JPH05502226A - new compound - 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] new compound The present invention describes a family of antibacterial and antimycoplasmal compounds, a method for their production, and Their use in human and veterinary medicine and in the manufacture of such compounds. This relates to intermediates.

A compound of general formula (A).

(In the formula, the R0 group contains 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. represents an optionally substituted 5-membered heteroaryl ring) is EP-A-008, 7953 (Beacham Group plc) and EP-A-0123378 (Beacham Group plc) Already disclosed by Ham Group plc), and substituted with its carboxylic acid group or R0 group. It is recognized as a monic acid A derivative.

Such compounds were found to have antibacterial and antimycoplasmal properties.

The compound of formula (A) described in EP-A-0087953 has a Re group substituted with phenyl, An example of an oxacylyl substituted with a group including substituted alkyl and chenyl. Ru.

Further, EP-A-0399645 (Beacham Group plc) (as claimed in this application) (published after the priority date), Ro is 5-furyloxazole-2 -yl, or 5-isoxazolyloxazol-2-yl moiety of formula (A) Compounds are disclosed.

Surprisingly, the Improved biological activity of different types of substituted oxacylyl derivatives compared to It turns out.

That is, the present invention provides a compound of formula (1). H (In the formula, R1 is a pyridyl group bonded to the oxasilyl moiety via its carbon atom. and this pyridyl group may be unsubstituted or the same or different up to 5 groups, preferably or may be substituted with up to three substituents).

Suitable substituents for the pyridyl group of R1 include, for example: (i) Halogen, cyano, azide, nitro, formyl, carboxy, carboxylic acid salt, sulfo, or sulfonate (ii) amino, ureido, carbamoyl, or or sulfonamide (each of these groups has a nitrogen atom that is further represented by the following item (iv), (V ), one group selected from the groups listed in (vi), or two groups that are the same or different. (ii) hydroxy, or mercapto (which may be substituted with Each group is hydrogen. As an example of a group suitable for positioning on the nitrogen atom of the pyridyl ring is the group listed in the previous section (iv), (v), (vi) and also the amino group (pyridyl group). Regarding substituents, it may be substituted with the groups listed in the preceding sections (iv), (v), and (vi). ) is included.

Specific substituents for this pyridyl group include, for example, hydroxy, halogen, cyano, nitro. (C,-,)alkyl (optionally substituted), aryl, heterocyclic group, 0 1~. alcoquine, carboquine and its salts, (01-l) alcoquine carbo Nyl, acyl, amino, mono- or di(C,~,)alkylamino, carba moyl, mono- or no(C,~,)alkylcarbamoyl, carbamoyl xo, mono- or di(C,~6)alkylcarbamoyl, anolamino, ( C, ~,)alkoxycarbonylamino, (C,-,)alkylthisu, aryl Thio, (01~,)alkylsulfinyl, arylsulfinyl, (C,~6 ) alkylsulfonyl, arylsulfonyl, sulfamoyl, mono- or di- -(C,~,)alkylsulfamoyl.

More specific examples of this pyridyl group include, for example, hydroxy dihalogen (e.g. (fluoro, chloro, bromo); (C, ~,)alkyl (e.g. methyl); (C , ~,) alkokino (e.g. methokino, ethokino); (C, ~I) alkylti O (e.g. 'thiomethyl): (C, ~,)alkylsulfinyl (e.g. methyl (C,~,)alkylsulfonyl (e.g., methylsulfonyl) di(C,~l)alkylamino (e.g. dimethylamino), di(C, ~6) Alkylcarbamoyl. Suitable for positioning on the nitrogen atom of the pyridyl ring. Examples of such groups include the groups listed in (iv), (v), and (vi) above, as well as amines. groups (groups listed in the preceding sections (iv), (v), and (vi) regarding substituents of pyridyl groups) may be replaced with).

Specific substituents for this pyridyl group include, for example, hydroxy, halogen, cyano, nitro. b, (01-l) alkyl (optionally ffi-substituted), aryl, heterocyclic group , Cl-1 alkoxy, carboquine and its salts, (C0~,) alkoxy carbonyl, acyl, amino, mono- or di(C,~,)alkylamino, carbonyl Rubamoyl, mono- or di(C,~,)alkylcarbamoyl, carbamoy mono- or di(C,~,)alkylcarbamoyl, acylamino , (C,~I)alcokynecarbonylamino, (C,~,)alkylthio, ali Rutisu, (01~,)alkylsulfinyl, arylsulfinyl, (C, ~,) alkylsulfonyl, arylsulfonyl, sulfamoyl, mono- or includes di(C,~,)alkylsulfamoyl.

More specific examples of this pyridyl group include, for example, hydroxy.

Halogen (e.g. fluoro, chloro, bromo); (C,~,)alkyl (e.g. (methyl); (C, ~,) acyloxy (e.g. methoxy, ethoxy); (C , ~l) alkylthio (e.g. thiomethyl): (C,-,)alkylsulfini (e.g. methylsulfinyl>; CC, ~,) alkylsulfonyl (e.g. (e.g., methylsulfonyl), di(01~,)alkylamino (e.g., dimethylalkylamino), di(C, ~6)alkylcarbamoyloxy (e.g., N, N-die tylcarbamoyloxy).

The term "aryl" as used herein includes up to five blanks that are not particularly newly defined. or phenyl, which may be substituted with up to three substituents, or naphthyl. It is something that

The pyrinol group at R' can be α-1 or β- with respect to the unpreferred pyridyl nitrogen atom. Those having a single substituent located on the carbon atom are preferable.

As used herein, the term "heterocyclic group" refers to oxygen, nitrogen, sulfur, etc., unless otherwise defined. Aromatic and non-aromatic single or non-aromatic rings containing up to 4 heteroatoms selected from yellow or a fused ring, and may be substituted with up to three substituents. Heterocycle is 4-5 , preferably 5 to 6 atoms.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

Substituents of the groups defined as optionally substituted above, such as alkyl, cycloalkyl, etc. to a kyl, alkenyl, cycloalkyl, alkynyl, aryl, or heterocyclic group. contains the following groups = (a) halogen, cyano, azide, nitro, phthalimide de, formyl, carboxy, carboxylate, sulfo, sulfonate, or Kisso: (b) Amino, imino, hydrazino, hydrazino, ureido, guanidino, cal bamoyl, or sulfamide (in each of these groups, the nitrogen is further represented by the following item (d), (e), one group selected from the groups listed in (f), or the same or different may be substituted with two groups).

(C) Hydroxy, oximino, hydroxymoyl, penbuhydroxymoyl , or mercapto (in each of these groups, hydrogen is represented by the following items (d), (e), (f)) may be substituted with one of the groups listed in ).

(d) R' group (R' represents aryl or heterocyclic group): (e) R@ group (R@ is (C,~,)alkyl, (C1~?)cycloalkyl, (C,~,)alkeni (C,~l)cycloalkenyl, and (02~l)alkynyl (each of these The groups are selected from the groups listed in each item (a), (b), (c), (d), and (f). may be substituted with one or up to three different groups): (f) R' Co-, R '0CO-, R" Co-, R'○C0-2RゝSo-, R' So, -, F ’, @So-, or R@S○,-, where R’ and Ro are the above terms (d), (e ) are the same as those defined respectively.

alkyl, cycloalkyl, alkenyl, cycloalkenyl, or alkynyl Suitable substituents on the group include, for example, halogen, cyano, azide, nitro, hydroxy, Oxo, carboquine, (C,~l)alkoxycarbonyl, carbamoyl, mono - or di(C,~,)alkylcarbamoyl, sulfo, sulfamoyl, mono no- or di(C,~,)alkylsulfamoyl, amino, mono- or di- -(C,~,)alkylamino, acylamino, ureido, (C,~,)alco oxycarbonylamino, 2,2,2-trichloroethquine carbonylamino, a Ryl, heterocyclic group, (C, ~1) alkoxy, acyloxy, 2-thenoyl, (C ,~,)alkylthisu, (C,~,)alkanesulfinyl, (C,~,)alkyl Cansulfonyl, hydroxyimino, (C,~,)alkoxyimino, hydrazi hydrazino, benzohydroquimoyl, guanidino, amidino, or imino Contains alkylamino.

Suitable substituents on aryl groups include, for example, halogen, soano, (C,~,)alkyl , phenyl, (C,~,)alkoxy, halo(C,~,)alkyl, hydroxy , amino, mono- or di(C,~l)alkylamino, anrulamino, nito B, carboquine, (C, ~l) alkanoyl, (C3-6) alkoxycarbonyl (01~,)alkoxycarbonyl (01~,)alkyl, (C+~,)a Rukylsulfonyloquine, (C.

~,)alkylthisu, (C,~,)alkylsulfinyl, (C,~,)alkyl sulfonyl, sulfamoyl, mono- or di(C,~,)alkyl sulfur amoyl, carbamoyl, mono- or di(C,-,)alkylcarbamoyl including.

Suitable substituents for heterocyclic groups include, for example, halogen, (C,~,)alkyl, (C,~,) , )alkoxy, halo(C,-,)alkyl, hydroxy, amino, mono- or is no (C, ~6) alkylamino, carboquine, (C, ~,) alkoxylic Bonyl, (C, ~,) alkoxycarbonyl (C, -,) alkyl, aryl, or contains oxo.

In the compound of formula (I), the pyridyl group R' is α-1β- with respect to the pyridyl nitrogen atom. may be bonded to the oxazole ring via a carbon atom located at 1 or α- . Preferably, in the compound of formula (I), the pyridyl group of R1 is and is bonded to the oxazole ring by a carbon atom in the β-position.

The compound of formula (1) can also be named "(l-norsen-2-yl)oxazole". good. Normonyl is 3-((2S, 3R, 4R, 5 S)-5-((2S,4S,5S)-2,3-epoxy 5-hydroxy-4- Methylpequin\.

)-3,4-dihydroxytetrahydrobilan-2-yl2-methylpropylene Boo-1(E)-enyl group is common.

H It fosters the same absolute configuration as the corresponding group of . Furthermore, R1 of the compound of formula (I) The substituents on the pyridyl group may contain one or more chiral centers.

The present invention encompasses all such isomer possibilities.

The compounds of formula (I) of the present invention are intended for pharmaceutical compositions and are each substantially pure. pure form, such as at least 50% pure, even more suitably at least 75% pure, Preferably it is provided in at least 95% purity (% is on a weight/weight basis).

Impure preparations of compounds of formula (I) may be prepared in a purer form for use in pharmaceutical compositions. It can be used. Although the purity of the intermediate compounds of the present invention is not critical, Qualitatively pure forms are preferred for compounds of formula (I). Books as much as possible Preferably, the compounds of the invention are obtained in crystalline form.

Some of the compounds of the present invention may be crystallized or recrystallized from organic solvents; It may be present in crystal solvents or crystal products.

The present invention includes such solvents within its scope. Similarly, compounds of the invention Some substances are crystallized or recrystallized using water-containing solvents; In such cases, hydration water may be formed. The present invention relates to stoichiometric hydrates, and examples Compounds containing variable amounts of water, produced by methods such as freeze-drying, are also within the scope. It includes.

The compounds of the present invention include, for example, the following compounds: 2-(l-norsen-2-yl) )-5-(2-pyridyl)oxazole 2-(1-norsen-2-yl)-5-(3-pyridyl)oxazole 2-(l-norsen-2-yl)-5-(4-pyridyl)oxazole 2-(1-norsen-2-yl)-5-(2-methyl-5-pyridyl)oxazo rule 2-(1-norsen-2-yl)-5-(1,2-dihydro-2-oxo-5- pyridyl)oxazole 2-(1-norsen-2-yl)-5-(2-methoxy -5-Biridyl)oxazole 2-(1-norsen-2-yl)-5-(1,2-dihydro-1-methyl-2 -Oxo5-pyridyl)oxazole5-(2-methoxy-5-pyridyl)- 2-(1-norsen-2-yl)oxazole 5-(2-chloro-5-pyridyl)-2-(1-norsen-2-yl)oxazo rule 5-(2,3-dichloro-5-pyridyl)-2-(+-normon-2-yl)o Xazole 5-(2-methylthio-5-pyridyl')-2-(1-norsen-2-yl)o Xazole 5-(2-methylsulfinyl-5-pyridyl)-2-(1-norsen-2-y ) Oxazole 5-(2-methylsulfonyl-5-pyridyl)-2-(1-norsen-2-yl ) Oxazole 5-(2-(N,N-diethylcarbamoyloxy)-5-pyridyl)-2- (1-Norsen-2-yl)oxazole 5-(2-bromo-5-pyridyl)- 2-(1-norsen-2-yl)oxazole 5-(2-fluoro-5-pyridyl)-2-(+-normon-2-yl)oxa sol 5-(2-nitoxy-5-pyridyl')-2-(1-norsen-2-yl)oxy Sasol 5-(3-bromo-5-pyridyl)-2-(1-norsen-2-yl)oxazo rule 5-(2-dimethylamino-5-pyridyl)-2-(1-norsen-2-yl ) Oxazole 5-(2-fluoro-3-pyridyl)-2-(1-normon-2-yl)oxa sol Compounds of formula (I) are described in EP-A-0087593, EP-A-0123378. It can be manufactured in the same manner as described above.

