JPH03501612A - 2,2-Disubstituted glycerol and glycerol analogs, compositions and methods of use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] 22-Double glycerol and glycerol m, fragrance and The present invention relates to 2,2-disubstituted glycerol and glycerol analogs, such and compositions containing such compounds and methods of using such compounds.

Related compounds have been described in various reports. For example, 5CRIP PAF REPORT, PJB Publishing, 1986 and exhibition hh tilt (≧, 20 volumes ( 1985) Chapter 20 pp. 193-202 contains a large number of materials synthesized by various researchers. Related compounds have been described. J, Med, CI+em, Volume 29, Issue 10, pp1812 to 1814 (1986) and Mu Kirigami ID Res.

Volume 28, I) P2S5-738 (1987) describes related PAF analogs. It is listed. Similarly, Mr. 1 and Shadow "Niyu Yu") Yu Alliance" - Volume 12 (1), R1 4 (1987) contains various disclosures relating to the compounds described and claimed herein. A number of related compounds synthesized by researchers have been described.

Mitsuri Sho Sadasei The invention described and claimed herein relates to a compound of formula I or a medicament thereof. and appropriate salts or solvates.

R1 is alkyl containing 6 to 22 carbon atoms or -C(0)-D, in which - is NR'R6, in the formula R5 is hydrogen, alkyl containing χ carbon atoms, aryl, heteroaryl, hetero alkyl, arylalkyl or cycloalkyl; R6 is alkyl, aryl, heteroaryl, heteroalkyl containing y carbon atoms R, arylalkyl, and at least one of R5 or R6 is alkyl is such that the sum of X and y is an integer from 1 to 22, or R5 and R6 together with the nitrogen to which they are attached form a heterocycloalkyl group so that it may be substituted with alkyl or arylalkyl; R2 is lower alkyl, trifluoromethyl, aralkyl or aryl; R3 is TUV, in the formula T is 10PO3-, 0-C(0)-0-, -0-, -S-, -NR''-, -NR "5Oz-1-0-C(0)-NR"- or -NR"-C(0)-0- (in the formula R1 represents H1 (lower alkyl or acyl); U is -(CHz)- (where e is an integer from 2 to 10) or 3) ri, and V is -A-B, in the formula A is a direct bond between υ and 8, -0-, -3-, -0-(CH2), -(in the formula n is 1.2 or 3), -0-C(0)- or -NCR''')-(formula (where R1 is as defined above) and B is alkyl, substituted alkyl, hetero substituted heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl R, aryl, heteroaryl, substituted heteroaryl or -C-N(RC)z [In the formula, W is ○, S or NR' (in the formula, R1 is H2 lower alkyl or CN) ), each R' is independently H or lower alkyl], and -A , -B group contains at least one nitrogen atom, and R4 is -X-CbHtb-+ where C is an integer from 1 to 6, and X is methylene , o, 5(0)c (wherein C is 0.1 or 2) or -NCR''' )-(wherein R1 is as defined above)].

However, when R1 is alkyl, T cannot be -opo.

Preferred compounds included in the invention are those in which R1 is -C(0)-D (wherein is NR'Rh and preferred as R5 and Rh is alkyl.

Most preferably one of RS and R6 is methyl and the other group is 6 to 19 carbons. alkyl containing atoms (most preferably 10 to 18 carbon atoms).

Preferred values of R''C in the formula R2 are lower alkyl, more preferably 1 to 3 carbon atoms. most preferably lower alkyl containing 1 or 2 carbon atoms. Also included among the suitable compounds of the present invention are those containing the following.

Preferred compounds of the invention include a suitable T [for which ~O-, -0-C(0)-0- , -0-C(0)-NR"- and -NR"C(0)-0- (wherein R1 is preferably is H or acyl, most preferably H). be caught. More preferred T is 10-, -0-C(0)-Ni+" and -NR"-C (0)-0-, and the most preferred T is -0-.

Preferred examples of U include -(CH2)-, especially e in the formula is 4°5.6 or It is an integer of 7. Another suitable U is -(C)lz)r-phenyl-(C Hz) f - (where f is defined previously).

A preferred example of ① is that A is a direct bond between U and B, and B is a heteroaryl or substituted heteroaryl, and A is a direct bond between U and B. , B is heterocycloalkyl or substituted cycloalkyl, and A is -0 - and B is heteroaryl or substituted heteroaryl.

A suitable R'4m is one where X is 0 or 5(0)zte and one of CbHzb*+ is 1. Contains certain compounds.

Also included are suitable salts of compounds represented by structural formula I, including cyclic and acyclic Preferred cyclic compounds include quaternary ammonium salts having a ring containing a quaternary nitrogen. preferred acyclic compounds are quaternary ammonium compounds with lower alkyl substituents. It is a quaternary ammonium compound.

The majority of the compounds of the present invention contain at least one non-sacrificial carbon atom. The present invention Any mixture of two or more of the different stereoisomers as well as any compound of spanning individual stereoisomers.

The present invention further provides a compound represented by structural formula I in combination with a pharmaceutically suitable carrier. It also includes pharmaceutical compositions consisting of compounds.

The invention further includes methods for treating allergies in mammals, including methods for treating allergies in mammals. It is characterized by administering an antiallergic effective amount of the compound represented by Formula 1. Ru.

The present invention also encompasses a method of treating inflammation in a mammal, wherein the mammal is provided with a compound according to structural formula I. characterized by administering an anti-inflammatory effective amount of the represented compound.

Another aspect of the invention is for the preparation of pharmaceutical compositions useful in the treatment of allergies or inflammation. and the use of a compound of formula I as a compound. Yet another aspect of the invention is a compound of formula I and a method for producing a pharmaceutical composition by mixing with a pharmaceutically suitable carrier. Ru.

Preferred species falling within the scope of the invention described and claimed herein include: (where X- is a negatively charged ion such as C!- or CH, SO□- ): OCHs OCHs II　I　II　I ■ In this specification, unless otherwise indicated, the following terminology is used as defined below: : Alkyl - straight chain containing 1 to 20 carbon atoms (preferably 1 to 18 carbon atoms) or represents a branched carbon chain; lower alkyl - a straight or branched chain containing from 1 to 6 carbon atoms; represents a branch carbon chain; Methylene - represents a divalent group -CH2-; cycloalkyl - 3 to 8 carbon atoms represents a saturated carbocyclic ring; heterocycloalkyl-3 to 7 atoms (preferably 2 to 7 atoms); 6 carbon atoms and 1 to 3 10-, -S- or -N-; represents a saturated ring containing a telo group); preferred heterocycloalkyl groups include morpho Mention may be made of lino, pyrrolidinyl, thiazolidinyl and thiacyridinium.

heteroalkyl - 1 to 10 carbon atoms and at least one -O-, -S- or or a saturated compound containing a hetero group selected from -N- represents a branched or unbranched chain; Azyru-alkyl-C(0)- or -cycloalkyl-C(0)- (in the formula cycloalkyl and cycloalkyl represent groups (as defined above); Aryl - a carbocyclic group containing from 6 to 14 carbon atoms with at least one aromatic ring (e.g. phenyl); aralkyl - a saturated branched chain containing 1 to 6 carbon atoms; and unbranched and one or more phenyl substituents (e.g. benzyl); heteroaryl-represents a 5- or 6-membered aromatic ring containing 1 to 4 heteroatoms; As a preferred heteroaryl, thiazolyl.

Thiazolium, imidazolyl, imidazolium, pyridinyl.

Includes pyridinium and thiazolyl; halochloro, bromo or fluor means oro; substituted aryl and heteroaryl - aryl as previously defined In aryls and heteroaryls, each substitutable carbon atom has one or more halide atoms. B, alkyl, =NR'', N(R')2.SR'''.

-OR" or -CO2R" (where R" is as defined previously) Intended as a possible point, each substitutable heteroatom is alkyl, NC R”)z, SR”, -OR' or -CChl? ” (where R’ is defined earlier intended as a possible point for substitution by Substituted Heterocycloalkyl - Heterocycloalkyl as defined above, with each substitution one or more convertible heteroatoms or carbon atoms (7) -NR", -N(R"), -SR", -OR" or -CO,R" (formula R1 in the middle is a point that allows substitution by (as defined above). substituted heterocyclo Alkyl also includes non-aromatic quaternary ammonium compounds; Substituted Alkyl and Substituted Heteroalkyl - Alkyl and Heteroalkyl are As defined, each carbon atom is H1:l, -N(R'')21-OR ’, -COZR” or -NCR”) 3 (wherein R” is as defined previously at the point of possible attachment of one or more substituents selected from the group consisting of , and each substitutable heteroatom is -NCR")2.-OR", or -CO2R'' is intended as a possible point of substitution.

From 9F8L Tsui Certain compounds of the invention may exist in isomeric forms.

The present invention covers all such compounds, both in pure form and in mixtures, including racemic mixtures. I'm thinking about isomers.

Compounds of the invention of formula I can be used in hydrated forms, solvated forms (e.g. dihydrates) as well as unsolvated forms. It can exist as a Japanese form. Generally, pharmaceuticals such as water, ethanol and the like The solvated form with a suitable solvent is equivalent to the unsolvated form for the purposes of this invention.

Certain compounds of the invention are acidic, e.g. these compounds are carboxyl or or have a phenolic hydroxyl group. These compounds can be prepared in pharmaceutically suitable salts. may be formed. Examples of such salts are sodium, potassium, calcium, and alkaline salts. metal, gold, copper and silver salts. Ammonia, alkylamines.

Pharmaceuticals such as hydroxyalkylamines, N-methylglucamine and similar Salts formed with suitable amines are also contemplated.

Certain basic compounds of the invention are pharmaceutically suitable salts, such as acid addition salts and and quaternary ammonium salts. For example, the thiazolidinyl nitrogen atom forms acid addition salts with strong acids. may be formed. Examples of acids suitable for salt formation are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, Enoic acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, Scorbic acid, maleic acid, methanesulfonic acid and others well known to those skilled in the art. other mineral acids and carboxylic acids.

Salts are prepared by conventional methods of contacting the free base form with a sufficient amount of the desired acid to form the salt. be done. Free base forms include salts such as sodium hydroxide, potassium carbonate, ammonia and Regenerated by treatment with a suitable diluted base aqueous solution such as a young aqueous solution of hydrogen carbonate. will be done.

Quaternary ammonium salts typically combine a tertiary amine group and an alkyl iodide group in the compound of are prepared by reacting with a compound containing a suitable leaving group, such as

For example, in the definition of R3, B is substituted heteroalkyl, substituted heterocycloalkyl or substituted heteroaryl, B may contain a quaternary nitrogen. defined before As such, the compounds of the present invention having an aromatic ring nitrogen atom also contain In the definition of (■), A may form a 10- or -S- and B is heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted In the case of substituted heterocycloalkyl, heteroaryl or substituted heteroaryl, B The heteroatom within the group is located at any position other than where it is bonded to the A group.

Free base forms differ from their respective salt forms and certain physical properties, such as solubility in polar solvents. Although different, for the purposes of this invention a salt is equivalent to its respective free base form. Ru.

All such acids, bases and quaternary salts are included as pharmaceuticals within the scope of this invention. All acid and base salts are suitable for the purposes of this invention. It is considered to be equivalent to the free form of the compound.

