WO1989012048A1 - Cis-2,6-diazabicyclo[3.3.0]octane derivatives and their medicinal use - Google Patents

Abstract

The invention relates to cis-2,6-diazabicyclo[3.3.0]octane derivatives represented by general formula (I), a peptic ulcer-treating agent containing same as active ingredient, and intermediates (II) and (III) for producing the compounds. In said formula X represents oxygen, sulfur, -NH- or -N<; X1 represents alkylene or alkenylene optionally forming a ring together with -N< when X represents -N<; Y represents alkylene; Y1 represents hydrogen, alkyl or alkenyl, said alkyl optionally forming substituted or unsubstituted cycloalkyl together with Y2; Y2 represents hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or heterocyclic ring; A represents hydrogen or hydroxyl optionally having a protective group; R, R1 and R2 each represents hydrogen or alkyl; R3 represents hydrogen, a protective group of nitrogen or alpha; R4 represents hydrogen or a protective group of nitrogen; and Z and W each represents oxygen or sulfur.

Description

 Specification

 Cis-1,2,6-diazabicyclo [3.3.0] octane derivatives and their pharmaceutical uses

 "Technical field"

 The present invention relates to cis-1,2,6-diazabicyclo [3.3.0] octane derivatives useful as drugs such as antithrombotics, antiulcers, and cerebral protective agents, particularly as antiulcers, and pharmaceutical uses thereof.

 "Background technology"

1976 Prostaglandin I ₂ (hereinafter referred to as PGI ₂ ) isolated by J. Vane et al. Has a variety of pharmacological actions (arterial smooth muscle relaxing action, antihypertensive action, anti-ulcer action, vasodilator action, Numerous PGI ₂ analogs have been synthesized because they have an inhibitory action on gastric acid secretion, an inhibitory action on platelet aggregation, an action on increasing renal blood flow, and an antiallergic action. That the eno Rue one ether structure is a destabilizing factor of PGI ₂ is variously converted, compounds in development as a stable PGI ₂ analogs Ci loprost (Medicinal Res. Review. 5, 1, 1985), OP- 41483 (Progress in Medicinal Chemistry 21, 238, 1984), CS-570 (Drugs of the Future, 918, 1986), TRK-100 (JP-A-59-134787) and the like.

These compounds are being developed as antithrombotic agents (preventive or therapeutic agents for cerebral thrombosis, myocardial infarction, arteriosclerosis, etc.) based on a more selective platelet aggregation inhibitory effect, but side effects (headache, headache, Flushing) have also been reported to occur frequently and are not yet on the market. In addition, since these compounds have many asymmetric carbons, they require many steps in production and require a great deal of labor and time. Further The final target compound is mostly oily and has problems in handling. In order to solve these problems, a compound having a reduced number of asymmetric carbon atoms (eg, Tilsuprost (Japanese Patent Application Laid-Open No. 56-133265), 12-azaprostacyclinatilog (Tet. Lett. 22, 253, 1981)) 12-azacarboprostacyclin analog (Tet. Lett. 24 »477, 1983), 10, 12-azacarboprostacyclin analog (Japanese Patent Laid-Open No. 57-72971)] Has also been synthesized, but has not yet been marketed.

 "Disclosure of the invention"

 Under the above circumstances, the present inventors have reduced the number of asymmetric carbon atoms as much as possible and left only the asymmetric carbon essential for the activity to synthesize a cis-1,2,6-diazabicyclo [3.3.0] octane derivative. After intensive studies, the compound represented by the formula (1) was found to have platelet aggregation inhibitory action, gastric acid secretion inhibitory action, anti-hyboxya action (brain protecting action), etc. The inventors have found that the method is more selective, and have further studied the manufacturing method thereof, thereby completing the present invention.

 The present invention relates to a novel and useful pharmaceutically useful formula (1)

[In the formula, each symbol means the following X represents oxygen, sulfur, —NH— or _ N <.

 X, represents alkylene or alkenylene, and the alkylene or alkenylene may form a ring together with the 1-N when X is -N.

 Y represents alkylene.

Y, represents hydrogen, alkyl or alkenyl, and the alkyl may form a cycloalkyl with Y ₂ , and the cycloalkyl may be substituted with alkyl.

 Y 2 is hydrogen, alkynole, anolecenyl, alkynyl, alkyl which may be substituted with alkyl, alkyl-substituted aminopurequinole, alkoxylenocre, alkenyloxylenole, alkynyloxylelequin, alkylthioalkyl, aralkyl 、, リ レ オ レ オ キ フ レ フ レ, 、 一 レ

(However, in the above definitions, aryl or aryl part is nodogen, trifluoromethyl, alkynole, alkoxy, nitrite, nodoxyl, amino, anorequila And may be substituted with a group selected from the group consisting of amino, alkoxypropyl, carboxyl, and cyano), heterocyclic-substituted alkyl, heterocyclic-substituted oxyalkyl, and heterocyclic-substituted thioalkyl.

 A represents hydrogen or hydroxyl which may have a protecting group.

R, R, and R _z each represent hydrogen or alkyl.

 Z represents oxygen or sulfur. ]

Cis-1,2,6-diazabicyclo [3.3.0] octane derivative, salt or ester thereof represented by the formula:

[Wherein the symbols mean the following.

 Y represents alkylene.

Y i represents hydrogen, alkyl or alkenyl, and the alkyl may form a cycloalkyl with Y ₂ , and the cycloalkyl may be substituted with alkyl.

 Υ2 Hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl which may be substituted with alkyl, alkyl-substituted aminoalkyl, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, alkynolethioalkyl, aryl- Aranolec, Aryloxyalkynole, Arylthioalkyl (However, in the above definitions, Aryl or Aryl is a nodogen, Trifzoleolomethinole, Anolequinole, Anolexoxy, Nitodoki, Noyodoroki May be substituted with a group selected from silyl, amino, alkylamino, alkoxycarbonyl, carboxy and cyano.), Heterocycle, heterodisubstituted alkyl, heterocycle substituted oxyalkyl, heterocycle substituted thioalkyl Representing the.

 The term represents hydrogen or hydroxyl optionally having a protecting group.

R and R, each represent hydrogen or alkyl. R 4 represents a hydrogen or nitrogen protecting group.

 Z and W each represent oxygen or sulfur. ]

 A compound represented by the formula: and the formula (8)

 [In the formula, each symbol means the following.

 R 3 is a hydrogen or nitrogen protecting group or group (B)

 A

One Y—C One Y ₂ (B)

 I

Y I

 (In the formula, it means the following of each symbol.

 Y represents alkylene.

Y, represents hydrogen, alkyl or alkenyl, and the alkyl may form a cycloalkyl with Y _z , and the cycloalkyl may be substituted with alkyl.

 Y 2 is hydrogen, alkyl, alkenyl, anolequinyl, cycloalkyl optionally substituted with alkyl, alkyl-substituted aminoalkyl, alkoxy cyanolealkyl, alkenolinoleoxy cyanolealkyl, alkynyloxyalkyl, alkylthioalkyl, arylalkyl, Aryloxyalkyl, arylthioalkyl

(However, in each of the above definitions, aryl or aryl is halogen, triphenylenomethyl, alkynole, anoreoxy, nitrite Mouth, nerdy droki? And it may be substituted with a group selected from the group consisting of amino, amino, alkzoleamino, alkoxycarbonyl, carboxy and cyano. ), Heterocyclic, heterocyclic-substituted alkyl, heterocyclic-substituted oxyalkyl, and heterocyclic-substituted thioalkyl.

 A represents hydrogen or hydroxyl optionally having a protecting group. )

Represents a group which can lead to

 R and R, each represent hydrogen or alkyl.

R ₄ represents a hydrogen or nitrogen protecting group. (However, R and

When both RI are alkyl, R ₃ and R ₄ are other than hydrogen. )]

And a pharmaceutical use of the compound (I).

 In the present specification, the groups represented by each symbol will be described in detail.

R, R, and with respect to R _2, the alkyl is preferably methylation, Echiru, propyl, i Sopuro building, butyl, carbon number 1-4 such as tertiary butyl, optionally Fuweniru or substituted Hue sulfonyl ( The substituent may be substituted by halogen, nitrodoxyl, nitro, amino, cyano, alkyl, or alkoxy.

X! In contrast, the alkylene may be either a straight chain or a branched chain, and may be cyclic. The carbon number is preferably 1 to 5 in the case of a chain, and preferably 3 to 7 in the case of a ring. Specific examples of the alkylene include methylene, ethylene, propylene, isopropylene, butylene, and ethylene. Examples thereof include sobutylene, pentylene, isopentylene, cyclopropylcyclopentane, cyclopentylene, cyclohexylene, and siccopenitylene.

 With respect to X, the alkenylene may be a straight chain or a branched chain, and may be cyclic. The carbon number is preferably 2 to 5 in the case of a chain, and preferably 3 to 7 in the case of a ring. Specific examples of the alkenylene include 2—propenylene, 2—butenylene, 3—butenylene, 4—pentenylene, and 3—methyl-1-butenylene , 41-1-4: entrylene, isopro- nylen, 2-cyclopentene,

2 — Examples include cyclohexylene.

With respect to X, with respect to X, when X is —N <, the ring formed together with the —N <is such that two bonds of the alkylene or alkylene are attached to two bonds of the —N <. It is bonded to form a ring, for example, a group represented by the following formula:

Regarding A, examples of the protecting group in hydroxyxyl that may have a protecting group include acetyl, chloroacetyl, trifluoroacetyl, pinolyl, benzoyl and other acyl, trityl, and the like. Ether-based protecting groups such as trityl, methoxymethyl, methoxymethyl, methoxyl, benzyloxymethyl, methylthiomethyl, etc., such as monomethoxytrityl and dimethoxycitryl; Ketal-based protecting groups such as methoxy isopropyl, tetranodidrofuranil, tetranodidrofuranyl, etc., trimethylsilyl, t-butyldimethylsilyl And benzyl such as benzyl, ρ-methoxybenzyl, ρ-methoxybenzyl, 3,4-dimethoxybenzyl, and 0-nitrobenzyl. The coordination of the hydroxyl group at the mouth may be either α or ^.

 Regarding Υ, the alkylene may be either a straight-chain or a branched chain, and preferably has 1 to 5 carbon atoms. As the alkylene, specifically, methylene, ethylene, propylene, isopropylene, Examples include butylene, isobutylene, pentylene, and isopentylene.

 Regarding Υ1, alkyl may be either a straight chain or a branched chain, and preferably has 1 to 4 carbon atoms. Examples of such a group include methyl, ethyl, propyl, isopropyl, butyl, Tertiary butyl is exemplified.

 Alkenyl with respect to Y i may be straight-chain or branched, and preferably has 2 to 8 carbon atoms, and specific examples of such a group include butyl, 2-propenyl, and 2-butenyl. Etc. are exemplified.

Y j number of carbon atoms of a cycloalkyl which the alkyl forms with Y _z regard is preferably rather is 3-9, specifically sik Ropuro building as such groups, sik Robuchiru, sik Ropenchiru, cyclohexyl, Examples include cycloheptyl and the like. In this case, the hydroxyl group related to Α forms a tertiary alcohol. The cycloalkyl may be substituted with an alkyl, but the lower alkyl may be a C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, etc. 4 are illustrated. Examples of such alkyl substituted cycloalkyls include 3-n-provircyclopentyl, 4-ethylcyclohexyl, 4-n-provircyclohexyl, and 4-isopropylcyclohexyl. Is done.

 With respect to z, the alkyl group may be straight or branched, and preferably has 2 to 10 carbon atoms, specifically, ethyl-propyl, isopyl pill, butyl, isobutyl. , Pentyl, isopentyl, hexyl, heptyl, octyl, 1-methylpentyl, 2—methylpentyl, 1,1-dimethylpentyl, 2,6—dimethylheptyl, 1,1dimethyl Tilhexyl, 3-methylpentyl, 1> 1-dimethylbutyl and the like are exemplified as preferred.

 Alkenyl, with respect to Y z, can be either straight or branched, and has a preferred carbon number of 2 to 10, and specifically includes bur, aryl, 3-butyr, 3-penthenol, 4 ^ intul, 1

—Me Chiru 3? Mentur, 3 — hexenyl, 1 — methyl 1 3

— Hexenyl, 2, 6 — Dimethyl 1-5 — Heptur, 2-pentyl, 3- Octyl, etc. are exemplified as preferred.

On the other hand, alkynyl may be either linear or branched, and preferably has 2 to 10 carbon atoms, specifically propargyl, butan-3-ynyl, pentane 1-thynyl, pentane 4-thinyl, 1-methylpentane 1-thynyl, hexane — 3—ynyl, 1—methylhexanthyl 3—ynyl, 2, 6-dimethylheptan-5-inyl, octane-3-inyl and the like are exemplified as preferred. The preferred number of carbon atoms of the cycloalkyl which may be substituted with alkyl for YZ is 3 to 8 (however, the number of carbon atoms of the substituent alkyl is not limited). The preferred number of carbon atoms is 1 to 10 regardless of the type of the branched chain. Specific examples of the cycloalkyl include cyclopropyl, cyclobutizole, cyclopentinole, cyclohexyl, cyclohexyl, and cyclohexinol, 3-n-f. Mouth Pinoresic Lopenchinole, 4-Echinolescicyclohexylene, 4-n-Propinolecyclohexynole, 4-isopropyl cyclohexyl and the like are exemplified as preferable ones.

 With respect to Y z, with regard to the aminoalkyl in the alkyl-substituted aminoalkyl, the alkyl moiety may be any of the branched chains, and the preferred carbon number is 1-10. The amino moiety may be mono- or di-substituted. Alkyl as a substituent for amino may be straight-chain or branched. The preferred number of carbon atoms of alkyl as a substituent is from 1 to I0. Specific examples of the alkyl-substituted aminoalkyl include, for example, ethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, isopropylaminomethyl, 1— [proviramino) ethyl , 1, 1 -dimethyl-1- (butylamino) methyl and the like.

The alkyl moiety in the alkoxyalkyl with respect to Y _z may be either linear or branched, and preferably has 1 to 10 carbon atoms. The alkoxy moiety may be a straight chain or a branched chain, and preferably has 1 to 10 carbon atoms. Specific examples of such a group include edoximetyl, n-propoxymethyl, 1-methyl-2-ethoxyethoxyl, 1, 1-dimethyl-2-yl. Toxexetil, 2 — n — Proboxexetil, 2 — n — Butoxyshethyl, 1, 1 — Dimethyl 1 2 — Isopropoxyshethyl, n — Propoxymethil, 1 — Proboxixyl, 1, 1 Jimetyl-2 I-n-propoxyshetil and the like.

 The alkyl moiety in the alkenyloxyalkyl for Y 2 may be either straight-chain or branched, and preferably has 1 to 10 carbon atoms. The alkenyloxy moiety may be either a straight chain or a branched chain, and preferably has 1 to 10 carbon atoms. Specific examples of such a group include 2-aliloxicetyl, 21-(2-butyroxy) ethyl, 1-methyl 2-aliluoxicetyl, 1, 1-dimethyl-1 2-aliloxicetil, 1, 1 —dimethyl 2 — (2 —butyroxy) ethyl and the like are exemplified.

The alkyl moiety in the alkynyloxyalkyl with respect to Y ₂ may be either linear or branched, and preferably has 1 to 10 carbon atoms. The alkynyloxy moiety may be either straight-chain or branched, and preferably has 1 to 10 carbon atoms. Specific examples of such a group include propargyloxexetil,

1, 1 —Dimethyl 2 —Prono. Examples thereof include lugiloxyxetil, propargyloxymethyl, 1,1-dimethyl-1-2-butan-2-ininylethyl, 1-methyl-2-propargyloxethyl and the like.

Alkyl moiety infra in alkylthioalkyl respect Y ₂ is rather good in either a straight chain or branched technique chains, preferred correct number of carbon atoms is 1 to 1 0. In addition, the alkylthio moiety is straight or The preferred number of carbon atoms is 1 to 10 regardless of the type of the chain. Specific examples of such groups include propylthiomethyl, ethylthioethyl, 1,1-dimethyl-2-ethylthioethyl, 1,1-dimethyl-1-2-n-propylthioethyl and the like.

Examples of the substituent in aryl (but may be substituted) with respect to Y ₂ include the following. That is, halogen such as fluorine, chlorine, bromine and iodine, alkyl such as trifluoromethyl, methyl, ethyl and propyl (preferably alkyl having 1 to 10 carbon atoms), methoxy , Ethoxy, propoxy, etc. (preferably alkoxy having 1 to 10 carbon atoms), nitro, nitrodoxyl, amino, methylamino, dimethylamino, getylamino, etc. Amino which may be substituted with alkyl (preferable number of carbon atoms of alkyl as a substituent for the amino is 1 to 10), alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like (preferable Or alkoxy having 1 to 10 carbon atoms), carboxyl, and cyano. The substituents are the same or different and are mono-, di-, or tri-substituted at the 0, m, and p positions. Such aryls include, for example, phenyl, 0-fluorophenyl, p-fluorophenyl, m-chlorophenyl, in-trifluoromethyl phenyl, m-methylphenyl, 3,4-dimethoxyphenyl, p-fluorophenyl —Nitrophenyl, p—Nydroxy thiphenyl, P—Methoxy deca ^ / bonylphenyl, p—Dimethylaminophenyl, 3,4—Difluorophenyl, 2,4 Dibromophenyl Zinyl and the like are exemplified.

Aralkyl represented by Y z (but may be substituted) Examples of the substituent in are the same as the substituents in the aryl group. The alkyl moiety can be either straight or branched and has a preferred carbon number of 1 to 10. Such aralkyls include, for example, 1-phenylenyl, 2-phenylenyl, 3-phenyl-n-propyl, 1,1-dimethyl-3, phenyl-n-propynole, 4— N-n-butyl,

5 — Huenru n? Phenyl, 6-phenyloxy and aralkyl in which a substituent has been introduced into the phenyl moiety, for example, 1- (P-fuzoleophenyl) ethyl, 1,1-dimethyl-1 3 —

(m—trifluoromethylphenyl) 1 n — propyl, 1, 1 1 dimethyl 4 — (P — black mouth) 1 n — butyl, 1 — methyl 1 3 — (m — Fluorophenyl) n-Propyl, 1

Examples thereof include (0-fluorophenyl) ethyl, 1,1 dimethyl-3- (3,4-difluorophenyl) -1-n-propyl and the like.

 Examples of the substituent in the aryloxyalkyl represented by Y 2 (which may be substituted) include the same substituents as those in the aryl. The alkyl moiety may be linear or branched, and preferably has 1 to 10 carbon atoms. The aryloxyalkyl includes phenoxymethyl,

1—Shenil, 2—Shenil, 1—Methyl

2—Phenomenon Shechill, 3—Phenomenon n—Propyl, 1,

1-methylenoxymethyl, 1,1-dimethyl-2-phenyloxyethyl and groups in which a substituent is introduced into the aryl moiety, for example, P—fluoroenoxymethyl, P—methyl Cylinders, m — Tri-funoreo Rome Cylinders, p — Rolfenoximetyl, 0—methoxyphenoxymethyl, 2,4—difluorofenoxymethyl, 3,4—difluorophenoxymethyl, 2,4,6—trimethylphenoxymethyl, 1 —

(P—Fluorophenoxy) ethyl, 2— (m—Trifluoromethylphenoxy) ethyl, 1—Metyl2— (m—Metylfenoxy) ethyl, 3— (0—Methofenoxy) Kishi) I II—Pup pill, 1, 1—Dimethyl (m—chlorophenoxy) Methyl, 1,1 Dimethyl—2— (2,4—Dimethylphenoxy) (P-fluoroethylene) methyl, 1-methyl-1 — (m-fluorophenol) ethyl, 1-methyl-1 (3,4—difluorofeno) 1- (2-, 4-, 6-trimethylphenoxy) -ethyl, 1-methyl- 1- (3, 4--dimethoxyphenyl) -ethyl, 1-methyl 1 — (2,4-dimethyl-6-methoxycarbonylphenyl) Le like.

_Examples of the substituent in aryl thioalkyl represented by Y _z (but may be substituted) include the same substituents as those in aryl described above. The alkyl moiety may be linear or branched, and preferably has 1 to 10 carbon atoms. As the arylthioalkyl, phenylthiomethyl,

1 _ phenylthioethyl, 2 — phenylthioethyl, 1-methyl-1- 2 phenylthioethyl, 3 — phenylthio II II 1-propyl, 1, 1 dimethylthioethylthiol, 1, 1 Dimethyl-2-phenylthioethyl and groups in which a substituent has been introduced into the aryl moiety, for example, P-fluorophenylthiomethyl, P-methyl Thiphenyldimethylthiomethylene, m_trifluoromethylphenylthiomethyl, 2,4—difluorophenylthiomethyl, 3,4, -difluorophenylthiomethyl, 2,4,6 — trimethylthiophenylinomethylthione , 1 — (P—Funole lo Fe Ninorechio) Etinole, 2 — (m—Trifluro rometifueruthio) ethyl, 1—Methyl 1 2 — (m—Methiofueruthio) ethyl, 3 — ( 0 — methoxy thiolthio) 1 n — propyl, 1, 1 — dimethyl ( _m — chloromethyl thiolthio) methyl, 1, 1 — dimethyl 1 2 — (2, 4 ー) Examples include dimethyl thiolthio) ethyl, 111-methyl-111- (P-fluorophenylthio) ethyl, 1-methyl-1-1- (m-fluorofluorothio) ethyl and the like.

The heterocyclic group represented by Y ₂ is preferably a 5- to 7-membered ring. Examples of the hetero atom include nitrogen, oxygen, and sulfur, and those having one or two hetero atoms in the hetero ring are preferable. Heterocycles include 2-phenyl, 3-phenyl, 2-phenyl, 3-phenyl, 4-phenyl, 5-thiazolyl, 5-thiazolyl, 2-pyridyl, 3-pyridyl, 4 — Pyridyl, 3-imidazolyl, 41-imidazolyl, N—n—propylpyperidin-1-yl, and the like.

The alkyl moiety in the heterocyclic-substituted alkyl represented by Y ₂ may be either linear or branched, and preferably has 1 to 10 carbon atoms. Examples of the hetero ring are the same as those described above. Specific examples of such groups include 3 _ (2-Chenyl) propyl, 1> 1 dimethyl 3-(2-phenyl) propyl, and 1,1 dimethyl 3-(3-phenyl) propyl pill, 3 — (2 — pyridyl) propyl, 1, 1 dimethyl 3 — (2 — pyridyl) propyl, 1, 1 — dimethyl 3 — (3 — imidazolyl) propyl, 3 — (2 —Furanyl) propyl, 1, 1 —dimethyl-3 — (4 —thiazolyl) propyl, 1,1 dimethylone 2 — (3 —chenyl) ethyl, 2 — (2 —pyridyl) ethyl , Piperidinomethyl, 4-ethylethylperazine-11-ylmethyl, morpholinomethyl and the like.

 The alkyl moiety in the heterocyclic-substituted oxyalkyl represented by Y z may be either linear or branched, and preferably has 1 to 10 carbon atoms. Examples of the hetero ring are the same as those described above for the hetero ring. Specific examples of such groups are preferably 3 — (2-Chenyloxy) propyl, 1, 1 — dimethyl 3 — (2 — chenyloxy) propyl, 1, 1 dimethyl — 3 — (3 — phenyloxy) Propyl, 1, 1 dimethyl-1-3- (2-pyridyloxy) propyl, 1,1 dimethyl-3- (3-imidazolyloxy) propyl, 3— (2-furanyloxy) propyl, 1> 1-dimethyl 2- (3-Chenyloxy) ethyl, 2- (2-pyridyloxy) ethyl, etc. are exemplified.

The alkyl moiety in the heterocyclic-substituted thioalkyl represented by Y 2 may be either a straight chain or a branched chain, and the preferred number of carbon atoms is 1 to 10. Examples of the hetero ring are the same as those described above. Specific examples of such a group are preferably 3 — (2-Chenylthio) propyl, 1,1 dimethyl —3 — (2 —Chenylthio) propyl, 1,1 —Dimethyl-3 (3—Cerylthio) Propyl, 3— (2—Biridylthio) pu pill, 1, 1—Dimethyl-3— (2—Biridylthio) propyl, 1,1, —Dimethyl-1 3— ( Examples thereof include 3 — imidazolylthio) propyl, 1, 1 — dimethyl-1 2 — (3 — ceenylthio) ethyl, and 21 — (2 — pyridylthio) ethyl.

The protecting groups for the nitrogen atom for R 3 and R ₄ include, for example, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6—trimethoxybenzyl, benzyloxy Cicarbonyl, t—butoxycarbonyl, acetinole, chloroacetyl, triphenylenoacetyl, ethoxycarbonyl, trimethylsilyl, t—butyldimethylsilanol, t—butyldiphenyl Examples include silyl and the like.

 The group leading to the group (B) with respect to R 3 is a group that is converted to the group (B) by a Grignard reaction or a nucleophilic reaction, and examples of such a group include 2-formylethyl, 3—Holmilp mouth pill, 3,3—Dialkoxypropyl (eg, 3,3—Diethoxypropyl), 3,3—Dimethoxypropyl, etc., 4,4-Dialkoxybutyl (eg, 4,4—Jetoxybutyl, 4,4—Dimethoxybutyl, etc.), 3,3—Diethoxypropyl, 3,3—Dimethoxybutyl, 3,3—Dialkylthiopropyl

(For example, 3,3-diethylthiopropyl, 3,3-dimethoxythiopropyl, etc.), 4,4-dialkylthiobutyl (4,4-dimethylthiobutyl, 4,4—diethylthiobutyl, etc.), 2- ( 1, 3 —dithian-2-ethyl) ethyl, 2 — (1, 3 —dithiolan-1-yl) ethyl, 3 — (1, 3 — dithian-1 2 — 2) (1), 3—dioxan-2-yl) ethyl, 2— (1,3—dioxane-1 2—yl) ethyl, 3— (1,3—dioxolan-1) 2 — yl) propyl, 3 — (1, 3 — dioxane 1 2 — yl) propyl, 2 — (2, 2 — dimethyl 1, 3 — dioxolan 1 4 — yl) ethyl, 2 — [(4 R)-2, 2 —Dimethyl 1, 3 —Dioxolan 1 4 —yl] ethyl,

2-[(4S) 1-2,2—Dimethyl_1,3—Dioxolan-1-ethyl] ethyl, 3—N-doxypropyl, 3,4—Dihydroxyl-butyl, 3R, 4 —Dihydrid xybutyl, 3 S, 4 —Dino, idroxybutyl, 3 —Pinodilooxypip pill,

3-acetooxy 1-4-methanesulfonyloxybutyl, 3-t-butyldimethylsilyloxy 1-4-p-toluenesulfonyloxybutyl, 3-butyr, 4 butul, 3-oxobutyl, 3, 4-epoxybutyl ,, 5 -epoxypentyl, 3 -acetoxy-1 4 -phenoxybutyl, 3 -acetoxy 5 -phenylpentyl, 3,3 -diethoxy 4; nthenyl, 3

—Oxo-1 4 pentenyl, octyl, 3 —Acetoxyoctyl, 3 —Oxooctyl, 3 —Acetoxy4, 4 —Dimethyl octyl, 3 —Acetoxy1-4-methyl-1 6 —Octyninil, 3 — (1,3—dioxane-2-yl) octyl, 3—acetoxy—5,9—dimethyl-8—decenyl and the like.

With respect to A, the protecting groups for hydroxyyl include, for example, acetinole, chloroacetinol, pinolloyl, benzoizole, tritinole, monomethoxytrityl, methoxymethyl, methoxethyl, methylthiomethyl, methylthiomethyl, Tetranodro d'obilanil, t-butyl dimethyl Lucyl, p-methoxybenzyl, benzyl and the like are exemplified as preferred.

 Examples of the ester of the compound represented by the formula (1) include lower alkyl esters such as methyl ester, ethyl ester, n-propyl ester, and n-butyl ester.

 Examples of the salt of the compound represented by the formula (1) include pharmaceutically acceptable salts, for example, salts with alkali metals (sodium, potassium lithium), and alkaline earths. Examples include salts with a class of metals (such as calcium, magnesium, and barium), ammonium salts, and salts with organic bases (such as triethylamine, optically active or phenylethylamine). Is done.

 The compound represented by the formula (1) of the present invention can be produced, for example, by the following method.

First law

 Equation (2)

 y

A— c-one Y ₁

 Υ2

(Wherein, Z, W, R, R,, R 4, Y, Y, Y ₂ and A are as defined above)

When R ₄ in the formula (2) is a protecting group for nitrogen, after removing the protecting group, When it is droxyl, it is preferably protected with a protecting group, and then, if necessary, further combined with a compound of the formula (2) wherein W is sulfur [compound represented by the following formula (2-1)]. Or a compound (for example, an alkyl halide) or a compound in which Z and W in formula (2) are oxygen [compound represented by the following formula (2-2)] and a meabin reagent or (3) by reacting it with phosphorus oxychloride.

[Wherein, R ₅ is one S—R ₆ (where R ₆ represents alkyl such as methyl or ethyl, preferably alkyl having 1 to 5 carbon atoms), halogen (chlorine, bromine, etc.), Alkoxy (alkoxy such as methoxy and ethoxy, preferably alkoxy having 1 to 4 carbon atoms). Z, R, R,,,,, Υ and Α are as defined above. After the compound represented by the formula (4)

R ₇ -X j-COOH (4)

(Wherein, R ₇ is a group reactive with carbonyl, a group reactive with thiocarbonyl, halogen, alkoxy, —S—A group reactive with (R ₆ ) such as hydroxyl, mercapto or amino) Or may form a cyclic amino together with when R ₇ is amino. X and are as defined above. The compound represented by the formula (1) is produced by reacting the compound represented by the formula (1), a salt thereof or an ester thereof.

 The reaction between the compound represented by the formula (2) or the compound represented by the formula (3) and the compound represented by the formula (4) is usually carried out by using ethoxyethane, tetrahydrofuran, getyl ether, dimethylforma. In a solvent such as mid, benzene, or acetonitrile, sodium hydride, potassium hydride, potassium tributoxide, n-butyllithium, sodium metal And the like. The reaction temperature is about 60 from room temperature.

When A in the formula (1) is a protected hydroxyxyl group, the compound in which A in the formula (1) is hydroxyl is produced by removing the protecting group by a conventional means. Can be. In the case where R ₄ is a protecting group for nitrogen, the compound having the formula (1) wherein R ₄ is hydrogen can be produced by removing the protecting group.