In particular, the invention provides compounds of formula (I[) (wherein R' is the same as defined above, and Zl, Z2, Z3 are the same or or a different one, each of which is a hydrogen or hydroxyl protecting group). to form a compound of formula (I), followed by removal of the hydroxyl protecting group if necessary. The present invention provides a method for producing a compound of formula (I) comprising:

The compound of formula (I[I) is a carboxylic acid anhydride, or a mixed anhydride, or an acid chloride, For example, trifluoroacetic anhydride, or trichloroacetic anhydride, or trichloroacetic anhydride. Cyclization may be performed using loacetyl.

Especially the latter one is used in the presence of birinone and 4-dimethylaminopyridine. is preferred. In this reaction, the hydroxyl group of the 1-normole-2-yl group is anol The tril\rose formed during cyclization requires subsequent deprotection. The chill group can be dissolved in charcoal dissolved in a solvent, e.g. water, alkanol, or mixtures thereof. It may be removed using potassium acid. Appropriate desorption to remove other anol residues The protection conditions are easily understood by experts. Also, l-norsen-2-i The hydroxyl group of the hydroxyl group was protected with carboxylic anhydride before cyclization, and the following Deprotection may be performed using conventional methods.

Suitable cyclizations of compounds of formula (III) include, for example, phosphorus oxochloride, phosgene, thiochloride. A chlorinating agent such as chlorine, or phosphorus pentachloride, and a tertiary agent such as triethylamine. It can also be carried out in the presence of a class amine or pyridine. This kind of anti- The reaction is carried out at low temperature in an organic solvent such as dichloromethane or tetrahydrofuran. It is carried out at high temperatures, e.g. -80°C to 100°C, for several hours to several days. Good. Preferably phosgene, or oxophosphorous chloride, at a temperature of O''C to 20°C. Is it preferable to use it?

In addition, for cyclization, triphenylphosphine and carbon tetrachloride are used as chlorination reagents to form a tertiary atom. an inert solvent such as acetonitrile, or may be carried out in acetonitrile-pyridine. This type of method is erotic , Vorbruggen and K. Krorikievec (Tetrahedron Le tt.

1981, 4471) describes the production of a compound of formula (III) and The cyclization of this compound to give the compound of formula (I) is particularly preferably carried out in the same place. good.

The compound of formula (I[[) above is novel and has been developed as a chemical intermediate in the above method. It is for use.

Accordingly, the present invention also provides compounds of formula (I[[) as defined above.

Compounds of formula (I[[) include, for example, the following compounds.

N-[2-year-old xo2-(3-pyridyl)ethyl]monamitobilidyl)ethyl Comonamide Soethyl Monamide Compounds of formula (I[[) are described in EP-A-0087593 (Beacham Group By reacting with isobutyl chloroformate in the presence of a suitable base such as ethylamine This intermediate is then converted into the amine hydrochloride of formula (iv): R'C0CHtNH,"CI-(IV) (wherein R1 is as defined above) ) in the presence of a suitable base, such as triethylamine.

The compound of formula (IV) as defined above has a pyridine which grows a β-aminoketone side chain. , known or easily obtained or conventional methods, such as Organic 5yu thesis (produced in the same manner as described in Co11.vol, V, 909) is obtained from the starting material values.

The present invention also provides compounds of formula (V): Z1 (In the formula, z’, z”, and z’ are the same or different, and each represents hydrogen or or a hydroxyl protecting group) in a compound of formula (VI): (wherein R1 is the same as defined above, M' is a metal cation, preferably is an alkali metal cation, more preferably a lithium or sodium cation. , R2 is an anionic stabilizing group and is naturally removed by the β-hydroxyl group. olefin, preferably trialkylsilyl or dialkylsilyl phosphonate group, most preferably trimethylsilyl or noethylphosphonate group. sulfonate group) and then remove the hydroxyl protecting group if necessary There is also provided a method for preparing a compound of formula (I) comprising:

The reaction between the compound of formula (V) and the compound of formula (VI) is carried out in an organic solvent such as tetrahydrochloride. Low to high temperature in furan, diethyl ether, or dimethyl sulfoxide For example, it may be carried out at a temperature of -80°C to 100°C.

Compounds of formula (V) in which z', z", and z" are each hydrogen, and their production method Zl, z2, z’ or hydroxyl retention as described in GB1587060 Derivatives thereof that are protecting groups may be prepared by conventional methods, such as those described below. Already that When this compound is manufactured with a hydroxyl protecting group, this The compounds may be used directly or in the same case in the above reactions, and may also be used for deprotection and/or Alternatively, it may be isolated.

Compounds of formula (VI) can be prepared in conventional manner according to EP-A-0123378 (Beacham ・It may be produced in a similar manner to the method described in Group plc), for example, a compound of formula (■) Compound· (In the formula, W is hydrogen or halogen, and R1 is the same as defined above. ) to a compound of formula (VI) (where M is lithium and R2 is trimethylsilyl) ) to Table Nis Waadworth Jr.'s method (Organic React ions +977.25.73), Yi Jie Corey and De El Boj Tet, Letters.

1978.5), Chee Ecchi Chan's Method (Ace, Chem, Re It may be converted by the method of J.S., 1977, 10, 442). Or, the expression (■) The compound is a compound of formula (VI) (wherein M is an alkali metal and R2 is diethylphosphor). Hungate's method (J, Org, Chem.

+981.46. MIO).

The compound of formula (■) defined above is a 2-substituted-5-pyridyloxazole, and has a publicly known is known or readily obtainable or can be manufactured by conventional methods. Ru. The synthesis of oxazole is a ``Comprehensive Complex Physical Chemistry'' Heterocyclic Chemistry) J (Catholic Chemistry and Reese Edition) Collection, 6. Chapters 4 and 18). As just one example, a suitable synthesis method is Using a pyridyl derivative as a starting material, for example a compound of formula (IV) as defined above, Next, follow the method described by G.L.U. Machina (J, Org, , 1980 Jinjou-, 2261) to convert to the compound of formula (■). Good too.

Furthermore, the present invention provides a compound of formula (■).

ZI (In the formula, z', z'', z'' are the same or different, and each represents hydrogen or is a hydroxyl protecting group, R1 is as defined above, and Y is a leaving group. ) with a strong base and then, if necessary, EP-A-0399645 (Beach The hydroxyl protecting group is removed in a manner similar to that described by Cham Group plc). The present invention provides a method for producing a compound of formula (1) comprising:

Suitable groups for Y include, for example, arylsulfonyl, i.e. p-4 sulfonyl, alkylsulfonyl, alkyl or arylsulfinyl, quaternary Ammoniums, such as trialkylammoniums, and dialkoxy, phosphorus Contains fins and oxides.

Suitable strong bases include, for example, 1,8-diazobicyclo(5,4°0)undeshio-7 -ene (DBU), 1,5-diazovinchlo(4,3,03non-5-ene (DBU), BN) is included.

The reaction is carried out in a solvent, e.g. acetonitrile, at a temperature in the range -20 to +80°C. It is better to do so.

The compound of formula (■) as defined above is novel and useful as an intermediate in the above method. .

Therefore, the present invention also provides a compound of formula (■) as defined above.

The compound of formula (■) is the compound of formula (IX) Z1 Z3 (In the formula, z’, z”, and z’ are the same or different, and each represents hydrogen or or a hydroxyl protecting group, Y is the same as defined above) to a compound of formula (X) Object/R’ CH○ (X) (wherein R1 is the same as defined above), or its corresponding analogous compound (formula ( The aldehyde functionality of compound X) is masked) under dehydrating conditions. You may build it.

Appropriate dehydration conditions include cyclization of the compound of formula (IIl[) to form the compound of formula (I). The conditions are the same as those described above.

Particularly suitable conditions include triphenylphosphine tetrachloride in the presence of triethylamine. Includes use in combination with carbon, or hexachloroethane.

The preparation of compounds of formula (IX) is described in EP-A-0399645 (The Beecham Group). PLC).

The compound of formula (X) is known as an aldehyde derivative of pyridine and is commercially available. manufactured by standard methods from known or readily obtained starting materials It is something that will be done.

The present invention also provides a compound of formula (XI): (wherein R', Z', Z", and Z' are the same as defined above) - Consists of isomerizing carbon double bonds by known carbon-carbon double bond isomerization methods Also provided are methods for making compounds of formula (I).

A suitable isomerization method is described by Tetrahedron, 1980.36.5 (57) and includes photochemical and addition-removal methods.

The compound of formula (XI) can be obtained by treating the above compound of formula (V) with a compound of formula (VI). can get. This reaction lacks stereoselectivity, and compounds of formulas (I) and (XI) These compounds can then be separated using conventional techniques such as chromatography. Wear.

The present invention also involves converting the compound of formula (I) into another compound of formula (I), which This can be done using conventional methods. Thus, for example, substitution of the pyridyl group of R' All or any of the groups are changed or converted. This includes carboquine substitution. Salt formation of groups, esterification, transesterification and deesterification of ester-containing substituents reduction of alkoxycarbonyl groups, removal of free carboxyl groups from carboxylates. Includes generation. Another example of such a conversion is the corresponding alkyl of formula (I) This is the production of alkanesulfinyl and alkanesulfonyl compounds from thio compounds. Ru. This latter transformation can be accomplished using conventional oxidizing agents such as percarboxylic acids, i.e. m-chloro This may also be carried out using perbenzoic acid in a suitable solvent.

As used herein, the term "hydroxyl protecting group" means It refers to any such group known to be removable. Adequate hydroxyl retention Protecting groups are defined as ``protecting groups in organic synthesis (Protecting groups in organic synthesis)'' by T. D. activeGroup in Organic 5ynthesis) J (Willi Interscience, New York), published in 1981] .

Hydroxylation of monoacid A and compounds of formulas (I), (V), (■), (IX), (XI) Syl groups can be protected at any stage of the above process by conventional techniques. This hydroxy Protecting groups can be removed by methods known in the art, including enzymatic methods.

A particularly suitable hydroxy protecting group is a silyl group, as it is easily removed under mild conditions. It is. Such groups can be synthesized using conventional silylating agents including halonrane and silazane. be introduced. For example, the following formula silylating agent is used.

L+Six　LzSiO-C=NSiLztBuMe2Si　OSO2CF3 (In the formula, Me is methyl, t-Bu is t-butyl, X is halogen, each group is halogen (C,~,)alkyl, (C,~6)alkoxy, aryl, or aryl (C, ~,)alkyl). A preferred silylating agent is trichloride. It is remethylsilyl. Particularly suitable hydroxy protecting groups are trimethylsilyl, t- butyldimethylsolyl, t-butyldiphenylsilyl group. preferred hide The roxyl protecting group is trimethylsilyl because of its easy removal.

Glycos of monoacid A and compounds of formulas (I), (V), (■), (IX), (XI) The functional group is the compound OR' of the following formula (XII) " R'-C-OR' 0R” (XI[) (In the formula, R3 is hydrogen or (C, ~,) alkyl, R4゜R8, R1 are each It is protected by forming a cyclic compound using (C, ~,) alkyl). Good too. In this cyclic derivative Zl and 22 together form part of: where R7 is (C,~,)alkyl.

R3 is hydrogen, methyl, ethyl, n- or iso-propyl, as appropriate; What is important is hydrogen. The groups R', R', R' are methyl, ethyl, n- or ino. -propyl, or n-1iso-1sec- or t-butyl, as appropriate; The most suitable is methyl.

Similarly, the hydroxyl group of a compound of formula (I) can be transferred to another compound of formula (I) as described above. may be protected before conversion.