The compounds of the present invention are produced by the following process: (A) Formula The compound with the formula L2A B lx (wherein R', R2, R', T, U, A and B is as previously defined and Ll and L2 are leaving groups); (B) on group B To prepare a compound of formula I which has a positive charge and is a direct bond between A and 8. Therefore, the compound of formula i is represented by formula B! ,l (where B is a free radical which is identical to the B group previously defined except for the bond) is a dissociation compound); (C) To prepare a compound of formula I in which T is -OCO□-, the formula cHz-QC(0 )-L' A compound of the formula %formula% (wherein L2 is a leaving group and U and ■ are as defined above) and to respond; (D) R' is C(0)NR5Rh (in the formula, R5 is H and R6 is alkyl) ) In order to produce a compound of formula alkylating the compound; In the above process, any functional groups may be protected if necessary or desired. , following one or more of the following steps if necessary or desired; (a) removing one or more protecting groups; (b) converting a compound of formula I into a compound of formula ■ (C) converting the compound so produced into a different compound; (C) converting the compound so produced into a salt or is converted into a solvate, (d) converting the compound so produced into a zwitterion;

The above process is typically carried out in the presence of an inert solvent at a temperature not exceeding the boiling point of the solvent. be done. Typical leaving groups L1 are -05O2CH3°-Br, -1 and -C1. be. Typical de-M groups 1,2 are -H, and metal ions. Of course many Other leaving groups may also suffice.

The intermediates jll 12, 13 + 14 + Is and i are known or It will be synthesized according to the reaction scheme and preparation examples below.

Compounds ■ and ■ below are conventional starting materials or prepared using conventional methods. There will be.

In compound H and throughout the reaction scheme R2 is alkyl, trifluoro Methyl, aryl or aralkyl.

When R2 is aryl in compound (2), the above compound is particularly suitable for R2 where R2 is phenyl. 5earles et al., MuoLEL, Chem, Volume 24, p1839 ( 1960), it will be manufactured by conventional methods. The teachings of 5earle are It is included here as a reference.

In compound ①, <R' is an alkyl containing 6 to 22 carbon atoms as defined above. It's a kill.

■　■　■ For structural formula I, as represented by formula ■ above, the reaction scheme is set for R'. Throughout, when R5 in structural formula (1) represents hydrogen, R5 is represented by H. R5 is H or higher If it has a different meaning, it is indicated as R5. used throughout the general process description L represents a leaving group, and throughout the general process description P represents any suitable protecting group. ing.

■ ■ H2OH Compound ■ can be deprotected, for example by ethereal hydrochloric acid or by catalytic hydrogenation. There will be.

To prepare compounds of the present invention in which R1 in formula I is alkyl, reaction with compound ■ In place of isocyanate, R'-L (for example, I, Br, CI , tosylate, mezilate, etc.). Compound ■ with strong salt such as NaH treatment with a group to form an alkoxide, followed by reaction with R'-L.

Va Compounds of the invention containing a 3-ether substituent (where T in the definition of R3 is 10- The following reaction may be used for the production of

C) 120R' I X■ X■ When converting compound X to compound Treat with nuclear reagent. The reaction is carried out without solvent or in the presence of an inert solvent; One example of such a solvent is dimethylformamide (“DMF”): When compound X■ is reacted with a primary or secondary amine, each of secondary amines in compound Secondary and tertiary amines are produced.

To produce a quaternary ammonium compound, typically compound XH is reacted with a tertiary amine. make them respond. Alternatively, compound X■ is reacted with a primary or secondary amine, and the resulting secondary A quaternary compound is produced by reacting a primary or tertiary amine with a suitable reagent.

To prepare the compounds of the present invention in which R3 contains a phosphate group [i.e., the following general reaction series will be used.

TV X■ VI I CH X■ Depending on the basicity of the -A-B moiety, the phosphate group of compound and becomes negatively charged, thereby forming the zwitterionic compound to be accomplished. The zwitterionic form of this compound is also within the scope of 2I and is included as part of the present invention. has been done.

Compounds of formula I in which carbon atom number 2 in the glycerol backbone is dialkyl substituted The following general reaction scheme may be utilized for the preparation of the product. In the reaction scheme , R4 is typically methyl or ethyl, but other suitable groups may also be substituted. Wear. R2 and R4 may be the same or different.

Diester XXI corresponds to R2 and R4 on carbon atom 2 without affecting It will be reduced to diol.

XXI[l　XXIV After protecting the oxygen on carbon atom 3, the bonded to glycerol backbone carbon atom 1 is The carbamate nitrogen in the side chain is substituted with %RS (wherein R5 is other than hydrogen), and the substituents of the 3-hydroxyl group undergo deprotection.

Phosphorylation of Compound XXV will be performed as described for Compound X. . or a hydroxyl of 3 carbon atoms as previously described for the compound TJjyJx Group hairalkyl side chain -(CH,). - may be combined to form an ether.

The silyl protecting group is removed by a conventional method to obtain a hydroxyl XX XX■ Mesylated compound XX■ readily reacts with H-A-B or A-B and is within the range of formula I. produces compounds contained in

To make compounds of the invention where R4 includes a thioether, compound XXX is treated with a base and and 1-alkylthiosulfonyl-4-methylbenzene to form the following compound Generate XX I.

XXX XXX 1 Compound XXX I is subsequently reduced at positions 1 and 3 to form the corresponding 1,3-diode generate a file.

xx　n Compound xxxn is converted into a suitable alkyl compound by heating appropriately if necessary under an inert atmosphere. May be treated with isocyanate. Apply protection, N-alkylation and deprotection steps. We will implement this as soon as possible.

xxxm XXXIV R2-C5CJzb++ CHzOSi(CH3)zC(CH3:hXXVI The 3-hydroxy compound XXX■ is alkylated using a protected alkyl chain reagent. Compound XXX■ is produced and then deprotected.

CH20(CH2)=-0-P XXX■ Compound XXX■ undergoes mesylation, thereby creating compound XXX■, followed by The mesylated compound is substituted with an appropriate H-A-B or AB to generate the compound 2. Ru.

A formula in which position 2 of the glycerol skeleton is substituted with sulfoxide or sulfone In the production of compound (■), thioether compound XXX■ is each used in equimolar or excess amount of metachloroperbenzoic acid (m-CPBA) to will undergo oxidation.

XXXIX XLI Substitution of mesylated protecting groups will be carried out as described above.

Preparation of compounds of the invention of formula I, in which in the definition of R3 T represents -NR''-So, - For the preparation, the following improvements are made to the -i reaction scheme.

LV The following reaction sequence may be utilized to prepare a range of compounds. Geo The compound Lll was monobrominated with carbon tetrachloride in the presence of I.liphenylphosphine. The remaining hydroxyl functions are protected by silylation.

lll Compound Lllll protects an intermediate compound containing a 3-hydroxyl group and protects the 3-position of the intermediate. It will be used in alkylation reactions.

IV Lν VI LνIf Compounds of the present invention in which T in the definition of R3 represents a carboxylic acid moiety; -0CO, - To make a product, a suitable alcohol is first treated with a strong base to form an anion. compound LVIIi by treatment with trichloromethyl chloroformate. obtain.

Compound LVIII is subsequently treated with V-U-0-Na'' to yield compound LIX.

IX When substituted with the appropriate primary or secondary amine in the above reaction, the carbamate (T·-QC(0)NR”-) will be produced.

IX To produce the reverse carbame-1, the following intermediate compound is trichloromethyl The intermediate product LX is treated with C1l-0-Na''. be done.

LXI Compounds LIX and LXI can be treated with a suitable base such as NaH followed by CI(31 and CH:+C(0)CI) or an appropriate alkylation such as acyl Treatment with a curing agent results in alkylation or acylation on the carbamate nitrogen, respectively.

Suitable for producing the compound of the present invention where ■ is A-B and A represents a thioether. The mercapto compound in question is treated with a strong base to generate the sulfur anion. sulfur ani On reacts with a mesylated compound such as compound X11O to cause mezilad substitution. let

CH, 0- (CHI)-S-B XII Similarly, ester (A=-0-C(0)-) and alkyl ether (A.- o-(coz), -) will be produced.

l II CHz-0-(CH2). -0-C-BXIV Certain compounds of the invention are prepared from endo- and exo-nitrogen containing starting materials. Ru. The final product of the invention may therefore contain exo or endo nitrogen bonds. cormorant. As used herein, “exo” refers to a nitrogen substituent, whereas “endo” indicates nitrogen contained within the ring.

To prepare compounds of the invention in which B represents substituted heteroalkyl, mesylation Compound ). If a protecting group is present, it can be subsequently cleaved to form a compound of the invention. give.

If B represents a heterocycloalkyl containing an amino group, then A is a direct bond. Certain compounds are prepared from mesylated intermediates as described above.

If B represents a substituted heterocycloalkyl (the substituent requires protection) protection of B to replace the mesylated intermediate (may or may not) shape is used. The compound is subsequently deprotected to produce the compound of the invention.

In this method, the mesylated intermediate Xll is substituted with a cyano compound, followed by alcohol to form an imino ester, which is then treated with a primary or secondary amine. It will be done.

C)1. OR' Xll +C)CN -→R2-c-R4CHz-0-(CHz)--CN The compounds of the present invention possess platelet activating factor ("PAF") antagonistic activity. example PAF is associated with platelet aggregation, smooth muscle contraction (particularly in lung tissue), vascular permeability, and neutrophil activity. It is important for the initiation of processes such as morphogenesis. Recently, PAF has been identified as a hidden factor in airway hyperreactivity. There is evidence to suggest that this is the case. Therefore, the compounds of the present invention can be used to treat PAF as a disease. or useful for those that are a factor in the disorder. This includes asthma and adult respiratory distress syndrome. Allergic diseases such as hives and rheumatoid arthritis and osteoarthritis This includes inflammatory diseases such as

The PAF antagonism of these compounds was demonstrated using standard pharmacological test methods described below. will be done. These test methods determine PAF antagonistic activity and determine the biological efficacy of PAF. is a standard test used to evaluate the usefulness of said compounds for neutralizing fruit. Ru. In vitro assays are simple screening tests, whereas in vivo assays It mimics the three-bed use of the compound described in .

HaL Mochioka test- Am1 size 61 kels: Ha’-’ (PPP)! Human blood collected from healthy male donors (50 Jd ) containing sodium citrate (3,8χ) and dextrose (2χ) Add solid solution (5 mfl). Blood was centrifuged at 110×g for 15 minutes. Carefully transfer the supernatant (PPP) to a polypropylene tube. Thrombocytopenic serum ( PPP) was obtained by centrifuging the PPP at 12,000 Microfuge B) was prepared. PPP is 3 o'clock after blood is drawn. Used within a few days.

Platelet Ai Shu Assay: When an aggregating agent such as PAF is added to PPP, platelets aggregate. The agglutinometer measures the light transmission through the PPP and compares it to the PPP. Quantify aggregation further. The agglutination assay was performed using a dual-channel agglutinometer (model 440). , Chronolog Corporation, Harbortown, PA). It was. PPP (0,45d) in the agglomerator cuvette was continuously stirred (3 7°C).

After the test compound solution or medium is added to the PPP and incubated for 2 minutes. , add 10-15 pl of PAF solution until a final concentration of 1-5 x 1 G''''M is achieved. Add as follows. Incubate until maximum light transmission is reached (usually 2 minutes). continue. Inhibition values are calculated by comparing the maximum aggregation obtained in the absence and presence of the compound. It was calculated by In each experiment, a standard PAF such as Albrasula An antagonist was used as a positive internal standard. Inhibitory concentration (IC5°) is 50% agglutination is the concentration of compound in micromoles at which PRP is inhibited and passes through each sample of PRP. The light transmission was measured in comparison to PPP. The test results are shown in Table A below. .

PAF is also known as bronchial stenosis in mammals.