 As for R 7, examples of the group reactive with carbonyl and thiocarbonyl include halogen (bromine, chlorine, iodine, etc.), active ester (tosyloxy, mesyloxy, etc.) and the like.

That is, the compound represented by the formula (4) is preferably ethyl-14-bromobutyrate, methyl-14-bromobutyrate, ethyl-4-4-bromo-2-butenilate, methyl-14. —Bu pi 2 —Butinylate, methyl 3 —Bromopropionate, ethyl 5 _bromopentanate, methyl 4 —Bromo-3 —methyl butyrate, ethyl 4 —Mesiloxy butyrate, For example, methyl 4-silylbutyrate is used. Et al is, Nono androgenic, alkoxy, - S - is a reactive group as R _6, Nono I de port hexyl, main Rukapu DOO, § Mino is Iba Kana Mi Roh like. That is, as the compounds represented by the formula (4), preferably, ethyl-14-aminobutyrate, methyl-14-amino-2-butenilate, methyl-13-amino Propionate, ethyl 1-5—amino pentane, methyl ethyl sopentylate, methyl 4—amino amino / cyclohexylate, ethyl 4—amino cyclohexylate, methyl Chilloo 4 — no, hydroxybutyrate, ethiru 4 — mercaptopuchilate.

 The first method is described more specifically as follows.

1 of the 1st law

 Equation (2-1)

(Wherein, Z, R, R!, Y, Y t, the compound represented by the consent if Y z and A a compound represented by the formula (4), is reacted with an ester of a salt thereof or its By the formula (1-1)

(Wherein, X!, Z, R, R,, R 2, Y, Y, Y z and A are as defined above)

Or a salt thereof or an ester thereof. The compound represented by the formula (2-1) is represented by the formula (2-2)

(, R, R, wherein, Y,, Υ ₂ and Α is the same defined above) such as the aforementioned protective group when the compound represented by A in the formula (2-2) unprotected It is produced by reacting with a thiocarbonylating agent after protecting with.

 Examples of the thiocarbonylating agent include phosphorus pentasulfide, a phosphorus pentasulfide-pyridin complex, a Lawesson reagent and the like.

Specifically, this reaction is carried out by reacting with phosphorus pentasulfide in an inert solvent such as toluene, dietoxetane or pyridin, or by dioxane or tetrahydrofuran. , Methylene chloride, black mouth form, acetonitrile, getyl ether, dimethoxieta (The reaction temperature is preferably from room temperature to the boiling point of the solvent, and the reaction time is preferably from 1 hour to 10 hours) in a solvent such as a solvent.

 In this case, a mixture of the monothio form (Z = 0) and the dithio form (Z = S) can be obtained depending on the reaction reagent and reaction time. These mixtures can be obtained by silica gel column chromatography. (Methanol = 20 to 30-1 or ethyl acetate-methanol = 10 to 20-1 is preferable)). (The ratio between the monothio and dithio isomers can be arbitrarily changed depending on the amount of the thiocarbonating agent.)

Act 1 2

 In the formula (4), the compound represented by the formula (3) is reacted with an amino or j to form a cyclic amine with a compound, a salt thereof or an ester thereof, whereby the compound represented by the formula (1) -2)

(Wherein, it represents a case where either represent Ν- situ NH- X _t, or N and X, capital is further formed a璟via carbon, Xt, Z, R, R ,, R 2, Y , Y t, Y ₂ and A compound represented by as defined above), a salt thereof or an ester thereof are produced.

In the case of this reaction, the mixture is usually heated and stirred at 100 to 200 ° C in an anhydrous solvent. This is performed by heating or stirring at 150 to 250'C in a high boiling point solvent such as xylene, tonolene, macrobenzene, or π-benzene.

 When A in the formula (1-2) is a protected hydroxyxyl, the compound in which A is hydroxyxyl can be obtained by removing the protecting group by a conventional method.

 The compound represented by the formula (3) is produced as described above as follows.

 (1) A method of reacting a compound represented by the formula (2-1) with an alkyl halide.

 (2) The compound represented by the formula (2-2) and oxychlorinated phosphorus or a meabine reagent (for example, triethyl oxonium tetrafluoroborate, trimethyl oxodifluorotetrafluoroborate, etc.) How to react.

 In the above reaction (2), the compound represented by the formula (2-1) is treated with an alkyl halide (eg, methyl iodide, methyl bromide, bromo bromide) and dimethoxetane, dioxane, tetrahydrofura. The reaction is carried out at a temperature of 0 to 50 in the presence of a base such as sodium hydride or sodium methoxide in an ether-based solvent such as methane. In the above reaction (1), when chlorination with oxychloride is carried out, the mixture is heated under reflux in oxychloride. It can be obtained by heating and stirring at a temperature of 0 to 50 in a solvent such as methylene chloride or carbon tetrachloride.

Law 1-3 When A is hydroxyl, the compound represented by the formula (2-2) is protected with a protecting group as described above, and then the compound represented by the formula (4), a salt thereof or an ester thereof is obtained. And, if necessary, removing a protecting group to obtain a compound of the formula (1-3)

(Where R, R

(Same meaning as above)

Or a salt thereof or an ester thereof.

 The reaction is carried out by heating and refluxing in a nonpolar solvent such as toluene and xylene in the presence of silver oxide.

 The compound of formula (2) is an important intermediate compound for producing the present investigation compound (1) as shown in the first method. The compound represented by the formula (2) can be produced, for example, by the following method.

Second law

 Equation (5)

^R 8 ° 2 ^C

(Five ) (Wherein, R ₈ represents alkyl)

 And a compound represented by the formula (6)

 A I

H ₂ N-Y-C-Y ₂ (6)

 I

 Y!

 (Wherein, Y, Υ, Υ 2 and Α are as defined above)

Reacting with the compound represented by the formula (7)

Y ゥ

(Wherein, Υ, Υε, Α and R ₈ are the same as defined above), and the compound is reduced to obtain a compound of the formula (2-3)

(Wherein, Y, Υ, Υ ₂ and Α are as defined above)

Can be obtained. Such a compound is reacted with a thiocarbonylating agent according to the method described in Method 1, 1 to obtain a compound of the formula (2-4)

(Wherein, Ζ, Υ, Υ!, Υ 2 and Α are as defined above)

Can be converted to the compound represented by

 Regarding R 8, examples of the alkyl include alkyl having 1 to 4 carbon atoms such as methyl, ethyl, and n-propyl.

 The reaction between the compound represented by the formula (5) and the compound represented by the formula (6) is usually carried out in a solvent such as anhydrous benzene, anhydrous toluene, anhydrous acetonitrile, anhydrous dimethyloxetane, or the like. The reaction is performed by heating and refluxing in the presence of 3A.

 The compound represented by the formula (5) can be produced according to the synthesis method of M. Shamma et al. (Collect. Czch. Chem. Commun., 35.3280, 1970). The compound represented by the formula (6) is produced according to the method described in J. Med. Cem., 26, 342, 1983, or according to the method described in JP-A-57-72971.

 The reduction of the compound represented by the formula (7) is carried out, for example, by a catalytic reduction method in the presence of a catalyst such as palladium carbon, palladium hydroxide, platinum oxide (preferably a solvent such as ethanol or methanol, and the pressure is 30 to A pressure of 60 atm and a temperature of 30'C to 80'C is appropriate), and sodium hydride, sodium cyano in the presence of an acid such as acetic acid, monochloroacetic acid, and hydrogen chloride. It is performed by a chemical reduction method such as σ-hydride.

Reaction of compound represented by formula (2-3) with thiocarbonylating agent Is performed in the same manner as described in Method 1.

Third law

 Equation (8)

(Wherein, R, R,, R 3 and R ₄ are as defined above)

[However, when R ₃ is a hydrogen or nitrogen protecting group in the formula (8), the compound represented by the formula (8-1)

Wherein R and R ₄ are as defined above, and R _3a is a group (B)

 A

One Y-C One Y ₂ (B)

 Y!

(Wherein, A, Y, Υ, and Upsilon the _ζ the same meaning as defined) represents a group can lead to]

After conversion into the compound represented by the formula (2-5), by introducing the group (Β)

(Wherein, R, RRA, Y, Y, and Y ₂ are the same as those described above).

 The compound represented by the formula (2-2) is produced by removing a protecting group from the compound represented by the formula (2-5) by a conventional means, and furthermore, the compound represented by the formula (2-2). As described above, the compound represented by the formula (2-1) is produced by thiocalponylation as described above.

 The compound represented by the formula (2-6) is optionally thiocarponylated according to the method described in 1 of the first method to obtain the compound represented by the formula (2-6).

 A— C— Y-,

 Y

(Wherein, Z, R, R,, R 4, Α, Υ, Υ! And Υ ₂ are as defined above)

Can be produced.

In the above reaction, the conversion of a compound in which R ₃ is a protecting group for hydrogen or nitrogen in the formula (8) to a compound represented by the formula (8-1) is carried out, for example, by converting the compound represented by the formula (8) Equation (9)

 R 3 a-R 9 (9)

Wherein R _3a is as defined above, and R ₉ is amide (or la Octam) and reactive groups. ]

 The reaction is carried out by reacting with the compound represented by

 Examples of the group reactive with the amide (or lactam) for R 9 include, for example, bromine, chlorine, iodine, mesyloxy, and tosyloxy.

 This reaction will be described in detail in the section on Method 7 below.

Equation (8) or formula (8 - 1) conversion from R ₃ or R _{3 a} group (B) of the compound represented by, for example glycidyl Nyaru reaction is carried out by a nucleophilic reaction or the like.

Is an earthenware pots Ru group leads based on (B) represented by R 3 or R _{3 a} is as described above in the earthenware pots Ru group leads based on (B) with respect to R 3.

 Here, the nucleophilic reaction is carried out by reacting a nucleophilic reactant with an epoxy compound in an anhydrous solvent (eg, tetrahydrofuran, dimethoxypentane, dioxane, benzene, dimethylformamide). The reaction is carried out at a temperature. Examples of such a nucleophilic reactant include sodium phenate, sodium P-fluorophenolate, sodium m-trifluoromethyl phenolate, sodium thiophenolate, aniline, Examples include pyrrolidine, piperidine, piperazine, N—methylbiperazine, isopropylamine, morpholine, monomethylamine, dimethylamine, getylamine, and t—butylamine. Is done.

The Grignard reaction involves reacting a ketone or an aldehyde with a Grignard reagent. The Grignard reagent is a compound represented by “Q—Mg—Halogen”. Q may be substituted with alkyl, alkenyl, alkynyl and alkyl. Examples thereof include cycloalkyl, aryl, aralkyl, heterocyclic-substituted alkyl, and heterocyclic ring. Examples of such Grignard reagents include, for example, n-pentylmagnesium bromide, 2-phenylphenylmagnesium bromide, 3-pentenyl remagnesium bromide, and butylmagnesium bromide. It is.

 Hereinafter, a specific example will be described.

In the reaction, for example, when R ₃ or R _{3A in} formula (&) or formula (8-1) is 3-butyr, the compound represented by formula (8) or formula (8-1) The 3,4-epoxy compound is prepared with a peroxide such as perbenzoic acid or peracetic acid, and then treated with sodium nucleocarbonate, a nucleophilic reactant, to obtain the group (B) in the formula (2-5). A compound in which the group corresponding to is 3—hydroxy-14-phenoxyprovir can be produced.

Also, for example, when R ₃ or R _3A in the formula (8) or (8-1) is 3,3-diethoxypropyl, this is treated with a weak acid to give 3-formylpropyl, and then Grignard reagent is used. By reacting with n-pentylmagnesium bromide, a compound in which the group corresponding to group (B) in formula (2-5) is 3-hydroxyhydroxyl can be produced. Further, for example, in the case where R ₃ or R _3a in formula (8) or (8-1) is 3-oxobutyl, a group corresponding to the group (B) in formula (2-5) is obtained. It is possible to produce a compound which is 3-doxydoxy-3- 3-methyloctyl.

Further, the reaction is carried out, for example, in the formula (8) or the formula (8-1) R ₃ or R 3 _a is 2 - (2, 2 - dimethyl chill one 1, 3 - Jioki source run-one 4 one I le) compounds of Echiru, 70% aqueous acetic acid, 90% Application Benefits Furuoro aqueous acetic acid When stirred in a solvent such as at room temperature at 50 to 2 hours to 10 hours, R ₂ or R _{2a in} the formula (8) or (8-1) is 3,4-dihydroxybutyl. Is obtained. Then, in the pyridin, only the primary alcohol was sulfonylated by mesylation or tosylation with an equimolar amount of tosyl chloride or mesyl chloride. Formula (8) or (8) In -1), a compound in which R ₃ or R 3a is 3—hydroxy-14-tosyloxybutyl or _3— hydroxy-14-mesyloxybutyl is obtained. Further, the secondary alcohol at the 3-position is acetylated with nobiridin acetic anhydride or converted into t-butylmethylsilyl with t-butylmethylsilyl chloride (triethylamine, methylene chloride). And reacts with sodium nucleocarbonate, a nucleophilic reagent (anhydrous solvent, dimethylformamide, dioxane, acetonitrinole, tonolene, ethyl acetate) In the formula (2-5), the group corresponding to the group (B) is 3 — t — butyldimethylsilyl 4 — funoxypropyl. Compounds can be produced. Examples of the nucleophilic reactant usable herein include those described above.

4th law

 Equation (8-2)

(8-2)

(Wherein, R 1, R 2 and R ₄ are as defined above)

And a compound represented by the formula (10)

 A I

 R 9 — Y— C— Y (10)

Y ₂

(Wherein, Α, Υ, ,,, Ύ, and R ₉ have the same meanings as described above) to give a compound represented by the formula (2-5).

 The compound represented by the formula (2-6) can be produced by thiocarbonylation of the compound according to the method described in 1 of the first method, if necessary.

 The alkylating agent of the formula (10) as a raw material is an alkyl ester, an aryl ester, an aralkyl ester, a heterocyclic-substituted ester, a lithium diisopropyl amide, an n-butyl lithium, a sodium methyl ester. By condensing with ethyl acetate in the presence of a base, reducing the resulting ketoester with lithium aluminum hydride to form a diol, and then halogenating or sulfonylating only the primary alcohol. Manufactured. Alternatively, ketone or aldehyde corresponding to the ester may be subjected to a Beorformatsky reaction with ethyl acetate moiecetate, and the resulting hydroxyester may be treated in the same manner as described above.

 This reaction is carried out in the same manner as in the method described in Method 3.

Fifth law

Equation (11)

Wherein R, R,, R 4 and Y are as defined above, and n represents 2 or 3.

And a compound represented by the formula (12)

Y ₂ -Hal (12)

[Wherein, Y ₂ is as defined above, and Hal represents halogen (chlorine, bromine, etc.)]

With the compound represented by the formula (13)

(Wherein, n, R, R i .R 4 .Y and Y ₂ are as defined above) are produced.

The compound is treated with a desulfurizing agent to remove the thioacetal group, and the compound of formula (14)

(Wherein R, R i .R ₄ .Y and Y ₂ have the same meanings as described above), and the compound is further reduced to obtain a compound of the formula (2-7)

(Wherein R, R _t , R,, Y and Y ₂ have the same meanings as described above).

 The reaction of the compound represented by the formula (11) with the compound represented by the formula (12) is carried out using an anhydrous solvent such as tetrahydrofuran or polyester in the presence of a base such as η-butyllithium. It is carried out under a temperature condition of one to eighteen to room temperature.

The reaction between the compound of the formula (13) and the desulfurizing agent is carried out in a suitable solvent (eg, water, acetonitril, methylene chloride, dimethylsulfoxide, methanol, tetrahydrofuran). 1 0 0 Temperature conditions Done below.

 As desulfurizing agents, mercuric chloride monocarbonate dome, mercuric chloride-mercury oxide, silver nitrate-N-chlorosuccinimide, copper chloride copper monoxide, cerium nitrate ( IV) Ammonia, silver oxide, etc. are shown.

 The reduction of the compound of the formula (14) is carried out in an alcoholic solvent such as methanol, ethanol or t-butanol at 0 to 50%. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride and the like.

 The compound represented by the formula (11) as a raw material is produced as follows. That is, the corresponding acetal is dissolved in a solvent such as methylene, chloroform, carbon tetrachloride, etc. in a solvent of 1 to: I. 5 equivalents of 1,3—dimercaptopropane or 1,2—dimercaptoethane And a catalytic amount of boron trifluoride etherate are added, and the mixture is stirred at room temperature to room temperature.

6th law

 Equation (15)

 (Wherein, Υ, Υ Υ and Α are as defined above)

Ammonia treatment of the compound represented by the formula (16)

(Wherein, Y, Υ _ζ and Α are as defined above)

After producing a compound represented by the formula, and subjecting the compound to an oxidation reaction.

 Three

Equation (17) 8

 By reacting with a compound represented by the formula: R i o -SH (17) (R ,. represents alkyl, phenyl or substituted phenyl)

(Wherein, H, Υ, Α, and are as defined above) are produced. Then, when the compound is reduced, a compound represented by the formula (2-3) can be produced. Ammonia treatment of a compound represented by the formula (15) is performed by dissolving the compound represented by the formula (15) in a methanol solution of ethanol and heating in an autoclave at 50 to 90 for 16 hours. It is performed by Oxidation of the compound represented by the formula (16) is performed by using chromonopyridine trioxide, pyridine dimethyl chloride, pyridinyl dimethyl chloride, dimethyl sulfoxide / oxalyl chloride as an oxidizing agent. The reaction is carried out by using dimethylsulfoxydino trifluoroacetic anhydride or the like, and —reacts with the oxidizing agent at 30 to 30 ° C. to convert 4-hydroxyl to ketone.

 The reaction between the compound represented by the formula (16) and the compound represented by the formula (17) thus obtained is carried out in a solvent such as methylene chloride, macropore form, and acetonitrile. Trimethyl chlorosilane is added dropwise at room temperature in the presence of a base such as pyridine, dimethylamino viridine and the like, and the mixture is heated to reflux at 60 to 80 and heated.

 Examples of the compound represented by the formula (17) include thiophenol, ethyl mercaptan and the like.

 The compound represented by the formula (18) can be purified by silica gel chromatography (ethyl acetate Z hexane = 3-1).

 The reduction reaction of the compound represented by the formula (18) is carried out in an alcohol-based solvent such as methanol, ethanol, and the like. This is done by adding a catalyst such as radium-carbon and heating at a temperature of 25 to 40'C for 5 to 16 hours.

 The compound represented by the formula (15) as a starting material is produced by the following two methods.

 ① Equation (19)

(19)

(Wherein, R ₄ is as defined above)

The compound is obtained by removing a protecting group for a nitrogen atom from a compound to be treated with an alkylating agent represented by the formula (10). The alkylation reaction is performed in the same manner as described in Method 4.

 (2) L-Linic anhydride (free hydroxyxyl is preferably protected by acylation) reacts with the compound represented by the formula (6), and the protecting group of the hydroxyl group is eliminated. , Equation (20)

(Wherein, Y, Y Υ ₂ and Α are as defined above)

Is obtained. When the compound is acylated with octogenated acetyl halide, the compound of formula (21)

(Wherein, Υ, Υ i, Υ _ζ , Α and Hal are as defined above) are produced.

The compound represented by the formula (21) is treated with triphenylphosphine After treatment with base, the formula (22)

(Wherein, Y, Υ, Υ ₂ and Α are as defined above)

Is obtained. The compound represented by the formula (15) is obtained by reducing the compound.

 More specifically, by applying the synthesis method described in J. Org. Chem., 52, 2941, 1987 (H. Niwa et al.), L-monocarboxylic acid is heated to reflux with acetic anhydride, acetyl chloride, etc. Then, the compound represented by the formula (6) is added and heated, and the resulting compound is heated at 50 to 70 ° C. with noethanol hydrochloride to remove the protecting group. Gives a compound represented by the formula (20).

 Examples of the halogenated acetinol halide to be reacted with the compound represented by the formula (20) include bromoacetyl bromide, bromoacetyl chloride and the like. The acylation by the compound is carried out in a solvent such as tetrahydrofuran, dioxane, dimethylformamide or acetonitrile, in a solvent such as pyridine, triethylamine, dimethylaminoviridine or the like. 120 to 50 in the presence of an organic base. The reaction is carried out at a temperature of C for 6 to 24 hours.

The compound represented by the formula (21) thus produced is dissolved in a solvent such as acetonitrile, benzene, toluene, and the like, and triphenylphosphine is added thereto, and the resulting mixture is 50 to 80. C and then add the reaction A compound represented by the formula (22) is produced by adding triethylamine, diisopropylpropylamine, etc., and heating at 50 to 80'C for 6 to 10 hours.

 The compound represented by the formula (15) is produced by reducing the compound represented by the formula (22), and the reduction is carried out using palladium Z-carbon, palladium hydroxide, platinum oxide, and rhodium acetate as a catalyst. It is preferable to carry out the reaction by catalytic reduction (ethyl acetate, methanol and ethanol are preferred as solvents).

 The intermediate compound represented by the formula (8) is produced by the following method.

7th law

 Equation (23)

(In the formula,! ^! Pov! ^ ₁₂ each represents a lower alkyl) and a compound represented by the formula (9), and a protecting group is introduced as necessary. Equation (8-3)

(Wherein, R _3A , R ₄ , RH and R ₁₂ are as defined above) are produced. In this reaction, the reaction between the compound represented by the formula (23) and the compound represented by the formula (9) is performed by dimethylformamide, acetonitril, dimethylsulfoxide, and In polar solvents such as lahydrofuran, dimethoxetane, dioxane, ether, etc., sodium hydride, sodium methoxide, and potassium tovexide The reaction is carried out at room temperature to 100 ° C. in the presence of such a base.

 Examples of the compound represented by the formula (9) include benzylbutamide, butoxycanoleboninolechloride, benzoyrecrolide, benzyloxycarbonylchloride, octylbromide, and 3 — Acetoxyl methyl slate, 3—Acetoxyl 4, 4 Jimetiloxy tilt silicate, 3—Acetoxyl 4—Metinol 6—Alkyl bromide , 3 — acetoxy 4 — phenoxy butyl mesylate, 3 — acetoxy 5, 9 — dimethyl 8 — decenyl tosylate, 3 — acetoxy 1 5 — phenyl pentyl bromide, 3 — butyrbromide, 3, 3 — jetipropyrbromide, 2 — (2, 2 — dimethyl-1,3, dioxolan 1 4 — dinole) Leh , 3 - (1, 3 over dithia down one 2 - I Honoré) Echiruburomai de, 3 - O key Sobuchiru Buromai de like.

 The compound represented by the formula (23) is subjected to the same operation as that described in, for example, Chem. Ber., 108, 3247, 1975 (H. Robert et al.) To obtain malononitrile and diacyl. For example, diacetyl, dipropionyl, etc.).

 The protecting group may be introduced by a method known per se.

8th law Equation (24)

(Wherein, R ₄ and R ₈ are as defined above)

Is reacted with ammonium acetate and then reduced, and if necessary, reacted with the compound represented by the formula (9) or by introducing a protecting group to the compound represented by the formula (8-4).

(Wherein, R ₃ and R ₄ are as defined above)

Is produced.

 After reacting the compound represented by the formula (24) with ammonium acetate, the compound is reduced to give the compound of the formula (8-5)

(Wherein, R ₄ is as defined above)

Is produced.

Compounds and reaction with acetic Anmoniumu methanol, a polar solvent such as ethanol represented by the formula (24), while adjusting the pH. 5 to 7 with acetic acid, the line under conditions of a temperature of 0 ~ 5 0 ^e C And again The reduction reaction is carried out according to the reduction reaction of the compound represented by the formula (7) in the second method.

 By introducing a protecting group into the compound represented by the formula (8-5), the compound represented by the formula (8-6)

^R 3b

(Wherein, R _3b represents a nitrogen-protecting group, and R ₄ has the same meaning as described above).

 The compound represented by the formula (24) can be produced according to the method described in J. Chem. Soc. Perkin. Trans I, 1177, 1987, and can also be obtained as an optically active substance. .

The introduction of the protecting group may be carried out by a method known per se, and a compound having a protecting group can be easily deprotected by a means known per se. As a deprotection means, when the protecting group is t-butoxycarbonyl, t-butyldimethylsilyl, etc., R ₃ or R ₄ is benzyl, P-methoxybenzyl, etc. by a chemical reduction method. In some cases, conventional means such as a catalytic reduction method are exemplified. The statements regarding the protecting groups described above apply for both R ₃ and R ₄ .

Ninth law

 Compound represented by formula (24) and formula (25)

H ₂ N—R 3 (25) (wherein, R ₃ is as defined above) With the compound represented by the formula (26)

(Wherein, R ₃ , R 4 and R ₈ are as defined above)

The compound represented by the formula (8-4) can be obtained by producing the compound represented by the formula and reducing the compound.

 As the compound represented by the formula (25), ammonia, 3,3—diethoxypropylamine, 2— (1,3—dioxolan 1-2—yl) ethylamine, 2— (1, 3 — dioxane 1 2 — yl) ethylamine, 4, 4 — dimethoxybutylamine, 3 — (1, 3 — dioxolan 1 2 — yl) propylamine, 3 — hydroxypropylamine , 3-Vivaloy oxypropylamine, 3,3-Getylthiopropylamine, 2-(1, 3-dithiane 2-yl) ethylamine, 3-(1, 3-dithiane 1) 2 — yl) propylamine, 2 — (2, 2 — dimethyl-1,3 — dioxolanone 4 — yl) ethylamine, 2 — [(4R) — 2, 2, dimethyl 1, 3 — dioxolan 1 4 — yl) ethylamine, 2 — [(4 S) — 2, 2 — dimethyl Chill 1, 3 — dioxolan 1 4 — yl] ethylamine, 3 — butyramine, 4 1 pentenylamine, 3, 4 — epoxybutylamine, 4, 5 — epoxypentylamine, 3 , 3 — dimethoxybutylamine, 3 —

(1,3—dioxane-2-yl) octylamine, 3,3—diethoxy-4-pentenylamine, etc. are preferred. Is shown.

 The reaction between the compound represented by the formula (24) and the compound represented by the formula (25) is generally carried out in a solvent such as anhydrous benzene, anhydrous toluene, anhydrous acetonitrile, anhydrous dimethyloxetane, or the like. It is carried out by heating and refluxing in the presence of 3A. The reduction of the compound represented by the formula (26) is performed in the same manner as the reduction of the compound (7) in the second method.

Law 10

When R ₄ in the formula (19) is hydrogen, the compound represented by the formula (19) is protected with a suitable protecting group and then subjected to a dehydration reaction to obtain a compound represented by the formula (27)

(Wherein, R _{4 a} represents a protecting group for the nitrogen)

A compound represented by the formula (28) is obtained by performing a ring closure reaction in the presence of a halogen or under acidic or basic conditions.

(Wherein R _4a is as defined above, and R and ₃ represent hydrogen or halogen)

Is produced. When the compound represented by the formula (27) is subjected to a ring-closing reaction in the presence of Halogen, a compound represented by the formula (28) in which R ₁₃ is halogen is obtained. The compound represented by the formula (8-5) can be obtained by desorbing R4a by _a conventional means as necessary.

 The resulting compound of the formula (8-5) is reacted with a compound of the formula (9) in the same manner as described in the third method to obtain a compound of the formula (8-7)

(Wherein, R _{3 a} and R ₄ are as defined above)

Can be obtained.

The dehydration reaction of the compound represented by the formula (19) is performed by heating under reflux in a solvent such as benzene or toluene in the presence of a catalytic amount of p-toluenesulfonic acid, boron trifluoride etherate or aluminum chloride. Hydroxyl at position 4 is pyridin. In the presence of a base such as dimethylamine, benzoyl-cook, acetyl-chloride, silk-cuff ride, mesyl-cuff ride, etc. After silylation or sulfonylation, triethylamine, pyridine. DBU (1,8-diazabicyclo [5.4.0] indenecene7), DBN (1,5-diazabicyclo [4.3.0] Examples of the method include heating with a base such as nonene 5), potassium carbonate, and sodium carbonate. The ring-closing reaction of the compound represented by the formula (27) is preferably carried out in a solvent such as chloroform, methylene chloride, tetrahydrofuran, and acetonitrile, preferably from 0 to 70%. A method of reacting a halogen (preferably iodine or bromine) at a reaction temperature of 'C, or a method of directly adding, for example, heating and stirring under acidic conditions such as an aqueous solution of sulfuric acid or hydrochloric acid to perform Michael addition, etc. You. When the cyclization is carried out by reacting with a halogen, 60, in a solvent such as benzene or toluene, in the presence of a radical initiator such as or, a'-azobisisobutyronitrile or benzoyl peroxyside. It is radically reduced by dropping tri-n-butyltin hydride while heating to ~ 80.

 The compound represented by the formula (19) is produced by reducing the compound represented by the formula (24).

 The reduction reaction is carried out in an alcoholic solvent such as methanol or ethanol, in the presence or absence of acetic acid or hydrochloric acid, with stirring at 0 to 50.

 When the compound represented by the formula (24) is reduced in acetic acid, for example, with sodium borohydride, the compound represented by the following formula is obtained in addition to the compound represented by the formula (19).

(Wherein, R ₄ and R ₈ are as defined above)

Are produced as by-products. Force gel force chromatography [R ₄ is a hydrogen atom, and the form / metanol is 20: 1, and R ₄ is a nitrogen protecting group (benzyl, t-butoxycarbonyl, etc.) In this case, it can be easily separated with ethyl acetate Z hexane = 1: 1].

1st law

Equation (29)

(Wherein, R _{3 is as} defined above)

Ammonia treatment of the compound represented by the formula (30)

(Wherein, R ₃ is as defined above)

And subjecting the compound to an oxidation reaction to give a compound of formula (31)

R ₁₄ -SH (31)

(R! ₄ represents alkyl, phenyl or substituted phenyl) by reacting with a compound represented by the formula (32)

(32)

(Wherein, R ₃ and R ₁₄ are as defined above)

 The compound represented by the formula (8-4) can be obtained by producing the compound represented by the following formula, reducing the compound, and protecting the nitrogen with an appropriate protecting group, if necessary.

 This step is performed by a method similar to that described in Method 6.

1st and 2nd law

 Equation (33)

R ₈ 0 ₂ C 0 ₂ R 8

(33)

(Wherein R ₃ and R ₈ are as defined above)

To the compound represented by the formula (34)

R ₁₅ -C 0 CH ₂ C 0 ₂ R 8 (34) (in the formula, R ₈ is as defined above, and R ₁₅ represents a group reactive with a secondary amine)

Reacting the compound represented by the formula (35)

R ₈ 0 ₂ (35)

(Wherein R ₃ and R ₈ are as defined above)

After obtaining the compound represented by the formula, the compound is cyclized in the presence of a base, and then heated and deesterified to obtain a compound of the formula (36)

(36)

(R ₃ and R ₈ in the formula are as defined above)

[The compound is substantially the same as the compound represented by the formula (24)] is obtained, and the compound is treated by the same method as in the eighth method to give the compound represented by the formula (8-4) A compound is obtained.