In either case, the protecting groups mentioned above are used, for example, by G.B. Flyton, K. N.H. Rogers, “Chemistry of pseudomonoacids” o’f Pseudomonic Ac1d), Part ■’ J (J, C, S , Perkin Trans, I, 1979.308) +: as described It may be removed by mild acid hydrolysis followed by alkaline hydrolysis.

The compounds of the present invention can be used to treat bacterial and mycoplasma-induced infections in animals, including humans. , e.g. treatment of human respiratory tract infections, otitis, meningitis, skin and soft tissue infections, cow milk Useful in the treatment of adenitis, a respiratory infection in animals such as pigs and cattle.

The compounds of the invention are suitable for use in Haemophilus species such as Haemophilus influenzae Ql. , Branhamella spp., e.g. Branhamella catarrhalis 1502, Streptococcus Cus spp., e.g. Streptococcus pyrogenes CN10, Streptococcus Staphylococcus, Niramonia PU7, Staphylococcus, such as Streptococcus, Active against plum-negative and grass-positive bacteria, including P. ureus. It is also active against mycoplasma. Furthermore, the compounds of the present invention Lococcus bacteria, such as Staphylococcus aureus, Staphylococcus aureus, Evidermis with other antibacterial agents, such as beta-lactam antibiotics, such as methicillin. , macrolides, aminoglycosides, and lincosamides (including multidrug resistance). ) is active against certain substances.

The present invention provides a compound of formula (I) (hereinafter simply referred to as the drug) and a pharmaceutical or veterinary drug. Providing a pharmaceutical or veterinary composition comprising a pharmaceutically acceptable carrier or excipient. This is what we provide.

The compositions may be formulated for administration by any route, depending on the disease being treated. . The composition may be a tablet, capsule, powder, granule, troche, liquid or gel formulation. For example, it may be in the form of an oral, topical or sterile parenteral suspension.

Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients, e.g. Binders, namely, Norotubu, Gum Arabic, Gelatin, Sorbitol, Tragan. or polyvinyl pyrrolidone, fillers such as lactose, sugar, corn Locono starch, calcium phosphate, sorbitol, or glinone: lubricants for tabletting, e.g. For example, magnesium stearate, talc, polyethylene glycol, or sodium chloride. Licani disintegrants, such as potato starch, and also acceptable wetting agents, such as lauryl. May contain sodium sulfate. Tablets contain the commonly known medicinal bractis It may be coated by a method. Oral liquid preparations include, for example, aqueous or oily suspensions; It may be in the form of a solution, emulsion, syrup, or elixir and may be mixed with water, Alternatively, it may be a dry product for reconstitution with another suitable medium. liquid like this The formulation contains conventional excipients such as clouding agents, i.e. sorbitol, nolotub, meth cellulose, crucose syrup, gelatin, hydrogenated edible fat, emulsifier, example Valecithin, sorbitan monooleate, or gum arabic: non-aqueous medium ( edible oils), such as tonsil oil, fractionated coconut oil, oily esters, glycerin alcohol, propylene glycol, or ethyl alcohol; preservatives such as p- Methyl or propyl hydroxybutyrate, or sorbic acid; if necessary, conventional It may also contain fragrances or colorants.

For topical application to the skin, the drug may be made into a cream, lotion, or ointment. Good too. The cream or ointment formulation used for this drug is a conventional formulation known in the art. , for example, standard textbooks on medicine and cosmetics, such as Barry Cosmetics (HarrysCo. smeticology) (Jitaj Godwi, London), and British Medicine It is listed in the pharmacopoeia.

Suppositories may contain traditional suppository bases, such as cocoa butter or other glycerides. Ru.

For parenteral administration, fluid unit dosage forms are prepared using the drug and a sterile medium. Book The drug will be suspended in the vehicle, depending on the vehicle and concentration used. Adjuvants, e.g. topical hemp An anesthetic, preservative, and buffering agent may be dissolved in the medium. assembled to improve stability The product is frozen after filling into vials, and the moisture is removed under vacuum. Then dry frozen powder Seal in vial. The drug is exposed to ethylene oxide before being suspended in a sterilizing medium. It can be sterilized by By including a surfactant or wetting agent in the composition, the drug can be uniformly distributed. It is better to facilitate dispersion.

For topical application to the ear, the drug may be mixed with a suitable liquid carrier such as water, glycerol, diluent, etc. Tanol, propylene glycol, polyethylene glycol, or fixed It may also be made into a suspension of liquid oil.

For topical application to the eye, the drug may be administered as a suspension in a suitable sterile aqueous or non-aqueous vehicle. Prescribe. Additives, such as buffers, i.e. sodium metabisulfite, or Preservatives including disodium detate, bactericides and fungicides, i.e. phenyl acetate. dimercury, or phenylmercuric nitrate, benzalkonium chloride, or chloride Hequindin: A thickening agent, such as hybromellose, may also be included.

The dosage of the topical composition will, of course, depend on the size of the area to be treated.

For the ear and eye, typical dosages range from 10 to 100 ml of the drug, respectively.

Veterinary compositions for intramammary treatment of udder diseases in animals, particularly bovine mastitis, are generally oil-based. It contains a suspension of the drug in a medium.

The composition may contain 0.1% to 99% by weight, preferably 10 to 60%, depending on the method of administration. % by weight of the drug. When the composition is in unit dosage form, each dosage unit It is preferable that the drug contains 50 to 500 μm of the present drug. Adult human treatment (average weight The dosage used for 70 kg (100 kg) per day depends on the route and frequency of administration; The dosage ranges from 0 to 3 g, such as from 250 to 2 g.

Alternatively, the drug may be administered as part of the total diet of non-human animals. In this case, the amount of this drug used is less than 1% by weight of the diet, preferably 0.5% by weight or less. The animal's diet consists of normal food, to which the drug is added. Alternatively, the drug may be included in a premix of a mixture with food.

A suitable method for administering this drug to animals is to add it to the drinking water of non-human animals. this suitable concentration of the drug in drinking water is about 5-50 μg/rd, e.g. 5-2 μg/rd. 00 μg/TLl.

Furthermore, the present invention provides the above-mentioned treatment for humans and non-human animals in need of treatment. a human or non-human animal comprising administering an effective amount of a compound of formula (I) Provides a method for treating bacterial and/or mycoplasma infections. be.

Alternatively, the pharmaceutical compositions described above may be used for such treatment.

In certain cases of such treatment, human or non-human animal bacterial or bacterial Methods for the treatment of Icoplasma-induced infections, especially respiratory infections in humans and non-human animals It provides:

Furthermore, the present invention relates to the manufacture of medicaments for use in antibacterial and/or antimycoplasma therapy. The present invention consists in using the compound of formula (I) as described above.

The following examples are intended to illustrate the invention and are not intended to limit its scope in any way. It's not.

The following abbreviations were used in the examples.

DMF N, N-dimethylformamide, DMS O dimethyl sulfoxide, THF Tetrahydrofuran, M g S Oa Anhydrous magnesium sulfate chromatography absorbs silica gel. It was used as a garment.

Monoacid A is described in GB 1587058 (Beacham Group, pIc) Add triethyl amine (1,1 eq.) and isobutyl chloroformate (1 eq.) to Ta. After 0.5 h at 0 °C, add appropriate ammonium salt (1 eq.) and triethylamine. (1 eq.) was added and the reaction mixture was stirred at O'C for 3 hours. Add ethyl acetate , the solution was washed with sodium bicarbonate and brine, and then dried to remove Mg504. ) and evaporated under reduced pressure. The resulting residue was chromatographed (Nrica gel, 0-20 % methanol in dichloromethane) to give the pure amide.

General method for preparing oxazole via monamide Trichloroacetyl chloride (g equivalent) The above monamide and 4-methylaminoamide in dichloromethane (10-/mmol) were added. In a solution of nopyridine (several crystal grains/mmol) and pyridine (20 equivalents) and cooled in a water bath. After 0.5 hours, this solution was diluted with an aqueous sodium bicarbonate solution. and evaporated under reduced pressure. The resulting residue was evaporated under reduced pressure. generated residue was dissolved in methanol (5 d/mmol), the solution was cooled to 0 °C, and then , potassium carbonate (3 eq.) was added. After 15 minutes, saline and ethyl acetate at 0°C. was added and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate and the extracts were combined. The mixture was washed with brine, dried (hso, ) and evaporated under reduced pressure. Generate The resulting residue was chromatographed using 0-20% methanol in dichloromethane. pure oxazole was obtained.

Example 1 2-(1-norsen-2-yl')-5-(2-pyridyl)ox2.2-shed Quino-2-(2-pyridyl)ethylamine dihydrochloride (2.6g; 9.19mm A 5M deuterium chloride (+6mj) solution of ol) was heated to 80 °C under an argon stream, The reaction was followed by 'Hn, m, r. After 2.5 hours, the reaction mixture was evaporated and Ethanol was added and reevaporated. Treat the residue with acetone to obtain the title compound. Collected by filtration (1.8 g; 92%).

v max (KBr) + 723 cl'; δH (DzO) 7.95-8. 91 (m).

The amine dihydrochloride (Ia) (1.8 g) was prepared from the title monamide by a general method. ; 8.6 mmol) of THF:water (1:l; 12 d) and triethylamine ( 2.4 mj; 17.2 mmol) and column chromatography. It was isolated as an amorphous solid (963 μm, 24%).

v maX(C)12CIz)3400-3100.1720.1665.16 40cm-'; λmax (EtOH) 226 (εm 20.586), 2 60nm (sh) (5300), dd, J 1.0, 6.0Hz, 6'-H) ;δ (CDCI, ) 12.7 (C-17), 18.9 (C-15), 20 ．． 8 (C-14), 31.7 (C-9).

39, 6 (C-8), 42.7 (C-4), 42.7 (C-12), 46 ．． 5 (C-1'), 55.7 (C-10).

61, 2 (C-11), 65.4 (C-16), 68.9 (C-6), 7 0.4 (C-7), 71. l (C-13).

75, 0 (C-5), 119.8 (C-2), 122.0 (C-3"), 128.0 (C'-5#), 137.1 (C-4'), 149.3 (C -6'), 151.9 (C-2'), 157.9 (C-3), 167 , 6(C-1), 196.4(C-2'); The monamide (200 μ) of the above (1b) was cyclized by a general method to form an amorphous solid. The title oxazole was obtained (60■, 31%) λmax (Ct(zclz) 3600-3100.1720.1650.1605.1580cm-'; λwax (EtO)I) 223 (e m 9.900), 312 nm (18 , 470); δ) I (CDCI, ) (Nakanzu<) 0.93 (38, d , J7. OHz, 17-Hs), 1.22-H).

δ (CDCIs) 12.7 (C-17), 19.7 (C-15), 20. 8 (C-14), 31.7 (C-9).

39, 6 (C-8), 42.7 (C-12), 42.9 (C-4), 55 ．． 6 (C-10), 61.2 (C-11).

65, 6 (C-16), 68.8 (C-6), 70.4 (C-7), 17 1.1 (C-13), 75.2 (C-5).

+12.9 (C-2), 119.2 (C-3'), 122.7 (C-5' ), 126.2 (C-4').

+37.0 (C-4'), 197.3 (C-5'), +48.3 (C -6'), 149.2 (C-3).

+49.8 (C-2''), 162.0 (C-2'): m/z 444 (M”, 10%), 200 (100%).

Example 2 2-(1-norsen-2-yl)-5-(3-pyridyl)oxy2,2-noethoxy Sea 2-(3-pyridyl)ethylamine (2.5g>) 5M Salt Ugly (20yd ) The solution was heated so'c+= for 16 hours. The reaction mixture was evaporated and then ethanol was added and the resulting mixture was evaporated. Add acetone and prepare the title compound ( 89a) was collected by filtration (1.7 g; 92%).

v max (KBr) 1709 cm-'; δ (DJ) 4.75 (2H, S , CH2), 8.22 (IH, dd, J6, 8Hz, 5'-H), 8.95 -9.15 (21 (,4'- and 6'-H), 9.33 (H, d.