PAF antagonism of the compounds of the invention against PAF-induced bronchial stenosis in guinea pigs can be evaluated in vivo by measuring the inhibition caused by

i4] pAp-in #P'dan - determination of hemostasis Non-stimulated guinea pigs were fasted overnight, and the following 'fJA 0, 9 ml/kg i, p, sialurethane (0.1 g/m dialibarbic acid, 0. Anesthetize with 4 g/m (7) ethyl urea and 0.4 g/- urethane). trachea Place the cannula in the tube and apply 55 strokes/min using a Barbard rodent respirator. Ventilate the animal with Connect the side arm to the tracheal cannula to the Barbard pressure transducer; Intratracheal pressure is measured continuously and recorded with a Barbard polygraph. Compound Insert a cannula into the jugular vein for administration. PAF to animals (0,4x/I <go, isotonic salt solution containing 25% BSA) is administered intravenously and within 5 minutes after administration. Record the peak increase in inflation pressure that occurs within the tube. The test compound was administered orally (0,4 2 hours prior to PAP) or intravenously (suspended in cellulose medium) or intravenously (in fluid). (10 minutes prior to PAF) as a tylsulfoxide solution .

As can be seen from the data in Table A above, the compound of formula (■) is effective against allergies and inflammation. It is an effective PAF antagonist, useful for treatment. I/Rugi and inflammation treatment The method of placement is part of the invention described herein.

When used to treat allergies, the compound should be administered at approximately 0,000 kg/kg per day. by the usual route of administration as a single or multi-day dose in an amount in the range of about 100 μ/a. will be administered.

Similarly, when used to treat inflammation, the compound may be administered at approximately 0.001 ■/kg per day. to about 100 kg/kg in single or multi-day doses. will be administered more frequently.

For the formulation of pharmaceutical compositions containing the compounds of the present invention, both solids and liquids are essential. It can be a suitable carrier as an active pharmaceutical.

Preparations in solid form include powders, tablets, dispersible granules, capsules, and medicated tablets. and suppositories. Solid carriers may contain diluents, fragrances, solubilizers, wetting agents, precipitants, etc. one or more substances that also act as anti-stagnation agents, binders or tablet disintegrants; Wax; it can also be an capsule-forming substance. In powder formulations, the carrier is fine. a finely divided solid that is a mixture with a finely divided active compound . In tablets, the active compound is combined with the carrier having the required binding properties in suitable proportions. , and tableted into the desired shape and size. Powders and tablets are about 5 to about 70 percent It probably consists of the active ingredients of the drug. Magnetocarbonate is a suitable solid carrier. Cium, stearic acid, magnesium, talc, sugar, lactose, pectin, dextrose Phosphorus, starch, gelatin, gum tragacanth, methylcellulose, carboxyme Examples include sodium chlorcellulose, low melting waxes, cocoa butter and similar can be lost. The term "formulation" refers to the active compound, the capsule-forming material that acts as a carrier, and the treatment. It is also intended to encompass methods of carrying the active ingredient (along with other carriers). or without) is surrounded by a carrier and is therefore associated with it. ing. Similarly, drug oblates are also included. Tablets, powders, medicated wafers and capsules can be used as solid side forms suitable for oral administration.

For the preparation of suppositories, mixtures of fatty acid glycerides or cocoa butter, etc. The low melting point wax is first melted and the active ingredients are uniformly dispersed therein while stirring. Ru. The molten homogeneous mixture is poured into conveniently sized molds and allowed to cool and thereby solidify. let

Liquid form preparations include solutions, suspensions, and emulsions. For example, for parenteral injection. Liquid formulations may be described, such as water or water-propylene glycol solutions. Polyethylene glycol and/or polypropylene that may also contain water It can be formulated as a solution in lene glycol. Aqueous solutions suitable for oral use are water with the addition of active ingredients, and suitable colorants, fragrances, stabilizers, sweeteners, solubilizers. It can be formulated by adding a thickening agent as necessary. Aqueous suspensions suitable for oral use are , viscous substances, i.e. natural or synthetic rubbers, resins, methylcellulose, carboxylic finely divided with sodium dimethylcellulose and other well-known suspending agents. It can be made by dispersing the active ingredient in water.

Liquid form preparations may also include solutions for intranasal administration.

Aerosols suitable for inhalation include solutions and solids in powder form; may be combined with a pharmaceutically suitable carrier such as an inert compressed gas.

Inhalation aerosols will be packaged in a pressure-tight container so that they can be delivered into the oral cavity for inhalation. or have a volumetric structure suitable for administration into the nasal passages, and A more precise amount of aerosol is released with each use.

Solid forms intended to be converted into liquid form preparations, both oral or parenteral, immediately before use. Body shape preparations are also included. Such liquid forms include solutions, suspensions and emulsions. can be lost. These particular solid form formulations are most conveniently provided as single agents; Used to provide a single liquid dosage unit. Or after converting to liquid form pre-determined from the liquid form in a syringe, teaspoon or other dose-measuring container. Many individual liquid doses can be obtained by measuring the desired dose. Sufficient amount of solids may be provided. Many liquid doses are prepared that way If used, the unused portion of the liquid dose should be kept at a low temperature ( In other words, it is best to store it in a refrigerator.

Solid form preparations intended to be converted into liquid forms contain, in addition to the active substance, fragrances. , coloring, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubles It may also contain a curing agent and the like. The solvent utilized in the preparation of liquid form preparations is water, isotonic water. , ethanol, glycerin, propylene glycol, etc. (as well as mixtures thereof) ) would be. Of course, the solvent used will be selected taking into account the route of administration. Liquid preparations containing wax, e.g. large amounts of ethanol, are not suitable for parenteral use. not present.

The compounds of the invention could also be administered transdermally. Transdermal composition Th is cream, It can take the form of a lotion, aerosol and/or emulsifier, and For this purpose, matrix or depot transdermal Can be included in patches.

Preferably, the pharmaceutical formulation is in single-dose form. In such form, the preparation is active a single dose containing a suitable amount of an ingredient (e.g., an amount effective to achieve a desired purpose) subdivided into. A single drug may be a packaged preparation, and the packaging may contain discrete quantities of the preparation. containing (e.g. packaged tablets, capsules and powders in vials or during the pull). The single drug may also be a capsule, wafer or tablet itself. or in any number of suitable packaging forms. Other compositions may be added as needed. can include therapeutic agents.

The amount of active compound per unit dose in the formulation is from about 0.001 to 1000, more preferably Suitably it varies from about 1■ to 100■ depending on the particular application or is divided into two cycles. Dew.

The actual dose used will depend on the patient's needs and the severity of the condition being treated. It will probably change depending on the situation. Determining the appropriate amount for a particular situation is not easy in this area. Ru. Generally, treatment is initiated with lower doses that are less than the optimal amount of the compound. after that, The dose is increased in small increments until the optimum effect under the circumstances is achieved.

For convenience, the total daily dose may be divided and administered in portions as needed during the day.

The amount and frequency of administration of the compounds of the invention and their pharmaceutically suitable salts may be taking into account factors such as the age, condition and weight of the patient as well as the severity of the symptoms. Adjustments will be made according to the judgment of the attending clinician. Typical for oral administration The recommended dosage regimen is 0.25 to 100 μ/day (preferably 10 to 20 μ/day). ■/day) and achieve symptom elimination in 2 to 4 divided doses.

Notice 1 Diethyl-2-ethyl-2-methyl tetran sulfate stirred with malonate paddle -butylammonium (129.88 g, 0.383 mol) and NaOH ( 30.60g) of 820 (370m) solution at 25 to 40°C. Diethyl malonate (71.9g).

0.382 mol) and CH31 (47,7 relative, 108.71 g, 0.76 6 mol) of CHzfJz (Company 370) is quickly added. Stir the system and Separate the H2Cl2 layer.

Evaporate the CHzlJz layer on a rotary evaporator to obtain a soft solid.

The solid was stirred with diethyl ether, filtered and the filtrate was rotary evaporated. Evaporation gives the title compound in the form of an oil. The oil was dissolved in diethyl ether (40 M), filter the solid and wash with diethyl ether. Dry the filtrate. Wash on NazSOa and evaporate in vacuo. It says to dry under high vacuum for 18 hours. The compound is obtained as a yellow oil.

Notice 2 N Lithium aluminum hydride (32,71 g) was stirred with a paddle under 2 atmospheres. , 0.862 mol) in dry diethyl ether (1,4f) Diesel of 2-ethyl-2-methyl 70nate (106.8 g, 0.528 mol) Carefully add thyl ether (40 M solution). Stir for 20 minutes at room temperature, then Reflux for 3 hours under N2 atmosphere.

Naz over 45 minutes at 20 to 25°C under N2 atmosphere without stirring vigorously. Add SOa.10HzO (100g). Continuing to stir for 18 hours is indicated. The compound forms as a white suspension.

Filter the suspension and wash the filter cake with diethyl ether. filtrate and Evaporating the washings in vacuo and drying under high vacuum yields the title compound as a soft wax-like solid. and get it.

NaH (8.92 g, 0.223 mol) was dissolved three times in hexane and once in DMF (2 30d), thermometer, fed-batch funnel, mechanical stirrer and N2 port/outlet. Place in a prepared 2 liter 3 neck round bottom flask. Diethyl methyl under nitrogen atmosphere Malonate (35.26g, 0.202mol) dissolved in DMF (108InR) Add the liquid over about 30 minutes or more. Stir for 30 minutes at room temperature and then heat to 20-25°C. Methyl thiotosylate (40.93 g, 0.202 mol) in dry DMF ( 68me) A suspension is generated when the solution is added over a period of 7 minutes or more. 64 hours at room temperature Stir for a while.

Add 120 (125d) to the reaction solution under N atmosphere at 22 to 28"C. .

) 120 (1,2I!) and diethyl ether (300mf ) and stir. Saturate the aqueous layer with NaCl. Separate and dilute the aqueous layer with diethyl ether. Extract with tel (3X 150d). Merging the ether layers, 11.0 (4XIO ○d) and saline solution (IX180 composition).

Drying over Na,SO, and rotary evaporation yields the title compound. Obtained as a clear yellow oil.

! Notice 4 -L Nino j So to So ≦ and Nis] So to Dan! Ukebon Yoyu Moxibustion〕≧Nihi Production Example 2 In the reaction shown above, if the 2-ethyl compound is replaced with the compound shown in Production Example 3, the following results are obtained. The compound is prepared in the form of a viscous, clear, slightly yellow oil.

1 Hiroshi 5 2-Methyl-2-propenyl-N-off-゛dylcarbamate 2-methyl 2- Propan-1-ol (23.8 g, 0.331 mol), n-octadecyl socyanate (88.7 g, 0.3 mol) and methylene chloride (300 Reflux the mixture of d) for 18 hours. Remove the volatile components under reduced pressure and store the remaining solids in the room. Thoroughly triturate with acetone (250 mf) at room temperature. The listed compound is removed by filtration as a white color. Obtained as a powder (m, p, 61.5-62.5°C).

l Hiroshi 6 3-N-off-゛dylcarbamoyl-2-methyl goo-deficient osmic acid (3 ,0 g, 0.0118 mol) of butyl hydroperoxide (3d) and Dissolve in t-butanol (597m).

Notation compound of Production Example 5! ! ! 71 (285g, 0.775mol) and t-buty Hydroperoxide (382ml 1.2.79mol) was added to tetraethyl ammonium acetate. acetone (5.7 g, 0.247 mol) 1) and cooled to 0°C. Add osmium solution over approximately 10 minutes . Stir in a water bath for 2 hours, then at room temperature for 48 hours.

Cool to 0"C, add an aqueous solution of NaHSO3 (794 g to 4,411), and The temperature is maintained between 0°C and 5°C.

Filter the brown precipitate, wash the precipitate with water, and add C1l□CZ2 (6.08L) /C) Dissolve in 130t (<3.041,) and wash. Remove the solvent and dilute the residue. Qi to ethyl ether (IL). Filter, wash with diethyl ether and dry The title compound is obtained as a white solid (m, p, 89.5-90.5).