Examples of the group reactive with a secondary amine in R ₁₅ include chlorine, bromine and iodine, such as nitrogen, tosyloxy, mesyloxy, nitrodoxyl, and trifluoromethansulfonyloxy. Is exemplified. The acylation reaction between the compound represented by the formula (33) and the compound represented by the formula (34) is carried out by a conventionally known method.

 Cyclization of the compound represented by the formula (35) may be carried out using an alcoholic solvent such as methanol, ethanol, or t-butanol, a non-polar solvent such as benzene, toluene, or xylene, or getyl ether or diisopropyl propylene. In ether solvents such as ter, tetrahydrofuran, dioxane, and dimethoxetane, sodium methoxide, sodium ethoxide, potassium butoxide, and hydrogenated sodium From room temperature to the boiling point of the solvent in the presence of bases such as lithium, hydrogenated sodium, sodium hydroxide, sodium hydroxide, sodium carbonate, sodium carbonate, DBN and DBU The reaction is carried out at the following temperature.

 Deesterification is carried out by heating in a solvent such as acetonitril, dimethylformamide, ethanol, and ethoxyethane.

The compound represented by the formula (33) can be obtained by converting succinic acid diester and the compound represented by the formula 5) into a suitable solvent (form: In methylene, tetrahydrofuran, dioxane, acetonitrile, etc., in the presence of a base (tritylamine, pyridine, dimethylaminopyridine, etc.) ) Or by reacting the oxosuccinic acid diester with the compound represented by formula (25).

Schiff base (37)

R ₈ O ₂ C.

co ₂ R ₈

 (37)

NR-

(Wherein R ₃ and R ₈ are as defined above)

By reducing with an appropriate reducing agent (sodium borohydride, lithium borohydride, etc.).

 For example, in the case of producing an alkali metal, an alkaline earth metal, an ammonium salt, or an organic base salt in the carboxyl of the side chain of the compound represented by the formula (1), the compound represented by the formula (1) is suitably used. In aqueous solvents such as methanol, ethanol, acetate, tetrahydrofuran, dimethoxetane, dioxane, etc. It is produced by using a base such as tritium, hydroxide hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, and barium hydroxide at 0 to room temperature. In this case, the base is preferably added in an equimolar amount, and the solvent is preferably lyophilized for solvent distillation.

A free compound represented by the formula (1) is produced by treating a salt of the compound represented by the formula (1) by a method known per se. The compound represented by the formula (1) and various starting materials Since the compound has an asymmetric carbon atom, the compound of the present invention may be used during the synthesis process or An optically active compound can be obtained by resolving the compound into optical isomers after synthesis. The present invention includes both an optically active compound and a racemate without optical resolution. As a method for resolving into optical isomers, fractionation and recrystallization with a salt with an optically active base (for example, optically active (+) — or — funetylamine), or filling with an optically active carrier as it is A means for passing a column is exemplified. In the compound of the present invention, the hydroxyl group of the substituent A is esterified with an optically active acid compound (for example, (-)-monocarboxylic acid chloride), and the resulting diastereomer is converted back into a free compound after decomposition. There is a way.

 When the novel compound represented by the formula (1) of the present invention, a salt thereof, and an ester thereof are used as a medicine, they are mixed with a suitable carrier, excipient, diluting barb, etc. to form powders, tablets, capsules, granules, It is administered in the form of injections, suppositories, ointments and the like. The dosage may vary depending on the patient's condition, weight, age, etc., but usually 1 to 500 mg per adult per day is appropriate.

 The novel compound represented by the formula (1) of the present invention, its salt and its ester, have been found to have platelet aggregation inhibitory activity, gastric acid secretion inhibitory activity, anti-hypoxia activity (brain protective activity) and the like. In particular, the compound of the formula (1), its salt and its ester of the present invention do not act on circulatory activity, have a gastric acid secretion inhibitory action and a gastric mucosal protective action, and are useful for peptic ulcer. It can be a prophylactic or therapeutic agent. Compounds of formulas (8) and (8) are also useful as synthetic intermediates. Experimental example 1 Effect on renal perfusion rat gastric acid secretion

Barbiter a fasted male rat weighing around 350 g Anesthetize with 300 mg / kg (sc) of lunatium, and use the method of Gosch et al. (Pretty Journal 'Ob' Pharmaco Mouth, Vol. 13, page 54, page 19) 8 years).

 The amount of acid secretion in the perfusate was measured by titration with a 0.05 N sodium hydroxide to pH 7 using an automatic titrator. One hour after administration of the gastric acid secretion-inducing drug, the test drug was intravenously administered, and the amount of acid secreted 1 hour after administration was B. Similarly, the amount of acid secretion A in the vehicle-administered group was calculated, and the inhibition rate was determined by the following equation. The amount of acid secretion was calculated by converting the amount of acid secretion at the first hour of administration of the inducer to 100% and converting it to%.

 Suppression rate (%)-(1 — Β ΖΑ) Χ ΐ 0 0

Experimental example 2 Effect on aspirin-hydrochloric ulcer

After a 20-hour fast of a male Wistar weighing around 200 g, the test solution was orally administered, and after 30 minutes, aspirin 100 nig / kg and 0.3 N hydrochloric acid solution Was orally administered and the stomach was removed 4 hours later. Area of mucosal damage portion of each rat (the Yuzuru ²⁾ was measured to calculate the ulcer index from the sum of the square root, the mean ulcer index of control and treated groups Compared with the rate of change

〔Example〕

 Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

Reference Example 1 3—Hydroxytactonitrile

 A solution of diisopropylamine (38 g) in tetrahydrofuran

A (1.5 mi) n-butyllithium hexane solution (250 mi) was added dropwise to (70 mi) under ice cooling. Then, the reaction mixture was cooled to -78'C with ice, and a solution of acetonitrile (15.4g) in tetrahydrofuran (20m) was gradually added dropwise. And stir for 15 minutes. Twenty-five η-hexanal dissolved in trimethyl hexamethylene linate (28 mL) was gradually added dropwise thereto, and the mixture was gradually added at 178'C for 1 hour and then gradually to room temperature. And stir at room temperature for 1 hour. This is poured into ice water, acidified with 3.5N hydrochloric acid and extracted with ether. After washing with sodium bicarbonate water and saturated saline, drying with sodium sulfate, the solvent was distilled off, and the obtained oily residue was purified by silica gel column chromatography (ethyl acetate n-). Purification with xane =) yields colorless oily 3-hydroxyhydroxytanotritol 2

7.9 g.

PMR (CDC £ ₃ / TMS) δ: 0.92 (3H, t, J = 6Hz), 1.50 (11H, in), 2.53 (2H, m), 4.00 (2H, m)

Reference Example 2 3 —Hide mouth xyloctylamine

 Lithium aluminum hydride (6 g) was suspended in 330 mi of tetrahydrofuran, and 3—hydroxyoctanotritol (16.7 g) was suspended in tetrahydrofuran (20 g). The solution dissolved in mi) was gradually added dropwise at 0 ° C under a nitrogen stream. After stirring at 50'C for 3 hours, the mixture was cooled on ice, and a saturated aqueous solution of sodium sulfate (12 mf) was carefully added dropwise. The precipitate is filtered off through cerite, and the tetrahydrofuran solution is distilled off to obtain 17.6 g of 3-hydroxyhydroxylamine.

P M R (C D C £ 3 ZT M S) δ:

 0.90 (3Η, t, J = 6Hz), 1.40 (13H, m), 3.00 (2Η, m), 3.80 (2Η, m)

Reference Example 3 5 —Methoxycarbylmethyl 4 — (3 —Hydroxyoctylamino) 1 3 —Pyrroline 1 2 —On

 5—Methoxycarbonylmethylpyrrolidine-1,4, -Dion (4.11 g) and 3—Hydroxyoctylamine (5.8 g) in 60 O mi of acetone Then, add 3 molecular sieves (5 g) and heat to reflux for 3 hours. After removing the molecular sieves by filtration, the solvent was distilled off, and the obtained oily residue was purified by silica gel column chromatography (form: chloroform / methanol = 20/1) to give a brown color. Obtain 2.6 g of oily 5-methoxycarbonylmethyl-4-(3-hydroxyoxytylamino)-1-3-pyrroline-2-one.

PMR (CDC £ a / TMS) δ: 0.90 (3H, t, J = 6Hz), 1.40 and 1.75 (10H, 2m), 2.65 (2H, m) 5 3.20 (2H, m), 3.73 (3H, s), 3.75 (1H 3 m), 4.33 ( 1H, brt, J = 6Hz), 4.63 (1H, s), 5.60 (2H, m) Reference Example 4 3 —cyclohexyl-1 3 —hydroxypropionyl

 A 1.5 M n-butyllithium hexane solution (250 mi) was added dropwise to a solution of diisopropylamine (38 g) in tetrahydrofuran (470 ml) under ice cooling. . Then, the reaction solution was ice-cooled to 178'C, and a solution of acetonitrile (15.4g) in tetrahydrofuran (20M) was gradually added dropwise. And stir for 15 minutes. To this, 25 g of hexamethylene phosphate dissolved in hexanemethylene phosphate triamide (1 mi) was gradually added dropwise, and the temperature was gradually lowered to 178 for 1 hour and then to room temperature. And stir at room temperature for 1 hour. This is poured into ice water, acidified with 3.5N hydrochloric acid, and extracted with ether. After washing with aqueous sodium hydrogen carbonate and saturated saline, drying with sodium sulfate, the solvent was distilled off, and the resulting oily residue was subjected to silica gel chromatography (ethyl acetate / n—). Purification by xan = ¼) yields 26.9 g of colorless oily 3-cyclohexyl-3 -hydroxypropionitrile.

 P M R (C O C £ 3 / T M S) δ:

0.7 ~ 2.1 (12H, m), 2.53 (1H, d, J = 7Hz), 2.55 (1Η, d,

Reference Example 5 4 — (P — Black Mouth Phenoxy) 1 3 — Hydroxy Sibutyronitrile

Glycidyl p-chlorophenylether 11.4 g in ethanol Dissolve in le 100 mi, 40 to 50. To C, while heating and stirring, 16.2 g of an aqueous solution of potassium cyanide and an aqueous solution of acetic acid were gradually dropped at the same time. The reaction solution was made alkaline with potassium hydroxide, extracted with a black form, and the organic layer was treated in a conventional manner to give a pale yellow oil (p-chlorophenoxy). —Acquire 12 g of Nyldroxybutyronitrile.

 P M R (C D C £ 3 / T M S) 6:

 2.73 (2Η, d, J = 6Hz), 4.01 (2Η, d, J = 6Hz), 4.29 (1H, quint, J = 6Hz), 6.83 (2H, m), 7.26 (2H, m)

Reference Example 6 4 — (P — Black mouth phenol) 1 3 — Hydroxybutylamine

 Lithium aluminum hydride (4.3 g) was suspended in 10 O mi of tetrahydrofuran, and 4-((P-chlorophenoxy) -13-octyloxyptyronitrile (12 g) ) Was dissolved in tetrahydrofuran (100 mi), and the solution was gradually added dropwise at 0 ° C under a nitrogen stream. After refluxing the reaction solution for 3 hours, the mixture was cooled on ice, and a saturated aqueous solution of sodium sulfate (9 mf) was carefully added dropwise. The precipitate is filtered off through celite, and the tetrahydrofuran solution is distilled off to obtain 5.8 g of 4- (P-chlorophenol) 13-hydroxyhydroxyamine.

P M R (C D C £ 3 / T M S) δ:

 1.5 to 1.9 (2Η, m), 2.8 to 3.3 (2H, m), 3.87 (2H, d, J = 6Hz), 6.83 (2Η, m), 7.20 (2H, m)

Reference Example 7 4-(P-Fluorophenoxy) 1 3-Hydroxybutyronitrile

Glycidyl-P—fluorophenyl ether 10 g Then, while heating and stirring at 40 to 50, 16 g of an aqueous solution of potassium cyanide and an aqueous solution of acetic acid were gradually added dropwise at the same time. The reaction mixture was alkalified with potassium hydroxide, extracted with black-mouthed form, and the organic layer was treated in a conventional manner to give pale yellow oily 4- (p-fluorophenoxy) 13-hydroxyhydroxybutyronitrile. You get 11 g.

 P M R (C D C £ 3 / T M S) 6:

 2.73 (2H, d, J = 6Hz), 4.01 (2H, d, J = 6Hz), 4.30 (1H, quint, J = 6Hz), 6.73 ~ 7.13 (4H, in)

Reference Example 8 4-Methyl-3-Oxokota 1 6-Intril

A 1.5 M n-butyllithium hexane solution (93.4 m) was added dropwise to a tetrahydrofuran solution (150 mi) of diisopropylamine (20 mi) under ice cooling. Then, the reaction solution was ice-cooled to 18'C, and a solution of acetonitrile (7.5 ml) in tetrahydrofuran (10 mi) was gradually added dropwise. Stir for 30 minutes. To this, 10 g of ethyl 2-methylhexa-14-innoate dissolved in hexamethylene trilinamide triamide (11 m) was gradually added dropwise, and the mixture was added at 178 for 2 hours. Then, gradually raise the temperature to room temperature and stir at room temperature for 1 hour. This is poured into ice water, acidified with 3.5N hydrochloric acid, and extracted with ether. Wash with sodium bicarbonate water and plain saline solution, dry with sodium sulfate, evaporate the solvent, and remove the resulting oily residue by silica gel gel chromatography (ethyl ethyl acetate). Purification with hexane = ½) gives 8 g of colorless oily 4-methyl-3--3-oxo-octa-nitrile. PMR (CDC £ 3 / TMS) δ:

 1.34 (3H, d, J = 8Hz), 1.94 (3H, t, J = 3Hz), 2.60 (2H, m),

3.16 (1H, m), 3.96 (2H, s)

Reference Example 9 4—Methyl 1 4—Phenoxy 1 3—Oxopentanonitrile

 A 1.5 M solution of n-butyllithium hexane (31 ml) was added to a tetrahydrofuran solution (500 ml) of diisopropylamine (67 mi) under ice cooling. 0 mi) was added dropwise. Then, the reaction solution was cooled on ice to 178 ° C, and a solution of acetonitrile (25 mi) in tetrahydrofuran (33 ml) was added.

) Is slowly added dropwise and stirred at 180 ° C for 30 minutes. To this was gradually added 42 g of methyl 2 -methyl 12-phenoxy 1-2-propionate dissolved in hexamethylene phosphinate triamide (38 mi). Add dropwise at — 8 CC for 2 hours, then gradually raise the temperature to room temperature and stir at room temperature for 1 hour. Pour this into ice water, acidify with 3.5N hydrochloric acid and extract with ether. After washing with aqueous sodium hydrogen carbonate and saturated saline, drying with sodium sulfate, the solvent was distilled off, and the residue was recrystallized from hexane ether to have a melting point of 67 to 69. To obtain 41 g of C 4 -methyl 4 -phenoxy 3 -oxopentanonitrile.

 P M R (C D C £ 3 / T M S) 6:

1.50 (6H, s), 3.88 (2H, s), 6.85 (2H, m), 7.2 (3H, m) Reference Example 10 1 —Aminoethyl-1- 1 —Cyclohexanol Lithium hydride Minium (7.6 g) was suspended in 300 mi of methyl ether, and 1-cyanomethyl-1- 1-cyclohexanol (24.5 g) was added to tetrahydrofuran. (Dissolved in 10 m The solution was slowly added dropwise under a stream of nitrogen. After stirring at 50 ° C for 3 hours, the mixture was cooled on ice, and a saturated aqueous solution of sodium sulfate (15 mi) was carefully added dropwise. The precipitate was filtered off through celite, and the tetrahydrofuran solution was distilled off to obtain 1-aminoethyl 1-cyclohexanol.

You get 1 3 g.

 P MR (CDC £ 3 / TMS) δ:

1.3 to 2.0 (12H, m) _s 2.38 C3H, br s), 3.13 (2H, t, J = 6Hz) Reference example 1 1 4 —Methyl 1 4-Fenoxy 1 3 —Hydroxy pentylamine

 Lithium aluminum hydride (7.6 g) is suspended in 20 Om of tetrahydrofuran, and 4-methyl 14-1 phenol-3-hydroxy pentanone 2- A solution of 0.3 g) in tetrahydrofuran (40 mi) was slowly added dropwise at 0'C under a nitrogen stream. After stirring at 50 ° C for 3 hours, the mixture was ice-cooled, and a saturated aqueous solution of sodium sulfate (12 mi) was carefully added dropwise. The precipitate is filtered off through celite and the tetrahydrofuran solution is distilled off to obtain 11 g of 4-methyl-14-phenoxy-13-hydroxypentylamine.

 P M R (C D C £ 3 / TM S) δ:

 1.22 and 1.25 (6Η, 2s), 1.5 to 2.0 (2H, m), 3.8 to

4.2 (2H, m), 3.80 (1H, dd, J = 3, ΙΟΗζ), 7.9 to 5.3

 (5H, m)

Reference Example 1 2 5 —Methoxycarbylmethyl 4-1- (4-methyl-3—hydroxydiheptylamino) 1 3—Pyrroline 1 2 1-one

5—Methoxycarbonylmethylpyrrolidinone 2,4—Dion (12 g) and 4—dimethyl-3—hydroxyheptylamine (12 g) were dissolved in 60 O mf of acetonitrile, and the mixture was dissolved in a molecular sieve 3 A (5 g). g) and heat to reflux for 3 hours. After removing the molecular sieve by filtration, the solvent was distilled off, and the obtained oily residue was applied to silica gel column chromatograph (form: form / methanol = 20/1). 5.8 g of brown oily 5 — methoxycarboxylic acid methyl 4 — (4-methoxytinole 3 — nitroxyheptylamino) 13 — pyrrolin 2 —one obtain.

 P M R (C D C £ 3 / T M S) δ:

 0.88 (6Η, m), 1.50 to 1.80 (7H, m), 2.65 (2H, m), 3.18 (2H, m), 3.55 (1Η, m), 3.70 (3H, s), 4.33 (1H, m) , 4.60 (1H, s), 5.65 (2H, m)

Reference Example 1 3 5—Methoxycarbylmethyl 4 1 (3—cyclohexyl 1—3—hydroxy cypropyramino) 1 3—pyrroline 1 2 1

 5—Methoxycarbonylmethylpyrrolidinone 2,4—Dion (4.35 g) and 3—Cyclohexyl-3-3—Hydroxypropylamine (4.8 g) Dissolve in 50 Omi of acetonitrile, add 3 molecular sieves (5 g) and heat to reflux for 3 hours. After removing the molecular sieves by filtration, the solvent was distilled off, and the obtained oily residue was purified by silica gel gel chromatograph (form / formal ethanol / ethanol = 20/1). This gives 2. lg of brown oil, 5—Methoxycarbonyl methyl 4— (3—Cyclohexyl 3—Nydroxy cypropyramino) 1-3—Pyrroline 12—one.

PMR (CDC £ 3 ZT MS) δ: 0.90 to 2.30 (13H, m), 2.65 (2H, m), 3.22 (2H, m), 3.47 (1H, m), 3.74 (3H, s), 4.35 (1H, m), 4.63 (1H, s) , 5.60 (2H, m)

Reference Example 1 4 5 —Methoxycarbylmethyl 4 — (4,4 —Dimethyl 1 3 —Hide-opening Kiloctylamino) 1 3 —Pyrroline 2 —On

 5—Methoxycarbonylmethylpyrrolidinone 2,4—Dion (12.6 g) and 4,4—Dimethyl-3—Hydroxysuccilamine (12.8 g) Dissolve in acetonitrile and heat to reflux for 5 hours. The solvent was distilled off, and the resulting oily residue was purified by silica gel column chromatography (hol-mouth form Z methanol = 20/1) to give brown oily 5-methoxycarbo. 2.98 g of 2-methyl 4- (, 4 -dimethyl 3 -hydroxy-cylamino) -3-one-pyrroline-one is obtained.

PMR (CDCJ £ ₃ / TMS) δ:

0.86 (3H ₅ s), 0.88 (3H, s) ₅ 0.91 (3H, m), 1.25 (6H, m), 1.75 (2H, m), 2.66 C2H, m), 3.22 (3H, m), 3.75 ( 3H, s), 4.35 (1H, t, J = 6Hz), 4.65 (1H, s), 5.50 (2H, m)

Reference example 1 5 5 —Methoxycarbonylmethyl 4- 1 (4,4-dimethyl-3—Hydroxy-1 6—Hepturamino) 1-3—Pyrroline-1 2—On

5—Methoxycarbonylmethylpyrrolidine-1,2,4—dione (11 g) and 4,4—dimethyl-1-3—hydroxy-6—hepturamine (15 g) were added to 70 Om Dissolve in acetonitrile, add molecular sieve (5 g), and heat to reflux for 4 hours. After removing the molecular sieve by filtration, the solvent is distilled off, and the obtained oily residue is purified by silica gel chromatography chromatography (form of hologram // metanol = 20/1). ) Yields a brown oil of 5-methoxycarbyl-4 (4, 4-dimethyl 3-nitrodoxy 1-6-hepturamino) 1-3-pyrroline-1 2 —Get 3.7 g of on. PMR (CDC £ a / TMS) δ:

 0.85 (3Η, s), 0.88 (3Η, s), 1.25 to 2.13 (4H, m), 2.60 (2H, m), 2.90 (1H, m), 3.20 (2H, m), 3.45 (1H, m) , 3.72 (3H, s), 4.33 (1H, m), 4.60 (1H, s), 5.03 (2H, m) 5.70 (3H, m)

Reference Example 1 6 5 —Methoxycarbonylmethyl 1 4 — (4 —Methyl-3 —Hydroxy 1-6 —Innilamino) 1 3 —Pyrroline 1 2 —On

 5—Methoxycarbonylmethylpyrrolidinone 2,4—Dion (9.5 g) and 4—Methyl-13—Hydroxysixa 16—Innilamine (9.5 g) Dissolve in 23 Om of acetonitrile, add 4 molecular sieves (5.0 g) and heat to reflux for 4 hours. After removing the molecular sieve by filtration, the solvent was distilled off, and the obtained oily residue was purified by silica gel chromatography with chromatographic chromatography (formula formanol = 20 Z1) to give a brown oil. 5—Methoxy carbonyl methyl 4— (4—Methylenol 3—Nydroxamine 6—Innilamine) 1 3—Pyrroline 1 2—On 3.0 g .

 P M R (C D C £ 3 / T M S) δ:

1.96 (3Η, d, J = 8Hz), 1.76 (3H, t, J = 2Hz), 1.40 to 2.30 (7H, m), 2.63 (4H, ra), 3.21 (2H, m), 3.46 (1H, s), 3.71 (3H, s), 4.33 (1H, m), 4.62 (1H, s), 5.57 ( 2H, m) Reference example 1 7 5 —Methoxy carbonylmethyl 1 4 — (3 — Hydroxoxy 1 4 —Phenoxybutylamino) 1 3 — Pyrroline 1 2 — One

 5—Methoxycarbonylmethylpyrrolidine- 1,2,4-dione (12.3 g) and 3—Hydroxy-1—4-phenoxybutylamine (13.0 g) Dissolve in acetonitrile and heat to reflux for 4 hours. The solvent was distilled off, and the resulting oily residue was purified by silica gel chromatography (chromatographic formanol = 20/1) to give brown oily 5-methoxycarbonylmethyl. 4.26 g of chill—4— (3—hydroxy-1—4-hydroxybutylamino) -1-31-pyrroline-12—one is obtained.

PMR (CDC £ ₃ / TMS) 6:

 1.87 (2H, m), 2.55 (1H, dd, J = 7, 18Hz), 2.82 (1H, dd, J = 6, 18Hz), 3.28 (2H, m), 3.71 (3H, s), 3.82-23 (3H, m), 4.36 (1H, t, J = 7Hz), 4.64 (1H, s), 5.81 to 6.11 (2H, m), 6.95 (3H, t, J = 7Hz), 7.29 (2H, t, (J = 7Hz) Reference Example 1 8 5 —Methoxycarbonylmethyl 4 -— (4- (P-fluorophenoxy) 13—Hydroxybutylamino) —3—Pyrroline-1 2-one

5—Methoxycarbonylmethylpyrrolidinone 2,4—Dione (7.57 g) and 4— (P—Fluoroenoxy) 13—Hydroxoxybutylamine (8.84) g) in 350 mi of acetonitrile, add molecular sieve 4A (5 g) and heat for 4 hours Reflux. After removing the molecular sieve by filtration, the solvent was distilled off, and the resulting oily residue was purified by silica gel chromatography (chloroform methanol = 20/1) to give a brown oil. 5—Methoxycarbonylmethyl 1—4— (4— (P—fluorophenoxy) 1—3—Hyd mouth xybutylamino) 1—3—Pyrroline—2—On to 8.1 Get 4 g.

P M R (C D C £ 3 / T S) 6:

1.87 (2Η, m), 2.55 (1H, dd, J = 7, 18Hz), 2.80 (1H, dd, J = 6, 18Hz), 3.28 (2H, m), 3.72 (3H, s), 3.82 to 4.20 (3H, m), 4.35 (1H, t, J = 7Hz), 4.63 (1H _S s), 5.70-6.00 (2H, m), 6.72-7.12 (4H, m)

Reference Example 1 9 5 —Methoxycarbonylmethyl 1 4 — [4 (m-trifnoreolomethinolef enoxy) 1 3 —Nidoxyloxybutylamino] 1 3 —Pyrroline 1 2 —On

 5—Methoxycarbonylmethylpyrrolidinone 2,4—Dion (7.13 g) and 4— (m—Trifluoromethylenoxy) 1-3—Hydroxybutylamine (1 Dissolve 2.2 g) in 300 m of acetonitrile and heat to reflux for 3 hours. The solvent was distilled off, and the resulting oily residue was purified by silica gel chromochromatography (formula formanol = 20/1) to give a brown oily 5-methoxymethoxyphenol. 3.27 g of lumetyl 4— [4— (m—trifluoromethylenoxy) 13—hydroxybutylamino] 13—piperone 2—one

P M R (C Ό C £ 3 / T M S) δ:

1.88 (2Η, m), 2.55 (1H, dd, J = 7, 18Hz), 2.82 (1H, dd, J-6, 18Hz), 3.28 (2H, m), 3.71 (3H _S s), 3.83-4.23 (3H, m), 4.35 (1H, t, J = 7Hz), 4.63 (1H, s), 5.82-

 6.12 (2H, m), 6.92 to 7.52 (4H, m)

Reference Example 20 (3S) —N—3—acetoxypropyl 13—acetoxy

 L-Lingoic acid (25 g) is suspended in acetyl chloride (200 mi) and heated under reflux for 2 hours. The solvent is distilled off, and the obtained oily residue is dissolved in methylene chloride (100 mL), 3-hydroxypropylamine (36.4 g) is added, and the mixture is heated under reflux for 2 hours. The solvent was distilled off and the obtained oily residue was purified by silica gel chromatography (ethyl acetate Z hexane = 1/1) to give a colorless oily (3S) -N-3-acetoxyp Pill-1 3-acetoxysuccinimide (7.0 g) is obtained.

^{C oc) 2 8 - 1 7.4} 2 ° (c = 0.938, CHC1 3)

P M R (C D C £ 3 / T M S) δ:

2.00 (2H _S m), 2.06 (3H, s), 2.15 (3H, s), 2.63 (1H, dd, Jgem = 18Hz, Jvic = 5Hz), 3 16 (1H, dd, Jgem = 18Hz, Jvic = 9Hz ), 3.65 (2H, t, J = 7.5Hz), 4.07 (2H, t, J = 6Hz), 5.41 (1H, dd, J-5, 9Hz)

Reference Example 2 1 (3 S) 1 N— 3 —Bivaloyloxypropyl 1 3 —Hydroxy Shisaku Shinimido

(3S) 1N—3—acetoxypropyl 13-acetoxysuccinimide (7 g) is dissolved in ethanol (130 £) and acetiluk mouth light (6 mi) And heated at 50'C for 7 hours. Solvent is distilled off and the resulting oil / residue is subjected to silica gel gel chromatography. The product was purified by a single method (formaldehyde in black mouth = 20/1) to obtain a 3-hydroxy compound (2.8 g). This was dissolved in tetrahydrofuran (50 m), pyridine (2 m) was added, and a pivaloy-luc mouth lid (2.8 mi) was gradually added dropwise at 0 ° C. The resulting oily residue was purified by silica gel chromatography with chromatograph (getyl a ternohexane = 1/1) to give (3S) —N—3—Pinoleuinoleoxypro Pinole 3—Hydroxysuccinimide (1.8 g).

 PMR (CDC / TMS) 6:

 1.23 (9Η, s), 2.00 (2H, m), 2.65 (1Η, dd, Jgem = 18Hz, Jvic = 5Hz), 3.08 (1H, dd, Jgem = 18Hz, Jvic = 9Hz), 3.62 (2H, t, J = 7.5Hz), 4.06 (2H, t, J = 6Hz), 4.63 (1H, dd, J = 5, 9Hz)

Reference Example 2 2 (3 S) — N— 3 — Vivaloy Roxypropyl 13 —Bromoacetoxysuccinimide

 (3S) -N- 3 -Bivaloyloxypropyl-1 3 -Hydroxysuccincinimide (1.8 g) was dissolved in tetrahydrofurofuran (35 mi), and pyridine ( 1 mi) was added, and bromoacetyl bromide (0.8 m) was gradually added dropwise at 0'C. After the usual treatment, the obtained oily residue was purified by silica gel gel chromatography (diethyl ether Z hexane = 1/1) to give (3S) -N-3 —Vivaloy-loxypropyl-13—Bromoacetoxysuccinimide (1.2 g) is obtained.