The title monamide was converted to the amine dihydrochloride (2b) (418 mg: 2 mmol) of THF: water (1:1; I(7) and triethylamine ( 0.6d; 4mmol) solution and column chromatography as an amorphous solid. Obtained by graphi (230■: 25%); v max (CHCla) 360 0-3100.1690.1655.1635 cm-'; (IH, d, J 6.5Hz, 6'-H), 9.22 (IH, bs, 2'-)1); δC (C DCIs) +94.1 (C-2'), 167, 5 (C-1), 154.0 (C-2'), 152.7 (C-3), 149.2 (C-6'>, 1 35.7 (C-4'), 130.3 (C-3'), 124.0 (C-5 ”), 119.4 (C-2), 75.0 (C-5), 71.1 (C-1 3), 70.4 (C-7), 68.9 (C-6), 65.3 (C-16) , 61.1 (C-11), 55.6 (C-10), 4.5 (C-1') , 42.8 (C-12), 42.7 (C-4), 39.7 (C-8), 31.7 (C-9), 20.8 (C-14), 18.9 (C-15), 1 ．． 2.7 (C-17): The monamide (150■) of (2b) above was prepared using a general method. to give the title oxazole as an amorphous solid (92■, 65%): λ max (EtOH) 305 (εm 24.230), 221 nm (10,2 60) ;v max (KBr) 3399.1648.1525cm-' ;δ [(cow), col　(Nakanzu<　)0.93　(3H, d, J　7.0 ) Iz, 17-L), 1.226C (CDCI 5) 161.6 (C-1) , 148.8 (C-2″), (148,0 (C-3), 146.8 (C- 5'), 145.2 (C-6'>, !24.5 (C-3'), 12 4.1 (C-4'), 123.8 (C-5''), 112.8 (C-2) , 75.2 (C-5), 71.5 (C-7), 70.4 (C-13), 68.9 (C-6), 65.6 (C-16>, 61.3 (C-11), 5 5.6 (C-10), 43.0 (C-4), 42.9 (C-12), 39 ．． 7 (C-8), 31.7 (C-9), 20.8 (C-14), 19.7 (C-15), 12.7 (C-17).

(Measurement value M”, 444.2265.C2, H, N20#Required value 444.22 60).

Example 3 2-(1-norsen-2-yl)-5-(4-pyridyl)oxy2,2-shed A solution of 2-(4-pyridyl)ethylamine, 3g) in 5M hydrochloric acid (50yd) was heated at 80'C for 16 hours. Evaporate the reaction mixture, add ethanol, It was then reevaporated. Treat the residue with acetone and collect the resulting red/brown solids by filtration. and dried (4.7 g; 87%) o'Hn, m, r, DJ in the spectrum It was found that a mixture of the title compound and its hydrate was present in the sample.

- and 6'-1 ().

The above amine dihydrochloride (3a) (1,5 6 g, 7.5 mmol) of THF:water (1:1) (lW) solution, Isolated by column chromatography as an amorphous solid.

'Hn, m, r, spectrum indicates that this material contains at least 20% impurities However, it turns out that this substance has progressed to the next stage.

νmax (KBr) 3393.17'10.1654.1635.1527cm −’ ; δ (CDCIs) 0.93 (3H, d, J 7.OHz, +7 -L), 1.22 (3H, s, J 6.3Hz, 14-Hs), 2.2 0 (3H, s, 15-Hs), 7.79 (2H, dd, 'Jl, 6.4.5H z, 3", 5" - The crude monamide (135■) of (3b) above was cyclized using a general method. The oxazole was obtained as an amorphous solid (41.132%).

λmax (EtOH) 312 (ε m 23,470), 223 nm (12, 110):vmax(KBr)3393. +647.1610.1582. 1520cm -': 5.9Hz, 2", 6" -L); δC (CDC1 ,) 161.6 (C-1), +50°2 (2x C-2'), 149.1 (C-3), 147.1 (C-5'), +35.2 (C-4'), 1 26.5 (C-4'), 117.9 (2x C-3'').

112, 8 (C-2), 75.2 (C-5), 71.2 (C-13), 7 0.4 (C-7), 68.9 (C-6).

65, 6 (C-16), 61.3 (C-11), 55.6 (C-10), 43.1 (C-4), 42.8 (C-12).

39, 7 (C-8), 31.7 (C-9), 20.8 (C-14), 19 ．． 7(C-15), 12.7(C-17); 2-(1-norsen-2-yl )-5-(2-methyl-5-birowmethylnicotinic acid (912; 6 mmol) A solution of dimethylformamide (8-) was dissolved in diethyl anophosphate at -15 °C under argon. (0.9 mj'; 6.5 mmol) followed by triethylamine (0.83 ml) ; 6 mmol). After 20 minutes, add ethyl isocyanoacetate (0.56 ml). ; 5 mmol) and triethylamine (209+njl; 15 mmol) Ethylformamide (6-) solution was added dropwise. After 2 hours at -15°C, reaction mixture The material was allowed to warm to room temperature over 2 hours. Dilute the reaction mixture with ethyl acetate and toluene. then washed with saturated sodium bicarbonate, water, brine and then evaporated to dryness. Ta. in a liquid chromatography eluting with a dichloromethane/methanol mixture. The impure title compound was obtained, chromatographically eluting with an ethyl acetate/hexane mixture. The title compound was obtained (507; 46%) using the graph again.

δH (CDCI i) 1.41 (3H, d, J 7.5H2, C02CH, CH-), 2.62 (3H,s, Ar-Me).

4.43 (2H, [+, J 7.5Hz, CO, CHzCHz), 7.2 5 (IH, d, J 8Hz, 3' -1 ().

The solution was heated at 100°C for 5 hours. The reaction mixture was diluted with water, evaporated and ethanol The title compound was obtained as an almost pure white solid (5 07■, 99%); 2Hz, 6'-H).

c) The compound with the title N-(2-oxo-2-(2-methyl-5-vinyl) Amine dihydrochloride (507■) of the above (4b).

2.27 mmol) to THF:water (1:l; 10 ml’) and triethyla prepared in a general manner in Min (0.63 ml; 4., 56 mmol), Isolated by column chromatography as an amorphous solid (400 μm, 38%).

λmaX (CHCIg) 3600-3100.1690.1660. l64 0.1595cm-'; λmax (EtO)1)23+(εm 19.39 0), 270nm (5,920); δH (CDC12) (Nakanzu <) 0.93 (3H, d, J 7.OHz, 17-82), 1.228. 2Hz, 4'-H), 9.09 (IH, d, J 1.4Hz, 6' -H); δC (CDCII) 12.5 (C-17), 18.8 (C-15), 20.5 (C-14), 24.5 (C-Me).

31.8 (C-9), 39.8 (C-8), 42.7 (C-12), 42.8 ( C-4), 46.2 (C-1').

55, 8 (C-10), 61.1 (C-11), 65.6 (C-16), 68.7 (C-6), 70.3 (C-13).

75,0 (C-5), 119.6 (C-2), +23.9 (C-3'), 128.0 (C-5'), +36.2 (C-4'), 148.8 (C -6'), 152.4 (C-3), 164.1 (C-2'), 167 , 8 (C-1), +93.8 (C-2'), ;476, 2523).

The above monamide (4C) (337■) was cyclized using a general method to obtain the title oxazo. was obtained as an amorphous solid (220 μm, 67%).

λmax (CH2C1 3700-3000.1650cm-'.

λmax (EtOH) 224 (εm 10.575), 302 nm (24, 380) ;-H), 7.79 (IN, dd, J 2.1.8.1Hz, 4'-H), 8.77 (IN, d, J 2. IHz.

6’-H)1 δC (CDC1z) 12.6 (C-17), 19.6 (C-15), 20 ．． 8 (C-14), 24.2 (C-Me).

31.8 (C-9), 42.8g C-12), 43.0 (C-4), 55.6 ( C-10), 61.2 (C-11).

65, 6 (C-16), 68.8 (C-6), 70.4 (C-7), 71 ．． 1 (C-13), 75.3 (C-5).

112, 9 (C-2), +21.7 (C-5'), +23.3 (C-4' ), 123.5 (C-3').

131.7 (C-4'), 144.6 (C-6'), 147.2 (C-5' ), 147.7 (C-3).

158,0 (C-2'), 161.6 (C-1); 2-(1-nonmol- 2-yl')-5-(1,2-dihydro-6-chloronicotinic acid (945 mg, A solution of 6 mmol) of DIJF (8 ml) was heated under argon at -15°C with cyanophosphorus. Diethyl acid (0.99m/, 6.5mmol), then triethylamine (0.99m/, 6.5mmol) , 83 ml, 6 mmol). After 20 minutes, ethyl isosoanoacetate (0 , 56 ml; 5 mmol) and triethylamine (2,09+nI!; 15 mm A DMF (6d) solution of ol> was added dropwise. After 2 hours at −15°C, the reaction mixture was warmed to room temperature over 2 hours. Dilute the reaction mixture with ethyl acetate and toluene , then washed with saturated sodium bicarbonate, water, brine and evaporated to dryness. Jiku The title compound was obtained by silica chromatography eluting with a lolomethane/methanol mixture. The compound was obtained (570 mg; 43%).

δH (CDC1j) 1.33 (3H, t, J7, OHz, C) IsCHzCO z -), 4.44 (2H, q, J7, OH2, CH, CI (2CO2-) , 7.45 (lH, d, J9.OHz, 3'-H), 8.02 (l) t , s, 2-)ri, 8.50 (18, dd, J2.0.9.0Hz, 4'-H) , 8.99 (IH, d, J2.0 above (5a) oxazole (501■) 6 A solution of N hydrochloric acid (10 liters) was heated to 95-100°C for 4 hours. Reaction mixture with water Dilute, evaporate, add ethanol and re-evaporate to give the title compound a nearly pure white color. Obtained as a colored solid (400 ml, 85%).

The title monamide was purified from the amine dihydrochloride of (5b) with THF/water (1:I; 6 mA') and triethylamine (0.46 rnl) in the general manner.

The operation was to evaporate the aqueous residue, redissolve it in methanol, and redissolve the solution in methanol. Filtered through flash silica. Add silica and evaporate The residue was eluted with a dichloromethane/methanol mixture using a silica column. The title compound was obtained (350 ml; 44%).

v max (KBr) 3373.1653.1527.1429 cm-'; λmax (EtOH) 211 (εm 17.365), 276 nm (14, 370); 4.58 (IH, s, 2-H), 6.54 (2H, d, J9.7H z, 3' -H), 8.07 (11 (, dd, J2.7P 9.6) 1z, 4'-H), 8.31 (IH, d, J 2.41 (z, 6"-H); ca , 5% NEt.

1 (substance contaminated with C1); δC (CD30D) 12.3 (C-17), 18.0 (C-15), 19 ．． 4 (C-14), 33.0 (C-9).

41, 7 (C-8), 43.8 (C-4>, 43.8 (C-12), 46 ．． 1 (C-1'), 57.0 (C-10).

61.1 (C-11), 66.3 (C-16), 70.0 (C-6), 70. 7 (C-13), 71.7 (C-7).

76,3 (C-5), 117.7 (C-5'), 120.7 (C-2), 120.8 (C-3'), 140.6 (C-4'), 14+, 2 (C- 6'), 153.2 (C-3), 165.5 (C-2''), 169.8 (C-1), 192.3 (C-2'); Monamidoku 100■ of (5c) above) was cyclized by a conventional method to give the title oxazole as an amorphous solid ( 60■; 62%): v max (KBr) 3385.1661.1623.1565 am-'; λmax (EtOH) 256 (Em 8.220), 302 nm (16, 505); 13.64 (IH, d, J 9.2Hz, 3”-H), 7 ．． 35 (IH, s, 4' -H), 7.78 (I) I, d, JδC ( d4-MeOH), 12.2 (C-17), 19.7 (C-15), 20. 3 (C-14), 32.9 (C-9).

41, 6 (C-8), 43.6 (C-12), 43.8 (C-4), 56 ．． 8 (C-10), 61.2 (C-11).

66, 3 (C-16), 69.9 (C-6), 70.6 (C-13), 7 1.6 (C-7), 76, 3 ((knee 5).

110, 5 (C-5'), 112.3 (C-2), 121.6 (C-3'' ), 122.5 (C-4').

131, 7 (C-4=), +39.6 (C-6'), 147.7 (C- 5'), 149.3 (C-3).

162.2 (C-2'), 164.6 (C-2''); Oxa of the above (5d) A solution of sol (100μ) in methanol (3-) was evaporated with excess ether at O'C under argon. treated with standard diazomethane.

After 24 h at 5-10 °C, argon was bubbled into the reaction mixture and then evaporated. Chromatography using dichloromethane/methanol mixture and elution with dichloromethane/methanol mixture Two separable components were obtained.

The less polar substance was identified as methoxypyridine (Example 6) and was expressed as a gum-like substance. isolated (15 ■, 14%).

