazolyl, 2-, 4-or 5-pyrimidyl, 2-pyrazinyl or 3-or 4-pyridazinyl etc.; Preferred heteroaryl 2-, 3-or 4-pyridyl; Described heteroaryl can be replaced arbitrarily by 1-3 group, and each substituting group is selected from alkyl, halogen, trihalomethyl group, CN, NO respectively ₂, OR ¹⁰Or NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Be selected from hydrogen, alkyl or trihalomethyl group respectively, described substituting group is gone up with ring and being connected of carbon atom (commutable carbon atom) will be made the substitution in ring base add up to 1-3;

DMF-represents N, dinethylformamide;

SEM-represents 2-(trimethyl silyl) ethoxyl methyl;

THF-represents tetrahydrofuran (THF);

DMAP-represents dimethyl aminopyridine;

DIPA-represents diisopropylamine;

DMSO-represents methyl-sulphoxide;

DBU-represents the diazabicylo undecylene;

DBN-represents diazabicyclononane;

LAH-represents lithium aluminum hydride;

FAB-represents fast atom bombardment;

CI-represents chemical dissociation;

EI-represents electronic impact;

HOBT-represents I-hydroxybenzotriazole;

EDCI-represents 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride;

LC/MS-represents liquid chromatography/mass spectrometry;

TFA-represents trifluoroacetic acid;

Tr-represents trityl; With

LRMS-represents the low resolution mass spectrum.

Equally, except as otherwise noted, the substituting group in the different embodiments described below is suc as formula defining in the I.

Preferred compound is suc as formula shown in the II:

Wherein q is 1-7, and m is 0-4, and n is 0 or 1, and p is 0-4, and Y is selected from-SO ₂-,-SO ₂NH-,-CONH-,-CO-,-C (NH) NH-or-CO (CH ₂) _wO-, perhaps when m is 2-4, Y except representing above-mentioned group, also expression-NHCONH-,-O-or-NHC (NH) NH-; And w, R ¹, R ⁶And R ⁷Define the same.Preferred R ⁶It is the phenyl of phenyl or replacement.

Most preferred formula II compound, wherein (1) q is 1-4; (2) n is 0 or 1; (3) m is 0-4 (more preferably 0-3, more more preferably 0-2); (4) p is 0-2; (5) Y be-CONH-,-CO-,-SO ₂-,-CO (CH ₂) ₂O-or-O-(when m more than or equal to 2, promptly when m is 2-4 Y also can be-O-); (6) R ⁶Be phenyl, wherein said phenyl can by one, two or three are selected from halogen, preferred fluorine or chlorine, CF respectively ₃, C ₁-C ₄Alkoxyl group, OCF ₃, NO ₂Or NR ¹⁰R ¹¹Group replace R wherein arbitrarily ¹⁰And R ¹¹Define the same.

For formula II compound, R ¹And R ⁷Hydrogen preferably.

For formula II compound, preferably work as R ⁶When being mono-substituted phenyl, described substituting group is in 3-or 4-position, and described substituting group is selected from fluorine, chlorine, methoxyl group or trifluoromethoxy; Work as R ⁶When being dibasic phenyl, described substituting group is 3, the 5-position, and described substituting group is identical and be selected from fluorine, chlorine, methoxyl group or trifluoromethoxy.

Compound of the present invention includes, but are not limited to: Compound of the present invention also includes, but are not limited to:

Some compound of the present invention can exist with different isomerization bodily form formula (for example enantiomer and diastereomer).The present invention comprises all these with isomer pure or form of mixtures, comprises racemic mixture.Also comprise the enol form.

Formula I compound can exist with non-solvent form and solvation form, comprises hydrated form, for example semihydrate.Usually, contain acceptable solvent on the pharmacology, as water, ethanol etc., these solvation forms are equal to non-solvent form of the present invention.

Some basic cpd of the present invention also can form acceptable salt, for example acid salt on the pharmacology.For example nitrogen-atoms can form salt with acid.The example of suitable salifiable acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, propanedioic acid, Whitfield's ointment, oxysuccinic acid, fumaric acid, succsinic acid, xitix, toxilic acid, methylsulfonic acid and other mineral acid well known to those skilled in the art and carboxylic acid.According to the conventional method with the sour contact preparation salify of free alkali and q.s.By with the suitable diluted alkaline aqueous solution, handle salt regeneration free alkali as dilute sodium hydroxide, salt of wormwood, bicarbonate of ammonia and sodium bicarbonate aqueous solution.

How many free alkali forms is being different from their corresponding salt forms aspect some physical property, the solvability in polar solvent for example, but different be that the salt of bronsted lowry acids and bases bronsted lowry then is equal to corresponding free alkali form in the object of the invention.

The salt of the bronsted lowry acids and bases bronsted lowry that all are such can be used as acceptable salt on the pharmacology within the scope of the invention, and the salt of all bronsted lowry acids and bases bronsted lowries can be regarded the free form that is equal to respective compound in the object of the invention as.

A large amount of chemical substances are known to have histamine H ₁Receptor antagonist activity.Many useful compounds can be categorized as thanomin, quadrol, alkylamine, thiodiphenylamine or piperidines.Representational H ₁Receptor antagonist includes, but are not limited to: astemizole (astemizole), azatadine, nitrogen _ Si Ting (azelastine), acrivastine (acrivastine), Parabromdylamine, cetirizine (cetirizine), chlorphenamine, clemastine, marezine, carebastine (carebastine), Cyproheptadine, carbinoxamine, remove carbonyl oxyethyl group Loratadine (descarboethoxyloratadine) (being also referred to as SCH-34117), diphenhydramine, doxylamine, Dimetindene, ebastine (ebastine), epinastine (epinastine), according to Cyanuric trifluoride (efletrizine), Fei Suofeilading (fexofenadine), hydroxyzine, ketotifen, Loratadine (loratadine), levocabastine (levocabastine), mizolastine (mizolastine), mequitazine, mianserin, R 64947 (noberastine), Meclozine, Nola's Si imidazoles (norastemizole), picumast (picumast), Pyrilamine, promethazine, terfenadine, tripelennamine, temelastine (temelastine), Trimeprazine and triprolidine.Other compounds can be measured it at H by known method at an easy rate ₁Activity in the acceptor comprises the specific blocking-up to the contractile response of isolated guinea pig ileum histamine.For example referring to disclosed WO98/06394 on February 19th, 1998.

For example, H of the present invention ₃Antagonist can be selected from following H ₁Antagonist combination: astemizole (astemizole), azatadine, nitrogen _ Si Ting (azelastine), Parabromdylamine, cetirizine (cetirizine), chlorphenamine, clemastine, carebastine (carebastine), remove carbonyl oxyethyl group Loratadine (descarboethoxyloratadine) (being also referred to as SCH-34117), diphenhydramine, doxylamine, ebastine (ebastine), epinastine (epinastine), Fei Suofeilading (fexofenadine), Loratadine (loratadine), levocabastine (levocabastine), mizolastine (mizolastine), Nola's Si imidazoles (norastemizole) or terfenadine.

H equally, for example of the present invention ₃Antagonist can be selected from following H ₁Antagonist combination: azatadine, Parabromdylamine, cetirizine (cetirizine), chlorphenamine, carebastine (carebastine), remove carbonyl oxyethyl group Loratadine (descarboethoxyloratadine) (being also referred to as SCH-34117), diphenhydramine, ebastine (ebastine), Fei Suofeilading (fexofenadine), Loratadine (loratadine) or Nola's Si imidazoles (norastemizole).

Representational combination comprises: H of the present invention ₃Antagonist and Loratadine (loratadine), H of the present invention ₃Antagonist with remove carbonyl oxyethyl group Loratadine (descarboethoxyloratadine), H of the present invention ₃Antagonist and Fei Suofeilading (fexofenadine) and H of the present invention ₃Antagonist and cetirizine (cetirizine).

One skilled in the art will know that what is called " upper respiratory tract " is meant top respiratory system-be nose, throat and dependency structure.

Compound of the present invention can known suitable method be prepared in the similar compound field according to preparing, the method described in for example above-mentioned document.

Can adopt preparation in the following method.Except as otherwise noted, be reflected at make under the suitable temperature reaction finish with rational speed.

General preparation route

Usually be prepared as follows compound of the present invention: the initial compounds that following general formula at first is provided: In next step, react then with following general formula compound:

L-(CH ₂) _m-Y-(CH ₂) _p-R ⁶Slough blocking group Z production I compound subsequently.

In above-mentioned general formula, R ¹, R ⁶, R ⁷, X, Y, m, n and p in the above-mentioned formula I definition.L represents activated form such as the OSO of leavings group such as Cl, Br, I and OH ₂CF ₃, independent separately formation or original position formation.

Following reaction scheme has been described each step of method therefor.