P M R (C D C £ 3 / T M S) δ:

1.22 (9Η, s), 1.98 (2Η, m), 2.65 (1H, dd, J = 5, 18Hz), 3.22 (1H, dd, J = 9, 18Hz), 3.66 (2H, t, J = 7.5Hz), 3.90 (2H, s) ₅ 4.06 (2H, t, J = 6Hz), 5.50 (1H, dd, J = 5, 9Hz) Reference Example 2 3 (IS) -6- (3—Vivaloy oxypropyl) 1cis-1 6—aza1 2—oxabicyclo C3.3.0] —Zeon

 (3S) —N—3—Bivaloyloxypropyl-3- (bromoacetoxysuccinimide) (1.2 g) was dissolved in acetonitrile (80 m), and triphenylphosphine was dissolved. (900 mg)

5 0. Heated at C for 5 hours. Add triethylamine (0.46 mi), heat at 50 ° C for 8 hours, and evaporate the solvent. The resulting oily residue was purified by silica gel column chromatography (ethylethylhexane acetate = 1/2) to give (1S) — 6 — (3 —bivaloyloxypropyl) 1cis — 6 — other 2 — Oxabicyclo [3.3.0] octa-4-ene-1,3,7-dione (640 mg) is obtained.

[A] ^{2 & - 6 7. 0 6 °} (c = 0.545, CHC1 3)

 P M R (C D C £ 3 T M S) δ:

1.25 (9Η, s), 2.02 (2Η, in), 2.70 (1H, dd, J = 5, 18Hz), 3.12 (1H, dd, J = 9 ₅ 18Hz), 3.56 (1H, m), 3.88 (1H , m), 4.12 (2H, t, J = 6Hz), 5.22 (1H ₅ m), 5.30 (1H, s) Reference example 2 4 (IS, 5 S) — 6 — (3 —Bivaloyoxy pill) Cis 1 6-aza 1 2-oxabicyclo [3.3.

0] octane-3,7-dione

 (I S) — 6 — (3 — Bivaloyloxypropyl)

6 — 1 2 — Oxabicyclo [3.3.0] 1 4 — Dissolve 3,7-dione (600 nig) in ethyl acetate (20 ffl £), add 5% rhodium-alumina (60 ig), and hydrogenate at room temperature for 5 hours. The catalyst was removed by filtration through celite, the solvent was distilled off, and the residue was purified by silica gel chromatography (ethyl acetate) to give (1S, 5S) with a melting point of 86 to 87. 3-Vivaloy-loxypropyl) 1-cis 1-6-aza 2-Oxabicyclo [3.3.0] octane 3,7-dione 470 m is obtained.

[O] ^{2 έ - 1 3. 8 ° (} c = 1.00, CHC1 3)

 P M R (C D C £ a / T M S) δ:

 1.22 (9H, s), 1.90 (2H, m), 2.75 (4H, 2s), 3.02 (1H, dd, J = 7, 15Hz), 3.72 (1H, dd, J = l, 15Hz), 4.08 (2H , t, J = 6Hz), 4.47 (1H, m), 5.13 (1H, m)

Reference Example 2 5 (I S, 5 S) — 6 — Benzyloxycarbone 2 — 16 — 1 2 — Oxabicyclo [3.3.0] Octane 1, 3 — 7

(5S) -N-benzyloxycarbonylmethyl-5-methoxymethoxylevonylmethinolepyrrolidine-1,4, -dion (45g) was converted to methylene chloride (500mi), Dissolve in acetic acid (150 mi) and slowly add sodium borohydride (15 g) under ice-cooling. Stir at room temperature for 2 hours and pour into ice water. After washing with water, aqueous sodium hydrogen carbonate and saturated saline, the solvent is distilled off to obtain a solid. Recrystallized from form-hexane (1: 1), melting point 13 3 -1 3 5 (1 S, 5 S) 16-benzyloxycarbonyl-6-aza 1 2 — 29 g of oxabicyclo [3.3.0] octane-13,7-dione is obtained as white crystals. C or ^z g 17 7 3. _{(C = 0 615, CHC1 3} )

P M R (C D C £ 3 / T M S) δ:

 2.88 (2H, s), 2.92 C2H, s), 4.80 (1H, m), 5.04 (1H, m), 5.29 (2H, s), 7.38 (5H, s)

Reference Example 2 6 (IS, 5S) —cis 6—aza 2 —oxa bicyclo [3.3.0] octane 1, 3, 7—dione

 (1 S, 5 S) — 6-Benzyloxycarbonyl -cis-1 -aza-2-oxabicyclo [3.3.0] octane-13, 7-dione (17 g) Dissolve it in form-methanol (1: 1) 400, add 10% palladium-carbon (1.5 g), and blow in hydrogen for 5 hours. The catalyst is removed by filtration through celite, and the filtrate is concentrated, and a solid is formed. When recrystallized from isopropyl alcohol methanol, the melting point is 139-14-1 (1S> 5S) -cis-6-aza1-2-oxabicyclo [3.3.0] octa 3,7-dione is obtained as a hundred-colored crystals, 7 g.

[] ^{2 - 8 8. 4 ° (c} = 1.00, EtOH)

PMR (CDC £ ₃ — CD ₃₀ D / TMS) δ:

 2.70 UH, 2s), 4.48 (1H, td, J = 2, 5Hz), 5.20 (1H, td,

(J = 2, 5Hz)

 When the same procedure is performed, the following compound is obtained, but is not limited thereto.

 (27) 5—Methoxycarbonyl methyl 4— (3—Cyclopentyl 1 3—Hydroxycypropyramino) 1 3—Pyrroline 1 2—On

PMR (CDC J2 ₃ / TMS) δ: 1.00-2.10 (11H, m), 2.70 (2H, m), 3.23 (2H, m),

 3.60 (1H, m), 3.75 (3H, s), 4.36 (1H, m), 4.64 (1H, s),

5.66 (2H, m)

 (28) 5—Methoxycarbonylmethyl 1 4— (5R, 9—Dimethyl 1 3—Hydroxy 8—Dequenylamino) 1 3—Pyrroline 1 2—On

PMR (CDC £ ₃ / TMS) 6:

 0.90 (3H, d, J = 6Hz), 1.05 to 2.15 (15H, m), 2.65 (2Η, m), 3.20 (2Η, m), 3.47 (1H, s), 3.72 (3H, s), 3.85 ( 1H, m), 4.34 (1H, m), 4.63 (1H, s), 5.18 (1H, m), 5.50 (1H, m)

(29) 5 —Methoxycarbonylmethyl 1-4 (4-Methyl-N-41-Phenoxy-1 3 —Hydroxy-pentylamino) 1-3 —Pyrroline 2 —On

 P M R (C D C £ 3 / T M S) 6:

 1.22 (6Η, s), 1.80 (2Η, m), 2.65 (2H, m), 3,30 (2H, m), 3.74 (3Η, s), 3.76 (1Η, m), 4.37 (1H, t, J = 7Hz), 4.67 (1H, s), 5.65 (2H, br d), 6.90-7.30 (5H, m)

 (30) 5 —Methoxycarbonylmethyl 1 4 — [2— (1—N-doxycyclohexane-1 1-ethyl) ethylamino] 1 3—Pyrroline 1 2—On

 P M R (C D C £ a / T M S) δ:

1.50 (10H, br s), 1.75 (2H, t, J = 6Hz), 2.65 (2H, 2d, J = 6, 7Hz), 3.19 (2H, q, J = 6Hz), 3.73 (3H, s), 4.34 (1H, dd, J = 6, 7Hz), 4.60 (1H _S s), 5.60 (1H, br s), 5.80 (1H, br t, J = 6Hz) (31) 5—Methoxycarbonylmethyl 1-4 (3—Methyl-3—Hydroxysuccinylamino) 1-3—Pyrroline-1 2—On PMR (CDC £ a / TMS) 6:

0.90 (3H, t, J = 6Hz), 1.22 (3Η, s), 1.30 and 1.75 (10Η, m), 2.65 (2H, m) ₅ 3.18 (2H, q, J = 6Hz), 3.73 (3H, s ), 4.35 (1H, t, J = 7Hz), 4.61 (1H, s), 5.56 (1H, br s) 5.75 (1H, br t)

 (32) 5 —Methoxycarbonylmethyl 1 4 — (5-Fe 13 1 —Hydroxycypentylamino) 13 —Pyrroline 1 2 —On PMR (CDC £ 3 / TMS) δ:

 1.50 to 2.20 (6Η, m), 2.66 (4H, m), 3.17 (2Η, q, J = 6Hz), 3.72 (3H, s), 4.33 (1H, t, J = 7Hz), 4.63 (1H, s ), 5.67 (2K, m), 7,22 (5H, br s)

 (33) 5 —Methoxycarbylmethyl 4 — (3 Hydroxy 3 —Phenylpropyramino) 13 —Pyrroline 1 2 —On PMR (CDC £ 3 / TMS) δ:

 1.98 (2Η, m), 2.40 (1H, m), 2.62 (2Η, m), 3.16 (2H, q, J = 6Hz), 3.71 (3H, s), 4.30 (IH, t, J = 6Hz), 4.54 (1H, s), 4.80 (1H, m), 5.70 (5H, br s), 7.31 (4H, m)

 (34) 5 —Methoxycarbonyl methyl 4 — (4,4 —Dimethyl 1 5 —Ethoxy 1 3 —Hydroxypentylamino) 1 3 —Pyrroline 1 2 —On

 P M R (C D C £ 3 / T M S) δ:

0.87 (3Η, s) ₅ 0.91 (3H, s), 1.20 (3H, t, J = 7Hz), 1.74 (2Η, m), 2.66 (2Η, m), 3.13 (2H, m), 3.31 (2H, s), 3.49 (2H, q, J = 7Hz), 3.74 (3H, s), 3.96 (1H, br s), 4.36 (1H, m), 4.63 (1H, br s), 5.50 (1H, br s), 5.70 (1H, m)

Example 1 2 — (3 — Hide mouth) 1 cis — 2, 6 — Diazabicyclo [3. 3. 0] Octane 1, 3, 7 — Zion

5—Methoxycarbylmethyl 4— (3—Hydroxyloctylamino) 13—Pyrroline12—On (2.55 g) is dissolved in ethanol. Then, platinum oxide (255 rag) was added, and the mixture was subjected to catalytic reduction at 50 atm and 50 atm for 7 hours. After the catalyst was removed by filtration through celite, the solvent was distilled off, and the obtained oily residue was purified with silica gel chromatograph (form: holm / methanol = 20/1). Purification by purification yields a yellow oil of 2 — (3 — hide-mouthed octyl) — cis — 2,6 — diazabicyclo [3. 3. 0] octane 1, 3, 7 — dione. Get 7 g.

MS: 268 (M +), 250 (M + -H 2 0)

PMR (CDC £ a / TMS) 6:

 0.90 (3H, t, J = 6Hz), 1.30 (10H, m), 2.56 (4H, m) '3.35 to 4.10 (4H, m), 4.39 (2H, m), 6.20 (1H, m)

Example 2 2 — (3-acetoxoctyl) 1cis 1, 2, 6 — diazabicyclo [3. 3. 0] octane 1, 3, 7 — dione

2— (3—Hyd mouth octyl) 1 cis—2,6—diazabicyclo [3.3.0] octane 1,3,7—dione (6.9 g) was added to acetic anhydride (6.9 g). Dissolve in 15 mi) and pyridin (20), add a catalytic amount of dimethylaminopyridin, and leave at room temperature overnight. The solvent was distilled off, and the resulting oily residue was purified by silica gel chromatography. Purification by filtration (form: holm / methanol = 20/1) yields a yellow 2- (3-acetoxyoctyl) -cis-1,2,6-diazabicyclo [3.3.0] Get 3 Octanes and 3 Margins (7 lg).

 P M R (C D C £ 3 / T M S) δ:

_{0.90 (3H S t, J =} 6Hz), 1.15~: L.95 (10H, m), 2.07 (3H, s),

2.40 (4Η, m), 2.90 (1Η, m), 3.75 (1H, in), 4.35 (2H, m),

4.80 (1H, m), 6.30 (1H, m)

Example 3 2 — (3-Acetoxyoctyl) 1cis 1, 2,6 diazabicyclo [33.0] octane 1 3 —one 1 7 —thione and 2 — (3 —acetosoxyoctyl) 1cis 1 2, 6-diazabicyclo [3.3.0] octane 3, 7-dithione

2 — (3 — acetoxyoctyl) per cis 2,6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione (8 g) into tetrahydrofuran (400m £) Dissolve, add Lawesson's reagent (5.2 g), and stir at room temperature for 1 hour. The solvent was distilled off, and the obtained oily residue was purified by silica gel column chromatography (chloroform / methanol = 30/1) to give a colorless oily 2- (3-acetoxoctyl) -1. Cis 1, 6 — diazabicyclo [3.3.0] octane 1 3 — on 1 7 — thione ((a), 6. lg) and 2 — (3 — acetoxyoctyl) 1 cis 1, 6 —Diazabicyclo [3.3.0] octane-1,3,7—dithione ((b), 1.6 g) is obtained. PMR (CDC £ ₃ / TMS) 6:

(a) 0.90 (3H, t, J = 6Hz), 1.10 to: 1.95 (10H, m), 2.07 (3H, s), 2.65 (2H, m), 2.90 (1H, m), 3.07 (2H, m) ), 3.70 (1H, m), 4.55 (2H, m), 4.82 (1H, m), 9.00 (1H, br s)

(b) 0.90 (3H, t, J = 6Hz), 1.10 to 1.95 (10H, m), 2.08 (3H, s),

3.20 (4H, m), 3.35 (1H, m), 4.20 (1H, m), 4.75 (3H, m),

8.70 (1H, br s)

Example 4 2 — (3 — Hydroxy-1-4-enoxybutyl) 1-cis-1, 2, 6-diazabicyclo [3.3.0] octane-1, 3, 7-Zion

 5 — METOKINE

4—Phenoxysipylamino 1 3—Pyrroline 1 2—On (2.

17 g) was dissolved in ethanol, and platinum oxide (250 mg) was added.

The catalytic reduction was carried out at 50 atm and 50 atm for 7 hours. After removing the catalyst by filtration through a cerite, the solvent was distilled off, and the obtained oily residue was subjected to silica gel chromatography (Cross-port Holm Z methanol = 20/1). Purification by purification yields a colorless, oily 2- (3-hydroxy-4-butyl) -cis-1,2,6-diazabicyclo [3.3,0] octane-1,3-geo To give 1.96 g.

 P M R (C D C £ 3 / T M S) 6:

 1.80 (2Η, br), 2.15-2.75 (4H, m), 2.95-4.10 (6H, m),

4.34 (2H, m), 6.80 to 7 · 40 (5Η, m)

Example 5 2 — (3 — acetoxy 4-hydroxy butyl) — cis 1 2> 6 — diazabicyclo [3. 3. 0] octane 1, 3, 7 — dione

2 — (4 — phenolic 3 — hydroxy) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione (1.96 g) Dissolve in acetic acid (0.8 mf) and pyridine (2 m £) Leave at room temperature overnight. The solvent was distilled off, and the resulting oily residue was purified by silica gel column chromatography (chloroform form Z methanol = 20/1) to give a yellow 2- (3-acetoxy-one). 4 1-phenoxybutyl) 1-cis-1,2,6-diazabicyclo [3.3.0] octane-1,3,7-dione (2.23 g) is obtained.

PMR (CDC £ ₃ / TMS) 6:

 1.62 ~ 2 ・ 12 (5Η, m), 2.22 ~ 2.65 (4Η, m), 2.70〜3.20

(1Η, m) _s 3.42 to 3.95 (1Η, m), 4.05 (2Η, m), 4.30 (2Η, m), 5.09 (1H, ra), 6.75 to 7.06 (3Η, m), 7.12 to 7.40 (2Η , m) Example 6 2-(3-acetooxy-1 4-phenoxybutyl)-cis-1, 2, 6-diazabicyclo [3.3.0] octane-1,3, 7-dione

 (i) 5—Methoxycarbonylmethyl 4 -— (2,4—Dimethoxybenzylamino) 1-3—pyrroline 2-one (20 g) with 400 methanol and platinum oxide (Lg) was added, and the mixture was stirred at 50 atm and 60'C for 5 hours under a hydrogen atmosphere in a photoclave. After filtration of the catalyst, the solvent was concentrated and the 2- (2,4-dimethoxybenzyl) 13,7-dioxosis-1,2,6-diazabicyclo [3.3.0] octane monohydrate was added to 1 3. Get 15 g.

Melting point: 130-134'C

Analysis value: C, ₅ H _{I 8} N ₂ 0 ₄ ′ As H ₂ 0

 Min: C: 58.43, H: 6.54, N: 9.09

 Found: C: 58.42, H: 6.26, N: 9.08

 M S: m / z 290 (M,)

(ii) 2 — (2, 4 — dimethoxybenzyl) Diazabicyclo [3.3.0] octane-1,3,7-dion (6.3 g) is dissolved in 100 ml of anhydrous dimethylformamide by heating, and 60% hydrogenated sodium is added thereto. Lithium (1.1 g) is added under cooling. After addition, heat at 50 to 70 for 1 hour and return to room temperature. To this, 3,4-epoxybutyl bromide (4 g) was gradually added dropwise. Stir at 50-60 ° C for 8 hours and pour into ice water. Neutralize with dilute hydrochloric acid and extract with black-mouthed form. After the conventional treatment, the obtained residual oil was subjected to silica gel column chromatography with a developing solvent having a form / methanol ratio of 20/1 to obtain a melting point of 90-91'C. 2— (2,4-Dimethoxybenzyl) —— 6— (3,4-epoxybutyl) —— cis-1,2,6-diazabicyclo [3.3.0] octane-1,3— 2.5 g of Zion are obtained.

P M R (C D C £ a / T M S) δ:

 1.50 to 2.20 (2H, m), 2.56 (4H, br s), 2.80 to 3.20 (4H, m), 3.82 (6H, s), 3.95 to 4.40 (4H, m), 4.81 (1H, d, J = 14Hz), 6.46 (2H, br s), 7.19 (1H, d, J = 8Hz)

(iii) 60% sodium hydride (155 mg) is suspended in 10 dimethylformamide, and phenol (274 nig) is added under ice cooling. After heating at 50 ° C for 1 hour, the mixture was cooled, and 2-(2, 4-dimethoxybenzyl)-6-(3, 4-epoxybutyl)-cis-2, 6-diazabicyclo [3.3. 0] A solution of 3,7-dione (700 mg) in dimethylformamide (10) was slowly added dropwise. Heat at 50 ° C for 5 hours, cool and pour into ice water. After extraction with a black form and processing in a conventional manner, the resulting residual oil is purified by silica gel chromatography chromatography (developing solvent black form formno). Purification with methanol (20/1) yields oily 2- (2,4-dimethoxybenzyl) -16- (3-hydroxy-14-phenoxybutyl) cis-1,2,6-diazabicyclo [ 3.3.0] Octan-1,3,7-dione is obtained as an oil (750 mg). Next, this was dissolved in pyridin 3, 1.5 me of acetic anhydride was added, and the mixture was stirred at room temperature for 7 hours. / 1) yields 2-((2,4-dimethoxybenzyl) -16- (3-acetoxy-14-phenoxybutyl) -cis-2,6 diazabicyclo [3.3.0] octa. -—3, 7-dione (570 mg). PMR (CDC £ 3 / TMS) δ:

1.7 ~ 2.10 (211, br), 2.05 (3H _S s), 2.50 (4Η, br s), 2.80 ~ 3.10 (2H, m), 3.79 (6H, s), 3.90 ~ 4.40 (5H, m), 4.75 (1H, d, J = 14Hz), 5.09 (1H _S m>, 6.40 (2H, brs), 6.70 to 7.30C6H, m)

(iv) 2-(2, 4-dimethoxybenzyl) 1-6-(3-acetoxy-1-phenoxybutyl) 1-cis-1, 6-diazabicyclo [3.3.0] octane-13, 7- Dione (500 mg) was dissolved in a mixed solvent of 30 JH £ of acetonitrile ¹ J water = 9 Z 1, and cerium (IV) diammonium nitrate (lg) was added. Stir for 12 hours at room temperature. Pour into iced water, neutralize with aqueous sodium bicarbonate, extract with porcine, and process in the usual manner. When the residual oil was purified by silica gel column chromatography (developing solvent clot mouth / methanol = 20/1), the same 2— (3—acetoxy-14-phenoxybutyl) as in Example 5 was obtained. ) 1 cis 1 2, 6 — Jizabicyclo [ 3.3.0] Octane 3, 7 — Get 270 m of Zion.

Example 7 2-[4-1 (p-fluorobenzoic acid) 13-hydroxyhydroxybutyl] cis-12, 6-diazabicyclo [3. 3. 0] octane 13, 7 —Zeon

 5—Methoxycarbylmethyl 4 1 (4— (p—Fluoroenoxy) 1 3—Hydroxybutylamino] 1 3—Pyrroline—2—On (4.8 3 g) was dissolved in ethanol, platinum oxide (480 mg) was added, and the mixture was subjected to catalytic reduction at 50 atm and 50 atm for 7 hours. The catalyst was removed by filtration through celite, the solvent was distilled off, and the resulting oily residue was purified by silica gel caram- chromatography (formula methanol = 20/1) to give a colorless oil. 2-[4-1 (P-fluoropheno)-1-3 -doxybutyl] 1-cis-1, 2-6-diazabicyclo [3.3.0] octane-1, 3-7- 4.38 g.

P M R (C D C £ 3 / T M S) δ:

 1.78 (2Η, br), 2.2 to 4.1 (10H, m), 4.34 (2H, br s),

6.70 〜 7.10 (4Η, m)

Example 8 2 — (3 — Cyclohexyl 3 — Hydroxip Mouth Pill) 1 cis 1 2,6 — diazabicyclo [3.3.0] Octane 1, 3, 7 — Zion

5—Methoxy cycasoleboninoleme chinore 1—4— (3—cyclohexylisolate—3—hydroxy cypropyrua mino) 1—3—pyrroline—2—one (2.6 g) It was dissolved in ethanol, platinum oxide (260 mg) was added, and catalytic reduction was performed at 40'C and 50 atm for 6 hours. After removing the catalyst by filtration through celite, the solvent was distilled off, and the obtained oily residue was purified by silica gel. Purification by column chromatography (chloroform / methanol = 20/1) yielded a yellow oil of 2-((3-cyclohexyl-3) -hydroxypropyl) -cis-1,2,6 —Diazabicyclo [3.3.0] octane-1,3,7 —Get 2.2 g of dione.

PMR (COC £ _s / TMS) δ:

0.70 to 2.10 (13H, m), 2.53 (4Η, m) ₅ 2.80 to 10 (4Η, m),

4.35 (2H, m), 6.60 (1H, m)

Example 9 2- (3-cyclohexyl 3-acetoxypropyl) 1cis-1,2,6—diazabicyclo [3.3.0] octane 3,7—dione

 2-(3-Cyclohexyl 1-3-acetooxypropyl) 1-2,2-6-diazabicyclo [3.3.0] octane-1,3,7-dione (3.4 g) Dissolve in acetic acid (7.5 ml) and pyridine (10 mi), add a catalytic amount of dimethylaminoviridine, and leave at room temperature overnight. The solvent was distilled off, and the resulting oily residue was purified by silica gel column chromatography (clo-form form methanol = 20/1) to give a yellow 2- (3-cyclohexane). Xylue 3- (acetoxypropyl) -cis-1,2,6-diazabicyclo [3.3.0] octane-1,3-dione (3.5 g) is obtained.

PMR (CDC £ ₃ / TMS) δ:

 1.17 and 1.73 (13H, 2m), 2.09 (3H, s), 2.50 (4H, m),

2.90 (1H, m), 3.71 (1H, m) ₅ 4.35 (2H, m), 4.70 (1H, m),

7.20 (1H, m)

Example 10 2 — (3—acetoxy 3—cyclohexylp mouth pill) 1cis-1,2,6—diazabicyclo [3.3.0] octa 1-cis 7-thion and 2-(3-acetoxy 3-cyclohexylpropyl) cis-1,2,6-diazabicyclo [3.3.0] octa One-third, seven-dithione

 2 — (3 — acetoxy 1 3 — cyclohexyl propyl) 1, 2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7-dione (5.5 g) is dissolved in tetrahydrofuran (300 mi), Lawesson reagent (3.6 g) is added, and the mixture is stirred at room temperature for 1 hour. The solvent was distilled off, and the resulting oily residue was purified by silica gel chrom chromatographic (Cross-form Holm Z methanol = 30/1) to give a colorless oily 2 — (3 —Acetoxy 3 —cyclohexyl propyl) 1 cis-1,2,6 — diazabicyclo [3.3.0] octane — 3 —one 1 7 —thion ((a) , 3.8 g) and 2 — (3 — acetoxyl 3 — cyclohexyl propyl) -cis 1, 2,6-diazabicyclo [3.3,0] octane 1, 3, 7-Dithion ((b), 0.8 g) is obtained.

 P M R (C D C £ 3 T M S) δ:

 (a) 1.15 and 1.73 (13H, 2m), 2.08 (3H, s), 2.63 (2H, m) 2.90 (1H, m), 3.06 (2Η, m), 3.70 (1H, m), 4.60 (3H, m) 9.05 (1H, br s)

 (b) 1.15 and 1.73 (13H, 2m), 2.09 and 2.11 (3H, 2s),

 3.20 (4H, m), 3.42 (1H, m), 4.15 (1H, m), 4.67 (3H, m) 8.40 (1H, br s)

Example 1 1 2 — (4-methyl-3—hydroxyheptyl) — cis-1,2,6-diazabicyclo [3.3.0] octane-3,7—dione 5-Methoxycarbonylmethyl 1-4 (4-methyl 1-3-nitrodroxyheptylamino) 13-Pyrrolin-2 -one (3.2 g) is dissolved in ethanol Then, platinum oxide (28 O mg) was added, and the mixture was subjected to catalytic reduction at 50 and 50 atm for 50 hours. After the catalyst was removed by filtration through celite, the solvent was distilled off, and the obtained oily residue was purified by silica gel chromatography with chromatograph (20: 1). Yellow oily 2 — (4 — methyl 1 — 3 hydroxypropyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 3, 7 — dione 3.0 get g.

PMR (CDC £ ₃ / TMS) 6:

0.90 (6H, m), 1.05 to: L80 (7H, m), 2.54 (4H, m), 2.80 to 4.10 (4H ₃ m), 4.36 (2H, m), 7.20 (1H, m)

Example 1 2 2-(4, 4-dimethyl 3-hide mouth) 1 cis 1, 2, 6-diazabicyclo [3.3.0] octane 3, 7-dione

 5 — methoxycarbyl methyl 4 — (4, 4 — dimethyl 3 — hydroxy octylamino) _ 3 — pyrroline _ 2 — on

(8.08 g) was dissolved in ethanol, platinum oxide (800 mg) was added, and the mixture was subjected to catalytic reduction at 40 atm and 30 atm for 16 hours. After removing the catalyst by filtration through a celite, the solvent was distilled off, and the obtained oily residue was purified by silica gel carat chromatography (cro-mouth formol methanol = 20/1). The result is a colorless, oily 2- (4,4-dimethyl-3-hydroxyoctyl) -cis-1,2,6-diazabicyclo.

[3.3.0] octane-3,7-dione is obtained in 7.48 g.

PMR (CDC £ ₃ / TMS) δ: 0.82 (3H, s), 0.85 (3H, s), 0.88 (3H, t, J = 6Hz), 1.10 to 1.35 (6H, m), 1.4 to 1.9 (2H, br), 2.25 to 2.75 (4H, m ), 2.8 to 4.1 (4H, m), 4.34 (2H, m), 6.40 (1H, m)

Example 1 3 2 — (4, 4 — dimethyl-3 — hydrid octyl heptyl) 1 cis-1, 2, 6-diazabicyclo [3.3.0] octane 3, 7 — dione

 5 — METAL CARBON MELT COOL 4 — (4, 4 — DIM

3-Hydroxy-6-Heptylamino-1-3-Pyrroline-1-one (7 g) was dissolved in ethanol, and platinum oxide (700 mg) was added. Then, catalytic reduction was carried out at 50 atm for 7 hours. The catalyst was removed by filtration through celite, the solvent was distilled off, and the obtained oily residue was purified by silica gel chromatography chromatography (cross-hole form / methanol-20/1). 2-(4, 4-dimethyl-3-hydroxyheptyl) cis-1, 2, 6-diazabicyclo [3.3.0] octane-1, 3-dione 6.7 g.

 P M R (C D C £ 3 / T M S) δ:

 0.84 (9Η, m), 1.05-2.00 (6H, m), 2.52 (4H, m), 3.03 (2H, m), 3.45 (1H, m), 3.80 (1H, m), 4.33 (2H, m) , 6.70 (1H, m)

Example 1 4 2-[3-Hydroxy-141 (m-trifluoromethylenoxy) butyl] -cis-1,2,6-Diazabicyclo [3.3.0] Octane 1, Margin

 5—Methoxycarbonylmethyl 4- 1 [3—Nodoxy 1

4 — (m — Trifnorolemethylf enoxy) butylamino) 1 3 — Pyrrolin 1 2 —one (3.27 g) was dissolved in ethanol, and Platinum oxide (330 mg) was added, and catalytic reduction was performed at 60'C and 30 atm for 16 hours. The catalyst was removed by filtration through celite, and the solvent was distilled off. The oily residue was purified by silica gel gel chromatographic chromatography (formula formanol = 20/1) to give a yellow oily 2- [3-hydroxy-14- (m-trifluorometylphenoxy). [Butylamino] 1-cis-1,2,6-diazabicyclo [3.3.0] octane-1,3,7-dione 3.15 g is obtained.

P MR (CDC £ ₃ / TMS) 6:

 1.81 (2H, br), 2.55 (4H, br s), 2.9-4 (8Η, m), 6.8

~ 7.5 (4H, m)

Example 1 5 2— (4—Methyl-1 3—Hydroxyocta-6—Innyl) 1cis-1,2,6—Diazabicyclo [3.3.0] octane 1,3,7—Dione

 5—Methoxycarbylmethyl 4 -— (4-Methyl-13—Hydroxocta-6—Innylamino) -13—Pyrroline-12-one (2.Tg) in methanol solution (20 In step mi), add the methanolic hydrochloride solution and the sodium hydroxide solution at the same time while maintaining the pH 4 to 6 gradually. After stirring at room temperature for 16 hours, add triethylamine to make the mixture slightly alkaline, and extract it with chloroform. The residue obtained after ordinary treatment was purified by silica gel chromatography (chromoform formanol = 20/1) to give a light yellow oily 2- (4-methyl-3-). 1-cis-1,2,6-diazabicyclo [3.3.0] octane-3,7-dione is obtained in an amount of 0.61 g.