λmax (CH2C12) 3600.1670.1620.1485 cm- ' ; δH (CDC1, + 2 drops of d, -MeOH), especially (this substance is Mo1, 22 (3H, d, J 6.3Hz, +4-f(,), 2.30(3 H, s, 15-H,), 3.98 (3H, s, Ar-(measured value・M''', 474.2371. C25l (,, Required value of N20□ 474.2366) Polarity A substance with high (60■, 48%).

v max (KBr) 3416.1664.16+2.1565.1541cm -'; (111I constant value: Mゝ, 474.2371. C□H,, N, 0□ Required value M 474.2366) Example 8 5-(2-methoxy-5-pyridyl)-2-(1-norcene-6-methoxynico Chinic acid (3,79g; 24.8mmol) in dichloromethane (60d) and DMF (a few drops) was treated with oxazyl chloride (2,6 to 29,8 mmol).

After approximately 2.5 hours the gold material has dissolved and the reaction mixture is then diluted with excess noadimethane. Dropped into ether solution. After 2 hours, argon was passed through the reaction mixture and then evaporated. chromatograph on silica, eluting with a dichloromethane/ethyl vinegar mixture. I put it on the fee. The less polar fraction contains the title compound (43(W), a highly polar A diazoketone (1.34 g) was isolated from the fraction. Add this substance to dichloromethane (], OOmI) and bubbled HCI gas for 40 minutes. Then the solution Argon was passed through it. The reaction mixture was washed with sodium bicarbonate and brine, then The title compound was obtained (1.4 g) by drying and evaporation at Niji max (C HzClz) 1785.1720.1700 cm-'; Dissolution of roketone (1.4 g, 7.55 mmol) in dichloromethane (70 yd) Add the liquid to tratramethylguanidinium and (1,43g: 9.06mmol) Processed with. After 1 hour, the mixture was evaporated and diluted with an ethyl acetate/hexane mixture. Chromatography on silica eluting gave the title compound (1.29g ;89%);v maX(CHzClt)2200.1695.1605c m-' ; δ) I (CDCI s) 3.98 (3tl, s, OMe), 4 ．． 45 (2H, s, COCH2N5), 6.87 (IH, d.

THF (40d) of the azide (1.29g; 6.72mmol) of the above (8b) , solution of 5 M HCI (3.35 ml; 16.8 mmol) in water (30 mJ) was hydrogenated over 10% Pd/C (250 ■) for 5 minutes. Filter the mixture through diatomaceous earth and evaporated to dryness. Add ethanol, re-evaporate and use acetone to the residue Trituration gave the title compound (1.54g, 96%).

v max (KBr) 1690.1637.1613 cm-low.

δH (dg-DMSO) 3.95 (3H, s, OMe), 4.56 (2H, m, collapse to S with D2COexch. , 94 g; 8.1 mmol) to THF/water (1:1:20 m/) and Torie Prepared in general manner in thylamine (22W, +6.23mmo I) and Isolated by ram chromatography as an amorphous solid (2.3 g; 58%).

λmax (EtOH) 274 (εm 12.235), 253 nm (14, 780); δC (CDCI I) 12.7 (C-17), 19.0 (C- 15), 20.8 (C-14), 31.7 (C-9).

39.6 (C-8), 42.7 (C-4), 42.8 (C-12), 46.0 ( C-1'), 54.3 (C-OMe).

55, 6 (C-10), 61.2 (C-11), 65.4 (C-16), 68.9 (C-6), 70.5 (C-13).

71, 2 (C-7), 75.0 (C-5), 111.5 (C-3'), 119.6 (C-2), 124.6 (C-5"), 137.9 (C-4") ), 149.1 (C-6″), 152.3 (C-3), 167, 4 (C- 210C-1), 192.7(C-2'); e) 5-(2-methoxy-5-bi linol)-2-(1-normo) by cyclizing the monamide of (8d) above using a general method. The title oxazole was obtained (74 g; 82%).

λmax (EtOH) 302 (εm 25.880), 232 nm (10, 630), δC (CDCI 1) 12.7 (C-17), 19.6 (C-1 5), 20.8 (C-14), 34], 7 (C-9).

39, 6 (C-8), 42.8 (C-12), 42.9 (C-4), 53 ．． 7 (C-OMe), 55.6 (C-10).

61.3 (C-11), 65.5 (C-16), 68.9 (C-6), 70. 4 (C-13), 71.2 (C-7).

75, 3 (C-5), Ill, 2 (C-3'), 113.0 (C-2) , 118.0 (C-5''), 121.8 (C-4), +34.5 (C-4 ': 1.142.9 (C-6''), 147.0 (C-3), 147.6 ( C-5').

161, ](C-2'>, 163.9(C-2').

Example 9 5-(2-chloro-5-pyridyl)-2-(1-norcene-26-chloronicothi dichloromethane (50-) and DMF ( The suspension of 4 drops) was treated with oxalyl chloride (1.05ml 1.12mmol).

After 2.5 hours, the solution was added to an ethereal solution of excess diazomethane. 2 hours later, The solution was bubbled with argon and then) ICI gas for 10 minutes. Argon Pass this mixture through, wash with sodium bicarbonate and brine, then dry steam. I let it emanate. The title compound was chromatographed on silica eluting with dichloromethane. 0.82 g; 96%).

λmax (CHzCIz) 1643.1530 cm-'; δH (CDC1z ) 4.65 (2H, s, C0CHzC1) 7.46 (IH, d, J 8) 1 z, 3-H), 8.20 (IH chloroketone (455■:2) of (9a) above ．． A solution of 4 mmol of dichloromethane (IOJ) was diluted with tetramethylguanidinium. The sample was treated with M&D (436 μm, 2.76 mmol). After 1.5 hours, mix the reaction The compound was evaporated and chromatographed eluting with dichloromethane to give the title compound. A compound (260+5596) was obtained (proof of instability against glue force).

λma+c (C) 12clz) 2100.1705.1580cm -'; δ old CDel, ) 4.58 (2H, s, COCH2C1,) 7.49 (IH, d , J8Hz, 3-H), 8.18 and of (9b) above (247mg; 1 ．． 26 mmol) of THF (9 Tnl), water (6 m/): 5 MH A solution of CI (0,63Td; 3.15 mmol) was added to 10% Pd/C (50 mg ) and hydrogenated for 5 minutes. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to dryness.

Ethanol was added to the residue and the solution was re-evaporated to give the title compound (250 x 1 82%).

v max (KBr) 3105-2800.1695.1583.1560cm -'; δH (d+-DMSO) 4.63 (2H, d, J 5.3H2, D2 0 exch, collapses into S.

C0C1(,NH29,7,78(1)1.d,J8.4Hz,3-)1),8 ．． 41 (It(, dd, J2.3.8.4) Salt (243.5 mg; Immol) to THF/water (1:l; 6+J) and triethylamine (0.3 ml; 2 mmol) in a conventional manner, It was isolated by chromatography as an amorphous solid (104; 21%).

v max (KBr) 3394.1704.1661.1630.1583cm -'; δ) I (CDCI,) especially < , 0.93 (3) 1. d, J 6.7Hz, 17-H,), 1.22 (3H, d, J 6.3Hz, 14-Hz), 2.20 (3H, s, 15-Hz), 4.78 (2H, d , J 5.4Hz.

1’-Hz), 5.82 (IH, s, 2-H), 6.66 (IH, t, J4 ．． 5Hz, NH), 7.50 (1,H.

The title compound was obtained by cyclizing the monamide (94■) of (9d) above using a general method. (48■; 52%).

δ) I (CDCh) < , 0.93 (3H, d, J 6.7Hz , +7-)1. ), 1.22δC (CDC13) 13.0 (C-17), 20.0 (C-15), 21.1 (C-14), 32.0 (C-9).

39, 9 (C-8), 43. '1 (C-12), 43.2 (C-4), 5 5.9 (C-10), 61.6 (C-11).

65, 8 (C-16), 69.2 (C-6), To, 6 (C-13>, 71.5 (C-7), 75.5 (C-5).

113,0 (C-2), 123.6 (C-5'), 124.8 (C-4' ), 124.8 (C-3').

134.0 (C-4'), 145.3 (C-6'), 146.2 (C- 3), +48.9 (C-5').

+50.7 (C-2'), 162.4 (C-2'); m/z 478 (M ”, 12%), 234 (100); 5-(2,3-dichloro-5-pyrine )-2-(1-normo-5,6-dichloronicotinic acid (1,92 g; 10 mm A suspension of DlilF (4 drops) in dichloromethane (5C7') of It was treated with Zaryl (1,05rd: 12 mmol). After 2.5 hours, An ethereal solution of excess diazomethane was added to the solution. After 2 hours, add alkaline to this solution. Then add an ethereal solution of ICI (5M 2 x 217) Ta. The mixture was diluted with dichloromethane and then washed with sodium bicarbonate and brine. It was washed and evaporated to dryness. chromatography on silica eluting with dichloromethane The title compound was obtained (1.7 g; chloroketone of the above (10a) (800 g; A solution of 3.56 mmol) of dichloromethane (20d’) was added to tetramethylguani. It was treated with zincium azide (619 mm; 3.92 mmol). After 1 hour, reaction The mixture was evaporated and chromatographed on silica eluting with dichloromethane. The title compound was obtained (313 g; 38%).

v maX(C)ltcIz)2105.1710cm-';δH(CDCI s) 4.55 (2H, s, cOcHzN-), 8.26 (1) 1. d, J2Hz , 4-H), 8.73 azide of the above (10b) (300 mg; 1.3 mmol ) of THF (10rnI, water (8mJ), 5M HCI (0,65i ;3.25 mmol) solution was hydrogenated with 10% Pd/C (60 mmol) for 10 minutes.

The mixture was filtered through diatomaceous earth, and the filter layer was thoroughly washed with water. Wash the filtrate with ethyl acetate. The aqueous phase was evaporated to dryness. Addition of ethanol and reevaporation yields the title compound. (250.280%).

v max (KBr) 3250-2800.1.711.1701 am-' : The title compound was mixed with the amine salt of (IOc) (520 mg; 2.+5 mm).

l) to T) IP/water (1:l; 12d) and triethylamine (0,W; 4 ．． 30 mmol) in a conventional manner and chromatographically determined the amorphous solid. (290 x 125%).

v max (KBr) 3200.1707. +659.1630.1533. 1412 cm-'; 2.0 Hz, 6"-H).

%〉.

Monamide (25f)mg; 0.47mn+ol) of the above (]Od) is commonly used. cyclization to give the title oxazole (123■, 51%).

v max (KBr) 3405.1649.1605 cm”’;λmax (EtOH) 314 (e m 22.746), 229 (11,423); δC (CDCI, + d, -MeOH) 12.3 (C-17), 19.7 ( C-15), 20.4 (C-14>.

31, 9 (C-9), 39.9 (C-8), 42.7 (C-12), 43 ．． 2 (C-4), 55.9 (C-1o).

61.1 (C-11), 65.7 (C-16), 65.7 (C-6), 7 0.3 (C-13), 70.6 (C-7).

75, 2 (C-5), 112.5 (C-2), 124.7 (C-3'), 125.5 (C-4'), 131.3 (C-5'), +33.7 (C -4'), 142.5 (C-2'), 144.6 (C-6').

+47.9 (C-3'), 149.6 (C-5'), +62.8 (C-2' ).

6-Methylthionicotinic acid (1,69g; 10.0mM) in dichloromethane:/ (50m/) Kiza IJ to chlorinate a suspension of DliilF (4 drops) (1,05 J12゜0mM). After 2 hours, the solution was diluted with diazomethane (approximately 40mM ) in ether (+oomm) at 5 °C and the mixture was stirred for 1.5 h. and the ambient temperature. Next, an ether solution of hydrogen chloride (approximately 0.8 N: 25 d) was added and the reaction mixture was stirred for a further 20 minutes.

The mixture was partitioned between dichloromethane (food) and water (100 mj) and carbonic acid Sodium was added to adjust the pH to 8.0. The organic phase was washed with brine and dried to remove Mg. 5O4) was evaporated to give the crude product (2g). Apply this to chromatography (silica 40g, solution hexane-ethyl acetate = 2:l), the title pyridine (1.49g, 70%).

λmax (CHC13) 1680 and 1580 cm-'; δH (CDC1ff ) Especially < , 2.60 (3H,s, -5CHa), 4.60 (21( , s, -CH2C1).