The preparation of piperidines (n=1)

Reaction scheme 1-X is-(CH ₂) _1-7Compound

Step 1

Compound 1 is dissolved in suitable solvent, for example in the methylene dichloride, and uses Grignard reagent; for example ethyl-magnesium-bromide is handled, and (1) D is a halogen in the compound 1, preferred iodine; (2) Z represents blocking group, for example trityl group, 2-(trimethyl silyl)-ethoxyl methyl etc. and (3) R ₁Can be hydrogen, alkyl or trihalomethyl group.Add suitable aldehyde 2 (M=(CH subsequently ₂) _0-6) generation compound 3.

Step 2

In step 2, compound 3 is dissolved in organic solvent, in methylene dichloride, uses tertiary amine base,, handle as dimethyl aminopyridine as triethylamine and acylation catalyst.Handle production 4 compounds with acetic anhydride subsequently.

Step 3

In step 3, compound 4 is dissolved in suitable organic acid, in acetate,, generate compound 5 as hydrogenation under the platinum oxide existence, under 16-60psi pressure in the suitable agent of urging.

Reaction scheme 2-X is-(CH ₂) ₂-compound

Step 1

In step 1; compound 1 is dissolved in suitable solvent or is selected from ethers and the mixed solvent of dialkylamine solvent; in preferred tetrahydrofuran (THF)/diisopropylamine; (1) D=halogen in the compound 1; preferred iodine; (2) Z represents blocking group, for example trityl group, 2-(trimethyl silyl)-ethoxyl methyl etc. and (3) R ²Represent the phenyl of benzyl or replacement.Adding formula 6 compounds add appropriate catalyst subsequently, as two (triphenylphosphine)-palladium chloride and cuprous iodides, stir under 21-60 ℃ temperature and generate compound 7.

Step 2

In step 2, compound 7 is dissolved in appropriate organic solvent, or in its mixture (example of solvent comprises methylene dichloride, methyl alcohol and acetate) and under the pressure of 16-60psi, use catalyzer,, carry out hydrogenation and make compound 8 as palladium or palladium hydroxide.

Step 3

In step 3, compound 8 is dissolved in suitable alcohol, in methyl alcohol, and, under the pressure of 16-60psi, use catalyzer with several hydrochloric acid (1M) processing, as palladium or palladium hydroxide, carry out hydrogenation and make compound 5A.

The preparation of reaction scheme 3-compound 10

(wherein R is group-(CH ₂) _m-Y-(CH ₂) _p-R ⁶).

Those skilled in the art will recognize that HCl molecule number (r) depends on the number of the base groups that exists in the compound 10.

With compound 5 and L-(CH ₂) _m-Y-(CH ₂) _p-R ⁶Reacting generating compound 9.L is a leavings group, as the activated form of Cl, Br, I and OH, as the OSO that generates separately or on the spot ₂CF ₃When Y be-C (O) NH-,-OCO and-SO ₂-and m be 2 o'clock, compound 5 and reagent are as (CH ₂=CH) C (O) O (CH ₂) _pR ⁶, (CH ₂=CH) C (O) NR ⁵(CH ₂) _pR ⁶(CH ₂=CH) SO ₂(CH ₂) _pR ⁶Reaction.

Be reflected at-temperature of 78-200 ℃ under, at suitable solvent, as carrying out in ether, tetrahydrofuran (THF), diox, methyl-sulphoxide, dimethyl formamide, water, methylene dichloride and the toluene, wherein contain or do not contain suitable alkali, as triethylamine, diisopropylaminoethyl lithium or sodium hydride.

When Z is trityl group, under about 25-100 ℃ temperature,, handle as the dilute solution of HCl or HBr with acid, with compound 9 deprotections, generate compound 10.Other blocking group is removed by method well known in the art.

Contain 7 yuan of heterocyclic compound

Reaction scheme 4-X is-CH ₂-compound

Step 1

In step 1, in the presence of the organic bases, under 0 ℃-Yue 50 ℃ temperature, in appropriate organic solvent, with compound 11 (according to being similar to European J.Med.Chem.1979,14,157-164 and Tetrahedron Letts.1990,31, the method preparation of listing among the 933-936) with the reaction of ZCl compound, generates compound 12.Z represents blocking group, is preferably carbobenzoxy.Suitable solvent comprises THF, ether Huo diox etc.Suitable alkali comprises triethylamine etc.

Step 2

In step 2, under 0-100 ℃ temperature, in appropriate organic solvent, in THF, ether Huo diox etc., use appropriate reductant, as BH ₃SMe ₂Deng, compound 12 is reduced into aldehyde 13.

Step 3

In step 3,, compound 13 and the Grignard reagent reaction that is formed by the iodo imidazoles are obtained alcohol 14 according to the same quadrat method in reaction scheme 1 step 1.

Step 4

In step 4,, use H under 25-75 ℃ the temperature, in the presence of metal catalyst and trace acid ₂In suitable polar organic solvent, compound 14 is reduced to compound 15.Suitable solvent comprises MeOH, EtOH and i-PrOH, preferred EtOH, and catalyzer comprises Pd/C or PtO ₂Deng.

Step 5

In step 5, under 0-100 ℃, preferred 25 ℃ temperature, in suitable tertiary amine base, exist down, and, in THF or ether etc.,, generate compound 16 compound 15 and LR reaction at suitable solvent as triethylamine.R is-(CH ₂) _m-Y-(CH ₂) _p-R ⁶, L is as defined leavings group in the top reaction scheme 3.

Step 6

Carry out step 6 according to the method that is similar in top reaction scheme 3 deprotection steps, make compound 17.

Reaction scheme 5-X is-(CH ₂) ₂-

Step 1

In step 1, under-25-80 ℃ temperature, in the presence of highly basic, aldehyde 13 and Wittig reagent are reacted in suitable ether solvents, make compound 19.Suitable solvent comprises THF, ether Huo diox etc.Highly basic comprises diisopropylaminoethyl lithium or potassium or two (trimethyl silyl)-lithium amide, sodium or potassium etc.Other suitable alkali is included in the suitable polarity aprotonic solvent, as NaH among the DMSO or KH.

Step 2

In step 2, under the about 80 ℃ temperature of 0-,, handle as HCl or HBr by using diluted mineral acid, enol ether is hydrolyzed into aldehyde 20.According to being similar to the method described in the reaction scheme 4 step 3-6, aldehyde 20 can be converted into target compound then.

Reaction scheme 6-X is-(CH ₂) ₃-to-(CH ₂) ₇-

Aldehyde 20 can be converted into aldehyde 21 according to being similar to the method described in the reaction scheme 5.According to being similar to the method described in the reaction scheme 4 step 3-6, compound 21 is converted into target compound then.Similarly reaction sequence can be applied in compound 22 and the higher homologue.

The preparation of tetramethyleneimine (n=0)

Reaction scheme 7

Step 1 Wherein n is 0-5, R ¹⁴Represent low alkyl group (for example methyl or ethyl).

In step 1, at suitable ether solvents, in THF, ether Huo diox etc., use highly basic, handle appropriate H orner-Emmons reagent as NaH, KH or diisopropylaminoethyl lithium etc., as trimethylammonium or triethyl phosphine acyl acetic acid ester.Phosphonic acid ester carbanion and aldehyde 23 reactions were obtained ester 24 in 30 minutes-24 hours being fit to finish under the temperature of reaction then.

Step 2

In step 2, under 0-80 ℃, preferred 25 ℃ temperature, at amine alkali, exist down as DBU, DBN or triethylamine etc., preferred DBU, at polar aprotic solvent, in acetonitrile or THF etc., with ester 24 and replacement or unsubstituted nitro-paraffin, reacted 24 hours as Nitromethane 99Min. or nitroethane, generate nitro ester 25.

Step 3

In step 3, under 25-80 ℃ temperature,, in methyl alcohol or ethanol etc., use hydrogen and suitable metal catalyst at suitable polar solvent, as Pd/C or Ra-Ni etc., the nitroreduction in the nitro ester 25 is become amine.With the amino ester that obtains in small amount of alkali, as existence such as salt of wormwood down, under 80 ℃ temperature at the most and in suitable polar solvent, be heated into ring, form lactan, make compound 26.

Step 4

In step 4, under 0-80 ℃, preferred 60 ℃ temperature, with compound 26 and appropriate reductant such as LAH or BH ₃Deng, preferred LAH,,, make compound 27 as reaction in THF, the ether Huo diox etc. 30 minutes-24 hours, preferred 3 hours at suitable solvent.

Be L-(CH with compound 27 with general formula then ₂) _m-Y-(CH ₂) _p-R ⁶Compound reaction, carry out deprotection according to the method for listing in the reaction 3 above being similar to subsequently and handle.

Initial compounds formula 23 is compound known, perhaps can obtain according to method well known in the art, for example is prepared by the step for preparing in top compound 13,20 and 22.