P MR (CDC £ ₃ / TM S) 6: 0.95 (3H, d, J = 7Hz), 1.40 to 2.35 (9H, m), 2.50 (4H, m), 2.85 (1H, m), 3.45 (1H, m), 3.70 (1H, m), 4.35 ( 2H, m), 6.10 (1H, m)

Example 1 6 2 — (4, 4 — Dimethyl 3 — Hydrate 6 — Hepturic) 1 cis 1 2, 6 — Diazabicyclo [3.3.0] octane 1 3, 7 — Zion

 5—Methoxy melamine 4— (4,4—Dimethyl 3—Hydroxy 1 6—Hepturamine) 1 3—Pyrroline 1 2—On U. 3 g To this solution, gradually add the methanol monohydrochloride solution and sodium cyanoporohydride while maintaining pH 4-6. After stirring at room temperature for 16 hours, add triethylamine to make it weakly alkaline, and extract with black hole form. Purification of the residue obtained after ordinary processing by silica gel gel chromatography (chloroform methanol = 20/1) gave a pale yellow oily 2 — (4, 4). — Dimethyl relay 3 —Nydroxic 6 —Heptenyl) 1 cis-1,2,6 —Diazabicyclo [3.3.0] octane 1,3,7 — Obtain 0.42 g of dione.

P M R (C D C £ a ZT M S) δ:

 0.86 (6Η, s), 1.15 to 2.10 (4Η, m), 2.52 (4H, m), 3.04

(1H, m), 3.45 (1H, m), 3.80 (1H, m), 4.35 (2H, m),

4.99 (1H, m), 5.70 (3H, m)

Example 17 2 — (5R, 9 — dimethyl-1 3 —hydroxyldecane) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 13, marzion

5 — MET SHIKANOREPONIRME CHIRU 4 1 (5 R, 9 — dimethyl — 3 —Hydroxy-1 8 —decenylamino) 3 —Pyrroline-1 2 —one (4.2 g) was dissolved in ethanol, and platinum oxide (400 rag) was added. The catalytic reduction was carried out at 40 atm for 60 hours. The catalyst was removed by filtration through celite, the solvent was distilled off, and the obtained oily residue was purified by silica gel chromatography with chromatograph (formula formanol ethanol = 20/1). , Yellow oily 2 — (5R, 9 — dimethyl-3 — hydroxyside) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione 4.0 g. PMR (CDC £ ₃ / TMS) 6:

_{0.87 (9H, d 5 J =} 7.5Hz), 1.00~1.95 (10Η, m), 2.53 (4H, m), 3.05 (1H, m), 3.45 (2H, m), 3.75 (1H, m), 4.36 (2H, m), 6.80 (1H, d, J = 10.5Hz)

Example 18-2— (5S, 9—dimethyl-1-3—hydroxy-1-8—decenyl) cis-1,2,6-diazabicyclo [3.3.0] octane-3,7—geo N

5 — methoxycarbonylmethyl 4 — (5S, 9 dimethyl — 3 —hydroxy 1 8 —decenylamino) 1 3 —pyrrolin 1 2 —one (2 lg) Slowly add the methanol-hydrochloric acid solution and sodium cyanoporohydride to the solution at a pH of 4-6 at the same time. After stirring at room temperature for 16 hours, add triethylamine to make the mixture slightly alkaline, and extract the form with black mouth. Purification of the residue obtained after ordinary processing by silica gel chromatography 'Chromatography (chloroform / methanol = 20/1) yielded a pale yellow oily 2- (5S, 9—dimethyl 1—hydroxide 8—decenyl) cis 1,2,6—diazabicyclo [3.3.0] octane 1 3, 7 — Obtain 0.73 g of Zion.

 P M R (C D C £ 3 / T M S) 6:

 0.90 (3H, d, J = 6Hz), 1.38 (8H, m), 1.60 (3H, s), 1.67 (3H, s), 1.97 (2H, m), 2.52 (4H, m), 3.46 (2H, m), 3.73 (1H, m), 4.36 (2H, m), 5.10 (3H, br t), 6.65 (1H, br d)

Example 1 9 2 -octyl-1,5 -dimethyl-cis -2,6 -diazabicyclo [3.3.0] octane-1,3,7 -dione

2.6 g of 60% sodium hydride is suspended in 100 mi of dimethylformamide, and 1,5-dimethyl-2-isocyanate 2,6—diazabisic mouth [3.3.0] octane-1,3,7 —Slowly add a solution of dione (10 g) in dimethylformamide at 0 ° C. After heating at 50'C for 2 hours in a nitrogen stream, octyl bromide (12 g) is gradually added dropwise at 0'C. After heating at 50 ° C for 2 hours in a stream of nitrogen, the mixture is treated in a conventional manner, and the resulting oily residue is purified by silica gel column chromatography (closed-mouth formaldehyde methanol = 20/1). And a melting point of 55 to 56, 2 -octyl-1,5 -dimethyl-2-cis-1,2,6 -diazabicyclo [3.3.0] octane-1,3,7 -dione (

4.2 g) is obtained.

 P M R (C D C £ a T M S) δ:

 0.88 (3Η, t, J = 6Hz), 1.33 (18H, m), 2.48 (4Η, m),

3.10 (2Η, m), 6.99 (1Η, br s)

Example 2 0 2 -octyl 1, 5 -dimethyl 2-, 6 -diazabicyclo [3.3.0] octane 3 -one 7 -zhong 2 —Octyl-1, 5 —Dimethyl-cis 2, 6 —Diazabicyclo [3.3.0] octane 3,7 —Dione (3.3 g) can be added to tetrahydrofuran (1550) m), add Lawesson's reagent (7.26 g) and stir at room temperature for 3 hours. The solvent was distilled off, and the obtained oily residue was purified by silica gel column chromatography (formula formanol = 30/1) to give a colorless oily 2-octyl-1,5-dimethyl. One cis-1,2,6-diazabicyclo [3.3.0] octane-13-one-17-thion (2.8 g) is obtained.

P M R (C D C £ 3 / T M S) 6:

 0.88 (3Η, m), 1.36 (18H, m), 2.40 and 2.67 (2H, 2d,

Jgera = 16.5Hz), 2.86 and 3.00 (2Η, 2d, Jgem = 18Hz),

3.10 (2Η, m), 9.08 (1Η, br s)

Example 2 1 2 — (3-Acetoxyoctyl) 1-1,5—dimethyl-2-isocyanate 2,6—diazabicyclo [3.3.0] octane-1,3,7—dione

1.3 g of 60% sodium hydride was suspended in 50 mi of dimethylformamide, and 1,5-dimethylcis-1,2,6-diazabic mouth [3.3.0] octane-13,7 —Slowly add a solution of dione (5 g) in dimethylformamide at 0 ° C. After heating at 50 • C for 2 hours in a nitrogen stream, 7 g of 3-acetoxoctyl iodide is gradually added dropwise at 0. After heating at 50 ° C for 2 hours in a nitrogen stream, the mixture was treated in a conventional manner, and the resulting oily residue was subjected to silica gel column chromatography (cloform form / methanol = 20/1). Purification yields a colorless, oily 2- (3-acetoxyoctyl) 1-1,5—dimethyluric-1,2,6—diazabicyclo [3.3.0] octane-13, 7—Get dione (2.4 g).

 P M R (C D C £ 3 T M S) δ:

 0.89 (3Η, t, J = 6Hz), 1.20-1.45 (16H, m), 2.08 (3Η, s),

2.47 (4Η, m), 2.85 to 2.95 (1Η, m), 3.70 to 3.80 (1Η, m),

4.80 (1H, m), 6.85 (1H, br s)

Example 2 2 6-Benzyl-2- (3-acetoxy-4-phenoxybutyl) -cis-2,6-diazabicyclo [3.3.0] octane-1,3,7 —Zeon

 2—Benzylcis-1,2,6—Diazabicyclo [3.3.0] octane1,3,7—Dion 1.5 g in anhydrous dimethylformamide

Dissolve in 20 and add 0.5 g of 60% sodium hydride under ice-cooling. After stirring at 40 to 50 hours for 1 hour, cool on ice and gradually add 2.5 g of 3-acetoxy-4-phenoxybutyliodide. The mixture was stirred at 30-40 ° C for 3 hours, processed in a conventional manner, and the resulting oily residue was purified by silica gel ram chromatograph (chlorophonolemanol = 20/1). Then, 6—Benziru 2— (3—Acetoxy 4—Fenoxysiptyl) 1 cis 1 2, 6—Ziabi scro (3.3.0) Octane 1 3, 7 — Geo 2.8 g.

Example 2 3 2 — (3 — acetoxin 4- 1-enoxy siptyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 13,

7 — Zion

 6—Benzyl 1 2— (3—Acetoxy 4—Fenoxybuty) 1 cis 1 2, 6—Diazabicyclo [3.3.0] Octane 1

3, 7—Dissolve 2.5 g of Zion in 50 ethanol, and add 10% ethanol. Add 250 nig of radiocarbon, 40 to 50 atm in autoclave And hydrogenate for 7 hours. The catalyst was removed by filtration through celite. Concentration of the filtrate yields 2- (3-acetoxy-4-phenoxybutyl) -cis-2,6-diazabicyclo [3.3.0] octane-13,7-dione 2. Get 1 g.

P M R (C D C £ 3 ZT M S) 6:

1.62 to 2.12 (5H, m) ₅ 2.22 to 2.65 (4H, m), 2,70 to 3.20 (1H, m), 3.42 to 3.95 (1H, m) ₅ 4.05 (2H, m), 4.30 (2H, m ), 5,09 (1H, m), 6.75-7.06 (3H, m), 7.12-7.40

 (2H, m)

Example 2 4 2— [3-acetoxy 1-4-(p-fluorophenoxy) propyl] 1 cis 1, 2,6-diazabicyclo [3.3.0] octane 1-3 -o 7-thion and 2- [3-acetoxy 4- (p-fluorophenoxy) propyl] -cis 1,2,6-diazabicyclo [3.3.0] octane 3,7—Dithion 2 — [3—Acetoxy 41 (P—Fluoroenoxy) pulp building] 1 cis 1 2,6 —Diazabicyclo [3.3.0] Octa Dissolve 3,7-dione (3.43 g) in tetrahydrofuran (50 £), add Lawesson's reagent (1.96 g), and add 3 hours at room temperature. Stir. The oily residue obtained was distilled off, and the resulting oily residue was purified by silica gel chromatography (formula formanol == 30/1) to give a colorless oily 2— [3—α 1-ethoxy-4— (p-fluorophenoxy) propyl] 1cis-1,2,6—diazabicyclo [3.3.0] octane13—one-17—thion ((a), 1.9 7 g) and 2-[3-acetoxy 1-4-(P-fluorophenoxy) propyl]-1-1, 2, 6-diazabicyclo [3.3. 0] octane-3,7-dithion ((b), 1.23 g) is obtained. PMR (CDC £ 3 / TMS) 6:

 (a) 1.75 to 2.22 (2H, m), 2.11 (3H, s), 2.63 (2 (, m), 2.80 to 3.05 (1H, m), 3.10 (2H, m), 3.5 to 4.0 (1H, m) , 4.04 (2H, m), 4.56 (2H, m), 5.10 (1H, m), 6.72-7.12 (4H, m), 8.92 (1H, br)

 (b) 1.8 to 2.7 (2H, m), 2.12 (3H, s), 3.21 (4H, m), 3.46

 (1H, m), 4.06 (2H, m), 4.1-4.9 (3H, m), 5.12 (1H, m), 6.68-7.12 (4H, m), 8.3 (1H, br)

Example 2 5 2 — (3 — acetoxy 4, 4 — dimethyl octyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane — 3 — on 1 7 —Thion and 2 — (3 —acetoxy 4,4 —dimethyloctyl) -cis-1,2,6 — diazabicyclo [3.3.0] octane-1,3,7 —dithione

2 — (3 — acetoxy 4> 4-dimethyl octyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione (2. 97 g) was dissolved in tetrahydrofuran (150 m), and Wesson's reagent (2.43 g) was added, followed by stirring at room temperature for 3 hours. The solvent was distilled off, and the resulting oily residue was purified by silica gel gel chromatography (clo-form formanol = 30/1) to give a colorless oily 2- (3 —Acetoxy 4, 4 —Dimethylooctyl) —cis 1 2> 6 — diazabicyclo [3.3.0] octane 1 3 — on 1 7 —thion ((a) , 1.69 g) and 2 — (3 — acetoxy-1,4,4 dimethyl octyl) cis — '2,6 — diazabicyclo [3.3,0] octane 1 3 , 7 — dithion ((b), 0.96 g) obtain.

 P M R (C D C £ 3 / T M S) δ:

(a) 0.87 (6H, s), 0.90 (3H, t, J = 6Hz), 1.22 (6H, br s), 1.5-2.1 (2H, m), 2.09 and 2.11 (3H, 2s), 2.62 (2H , m), 2. to 3.1 (1H, m), 3.06 (2H _S br s), 3.3 to 3.9 (1H, m), 8.82 (1H, br s)

 (b) 0.88 (9H, br s), 1.22 (6H, br s), 1.5 to 2.4 (3H, m), 2.10 and 2.13 (3H, 2s), 3.20 UH, m), 3.6 to 4.3 (1H, m ), 4.45 to 95 (3H, m), 8.64 (1H, br s)

 The following compounds are obtained by synthesizing according to Examples 1 to 19.

(26) 2 — (3 —cyclopentyl 3 —hydroxy propyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione

 P M R (C D C £ 3 / T M S) 6:

1.54 (10H, m), 2.53 (4Η, m), 2.85 (1H, m), 3.35 (2H, m), 3.90 (1H _S m), 4.35 (2H, m), 7.15 (1H, m)

 (27) 2-(3-methyl 1-3-hydroxy) 1, 2, 6-diazabicyclo [3.3.0] octane 1, 3-7

P MR (CDC £ ₃ / TMS) 6:

 0.90 (3Η, t, J = 6Hz), 1.20 (3H, s), 1.30 (8H, m), 1.65 (2H, m), 2.51 (4H, m), 3.13 (1H, m), 3.66 (1H, m), 4.36 (2H, m), 7.29 (1H, br s)

(28) 2-[2 — (1 — hydroxyoxyhexane 1 — yl) ethyl] 1cis 1, 2, 6 — diazabicyclo [3, 3.0] Octane 3, 7 — Zion

PMR (COC £ ₃ / TMS) 6:

 1.50 (10H, m), 1.66 (2H, t, J = 7Hz), 2.50 (5Η, m), 3.15 (1H, m), 3.66 (1H, m), 4.37 (2H, m), 6.95 (1H, br s)

(29) 2 — (4 —Methyl 1 3 —Hide mouth 4 —Henoki pentyl) 1 cis 1 2> 6 — Diazabicyclo [3.3.0] Octane 3, 7 — Zion

 P M R (C D C £ 3 / T M S) δ:

 1.21 (6Η, s), 1.70 (2Η, br), 2.53 (4H, m), 3.00 to 4.00 (4Η, m), 4.37 (2H, m), 6.70 (2H, br s), 6.90 to 7.40 (5H , M)

 (30) 2 — (3 — Hydroxy 3 — Phenylpropyl) 1 cis 1, 2, 6 — Diazabicyclo [3.3.0] octane 1, 3, 7-Zion

 P M R (C D C £ 3 / T M S) 6:

 1.93 (2Η, m), 2.50 (4H, m), 3.16 (1H, m), 3.40 (1H, s), 3.69 (1H, m), 4.28 (2H, br s), 4.62 (1H, rn), 7.30 (5H, br s)

 (31) 2- (4-methoxybenzyl) cis-1,2,6 — diazabicyclo [3.3.0] octane 1,3,7 — dione, melting point 161-16-164 * C

 (32) 2-benzyl-cis-1, 2, 6-diazabicyclo [3.3.0] octane-3, 7-dione

 P M R (C O C £ 2 / T M S) 6:

2,35 to 2.72 (4H, m), 3.98 (1H, d, J = 15Hz), 4.00 to 4.40 (2H, m), 5.02 (1H, d, J = 15Hz), 7.05-7.50 (5H, m)

(33) 2 — [3 — acetooxy 1 4 — (P —fluorophenoxy) butyl] 1cis 1, 2, 6 — diazabicyclo [3. 3. 0] octane 3> 7 — dione

 P M R (C D C £ 3 ZT M S) δ:

 1.55 to 2.10 (2H, m), 2.10 (3H, s), 2.22 to 2.66 (4H, m), 2 * 8 to 3.2 (1Η, m), 3.5 to 4.0 (1H, m), 4.02 (2H, m ), 4.32 (2H, m), 5.09 (1H, m), 6.46 (1H, far s), 6.72 ~

 (7.12 H, m)

 (34) 2-[3-acetooxy 1-41 (m-trifluoromethyl phenyl) butyl] cis-1, 2, 6-diazabicyclo [3.3.0] octane-1, 3, 7-dione

PMR (CDC £ ₃ / TS) δ:

 1.85 to 2.23 (2Η, m), 2.11 (3H, s), 2.25 to 2.68 UH, m), 2,7 to 3.2 (1H, m), 2.6 to 4.1 (1H, m), 4.12 (2Η, t, J = 5Hz), 4.36 (2Η, m), 5.11 (1H, m), 6.63 (1H, br s), 6.95-.55 (4H, m)

 (35) 2 — (3—acetoxy-1,4,4-dimethyoctyl) —cis-1,2,6—diazabicyclo [3.3.0] octane-1,3,7—dione

 P M R (C D C £ 3 ZT M S) 6:

1.87 (6H _S s), 1.90 (3H, t, J = 6Hz), 1.22 (6Η, m), 1.77 (2Η, m), 2.09 (3Η, s), 2.10 (3Η, s), 2.25 to 3.16 ( 5Η, m), 3.35 to 3.83 (1Η, m), 4.35 (2Η, π, 4.75 (1Η, m), 6.80 (1Η, m) (36) 2-(3-acetoxy 3-cyclopentyl) one cis-2, 6-diazabicyclo [3.3.0] octane 1, 3-7

 P R (C Ό C £ z / T M S) δ:

 1.60 (11H, m), 2.05 (3H, s), 2.45 (4Η, m), 2.82 (1H, m), 3.72 (1H, in), 4.30 (2H, m), 4.79 (1H, m), 6.33 (1H, br s)

 (37) 2 — (3 — acetoxyl 5 R, 9 — dimethyltilde nil) — cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1 3,

7 — Zion

 P M R (C D C £ 3 / T M S) δ:

 0.87 (9Η, d, J = 7Hz), 1.00 to 1.95 (10Η, m), 2.06 (3H, s), 2.50 (4H, m), 2.90 (1H, m), 3.72 (1H, m), 4, 35 (2H, m), 4.90 (1H, m), 6.58 (1H, m)

 (38) 2- (3-Acetoxy-1,4,4-dimethylheptyl)-cis-1,2,6-diazabicyclo [3.3.0] octane-1,3,7

 P M R (C D C £ a / T M S) δ:

 0.87 (6Η, s), 0.90 (3Η, m), 1.20 (6H, m), 2.08 and 2.10 (3Η, 2s), 2.47 (4H, m), 2.85 (1H, m), 3.60 (1H, m) , 4.35 (2H, m), 4.75 (1H, m), 6.20 (1H, m)

 (39) 2-(3-Acetoxy 4-Methylocta-6-Innil) -cis 1-2,6-Diazabicyclo [3.3.0] octane -3, 7 — Zion

PMR (CDC £ 3 / TMS) δ: 1.00 (3H, d ₅ J = 6Hz), 1.78 (6H, m), 3.09 (6H, m), 2.50 (4H, m), 2.89 (1H, m), 3.72 (1H, m), 4.35 (2H, m), 4.86 (1H, m), 7.00 (1H, br s)

 (40) 2-(3-acetoxy- 1-4-methyl-4-phenoxypentyl) 1-cis-1, 2, 6-diazabicyclo [3.3.0] octane-1, 3-7

PMR (CDC £ ₃ / TMS) 6:

 1.22 (6Η, s), 2.09 (2Η, m), 2.13 (3H, s), 2.46 (4H, m), 2.80 to 3.00 (1H, m), 3.72 (1H, m), 4.32 (2H, m) , 5.03 (1H, m), 6.90-7.30 (5H, m)

 (41) 2 — (3 — acetoxy 3 — phenyloctyl) 2,6 — diazabicyclo [3.3.0] octane 1, 3, 7-dione

 P M R (C D C £ 3 / T M S) δ:

 2.06 (3Η, s), 2.08 (2Η, m), 2.43 (4H, m), 2.93 (1H, m), 3.70 (1H, in), 4.26 (2H, m), 5.70 (1H, t, J = 7Hz), 7.32 (5H, br s)

 (42) 2- [2— (1-Tetrahydrovironyloxycyclohexyl-1-ethyl) ethyl] cis-1,2,6-diazabic mouth [3 * 3.0] octane-13 , 7 — Zion

 P M R (C D C £ 3 / Ί M S) <5:

 1.50 (18H, m), 2.55 (H, m), 3.50 (2H, m), 3.90 (2H, m), 4.35 (2H, m), 4.72 (1H, br s), 6.83 (1H, br s)

(43) 2 — (3 — acetoxy 3 — methyl) 1 cis — 2, 6 — diazabicyclo [3.3.0] octane 3, Ί — di One

PMR (CDC £ ₃ / TMS) 6:

 0.90 (3H, t, J = 6Hz), 1.20 (3H, s), 1.35 (8H, m), 1.66 (2H, m), 2.10 (3H, s), 2.80 (4H, m), 3.20 (1H, m), 3.70 (1H, m), 4.30 (1H, m), 4.80 (1H, m), 8.63 (1H, m)

(44) 2-(3-acetoxy-1,4 dimethylheptyl)-cis-1, 2, 6-diazabicyclo [3.3.0] octane-3-on-7-thion

 P M R (C D C £ 3 / T M S) δ:

 0.83 (9Η, m), 1.20 (4H, m), 1.75 (2H, m), 2.07 and 2.09 (3Η, 2s), 2.55 (2H, m), 2.85 (1H, m), 3.05 (2H, m) , 3.60 (1H, m), 4.55 (3H, m), 8.40 (1H, m)

 (45) 2 — (3 — acetoxy-1,4,4-dimethylheptyl) — cis-1,2,6 — diazabicyclo [3.3.0] octane-1,3,7-dithione

 P M R (C D C £ 3 / T M S) δ:

 0.87 (9Η, m), 1.23 (4H, m), 1.90 (1Η, m), 2.10 and 2.12 (3H, 2s), 2.60 (1H, m), 3.20 (4H, m), 3.40 (1H, m) , 3.85 (1H, m), 4.70 (3H, m), 8.70 (1H, m)

 (46) 2 — (3 — acetoxyl 4 — methylheptyl) 1 cis — 2, 6 — diazabicyclo [3.3.0] octane 1 3 — on 1 7 — thion

 P R (C D C £ 3 / T M S) 6:

0.87 (6H, m), 1.27 (4H, m), 1.75 (3Η, m), 2.07 (3H, s), 2.65 (2H, m), 2.90 (1H, m), 3.07 (2H, m), 3.70 (1H, m), 4.55 and 4.75 (3H, 2m), 8.74 (1H, br s)

 (47) 2 — (3 — acetoxy 4 — methylheptyl) 1cis -2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dithione

 P M R (C D C £ 3 / T M S) δ:

 0.90 (6Η, m), 1.27 (4H, m), 1.83 (3Η, m), 2.07 (3fi, s), 2.09 (2H, s), 3.20 (4H, m), 3.30 (1H, m), 4.15 (1H, m), 4.70 (3H, m), 8.20 (1H, br s)

 (48) 2 — (3 —acetoxy 5 R, 9 —dimethyldecanyl) —cis-1,2,6 —diazabicyclo [3.3.0] octane 13 —one 7 —thion

PMR (CDC £ ₃ / TM S) δ:

 0.84 (9Η, d, J = 7Hz), 0.97 to 1.92 (10Η, m), 2.04 (3H, s), 2.60 (2H, m), 3.04 (2H, m), 2.90 (1H, m), 3.67 ( 1H, m), 4.55 (2H, m), 4.90 (1H, m), 8.59 (1H, br s)

 (49) 2 — (3 — acetoxy 3 — cyclopentyl) cis — 2, 6 — diazabicyclo [3.3.0] octane 1 3 — on 1 7-thione

 P M R (C D C £ 3 / T M S) δ:

1.00 to 2.25 (11H, m), 2.06 (3H, s), 2.60 (2H, m), 2.80 (1Η, m) ₄ 3.05 (2H, m), 3.70 (1H, m), 4.53 (2H, m) , 4.80 (1H, m), 8.80 (1H, br s)

(50) 2-(3-acetoxy 4-phenoxyheptyl)-1, 2-6-diazabicyclo [3.3.0] octane 3-one-7-thion PMR (CDC £ 3 TMS) 6:

 1.6 to 2.3 (2H, m), 2.10 (3H, s), 2.56 (2H, m), 2.75 to 3.36 (3H, m), 3.4 to 4.2 (3H, m), 4.50 (2H, m), 5.10 (1H, ra), 6.70-7.10 (3H, m), 7.10-7.43 (2H, m)

 (51) 2 — (3—Acetoxy 4—Methyl octa 6—Innil) 1 cis 1 2, 6—Diazabicyclo [3.3,0] Octane 1 3— One-one 7 — Thion

 PMR (CDC £ 3 TMS) 6:

 0.96 (3H, d, J = 7Hz), 1.40 to 2.20 (5Η, m), 1.75 (3Η, t, J = 2Hz), 2.06 (3H, s), 2.62 (2H, m), 2.90 (1H, m ), 3.04 (2H, m), 3.65 (1H, m), 4.50 (2H, m), 4.82 (1H, m), 8.70 (2H, br s)

 (52) 2 — (3 — acetoxy 4-methyl pentyl) 1 cis 1 2, 6 — diazabicyclo [3.3.0] octane 1 3 — o N-1 7 — Thion

 P M R (C D C £ 3 T M S) δ:

 1.24 (6Η, s), 2.08 (2Η, m), 2.14 (3H, s), 2.50-2.70 (2Η, m), 2.80-3.10 (1Η, m), 3.08 (2Η, br d), 3.60-3.95 (1Η, m), 4.53 (2Η, m), 5.01 (1H, m), 6.90 to 7.30 (5Η, m), 8.10 (1Η, br s)

 (53) 2 — (3—Acetoxy 4—Methyl 1—4—Phenoxy pentyl) 1 cis—1,2,6—Diazabicyclo [3.3,0] Octane 1—3, 7 — dithione

 P M R (C D C £ 3 / T M S) δ:

1.25 (6Η, s), 2.10 (2Η, m), 2.13 and 2.16 (3H, 2s), 3.19 (4H, m), 3.20 to 3.60 (1H, m), 4.00 to 4.40 (1H, m) _s 4.60 (1H ₅ m), 4.76 (1H, m), 5.03 (1H, m), 6.90 to 7.30 ( 5H ₅ m), 8.05 (1H, br s)

 (54) 2 — (3 — acetoxoxy 3 _ phenyloctyl) per cis 1, 2, 6 — diazabicyclo [3.3.0) octane 3 — on 17 — thion

 P M R (C D C £ 3 / T M S) δ:

 2.10 (5Η, br s), 2.58 (2H, m), 3.02 (2Η, m), 3.72 (2H, m), 4.46 (2H, m), 5.70 (1H, m), 7.36 (4H, s), 8.30 (1H, br s)

 (55) 2 — (3 — acetoxy 1-1 -methylheptyl) 1 cis -2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione

 PMR (CDCJ ^ S / TMS) δ:

 0.87 (6Η, m), 1.23 H, m), 1.75 (3H, m), 2.07 C3H, s), 2.50 (H, m), 2.85 (1H, m), 3.70 (1H, m), 4.33 (2H , m), 4.77 (1H, m), 6.73 (1H, m)

 (56) 2 — [4-1 (4-phenoxy) 1-3-xybutyl butyl] 1 cis 1, 2, 6-diazabicyclo [3. 3 0] octane 1, 7- Zion

 (57) 2 — (-(4-methylthiophene) 1 3 —hydroxybutyl) 1 cis 1 2, 6 — diazabicyclo [3.3.0] octane 3, 7 — dione

(58) 2 — (4, 4 —dimethyl 5 —ethoxy 3 —hydroxypentyl) 1 cis 1, 6 —diazabicyclo [3.3.0] Octane one, three, seven—dione

 P M R (C D C £ 3 / T M S) 6:

 0.86 (6H, m), 1.16 (3H, t, J = 7Hz), 1.80 (2Η, m), 2.50 (4Η, m), 3.26 (2Η, s), 3.45 (3H, m), 3.75 (2H, m), 4.35 (2H, m), 6.45 (1H, br s)

 (59) 2 — (3 —hydroxy-4- 1-phenylbutyl) -cis 2, 6 — diazabicyclo [3.3.0] octane 1, 3,7-dione

 P M R (C D C £ 3 T M S) δ:

 1.75 (4Η, m), 2.50 (4H, ra), 2.75 (2Η, m), 2.95 (1H, m), 3.45 (1H, s), 3.70 (2H, m), 4.26 (2H, m), 6.63 (1H, m), 7.23 (5H, m)

 (60) 2 — (3 — hydroxy 4 1-phenylpentyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione

 P M R (C D C £ a / T M S) 6:

 1.30 (6H, m), 2.40 (5H, m), 3.50 (2Η, m), 4.05 (1H, m), 4.26 (2H, ra), 6.59 (1H, m), 7.25 (5H, br s)

 (61) 2 — (3 — hydroxy 1 4 — methyl octyl) 1, 2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7-dion

 PMR (CDC £ a / TUS) 6:

0.85 (6H, m), 1.25 (5H, m), 1.65 (4H, m), 2.51 (4Η, m), 3.95 (1H, m), 3.40 (1H, m), 3.75 (1H, m), 4.35 (2H, m), 6.30 (1H, m) (62) 2 — (3 —hydroxyl 5 — phenylpentyl) — cis 1, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione

PMRCCDC £ ₃ / TMS) δ:

1.70 (4Η, m), 2.50 (4Η, m), 2.70 (2H, HI), 3.40 (1H, m), 3.70 (2H ₅ m), 4.30 (21, m), 6.60 (1H, m), 7.21 (5H, far s)

(63) 2-[3-acetoxy 1-4 (4-chlorophenoxy) butyl] 1 -cis 1, 2, 6-diazabicyclo [3.3.0] octane 1, 7 — Zion

 (64) 2 — [3 — acetoxy 4 — (4-methyl phenyl) butyl] 1 cis 1, 2, 6 — diazabicyclo [3. 3. 0] octane 1, 7 — Zeon

 (65) 2-(3-acetoxy-4-1-butylbutyl) -cis-2,6-diazabicyclo [3.3.0] octane-1,3-7-dione