Tetramethylguanidinium azide (0.47g; 2.9mM) was added to 5=chloro dichloroacetyl-2-methylthiopyridine (0.41g; 2.0mM) Methane (25 rn!) was added to the ice-cooled solution under argon. The mixture was stirred for 0.75 h. Stir, reduce volume and apply to a silica column (10 g) eluting with dichloromethane. The title compound (0.36 g; 85%) was obtained.

λmax (CHCIs) 2100.1695 and 1585 cm-'; δH (CDC1z) Above all, 2.60 (3) 1. s, -5CH,), 4.48 (2H, S, -CH2N2).

5-azidoacetyl-2-methylthiopyridine (0.35g + 1.6mM) Dissolved in THF (12rnI) and added water (8-) and 5N hydrochloric acid (0.84ml) to this solution. J; 4.2mM) was added. This mixture was mixed with 10% palladium on charcoal (0,1 9 g) for 13 minutes, filtered through a layer of Celite, and diluted the filtrate with ethyl acetate for 13 minutes. Washed twice and evaporated to give the required product as a yellow solid (0.2g; 47%): v max (KBr) 3400. ! 700. and 1615cm-'; Mona Mito was prepared from the above amine salt (0.20 g; 0.78 mj) in a general manner, An amorphous solid was isolated (0.10g+25%).

LJ max (KBr) 3420.1695.1660.1630 and 158 0cm-'; λmax (EtOH) 223nm (εm19.300) and 311 nm (19,050); δ1 ((CD, OD) especially < 0.96 ( 3) f, d, positive 7.0Hz, 17-Hz) 1.21 (3H, d, J6゜5 Hz, 14-H,), 2.17 (3) 1. s, +5-H), 2.61 (3H,S, -5CH3), 4.69(2)1. @s.

2.0Hz, 6'-H); δC (CD, 0D) 12.3 (C-17), 13.4 (-SCH3), 19 , I (C-15), 20.4 (C-14) 33, 0 (C-9), 41.7 ( C-8), 43.8 (C-4 and C-12>, 47.0 (C-1').

56,9 (C-10), 61.3 (C-11), 66,4 (C-16), 70.1 (C-6), 70.7 (C-7).

71,7 (C-13), 76,3 (C-5), 120.7 (C-2), 1 22.0 (C-3'), 127.9 (C-5'), 136.2 (C-4' ), 150.3 (C-6'), 153.4 (C-3), 168.1 ( C-2'), 169.8 (C-1) and 195.0 (C-2'); Mutual (FAB, thioglycerol) 509 (MH”).

The above monamide (0.30 g: 0.59 mM) was cyclized using a general method to obtain the title compound. Oxazole was obtained (0.16 g; 53%); v maw (KBr) 3400 or ], 650c "'; λmax (EtOH) 328 nm (εm29.940 ); δH (CD, OD) < 0.95 (38, d, J 7. OH z, 17-Hl), 1.19 (3H, d.

J6.5Hz, 14-L), 2.30 (3H, s, 15-Hz), 2. 58 (3H, s, -3CH+), 6.27 (18°6C (CDIOD) 12.3 (C-17), 13.5 (-SCL), 19.9 (C-15), 20.4 (C-14).

33,, I (C-9), 4], 7 (C-8), 43.8 (C-12) , 44.0 (C-4), 56.9 (C-10), 61D3 (C-11), 66, 4 (C-16), 70.0 (C-6), 70.7 ( C-7), 71.7 (C-13), 76,4 (C-5), 113.5 (C- 2), 121.3 (C-5″), 122.3 (C-3″), 124.1 ( C-4).

132.7 (C-4'), 145.7 (C-6'),! 48.6 (C- 3), 149.8 (C-5').

1.61.7 (C-2'') and 163.0 (C-2'); ml z 490 (M”, 23%) and 246 (100), measured value (Mo.

490.2] 4'1. Required value of CziH+tNJ+S 490.21.38).

Oxabul (0,124g + 0.25mM) of the above (], Ie) The solution was cooled to 5°C under argon and diluted with m-chlorofluoric acid (9ml). 0.052 g; 0.30 mM) in dichloromethane (1-).

After 0.5 hours, ethyl acetate (1.0d) was added followed by sodium bicarbonate solution (0.5d). d) was added and mixed thoroughly. The organic phase was separated, washed with brine and dried to remove Mg5. O, ), evaporate, glue column (3 g eluent, diluted with 5-10% methanol) chloromethane solution) to obtain the title oxazole (0.09g; 70%) .

v maX (KBr) 3400.1650.1600 and 1550 cm-'; λmax (EtOH) 324 nm (εm21.058); δH (CD, OD ) Especially 0.95 (3H, d, J7, OHz, 17-H-), 1.2 0 (3H, d, J6, 5Hz, 14-H-), 2.33 (3H, s, 15-H-), 2.92 (38,s, -5OCHt), 6.31 (18° 6 C (CD, OD) 12.3 (C-17), 20.0 (C-15), 2 0.3 (C-14), 33.1 (C-9).

41, 2 (-SOCHHz), 41.8 (C-8), 43.8 (C-12), 44.1 (C-4), 56.9 (C-10).

6], 3 (C-11), 66, 4 (C-16), 70.1 (C-6), 70.7 (C-7), 71.7 (C-13).

76, 4 (C-5), 133.3 (C-2), 120.8 (C-4'), 126.8 (C-3°’), 127.1 (C-5#), +34.3 (C -4'), 146.4 (C-6'), 147.5 (C-3), 151 ．． 2 (C-5'), 163.9 (C-2') and 164.7 (C-2' ); 5-(2-methylsulfonyl-5-pyridyl)-2-(1-normole-2 -yl)oxazole Example 12 Oxozole (0,067g+0128mM) dichloromethane ( 5-) The solution was diluted with m-chloroperbenzoic acid (0,026 g:0, 15mM) in dichloromethane (Iip). After 2 hours, ethyl acetate (5-) and sodium hydrogen carbonate (0.2 ml) were added and mixed thoroughly. organic phase Wash with brine, dry (Mg5CL), evaporate, and transfer the residue to a glue column ( 2g; Eluent: 5-10% methanol or chloromethane solution) Obtained xazole (0,048g, 72%) maw (KBr) 3440.1710.1650 and 1600cm-'; λmax (EtOH) 327 nm (εm23.000); δH (CD, OD ) Especially 0.95 (3tl, d, J 7.OH2, +7-83), 1 ．． 20 (3) 1. d, J6, 5Hz, 14-Hz), 2.34 (31 (, S, 15-Hz), 3.27 (3H, S, -8O□CHz), 6. 30 (IHB δC (CD, 0D) 12.3 (C-17), 20.0 (C-15), 20. 4 (C-14), 33.1 (C-9).

40.6 (-3O2CH,), 41.8 (C-8), 43°8 (C-12), 4 ．． 1 (C-4), 57.0gC-10).

61, 3 (C-11), 66, 5 (C-16), 70.1 (C-6), 7 0.8 (C-7), 71.7 (C-13).

0376, 4 (C-5), 113.3 (C-2), 122.7 (C-4' ), 128.0 (C-3'), 129.2 (C-5'), +34.1 (C-4'), 1.46.5 (C-6'), +47°1 (C-3), 151.8 (C-5'), 157.8 (C-2') and 164.4 (C- 2’);=2-year-old xo-5-pyridyl)oxazole 6.7.13-tryst The above (5d) xaxazole (230a+g; 0.5 mmol) in THF (1 (W) The solution was mixed with DMAP (catalytic amount), then trimethylamine (0.56mj : 4 mmol), then trimethylnoryl chloride (0,38i: 3 mmol) 1). After 1 hour, the mixture was evaporated, dissolved in ethyl acetate, water and then Washed with brine, dried and evaporated. with dichloromethane/methanol mixture The title compound was obtained by eluting chromatography (245 73%) .

v max (KBr) (CHzClz) 1680.1660.1635cm-' ;-H), 7.65-7.77 (2H, m, 4' and 6''-Hl) .

The benzene of the oxazole (240 mg: 0.36 mmo+) of the above (], 4a) (7-) solution was mixed with triethylamine (74μI; 0.53mmol) and dichloride. It was treated with ethyl carbamoyl (45 ml: 0.36 mmol). at reflux temperature After 18 hours, the reaction mixture was eluted with a dichloromethane/methanol mixture. ・The title crude compound was obtained by chromatography (130■), using as eluent Chromatography using 30% ethyl acetate/hexane gave the title compound ( 100■=36%) 6.3) 1z, +4-Hz), 1.22(t, I7.3Hz , Et), 1.28 (t, I7.3Hz, Et), (total lysyl)-2-(1-no rumole-2-yl)oxazole (146) oxazole (100mg) :0.13 mmol) in methanol (3 ml) was mixed with DMAP, 2Hcl (I After 40 minutes, the reaction mixture was diluted with dichloromethane and added with saturated sodium bicarbonate. Washed with thorium and saline, dried and evaporated. Dichloromethane/methanol mixture Chromatography on silica eluting with the compound gave the title oxazole (44 :64%:); v maX (KBr) 3421.1718.1652 cm-', λwax (E tO) 1) 303% m (εm27.415); 15), 20.7 (C-14 ), 31.6 (C-9), 39.5 (C-8), 42.1 and 42.2 (2XCdanzMe), 42.7 (C-12), 42.9 (C-4), 55 ．． 5 (C-10), 61.2 (C-11), 65.4 (C-16), 68 ．． 8 (C-6), 70.3 (C-13), 71.1 (C-7), 76, 7 (C-5), 112.8 (C-2), 116.5 (C-3″), 122. 3 (C-5″), +23.6 (C-4’), 134.6 (C-4’), 143.7 (C-6'), 146.4 (C-5"), I47.8 (C -3), 153.2 (C-2'), 158.0 (Co), 161.7 (C -2’); m/z M”, 559 (5%), 100 (100%) :5-(2-bromo-5-pyridyl)-2-(+-normone-6-bromonicothi A suspension of phosphoric acid (1,60 g; 8i) in dichloromethane (40- Thylamine (1,22 mj; 8.8 mmol), then isobutyl chloroformate (1,04d; 8 mmol) and after 0.75 hours this solution was Added to a 5°C solution of azomethane ether. 4 hours at 5°C, then at ambient temperature After 1.5 hours at ℃, argon was passed through the mixture and the mixture was evaporated. Chromatography (silica; 20 g; eluent 6: hexane: ethyl acetate = 1:I) to obtain the title pyridine (0.48 g; 26%).

v maX (CI (C1z) 2100.1620 and 1575 cm-'; 5- Diesel of diazoacetyl-2-bromopyridine (0.48g: 2.Immol) A solution of diethyl ether (100 ml) at 5°C was diluted with excess IN hydrogen bromide. After 0.75 hours, the mixture was treated with sodium bicarbonate and salt. Washing with water, drying and evaporation gave the title compound (0.54g + 100% ).

v max (CIC1z)+690 and 1575 cm-'; the above (15b) Bromoketone (0.54g + 2, Immol) in dichloromethane (30d) The solution was heated to 5°C and added with tetramethylguanidinium at (0.37 g; 2.3 m mo1) for 0.5 h at 5°C and 0.25 h at ambient temperature before incubation. The reaction mixture was evaporated and chromatography (silica: 15 g; eluent: 10% dichloromethane solution of ethyl acetate) to obtain the title pyridine (0.38 g ;84%);v max (CDCIs) 2100.1705 and 1575 cm -'; 3, 0Hz, 6-H).

hydrogenate for minutes, filter the mixture through Celite, and evaporate the filtrate to dryness, leaving ethanol behind. Addition to the residue and re-evaporation of the solution yield a material containing the title compound (350 μ, 60% yield).

v max (KBr) 3600-2000(b), 1700 and 1500c m-'; d, J 2.5Hz, 6-H).

The title monamide was mixed with the amine salt (15a) (340 mg; l 3 mmol) THF/water (1:l; W) and triethylamine (360μl; 2.6mmol) l) prepared in a conventional manner and isolated by chromatography as a white foam. 210cm, 30% yield).

λmax (EtOH) 239%m (εm19,700); 6H (CD30D ) 0.95 (3H, d, J 7.OHz, 17-Hs), 1.20 (3 H, d, J 6.5 Hz, 14-H,), 2.17 (3H, s, +5- H, ), 4.68 (2H,s, l' - H2), 5.88 (IH,s, 2-H).