Those skilled in the art are very easy to find aforesaid method can several changes.For example, substituent R ¹And R ⁷May reside in the raw material, or can in any step easily of this method, import.

The following examples are used for setting forth but do not limit the present invention.

Embodiment 1

Steps A

Under-78 ℃ to contain oxalyl chloride (13.8g, 9.5ml, drip in methylene dichloride 109mmols) (300ml) the liquid flask DMSO (19.9g, 255mmols).After gas stops to emit, mixture was stirred 8 minutes, add then and contain alcohol 28 (10.0g, methylene dichloride 27.2mmols) (50ml) solution.Be reflected at-78 ℃ and kept 50 minutes down, (45ml 255mmol), was heated to room temperature with 45 minutes with reaction to add triethylamine.Reactant NH ₄The Cl solution dilution, and use dichloromethane extraction.The organic phase salt water washing that merges, MgSO ₄Drying is filtered and is concentrated.With crude product by silica gel (methylene dichloride that contains 10-30%) chromatogram make light yellow oily product 29 (7.7g, 77%): LRMS (Cl, M+H)=367.

(95%, 2.0g adds anhydrous THF (600ml) in flask 79mmol) to containing NaH under nitrogen atmosphere.By syringe in this mixture, drip trimethyl phosphono acetate (14.0g, 77.5mmols).Observe gas and emit, and obtain the heavy-gravity white mixture.With 30 minutes this mixture is warming up to 35 ℃, and then is cooled to room temperature.(14.5g, anhydrous THF (200ml) 39.6mmols) joins in the reaction mixture will to contain aldehyde 29 by syringe.TLC (40%EtOAc-Hex) shows that stirring 45 minutes afterreactions under the room temperature finishes.Contain water section with the reactant dilute with water and with the EtOAc extraction.The organic phase salt water washing that merges, MgSO ₄Drying is filtered and is concentrated and obtains solid, with this solid at Et ₂(1: recrystallization obtains the 5.9g pure substance to the O-hexane 2v/v).With mother liquor by silica gel (the 40%EtOAc-hexane---＞60%EtOAc) chromatogram obtains the 7.7g material again, productive rate amounts to 81%.LRMS (Cl, M+H)=423.C ₂₈H ₂₆N ₂O ₂The CHN ultimate analysis: C, 79.25; H, 6.22; N, 6.60: measured value C, 79.11; H, 6.39; N, 6.66.Fusing point=129-130.5 ℃.

Step B

Contain compound 30 (11.0g, CH 26.1mmols) ₃Add CH in the CN solution (300ml) ₃NO ₂(29.3g, 26ml, 480mmols), add subsequently DBU (5.1g, 5.0ml, 33.4mmols).Reaction mixture stirred in nitrogen atmosphere 18 hours, did not observe raw material by TLC (40%EtOAc-Hex) thereafter.Decompression is evaporating solvent down, and directly (50%EtOAc-Hex---＞70%EtOAc) chromatography obtains 13.1g (thick productive rate＞100%) colorless oil product by silica gel with resistates.LRMS(Cl，M+H)=484。CHN ultimate analysis (C ₂₉H ₂₉N ₃O ₄): C, 72.03; H, 6.04; N, 8.69: measured value C, 72.06; H, 6.34; N, 8.66.Fusing point=97.5-99.5 ℃.

Step C

(2 * 5g, (60-20 is v/v) in the solution 20.7mmols) to be dissolved in anhydrous EtOH-THF with compound 31.Add Ra-Ni (～2 * 5g) and the Parr container is forced into 50psi with hydrogen.After rocking 4-6 hour, TLC demonstration reduction generates the reaction of amino ester and finishes (10%MeOH-EtOAc).Remove catalyzer by diatomite filtration.Decompression evaporation down obtains the amino ester intermediate, subsequently by containing a small amount of K ₂CO ₃MeOH in reflux and to become ring to generate lactan in 3 hours.Remove by filter K ₂CO ₃And evaporating solvent obtains oily matter, then by silica gel (10%MeOH-CH ₂Cl ₂The 10%MeOH+2%NH of---＞ ₄OH) chromatography obtains 8.1g (92%) product, is the canescence amorphous solid.LRMS(Cl，M+H)=422。CHN ultimate analysis (C ₂₈H ₂₇N ₃O * 1.5 mole H ₂O): C, 74.91; H, 6.57; N, 9.36: measured value C, 74.76; H, 6.17; N, 9.14.Fusing point=171-173.5 ℃.

Step D

In THF (12ml) solution that contains LAH (180mg, 4.80mmols, 10 equivalents), add the THF solution that contains compound 32 under the room temperature.With 3 hours with mixture heating up to 60 ℃, be cooled to room temperature then.Reaction is by adding solid Na ₂SO ₄* 10H ₂The O quenching.Add after 20 minutes 5%NaOH (～1ml) make the heavy-gravity gray mixture become colorless and homogeneous phase.After spending 20 minutes again, mixture is by diatomite filtration, and filter cake washs with THF and MeOH.Decompression is concentrate eluant down, then by silica gel chromatography (10%MeOH-CH ₂Cl ₂The 10%MeOH+2%NH of---＞ ₄OH) obtain 168mg (73%) product 33, be moistening foam.LRMS(Cl，M+H)=408。

Step e

Under the room temperature to containing compound (+/-) 33 (315mg, CH 0.774mmols) ₂Cl ₂Add Et in the solution (6ml) ₃N (2ml, 14.4mmols), add subsequently to the chlorine SULPHURYL CHLORIDE (215mg, 1.09mmols).Mixture stirred in nitrogen atmosphere 21 hours, was evaporated to 1/2 volume then, and by silica gel chromatography (1%MeOH-CH ₂Cl ₂---＞3%MeOH) obtains amorphous white solid.Obtain fluffy white foam shape thing with hexane-acetone development evaporation subsequently.LRMS (Cl, M+H)=582 shape thing.

Step F

Compound 34 is carried out standard HCl deprotection reaction, obtain the hydrochloride of compound 35, be the light tan solid.LRMS(Cl，M+H)=340。

Embodiment 1A: chirality is synthetic

Steps A

In the Parr electromagnetic shaker, will contain ethanol (20ml) solution of 36 (2.0g) and 10%Pd/C (0.3g) hydrogenation 24 hours under 60psi.Evaporated filtrate under filtering catalyst also reduces pressure then.The oil of remnants is dissolved in the methylene dichloride (20ml).In this solution, add two dimethyl dicarbonate butyl esters (2g), add 4-dimethyl-aminopyridine (0.05g) then.Reaction mixture stirred 1 hour down at 70 ℃, then reduction vaporization.Then with product by quick silica gel (50ml) chromatogram.With 8% methyl alcohol-methylene dichloride wash-out, and reduction vaporization obtains colorless oil title compound 37 (1.1g), MS (Cl) m/e=146 (M-56).

Step B

Cooling contains the dichloromethane solution of compound 37 (1.1g) and triethylamine (0.84ml) in ice bath, and under agitation drips methylene dichloride (5ml) solution that contains methylsulfonyl chloride (0.47ml).Reaction mixture stirs and washed with water then in 1 hour, filters with dried over sodium sulfate and by silica gel plug.Evaporated filtrate obtains methanesulfonates 37a, then it is dissolved in the acetone (30ml) that contains sodium iodide (1.6g).In oil bath (70 ℃), heating under the reaction mixture stirring was cooled off in 24 hours then.Remove by filter insoluble salt and decompression evaporated filtrate down.Be dissolved in bottom product in the methylene dichloride and wash with water, dried over sodium sulfate is also filtered by silica gel plug.Decompression evaporated filtrate down obtains oily title compound 38 (1.53g), MS (FAB) m/e 280 (MH) ⁺

Step C

The dimethyl formamide solution (10ml) that will contain compound 38 (1.53g) and triphenylphosphine (1.9g) in oil bath (90 ℃) heated 24 hours.Then decompression down evaporation reaction mixture and with bottom product by quick silica gel (50ml) chromatogram.Obtain the title compound 39 (1.56g) of white powder, MS (FAB) m/e=446 (M) with 10% methyl alcohol-methylene dichloride wash-out and reduction vaporization ⁺

Step D

Join in tetrahydrofuran (THF) (10ml) solution that contains compound 39 (1.0g) at-78 times hexane solutions (0.9ml) the 2.5M butyllithium.Then this solution was at room temperature stirred 30 minutes, the solution that forms is cooled to-78 ℃ again, add tetrahydrofuran (THF) (5ml) solution that contains aldehyde (0.38g) then.Filter reaction mixture and decompression be evaporated filtrate down.With the crude product that obtains by quick silica gel (50ml) chromatogram.With 5% methyl alcohol-methylene dichloride wash-out, obtain white powder title compound 40 (0.34g) behind the reduction vaporization, MS (FAB) m/e=264 (MH) ⁺

Step e

To contain compound 40 (0.32g) and contain ethanolic soln (5ml) hydrogenation under atmospheric pressure 24 hours of PtO (0.085g).Cross elimination catalyzer and decompression evaporated filtrate down then.The crude product that obtains is by quick silica gel (30ml) chromatogram.With 10% methyl alcohol-methylene dichloride wash-out and decompression evaporation down, obtain the gummy title compound 41 of resin (0.23g), MS (FAB) m/e=266 (MH) ⁺

Step F

With the middle stirring of compound 41 (0.1g) and 4M HCl Zai diox (2ml) 30 minutes, evaporation reaction mixture under the decompression then.Bottom product is dissolved in the methyl alcohol (2ml), and stirred solution adds Biorad AG 1-X8 (OH simultaneously ^-Form) ion exchange resin, until the pH of solution value more than 8.Remove by filter resin, evaporated filtrate obtains the gummy title compound 42 of resin (0.061g) then, MS (Cl) m/e=165 (MH) ⁺

Obtain the R-enantiomer according to similar method.