PMR (CDC jg ₃ / TMS) 6:

 1.76 (2H, η, 2.00 (3Η, s), 2.51 (4H, m), 2.88 (3H, m), 3.73 (1H, m), 4.30 (2H, m), 5.00 (1H, m), 6.70 ( lH, br s), 7.23 (5H, m)

 (66) 2 — [2 — (2, 2 —dimethyl 1, 3 — dioxolan 1 4-ethyl) ethyl] 1-cis 1, 6 — diazabicyclo [3.3.0] octane 1 3, 7 — Zion

(67) 2 — (3—Acetoxy 1—Methyl octyl) One system—2, 6—Diazabicyclo [3.3.0] Octane 1—3, 7—Zone PMR (CDC £ a / TMS) 6:

 0.85 (6H, m), 1.21 (6H, m), 1.75 (3H, m), 2.04 (3H, s), 2.45 (4H, m), 2.85 (1H, m), 3.70 (1H, m), 4.30 (2H, m), 4.75 (1H, m), 6.39 (1H, br s)

 (68) 2-(3-acetoxy 5 _ phenylpentyl)-cis 1, 6-diazabicyclo [3.3.0] octane 3> 7-gio N

 PMR (CDC £ a / TMS) 6:

 1.85 (4H, m), 2.05 (3H, s), 2.45 (6Η, m), 3.72 (2H, m), 4.30 (2H, m), 4.80 (1H, ra), 6.55 (1H, br s), 7.20

 (5H, m)

 (69) 2-[3-acetoxy 1-4 (4-chlorophenoxy) butyl] -cis-1, 2, 6-diazabicyclo [3.3.0] octane One 3 — one one 7 — thion

 (70) 2-(3-Acetoxy 5-Phenylpentyl)-1-2, 6-Diazabicyclo [3.3.0] Octane 1-3-On-7-Thio N

 P M R (C D C £ 3 / T M S) δ:

1.80 (4Η, m), 2.05 (3H, s), 2.55 (4Η, m) '3.02 (2H, m), 3.70 (2H, m) _s 4.30 (1H, m), 4.50 (1H, m), 4.80 (1H, m), 7.21 (5H, m), 8.20 (1H ₅ br s)

 (71) 2 — (3 — acetoxy 4 — phenylpentyl) — 1, 2, 6 — diazabicyclo [3.3. 0] octane 3 — on 1 7 — thion

PMR (CDC £ 3 ZT MS) δ: 1.26 (3H, d, J = 7Hz), 1.62 (2H, m), 2.10 (3H, s), 2.52 (2H, m), 2.90 (4H, m), 3.70 (1H, m), 4.15 (1H, m), 4.45 (2H, m) _s 4.98 (1H, m), 7.26 (5H, br s), 7.76 (1H, m)

 (72) 2-(3-Acetoxy 1-4-methyl) 1 cis-2, 6-diazabicyclo [3.3.0] octane 3-on 1 7-Zion

 P M R (C D C £ a / T M S) 6:

0.88 (6Η, m), 1.23 (5H, m) ₅ 1.65 (4H, m), 2.06 (3H, s), 2.56 (2H, in), 2.80 (1Η, m), 3.05 (2H, m), 3.70 (1H, m), 4.60 (3H, m), 8.05 (1H, br s)

 (73) 2 — (4,4 diethoxybutyl) cis-1,2,6-diazabicyclo [3.3.0] octane 1,3,7 —dione

P M R (C D C £ a / T M S) δ:

1.21 (6Η, t, J = 7Hz), 1.63 (4Η, br s), 2.50 (4H, m), 3.55 (6H, m), 4.36 (2H ₅ br s), 4.50 (1H, m), 7.15 ( 1H, br s)

 (74) 2 — (3 — acetoxy 4, 4 — dimethyl 5 — ethoxypentyl) 1 cis 1, 2 — 6 — diazabicyclo [3.3.0] octane 1 3, 7 — Zion

 (75) 2 — (3 — acetoxoxy 4, 4 — dimethyl-5-ethoxypentyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1 3 — on 1 7 —Thion

(76) 2 — (3—Acetoxy-1,4,4-dimethyl-5—Ethoxypentyl) cis-1,2,6—Diazabicyclo [3.3.0] Octane-1,3,7-dithione

 (77) 2 — [3—Acetoxy 1–4 (4—methyl butyl) butyl] 1 cis 1–2, 6—Diazabicyclo [3.3.0] octane 3— One-one 7 — Thion

 P M R (C D C £ 3 / T M S) δ:

 1.8 to 2.1 (2Η, m), 2.09 (3H, s), 2.27 (3H, s), 2.56 (2H, m), 2.74 to 3.15 (3Η, m), 3.80 (1Η, m), 4.02 (2Η, m), 4.50 (2Η, m), 5.05 (1Η, m), 6.77 (2H, d, J = 7Hz), 7.08 (2H, d, J = 7Hz), 8.25 (1H, m)

 (78) 2 — [3—Acetoxy 4— (4-methyl hex) butyl] 1 cis 1 2, 6—Zhabicyclo [3.3.0] Octane 3, 7 — dithione

 P M R (C D C £ a / T M S) 6:

 2.00 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 3.19 (4Η, m), 3.50 (2Η, m), 4.06 (2Η, m), 4.60 (1H, m), 4.85 (1H, m), 5.10 (1H, m), 6.82 (2H, d, J = 8Hz), 7.10 (2H, d, J = 8Hz), 8.05 (1H, m)

 (79) 2 — [3—Acetoxy 1–4 (4—Chlorophen) Petit] 1 cis 1–2, 6—Diazabicyclo [3.3.0] octane One 3, seven — dithione

 P M R (C D C £ 3 T M S) δ:

2.10 (2Η, m), 2.12 (3H, s), 3.20 (4Η, m), 3.40 (1H, in), 4.10 (2H, m), 4.30 (1H, m), 4.65 (1H, m), 4.85 (1H, m), 5.15 (1H, m), 6.87 (2H, d, J = 9 Hz), 7.27 (2H, d, J = 9 Hz), 8.35 (1H, m) (80) 2 — [3 — (1, 3 — dithiane 2 — yl) propyl) — cis 1, 6 — diazabicyclo [3.3.0] octane 1 3,

7 — Zion

P MR (CDC £ ₃ / TMS) δ:

1.76 (4Η, m), 2.06 (2H _a m), 2.50 (4H, m), 2.85 C5H, m), 3.68 (IH, m), 4.08 (1H, m), 4.36 (2H, m), 6.63 ( 1H, m)

(81) 2— C 4-(1, 3 — dithian 1 2 — yl) octyl] — cis 1, 6 — diazabicyclo [3.3.0] octane 1 3,

7 — Zion

P MR (CDC £ ₃ / TS) δ:

0.93 (3Η, t, J = 7Hz), 1.42 (4H, m), 1.76 (6Η, m), 2.06 (2Η, m), 2.50 (4Η, m), 2.85 (5H, m), 3.66 (1H ₅ m), 4.05 (1H, m), 4.30 (1H, m), 6.76 (1H, br s)

 (82) 2 — (3 — oxooctyl) 1 cis 1, 2, 6 — diazabisicro [3.3.0] octane 1 3 — on 1 7 — thion

P MR (C D C £ 3 / T M S) δ:

0.89 (3Η, t, J = 7Hz), 1.30 (6Η, m), 2.41 (2Η, t, J = 7Hz), 2.56 (2H, m), 2.83 (2H _S m), 3.10 (2H, m), 3.30 (IH, m), 3.61 (1H, m), 4.53 (2H, m), 8.41 (1H, m)

 (83) 2 — (2,4-Dimethoxybenzyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione Melting point: 185-189'C

Analyzed value: As C ₁₅ H ₁₈ N ₂ 0 ₂ S ₂

 Calculated: C; 55.88, H; 5.63, N; 8.69

Found: C; 55.80, ΗΪ 5.65, Ν; 8.17 MS: rn / z 322 (M +)

 (84) 2 — (2, 4, 6 — trimethoxybenzyl) 1 cis 1, 2, 6 — diazabisic mouth [3. 3. 0] octane 1 3, 7 — dione Melting point: 20 9 ~ 2 1 2

PMR (CDC £ ₃ ZT MS) 6:

 2.3 to 2.8 (4H, m), 3.83 (9H, s), 4.0 to 4.3 (3H, m), 4.92 (1H, d, J = 13Hz), 6.16 (2H, s)

 (85) 2 — (4-method) 1 cis 1 2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione

 P M R (C D C £ 3 / T M S) 6:

 2.48 (2H, in), 2.68 (2H, m), 3.83 (3H, s), 4.43 (2H, m), 4.85 (1H, m), 6.95 (2H, d, J = 9Hz), 7.28 (2H, m d, J = 9Hz)

(86) 2-(3 9 —Hide mouth x 4 — Phenoxybutyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] Octane 1, 3, 7 — Zion

Melting point: 1 3 7 to 1 3 8

Min folding value: as C ₁₆ H _2O N _z 0 ₄

 Calculated: C; 63.14, H; 6.62, N; 9.20

 Found: '62.62, H; 6.64, N; 9.10

P M R (C D C £ a / T M S) 6:

 1.85 (2H, m), 2.53 (4H, m), 3.50 (2Η, m), 3.93 (3H, s) 4.37 (2H, m), 6.05 (1H, br s), 6.95 (3H, m), 7.21

 (2H, m)

(87) cis 1 2, 6 — diazabicyclo [3.3.0] octane-3, 7 — dione (88) 2 — (3 — butyr) 1 cis 1 2, 6 — diazabisik mouth [3.3.0] octane 1 3, 7 — dione

 (89) 2 — (3,4 — Epoxybutyl) 1cis-1,2,6 — diazabicyclo [3.3.0] octane 1,3,7 — dione

 (90) 2 — [3 —Hide mouth 3 1 — (2 —Chenyl) propyl] 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane — 3, 7 — Zion

 (91) 2 — (3, 4 — dibutyl mouth butyl) 1cis 1 2,

6 — diazabicyclo [3.3.0] octane 3, 7 — dione

(92) 2 — [3 — acetoxy 4 — (4 — methoxyphenoxy) butyl] 1 cis 1, 2, 6-diazabicyclo [3.3.0] octane 1, 7 —Zeon

 (93) 2 — (3—acetoxy 1, 4—4 dimethyl 6—heptyl) 1 cis 1, 2,6—diazabicyclo [3.3.0] octane 3, 7 —dione

 (94) 2 — [3 —Hide mouth 4 – (3 —Chenyloxy) butyl] 1 cis 1 2, 6 — Diazabicyclo [3.3.0] Octane 1 3, 7 — Zeon

 (95) 2 — (3 —Hide mouth 4 — Tosyloxybutyl) —cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1 3,

7 — Zeon

 (96) 2 — (4 — isopropyramine 1 3 — hydroxypropyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1, 3, 7 — dione

(97) 2 — (3 — hydroxy 4 — phenylthiobutyl) — Cis 1 2> 6 — diazabicyclo [3, 3.0] octane 3, 7 — Zion

 (98) 2 — (3 — Hydroxy 1 — N—methylbipera dinobutyl) 1 cis 1, 2, 6 — Diazabicyclo [3.3.0] Octane 3, 7 — Zion

 (99) 2 — (5—Ethylthio-1 3—Hydroxy Cipentyl) 1 cis 1 2, 6 — Diazabicyclo [3.3.0] Octane 1, 3, 7 — Zion

 (100) 2 — [3 — Hydroxy 1 5 — (2 — Chenyl) pentyl] 1 cis 1 2, 6 — Diazabicyclo [3. 3. 0] Octane 1 3, 7 — Zion

 (101) 2-[3-Acetoxy- 3-(3-Fluorophenyl) propyl] 1 cis-1, 2, 6-diazabicyclo [3.3.0] octane 1 3-O N-1 7 — Thion

 (102) 2-[3-acetoxy-3-(3-fluorophenyl) propyl] -cis-1, 2-6-diazabicyclo [3.3.0] -octane-1,3 7—dithione

 (103) 2 — [3 — acetone 4 — (3 — fluorenoxy) butyl] 1 cis 1 2, 6 — diazabicyclo [3.3.0] octane 1 3 — one 7 — thion

 (104) 2 — [3 — acetoxy 4 — (3 — fluorenoxy) butyl) 1 cis 1 2> 6 — diazabicyclo [3.3.0] octane 3, 7—dithione

(105) 2 — (3 — acetoxylene 4- 1-thiothiol)-cis 1,2, 6 — diazabicyclo [3.3.0] octane 1 3 — 1 2 7

 (106) 2 — (3 —acetoxy 4-phenylthiobutyl) 1 cis-1,2,6-diazabicyclo [3.3.0] octane 1,3,7 dithione

 (107) 2— (3—Acetoxy-4-4-morpholinobutyl) -cis—26-Diazabicyclo [3.3.0] octane-1,3,7-dione

(108) 2 — (3 — acetoxoxy 1 4 — morpholinobutyl) 1 cis 2 6 — diazabicyclo [3.3.0] octane 1 3 — on 7 thion

(109) 2 — [3 —Acetoxy 4- (N-propylpyveridine-4-yl) butyl] 1 cis 1, 2,6 — diazabicyclo [3.3.0] octane 1 3 —O 7-Thion

 (110) 2— [3—Acetoxy 1—4— (N—Propyl Piberidine 1—4—yl) butyl] 1—cis 1,2,6—Diazabicyclo [3.3.0] Octane 1 3 , 7—dithione

 (111) 2— [3—acetoxy-1- (4-probicyclohexyl) butyl) -cis-1,2,6-diazabicyclo [3.3.0] octane-1,3-dione

 (112) 2 — [3 — acetoxy 4 — (4 — propylcyclohexyl) butyl] 1 cis 1 2, 6 — diazabicyclo [3.3.0] octane 3 — one 1 7 — Thion

(113) 2- (3-acetoxy-5-ethylthiopentyl) -cis-1,2,6-diazabicyclo [3.3.0] octane-3-one-7-thione (114) 2 — (3 — acetoxy-5-ethylthiopentyl) cis-1,2,6 — diazabicyclo [3.3.0] octane-1,3,7-dithione

 (115) 2 — [3—Acetoxy 1 5 — (2—Chenyl) pentyl] 1 cis 1 2, 6 — Diazabicyclo [3.3.0] octane 1 3 — On 1 7—Thion

 (116) 2 — [3 — acetoxy 3 — (3 — pyridyl) propyl] 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octane 1 3, 7 — Zion

 (117) 2-[3-acetoxy 3-(3-pyridyl) propyl]-cis-1, 2, 6-diazabicyclo [3.3.0] octane-3-on One 7 — thion

 (118) 2 — [3 — acetoxy 3 — (3 — pyridyl) propyl] 1 cis 1, 2, 6 — diazabicyclo [3. 3. 0] octane 1, 3, 7 — Dithion

 (119) 2 — [3—Acetoxy 1–4 (3—Chenyloxy) butyl] 1 cis 1 2, 6 — Diazabicyclo [3.3.0] 1 octane 1 3 — One 7—Thion

 (120) 2 — [3 — acetoxyl 4 — (3 — chenyloxy) butyl] 1 cis 1, 2, 6 — diazabicyclo [3. 3. 0] octane 3, 7 — dithione

 (121) 2-[3-acetoxy 41-(4-fluo-en) butyl-1 1, 5-dimethyl-cis 1-2, 6-diazabicyclo [3.3.0] Octane 3 — On 1 7 — Thion

(122) 2 — (3 — acetone 1,2,6-Diazabicyclo [3.3.0] octane-3,7-Dithione

 (123) 2— (3—Acetoxy 4, 4—Dimethyl 1 5—Ethoxypentyl) 1-1, 5—Dimethyl cis 1 2, 6—Diazabicyclo [3.3.0] Octane 1 3 —One-one 7 —thion

 (124) 2 — (3—Acetoxy-1,4,4-dimethyl-5—ethoxypentyl) 1-1,5—Dimethyl-1-cis 2,6—Diazabicyclo [3.3.0] Octane-1 3, 7—dithione

 (125) 2 — [3 — acetooxy 1 4 — (3 — trifluoromethylphenoxy) butyl] 1, 1, 5 — dimethyl cis 1, 2, 6 — diazabicyclo [3.3.0] octane One 3 — one one 7 — thion

(126) 2— [3—Acetoxy 1—4— (3—Trifluoromethyl phenyl) butyl] 1,5—Dimethyl—cis 1,2,6—Diazabicyclo [3.3.0] Octa 3-1, 7-dithione

 (127) 2 — (3 — acetooxy 1 — 4-methyl 4 — phenoxy pentyl) 1, 5 — dimethyl cysis 1, 2, 6 — diazabisik mouth [3.3.0] octane 1 3 — o 7-Thion

 (128) 2 — (3 — acetoxy 1-4-methyl 1-4-pentyl pentyl) 1, 5 — dimethyl cysis 1, 2, 6 — diazabisik mouth [3.3.0] octane 1, 3, 7 —Dithione

 (129) 2— (3-acetoxy—4, 4-dimethylthiononyl)

1, 5 — dimethyl cis 1, 2, 6 — diazabicyclo [3.3.0] octane 3 — on 1 7 — thion

 (130) 2— (3—Acetoxy 4, 4—Dimethylononyl)

1, 5 — dimethyl cis 1, 2, 6 — diazabicyclo [3.3.0] Octane one, three, seven — dithione

Example 1 3 1 7- (3-Ethoxycarbonylpropylthio) —2— (3—acetoxyoctyl) 1cis-1,2,6—diazabicyclo [3.3.0] octa6—ene One 3 — on

 2- (3-acetoxyoctyl) cis-1,2,6-diazabicyclo [3.3.0] octane-3-one-1 7-thione (4.24 g) was added to anhydrous dimethoxetane (2 Dissolve in 50 mi) and add 60% sodium hydride (675 mg) at 0%. To this, add ethyl 4-promobutyrate (2.4 mi) dropwise and stir at 50 ° C for 4 hours. After cooling, pour the mixture into ice water, extract with black hole form, treat in a conventional manner, and evaporate the solvent. The residual oil obtained was purified by silica gel chromatography (chromoform formanol = 50/1) to give 7- (3-ethoxycarbonylpropylthio) as a yellow oil. 2 — (3 — acetoxyoctyl) 1 cis- 1, 2, 6 — diazabicyclo [3.3.0] octa 1-6-3-on (4.74 g) is obtained.

P M R (C D C £ 3 / T M S) δ:

 0.90 (3Η, t, J = 6Hz), 1,27 (11H, ra), 1.52 (2H, m), 1.83 (2H, m), 2.07 (3H, s), 2.32 (2H, t, J = 6Hz) ), 2.70 (4H, m), 2.90 (1H, m), 3.10 (2H, t, J = 6Hz), 3.70 (1H, m), 4.15 (2H, q, J = 6Hz), 4.72 (3H, m )

Example 1 3 2 7 — (3-Methoxycarbonylpropylthio) -2- (3-hydroxyl xyoctyl) cis-1,2,6-diazabicyclo [3.3.0] octa-6—e 3-one and 7- (3-methoxycarbonylpropylthio) 1-2- (3β- (2) 6-Diazabicyclo [3.3.0] oct 6- 1 3-On

 7- (3—Ethoxycarbonylpropylthio) 1-2— (3—acetoxyoctyl) cis-1,2,6—diazabicyclo [3.3.0] octa 6—en-3—one (7 2 (0 mg) in anhydrous methanol (40 m), add potassium carbonate (100 mg), and heat to reflux for 2 hours. This is poured into ice water, salted out, and extracted with black-mouthed form. The oily residue was purified by silica gel column chromatography (chloroform formanol = 65/1), and the melting point was 50 to 52. — (3 —Methoxycarbonylpropylthio) 1 2 — (3 α-Hydroxyoctyl) 1cis 1, 2,6 — diazabicyclo [3.3.0] octa 6 — 1 3 — on (( a), 240 mg) and 7- (3-Methoxycarbonylpropylthio) -1-2- (3-hide mouth xyoctyl) -cis-1,2,6-diazabicyclo [3.3.0] octa white oil 1- 6-en-3--on ((b), 230 mg) is obtained.

(a) PMR (CDC £ 3 / TMS) δ:

0.90 (3Η, t, J = 6.0Hz), 1.35 (10Η, m), 2.00 (2H, m), 2.4 (2H, t, J = 6.0Hz), 2.75 (4H, m), 2.93 (1H , m), 3.10 (2H ₅ t, J = 7 Hz), 3.43 (2H, m), 3.70 (3H, s), 3.90 (1H _S m), 4.30 (1H, m), 4.67 UH, m)

 Melting point: 50 ~ 52'C

Min folding value: as _{C 19 H 32 N 2 0 4} S

 Calculated values: C; 59.35, H; 8.39, N; 7.29

Obtained: C; 59.10, H; 8.48, N; 7.26 MS: m / z 384 (M +), 366 (M + -H z 0)

IR (KBr): 3400, 2900, 1735, 1660, 1580 cm— ¹

(b) P R (C D C £ 3 / T M S) δ:

 0.90 (3H, t, J = 6Hz), 1.35 (10H, m), 2.00 (2H, ra),

2.43 (2H, t, J = 6Hz), 2.75 (4H, m), 3.10 (2H, t, J = 7Hz), 3.40 (4H, m), 3.70 (3H, s), 4.35 (1H, m), 4.60 (1H, m) partial folding value: as a _{C, 9 H 3 Z N 2} 0 4 S · ½H Z 0

 Calculated values: C; 57.99, H; 8.47, N; 7.14

 Obtained: C; 57.96, H; 8.48, N; 7.12

MS: m / z 384 (M +), 366 ( «+ -H 2 0)

Example 1 3 3 7 — (3-ethoxycarbonylpropylthio) -2- (3-acetoxyl-3-cyclopentylpropyl) -cis-2,6 diazabicyclo [3.3.0] ] Oct. 1-6-3-On

2-(3 Acetoxy 1-3-cyclopentinolef 'ropinole) 1-2, 2-diazabicyclo [3.3.0] octane-3-on-7-thion (2. 1) is dissolved in anhydrous dimethoxetane (120 mi), and 60% sodium hydride (350 mg) is added at 0 ° C. Ethyl 4-bromobutyrate (l.lmi) is added dropwise thereto, and the mixture is stirred at 50 and 4 hours. After cooling, the mixture is poured into ice water, extracted with chloroform, treated in a conventional manner, and the solvent is distilled off. The obtained oily residue was purified by silica gel chromatography with chromatographic chromatography (formula: 50/1) to give 7- (3-ethoxycarbonylpropyl yellow oil). Pyrthio) 1 2 — (3 — acetoxyl 1 — 3-cyclopentyl propyl) cis 1, 6 — diazabicyclo ί 3.3 0] to obtain 6-one-three-on (2.3 g).

P M R (C D C £ 3 ZT M S) 6:

 1.22 (3H, t, J = 7.5Hz), 1.20-2.20 (13H, m), 2.05 (3Η, s), 2.39 (2Η, t, J = 6Hz), 2.67 (4H, m), 2.95 ( 1H, m), 3.06 (2H, t, 6.0Hz), 3.57 (1H, m), 4.13 (2H, q, J = 7.5Hz), 4.30 (1H, m), 4.60 (1H, m), 4.80 ( 1H, m) Example 1 3 4 7 — (3-Ethoxycarbonylpropylthio) 1 2 — (3 — acetooxy 1 3 — cyclohexylpropyl) 1 cis 1 2, 6 — diazabisic π [3 . 3.0] Octa 1-3-Zion

 2-(3-acetooxy-3- 3-cyclohexyl propyl) 1, 2,6-diazabicyclo [3.3.0] octane-1,3,7-dithione (5.2 g) Dissolve in toxetane (300 m) and add 60% sodium hydride (828 mg) at O'C. To this is added dropwise ethyl 4-bromobutyrate (2.7 mi), and the mixture is stirred at 50 ° C for 4 hours. After cooling, the mixture is poured into ice water, extracted with black-mouthed form, treated in a conventional manner, and the solvent is removed. The obtained oily residue was purified by silica gel gel chromatography (chloroform Z-methanol = 50/1) to give a yellow oily 7- (3-ethoxypropylonylpropylthio) 1-2- (3-acetoxy-3-cyclohexylprovir) 1-cis-1,2,6-diazabicyclo [3.3.0] octa-6-en-3-3-thione (5.5 g) is obtained.

PMR (CDC £ ₃ / TMS) δ:

1.10 and 1.70 (15H, 2m), 1.24 (3H, t, J = 7.5Hz), 2.06 and 2.08 (3Η, 2s), 2.40 (2H, t, J = 6Hz), 2.80 3.93.90 (9H, m), 4.15 (2H, q, J = 7.5 Hz), 4.65 (2H, m) Example 1 3 5 7 — (3—methoxycarbonylpropylthio) 1 2 — (3 ” —Hydroxy 1-3 —Cyclohexyl propyl) —cis 1,2,6 —Diazabicyclo [3.3.0] Octa 6 —Gene 3 —On and 7 — (3 —Met 2- (3 iff—Hide mouth 3-3—cyclohexylpropyl) 1-cis-1,2,6-Diazabicyclo [3.3,0] octa-1 6 — 1 3 1 ON

 7 — (3 — Ethoxycarbonyl propylthio) — 2 — (3 -Acetoxyl 3 — Cyclohexyl propyl) 1 cis 1, 2, 6 — Diazabicyclo [3.3.0] Dissolve Oct-6-en-3-one (1.4 g) in anhydrous methanol (80 mi), add lithium carbonate (200 mg), and heat to reflux for 2 hours. This is poured into ice water, and after salting, it is extracted with black-mouthed holm. After the usual treatment, the solvent was distilled off, and the resulting oily residue was purified by silica gel gel chromatography (chloroform Z methanol = 65/1). 7- (3 -Methoxycarbonylpropyl) thio 2-(3α-Hydroxyl 3 -cyclohexylpropyl) 1 -cis 1,2,6 diazabicyclo [3.3.0] Octa-6—ene-1—one ((a), 450 rag) and white oily 7— (3—methoxycarbonylpropylthio) 1-2— (3 iff—hydroxy 1-3-cyclohexylprovir) 1-cis-1, 2, 6-diazabicyclo [3.3.0] octa-16-ene-3-on ((b), 44 mg) obtain.

(a) P M R (C D C £ a / T M S) δ:

1.19 and 1.73 (13H, 2m), 2.02 (2H, in), 2.46 (2H, t, J = 7.5Hz), 2.77 (4H, m), 2.95 (1H, m), 3.10 (2H, t, J = 7fiz), 3.20 (2H, m), 3.71 (3H, s), 4.30 m) ,

4.66 (1H, m)

 Melting point: 86-88'C

Analysis value: C ₂₀ H ₃₂ N ₂ (as S

 Minors: C; 60.58, H; 8.13, N; 7.06,

 Found: C; 60.37, H; 8.13, N; 6.95

MS: m / z 396 (M +), 378 (+ -H 2 0)

(b) PMR (CDC £ 3 / TMS) δ:

1.17 and 1.72 (13H, 2m), 2.02 (2H, m), 2.44 (2H, t, J = 7Hz), 2.73 (4H, m), 3.11 (2H, t, J = 6Hz), 3.35 (4H, m ), 3.69 (3H, s) , 4.36 (1H, m), 4.60 (1H, m) min圻値: C _2. As _{H 32 N 2 0 4 S ·} ½H 2 0

 Minors: C; 59.23, H; 8.20, N; 6.91

 Obtained: C; 58.75, H; 8.03, N; 6.92

MS: m / z 396 (M +), 378 (M + -H z 0)

IR (neat): 3400, 2900, 2850, 1730, 1660, 1580 cm " ¹ Example 1 3 6 7 — (3—Ethoxycarbonylpiruthio) 1-2 — (3—Acetoxy 4 —methylheptyl) One cis one, two, six — diazabicyclo [3.3.0] one octa six — three — thion

2- (3-acetoxy-1 4-methylheptyl) cis-1,2,6-diazabicyclo [3.3.0] octane-13, dithiothone (4.1 g) was treated with anhydrous dimethoxine. Dissolve in tan (250 mi) and add 60% sodium hydride (670 mg) at 0 ° C. To this was added dropwise ethyl 4-butane molybrate (2.4 mi), and at 50'C at 4 o'clock. While stirring. After cooling, this is poured into ice water, extracted with black-mouthed form, processed in a conventional manner, and the solvent is distilled off. The obtained oily residue was purified by silica gel chromatography (chromatography: 50/1) and the yellow oily 7- (3-ethoxycarbonyl) was obtained. (Rovirthio) 1 2 — (3 — Acetoxy 1 4 — Methylheptyl) — cis 1 2, 6 — Diazabicyclo [3.3.0] Octa 16 — 1 3 — Thion ( 4.6 g) is obtained.

 P M R (C D C £ 3 / T M S) δ:

 0.93 (6Η, m), 1.27 (3H, t, J = 7.5Hz), 1.30 and 1.99 (9Η, 2m), 2.09 and 2.11 (3H, 2s), 2.42 (2H, t, J = 6Hz), 2.85 ( 2H, m), 3.10 (2H, m), 3.20 (1H, m), 3.30 (2H, m), 4.15 (2H, q, J = 7.5Hz), 4.20 (1H, m),

 4.67 (3H, m)

Example 1 3 7 7- (3-Methoxycarbonylpropyl) —2— (3-hydroxy-1-4-methylheptyl) -cis-1,2,6-Diazabicyclo [3,3.0] Octa 6 — ene 1 3 — thion and 7 — (3 — methoxycarbonylpropylthio) 1 2 — (3-nitrodoxy 4 — methyl heptyl) 1 cis 1, 2 — 6 — JAZABI CYCLO [3.3.0] octor 6-3-1

7 — (3 —ethoxycarbonylpropyl) 1 2 — (3 -acetoxy 1 4 —methylheptyl) 1 cis 1 2, 6 — diazabicyclo [3.3.0] octa 1 Dissolve 6-en-3-thione (4.2 g) in anhydrous methanol (200 mi), add potassium carbonate (600 mg), and heat to reflux for 2 hours. Put this in ice water, and after salting, Extract with the black mouth Holm. After the usual treatment, the solvent was distilled off. Purification of the residue by silica gel carb chromochromatography (formula formanol methanol = 65/1) yielded 7- (3—Methoxycanolevonyl propylene) as a white oil. 1 2— (3 α-nitrodoxy 1-4-methylheptyl) 1-cis-1, 2, 6-diazabicyclo [3. 3 0] octa-6--1-3-thion ((a), 1 1) and 7- (3-Methoxycarbonylbromothio) 1-2- (3-doxydroxy-4-methylheptyl) -cis-1,2,6-diazabicyclo [3.3.0] 1-6—en1-3—zion ((b), 0.95 g) is obtained.