1 Hiroshi 7 In place of 2-methyl-2-propen-1-ol by the method described in Preparation Example 5 above, By replacing the compound shown in the first column of the table below, we get the compound shown in the second column. A product is produced.

Reaction substrate product ■１　'Notice　18 In the method of Production Example 6, substitute the appropriate reaction substrate olefin listed in the table below. The diol shown in the second ml is then produced.

11 Hiroshi 9 1---Anisyldiphenyl methyl-2-methyl-3 (N-octadecylka Rubamoyl) glycerol The title compound of Production Example 6 was dissolved in pyridine (4.05L). p-anisyl-chlorodiphenylmethane (277 g, 0.397 mol) Add wo. Stir at room temperature until the reaction is complete as monitored by TLC.

Remove pyridine under reduced pressure. Dissolve the residue in CLC/z (3,4 L) and add H2O (2 times) and saturated NaCl solution (1,51). Dry with NazSO. After filtration, the solvent is distilled off from the filtrate.

The residue was dissolved in hexane and chromatographed on silica gel. Elute with ethyl acetate (4:1). Collect appropriate fractions, concentrate under slight pressure, and write The compound is obtained as an off-white solid (68-70°C).

Lj Notice 10 In the method described in Preparation Example 9 above, the appropriate 2.3- When replaced with diol, the 3-protected hydroxy compounds shown in the table below are generated. do.

System'@11 J-Methyl-N-off-゛dylcarbamoyl-2-meNaH with petroleum ether Wash and suspend NaH in tetrahydrofuran (“THF”) (520 ml).

The title compound of Production Example 9 above was dissolved in THF (2,071), and this solution was dissolved in NaH Add to the solution in a constant stream over 0.5 hours. Add THF (1,381) and stir at room temperature for 2.5 hours. CH3I (239m) THF (690 female ) Full moon the solution. Stir at room temperature and dilute with C (hexane-vinegar) until the starting material disappears. The progress of the reaction is monitored with ethyl acid; 4; 1).

Deurination protection ■ The reaction mixture was cooled to -5°C and diluted with hydrochloric acid-ether solution C648m over 45 minutes. 1) Full moon. Stir at −5°C for 0.5 h, and the starting materials disappeared as described above. The progress of the reaction is monitored by TLC until . Concentrate the residue under vacuum at room temperature. obtain. The residue was dissolved in CH,C/2 (3.5 L), )120 (4X, '2.3 L), then washed with saturated NaCl solution (2,3 L).

After drying with Mg5Oa, filtering, washing, and distilling off the solvent, a reddish amber color appears. get the top. Perform chromatography on silica gel. Elute with CH2Ch and dissolve Less polar impurities at the solvent front were removed, followed by hexane-ethyl acetate (4:1 ) and hexane-ethyl acetate (2:1) successively. Insert appropriate fractions into the chamber. Concentration at room temperature gives the title compound as a red-orange solid.

! Lj Notice 12 In the reaction described in Production Example 11, l-0-(p-anisyldiphenyl) Methyl-2-methyl-3-(N-octadecylcarbamoyl)glycerol When the reaction substrate shown in column 1 of the table below is substituted, the product shown in column 2 below is obtained. Manufactured.

+1 1 3 3-1 nia-(((1,1-dimethylethyl)dimethylsilyl)oxy]hebuty 2-methoxy-2-methylpropyl-N-methyloxychloride Rubamate C)lzO(CHz)70si(CHx)zC(C1h)*Manufacturing side 1 Dissolve the listed compound in 1 in DMF (30M) and stir at 18°C under N2 atmosphere. NaN(SiCCHz)*)z(110mft1.0 Add the THF solution of M). Stir at 18°C for 1.5 hours, followed by 18-2 Br(CHz)tOsi(CHx)zc(CHa)a (34,0g 10.11 mol) of DMF solution (100 m) is added. After stirring at room temperature for 1 hour, Heat to 50°C for 18 hours. Partition between H,O-diethyl ether.

Concentrate the ether extract on a rotary evaporator. The residue in cH, cl, (500d) and N20 (250d) to separate the "milky layer". water Extract the layers at CHzCfz (2x-250m) and combine the organic layers. HzO(2x C) 12cZzKF solution was dried with NazSO, and filtered. After filtration, the solvent is shaken out from the filtrate under slight pressure. High vacuum drying turns the listed compound into a dark amber color. Obtained as a colored oil.

Manufacturing-Delivery-H In Production Example 13, 3-(N-methyl-N-octadecylcarbamoyl)-2- Methyl-2-methyl-xyglycerol was subjected to the reaction shown in the first 11@ of the table below. Substitution of the substrate produces the product shown in the second column.

Lj Notice 15 -7-hydroxyheptyloxy-2-methoxy-methylpropyl-N- Methyl off-'dylcarbamate Production Example 13 (59.84g, most Dissolve 0.091 m/l/) in THF. At 15-18°c For more than 10 minutes 7 (C) + 3 (CHz) 3) JF ・3HzO divided into three parts Added. Stir at room temperature under N2 atmosphere for 3 hours, then add N20 and diethyl ether. distribute between. The progress of the reaction is monitored by TLC on the ether layer.

The reaction mixture was concentrated under slight pressure and the residual dark oil was dissolved in C1hCfz(300-). Understand. 1 (wash 3 times with 20 ml), dry with Mg5Os, filter, and filter the filtrate. Concentrate to 150-200 in a tally evaporator. Flush over silica gel Purification by chromatography gives the title compound.

111' Notice 16 In Production Example 15, 3-(7-(((Ll-dimethylethyl)dimethylsilyl) ]oxy]hebutyloxy-2-methoxy-2-methylpropyl)-N-methyl Octadecyl carbamate is placed in the following reaction substrate shown in column 1 of the table below. In other words, the product shown in column 2 below is produced.

−Ikki Kazutori−■− 3-(7-methanesulfonyloxyheptyloh + X--methoxy-2-methane Tylpropyl methyloff-cylmethanesulfonyl chloride (0.94g, 8.2 mmol) to dry 7 sen (18 m) solution 3-1 nia - (+ nit roxy)hebutyloxy Sylcarbamate (4.26 g. 17.8 mmol) and triethylamine (0.83 g, 8.2 mmol) in a stirred benzene solution (38 mF) for 5 hours. Add at 7°C. After 2 hours, dilute with twice the sample volume of diethyl ether. , monitor the progress of the reaction by C.

If necessary, further dilute with diethyl ether (15o1n1), (CH3GHz ) J-H (Filter off J and evaporate the filtrate in vacuo. Dry under high vacuum and remove as necessary. Purification of the sample by flash chromatography yields the title compound in a viscous form. Obtains as a slightly amber oil.

Regulatory Notice 18 In Example 17, 3-(7-(hydroxy)butyloxycou-2-meth) xy-2-methylpropyl-N-methyloctadecylcarbamate in the table below. When the reaction substrate in column 1 is substituted, the product shown in column 2 below is produced.

L=3-methyloff-゛zylcarbamoyloxy-2-methoxy2-methyl Propyl-2-bromoethyl boss-2-bromoethyl; J7'-t (2.60g) Dissolved in cHc/z (10d), 3-hydro xy-2-methoxy-2-methylpropyl-N-methyloctadecylcarbame (2,16 g) and hydrethylamine (2,79 g) in CHCl 3 (5 0m) at 0°C. After addition is complete, leave it to cool to room temperature. Warm and stir at room temperature for 24 hours. Evaporation under vacuum gives a brown semi-solid. excess of diethyl ether and filter. The filtrate was condensed to give a dark brown oil. Ru.

15 I The final product of step 1 was mixed with HzO (100mj) and THF (150d). Boil for 2 hours. Cool the reaction to room temperature and dilute with diethyl ether. workman Separate the aqueous layer and extract the aqueous layer repeatedly (3×60 mff). ether extract are combined and dried with Na25Oa.

Filter and evaporate under vacuum to give an oil. redissolving the oil in C) IC13; After drying over NazSOa, filter and evaporate under vacuum. Written when dried in vacuum The compound is obtained as a brown oil.

Notice 20 1-bromoethyl-4-(11-dimethylethyl dimethylcyC)Iz(J2 (300d) in 1-bromomethyl-4-hydroxymethylhenzene (20,75 g) was stirred with diisopropylethylamine (14.01 g) at 18°C, and t -Butyldimethylsilyl chloride (16,34g) in CH2Cl2 (100m ) Add the solution. Stir at room temperature for 1.5 hours, then reflux for 19 hours under N2 atmosphere. Flow. Monitor the progress of the reaction by TLC.

The solution was evaporated under vacuum at 30°C and the remaining soft solid was dissolved in hexane (350d). Stir. Filter the solids and wash appropriately with hexane. Filter the filtrate at 350°C. Evaporation of the washings and washes under vacuum yields the title compound as a crude product as a reddish oil. obtained in the form of

Notice 21 3-4-(Ll-dimethylethyl dimethylethyl oxymethylphenylmethyl 　Xy　-2-methoxy-2-methylprotyl N-methyloff　-゛zylcal Bamate) 13 Dry dimethylformamide (MP”) (240 td) of the title compound of Production Example 11 ) solution was stirred and the sodium bis(trimethifresilyl)amide ( 46.5d, 1.0m) of THF' is added to the solution at 22 to 24°C. . Stir for 1.5 hours at room temperature. DMF (20d) solution of the title compound of Production Example 2o The solution was added at 21 to 23 °C, stirred at room temperature for 1 hour, and then heated to 50 °C. Keep for 3 hours.

The sample was partitioned between 820 and diethyl ether and reacted by TLC of the ether layer. Monitor progress.

The reaction solution was concentrated by rotary evaporation, and the residue was dissolved in diethyl ether (4 00d). Filter through a 3 inch column of Celite. filtrate Evaporation on a rotary evaporator gives the title compound as an amber oil. get it.

↑1 Notice 2 3-4-hydroxymethyl phenylmexy-2-fuxy 2-methylpoxy The title compound of Lopyru-N-methyloc-゛zylcarba Production Example 21 (31,89 g) in THF (250 m) and cooled in a water bath while adding tetrabutyl anhydride. Quickly add Monium Fluoride 3H20. N2 at 2 o'clock in the atmosphere at room temperature Continue stirring for a while.

Concentrate with a low evaporator, 820 and diethyl ether (120 m R: 150 mρ) and separated. Extract the aqueous layer with diethyl ether, Combine the ether extracts and dry over NazSOa. Filter and concentrate the filtrate in vacuo. Shrink. Drying the residue in vacuo yields the title compound as a viscous oil as a crude product. obtained in the form of

The crude product was purified by Franch chromatography on silica gel and Elute with methylene chloride (1:9).

Notice 22A 1-Hydroxy-2-methyl-2-methylthio-3-N-methyl-N-off- 3-protected alcohol in the reaction described in Example 22 Substituting the mol gives the title compound.

+1’@23 -4- Methylsulfonyl oxymethyl phenylmethoxy -2-methoxy -2-Methylpropyl-N-methylo The title compound of Production Example 22 and (CH3C H2) Stir a benzene (50 relative) solution of 3N (1.35d, 0.98g) and the base of C) 13SO□C/(0.75d, 1.11g) at 10-12°C. 20d solution is added. Warm slowly to room temperature and stir for 2.5 hours. The title compound is obtained.

After 2.5 hours at room temperature, the reaction mixture was diluted with diethyl ether (200 ml) and The by-product, (CH3CH2)3N-HCI, is filtered off through Celite. filtrate is evaporated and dried under high vacuum to produce crude compound as a viscous oil. Get it in the form of things.