Embodiment 2

Steps A

Under the room temperature to contain the compound 33 that embodiment 1 step D obtains (600mg, add in MeOH solution 1.48mmols) methyl acrylate (0.300ml, 3.33mmols).Reaction mixture at room temperature stirred 2 hours, was heated to 60 ℃ then and spent the night.Evaporating solvent and with resistates directly by silica gel (5%MeOH-CH ₂Cl ₂---＞be chromatogram 10%MeOH), makes 574mg (78%) compound 43, is pale solid.LRMS(Cl，M+H)=494。

Step B

(0.160g adds trimethyl aluminium (0.700ml, concentration is 2M in toluene) in toluene 1.25mmols) (5ml) solution to containing p-Chlorobenzoic acid amide under 0 ℃.Stir the mixture under 0 ℃ and also stirred 40 minutes under the room temperature in 15 minutes.Then at the toluene-CH that in the aniline title complex, adds compound 43 under 0 ℃ ₂Cl ₂Solution (10ml, 1: 1, v/v).After 30 minutes, with 3 hours with mixture heating up to 80 ℃, standing over night at room temperature then.Reaction is by adding solid Na ₂SO ₄* 10H ₂O, add the MeOH quenching subsequently.Stir after 20 minutes, mixture passes through diatomite filtration concentrating under reduced pressure then.With silica gel chromatography (10%MeOH-EtOAc---＞contain 1%NH ₄The 15%MeOH of OH) obtains 624mg (97%) compound 44 of white foam shape.Irms(Cl，M+H)=589。

Step C

In containing preceding step, add in compound 44 De diox (10ml) solution 4M HCl-diox (2 * 2ml) solution, and with 6 hours with mixture heating up to 80 ℃.This mixture is cooled to room temperature, and evaporation obtains gummy foam under the decompression.(this resistates of 3 * 10ml) drip washing and decantation go out supernatant liquid with ether.To place under this product high vacuum, obtain tawny solid chemical compound 45 (400mg dihydrochloride).MS(Cl)347(M+1)。

Embodiment 3

Steps A

With ethyl-magnesium-bromide (concentration is 3M in the ether for 23ml, 69.1mmol) be added drop-wise to 0 ℃, (25.1g is in methylene dichloride 57.6mmol) (280ml) solution to contain 4-iodo-trityl group imidazoles.Mixture stirred 30 minutes down at 0 ℃, removed cooling bath and will stir 60 minutes under the yellow solution room temperature that obtain.Dropping 4-pyridine-formaldehyde (6.1ml, 63.4mmol).The reactant very thickness that becomes.The little five equilibrium sample of reaction mixture is distributed in ethyl acetate and saturated ammonium chloride.TLC (5% ethanol/methylene) shows that raw material consumes.React with the saturated ammonium chloride quenching.The mixture that obtains is dissolved in methylene dichloride (in the needs～1.5L), and to be transferred in the separating funnel, uses dichloromethane extraction.Combining extraction liquid is also used the salt water washing, and anhydrous sodium sulfate drying filters and concentrates on enough silica gel, so that obtain free flowing powder.This powder packed into be equipped with in advance in the chromatographic column of 10% ethanol/methylene.Obtain 22.5g (93%) white solid compound 47 with same solvent elution.

NMR? ¹H(400MHz，CDCl ₃)：8.56(2H，d，J=6.0Hz)，7.47(1H，d，J=1.4Hz)，7.36(11H，m)，7.13(6H，s)，6.63(1H，s)，5.79(1H，s)，4.43(1H，s).MS(Cl)：418(M+1，26)，243(100)，167(45)。

Step B

With acetic anhydride (9.7ml, 51.4mmol) join contain compound 47 (21.4g, 51.1mmol), triethylamine (35.6ML, 255.7mmol) and dimethyl aminopyridine (0.13g is in the room temperature suspension of methylene dichloride 1.0mmol) (800mL).This suspension stirring is spent the night.Last all solids all dissolves.TLC (10% ethanol/methylene) shows that raw material consumes.This mixture is transferred in the separating funnel, with methylene dichloride dilution and with saturated ammonium chloride and salt water washing, anhydrous sodium sulfate drying and filtration.Concentrated filtrate also obtains 22.8g (97%) white solid compound 48 with resistates and the methylbenzene azeotropic (3 *) (removing residual acetic acid and acetic anhydride) that obtains.

NMR? ¹H(400MHz，CDCl ₃)：8.61(2H，d，J=6.1Hz)，7.46(1H，d，J=1.4Hz)，7.38(11H，m)，7.15(6H，s)，6.83(1H，s)，6.80(1H，s)，2.20(3H，s)。

Step C

Compound 48 is dissolved in the warm acetate (100mL), and transfers in the Parr hydrogenation bottle, use purging with nitrogen gas.The adding platinum oxide (1.13g, 4.96mmol).Under 60psi, the mixture hydrogenation in the Parr hydrogenation apparatus that obtains is spent the night.With sub-fraction quenching in 1N NaOH and ethyl acetate.TLC (10% ethanol/methylene) demonstration raw material has consumed the formation with rudimentary Rf product.With the hydrogenation one day again of this mixture.TLC shows raw material consumption.Mixture is by diatomite filtration and concentrated.Add 1N sodium hydroxide and methylene dichloride and make the layering therein of this resistates.Adding solid sodium chloride improves and separates and with this mixture of dichloromethane extraction.Combining extraction liquid is also used the salt water washing, concentrates so that obtain free flowing powder with anhydrous sodium sulfate drying and on enough silica gel.This powder packed into be equipped with in advance in the chromatographic column of silicon-dioxide and 10% ethanol/methylene.Use 5%NH ₄OH (dense)/10% methyl alcohol/85% methylene dichloride wash-out obtains the compound 49 of 15.9g (79) white glass shape.

NMR? ¹H(400MHz，CDCl ₃)：7.33(10H，m)，7.14(6H，m)，6.51(1H，s)，3.04(2H，m)，2.57(2H，dd，J=2.4，12.1Hz)，2.44(2H，d，J=7.0Hz)，1.76(1H，m)，1.66(2H，d，J=12.5Hz)，1.10(2H，dd，J=3.7，12.4Hz)。MS(LC/MS)：408(M+)

Step D

(R is the 4-chloro-phenyl-)

With the 4-chlorobenzene sulfonyl chloride (0.12g, 0.56mmol) join and contain 49 (0.21g, 0.51mmol) and triethylamine (0.11ml is in the solution at room temperature of methylene dichloride 0.76mmol) (3ml).The mixture stirring that obtains is spent the night.TLC (10% ethanol/methylene) shows raw material consumption.This solution is transferred in the separating funnel,,, on enough silica gel, concentrated so that obtain free flowing powder with anhydrous sodium sulfate drying and filtration with methylene dichloride dilution and water and salt water washing.This powder packed into be equipped with in advance in the chromatographic column of silicon-dioxide and methylene dichloride.With methylene dichloride, obtain 0.26g white solid compound 50 with 10% ethanol/methylene wash-out then.

NMR? ¹H(400MHz，CDCl ₃)：7.68(2H，d，J=8.6Hz)，7.49(2H，d，J=8.5Hz)，7.32(10H，m)，7.12(6H，m)，6.49(1H，s)，3.74(2H，d，J=11.5Hz)，2.41(2H，d，J=7.0Hz)，2.24(2H，dd，J=2.36，11.8Hz)，1.69(2H，d，J=13.0Hz)，1.61(1H，m)，1.28(2H，dd，J=4.2，12.8Hz)。MS(LC/MS)：582(M+)。

Step e

To contain 50 (0.299g, 0.56mmol) mixture heating up to 80 of methyl alcohol (6ml) and 1N HCl (3ml) ℃.After 3 hours, mixture is quenched in 1N sodium hydroxide and the ethyl acetate with little five equilibrium sample.TLC (10% ethanol/methylene) shows raw material consumption.This mixture is cooled to room temperature and concentrated.Be dissolved in resistates in water and the ether and transfer in the separating funnel.Water layer washs with ether.Concentrated water layer obtains the glassy compound 51 of 0.154g (75%).