(a) Analysis value: C ₁₉ H ₃₂ C ₃ N ₂ S _Z * ZH ₂₀

 Calculated values: C; 55.72, H; 8.12, N; 6.84

 Found: C; 55.97, H; 8.10, N; 6.75

 M S: ra / z 400 (M +)

 P M R (C D C ZT M S) δ:

0.88 (6H, in), 1.40 (9H, m), 2.00 (2H, m), 2.43 (2H, t, J = 7Hz), 2.75 (1H, m), 2.90 (2H, m), 3.10 (2H, m t, J = 7Hz) ₅ 3.33 (4H ₅ m), 3.68 (3H, s), 4.60 (3H, m)

IR (neat): 3400, 2950, 2850, 1720, 1580 cm— ¹

() Analysis value: C ₁₉ H ₃₂ N ₂ 0 ₃ S _z · H ₂₀

 Calculated: C; 55.72, H; 8.12, N; 6.84

 Obtained: C; 55.58, H; 7.92, N; 6.59

MS: ra / z 400 (M +), 382 (M + -H 2 0)

 P MR (CDC £ 3 / TMS) δ:

0.88 (6H, m), 1.40 (9H, m), 2.02 (2H, m), 2.43 (2H, t, J = 7Hz), 2.90 (2H, m), 3.10 (2H, t, J = 7Hz), 3.33 (2H, m), 3.55 (1H, m), 3.69 (3H, s), 3.85 (1H, m), 4.10 (1H, m), 4.66 (2H, m)

IR (neat): 3400, 2950, 2850, 1720, 1580 cm " ¹

Example 13 8 7- (3-Methoxycarbonylpropylthio) 1-2- (3o-Hydroxoxyoctyl) -cis-12,6-Diazabicyclo [3.3.0] octa-6- 1-Thion and 7- (3-Methoxycarbonylpropylthio) 1-2- (3β-Hydroxyoctyl) -cis 1,2,6-Diazabicyclo [3.3.0] octa 6-en-3— Zion

 7- (3-ethoxycarbonylpropylthio) 1-2- (3-acetoxysoctyl) -cis-1,2,6-diazabicyclo [3.3.0] octa-6-en-13-thion ( 2.7 g) is dissolved in anhydrous methanol (150 m), potassium carbonate (400 rag) is added, and the mixture is heated under reflux for 2 hours. This is poured into iced water, and after salting, it is extracted with a black mouth form. The oily residue was purified by silica gel chromatography (chlorophore phenol chromatography = 65/1) to give 7- (3 —Methoxy carbonyl propylthio) 1 2 — (3 or —Hydroxyoctyl) 1cis 1, 2,6 —Diazabicyclo [3.3.0] Octa 1 6 —Oen—3 —Thion ((a), 8 90 mg) and 7- (3-Methoxycarbonylpropylthio) 1-2- (3-hydroxyl-octyl) -cis-1,2,6-diazabicyclo [3.3.0] octa-6- as a white oil 1-Thion ((b), 870 mg) is obtained.

(a) Melting point: 81-83 24 minutes Qi value: as C ₁₉ H ₃₂ N ₂ 0 ₃ S ₂

 Calculated values: C; 56.97, H; 8.11, W; 6.99

 Found: C; 56.97, H; 8.05, N; 6.99

MS: m / z 400 (Μ ⁺ ), 382 (M ⁺ -H _z 0)

PMR (CDC £ ₃ / TMS) δ:

 0.88 (3H, m), 1.30 and 1.63 (10H, 2 m), 1.99 (2H, m), 2.42 (4H, t, J = 7.5Hz), 2.88 (2H, m), 3.08 (2H, t,

 J = 6Hz), 3.20 (1H, m), 3.38 (3H, m), 3.67 (3H, s),

 4.60 (2H, m)

(b) Analysis value: C ₁₉ H ₃₂ N ₂ 0 ₃ S ₂ · H ₂ 0

 Calculated: C; 55.72, H; 8.12, N; 6.84

 Found: C; 55.25, H; 8.03, N; 6.93

MS: m / z 400 (IT ), 382 (M + - H 2 0)

PMR (CDC J2 ₃ / TMS) δ:

 0.88 (3H, m), 1.35 (10H, m), 1.99 (2H, m), 2.40 (2H, t, J = 7Hz), 2.90 (2H, m), 3.08 H, t, J = 6Hz), 3.30 (2H, m), 3.60 (1H, m), 3.67 (3H, s), 4.12 (1H, tn), 4.64 (2H, m)

IR (neat): 3400, 2900, 2850, 1730, 1580 cm " ¹

Example 13 9 7- (3-Ethoxycarbonylpropylthio) -2-octyl-1,5-dimethyl-2-isocyanate 2,6—diazabicyclo [3.3.0] octa-6—ene-1 3 — On

2 —Octyl-1, 5 —Dimethyl-1cis-2,6 —Diazabicyclo [3.3.0] octane-1 3 _one1 7 —Thion (920 mg) was added to anhydrous dimethoxetane (1 lm £) dissolved in 6% water Add sodium boriding (150 岖) with zero. To this is added dropwise ethyl 4-bromobutyrate (0.73 m), and the mixture is stirred at 80 and stirred for 2 hours. After cooling, this is poured into ice water, extracted with black-mouthed form, processed in a conventional manner, and the solvent is distilled off. The resulting oily residue was purified by silica gel chromatography (chromoform formometanol-50/1) to give 7- (3-ethoxycarbonylpropylthio) as a yellow oil. —Octyl 1, 5 —Dimethylus 1, 2, 6 —Diazabicyclo [3.3.0] Octir 6 —En 1 3 —On (1.04 g) is obtained.

Analysis value: C ₂₂ H _3B N ₂ 0 ₃ S · ½H ₂ 0

 Total value: C; 62.97, H; 9.37, N; 6.68

 Found: C; 63.48, H; 9.32, N; 6.61

M S: m / z 410 (M +)

PMR (CDC £ ₃ / TMS) 6:

 0.87 (3H, m), 1.33 (21H, ra), 2.00 (2H, m), 2.40 (2H, m), 2.70 (211, m), 3.05 (4H, m), 4.13 (2H, q, J = 6.5 Hz) Example 1 4 7 7-(3-carboxypropylthio)-2-octyl-1, 5-dimethylysis-1, 2-6-diazabicyclo [3.3.0] Oct 6-1-3-on

7 — (3 — ethoxycarbonylpropylthio) — 2 — octyl-1,5 —dimethyl-2-isocyanate 2,6 —diazabicyclo [3.3.0] octa 6 —one3 —on (1.4 g) is dissolved in acetate (24 ml) and water (15 mi), and 1N sodium hydroxide (3,84 mi) is gradually added dropwise at 0'C. After stirring at room temperature for 2 hours, the crude product is treated with 7- (3-carboxypropylthio) 12 —Octyl 1, 5 —Dimethylus 1, 6 —Diazabisik mouth [3.3.0) Octa 6 —En 1 3 —On (1.5 g) is obtained. (When recrystallized from petroleum ether, melting point 56 ~ 60'C)

Analytical value: C _2O H ₃₄ N ₂ 0 ₃ S * ½As H ₂ 0

 Calculated: C; 61.35, H; 9.01,; 7.15

 Found: C; 61.26, H; 8.94, N; 7.14

MS: m / z 382 (M +), 339

P MR (C D C £ 3 / T M S) 6:

0.86 (3H, m), 1.26 C18H, m), 2.00 (2Η, m), 2.40 (2H ₅ πθ, 2.70 (4H, m), 3.02 (4H, ra)

IR (KBr): 2900, 1720, 1630, 1590 cm " ¹

Example 1 4 1 7 —Methylthio-1 —octyl-1,5, dimethyl-1-cis 2,6 —diazabicyclo [3.3.0] octa 6 —en-3 —one

2-octyl-1,5—dimethyl-2-isocyanate 2,6—diazabicyclo [3.3.0] octane-3-one-7—thion (500 m) is dissolved in anhydrous dimethoxetane (6 m), Add 60% sodium hydride (75 nig) at O'C. To this is added dropwise methyl iodide (0.5 mi) and the mixture is stirred at 50'C for 4 hours. After cooling, the mixture is poured into iced water, extracted with black-mouthed form, processed in a conventional manner, and the solvent is distilled off. The obtained oily residue was purified by silica gel gel chromatography (chloroform Z methanol = 50/1) to give a yellow oily 7-methylthio-1-2-octyl-1,5-dimethylsis. 1, 2, 6 Jazabisik mouth [3.3.0] Obtains 6-en 3-on (90 nig). PMR (CDC £ a / TMS) δ:

 0.86 (3H, t, J = 6Hz), 1.23 (3H, s), 1.26 (12H, s), 1.30 (3H, s), 2.40 (3H, s), 2.49 (1H, d, J = 18Hz), 2.72 (2H, d, J = 10Hz), 2.79 (1H, d, J = 18Hz), 3.05 (2H, m)

Example 1 4 2 7 — (3 — Carboxypropylthio) 1 2 — (3 o —Hydroxyoctyl) 1cis 1, 2, 6 — diazabicyclo [3.3.0] oct 6 — 1 3 — on

 7 — (3 — Ethoxycarbonylpropylthio) — 2 — (3a-Hydroxyoctyl) 1cis 1, 2, 6 — Diazabicyclo [3.3.0] Octa 1 6 — 1 1 3 — On (0. 5 g) is dissolved in acetate (8 mi) and water (5 mi), and 1N sodium hydroxide (1.5 m) is gradually added dropwise at 0'C. After stirring at room temperature for 2 hours, the mixture was treated in a conventional manner to give 1- (3-carboxypropylthio) 1-2- (3a-hydroxyl-octyl) -cis-1,2,6-diazabicyclo [3.3.0] octa 6 —Year 3 —On (0.26 g) is obtained.

P M R (C D C £ 3 / T M S) 6:

 0.87 (3H, t, J = 6Hz), 1.29 (12H, m), 2.00 (2H, m), 2.44 (2H, m), 2.56 (lfl, br s), 2.80 (2H, m), 3.11 (2H , t, J = 7Hz), 3.40 (1H, m), 3.90 (1H, m), 4.34 (2H, m), 4.67 (1H, m), 7.39 (1H, br s)

Example 1 4 3 7- (3—Methoxycarbonylpropyl) 1-2— (3—Hide-mouth xyoctyllysis 1-2,6—diazabicyclo [3.3.0] octa 6—e N 3 — ON

2- (3-acetoxyoctyl) -cis-2,6-diazabicyclo-3.3.0 octane-1,3,7-dione (770 mg) It was dissolved in 28 anhydrous xylene (30 mL), and methyl-14-bromobutyrate (0.8 mL) and silver oxide (600 mg) were added, and the mixture was refluxed for 8 hours. After the usual treatment, the solvent was distilled off, and the obtained oily residue was purified by silica gel chromatography (chloroform / methanol = 30/1) to give 7- (3- —Methoxycarbonylproviroxy) 1 2 — (3—Acetoxyoctyl) 1cis 1, 2,6 —Diazabicyclo [3.3.0] octa 1 6 —En 1 3 —one (640 mg) . Then, it is dissolved in methanol (30 m), added with lithium carbonate (200 mg), and heated under reflux for 2 hours. This is poured into ice water, and after salting, it is extracted with black-mouthed form. The oily residue obtained was subjected to a conventional method and the solvent was distilled off. The obtained oily residue was purified by silica gel gel chromatography (form-form / methanol = 65/1) to give 7- (yellow oil). 3 —Methoxycarbonylpropyloxy) ― 2-(3 —Hydroxyxoctyl) 1 cis-1,2,6 —Diazabicyclo [3.3.0] octa 6 —En 1 3 —On (1 5 0 mg).

_{Analysis: C 19 H 32 N 2 0} 5 - as H ₂ 0

 Total value: C; 59.03, H; 8.87, N; 7.25

 Obtained: C; 59.69, H; 8.79, N; 7.53

M S: m / z 368 +)

 P M R (C D C £ a / T M S) 6:

 0.88 (3H, m), 1.35 (10H, m), 2.01 (2H, m), 2.40 (2H, m), 2.70 (6H, m), 3.30 (2H, m), 3.68 (3H, s), 3.95 (1H, m), 4.20 (3H, in), 4.50 (1H, m)

IR (neat): 3400, 2900, 1730, 1640 cm " ¹ Example 1 4 4 7 — (4—Methoxycarbylbiperidino) 1 2 — (3—Hydroxyoctyl) 1cis 1, 2, 6 — Diazabisicro [3.3.0] Oct 6 — 3

 a) 2-(3-acetoxoctyl) 1 cis-1, 2, 6-diazabicyclo [3.3.0] octane-3-on-7-thione (2.04 g) was added to anhydrous dimethoxetane (50. mf) and slowly added dropwise to a suspension of 60% sodium hydride (326 mg) in anhydrous dimethyloxetane (100 mi). Under ice cooling, methyl iodide (1 mi) is added dropwise, and the mixture is stirred at room temperature for 2 hours. After the usual treatment, the solvent was distilled off. The resulting oily residue was purified by silica gel column chromatography (chloroform form Z methanol = 30/1) to give a colorless oily 7-methylthio-1 2 — (3—Acetoxy) 2, 6—Diazabicyclo [3.3.0] octor 6—Yen 3—On (1.8 g) is obtained.

 PMR (CDC £ 3 3 TM S) 6:

 0.88 (3H, t, J = 6Hz), 1.27 (10Η, m), 2.07 (3H, s), 2.45 (3H, s), 2.80 UH, m), 3.65 (1H, m), 4.40 (1H, m ), 4.65 (1H, m), 4.80 (1H, m)

b) A mixture of the above methylthio form (780 mg) and 4 -ethoxycarbonylbipyridine (3 m) was heated at 150 ° C for 3 hours, and then silica gel chromatography. Purify with black mouth form Z methanol = 30/1). The obtained acetate compound (540 mg) is dissolved in methanol (600 m), potassium carbonate (300 mg) is added, and the mixture is heated under reflux for 2 hours. This is poured into iced water, salted out, and then extracted with black-mouthed form. After the usual treatment, the solvent was distilled off. The oily residue thus obtained was purified by silica gel gel chromatography (Cross mouth Holm Z methanol = 5/1) to give a colorless oily oil (4-Methoxycarbobiperidino). 2 — (3 — hydroxy octyl) 1 cis-1, 2, 6-diazabicyclo [3.3. 0] octa 1-6-1-3-one (240 mg) is obtained.

M S: m / z 393 (M +)

1 R (neat): 3400, 2900, 1720, 1650, 1600 cm- ¹

P MR (CDC £ ₃ / TM S) δ:

0.88 (3Η, m), 1.28 (10H, m), 1.70 (4H, m), 2.40 (1H, m), 2.60 (4H, m), 2.93 (2H, m), 3.40 (4H, m) _s 3.70 (3H, s), 3.90 (1H, m), 4.30 (1H, m), 4.40 (1H, m)

Example 1 4 5 7 — (4-Methoxycarbonylcyclohexane 1 1 —methylamino) 1 2 — (3 —hydroxy 3 —cyclohexylpropyl) 1cis 1, 2,6-diazabicyclo [3.3.0] octa 6—en 3—on

 7—Methyl thiol 2 — (3-Acetoxyoctyl) cis 1

2,6-diazabicyclo [3.3.0] octa 6-one-3-one (1.72 g) and 4-methoxycarbonylcyclohexane1-1-methylamino (1.1 mi) The mixture is heated at 150 ° C. for 3 hours and then purified by silica gel column chromatography (chloroform nomanol = 30/1). The obtained acetate (1.9 g) was dissolved in methanol (60 m), and potassium carbonate was dissolved.

(200 mg), and heat at 2 o'clock for reflux. This is poured into ice water, salted out, and extracted with black-mouthed form. The mixture was treated in a conventional manner, the solvent was distilled off, and the resulting pond residue was subjected to gel chromatography on a silica gel. Purification by roloformuzumethanol = 5/1) gives a melting point of 180 to 1995, 7- (4-methoxycarbonylcyclohexane-1 1-methylamino) 1-2. — (3 — Hydroxy 3 — cyclohexylprobiol) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octa 6 — en 1 3 — on (2 50) mg).

Melting point: 180-195'C (decomposition)

MS: m / z 433 (M ⁺ ), 416 (M ⁺ -0H)

IR (KBr): 3400, 2900, 1720, 1665, 1620 cm— ¹

 According to the examples of Examples 13 1 to 14 · 5, the following compounds are obtained similarly.

 (146) 7 — (3 —ethoxycarbonylpropyl) — 2 —

(3 — acetoxy 3 — cyclohexyl propyl) 1 cis 1, 2, 6 — diazabicyclo [3. 3. 0] oct 6 6 — 3 1 — on PR (CDC £ 3 TMS) δ:

1.15 and 1.70 (15H, 2m), 1.26 (3H, t, J = 7.5Hz), 2.07 (3Η, s), 2.42 (2Η, t, J = 6Hz)., 2.70 (4H, m), 2.90 (1H , m), 3.09 (2H, t, J = 6Hz), 3.55 (1H, m), 4.15 (2H, q, J = 7.5H ₂ ), 4.30 (1H, m), 4.62 (2H, m)

 (147) 7-(3 —ethoxycarbonylpropyl) — 2 — (3 —acetoxy 4, 4 dimethylheptyl) 1 cis-1 2,

6 — JAZABI CYCRO [3.3.0] octa 6 — gen 1 3 — on

P M R (C D C £ 3 T M S) δ:

0.85 (9Η, br s), 1.23 (3Η, t, J = 7.5Hz), 1.20 (6H, m), 1.90 (2H, m), 2.07 and 2.09 (3H, 2s), 2.40 (2H, t, J = 6Hz), 2.69 (4H, m), 2.80 (1H, m), 3.07 (2H, t, J = 6Hz) 3 2

3.60 (1H, m), 4.13 (2H, q, J = 7.5Hz)

 (148) 7-(3 —ethoxycarbonylpropylthio) 1 2 —

(3—acetoxyl 5R, 9—dimethyldecanyl) 1cis-1,2,6-diazabicyclo [3.3.0] octa 6—en 3—on P M R (C D C £ a / T M S) δ:

0.85 (9Η, d, J = 7Hz), 1.24 (3Η, t, J = 7.5Hz), 0.95 to 2.15 (15H, m), 2.03 (3H, in), 2.40 (2H, t, J = 6Hz) ), 2.67 (4H, m), 2.90 (1H, m), 3.07 (2H, t, J = 6Hz), 3.65 (lfl, ra), 4.13 (2H, q, J = 7.5Hz), 4.30 (1H, 'm), 4.60 (1H, m), 4.90 (1H ₅ m)

 (149) 7- (3-ethoxycarbonylpropylthio) 1 2 — (3—acetoxy 4 —methylheptyl) 1 cis 1 2, 6 — diazabicyclo [3.3.0] octa 1 6 — 3-ON

 P MR (C D C £ a ZTM S) 6:

0.86 (6H, m), 1.26 (3H, t, J = 7.5Hz), 1.26 and 1.75 (9Η, 2m), 2.07 (31, s), 2.41 (2H, t, J = 6Hz), 2.70 (4H, m), 2.90 (1H, m), 3.08 (2H, t, J = 6Hz), 3.65 (1H, m) ₅ 4.14 (2H, q, J = 7.5Hz), 4.33 (1H, m), 4.65 (2H _S m)

(150) 7-(3 -Ethoxycarbonylpropylthio) — 2 — (3 —Acetoxy 4, 4 dimetyloctyl) 1 cis 1 2,

6 — Jazabicyclo [3.3.0] octor 6 — Energy 3 — On Value: C ₂₄ H ₄ . As _{N 2 0 5 S · ½H 2} 0

 Min: C: 61.51, H: 8.60, N: 5.98

 Measured value: C: 59.99, H: 8.38, N: 5.82

MS: ni / z 468 (M +) PMR (CDC ZT MS) δ:

 0.86 (6H, s), 0.90 (3H, t, J = 6Hz), 1.22 (6H, br s), 1.25 (3H, t, J = 7.5Hz), 1.5 to 2.2 (4H, m), 2.08 and 2.10 (3H, 2s), 2.41 (2H, t, J = 7Hz), 2.70 (4H, m), 2.9 (1H, m), 3.07 (2H, t, J = 7Hz), 3.56 (1H, m), 4.02 ~ 4.86 (5H, m)

 (151) 7 — (3 —ethoxycarbonylpropyl) 1 2 — (3 —acetoxy 3 —cyclopentylpropyl) 1 cis 1,

6 — Jazabicyclo [3.3.0] octa 1 6 — gen 1 3 — zhong

 PMR (CDC £ 3 TMS) 6:

 1.24 (3H, t, J = 7.5Hz), 1.220 (13H, m), 2.06 and 2.08 (3Η, 2s), 2.40 (2H, t, J = 6Hz), 2.83 (2H, m ), 3.07 (2H, t, J = 6Hz), 3.20 (1H, m), 3.26 (2H, m), 4.13 (2H, q, J = 7.5Hz), 4.20 (1H, m), 4.64 (2H, m), 4.80 (1H, nt)

(152) 7- (3-Methoxycarbonylpropyl) _2 — (3-acetoxy4,4-dimethylheptyl) cis-12,6-diazabicyclo [3.3.0] O pin definition one 6 - E down one 3 - thio emissions analysis: as _{C 22 H 36 N 2 0 5} S · ½H 2 0

 Calculated values: C: 58.77, H: 8.29, N: 6.23

 Measured value: C: 58.71, H: 8.25, N: 6.00

MS: m / z 440 (M +)

P M R (C D C £ 3 / T M S) 6:

0.84 (9H, m), 1.20 and 1.78 (6H, 2m), 2.02 (2H, m), 2.07 and 2.08 (3H, 2s), 2.42 (2H, t, J = 7Hz), 2.58 (4H, m), 3.00 (1H, m), 3.07 (2H, t, J = 7Hz), 3.60 (1H, m ), 3.66 (3H, s), 4.34 (1H, m), 4.70 (2H, m)

IR (neat): 2950, 2850, 1720, 1680, 1580 cm— ¹

(153) 7- (3—Methoxycarbonylpropylthio) 1-2— (3-acetoxy1,4,4-dimethyloctyl) cis-1,2,6—diazabicyclo [3.3.0] octa-6 — 1 3 — ON Analysis: C ₂₃ H ₃₈ N _z 0 ₅ S · ¼H ₂₀

 Min: C: 60.17, H: 8.45, N: 6.10

 Obtained values: C: 59.91, H: 8.30, N: 5.98

MS: m / z 455 (Μ ⁺ +1), 454 (M +), 411 (M ⁺ -Ac)

P M R (C D C £ 3 / TM S) δ:

0.86 (6H, s), 0.90 (3H, t, J = 6Hz), 1.22 (6H, br s), 1.5 to 2.2 (4H, m), 2.42 and 2.09 (3H, 2s), 2.43 (2H _: t, J = 7Hz), 2.70 (4H, m), 2.9 (1H, m), 3.08 (2H, t, J = 7Hz), 3.32 to 3.77 (1H, m), 3.67 (3H, s), 4.13 to 4.87 ( 3H, m)

 (154) 7 — (3 — ethoxycarbonylpropylthio) 1 2 — (3 — acetoxoxy 1 — 4-methyl-2- 1) — cis

— 2, 6 — Jahabicyclo [3.3.0] 1-6 — 1 3 1 ON

 P M R (C D C £ 3 / T M S) S:

0.97 (3H, d, J = 7Hz), 1.23 (3Η, t, J = 7Hz), 1.75 (3H, t J = 2Hz), 1.97 (7H, m), 2.05 (3H, s), 2.40 (2fl, t, J = 7Hz), 2.73 (4H, m), 3.06 (2H, t r J = 7Hz), 3.60 (2H, m), 4.12 (2H, q, J = 7Hz), 4.33 (1H, m), 4.60 (1H, m), 4.85 (1H, m)

 (155) 7 — (3 —ethoxycarbonylpropylthio) — 2 — (3 —acetoxy — 3 —phenylpropyl) -cis-1,2,6-diazabicyclo [3.3.0] Oct. 1 — 3 — On

P M R (C D C £ a / T M S) 6:

 1.23 (3H, t, J = 7Hz), 1.66 (2Η, m), 2.00 (2H, m), 2.07 (3H, s), 2.40 (2H, t, J = 7Hz), 2.70 (4H, m), 3.07 (2H, t, J = 7Hz), 3.68 (2H, m), 4.12 (2H, q, J = 7Hz), 4.25 (1H, ra), 4.57 (1H, br s), 5.71 (1H, t, J = 7Hz), 7.35 (5H, m)

 (156) 7- (3-Ethoxycarbonyl propylthio) — 2 — (3—Acetoxy 4 —Methyl-4 4-phenoxypentyl) 1 cis-1 2,6 —Diazabicyclo [3. 3.0] Octa 1 6 — En 1 3 — On

PMR (CDC £ ₃ TMS) δ:

1.22 (6Η, s), 1.23 (3Η, t, J = 7H ₂ ), 2.06 (4Η, m), 2.13 (3H, s), 2.40 (2H, t, J = 7Hz), 2.77 (5H, m) , 3.08 (2H, t, J = 7Hz), 3.50-3.90 (1H, m), 4.13 (2H, q, J = 7Hz), 4.32 (1H, m), 4.61 (1H, m), 5.01 (1H, m), 7.00 (2H, m), 7.25 (3H, m)

(157) 7- (3-Ethoxycarbonylpropylthio) 1-2- (3-acetoxy4-methyl-4-phenoxypentyl) -cis-12,6-diazabicyclo [3. 3.0] Octa 1-6 — ene 1 3 — Thion PR (CDC £ 3 / TM S) 5:

1.25 (6H, s), 1.25 (3H, t, J = 7Hz), 1.90~2.10 (2H, m), 2.03 (3H 5 s), 2.15 (2H, m), 2.40 (2H, t, J = 7Hz ), 2.82 (2H, br s ), 3.07 (2H, t, J = 7Hz) 5 3.28 (2H, br s), 3.90~4.40 (2H, m), 4.13 (2H, q s J = 7Hz), 4.64 (2H, br), 5.05 (1H, m), 7.02 (2H, m), 7.34 (3H, m)

 (158) 7- (3-Ethoxycarbonylpropylthio) 1-2- (3-acetoxy-4-phenoxybutyl) cis-1,2,6-Diazabicyclo [3.3.0] octa-1 6 — 1 3 — Thion

(159) 7- (3-Ethoxycarbonylpropylthio) 1-2- (3-acetoxy-14-phenylbutyl) cis-1,2,6-Diazabicyclo [3.3.0] octa-1 6 — 1 3 — Thion

(160) 7 — (3 —ethoxycarbonylpropyl) 1 2 — [3 —acetoxy 1 4 1-(P —fluorophenoxy) butyl]

— Cis-1 2, 6 — diazabicyclo [3.3.0] octa 6 — ene 1 3 — thion

 P M R (C D C £ 3 / TM S) 6:

1.24 (3H, t, J = 7Hz), 1.8~2.2 (4H 5 m), 2.06 (3H, s), 2.40 (2H, t-like, J = 6Hz), 2.5~3.0 (5H, ra), 3.07 (2H, t, J = 7Hz) ₅ 3.7 to 4.1 (3H, m), 4.12 (2H, q, J = 7Hz), 4.35 (1H, m), 4.60 (1H, m), 5.08 (1H, m) , 6.7 to 7.1 (4H, m)

 (161) 7- (3—Methoxycarbonylpropyl) 1 2— (5R, 9—Dimethyl-1 3α—Hydroxide)

— 2, 6 — Jabi sichiro [3.3.0] octor 6 — 3 One on

Min folding Value: C ₂₃ H _4. N _z 0 ₄ S · H _Z 0

 Calculated values: C; 61.44, H; 9.19, N; 6.23

 Found: C; 61.76, H; 9.11, N; 6.25

MS: m / z 440 (M +), 422 (M ⁺ -H _z 0)

 Ρ Μ R (C D C £ 3 / Τ Μ S) δ:

 0.86 (9Η, m), 1.20 and 1.55 (12H, 2m), 2.03 (2H, m), 2.42 (2H, t, J = 7Hz), 2.72 (4H, m), 2.95 (1H, m), 3.08 ( 2H, t, J = 7Hz), 3.33 (2H, m), 3.67 (3H, m), 3.83 (1H, m), 4.27 (1H, m), 4.64 (lfi, m)

IR (neat): 3400, 2950, 2850, 1730, 1660, 1580 cm- ¹ (162) 7- (3-methoxycarbonylpropyl) 1 2 — (5 R, 9 —dimethyl 39-high 1 cis — 2, 6 — diazabicyclo [3.3.0] octa 1 6 — en 1 3 1 on

As _{C 23 H 40 N 2 0 4} S · H 2 0: analysis

 Calculated values: C; 60.23, H; 9.22, N; 6.11

 Obtained: C; 59.96, H; 8.90, N; 6.24

MS: m / z 440 (M +), 422 (M + -H 2 0)

 Ρ R (C D C £ 3 ZT M S) δ:

0.85 (9Η, m), 1.20 and 1.55 (12H, 2m), 2.01 (2H, m), 2.41 (2H, t, J = 7Hz), 2.73 (4H, m), 3.08 (2H, t, J = 7Hz) ), 3.38 (2H, m), 3.56 (1H, ra), 3.68 (3H, s), 4.30 (1H, m), 4.55 (1H ₅ m)

IR (neat): 3400, 2900, 2850, 1730, 1660, 1580 cm " ¹ 3 8

(163) 7- (3—Methoxycarbonylpropylthio) 1 2 — (3—cyclopentinole 1 3ατ—Hydroxycypropyr) 1cis 1,2,6—Diazabicyclo [3.3.0] 6 — 1 3 1 ON

Melting point: 8 1 ~ 8 2 ΐ

Min folding value: as _{C 19 H 3 O N 2 0} 4 S

 Calculated values: C; 59.50, H 7.88, N; 7.30

 Found: C; 59.44, H; 7.92 ,; 7.26

MS: m / z 382 +) , 364 (M + -H 2 0)

PMR (CDC £ ₃ / TMS) 6:

1.50 (11H, m), 2.02 (2H, m), 2.41 (2H, t, J = 7Hz), 2.71 (4H 3 m), 2.90 m), 3.07 (2H, t s J = 7Hz), 3.34

(1H, ra), 3.66 (3H, s), 3.85 (1H, m), 4.26 (1H, m), 4.60 (1H, ra)