For purification, perform flash chromatography of the crude product on silica gel. , acetone-methylene chloride (5:95) U-methyloff--”, t/L/ htb-hamoyloxy-2], ytoxy2-methyl-3-N-2-chloro Roethilue Arrestry Carponyloxy Propane The title compound of Production Example 11 and β-chloroethyl isocyaner 1 (0.74 g, 7 mmol) and pyridine (30 m□Q) and stir at room temperature for 17 hours. . Add diethyl ether (100 mR) to ice water (2xloOm) and 6 dilute FI Wash with CI (3X100id).

Drying with MgSO4, filtration and concentration yields the crude product of the title compound as a colorless oil. (2.6 g) is obtained.

The crude product was dissolved in pyridine (4M) and β-chloroethyl isocyanate (0, Add 5d) and stir at room temperature for 66 hours. diethyl ether (100ml) Add ice water C3 x 100 d) and wash with 6 dilute HCI (2 x 100 d).

Dry over 11g5o, filter and concentrate to give the title compound as a colorless oil.

Cf　(CJ)　5NC(0) instead of CZC)hc)IJc(0) Using different starting materials will produce longer alkyl chain analogs.

11 Notice 2 U-Methyloff-゛Sylcarbamoyloxy-2-methoxy-2-methyl-3 -N-2-Iodoethyl Compound (1.0 g) of Amitsuka Production Example 24, N Mix a1 (0.8g) and 2-butanone (15d) and heat at 17:00 under N2 atmosphere. Reflux for a while. The resulting white solid is filtered and washed with diethyl ether. Concentrate to dryness and a viscous orange oil.

The orange oil was chromatographed on silica gel and ethyl acetate-C)12 Elution with c72 (2:9B) gave the title compound as a yellow oil, which was It solidifies into a yellow solid over time.

−Production, production, production, and production 12+9 Nidy-N-methyl carbamoyloxy-2-methoxy-2-methy Ru-3-N-2-chloroethyl-N-acetyl aminocarbonyloxy-7' C1/<7-The title compound of Production Example 24 (0.8 g, 1.5 mmol) was added to T Dissolved in HF (10 mff) and diluted with acetone and dry ice under N2 atmosphere. Cool to 5°C and add LiN(Si(CH3:h)z (2 components). -78° Stir at C for 15 minutes. With a syringe C)1. C (0) CI (0,5 decimated) and stirred at -78°C for about 24 hours.

Add saturated NaHCOs solution (20 m) and stir for 10 minutes. diethyl ether ( 5M), followed by saturated NaHCO, (20m) # and HzO (30mf). Wash with

Drying over hgsoa, filtration and concentration yields the title compound as a yellowish oil (1, 0 g). Purity was determined by TL using ethyl acetate-CHz (J+: (1:4) Monitor at C.

For further purification, perform silica gel chroma I-graphy of the crude product and acetic acid Elute with ethyl-CH□ (Jz (1:9)).

II Hiroshi 28 1-n-hexadecyl t+>-2-methyl-2-prog7 hexadecyl promi (20.99g), 3-hydroxy-2-methyl propene (20.85g) ), KOH (14.4 g) and (CH3(CH2)3)-1jT in a dry vent. In addition to ZEN (20M), heating was carried out under reflux, while argon was added under a slightly positive pressure using a balloon. Keep the reaction system in the atmosphere. TLC using hexane-diethyl ether (9:1) Monitor the reaction progress by

Cool the reaction system and add diethyl ether (75d). IN HCZ (2 XIOM), saturated NaHCO3 (IX150ml) and saline (2X10 Wash with M). Dry with Na25O.

Filtration and distillation of the filtrate yielded the title compound as a waxy solid (b, p).

182-185°C).

-1 notice 28 Table of 2-n-hexadecyloxymethyl-2-methyloxene Production Example 27 The above compound (9.49 g) was dissolved in CHz (Jz (200 relatives)), and m-chlorofilter was added. Add benzoic acid (6.90 g) in portions over 5 minutes. Ethyl acetate-hexane The progress of the reaction is monitored by TLC using San (1:9).

Once the reaction was completed, the reaction solution was washed with saturated NaHCO3 (2 x 200 m), then c H, ct, when the solution was stirred with 10% NaH3O3 aqueous solution for 20 minutes, the organic layer was Cloudy with white precipitate. The organic layer was saturated with 10 ml of Na)lcO3(I), followed by Na Remove the precipitate by washing with 0H (IN, 2×200I11i).Clean with MgSO4 Drying the H2Cl2, filtering and condensing the filtrate yields the title compound as a clear oil. get it.

11° Notice 29 2-Methyl-2-propenyl-N-methyl-N-off-yl H2 THF (90 papers) of the title compound of Production Example 5 (18.0 g, 49.0 mmol) ? The solution was stirred and lithium bis(trimethylsilylhexane solution (LM, 5 4mf) dropwise over 25 minutes. The resulting yellow suspension was heated under an inert atmosphere for 25 minutes. Stir for 1 minute, then dissolve CHsT (7.67 g. 54.0 mmol) in THF (15d). Add the liquid dropwise over 10 minutes. Stir at room temperature for 25 hours. NH4fJ aqueous solution ( 2, d, 6) 1) Next, add CH2CZt (5M). silica gel powder Filter through a pad and wash the pad with CHzCtz (50%).

The filtrate and washings were combined and the solvent was distilled off under reduced pressure, leaving a yellow oil. remaining yellow The colored oil was chromatographed on silica gel using ethyl acetate-petroleum ether. The title compound was obtained as an oil by stepwise gradient elution (1:24 followed by 1:9). get it.

'H NMR (CDCf3; δ value for internal T?IS): 5.00 (br s, IH), 4.94 (br s, Lfl), 4.53 (s, 2H), 3. 29 (br　t, 2H), 2.94 (s, 3H).

1, 78 (s. 3H), 1.15-1.6 (multiple nm, 32H), 0.9 2(t,3H).

Mass spectrum (electron impact): 382 [(M+1)”: 100χ1.

381[M’　;41χ1 1 notice l 3O N-methyl-N-off-sylcarbamine, O-(n- hexadecyloxy)-2-methyl-2-propene to the title compound of Production Example 29. Replaced and treated with m-chloroperbenzoic acid as described therein. The title compound is obtained as a colorless oil which solidifies on standing at room temperature.

'H NMR (CDCh): 4.25 (d, J=12.5Hz, IH), 3.96 (d, J=12.5Hz, LH).

3, 26 (t, J=7.5Hz, 2N), 2.90 (s.3) 1), 2.7 8(d, J=5)1z, IH).

2, 68 (d, J = 51 (z.LH), 1.52 (m, 2H), 1.38 ( s, 3H), 1.26 (m, 30H), 0.88 (t, 3H).

MS ■uL: 398 [(M+1)'; 100χ], 310 (22%) , 284 (43χ).

Blue 11 Notice 31 Table of 1-hex-acyloxy-2-methyl-2-methoxyglyceride Production Example 28 A solution of the above compound in CH30H (150 mR) was stirred, cooled to 0°C, and p- Add toluenesulfonic acid (200 μl). Ethyl acetate-hexane (1:3) The reaction progress is monitored by TLC using .

Concentrate in vacuo and ClIC! 3 (200mf). NaHCO: + ( 10χ, 3 x 50 m), washed with saline (2 x 50 m) and washed with MgSO. Dry with Ru. Filter to remove the drying agent and concentrate the filtrate to obtain the title compound in the form of a crude product. . Franch chromatography eluting with ethyl acetate-hexane (1:3) It is separated and purified by

＋l　’＠　32 12 years ago, 5K1 R2, J) 纺Z2l2kuI C■zOH CHzOC(0) CI Mix the title compound of Production Example 31 (0.463 g) and THF (10 components) at O'C. match. Add trichloromethyl chloroformate (0.193d) in one portion.

Stir under argon atmosphere for 18 hours while warming to room temperature.

Concentration of the reaction mixture in vacuo yielded the title compound as a pale yellow oil and 3-hexyl ester. Oxy-2-methoxy-2-methylpropyl-2-chloroethyl carbamate CHzOc　(0)　N)ICH□CH, (J manufacturing side 31 notation compound (0,8 345 g) and β-chloroethyl isocyaner) (0,227, vf) were dried. Add to dry pyridine (25d) and stir at room temperature under argon atmosphere for 17 hours.

Concentration in vacuo gives the title compound.

Calculation on Merck silica gel (20 g) eluting with ethyl acetate-hexane (1:4). The title compound is purified by ram chromatography. Collecting the appropriate fractions The title compound is obtained.

-k" L 2 salmon once 3-(11-dimethylethyl dimethylethyloxy-2-methylthio-2 -Methylpropyl n-off -゛Silcarba CJ 0-5i-C (CH Yu) 3 □ CH3 3-octadecylcarbamoyloxy-2-methyl-2-methylthio-1-pro Patul (37.28 g, 0.0864 mol) and diisopropylethyl acetate Stir a solution of min (15.87d, 0.0911 mol) in DMF (200 mol) 1 at 18°C under N2 atmosphere. -Butyldimethyl silyl chloride (1 3.03 g, 0.0864 mol) of Dumun F (75 ml) solution was poured over 8 minutes. and fed-batch. The solution was stirred for 3 hours at room temperature and 15 minutes at 32”C. The reaction proceeded between ethyl acetate and hexane ( 1:4).

Continue stirring as needed. The reaction mixture is evaporated under vacuum to give a soft solid.

The soft solid was packed into a column of silica gel as a warm solution in ethyl acetate. - Carry out Fransch chromatography eluting with hexane (189).

The eluate containing the title compound was dried over Na2SO4 and evaporated under vacuum to yield the title compound. The product was obtained as a viscous oil (41.82 g, 89% yield) which gradually turned white. Solidifies to a solid (+111) 20-22°C).

+l Hiroshi 35 1-　N-Methyl-N-off。゛Dylcarbamoyloxy-2-methyl-2- Methylthio-3-t-butyldimethylthi1CH3CH3 The 2-methylthio compound from Preparation Example 34 with sodium hydride and C)131 When processed as described in Preparation Example 11, the title compound is prepared in the form of an oil.

One letter, one dish, one dish the next day. 1-　N-methyl-N-off。-゛silcarbamoyloxydi-2-methylsulf Inyl 2-methyl-3-methylsulfonyloxyhebutyloxy propane 2-methylthio compound Th from Preparation Example 18 (1.64 g, 2.57 mmol) and m-chloroperbenzoic acid (0.47 g, 2.70 mmol) in CH2 (J , (40 mf). Stir the solution at room temperature. Na25Oa (IXl, IM) Wash with 1 (20 (2χ)) and dry with Mg5Oa. A mixture of phoxide, sulfide and sulfone is obtained.

The mixture was washed again with NaHCf) + (2Xl, IM) and N20 (LX), This was followed by drying with Mg5Oa, evaporation under vacuum, and drying under high vacuum for 18 hours. An amber oil (1.42 g) was obtained, which was composed of sulfoxide:sulfide (3:1). Contains.

A flash column of silica gel was eluted with ethyl acetate-hexane (1:2). After performing ram chromatography and collecting the appropriate fractions, the title compound is separated into two diaphragms. Obtained in the form of an oil as a mixture of stereoisomers.

Lj notification l37 -　N-methyl-N-off　-゛Sylcarhamoyloxydi-2-methyl-2-methy Rusulfonyl-3-methylsulfonyloxyhebutiooxypropane 2-methylthio compound of Production Example 18 (2.75 g, 0.0043 mol) and m-chloroperbenzoic acid (2.50 g, 0.0145 mol) in CHzC! z(4 ON) Stir the suspension.

After stirring at room temperature for 18 hours, additional In-chloroperbenzoic acid (0.82 g.

0.0040 mol) and continued stirring for 5.5 hours.

The reaction mixture consisted of Na)lcOz (3X401n1.1.IM) and N20(I Wash with X50mf) and dry with Na25Oa. The desiccant is filtered and the filtrate is Evaporate under vacuum. Drying the residue in vacuo for 15 hours converts the title compound into a viscous oil. Obtained as a solid product.