NMR? ¹H(400?CD ₃OD)：8.80(1H，d，J=1.4Hz)，7.75(2H，d，J=8.8Hz)，7.62(2H，d，J=8.8Hz)，7.32(1H，s)，3.77(d，J=11.8Hz)，2.66(2H，d，J=7.2Hz)，2.29(2H，DT，J=2.5，12.1Hz)，1.73(2H，d，J=11.7Hz)，1.60(1H，m)，1.32(2H，m)。MS(Cl)：340(M+1)

Embodiment 4 steps A R is the 4-chloro-phenyl-.With 1-3-(dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.20g, 0.68mmol) join and contain 49 (0.21g, 0.52mmol), the 4-chloro-benzoic acid (O.07g, 0.57mmol), N-methylmorpholine (O.17ml, 1.56mmol) and hydroxybenzotriazole (0.08g is in the solution of dimethyl formamide 0.62mmol) (2ml) and methylene dichloride (2ml).The mixture stirring that obtains is spent the night.TLC (10% ethanol/methylene) shows raw material consumption.This mixture is transferred in the separating funnel,, and filtered, on enough silica gel, concentrate so that obtain free flowing powder with methylene dichloride dilution and water and salt water washing, anhydrous sodium sulfate drying.The powder that obtains packed into be equipped with in advance in the chromatographic column of silicon-dioxide and 10% ethanol/methylene.Obtain the limpid oil of 0.26g with same solvent elution.NMR shows in this product and contains dimethyl formamide.Product is dissolved in the ethyl acetate, washes and use anhydrous sodium sulfate drying with water, filtering and concentrating obtains 0.237g (83%) compound 52.

NMR? ¹H(400MHz，CDCl ₃)：7.34(14H，m)，7.13(6H)，6.52(1H，s)，4.65(1H，m)，3.68(1H，m)，2.98(1H，m)，2.74(1H，m)，2.47(2H，d，J=7Hz)，1.96(1H，m)，1.70(2H，m)，1.16(2H，m)。MS(LC/MS)：546(M+)。

Embodiment 5 steps A

R ¹Be H and R ²It is the 4-chloro-phenyl-.To contain compound 49 (2.0g, 4.9mmol) and N-(4-chloro-phenyl-) acrylamide (0.98g, toluene 5.4mmol) (50ml) mixture heating up refluxes and to spend the night.TLC (10% ethanol/methylene) shows raw material consumption.Mixture is chilled to room temperature, concentrates on enough silica gel, the mobile powder gains freedom.The gained powder is stated from and is filled with on silica and the 10% ethanol/methylene chromatographic column, with 10% ethanol/methylene wash-out, then, obtain the title compound that 1.17g has trace impurity again with 5% ammonia (dope)/10% methyl alcohol/85% methylene dichloride wash-out, and the pure oily compound 53 of 1.50g.Merge productive rate 2.67g (92%).

NMR? ¹H(400MHz，CDCl ₃)：7.46(2H，d，J=11.8Hz)，7.34(1H，s)，7.32(10H，m)，7.23(2H，d，J=11.8Hz)，7.14(6H，m)，6.55(1H，s)3.04(2H，d，J=15.3)2.68(2H，m)，2.51(4H，d，J=8.3Hz)，2.07(2H，t，J=14.7Hz)，1.80(3H，m)，1.28(2H，m)。MS?(LC/MS)：589(M+)。

Embodiment 6

R is 3, the 5-dichlorophenyl.With 3, (0.21g, 11mmol) (0.3g is in methylene dichloride 0.74mmol) (5ml) solution for the compound 49 of adding room temperature for the 5-dichlorophenyl isocyanate.The gained mixture stirs and spends the night.TLC (5% ammonia dope/10% methyl alcohol/85% methylene dichloride) shows raw material consumption.Mixture concentrates on capacity silica gel, obtains free flowing powder.Obtaining powder is stated from the chromatographic column that is filled with silica and 20% acetone/methylene dichloride.With 20% acetone/methylene dichloride wash-out, use 5% ethanol/methylene wash-out subsequently again, obtain 0.37g (83%) compound 54, be white solid.

NMR? ¹H(400MHz，CDCl ₃)：7.53(1H，m)，7.36(10H，m)，7.12(6H，m)，6.97(1H，m)，6.71(1H，m)，6.56(1H，s)，4.04(2H，d，J=17.3Hz)，2.86(2H，m)，2.52(2H，d，J=9.1Hz)，1.95(1H，?m)，1.72(2H，d，J=17.1Hz)，1.16(2H，m)。MS(LC/MS)：596(M+)。

Embodiment 7 steps A

Trimethyl aluminium (1.2ml, 24mmol, 2M toluene liquid) is added the 3-chloroaniline, and (0.10g is in 0 ℃ of solution of toluene 0.8mmol) (7.5ml).Remove cooling bath after 5 minutes, mixture was in stirring at room 30 minutes.Add compound 55 (0.48g, toluene 0.1mmol) (10ml) liquid by conduit.This mixture refluxes and spends the night.TLC (10% methyl alcohol/85% methylene dichloride) shows raw material consumption.Mixture is chilled to room temperature,, makes it quenching with saturated metabisulfite solution with the ethyl acetate dilution.The gained mixture stirs and spends the night, and makes mixture become alkalescence with 1N NaOH (3ml), is transferred to separating funnel, with ethyl acetate extraction.United extraction liquid with water and salinity washing, with anhydrous sodium sulfate drying, concentrates with capacity silica gel, obtains free flowing powder.The gained powder is stated from the chromatographic column of filling silica and 3% ethanol/methylene,, obtains 0.31g (66%) compound 56, be white foam shape thing with 3-10% ethanol/methylene wash-out.

NMR? ¹H(400MHz，CDCl ₃)：7.71(1H，m)?7.29(12H，m)，7.14(6H，m)，7.05(2H，m)，6.55(1H，s)，3.04(2H，m)，2.68(2H，m)，2.51(3H，m)，2.09(2H，m)，1.81(2H，m)，1.58(2H，m)，1.3(2H，m)。MS(LC/MS)：589(M+)。Step B Compound 56 among methyl alcohol (18ml) and the 1N HCl (6ml) is warmed to 60 ℃.By with 1N sodium hydroxide and ethyl acetate with reactant one aliquot quenching, and monitoring reaction progress.Show raw material consumption with TCL (5% ammonia dope/10% methyl alcohol/85% methylene dichloride).Mixture is cooled to room temperature and concentrated.Residue all is not dissolved in ether/water, with 1N NaOH it is transferred to alkalescence, dilute with methylene dichloride, this mixture is transferred in the separating funnel, use dichloromethane extraction, united extraction liquid, and use the salt water washing, anhydrous sodium sulfate drying also filters, and concentrates on enough silica gel and obtains free flowing powder.The powder that obtains packed into be equipped with in advance in the chromatographic column of silicon-dioxide and 10% ethanol/methylene,, use 5% ammonia dope/10% ethanol/methylene wash-out again with 10% ethanol/methylene wash-out.Obtain limpid oily title compound.This thing is dissolved in methylene dichloride again and with excessive HCl (4M diox) processing, vacuum concentration obtains the compound 57 of 0.205g (44%) transparent glass shape thing.

NMR? ¹H(400?CD ₃OD)：8.85(1H，s)，7.50(2H，d，J=11.4Hz)，7.40(1H，s)，7.05(2H，d，J=11.4Hz)，4.251(2H，s)，4.15(2H，t，J=7.5Hz)，3.46(2H，d，J=16.2Hz)，3.35(3H，m)，3.02(2H，t，J=16.2Hz)，2.95(6H，s)，2.74(2H，d，J=9.0Hz)，2.25(2H，m)，1.93(2H，d，)，1.60(2H，m)。MS(FAB)：357(M+1)。

Embodiment 8 steps A

N-Butyl Lithium (concentration is 1.6M in the hexane for 30.4ml, 48.6mmol) joined contain diisopropylamine (6.63ml is in-78 ℃ tetrahydrofuran (THF) (75ml) solution 50.6mmol).After 30 minutes, contain compound 58 (7.5ml, the tetrahydrofuran (THF) of 40.5mmol (30ml) the slow adding by conduit.Be reflected at-78 ℃ and stirred 1.5 hours down, add by conduit then and contain N-phenyl trifluoromethanesulfonate Toluidrin (15.3g, tetrahydrofuran (THF) 44.5mmol) (50ml).With mixture heating up to ambient temperature overnight.TLC (20% ethyl acetate/hexane) shows raw material consumption.Add triethylamine (to prevent that triflate is in acid hydrolysis on the silica gel) and the mixture that obtains concentrated on enough silica gel and obtain free flowing powder.This powder packed into be equipped with in advance in the chromatographic column of silicon-dioxide and 20% ethyl acetate/hexane.Make 59 of 10.8g (83%) yellow oily with same solvent elution.