6 C (CD20D) 12.2 (C-17), 18.9 (C-15), 20 ．． 2 (C-14), 41.6 (C-8).

43, 7 (-12 and C-4), 47.2 (C-1'), 56.8 (C-1 0), 61.2 (C-11).

66, 2 (C-16>, 7o, 0 (C-6), 70.6 (C-7), 7 1.5 (C-13), 76, 1 (C-5).

120.4 (C-2), 129.7 (C-3’), 131.5 (C-5” ), 139.2 (C-4').

147, 6 (C-3), 150.6 (C-6'), 153.7 (C-2' ), 169.8 (C-1) and 195°0 (C-2'); m/z (FAB, 3-NOBA/Na) 565 (MNa'', 2%) and 176 (100).

The above (+5e) monamide (0.2g) was cyclized by a general method to obtain the title oxa Obtained sol (0.07g; 40%): λmax (EtOH) 313%m (εm25.050); 14-Hz), 2.31 (3H,s, 15-Hz ), 6.28(l)1. s, 2-H), 7.66-7°71 (2Lm.

δC(CD, OD)+2.3gC-17), 19.9(C-15), 20.3( C14), 33.0 (C-9).

41, 7 (C-8), 43.8 (C-12), 44.0 (C-4), 56 ．． 9 (C-10), 61.3 (C-11).

66, 4 (C-16), 70.1 (C-6), 70.7 (C-7), 7] , 7 (C-13), 76, 4 (C-5), 113°3 (C-2), 12 5.3 (C-5#), 125.9 (C-4'), 129.8 (C-3'') , 135.3CC-4#), 141.8(C-3), 146.4(C-6 ″), 147.5 (C-5’), 150.8 (C-2’) and 163.7 (C-’).

2-fluoronicotinic acid (0,565 g: 4 mmol) in dichloromethane (1, 0m1) and DF! , l (0.2 ml) of xalyl < 0.45 m 1:4.8 mmol) and allowed to react for 1 hour. The resulting solution is then to an ethereal solution of excess diazomethane, and after 2 hours add dihydrogen chloride of IN. Ethyl ether <20ml (1.20mmol) solution was added and the reaction mixture was stirred for 1 hour. Leave to stand for a while, then wash with sodium bicarbonate and saline, and dry. , evaporated. Column chromatography eluting with hexane ethyl acetate of 21 The title compound was obtained (0.44 g: 65%).

νmax (DCM) 1700 and 1595 cm-'; δH (CDJD)4. 64 (2H, s, -COCHzcl), 7, IQ (IH, dd, J 8. 5. and 6-H).

b) 5-azidoacetyl-2-fluoropyridine chloroketone of the above (16a) (1,0 g; 6 mmol) in dichloromethane (5(W)) at 5°C. Treated with tylguaninonium azide (1.0 g + 6.5 mmol) and incubated at 5°C. ．． 75 hours, then 0.5 hours to ambient temperature before concentrating the reaction mixture; Noriyoku column eluted with dichloromethane to 10% ethyl acid/nochloromethane ( 30 g) to obtain the title AND (0.5 g: 50%).

v max (C1lC1z) 2100.1700 and 1590 cm-'; 6- H) THF (15 mj ), water (9 mA’), 5 NHCI (0,75 mA’) solution with 10% Pd/ Hydrogenated for 2 x 5 minutes in the presence of C (75 mg and 35 μl) and filtered the mixture through a bed of Celite. Filtration and evaporation gave a material containing approximately 10% of the title compound: δH(D,O) Above all <7.25 (11 (, d, J 8.5Hz), 8.44-8.5 6 (If-1, m) and 8.82 (IH, bs).

The title monamito was prepared from the amine salt of (16c) by a conventional method, and the chroma (0.06gj<1'-)1t), 5 ．． 86 (IH, s, 2-H), 6.75 (IH, ++-Nd), 7. To (l)1. dd, J8.5 and 2.3) 1z, 3″-H), 8.42 (]) I1 L J, 8.5Hz, 4″-H) and 8.92(l)I, S, 6’-H).

Dry THF (8 ml) solution under argon at 5°C with Dl + AP (catalytic amount), triethylamine ( 0.34d; 2.44mmol): triethylamyl chloride (0.23ml; 1.8 mmol) and the reaction mixture was stirred for 2 hours. Next, this The mixture was filtered, the filtrate was evaporated and the residue was chromatographed (glue force 7 g, solvent The title compound was obtained by applying syneresis (40% ethyl acetate/hexane) (0.19 g ;89%).

δH(CDCI*)0.06-0.28(27H,m,3　X　(CH+)ss i-), 0.92 (3H, d, J monamito of (16e) above (0.19 g; 0. DMAP (catalytic amount ), birinone (65: 0.81 mmol), trichloroacetyl chloride (60 :0.54 mmol) and the reaction mixture was stirred for 1 hour. Then this The mixture was diluted with dichloromethane, washed with sodium bicarbonate solution and brine, and dried. (Mg5O,), evaporated, chromatography (soldering force 6g, eluent hexa ethyl acetate = 31) to obtain the title oxazole as a foam (34 ■, 1894): δH (CDCI,) < 0.05-0.24g278 ．． m, 3X (C)I2)ssi-), 0.9O-H), and 8.5 3 (IH, s, 6'-H).

Dry TH of the oxazole (34 mg; 0.049 mmol) of the above (16f) The F(1,7+nA') solution was treated with 0.4N hydrochloric acid (0, This solution was then treated with saturated sodium bicarbonate solution (1.5 ml). ) and partitioned between ethyl acetate and brine. Concentrates the organic phase to reduce warp and color. (Silica 800■: eluent 7.5% methanol/dichloromethane) The following oxazole was obtained (16■ 70%) 4'-H) and 8.53 (18,s, 6'-H); m/z 462 ( M”, 15%) and 218 (+00); 5-(2-ethoxy-5-pyri Zyl)-2-(1-normone-azide (16b) above (Q, 2 g); 1. 2 mmol) of THF (10 d), water (6 ml), s NHCl (0, sd) (7) solution 10% Pa/C (50mg and 50mg) +7) presence 2x Washed with water for 5 minutes. The mixture is filtered through a pad of Celite and evaporated to dryness.

Addition of ethanol to the residue and reevaporation of the resulting solution yields approximately 35% of the title compound. A substance containing (0.25 g) is obtained (0.25 g); δH (D, 0) among others <1. 41 (3H, t, J 7.0Hz), 4.47 (2H, q, J7.0Hz).

The title monamide was extracted from the amine salt (0.25 g: 1 mmol) of the above (+7a). It was prepared by a conventional method and obtained by monamide chromatography (115■:22 %).

δH (CD30D) 0.96 (3H, d, J 7.OHz, 17-Hz) , 1.21 (3H, d, J 6.5Hz.

+4-Hz), 1.40 (3H, L, J7.0)lz, -CH2CH2) , 2.17 (3H,3,15-H,).

4, 43 (2H, q, J 7. OHz, -CHI C dan,), 4.68 ( 2H,s, l'-Hz), 5.90 (IH,s.

m/z 506 (M”, 12%) and 150 (100).

The above (17b) monamide (95 mg; 0.185 mmol) was added using a general method. Cyclization to give the title oxazole (35 lbs., 40%).

λmax (EtOH) 303.5 nm (e m24.000); δH (CD CIs) 0.95 (31 (, d, J 7. OHz, +7-H,), 1. 23 (3H, d, J 6.5Hz.

14-Hz), 1.43 (38,t, J7.0)1z, Cdan-C)+20 -), 2.33 (3H,s, 15-H-).

4, 40 (2H, Iq, J7.OHz, Cdan2CHzO-), 6.2 9 (IH, s, 2-14), 6.78 (IH, d.

m/z 488 (M”, 24%) and 244 (100).

5-bromonicotinic acid (1,61 g; 8 mmol) was added as described in (16a) above. The title product was isolated (1.6 g; 85%).

v mar (CHCIs) 1420 cm-'.

b) 5-Acidacetyl-3-bromopyridine The above (+8a> chloroketone) The reaction was carried out as described in (+6b) above, and the title azide was isolated (1.2 g; 69%).

v max (C) 1c1z) 2100 and 1710 cm-'; 8, 80 (I H, m, 2-H) and 8.89-9.08 (IH, m, 6-8).

The azide ketone of the above (18b) is reacted as described in the above (16c), and the title The compound was isolated as a yellow solid (0.5 g): δH(D,0) esp. 4.70(2)1. s, -COCdan2NH2), 8.82(IH,s, 4-H).

9, 03 (IH, s, 2-1 (), and 9.14 (1) 1. s, 6- H).

The title monamide was mixed with the amine salt (18c) (500 mg + 1.5 mmol) from THF/water (1:l; 5+J) and triethylamine (360μl; 2.6m mol) and isolated by chromatography as a yellow foam. Did (280■: 34%): λmax (EtOH) 214.5 nm (εm31.900); δH (CDs OD) 0.95 (3H, d, J 7.OHz, 17-L), 1.20 ( 3H, d, J 6.5Hz.

14-Hz), 2.16 (3) 1. s, 15-Hz), 4.70 (2H , s, I'-H2), 5.88 (18, s.

2-H), 8.52-8.58 (IH, m, 4'-H), 8.39 (IH , d, J 2. OHz, 2'-H) and 9.10 (IH, d, J 1 ．． 5Hz, 6’-H); δC (CDIOD) 12.2 (C-17), 18.9 (C-15), 20.2 (C-14), 32°9 (C-9).

43, 7 (C-4 and C-12), 47.3 (C-1'), 56.6 ( C-10), 61.2 (C-11).

66, 2 (C-16), 69.9 (C-6), 70.6 (C-7), 71 ．． 6 (C-13), 76, 2 (C-5).

120, 4 (C-2), 120.6 (C-5'), 133.6 (C-3" ), 139.3 (C-21).

148, 2 (C-4'), 153.5 (C-3), +55.3 (C-6' ), 169.8 (C-1) and 194.6 (C-2'); e) 5-(3-bromo-5-pyridyl)-2-(]-normone of the above (+8d) The monamide was cyclized in a conventional manner to give the title oxazole (105■, 50 %); λmax (EtOH) 317 nm (εm20.469); δ) I (C DsOD) 0.95 (3H, d, J 7.OHz, 17-Hz), 1. 20 (38, d, J 6.5Hz.

14-Hz), 2.32 (3H,s, +5-H,), 6.29(IH,s , 2-H), 7.75 (IH,s, 4'-H).

δC (CD, OD) 12.3 (C-17), 20.0 (C-15), 20 ．． 4 (C-14), 33.1 (C-9).

41, 8 (C-8), 43.8 (C-12)), 44.1 (C-4), 5 6.9 (C-10), 61.3 (C-11).

66, 5 (C-16), 70.1 (C-6), 70.8 (C-7), 71 ．． 7 (C-13), 76, 5 (C-5).

113, 3 (C-2), 122.3 (C-3'), +26.7 (C-4' ), 127.5 (-5'), +35.0 (C-4'), 144.2 (C-6'), 146.8 (C-3), 150.5 (C-2'), 1 51.1 (C-5'') and 163.9 (C-2'); 5-bromo-2-dime A solution of 1.2 g (6 mmol) of thylaminopyridine in dry THF (20 mN) was added. n-butyl at -100°C under a rugone atmosphere, maintaining the temperature below -85°C, - After 1 hour at 90°C, N-1-methoxy-N-1-methyl-N-(t-butyl (oxycarbonyl)-glycinamide (0.44 g; 2 mmol) in dry THF ( log) solution and maintain the reaction temperature at -85°C. After 2 hours, cool the cooling bath. Cool and add saturated ammonium chloride solution (20 m/). Mixture with ethyl acetate Extract, wash the organic phase with brine, dry with hsO, ), evaporate and remove the residue. Chromatography (silica 17g: eluent hexane: ethyl acetate = 2: 1) to obtain a substance containing the title compound (0.06 g): 2, 5Hz, 6-H).

Pyridine (200 mg) of the above (19a); 0.7 mmol of methanol (3, 4 mA > The solution was treated with concentrated HCI (1,7d) at 5°C and incubated at 5°C for 0.5 h. , then after 2.5 hours at ambient temperature the solution was evaporated to dryness and the residue was dissolved in diethyl ・Impure product containing the title compound after grinding with ether and drying under vacuum (200 mg); The title monamide was converted to the amine salt (+9b) (19 0mg; 0.7mmol)'iz et al. THF/water (1:1; 3+J) and Torie Prepared in thylamine (300 ul; 2.1 mmol) in a conventional manner and cooled. Isolated by chromatography as a pink foam (135μ, 38%): 126 (100).