System'@38 3-dibenzylamino-2-hydroxy-2-methyl-1-(N-methyl-N- Off −゛Dilcarbamoyloxypropane□ CHI! -N (CH2C6H5)! The title compound of Production Example 30 (8.85g, 22.3 mmol) and dibenzylamine (27.9 g, 141 mmol) ) is stirred and heated to 130° C. for 19 hours under an inert gas atmosphere. Obtained Cool the solution to room temperature and add CH2C1 (235In1) and diethyl ether. (35d). Stir the solution and add hydrochloric acid ether solution (50d, 170ml) Li.

mol, 3.4M) is added. The thick suspension is stirred and then filtered. Micro-pressure filtration Remove the solvent from the solution. The remaining gummy material was dissolved in diethyl ether (210d) and Redissolve in the mixture of CH3CH2 (115d) and dissolve the resulting solution in saturated brine (115d). 50d). Filter through anhydrous Mg5Os and distill off the solvent from the filtrate under slight pressure. The remaining oil was chromatographed on silica gel and chromatographed with ethyl acetate. Elution with xane (1:4) gives the title compound as an analytically pure oil. .

Lj Notice 39 3-dibenzylamino-2-methyl-2-methoxy-LIN-methyl-N-off -゛2-Hydroxy compound from the previous production example of dylcarbamoyloxypropane As described in Production Example 11 (when treated with Na1 (and CH31), the indicated compound is obtained in the form of an oil.

'HNMR (CDC/3): δ7.33.7.29 (m, l0H), 4.0 8 (d, J=10Hz, IH).

3.96 (d, J = 1011z, IH), 3.71 (d, J = 13.41 (z , IH), 3.59 (d.

J = 13.4Hz), 3.21 (s, 3H), approximately 3.2-3.0 (cannot be determined) Multiplet without, approx. 28), 2.85/2.6Hsl wide singlet, approx. 38) , 1.5-1.4 (br m, 2H), 1.25 (m, 30 tl), 1. 2Hs, 2) ILo, 88(t, 38).

MS (FAB): 609 [(M+1)”; 99χ], 607 [(?l -1)”; 100χ], 5313-amino-2-methoxy-2-methyl- L = N-methyl-3-dibendi from Preparation Example 39 in a Parr shaking hydrogenation apparatus. Ruamino-2-methoxy-2-methyl-1-(N-methyl-N-octadecylcarboxylate) Rubamoyloxy)propane (9.34 g, 153 mmol), glacial acetic acid (0, 981 g, 16.4 mmol), 5% palladium on carbon catalyst (1.88 g) and and absolute ethanol (130d). The mixture has 15 p, s, i, at room temperature. Shake under hydrogen pressure for 110 minutes. The catalyst was removed by filtration through Celite and under slight pressure. The solvent was distilled off from the filtrate, and cozcxz (150 m) and water (100 d) were added. Saline (50d) and 1.1M sodium bicarbonate aqueous solution (50mR, 1,1 M). Separate the layers and boil the aqueous layer at CHzCZz (3X45m). Extract. The combined extracts were mixed with water (100 mR) and saline (2X 150 mR). and filtered through anhydrous Mg5On to remove the solvent under reduced pressure.

The remaining oil was subjected to silica gel chromatography to obtain CHzCZz-CH3 0H (stepwise concentration gradient solution from 95:5 to 90:10 to 78:22) The title compound was eluted with an analytically pure gummy material (containing 0.2 mol of water). get as.

'HNHM (CDC/3): δ4.18 (d, J=lOHz, IH), 3 ．． 98(d, J=10)1z, Iff).

3.3-3.2 (poorly split multiplet, 2H), 3.28(s, 31( ).

2.90 (s, 3H), 2.72 (s, 2H), 1.70 (s, DzO-variant Can be exchanged.

>2H), 1.52 (br m, 2H), 1.27 (m, 30H), 1 ．． 17(s, 3) 1).

0.89(t, 31().

MS (FAB): 429 [(M+1)”; 100χ].

Notice 41 3-Nynylsulfonylami-2-methoxy-2-methylpro and RuN-meth Chill-N-Off-Dylcarbamate Production Example 40 (1.0g, 2.33 mmol) and (CH3CH2)3N (283■, 2.80 mmol mol) in dry THF (15d) was stirred and the 2-chloroethanesulfur Dry T)IF (1 ml) solution of Honyl chloride (456 ml, 2.80 mmol) Add. The resulting mixture is stirred for 4 hours at room temperature under an inert gas atmosphere. reaction mixture The material was filtered, the filtrate was concentrated under reduced pressure, and the residue was diluted with ethyl acetate-brine (35d:35 d) distribute between. Separate the layers and extract the aqueous layer with ethyl acetate (2x15m).

The combined extracts were washed with brine (35d), filtered through anhydrous MgSO4, Remove the solvent from the filtrate under slight pressure. The remaining oil was chromatographed on silica gel. The title compound was obtained as an oil by elution with ethyl acetate-hexane (2:3). It showed the following spectral characteristics.

'HNMR (CDCL:+): δ6.54 (dd, J=10.17.5Hz, 2H), 6.23 (d, J=17.5) 1z, IH), 5.90 (d, J= 10Hz, 1N), 5.0Hbr m, 1B), 4.12 (d, J=11H z, LH), 4.04 (d, J=11) 1z, LH), 3.27 (s, 3) 1).

3.20 (br t, 2) 1), 3.04 (d, J<10Hz, 2H), 2.90 (br　s, 3H).

1.52 (br m, 2H), 1.28 (m, 30tD, 1.23 (s, 3 H), 0.88 (t.

3H).

Spectrum: 519 [(M+1)” 1.429 (100χ) ;536 [(M+1+NH3)”].

]2-methyl-2-propen-1-ol 26.0 g; 0.36 mol) and N,N-dioctylchlorocarbonylamine (48.8 g; 0.12 mol; normal Synthesized from dioctylamine and trichloromethyl chloroformate by ) in dry tetrahydrofuran (126 ml) was heated to 50°C under nitrogen at 17:00. Heat for a while. 2-Methyl-2-propen-1-ol (34.6g; 0.48 mol) and a third amount of alcohol (8.65 g; 0.36 mol) is introduced. Continue heating at 50° for an additional 31 hours before heating. 80″ for another 38 hours under nitrogen Heat the reaction mixture to C. The mixture was concentrated under reduced pressure and the residue was filtrated with silica gel. Perform rush chromatography and elute with ethyl acetate-hexane (5:95) The title compound is then obtained as an oil.

'11 3-7-r3-N-methyl-N-off-゛zylcarbamoyloxy-2- Methoxy-2-methylenechloroboxy hebutylthiazolium methane sulfate ゛'The title compound of Production Example 17 (1.46 g, 2.3!5 mmol), thiazo (5 g, 587 mmol) and tetrabutylammonium iodide (43 , 4■, 0.18 mmol) was heated to 80°C for 5 hours under N2 atmosphere. The progress of the reaction during heating is monitored by TLC.

Distill to remove excess thiazole and dry the residue on a rotary evaporator. The title compound is obtained as an amber gum. Drying the sample under high vacuum The title compound is obtained as a brown glass (yield 1.50 g) on silica gel. When purified by flash chromatography, the sample becomes CH2CZ2-CH3 Elutes with 0H-H2O (81:18:1). Dry with Na25O, and Processing in a creevaporator and drying on high vacuum gives a white gum.

To further purify the title compound, it was dissolved in diethyl ether and dried over MgSO4. Ru. Evaporation of the solvent and drying on high vacuum yields a white amorphous solid.

The sample is dissolved in hexane (7 ml) at -11°C. Soft white that melts at room temperature Filtration of the colored solid yields a viscous oil.

The sample was redissolved in hexane, stirred with Dalcoro 60 (0.3 g), filtered, and then vacuumed. Removal of the underlying solvent and drying under high vacuum yields an off-white adhesive glass. obtain. When dried in a high-pressure vacuum, the title compound was obtained as a wax-like rubber, In the method described in Example 1, the 1tAl in Table 2 below darkens over time. Using appropriate starting materials selected from the following formulas, the final products shown in columns 2 and 2 are obtained.

3- 4- 3- N-methyl-N-off-゛zylcarbamoyloxy-2- Methoxy-2-methylpropoxy butylthiamine mensulfone In the method described in Preparation Example 13, silylated bromobutanol was treated with a similar protected bromobutanol. Replace with Mohepta tool. As described in Production Example 15 <N(C)IzCLC Deprotect with HzCLLF.3H20 and mesylate as described in Preparation Example 17. . Introducing the thiazole as in Example 1 gives the title compound.

One disaster, one look, one place, one land. The compound shown in 111 in Table 4 is a standard treated with Pd carbon (10χ) under H2 atmosphere. The debenzylated compound shown in column 2 is synthesized under quasi-reaction conditions.

3-　N-methyl　-゛zylcarbamoyloxy-2-methoxy-2-methy Lepropyl-2-thiazo 1o ethylphosph 1:25 The title compound of Production Example 19 (2.96 g), thiazole (8.4 g) and tet Mix butyl ammonium iossite (1°36g) at room temperature, Heat on a heated oil bath to 120°C for 2 hours and 15 minutes. Add ether and stir Stir to remove insoluble matter. The filtrate was concentrated and purified on silica gel with CHCra-C)+30 Flash chromatography eluting with H-LO (65:25:3) Purify by Combine the appropriate fractions and remove the solvent at 30 °C under high vacuum. A sticky brown solid is obtained.

The sticky brown solid is dissolved in methanol and precipitated with ethyl acetate. When filtered An off-white hygroscopic solid is obtained.

Drying under high vacuum over P2O at room temperature for 2 days yields the title compound as the bromine salt. .

Nu Aeon's The crude product (0.6 g) was converted to C)l(J3:C1+30H:)lzo(75 :24:1) by flash chromatography (24:1). After the second chromatography, the appropriate fractions were combined and 30-30 min under high vacuum. The solvent was distilled off at 5°C, followed by P, 0. It says to dry under high vacuum for 2 days. The zwitterionic form of the compound is obtained as the monohydrate.

5'6 According to the method described in Example 5, the reactions of surfaces 1 and 2 in Table 6 below were placed. When this is changed, the product shown in vertical pipe 3 is missed.

1--N-mer - Roboxy Rubenzil 1mm Mensulfo - The indicated compound (2.24 g) of Production Example 23 and thiazole (2 components) were mixed under N2 atmosphere for 8 hours. Heat to 0°C until reaction is complete (monitored by TLC).

Excess thiazole is distilled off on a water bath (35-40°C) (dry eye thiazole captured by a strap). Obtained in the form of a product.

For purification, the title compound was purified using a silica gel column with CH□C1z-Cl(:+ Flash chromatography using 0H-1 (20 (80: l'a: 0.25) Raffy gives the title compound as a white waxy solid.

Stir in hexane (5d) and pass the resulting cloudy solution through a medium sintered glass. Filter, then wash the white solid filter cake with fresh hexane (2X3d). The white wax-like solid is further purified by washing.

Evaporation of the filtrate gives the title compound as a viscous oil, which is composed of P2O, It solidifies upon drying under high vacuum (n+, p, 33 to 42°C).

3-7-medoxy71-dimethyl-410-dioxo-5,9-dioxa-1 1-Diazano Cosyl-Thiazium Yoji L-YuXl-3 Anal Criticism The title compound of Production Example 25 (0.4 g) and thiazole were mixed and heated at room temperature for 17 hours. Stir and check the progress of the reaction by TLC (C1+30H-CH2Cl; 1:9) Monitor by.