NMR? ¹H(400MHz，CDCl ₃)：7.30(5H，m)，5.73(1H，m)，3.63(2H，s)，3.13(2H，dd，J=3.0，6.4Hz)，2.72(2H，t，J=5.7Hz)，2.45(2H，m)。Step B

(5.9ml 42.1mmol) joins and contains 59 (10.8g is in the solution at room temperature of 3: 1 mixtures (50ml) of tetrahydrofuran (THF) 33.7mmol) and diisopropylamine with trimethyl silyl acetylene.Add dichloro two (triphenylphosphine) palladium (II) (1.42g, 2.0mmol) and cuprous iodide (I) (1.1g, 5.7mmol).The color of reactant is from redness to the brown black that becomes again.After 1 hour, TLC (5% ethyl acetate/hexane) shows raw material consumption.Reaction is diluted with ether and is transferred in the separating funnel, water, 3/1 saturated ammonium chloride/ammoniacal liquor (dense) and salt water washing, and anhydrous sodium sulfate drying also filters, and concentrates so that obtain free flowing powder on enough silica gel.The powder that obtains packed into be equipped with in advance in the chromatographic column of silicon-dioxide and 10 ethyl acetate/hexane.Make 6.1g (67%) yellow solid 60 with same solvent elution.

NMR? ¹H(400MHz，CDCl ₃)：7.35(5H，m)，6.14(1H，m)，3.63(2H，s)，3.08(2H，m)，2.63(2H，t，J=5.7Hz)，2.33(2H，m)，0.23(9H，s)。Step C

Tetrabutylammonium (concentration is 1M in the tetrahydrofuran (THF) for 27ml, 27.0mmol) joined contain compound 60 (6.1g is in the solution at room temperature of tetrahydrofuran (THF) 22.5mmol) (100ml).After about 2 hours, TLC (20% ethyl acetate/hexane) shows raw material consumption.Reaction mixture dilutes with ethyl acetate and transfers in the separating funnel, water and salt water washing, and anhydrous sodium sulfate drying filters also concentrated so that obtain free flowing powder on enough silica gel.The powder that obtains packed into be equipped with in advance in the chromatographic column of silicon-dioxide and 10 ethyl acetate/hexane.Make 3.4g (76%) yellow solid 61 with same solvent elution.

NMR ¹H(400MHz，CDCl ₃)：7.36(5H，m)，6.17(1H，m)，3.65(2H，s)，3.11(2H，m)，2.91(1H，s)，2.64(2H，t，J=5.6Hz)，2.35(2H，m)。Step D

(3.42g, 17.3mmol) (6.3g 14.4mmol) is dissolved in tetrahydrofuran (THF) (100ml) and the diisopropylamine (40ml) with 1-trityl group-4-iodo imidazoles with 61.Add dichloro two (triphenylphosphine) palladium (II) (1.22g, 1.7mmol) and cuprous iodide (I) (0.4g, 1.7mmol).Reaction mixture at room temperature stirs and spends the night.TLC (5% ethanol/methylene) shows raw material consumption.Reaction is diluted with methylene dichloride and is transferred in the separating funnel, water, 3/1 saturated ammonium chloride/ammoniacal liquor (dense) and salt water washing, and anhydrous sodium sulfate drying filters also concentrated.Resistates recrystallization from ethyl acetate is obtained 7.02g (98%) light yellow solid 62.

NMR? ¹H(400MHz，CDCl ₃)：7.44(1H，d，J=1.1Hz)，7，40(14H，m)，7.18(6H，m)，7.06(1H，d，J=1.5Hz)，6.12(1H，m)，3.64(2H，s)，3.12(2H，m)，2.64(2H，t，J=5.7Hz)，2.39(2H，m)。MS(FAB)：505(M+)。Step e

(7.0g 14.1mmol) is dissolved in the mixture of tetrahydrofuran (THF) (250ml), methyl alcohol (200ml) and methylene dichloride (100ml) and uses purging with nitrogen gas with compound 62.Adding Pd/C (1.0g) also under the pressure of 60psi is spending the night the suspension hydrogenation in the Parr device that obtains.TLC (5% ethanol/methylene) shows the raw material of residue a great deal of.With mixture by diatomite filtration, add fresh 10%Pd/C and with mixture in hydrogenation two days again in the Parr device under the pressure of 60psi.TLC (5% ethanol/methylene) shows the raw material of residue a great deal of.Add 20%Pd (OH) ₂/ C (1.0g) and acetate (60ml), and with mixture under the pressure of 60psi in the Parr device again hydrogenation spend the night.Filtering mixt also concentrates.TLC (5% ammoniacal liquor (dense)/ethanol/methylene) shows many new spot.Be dissolved in resistates in the acetate (75ml) and add 20%Pd (OH) ₂/ C (1.0g) is with mixture hydrogenation two days under the pressure of 50psi.Reaction is by diatomite filtration and with the filter cake methanol wash.Concentrated filtrate and with resistates and toluene (3 *) azeotropic to remove residual acetic acid.This resistates is dissolved in 1N NaOH and the methylene dichloride, transfers in the separating funnel and use dichloromethane extraction.Combining extraction liquid, water and salt water washing, anhydrous sodium sulfate drying also concentrates, and makes the 6.8g amber oil.With 4% ammonia dope/10% methyl alcohol/86% methylene dichloride wash-out, obtain 0.7g (10%) compound 63 with silica gel chromatography.

NMR? ¹H(400MHz，CD ₃Cl ₃)：7.29(15H，m)，7.13(6H，m)，6.49(1H，s)，3.58(2H，m)，2.94(2H，m)，2.54(2H，t，J=8.0Hz)，1.98(2H)，1.66(2H，m)，1.54(3H，m)，1.29(2H)。Step F

(0.019g 0.054mol) is dissolved in the methyl alcohol (1ml), adds 1MHCl (2) with compound 63.With the solution that purging with nitrogen gas obtains, add 10%Pd/C (0.005g) and mixture is led to H with the hydrogen capsule ₂Stirring is spent the night.Mixture is by diatomite filtration, and filter cake also concentrates with methanol wash and obtains the limpid oil of 0.0128g. ¹HNMR analyzes demonstration and does not react.Should be dissolved in again in the methyl alcohol (1ml) by oil, add HCl (1).Solution with purging with nitrogen gas obtains adds 20%Pd (OH) ₂/ C (0.01g) also stirs mixture and to spend the night in the hydrogen capsule.Mixture is by diatomite filtration, and filter cake also concentrates with methanol wash and obtains the limpid oily compound of 0.0085g 64.

NMR? ¹H(400MHz，CD ₃OD)：8.87(1H，s)，7.41(1H，s)，3.45(2H，m)，3.04(2H，m)，2.85(2H，m)，2.05(2H，m)，1.75(3H，m)，1.53(3H，m)。

Use compound (64) production I compound then, for example according to the step in the foregoing description.

Embodiment 9

Commercially available ethyl isonipecotate is protected with di-tert-butyl dicarbonic acid ester; this ethyl ester lithium aluminium hydride reduction; according to A.Villalobos at " journal of medicinal chemistry " (Journal of MedicinalChemistry) 1994; 37; method described in the 2721-2734 is converted into required iodide 69 with iodine with intermediate ethanol.

In the 500ml round-bottomed flask, pack into iodide 69 (10.0g, 30.75mmol), triphenylphosphine (16.9g, 64.6mmol) and the 150mL acetonitrile.

This solution backflow was heated 16 hours down, be cooled to room temperature vacuum concentration yellowly oil then.Crude product is further purified by silica gel chromatography, uses 4: 1 hexanes: ethyl acetate-100% ethyl acetate is carried out gradient elution, uses 95: 5 methylene dichloride: methanol-eluted fractions De Dao phosphonium salt 70 (7.13g) at last, and productive rate is 40%.

Zhuan Ru phosphonium salt 70 in the 500mL round-bottomed flask (7.13g, 12.14mmol), (4.5g 13.14mmol) and 250mL exsiccant tetrahydrofuran (THF), is cooled to 4 ℃ with reaction mixture to n-trityl imidazole-formaldehyde.(14ml, concentration is 1M in the Zai diox, 14mmol) also this solution slowly is heated to room temperature, disappears by TLC monitoring aldehyde to drip potassium tert.-butoxide.Add potassium tert.-butoxide (2.4mL, 2.4mmol) and at room temperature stirring reaction after 4 hours again.Amount to after 16 hours, filtering reaction also is condensed into oil with filtrate.Use hexane on silicagel column: eluent ethyl acetate obtains pure alkene 72 (3.2g), and productive rate is 51%, is the E/Z mixture of isomers.