The above monamide (19C) was cyclized using a general method to obtain the title oxabul. (70■55%): λmaw (EtOH) 330nm (εm23.500); 2.5Hz, 6 ’　-H); δC (CD30D) 12.3 (C-17), 1.9.8 (C-15), 2 0.4 (C-14), 33.1 (C-9).

38, 5(”’N(CHl　)ri, 41.7(C-8), 43.8(C-1 2), 43.9 (C-4), 56.9 (C-10), 61.3 (C-11 ), 66,4 (C-16), 70.1 (C-6), 70.8 (C-7), 71.7 (C-13), 76,5 (C-5), 107.5 (C-2), 113.6 (C-5"), 113.7 (C-4").

120.9 (C-3'), 134.6 (C-4'), 144.7 (C- 6'), 148.3 (C-5') 150.2 (C-3), 160.1 ( C-2'') and 161.9 (C-2) 15-(2-fluoro-3-pyridyl )-2-(1-normonolithium diisopropylamide mono(tetrahydro) solution of Furan) (5,72 J, 1.5 M in siloxane; 8.6 mmol) 2-fluoropyridine (0,741d!; 8.5m mol) in THF (16 J) while maintaining the temperature below -70°C. I understood.

After 2.5 hours at -80°C, N-1-methoxy-N-i-methyl-N-( T of t-protoxycarbonyl) glycinamide (0.88 g; 4+++ mol) A solution of HF (16d) was added keeping the temperature below -70'' and after 2 hours acetic acid was added. (0.68d) was added, stirred thoroughly and the reaction mixture was partitioned between ethyl acetate and water. Ta. The organic phase was washed with brine, dried (Mg5O,), evaporated and the residue was chromatographed. Toography (25 g of silica, eluent: hexane: ethyl acetate = 1: l) , the title compound was obtained (120■: 11%); δH (CDCIs) 1.47 (9H, s, (Cdan 5) sc-), 4.63 (2H,S, -COCH,N)I-).

5, 40 (IH, wide width S, >NH), 7.33-7.43 (IH, m, 5 -H) and 8.39-8.50 (2H, m, 4H and 6-H).

b) 2-amino-1-(2-fluoro-3-pyridyl)ethane-1-one tri Fluoroacetate The protected aminomethyl ketone (243 0.95 mmo) of (20a) A dichloromethane (12+J) solution of l) was dissolved in trifluoroacetic acid (2,5d) at 5°C. After 10 minutes at 5"C and 2 hours at ambient temperature, the mixture was evaporated and The sticky residue is dried in vacuo, and the resulting residue is combined with dry diethyl ether. The cream-colored solid obtained is separated and dried to give the title compound. was obtained (250■): δH (D20) < 4.62 (2H, s, -COCH, NH,), 7.50-7.62 (IN, m.

5-H), and 8.45-8.60 (2H, m, 4-H and 6-i().

The title monamide was mixed with the amine salt (20b) (250 mg; 0.95 mmol). ) to THF/water (1:l; 4+J) and triethylamine (390ul; 2 ．． 85 mmol) in a conventional manner. An impure product was obtained (270 ■), which contained the titled monamide; (IH, m, 5'-H) and 8.40-8.47 (2H, m, 4' and 6'-H).

The above (20c) monamide (270 mg; 0.56 mmo+) was added using a general method. to give the title oxazole (27■, 10%): λmax (Et OH) 317 nm (εm22.690); 14, -L) + 2.33 (3H, s, 15-Hz), 6.30 (1) 1. s, 2-H), 7.40-7. 49 (IH, m.

5”-H), 7.57(1)1.d, J 4.OHz, 4’-H Fluorine bond) and 8.12-8.34 (2H, m, 4'-H and 6'-H); Examples of normonyl derivatives that are important for human diseases Squirrel, influenzae Q1. Branhamella catarrhalis 1502; Strep Tococcus virogenes CN10, Strebcoccus pneumoniae PU2 The activity against Staphylococcus oxford) was tested at 5% in vitro. Tested by serial dilution method in nutrient agar with blood for chocolate addition.

The MIC value was measured by culturing at 37°C for 18 hours and was in the range of 0.25 to 32 μg/pod. It turns out that

i grain! H (In the formula, R1 is a substitutable pyridyl group) has antibacterial and anti-myfplasmic properties. Pharmaceutical compositions, veterinary pharmaceutical compositions, and preparations thereof, comprising such compounds A, which are useful for treatment. Methods of preparation and intermediates used in the preparation of such compounds are also described.

international search report Internal saying # Cψ glance - chant red O - 1 ^ () 畦 CI Shin - + -, PCT/GB901019 33 International Search Report

Claims (16)

[Claims] 1. Compound of formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R1 represents a pyridyl group, attached to the oxazolyl moiety through its carbon atom, the pyridyl group is unsubstituted or may be substituted with one or up to five different substituents). 2. The substituent to the pyridyl group of R1 is: (i) Halogen, cyano, azide, nitro, formyl, carboxy, carboxylic acid salt, sulfo, or sulfonate; (ii) amino, ureido, carbamoyl; or sulfonamide (the nitrogen atom of each of these groups is further represented by the following (iv) (v) (v) Substituted with one or the same or different divalent group selected from the groups listed in item i) ); (iii) Hydroxy or mercapto (the hydrogen of each of these groups is as shown in (iv) below) , (v), (optionally substituted with one of the groups listed in (vi)); (iv) Rp group (wherein Rp represents an aryl or a heterocyclic group); (v) Rq group (wherein Rq is (C1-6) alkyl, (C3-7) cycloalkyl (C2-6) alkenyl, (C3-6) cycloalkenyl, or (C2-6) 6) Alkynyl, each of which is (i), (ii), (iii), ( iv), up to three same or different groups selected from the groups listed in (vi) ); (vi) RpCO-, RpOCO-, RqCO-, RqOCO-, RpSO-, RpSO2-, RqSO-, and also RqSO2- (formula In the middle, Rp and Rq are the same as defined in sections (iv) and (v), respectively); (vii) divalent Y° group (heterocycle together with the divalent carbon atom of the bonded pyridyl group, or forming a carbocyclic ring). 3. The substituent to the pyridyl group of R1 is hydroxy, halogen, cyano, or nitro substitution (C1-6) alkyl, aryl, heterocyclic group (C1-6) alkyl, which may be Koxy, carboxy and its salts, (C1-6) alkoxycarbonyl, acyl, acyl Mino, mono- or di-(C1-6) alkylamino, carbamoyl, mono- or di-(C1-6)alkylcarbonyl, carbamoyloxy, mono- or is di-(C1-6)alkylcarbamoyl, acylamino, (C1-6)alco oxycarbonylamino, (C1-6) alkylthio, arylthio, (C1-6 ) Alkylsulfinyl, arylsulfinyl, (C1-6) alkylsulfonyl Nyl, arylsulfonyl, sulfamoyl, mono- or di-(C1-6)al 2. The compound of claim 1 which is kylsulfamoyl. 4. 2. A compound according to claim 1, wherein the pyridyl group is a single substituent. 5. The pyridyl group R1 is defined by a carbon atom in the β-position relative to the pyridyl nitrogen atom. 2. A compound according to claim 1, which is attached to an oxazole ring. 6. A group consisting of: 2-(1-normon-2-yl)-5-(2-pyridyl)oxazole; 2-(1-normon-2-yl)-5-(3-pyridyl)oxazole; 2-(1-normon-2-yl)-5-(4-pyridyl)oxazole; 2-(1-normon-2-yl)-5-(2-methyl-5-pyridyl)oxazo Rule; 2-(1-normon-2-yl)-5-(1,2-dihydro-2-oxo-5- pyridyl)oxazole; 2-(1-normon-2-yl)-5-(2-methoxy C-5-pyridyl)oxazole; 2-(1-normon-2-yl)-5-(1,2-dihydro-1-methyl-2- Oxo-5-pyridyl)oxazole; 5-(2-methoxy-5-pyridyl)- 2-(1-normon-2-yl)oxazole; 5-(2-chloro-5-pyridyl)-2-(1-normon-2-yl)oxazo Rule; 5-(2,3-dihydro-5-pyridyl)-2-(1-normon-2-yl)o Xazole; 5-(2-methylthio-5-pyridyl)-2-(1-normon-2-yl)oxy Sasol; 5-(2-methylsulfinyl-5-pyridyl)-2-(1-normon-2-y ) Oxazole; 5-(2-methylsulfonyl-5-pyridyl)-2-(1-normon-2-yl ) Oxazole; 5-[2-(N,N-diethylcarbamoyloxy)-5-pyridyl]-2-( 1-normon-2-yl)oxazole; 5-(2-bromo-5-pyridyl)- 2-(1-normon-2-yl)oxazole; 5-(2-fluoro-5-pyridyl)-2-(1-normon-2-yl)oxa Sol; 5-(2-ethoxy-5-pyridyl)-2-(1-normon-2-yl)oxa Sol; 5-(3-bromo-5-pyridyl)-2-(1-normon-2-yl)oxazo Rule; 5-(2-dimethylamino-5-pyridyl)-2-(1-normon-2-yl) Oxazole; 5-(2-fluoro-3-pyridyl)-2-(1-normon-2-yl)oxa Compounds selected from sol. 7. Compound of formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R1 is defined in claim 1. Z1, Z2, and Z3 are the same or different, and hydrogen or hydrogen cycloyl protecting group) to form a compound of formula (I), then optionally 2. A process for preparing a compound according to claim 1, which comprises removing the hydroxy protecting group. 8. A compound of formula (III) as defined in claim 7. 9. A group consisting of: N-[2-oxo-2-(2-pyridyl)ethyl]monamide; N-[2-oxo -2-(3-pyridyl)ethyl]monamide; N-[2-oxo-2-(4-pyridyl) zyl)ethyl]monamide; N-[2-oxo-2-(2-methyl-5-pyridyl) ) ethyl] monamide; N-[2-oxo-2-(1,2-dihydro-2-oxo-5-pyridyl)ethyl Monamide; N-[2-(2-methoxy-5-pyridyl)-2-oxoethyl]monamide; N-[2-(2-chloro-5-pyridyl)-2-oxoethyl]monamide; N-[2-(2,3-dichloro-5-pyridyl)-2-oxoethyl]monamide ; N-[2-(2-methylthio-5-pyridyl)-2-oxoethyl]monamide; N-[2-(2-bromo-5-pyridyl)-2-oxoethyl]monamide; N-[2-oxo-2(2-fluoro-5-pyridyl)ethyl]monamide; N-[2-oxo-2(2-ethoxy-5-pyridyl)ethyl]monamide; N-[2-(3-bromo-5-pyridyl)-2-oxoethyl]monamide- N-[2-(2-dimethylamino-5-pyridyl)-2-oxoethyl]monami Do; From N-[2-(2-fluoro-2-pyridyl)-2-oxoethyl]monamide Selected compounds. 10. Compound of formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, Z1, Z2, and Z3 are the same, or or different, hydrogen or hydroxy protecting group, respectively) of formula (VI) Compound: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) (wherein R1 is defined in claim 1) is the same as defined above, M+ is a metal cation, and R2 is naturally β-hydroxyl. is an anion-forming group that is removed by a group to form an olefin), and then Preparation of the compound of claim 1 comprising optionally removing the hydroxyl protecting group with Method. 11. Compound of formula (VIII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VIII) (In the formula, Z1, Z2, and Z3 are the same) one or different, each being hydrogen or a hydroxyl protecting group, and R1 is (same as defined in requirement 1, where Y is a leaving group) is treated with a strong base to remove the necessary A process for producing a compound according to claim 1, which comprises removing the hydroxy protecting group if necessary. . 12. A compound of formula (VIII) as defined in claim 11. 13. Compound of formula (XI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XI) (In the formula, R1, Z1, Z2, Z3 are isomerizing the carbon-carbon double bond (same as defined in claim 7) A method for producing the compound according to claim 1, comprising: 14. A compound of formula (I) and a pharmaceutically and veterinarily acceptable carrier or excipient and a veterinary pharmaceutical composition. 15. 7. A compound according to any one of claims 1 to 6 for use in therapy. 16. An effective amount of a compound according to any one of claims 1 to 6 is administered to a human in need of treatment; can be administered to non-human animals to cause bacterial and/or or treatment methods for mycoplasma sexually transmitted infections.