To further purify the compound, silica gel (10 0g), CLClz (300m), 10% CH 30H-CH2Cl2 (200d) and HzOCH30HCH2Cl2 ( 5:, 30:100). Drying the appropriate fractions yields the indicated compounds. It is obtained as a hygroscopic yellow solid, which is suspended in diethyl ether and filtered. Ru.

3-Acetyl-711-dimethyl-311-diaza-59-dioxa-410- Dioxo-7-medoxino cosyl didinium chloride 11 The title compound (1, og) of Production Example 26 was added to pyridine (12d) under N2 atmosphere. Reflux for 18 hours. By C with ethyl acetate-CLClz (1:4) Monitor reaction progress.

Pyridine was removed under vacuum and the crude product was chromatographed on silica gel. Elution with 5-20% CH30HCHzClz gives the title compound in crude form.

The crude product is dissolved in CHlClz and filtered to give a clear yellow solution, the filtrate is Concentrate to dryness. Add diethyl ether and concentrate to dryness again to obtain a yellow rubbery solid. get. When dried overnight in a vacuum oven, the listed compound becomes a chlorine salt.1-2- 2-methoxy-2-methyl-3-N-ethyl-N-off-cylaminocarbo Nyloxypropyloxycarbonylaminoethyl-viridinium Mouth 1 Do 11 Production Example 240 Compound ¥1IJ (80h+ff1) was dissolved in pyridine (10d'). Dissolve and reflux under N2 atmosphere for 18 hours. CHC/3CH30H)IzO(65 :25:4) to monitor the reaction progress by TLC. reaction completed Remove the solvent on high vacuum. The residue was chromatographed using TLC grade silica gel (25 g). Carry out chromatography and dissolve with CH:1O)I CHC/3 (15:85). put out Remove the solvent using a rotary evaporator, add CHCl5 and M Dry with gSO4. Filter and remove the solvent to obtain an oil. oily substance is wax Dry under vacuum until solidified to a similar solid.

The resulting waxy solid was redissolved in cHzct and dried over MgSO4. filter Evaporation of the solvent under high vacuum yields the title compound as a yellow-green gummy solid. Ru.

7-medoxy711-dimethyl-410-dioxo-59-dioxa-3,1 1-diazanocosyl 1-methyl ammonium according to the method described in Example 10. When pyridine is replaced with (C113)3N (3d), the title compound becomes the chlorine salt. obtained in the form of a white solid (m, p, partially 110-130°C).

Substituting thiazole for pyridine in the method described in Example 10 and producing β-chloroethyl isocyanate in Preparation Example 24 was converted to C1(CHt”) sNC Substituting another starting material such as (0), 6.14-diaza-10,14- Dimethyl-8,2-dioxa-7,13-dioxo-10-methoxide triaco Tantanylthiazolium is obtained as the chlorine salt in the form of a gummy yellow solid.

3- 7- 3- N-methyl-N-off-゛zylcarbamoyloxy-2- Ethyl-2-methylenebroboxy hebutylazo1ium methanesulfo-1 0SOzCHs” The appropriate compound of Preparation Example 18 (694,1■, 1.12 mmol) and thiazo (2.4 g, 28.2 mmol) was heated at 80°C under N2 atmosphere for 22 hours. heat. TLC of the reaction mixture is performed to monitor reaction progress.

water bath (temperature maintained at 35°C), distilling the thiazoles under reduced pressure. Remove. The residue (602,4■) was subjected to flash chromatography using a silica gel column. Carry out chromatography, CHtCh-CHiOH-H,0 (80: 18: Elutes at 0.25).

The eluted compound (514,4■) was dissolved in CHzCfz and dried with MgSO4. Then remove the solvent using a rotary evaporator and transfer to a high vacuum bottom-tally evaporator. Drying in a turf gives the title compound as a mixture of oil and wax.

The appropriate compound of Preparation Example 18 (1.53 g, 2.40 mmol) was added to thiazole ( 5.0 g, 58.7 mmol) and heated to 80°C under N2 atmosphere for 18 hours. heat.

The thiazole was distilled off at 25-30°C under reduced pressure, and the resulting residue was distilled into CH2C. Melt in l2. Filter the solution and load the filtrate onto a silica gel column. Hz Flash eluting with CZz-ClhOH-HzO (81:18:1) Perform chromatography. When appropriate fractions are collected and evaporated, a soft glass-like substance is formed. Obtain mucilage.

The gum is dissolved in diethyl ether, filtered and evaporated under vacuum at 28°C.

The residue is dried under high vacuum. The residue was dissolved in hexane, and after evaporation of the solvent, it was purified over P2O3. Produces a soft brown wax when dried under high vacuum. Dissolve the sample in CH, CI, When washed with Na) ICO3 solution (2 x 1.1 M) and dried, the title compound was removed by 1 ．． Obtained as the 25-hydrate.

As described in Example 13, the compound shown in the vertical jfAI below was treated with thiazole (2 m, 28.2 mmol) gives the compound shown in @1 column 2.

3-(2-IH-imizol-1-yl ethyl sulfonyl amino- -Methoxy-2-methylpropyl methyl off-silcarbame I. Leaves F (12m) of the title compound of Production Example 41 (400cm, 0.772mmol) Imidazole (526 mg, 7.72 mmol) was added to the solution followed by NaH (61,6 1M.

1.54 mmol (60%) is added. The resulting mixture was heated under an inert gas atmosphere. , stir at room temperature for 24 hours. Filter the reaction mixture and remove the solvent from the filtrate under slight pressure. do. The residue was dissolved in CH3CN　Z　(10mj　) and diethyl ether (15d ) and wash the solution with a saline (20d)-water (5mA) mixture. Ru. The aqueous layer is back extracted twice with 10 d volumes of CH2Cf2. The combined extracts are anhydrous. Filter through Mg5O, and evaporate the solvent from the filtrate under slight pressure. The oily residue is Chromatography was performed on lica gel, CHzClz CH: +0H (90: 10) gives the title compound as an analytically pure, slightly sticky solid. Ru.

'HNMR (CDCl2): δ7.63 (s, IH), 7.10 (obvious Heavy line, IH).

7.00 (obvious singlet, 1) 1) + 5.4Hbr s, D, 0-conversion possible Noh.

IH), 4.47 (t, J=7.5Hz, 2H), 4.20 (d, J=12 ．． 5flz, ], 1().

3.95 (d, J=12.511z, IH), 3.48 (t, J=7.5Hz , 2H), 3.3-3.0 (complex m, 4) 1), 3.26 (s, 3H), 2.90 (two nearby peaks).

3H), 1.5N distorted triple line, 2H), 1.28 (m, 30H), 1 ．． 20 (s, 38), 0.90 (t, 3) 1).

Next day (FAB): 587 [(M+1)”; 100χ1゜410-diaza- 610-dimethyl-6-medoxy-8-oxa-9-oxo-3-sulfonylo Fucosyl-3-methylimidium methyl sulfur The title compound of Example 15 (115 mg, 0.196 mmol) was dissolved in toluene (2 ml) solution of dimethyl sulfate (49.4 mm, 0.393 mmol) is added.

The resulting solution is heated to 50°C for 2 hours under an inert gas atmosphere. Remove solvent under reduced pressure. The residual oil was subjected to silica gel chromatography and purified with CI (zcZz : C1 (30) 1: When eluted at HzO (65: 25: 4) The title compound is obtained as an analytically pure gum.

'HNMR (CDCZ3): δ9.49 (s, IH), 7.60 (br s , IH), 7.26 (br S.

II (), 6.46 (br m, IH), 4.76 (m, 2H), 4.2 -3.9 (m, 2H).

3.96 (s, 3H), 3.74 (s, 3H), 3.69 (t, J=6Hz , 2H), 3.3-3.1 (overlapping multiplets, 4H), 3.27 (s, 3E), Lgi(s,, 3K).

1.51 (n+, 2H), 1.27 (m, 308), 1.23 (s, 3) 1 ), 0.88 (t, 3H).

MS Dandan L: 601 (M"Gate of quaternary cations").

monohexyloxy-mexy-2-methyl-3-2-(NN-dimethy Ruamino Ekishi Carbonyl Otori] Jishiroshi±Z CH2-QC(0) CI The title compound of Production Example 32 (0,3242 g) and benzene (5 ml) were heated at 0°C. dimethylaminoethanol (0,088m) and (C)13CH Add 3N (20 composition). The solution is stirred for 0.5 h and concentrated under vacuum. melt The liquid is diluted with petroleum ether (5-) and filtered.

The filtrate was washed with petroleum ether and concentrated 2X5d) to give the title compound as an orange oil. and generate it.

Using silica for TLC (40 g), ethyl acetate-hexane-(C1lsCH□), Separate by chromatography, eluting with IN (25:2:73).

Appropriate fractions are collected and concentrated to yield the title compound.

Treatment of the title compound of Example 17 with C) 131 under standard reaction conditions yields triethyl alcohol. An ammonium compound is obtained.

In place of dimethyl ethanol in Example 17, as shown in vertical WA1 of Table 18 below, The product shown in Line 2 is produced using the compound shown in Table 2.

1-hexyloxy-2-methoxy-2-methyl-3-2-2-methyl Mizol-1-yl ethoxycarbonyl oxypropane Bromocarbonate compound of Example 18 and 2-butanone (15d) Methylimidazole (1.25 equivalents) was mixed and heated under argon atmosphere for 18 hours. Heat reflux.

The reaction solution was concentrated in vacuo, and CHCZ3: CH30H (7: 3) followed by C) Ic13: C1 (30H: H2O Purify by chromatography eluting with (7,0:3.5:0.5) The title compound is obtained as a clear oil.

+2039932) 1-hexacyloxy-2-methoxy-2-methyl-3-2-2-methyl-3 -N-methylimidazole-(/l/technical) Bread Yoshito e The title compound of Example 19 (0,2453 g) in dry benzene (15d).

0.493 mmol) and CH31 (0.046d, 0.741 mmol 1 ．． 5 equivalents) and heated to reflux for 3 hours. Collecting the resulting precipitate yields the indicated compound. obtain. MS: FAB (M-iodine) 511゜1-hex-゛yloxy-2 -methoxy 2-methoxy 3-2-NN-dimethylamino ethoxy carbonylate Le Oki 2 Eco” Shishi Z In the method described in Example 19 above, 2-methylimidazole is placed in pyridine. The title compound is obtained as the bromine salt.

-Disaster-U As described in Example 20, the reaction substrates in column 1 of the table below were converted to C) 131. On treatment, the product shown in Section 2 below is obtained.

-Ten Isse-5-■1 When the reaction substrate shown in vertical plane 1 below is substituted in the method described in Example 10, The product shown in profile 2 below is made.

Anti-breath one group-1 life-bottom one Arashi one-Shoichi Fruit-”L”1-Hani In Example 23 above, instead of pyridine, the appropriate starting materials shown below are used. and the product shown below is obtained.

The title compound of Production Example 17 (1.87 g, 3.01 mmol) and R-(-)- Thiazolidine-4-carboxylic acid, sodium salt (0.74 g; 3.01 mmol ) in dry dimethyl sulfoxide (3M) was heated to 50°C under nitrogen atmosphere for 9 hours. heat. The reaction mixture was diluted with 9M saturated NaC! Pour into aqueous solution, diethyl ether (4 Extract with X50d).

The combined extracts are washed with water and dried over anhydrous Na, SOa. Filter off the desiccant, Remove the solvent from the filtrate under vacuum. The residue was chromatographed on silica gel. Elution with acetone-methylene chloride (1:9) gives the title compound. Must If necessary, the product so isolated can be rechromatographed using the same solvent system. The title compound is obtained as an analytically pure oil.