Alkene 72 (3.2g), PtO pack in the 500mL round-bottomed flask ₂(0.75g) with 150mL methyl alcohol, and three road plugs that have the hydrogen capsule are housed.In hydrogen, stirred the heterogeneous reaction thing 2 hours.Filtering catalyst also concentrates this filtrate to oily (3.2g).Thick intermediate is dissolved in the 180mL diox again and at room temperature (20mL 20mmol) handled 24 hours with containing 1MTFA De diox.With sodium hydroxide (1M) with the pH regulator of reaction mixture to greater than 8, add ethyl acetate and layering.Organic phase salt water washing, dried over mgso also is condensed into semisolid.(methylene dichloride: meoh eluate) purifying obtains pure compound 73 (1.8g, productive rate 69%) by chromatogram with this crude product.

Embodiment 10

(3.5g adds anhydrous THF (30mL) in flask 6.11mmol) to Han You phosphonium salt 39 under nitrogen atmosphere.This mixture be cooled to 0 ℃ and by syringe drip t-BuOK (1.0M solution, 8g, 8mmols).The yellow mixture that obtains was stirred 20 minutes, add by syringe then and contain 3-carbon aldehyde (2.4g, 8mLTHF solution 6.55mmol).Reaction mixture stirred 24 hours down at 25 ℃, added NH then ₄The quenching of Cl solution.Containing water section extracts with EtOAc.The organic phase salt water washing that merges, MgSO ₄Drying is filtered and is concentrated.Through silica gel chromatography (the 40%EtOAc-hexane---＞60%EtOAc) obtain 2.6g (71%) compound 74.MS(electrosrpay，M+H)=534。

To the compound 74 that is dissolved in methyl alcohol (2.3g, 4.3mmol) the middle PtO that adds ₂(0.4g).The hydrogen capsule was placed on the reaction mixture top, at 25 ℃ of following continuously stirring 2-3 hours.Then with reaction mixture at SiO ₂Enterprising circumstances in which people get things ready for a trip spectrum processing (100% hexane is incremented to the 75%EtOAc-hexane) are removed catalyzer and are obtained pure products 75,2.24g (97%).MS(electrosrpay，M+H)=536。

(2.0g 3.7mmol) adds 4MHCl-diox (10mL) in the De dioxane solution to containing compound 75 under 25 ℃.Mixture stir about 6 hours is cooled to 0 ℃ then, adds 5%NaOH and makes that pH is 7.Extract mixture with EtOAc, the salt water washing of the organic phase of merging, MgSO ₄Drying, filtering and concentrating obtain 1.14g (100%) compound 76.MS(electrosrpay，M+H)=436。

(200mg 0.46mmol) 4 hours, obtains 140mg compound 77 to use 4M HCl-diox (5mL) to handle 76 under 80 ℃ again.MS(Cl，M+H)=194。

Be prepared as follows compound according to being similar to above-mentioned step.

Mass-spectrometric data

The compounds of this invention can be used as histamine H ₃The agonist of acceptor or antagonist.The compounds of this invention and H ₃The bonding force of acceptor can be proved by the following method:

H ₃Receptor binding assays

H in this experiment ₃The source of acceptor is the guinea pig brain.Used animal weight is 400-600g.Use Polytron this tissue of homogenize in the solution of 50mM Tris, pH7.5.The ultimate density of organizing in the homogenize damping fluid is 10%w/v.The grumeleuse and the chip of tissue are removed in homogenate centrifugal 10 minutes with 1000xg.Then with the supernatant liquid that obtains centrifugal 20 minutes with 50000xg, for deposited film, subsequently in the homogenize damping fluid with this film washing 3 times (each 50000xg, 20 minutes).Freezing this film is also preserved until use under-70 ℃.

With the compound dissolution that remains to be tested in DMSO, then binding buffer liquid (50mMTris, pH7.5) in dilution make that ultimate density is 2 μ g/ml, wherein contain 0.1%DMSO.Then film (400 μ g albumen) is joined in the reaction tube.Add 3nM[ ³H] R-Alpha-Methyl histamine (8.8Ci/mmol) or [ ³H]-N-methylhistamine (80Ci/mmol) beginning incubation, and under 30 ℃, cultivated 30 minutes.Filter, from unconjugated part, isolate the bonded part, by the amount of liquid scintillation spectrometer quantitative assay and membrane-bound radioligand.All cultivations are all carried out in duplicate, and the standard error in all experiments is lower than 10%.Dilution can suppress the compound of 70% above radioligand and acceptor special combination to measure K continuously _j(nM).

The K of compound 45,78,79,81-97 and 113-118 _jScope is 0.1-220nM.Compound 45,79,81,82,83,84,86,87,88,89,91,94,96 and 116 K _jScope is 0.1-20nM.

Acceptable carrying agent can be solid or liquid on compound of the present invention, inert material, the pharmacology.The preparation of solid form comprises pulvis, tablet, dispersible granules, capsule, cachet and suppository.Pulvis and tablet can comprise about 5-70% activeconstituents.Suitable solid carrier is known in the art, for example magnesiumcarbonate, Magnesium Stearate, talcum, sugar, lactose.Tablet, pulvis, cachet and capsule can be used as solid dosage and are suitable for oral.

In order to prepare suppository, at first melt low melt wax, as the mixture of glycerin fatty acid ester or Oleum Cocois, by stirring wherein with the activeconstituents homodisperse.Then the fused uniform mixture is poured in the mould of appropriate size, cooling is solidified then.

Liquid absorption member comprises solution, suspension and emulsion.The example that can mention is water or the water-propylene glycol solution that is used for non-enteron aisle injection.

Liquid absorption member also can comprise the solution that is used for intranasal administration.

The aerosol that is fit to suck can comprise the solid of solution and powder type, and they can learn upward acceptable carrier by bound drug, as the inertia pressurized gas.

Also comprise and face the solid preparation that can be converted into the liquid form preparation of oral or parenteral admistration before using.Liquid absorption member comprises solution, suspension and emulsion.

Compound of the present invention also can transmit through skin.Endermic composition can adopt emulsifiable paste, lotion, aerosol and/or emulsion dosage form, can comprise the matrix that is usually used in this field or the transdermal patch of storage type.

The preferred oral compound.

The preferred agents preparation is a unit dosage form.In this form, preparation is divided into and contains the appropriate amount active ingredient, for example reaches the unitary dose of the active ingredient of required purpose significant quantity.

According to special use, the content of active compound will change to some extent in the unit dose formulations, or about 0.1mg-1000mg, more preferably from about 1mg-500mg.

The actual dose that uses can change to some extent according to patient's the needs and the severity of illness to be treated.Be used for the determining of correct dose of concrete situation, belong within the art technology scope.Usually, begin with the smaller dose treatment that is lower than the compound optimal dose.Progressively on a small quantity increase dosage until reaching best effect in this case thereafter.For convenience, if desired, the dosage that every day is total is divided into several parts, and takes in one day in batches.

The dose and the frequency of acceptable salt will be adjusted to some extent according to clinicist's judgement on The compounds of this invention and its pharmacology, need the factors such as severity of consideration as age, patient symptom and body weight and symptom to be treated.Usually the dosage of recommending is every day oral 1mg-2000mg, preferred 10-1000mg, is divided into 1-4 part and takes to alleviate illness.When in the dosage range time spent for oral administration, compound be do not have toxic.

The example of following pharmaceutical dosage form contains compound of the present invention.Term used herein " active compound " is to be used to refer to one of formula I compound or its salt.At its pharmaceutical composition, scope of the present invention is not limited by the embodiment that is provided.Pharmaceutical dosage form EXAMPLE Example A

Tablet

Sequence number	Composition	The mg/ sheet	The mg/ sheet
1． 2． 3． 4． 5．	Active compound lactose USP W-Gum, food grade, be 10% paste W-Gum in the pure water, the food grade Magnesium Stearate amounts to	100 122 30 45 3 300	500 113 40 40 7 700

The preparation method

The the 1st and 2 was mixed 10-15 minute in suitable mixing tank.Make this mixture with the 3rd granulation.If desired, by wide-meshed screen (for example 1/4 ", 0.63cm) the moist particle of milling.Dry moist particle.As needs, the screening dry granules was also mixed 10-15 minute with the 4th.Add the 5th and mixed 1-3 minute.On a suitable tabletting machine, mixture is compressed to suitable size and weight.

Embodiment B

Capsule

Sequence number	Composition	The mg/ capsule	The mg/ capsule
1． 2． 3． 4．	Active compound lactose USP W-Gum, food grade Magnesium Stearate NF amounts to	100 106 40 4 250	500 123 70 7 700

The preparation method

In a suitable mixing tank, the 1st, 2 and 3 was mixed 10-15 minute.Add the 4th and mixed 1-3 minute.On a suitable capsule envelope machine, this mixture packed in suitable two the hard gelatin capsule up and down.

Although the present invention is described in conjunction with above-mentioned specific embodiment, they are many to substitute, change and change is conspicuous to those skilled in the art.All these substitute, change and change and all drop within the spirit and scope of the present invention.

Claims (20)

1. formula I compound

Or acceptable salt or solvate on its pharmacology, wherein:

X is the alkenyl or alkynyl that contains the straight chained alkyl of 1-7 carbon atom or contain 2-4 carbon atom; Wherein said alkyl or alkenyl can be by 2 R at the most ⁷Group replaces arbitrarily;

N is 0,1 or 2,

M is 0-4;

P is 0-4;

When m was 0-4, Y represented-SO ₂-;-CS-;-CO-;-CONR ⁵-;-CO (CH ₂) _wO-(wherein w is 1-4);-COO-;-CON (OR ⁵)-;-C (NR ⁵) NR ⁵-;-SO ₂NR ⁵-or-CSNR ⁵-;

When m was 2-4, Y represented above-mentioned all groups, and when m was 0-4, Y represented-CHOR in addition ⁵-;-O-;-NR ⁵CONR ⁵-;-NR ⁵CO-;-NR ⁵-;-OCONR ⁵-;-NR ⁵C (NR ⁵) NR ⁵-;-NR ⁵CSNR ⁵-;-NR ⁵CS-or-NR ⁵SO ₂-;-NR ⁵C (O) O-; Or-CSNR ²-;

Each R ⁵Independent expression hydrogen, alkyl or benzyl;

R ⁶Be selected from:

(1) aryl,

(2) heteroaryl,

(3) 3-7 unit heterocyclic group,

(4) contain 1-3 and be selected from alkyl, halogen, trihalomethyl group, CN, NO respectively ₂, OR ¹⁰Or NR ¹⁰R ¹¹Substituent substituted aryl, wherein R ¹⁰And R ¹¹Independently be selected from H, alkyl or trihalomethyl group,

(5) contain 1-3 and be selected from alkyl, halogen, trihalomethyl group, CN, NO respectively ₂, OR ¹⁰Or NR ¹⁰R ¹¹Substituent substituted heteroaryl, wherein R ¹⁰And R ¹¹Define the same; Or

(6) contain 1-3 and be selected from alkyl trihalomethyl group or NR respectively ¹⁰R ¹¹Substituent substituted heterocyclic radical, wherein R ¹⁰And R ¹¹Define the samely, described substituting group is gone up carbon atom with ring and is connected, and makes the 1-3 that adds up to of substitution in ring base; Wherein heterocycle contains commutable nitrogen-atoms, and described nitrogen-atoms can be replaced arbitrarily by low alkyl group;

When Y is-SO ₂-, R except above-mentioned group so ⁶Also expression contains the alkyl or the group-NR of 1-7 carbon atom ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Define the same;

Each R ¹Independently be selected from hydrogen, alkyl or trihalomethyl group;

Each R ⁷Independently be selected from hydrogen, alkyl, trihalomethyl group, phenyl or benzyl, wherein said phenyl and benzyl can be selected from alkyl, halogen, trihalomethyl group, CN, NO respectively separately by 1-3 ₂, OR ¹⁰Or NR ¹⁰R ¹¹Substituting group replace R wherein arbitrarily ¹⁰And R ¹¹Define the same.

2. according to the following formula: compound of claim 1:

Wherein:

Q is 1-7;

M is 0-4;

N is 0 or 1;

P is 0-4;

When m was 0-4, Y was selected from-SO ₂-,-SO ₂NH-,-CONH-,-CO-,-C (NH) NH-or-CO (CH ₂) _wO-; And

When m was 2-4, Y represented above-mentioned all groups, in addition when m is 0-4, Y representative-NHCONH-,-O-or-NHC (NH) NH-; And

W, R ¹, R ⁶And R ⁷Define the same.

3. according to the compound of claim 2, wherein q is 1-4; M is 0-3; P is 0,1 or 2; Y is-CONH-,-SO ₂-or-CO-; R ⁶It is the phenyl of phenyl or replacement; Each R ¹Be selected from H or alkyl respectively separately; Each R ⁷Be selected from H or alkyl respectively separately.

4. according to the compound of claim 3, wherein (1) n is 0; (2) Y be-CONH-or-SO ₂-; (3) R ⁶Be (a) mono-substituted phenyl, wherein said substituting group is in 3-or 4-position, and described substituting group is selected from fluorine, chlorine, methoxyl group or trifluoromethoxy, or (b) di-substituted-phenyl, wherein said substituting group is 3, the 5-position, and described substituting group is identical and be selected from fluorine, chlorine, methoxyl group or trifluoromethoxy; And (4) R ¹And R ⁷Be H.

5. according to the compound of claim 4, wherein q is 2.

6. the compound according to claim 1 is selected from:

7. according to the compound of claim 2, wherein n is 1; Y is selected from-SO ₂-,-CONH-,-CO-or-CO (CH ₂) _wO-; And when m was 2-4, Y also was selected from except above-mentioned group-CHCONH-or-O-.

8. according to the compound of claim 7, wherein (1) q is 1 or 2; (2) n is 1; (3) m is 0-3; (4) p is 0,1 or 2; (5) Y be-CONH-or-SO ₂-; (6) R ⁶Be (a) mono-substituted phenyl, wherein said substituting group is in 3-or 4-position, and described substituting group is selected from fluorine, chlorine, methoxyl group or trifluoromethoxy, or (b) di-substituted-phenyl, wherein said substituting group is 3, the 5-position, and described substituting group is identical and be selected from fluorine, chlorine, methoxyl group or trifluoromethoxy; And R ¹And R ⁷Be H.

9. compound according to Claim 8, wherein q is 2.

10. one kind comprises acceptable carrying agent and claim 1 compound or its salt of significant quantity or the pharmaceutical composition of solvate on the pharmacology.

11. treatment atopic reaction, inflammation, cardiovascular disorder, ypotension, glaucoma, dyssomnias, gastrointestinal tract disease, gi tract motility are crossed state, central nervous system disorder, nervus centralis hypo and hyperactivity, Alzheimer's, schizophrenia, obesity and migrainous method strong and that motility weakens, comprise compound or its salt or the solvate of using the claim 1 of significant quantity to the patient of this treatment of needs.

12. the method for treatment upper airway allergic responses comprises and uses claim 1 compound or its salt or solvate and and histamine H ₁Receptor antagonist combines.

13. according to the method for claim 12, wherein said H ₁Antagonist is selected from: Loratadine (loratadine), remove carbonyl oxyethyl group Loratadine (descarboethoxyloratadine), Fei Suofeilading (fexofenadine) and cetirizine (cetirizine).

14. according to the method for claim 13, wherein said H ₁Antagonist is selected from: Loratadine (loratadine) or remove carbonyl oxyethyl group Loratadine (descarboethoxyloratadine).

15. the compound or its salt of claim 1 or solvate be in the application of preparation in the medicine, this medicine is used for the treatment of atopic reaction, inflammation, cardiovascular disorder, ypotension, glaucoma, dyssomnias, gastrointestinal tract disease, gi tract motility and crosses state, central nervous system disorder, nervus centralis hypo and hyperactivity, Alzheimer's, schizophrenia, obesity and migraine strong and that motility weakens.

16. the application in the preparation medicine of claim 1 compound or its salt or solvate, this medicine and the histamine H that is used as that has made ₁The medicine of receptor antagonist is used in combination, and described combination is used for the treatment of upper airway allergic responses.

17. according to the application of claim 16, wherein said H ₁Antagonist is selected from: Loratadine (loratadine), remove carbonyl oxyethyl group Loratadine (descarboethoxyloratadine), Fei Suofeilading (fexofenadine) and cetirizine (cetirizine).

18. according to the application of claim 16, wherein said H ₁Antagonist is selected from: Loratadine (loratadine) or remove carbonyl oxyethyl group Loratadine (descarboethoxyloratadine).

19. being used for the treatment of atopic reaction, inflammation, cardiovascular disorder, ypotension, glaucoma, dyssomnias, gastrointestinal tract disease, gi tract motility, the compound or its salt of claim 1 or solvate cross state, central nervous system disorder, nervus centralis hypo and hyperactivity, Alzheimer's, schizophrenia, obesity and migrainous application strong and that motility weakens.

20. claim 1 compound or its salt or solvate and histamine H ₁Receptor antagonist combines and is used for the treatment of the application of upper airway allergic responses.