Sou-jung-5 part 7-2-methoxy-2-methyl-3-methyloff-゛zylcarbamoyloxy Propoxy hebutyl-2-amino-3-methylthio propionate R-(-)-thiazolidine-4-carboxylic acid in the method described in Example 25 When sodium salt of S-methyl-L-cysteine is used instead of sodium salt, The title compound is obtained.

cusp-shi-■-u 3-7-3-py1dinyloxyhepyloxy-2-methoxy-2-methy Lupropyl methyloff-゛Silca production example 17 described compound (500■, 0 ．． 804 mmol), 3-hydroxypyridine (380 mmol, 3.90 mmol ) and tetrabutylammonium iodide (0,060 mmol). Heat at 130°C for 1 hour. Filter the reaction mixture through a pad of silica gel It is written as eluting with acetone-methychloride water (100:10:1). The mezilad salt form of the compound is obtained as a yellow semi-solid.

Dissolve Mezilard salt in methylene chloride, and the solution is a sodium bicarbonate aqueous solution, Wash with water and saline. Dry the organic layer with anhydrous sodium sulfate and filter. The filtrate is then concentrated in vacuo.

Drying the resulting residue over phosphorus pentoxide gives the free base form of the title compound as a dark green oil. Obtained as a solid product.

Free base (75■; 0.112 mmol) in 0.5 ml methylene chloride Dissolved, 0.04m of 3.4? 1 hydrochloric acid solution in ether is added. Stir for 5 minutes at room temperature. Stirring, removing volatile components, and drying under vacuum over phosphorous pentoxide yields the title compound in 1 hydrate. It is obtained as an analytically pure brown semi-solid in the form of the hydrate hydrochloride.

The following formulations illustrate several dosage forms of the compositions of the invention. In each, The term “active compound” refers to 3-(7-(3-(2,3-dihydro-2-imino) 2-methoxy-2-methylpropyl-N- Represents methyl octadecyl carbamate. However, this compound is effective in It is contemplated that other compounds of formula 1 may be substituted.

·· Lots of Real-"L~masu-"5 1 Active compound 1050 2 Lactose USP 212 563 3 Cornstarch, edible 3040 As a 10% paste in purified water 4 Cornstarch, edible 4540 5 Magnesium stearate 37 Total 300 700 Manufacturing method excluded Mix the first and second items in a suitable mixer for 10-155 minutes. third Granulate the mixture with that of the item. The wet granules are passed through a coarse sieve (e.g. 1 74"). Dry the wet granules. If necessary, sieve the dry granules. Mix with part number 4 and mix for 10-155 minutes. Add product number 5 and 1-3 Mix for a minute. Compress the mixture to the appropriate size and weight on a suitable tablet machine. Ru.

Real-”L”1-and 1 Active compound 1050 2 Milk' + fMU SP 196 5733 Cornstarch, edible 407 0 4 Magnesium stearate NF 4 7 total 250 700 manufacturing method Mix the first, second and third items in a suitable mixing machine for 10-155 minutes. Ru. Add part number 4 and mix for 1-3 minutes.

Mix appropriate two-part hard gelatin capsules on a suitable capsule making machine Fill it with things.

Real-”L2 attachment-5゜ Active compound 1050 For reconstitution, sterile water for injection or bacteriostatic water for injection is added.

Fruit-"L Nimasu-"- Possible to stop Bottom - beans Active compound’! 71 100 Methyl p-hydroxybenzoate 1.8 Propyl p-hydroxybenzoate 0. 2 Sodium bisulfite 3.2 Edetate disodium 0.1 Sodium sulfate 2.6 Water for injection q, s, ad 1.0 ai! Manufacturing planning 1. Add P-hydroxy to a portion of the water for injection (85% of final volume) at 65-70°C. Dissolve the benzoic acid ester compound.

2. Cool to 25-35°C. Sodium bisulfite, edetate disodium Add and dissolve sodium sulfate.

3. Add active compound and dissolve.

4. Add water for injection to bring the solution to final volume.

5.0.22 Filter the solution through a membrane run and fill a suitable container.

6. Finally, sterilize the unit by autoclaving.

Real - JLJ student once Active compound 10.0 Phenylmercury acetate 0.02 Aminoacetic acid, USP 3°7 Sorbitol solution, USP 57.0 Benzalkonium chloride solution 0.2 hydroxide for pill production) IJum IN solution purified water, USP 1.0 in total amount d Real-Leaving LJL once Active compound 1.0-20.0 Benzyl alcohol, NF 20.0 Mineral oil, USP 50.0 White petrolatum, USP, total production capacity of 1.0g Disperse the active compound in a portion of mineral oil. Calculated amount of white petrolatum, remainder of mineral oil and Mix benzyl alcohol and heat to 65°C, then heat to 50°-55° while stirring. Cool to C. The dispersed active compound is added to the above mixture with stirring. room Cool until warm.

Disaster - Goichi spot once Active compound 1.0-20.0 Stearic acid, USP SO.

Glyceryl monostearate 100.0 propylene glycol, USP o.

Sorbitan Monobalmitate Polyethylene 50.0 Sorbitol Solution, USP 30.0 Benzyl alcohol, NF 10.0 Purified water, USP total amount 1.0g Production method Stearic acid, glyceryl monostearate and sorbitan monovalmitate Heat the polyethylene to 70°C. Sorbitol solution, benzyl acetate in separate containers Dissolve half of the alcohol, water and propylene glycol and heat to 70°C.

Add the aqueous phase to the oil phase while stirring at high speed. Active on residual amounts of propylene glycol The compound is dissolved and added to the emulsion, and the temperature of the emulsion at that time is 3. 7°-40°C. Stir to mix evenly and cool to room temperature.

Although the invention has been described with respect to the specific embodiments shown above, it will be appreciated by those skilled in the art that Alternatives, modifications and variations thereof will become apparent. all such alternatives , modifications and variations are considered to be within the spirit and scope of the invention.

Submission of translation of written amendment (Article 184-8 of the Patent Act) August 1st, 1990 Toshi Ue, Commissioner of the Patent Office 1)! 1. Display of patent application PCT/US89100336 2. Name of the invention 2.2-Disubstituted glycerol and glycerol analogs, compositions and uses Method 3. Patent applicant Address: New Chassis, USA 07033. Kenilworth.

Gearloping Hill Road 2000 people Name Schiering Corporation 4. Agent Address: Shin-Otemachi Building, 206-ku, 2-2-1 Otemachi, Chiyoda-ku, Tokyo 5. Date of submission of written amendment Related compounds have been described in various reports. For example, 5CRIP PAF REPORT, PJB Publishing, 1986, Nimumu 3 [(Sendan.

Volume 20 (1985) Chapter 20 ρp193-202 and EP-AO14776 8 describes a large number of related compounds synthesized by various researchers.

Procedural amendment August 6, 1990

Claims (1)

[Claims] 1. Structural formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼I A compound represented by or a pharmaceutically suitable salt or solvate. {In the formula: Rl is alkyl containing 6 to 22 carbon atoms or -C(O)-D, in the formula -D is NR3R6, in the formula R5 is hydrogen, alkyl containing X carbon atoms, aryl, heteroaryl, hetero alkyl, arylalkyl or cycloalkyl; R6 is alkyl, aryl, heteroaryl, heteroalkyl containing y carbon atoms R, arylalkyl or cycloalkyl, and at least R5 or R6 If one is alkyl, the sum of X and y is an integer from 1 to 22. or R5 and R6 together with the nitrogen to which they are attached it is substituted with arylalkyl so as to form a cycloalkyl group may be; R2 is lower alkyl, trifluoromethyl, aralkyl or aryl; R3 is TUV, in the formula T is -OPO3-, -O-C(O)-, -O-, -S-, -NRa-, -NRa represents SO2-, -O-C(O)-NRa- or -NR2CO2-, in the formula R a is H, lower alkyl, or acyl; U is -(CH2)e- (in the formula, e is an integer from 2 to 10) or ▲mathematical formula, chemical There are formulas, tables, etc. (in the formula, each f is independently 1, 2, or 3). ,and V is -A-B, in the formula A is a direct bond between U and B, -O-, -S-, -O-(CH2)n- (n in the formula is 1, 2 or 3), -O-C(O)- or -N(R2)- (wherein Ra is as defined above) and B is alkyl, substituted alkyl, heteroalkyl , substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, a Reel, heteroaryl, substituted heteroaryl, or ▲ mathematical formula, chemical formula, table, etc. ▼ [In the formula, W is O, S or NRb (In the formula, Rb is H, lower alkyl or CN), Rc is independently H or lower alkyl], and - the AB group contains at least one nitrogen atom; and R4 is -X-CbH2b+1 [wherein b is an integer from 1 to 6, and X is methyl Ren, O, S(O)c (wherein c is O, 1 or 2) or -N(Ra)- (wherein Ra is as defined above); provided that R1 is alkyl If so, T cannot be -OPO3}2. R1 is -C(O)-D, The compound of claim 1, wherein D is as defined in claim 1. 3. 3. A compound according to claim 1 or 2, wherein R2 is lower alkyl. 4. T is -O-C(O)-O-, -O-, -O-C(O)-NRa- or -N Ra-CO2-, where Ra is as defined in claim 1. A compound according to any one of Items 1, 2, or 3 of the desired scope. 5. 5. The compound of claim 4, wherein T is -O-. 6. Claims 1 to 5, where U is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound according to any of the above. 7. A is a direct bond between U and B, and B is a heteroaryl or a substituted heteroaryl 7. A compound according to any one of claims 1 to 6, which is aryl. 8. A is a direct bond between U and B, and B is heterocycloalkyl or is substituted heterocycloalkyl, according to any one of claims 1 to 6. Compounds listed. 9. A is -O- and B is heteroaryl or substituted heteroaryl, A compound according to any one of items 1 to 6 of the desired scope. 10. Claims where in R4 b is 1 and X is O or S02 A compound according to any one of items 1 to 9. 11 formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲Mathematical formulas, There are chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲Mathematical formulas, There are chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲Mathematical formulas, There are chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲Mathematical formulas, There are chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲Mathematical formulas, There are chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼▲Mathematical formulas, The compound according to claim 1, which has a chemical formula, table, etc. ▼. 12. A process for preparing a compound of formula I as defined in claim 1, comprising the steps of: each, (A) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Formula for the compound i1 L2-A-B i2 (In the formula, R1, R2.R4, T, U, A and B are as claimed. as defined in Range 1, where L2 and L2 are leaving groups); (B) a compound of formula I in which group B has a positive charge and A is a direct bond between U and B; To prepare a compound of formula i1, a compound of formula B i3 (wherein B is a free compound and is defined in claim 1) (identical to group B except for one bond); or (C) To produce a compound of formula 1 where T is -OC02-, the formula ▲ mathematical formula, chemical formula , tables, etc. ▼i4 (where R1, R2, R4 and L1 are as defined earlier) The compound with the formula L2-OUV i5 (wherein L2 is a leaving group and U and V are as defined above) let; (D) R1 is C(O)NR5R6 (in the formula, R5 is H and R6 is alkyl) ) In order to produce a compound of formula I, which is, the formula ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ Alkylating the compound of i6; Here, in the above process, the functional groups are protected if necessary or desired. , following one or more of the following steps as necessary or desired; (a) removing one or more protecting groups; (b) converting a compound of formula I to a different formula; (c) converting the compound so produced into a salt or a solvent; Convert to Japanese, (d) converting the compound so produced into a zwitterion; The manufacturing method comprising: 13. having structural formula I defined in any one of claims 1 to 11; A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier. 14. For manufacturing pharmaceutical compositions useful for treating allergies or inflammation The use of a compound of formula I as defined in any of claims 1 to 11 in . 15. Compounds of formula I as defined in any of claims 1 to 11 can be used for pharmaceutical purposes. A method for producing a pharmaceutical composition, the method comprising mixing the composition with a pharmaceutically acceptable carrier.