 (164) 7-(3 -Methoxycarbonylprovirthio) 1 2 — (3 or—N-hydroxy 4 -Methylheptyl) 1 cis 1 2, 6

- Jiazapishiku b [3 3 0..] O pin definition one 6 - E down one 3 - one minute folding values: the set to _{C 19 H 32 (N 2 S} · ½H 2 0

 Calculated: C 57.99, H; 8.45, N; 7.12

 Found: C; 58.18, Hi 8.39, N; 7.17

MS: m / z 384 (M +), 366 (M ⁺ -H _z 0)

 Ρ Μ R (C D C / Τ Μ S) δ ι

0.85 (6Η, m), 1.40 (9Η, m), 2.00 (2Η, m), 2.40 (2Η, t, J = 7Hz), 2.72 (4Η, m), 3.10 (5Η, m), 3.68 (3H, s), 3.85 (1H, m), 4.28 (1H, m), 4.63 (1H, m) IR (neat): 3400, 2950, 2850, 1730, 1660, 1580 cm— '

(165) 7 — (3 —methoxycarbonylpropyl) 1 2 — (3 α-hydroxy-4,4-dimethylhexyl) cis-1

2> 6 — Jazabicyclo [3. 3. 0] 1-6-1-3

Melting point: 82-94

ANALYSIS: The as the _{C 20 H 34 N z 0 4} S

 Calculated values: C; 60.27, H; 8.60, N; 6.95

MS: m / z 398 (M +), 380 (+ -H z 0)

 Ρ Μ R (C D C £ 3 / Τ Μ S) δ:

 0.85 (9Η, m), 1.23 (6Η, m), 2.03 (2Η, m), 2.42 (2Η, t, J = 7Hz), 2.73 (4H, m), 3.09 (2H, m), 3.10 (2H, t, J = 7Hz), 3.68 (3H, s), 3.90 (1H, m), 4.30 (1H, m), 4.64 (1H, m)

 (166) 7- (3-Methoxycarbonylpropylthio) 1 2 — (3 / 9—Hide mouth 4,4,4-dimethylheptyl) 1cis

2, 6-diaza bicyclo [3. 3. 0] 1-6-1-3

Min folding values: the set to _{C 2 o H 34 N 2 0} 4 S · H 2 0

 Calculated values: C; 57.67, H; 8.71, N; 6.72

 Obtained: C; 57.99, H; 8.47, N; 6.82

M S: m / z 398 (M +)

PMR (CDC / TMS) δ:

0.84 (9Η, m), 1.32 and 1.50 (6H, 2m), 2.02 (2H, m), 2.43 (2H, t, J = 7Hz), 2.74 (4H, m), 3.10 (2H, t, J = 7Hz ), 3.35 (4H, m), 3.69 (3H, s), 4.35 (1H, m), 4.60 (1H, m) IR (neat): 3400, 2950, 2850, 1730, 1650, 1580 cnr ¹

(167) 7- (3—Ethoxycarbonylpyrthio) 1 2 — (3α-Hydroxyoctyl) 1 cis 1 2, 6 — Diazabicyclo [3.3.0] Octa 1 6 —En 1 3 —On

Analysis value: C _z . H ₃₄ Ii ₂ 0 ₄ as S · ½Η ₂ 0

 Calculated: C; 58.93, Η; 8.66, Ν; 6.87

 Obtained: C; 58.41, Η; 8.54, Ν; 6.73

MS: ra / z 398 (M +), 380 (M + - H 2 0)

PMR (CDC £ ₃ / TMS) 6:

0.88 (3H, ra), 1.30 (13H, m), 2.0 (2H, m), 2.41 (2H, t, J-6Hz), 2.75 (4H, m), 2.92 (1H, m), 3.09 (2H, t, J = 7Hz), 3.38 (2H _S m), 3.76 (1H, m), 4.14 (2H, q, J = 7Hz), 4.28 (1H, in) ₃ 4.65 (1H, m)

 (168) 7 — (3 —ethoxycarbonylpropylthio) 1 2 — (3 / 5—hide mouth xyoctyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octa 1 6 — ene 3 — on

Analysis value: C _z . H ₃₄ N ₂ 0 ₄ S '½ as H ₂ 0

 Calculated values: C; 58.93, H; 8.66, N; 6.87

 Found: C; 58.61, H; 8.58, N; 6.80

MS: m / z 398 (M +), 380 (M * -H 2 0)

 P M R (C D C £ 3 / T M S) δ:

0.88 (3H, m), 1.25 (13H, m), 2.01 (2H, m), 2.40 (2H, t, J-7Hz), 2.72 (4H, m), 3.10 (2H, t, J = 7Hz), 3.36 (, tn), 4.13 (2H, q, J = 7Hz), 4.33 (1H, m), 4.60 (1H, ra)

 (169) 7- (3—Methoxycarbonylpropylthio) -1-2— (5S, 9-dimethyl-13-α-Hide mouth xidedinyl) -cis

— 2, 6 — Jahabicyclo [3.3.0] octor 6 — No. 3

Minute value: C ₂₃ H _{4 O} N ₂ 0 ₄ S · Η ₂₀

 Calculated: C; 61.43, Η; 9.19, Ν; 6,23

 Found: C; 61.39, Η; 9.11, Ν; 6.16

MS: m / z 440 (M +), 422 (M + -H 2 0)

PMR (CDC £ ₃ TMS) δ:

 0.86 (9H, m), 1.20 and 1.55 (12H, 2m), 2.03 (2H, m), 2.42 (2H, t, J = 7Hz), 2.72 (4H, m), 2.92 (1H, m), 3.08 ( 2H, t, J = 7Hz), 3.33 (2H, m), 3.66 (3H, s), 3.83 (1H, m), 4.30 (1H, m), 4.64 (1H, m)

 (170) 7 — (3-methoxycarbonylpropyl) 1 2 — [3ι5-hydroxyl-butyl (m-trifluorophenoxy) butyl) 1-cis 1, 2, 6-diazabicyclo [3. 3.0] Octa 1 6 — 3 — On

 P M R (C D C £ 3 / T M S) 6:

 1.5 to 2.2 (4H, m), 2.42 (2H, t-like, J = 7Hz), 2.77 (4Η, m), 3.10 (2Η, t, J = 7Hz), 3.47 (2H, m), 3.67 (3H , s), 3.77 to 4.15 (4H, m), 4.40 (lfl, m), 4.62 (1H, m), 7.0 to 7.55 (4H, m)

(171) 7- (3—Methoxycarbonylpropylthio) 1 2 — (4,4 1-dimethyl-3 1-hide mouth xyloctyl) 2, 6 — Jabi sikkuro [3.3.0] oct 6 — 3 3 —

Analytical value: C ₂₁ H ₃₆ N ₂ 0 ₄ S · ¼H ₂₀

 Calculated: C; 60.47, H; 8.82,; 6.72

 Found: C; 60.44, H; 8.78, N; 6.69

MS: m / z 413 (M + + l),

PMR (CDC £ ₃ · / TMS) δ:

 0.83 and 0.86 (3H, 2s), 0.90 (3H, t, J = 6Hz), 1.24 (6H, br s), 1.57 (2H, m), 2.00 (2H, m), 2.43 (2H, t-like, J = 7Hz), 2.74 (4H, m), 2.92-- 3.30 (2H, m), 3.10 (2H, t, J = 7Hz), 3.41 (2H, t, J = 7Hz), 4.36 (1H, m), 4.61 (1H, m)

(172) 7 — (3 —Methoxycarbonylpropylthio) 1 2 — (3α-hydroxy-14-phenoxybutyl) 1cis 1, 2,6 — diazabicyclo [3.3.0] octa 6 — 3 ON Minute value: C ₂₁ H ₂₈ N ₂ 0 ₅ S · Η ₂

 Calculated: C; 57.52, Η; 6.89, Ν; 6.39

 Found: C; 57.52, Η; 7.13, Ν; 6.22

MS: m / z 420 (M ⁺ )

PMR (CDC £ ₃ / TMS) δ:

 1.45 to 2.25 (4H, m), 2.43 (2H, t, J = 7Hz), 2.75 (4H, in), 3.09 (3H, m), 3.42 (1H, m), 3.68 (311, s), 3.6 to 4.1 (4H, m), 4.33 (IK, m), 4.62 (1H, m), 6.95 (3H, t, J = 7.5Hz), 7.29 (2H, t, J = 7.5Hz)

(173) 7 — (3-Methoxycarbonylpropylthio) one 2 — (5 S, 9 — dimethyl 1 3 5 — hydridone) 1 cis — 2, 6 — diazabicyclo [3. 3. 0] 6 1 — 3 — on

Min folding value: as _{C 23 H 40 N 2 0 4} S · Η 2 0

 Calculated: C; 60.23, Η; 9.22, Ν; 6.11

 Found: C; 60.66, Η; 9.04, Ν; 6.06

MS: m / z 440 (M +), 422 (M + -H 2 0)

PR (CDC £ ₃ / TMS) δ:

0.85 (9H ₅ in), 1.20 and 1.62 (12H, 2m), 2.02 (2H, m), 2.41 (2H, t, J = 7Hz), 2.76 (4H, m), 3.07 (2H, t, J = 7Hz) ), 3.35 (2H, m), 3.56 (1H, m), 3.67 (3H, s), 4.33 (1H, m), 4.58 (1H, m)

 (174) 7- (3-Methoxycarbonylpropylthio) 1-2-(, 4-Dimethyl-3ατ-Hide-mouth Xyloctinole) cis-1,2,6-Diazabicyclo [3.3.0] octa-1 6 — 1 3

Melting point: 65-66 * C (crystallized from hexane-ethyl ether-ethyl acetate)

Min folding value: as _{C 21 H 36 N 2 0 4} S

 Calculated: C; 61.13, H; 8.79, N; 6.79

 Obtained: C; 60.81, H; 8.80, N; 6.72

M S: m / z 412 (M +)

P M R (C Ό C £ 2 / T M S) 6:

0.82 and 0.86 (3H, 2s), 0.90 (3H, t, J = 6Hz), 1.23 (6H, br s), 1.54 (2H, m), 2.00 (2H, m), 2.42 (2H, t-like, J = 7Bz), 2.77 (4H, m), 2.8-3.3 (1H, m), 3.09 (2H, t, J = 7Hz), 3.68 (3H, s), 3.7-4.1 (1H, m) ), 4.28 (1H, m), 4.65 (1H, m)

 (175) 7 — (3 —Methoxycarbonylpropylthio) 1 2 — [3 or—N-doxyloxy 4- (m-trifluorophenoxy) butyl] 1-cis 1,2,6-Diazabicyclo [3.3 . 0] Okta

— 6 — One 3 — On

 P M R (C D C £ a / T M S) 6 I

 1.5 to 2.2 (4Η, m), 2.44 (2H, t, J = 7Hz), 2.77 (4Η, m), 3.10 (3Η, m), 3.69 (3Η, s), 3.73 to 16 (5Η, ra), 4.35 (1H, m), 4.64 (1H, m), 6.9 & ~ 7.52 (4H, m)

(176) 7- (3-Methoxycarbonylpropylthio) -1-2- (3-hydroxy-4-phenoxybutyl) -cis-1,2,6-diazabicyclo [3.3.0] octa-6-ene-3—one Analysis value: C ₂₁ H ₂₈ N ₂ 0 ₅ S · H ₂ 0

 Calculated values: C; 57.52, H; 6.89, N; 6.39

 Found: C; 57.06, H; 6.72, N; 6.30

MS: m / z 421 (M ++ 1), 02 (M + - H 2 0)

P M R (C D C £ a / T M S) 6:

1.53 to 2.20 (4H, m), 2.44 (2H, t, J = 7Hz), 2.76 (4H, m), 3.10 (2H, t, J = 7Hz), 3.3 to 3.6 (3H, m), 3.69 (3H , s), 3.95 (3H, m) ₅ 4.40 (1H, m), 4.60 (1H, m), 6.96 (3H, t, J = 8Hz), 7.30 (2H, m)

(177) 7 — (3 — methoxycarbonylpropylthio) 1 2 — [3 or — hydroxy 14 1 (p-fluorophenoxy) 1 cis 1, 2, 6-diazabicyclo [3.3.0] octa 1 6 3-on

Melting point: 9 9 'C

Min folding values: the set to _{C Z 1 H 27 FN 2 0} 5 S

 Calculated values: C; 57.52, H; 6.21, N; 6.39

 Obtained: C; 57.43, H; 6.41, N; 6.28

MS: m / z 439 (M + + 1), 20 (M + -H 2 0)

 P M R (C D C £ 3 / T M S) δ:

 1.4 to 2.2 (4H, m), 2.45 (2H, t, J = 7Hz), 2.78 (4H, m), 3.11 (3H, m), 3.69 (3H, s), 3.7 to 4.1 (5H, m), 4.35 (1H, m), 4.66 (1H, m), 6.93 (4H, m)

(178) 7 — (3 —Methoxycarbonylpropyl) 1 2 — [35—Hydroxy 14 — (p-fluorophenoxy) butyl] 1cis 1,2,6 — diazabicyclo [3.3 . 0] 1 6 3-ON

Melting point 8 2 to 8 2.5

Analysis: as _{C Z 1 H 27 FN 2 0} 5 S

 Calculated values: C; 57.52, H; 6.21, N; 6.39

 Obtained: C; 57.43, H; 6.41, N; 6.28

MS: m / z 439 (M + + 1), 20 (M + -H 2 0)

P M R (C D C £ a T M S) δ:

1.6 ~ 2.1 (4H, m), 2.42 (2H, t, J = 7Hz), 2.75 (4H, m), 3.09 (2H, t, J = 7Hz), 3.35 ~ 3.63 (3H, m), 3.66 (3H , s), 3.92 (3H, br s), 4.37 (1H, m), 4.60 (1H, m), 6.90 (4H, m) (179) Ί — (3—ethoxycarbonylpropylthio) one 2 —

(3—high.droxy-1—4-phenoxybutyl) 1cis-1,2,6-diazabicyclo [3.3.0.] Octa6—en3—on Refraction: C ₂₂ H ₃ . FN ₂ 0 ₅ as S · Η ₂ 0

 Minors: C; 58.39, Η; 7.13, Ν; 6.19

 Found: C; 58.05, Η; 7.01, Ν; 6.24

MS: m / z 435 (Μ ⁺ +1), 16 (M ⁺ -H ₂₀ )

PMR (CDC £ ₃ ZT MS) 5:

1.25 (3Η, t, J = 7Hz), 1.5 to 2.2 (4H _S m), 2.42 (2H, t, J = 7Hz), 2.75 (4H, m), 3.09H, t, J = 7Hz, 3.2 to 4.0 (6H, m), 4 * 13 (2H, q, J = 7Hz), 4.38 (1H, m), 4.62 (1H, m), 6.95 (3H, m), 7.29 (2H, m)

 (180) 7-(3 -Methoxycarbonylprovirthio) 1 2 — (4 -Methyl-3 α-hydroxylocta 6 -innyl) 1 cis-1, 2, 6-diazabisic π [3. 3. —Yen 1 3 —On

PMR (CDC ₃ TMS) 6:

0.96 (3H, d, J = 7Hz), 1.35-2.30 (8Η, m), 1.74 (3H, t, J = 2Hz), 2.40 (2H, t, J = 7Hz) ₎ 2.72 (4H, m) , 2.93 (1H, m), 3.06 (2H, t, J = 7Hz), 3.35 (1H, m), 3.65 (3H, s), 3.83 (1H, m), 4.28 (1H, nr), 4.61 (1H , m)

(181) 7- (3-Methoxycarbonylpropylthio) 1-2- (4-methyl-3- / S-hydroxy-6-innyl) -cis-12,6-diazabicyclo [3.3.0] Doctor 6 — 1 3 — On 1

P M R (C D C £ a / T M S) 6:

0.97 (3H, d, J = 7Hz), 1.40 to 2.29 (8H, m), 1.78 (3H ₁ t, J = 2Hz), 2.42 (2H, t, J = 7Hz), 2.73 (4H, m), 3.09 (2H, t, J = 7Hz), 3.40 (3H, ra), 3.70 (3H, s), 4.33 (1H, m), 4.60 (1H, m)

 (182) 7 — (3 —methoxycarbonylprovirthio) 1 2 — (3 1 hydroxy 1 5 — phenylpentyl) 1 cis 1 2,

6 - Jiazabishiku b [.. 3 3 0] O pin definition one 6 - E down one 3 - on- min圻値: the set to _{C 22 H 3O N 2 0 4} S · ¼H 2 0

 Calculated values: C; 62.46, H; 7.27, N; 6.62

 Found: C; 62.60, H; 7.42, N; 6.46

MS: m / z 418 (M ⁺ )

 P M R (C D C £ 3 / T M S) 6:

 1.65 (9H, m), 1.99 (2H, m), 2.41 (2H, t, J = 7Hz), 2.73 (5H, m), 3.07 (2H, t, J = 7Hz), 3.35 (1H, m), 3.66 (3H, s), 3.88 (1H, m), 4.18 (1H, m), 4.57 (1H, m), 7.20 (5H, m)

 (183) 7- (3—Methoxycarbonylprovirthio) 1 2 — (3 / 9—Hydroxy 5—Phenylpentyl) 1 cis 1 2,

6 - Jiazabishiku b [3. 3.0] O pin definition -6 - E Hmm 3 - on- partial folding value: C ₂₂ H _3. N ₂ 0 ₄ S 'ΆΗ ₂₀

 Calculated values: C; 62.46, Η; 7.27, Ν; 6.62

 Found: C; 62.46, Η; 7.34, Ν; 6.64

M S: m / z 418 (M +)

PR (CDC £ 3 / TMS) 6: _{1.25~: U90 (7H S m)} , 2.01 (2H, m), 2.42 (2H, t, J = 7Hz), 2.75 (5H 5 m), 3.10 (2H, t, J = 7Hz), 3.37 (3H, ra), 3.66 (3H ₃ s), 4.30 (1H, m), 4.60 (1H, m)

(184) 7 — (3-Methoxycarbonylpropylthio) 1 2 — (3α-hydroxy-14-phenylpentyl) 1 cis 1, 2,6 — diazabicyclo [3.3.0] octa 6 — Power 3 — ON Analytical value: C ₂₂ H ₃ . As _{N 2 0 4 S · Η 2} 0

 Calculated: C; 61.80, Η; 7.31, Ν; 6.55

 Found: C; 61.41, Η; 7.18, Ν; 6.35

M S: ra / z 418 (M +)

PMR (CDC £ a / TMS) 6:

 1.29 (1H, d, J = 8Hz), 1.33 (3Η, d, J = 7Hz), 1.67 (2H, m), 1.99 (2H, m), 2.42 (2H, t, J = 7Hz), 2.82 (5H , m), 3.06 (2H, t, J = 7Hz), 3.46 (2H, m), 3.67 (3H, s); 4.01 (1H, m), 4.60 (in, m), 7.22 (5H, m)

 (185) 7 — (3 —Methoxycarbonylpropylthio) 1 2 — (3 ατ—Hydrox 4- 4-metyloctyl) 1 cis 1 2, 6

—Diazabikuro [3.3.0] octa 6 —en 3 —on Analytical value: C ₂ . As _{H 34 N 2 0 4 S ·} ¼Η 2 0

 Calculated: C; 59.60, Η; 8.63, Ν; 6.95

 Found: C; 59.54, Η; 8.42, Ν; 6.90

MS: m / z 398 (M ⁺ )

 P M R (C D C £ a / T M S) 6:

0.86 (6H, m), 1.00 to 1.80 (11H, m) _s 2.02 (2H, m), 2.42 (2H, t, J = 7Hz) ₅ 2.74 (4H, m), 3.09 (3H, t, J = 8Hz), 3.20 (1H, m), 3.67 (3H, s), 3.85 (1H, m), 4.28 (1H, m), 4.65 (1H, m)

 (186) 7- (3-Methoxycarbonylpropylthio) 1 2 — (3 iS —Hydroxoxy 4 —Metyloctyl) 1cis 1 2, 6

—Diazabicyclo [3.3.0] octa 6 —en 3 —on Component value: C ₂ . As _{H 34 N 2 0 4 S ·} H Z 0

 Calculated values: C; 58.94, H; 8.66, N; 6.87

 Obtained: C; 59.24, H; 8.56, N; 7.01

MS: m / z 398 (M ⁺ )

 P M R (C D C £ 3 / T M S) δ:

 0.85 (6H, m), 1.00-: 1.85 (9H, m), 2.02 (2H, m), 2.41 (2H, t, J = 7Hz), 2.73 (4fl, m), 3.10 (2H, t, J = 8Hz), 3.36 (3H, m), 3.46 (1H, s), 3.66 (3H, s), 4.32 (1H, m), 4.56 (1H, m)

 (187) 7- (3—Methoxycarbonylpropylthio) 1-2— (3β—Hydroxy-1-4-phenylpentyl) cis-1 2,

6 - Jiazabishiku b [.. 3 3 0] Okuta one 6 - E down one 3 - on-analysis: C _Z2 H _3. N _Z 0 ₄ S · 5 / 4Η ₂₀

 Calculated: C; 59.98, Η; 7.14, Ν; 6.34

 Found: C; 59.91, Η; 7.42, Ν; 6.35

P M R (C D C £ 3 / T M S) δ:

1.34 (3Η, d, J = 7Hz), 1.47 (4Η, m), 2.05 (2H, m), 2.45 (2H, t, J = 7Hz), 2.69 (4H, in), 3.14 (2H, t, J = 7Hz), 3.48 (3H, m), 3.70 (3H, s), 4.25 (1H, m), 4.59 (1H, m), 7.22 (5H, m) (188) 7- (3-Methoxycarbonylpropylthio) 1-2— (3 or—Hydrox-14-phenylphenyl) -cis-1,2,6 diazabicyclo [3.3.0] octa-16 One three — on

P M R (C D C £ a / T M S) δ:

1.65 (3Η, m), 2.00 (2H ₅ m), 2.43 (2H, t, J = 7Hz), 2.73 (6H, m), 2.98 (1H, m), 3.08 (2H, t, J = 7Hz), 3.32 (1H, m), 3.68 (3H, s), 3.85 (1H, m), 4.19 (1H, m), 4.60 (1H _S m), 7.24 (5H, br s)

 (189) 7- (3-Methoxycarbonylpropyl) 1 2 — (3 9-Hydrox 1 4 —phenylbutyl) 1 cis 1 2, 6

-JAZABI CYCLO [3.3.0] octor 6-1-3-ON

P M R (C D C £ 3 / T M S) δ:

1.65 (3Η, m), 2.03 (2H, m), 2.43 (2Η, t, J = 7Hz), 2.73 (6H, m), 3.10 (2H ₅ t ₃ J = 7Hz), 3.40 (2H ₅ t, J = 7Hz), 3.68 (3H, s), 3.80 (lH, m), 4.30 (1H, m), 4.59 (1H, ra) 7.26 (5H, br s)

 (190) 7 — (3—Methoxycarbonylpropyl) 1 2 — (3 or —hydroxyl 3 —phenylphenol) 1cis 1,2,6 —Diazabicyclo [3.3.0] 1-6-3-On PMR (CDC £ a / TMS) 6:

1.11 (1H, d _s J = 6Hz), 1.60 to 2.20 (4H, m), 2.42 (2H, t, J = 7Hz), 2.75 (4H, m), 3.00 (1H, m), 3.10 (2H, t) , J = 7Hz), 3.68 (3H, s), 3.96 (1H, m), 4.33 (1H, m), 4.56 (2H, m), 7.33 (4H, m)

(191) 7-(3 —Methoxycarbonylpropylthio) 1 2 — (3 /? — Hydroxy 3 —phenylpropyl) 1 cis 1, 2,6 — diazabicyclo [3.3.0] octa 1 6 —en 1 3 — on PMR (CDC £ ₃ / TMS) δ:

 1.96 (4Η, ra), 2.40 (2H, t, J = 7Hz), 2.63 (2Η, m), 2.78 (3Η, m), 3.09 (2Η, t, J = 7Hz), 3.43 (2H, m), 4.28 (1H, m), 4.56 (2H, m), 7.31 (4H, m)

 (192) 7- (3—methoxycarbonylpropyl) 1 2 — (3—cyclopentyl 1 3—hydroxypropyl) 1cis

— 2, 6 — Jazabikuro [3.3.0] Octa 1 6 — 1 3 1

Min folding Value: C _{1 9} H _{3. N 2 0 4 S · ¼H 2} 0

 Calculated: C; 58.97, H; 7.94, N; 7.24

 Obtained: C; 58.94, H; 8.04, N; 7.06

MS: m / z 382 (M +), 364 (Μ ⁺ -Η ₂₀ )

PMR (CDC £ 3 TMS) 6:

 1.60 (11H, m), 2.01 (2H, m), 2.41 (2H, t, J = 7Hz), 2.72 (4H, m), 3.08 (2H, t, J = 7Hz), 3.32 (3H, m), 3.67 (3H, s), 4.31 (1H, m), 4.55 (1H, m)

IR (neat): 3400, 2950, 2850, 1730, 1660, 1580 cm " ¹

(193) 7-(3 — methoxycarbonylpropyl) 1 2 — (3 — cyclopentyl-3-hydroxypropyl) 1 cis

— 2, 6 — Diazabicyclo [3.3.0] Octa 1-6

Analysis value: C,, H ₃₀ N ₂ 0 ₃ S ₂ ′ H ₂ 0

Calculated values: C; 54.78, H; 7.74, N; 6.72 Obtained: C; 54.57, H; 7.39, N; 6.82

^{MS: m / z 398 +)} , 380 (M + -H 2 0)

 P M R (C D C! L a ZT M 3) 6:

1.60 (11H, m), 2.03 (2H, m), 2.42 (2H, t, J = 7Hz), 2.90 (2H, m), 3.09 (2H, t, J = 7Hz) ₅ 3.30 (3H, m), 3.55 (1H, m), 3.69 (3H, s), 4.12 (1H, m), 4.65 (2H, in)

 (194) 7- (3—Methoxycarbonylprovirthio) 1 2— (3—Cyclohexyl-1 3α—Hydroxycyprovir) 1cis

— 2, 6 — diazabicyclo [3.3.0] octa 6 — 3 — thion

Melting point: 104-: L05

Min folding values: the set to _{C 2O H 32 N 2 0 3} S 2

 Total value: C; 58.22, H; 7.82, N; 6.79

 Found: C; 58.12, H; 7.83, N; 6.60

MS: m / z 412 (M +), 394 (M + -H 2 0)

 (195) 7 — (3 — methoxycarbonylpropyl) 1 2 — (3 — cyclohexyl 3/9 — hydroxypropyl) 1cis

— 2, 6 — diazabicyclo [3.3.0]

Analysis value: C ₂₀ H ₃₂ N ₂ 0 ₃ S ₂ · H ₂₀

 Calculated: C; 56.98, H; 7.89, N; 6.64

 Found: C; 56.56, H; 7.80, N; 6.95

MS: m / z 412, 394 (M + -H 2 0)

 P M R (C D C £ 3 XT M S) δ:

1.13 and 1.73 (13H, 2m), 1.99 (2H, m), 2.42 (2H, t, J = 7Hz), 2.90 (2H, m), 3.08 (2H, t, J = 7Hz), 3.30 (3H, m), 3.68 (3H, s), 4.10 (1H, m), 4.65 (3H, m)

IR (neat): 3400, 2900, 2980, 1730, 1580 cm— ¹

 (196) 7 — (3 — methoxycarbonylpropyl) 1 2 — (3 — cyclopentyl 1 3 or dinodoxyprovir) 1 cis 1 2, 6 — diazabicyclo [3.3.0] Octa 1-6

Melting point: 84-85

Analysis: as _{C 1 9 H 30 N 2 0} 3 S 2

 Calculated values: C; 57.26, H; 7.59, N; 7.03

 Obtained: C; 56.84, H; 7.56, N; 7.03

MS: m / z 398 (Μ +), 380 (M + -H 2 0)

 (197) 7 — (3 —Methoxycarbonyl propylthio) 1 2 — [3α — Hydroxoxy 1 4-1 (ρ — Fluorophenoxy) buty!) 1 cis 1 2, 6 — Diazabisik B [3.3.0] octa 6 — ene 1 3 — thion

Analytical value: C ₂₁ H ₂₇ N ₂ 0 ₄ S ₂ F · ¼Η ₂₀

 Calculated: C; 54.94, Η; 6.04, Ν; 6.10

 Obtained: C; 54.79, Η; 5.91,; 5.90

M S: m / z 45 (M +)

P M R (C D C £ 3 T M S) δ:

 1.7 to 2.2 (4H, m), 2.45 (2H, t, J = 7Hz), 2.92 (2H, m), 3.10 (2H, t, J = 7Hz), 3.36 (4H, m), 3.71 (3H, s ), 3.93 (3H, m), 4.28-5.85 (3H, m), 6.70-7.18 (4H, m)

(198) 7-(3 —Methoxycarbonylpropyl) 1 2 — [3 9—Hydroxy-1 4 — (P-Fluorophenoxy) butyl] 1cis 1, 2,6 — diazabicyclo [3.3.0] Octa 1 6 1 1 3 —Thion

Analysis value: C ₂₁ H ₂₇ N ₂ 0 ₄ S ₂ F · ½H _Z 0

 Calculated: C; 54.41, ΗΪ 6.09, Ν; 6.04

 Found: C; 54.44, Η; 5.88, Ν; 6.10

M S: m / z 454 (M +)

PMR (CDC £ ₃ / TMS) δ:

1.7~2.2 (, m), 2.44 ( 2H, t, J = 7Hz), 2.95 (2H, br s), 3.10 (2H S t- like, J = 7Hz), 3.23~3 · 54 (4H, m) , 3.69 (3H, s), 3.92 (3H, m), 4.36 to 4.82 (3H, m), 6.72 to 7.12 (4H ₃ m)

 (199) 7- (3—Methoxycarbonylpropylthio) -1-2— (3 (5—Hydroxy-1-5-phenylpentyl) -cis-1,2,6-Diazabicyclo [3.3.0] octa-6 —Yen 3 —Zhong

Analysis value: C _2Z H ₃₀ N _z 0 ₃ S _z

 Calculated values: C; 60.80, H; 6.96, N; 6.45

 Found: C; 60.63, H; 6.94, N; 6.34

MS: m / z 434 (M ⁺ )

 PMR (CDC £ 3 ZTMS) 6:.

1,40 to 2.16 (8H, m), 2.41 (2H, t, J = 7Hz), 2.70 (2H, m), 2.89 (2H, m), 3.10 (2H, t, J = 7Hz), 3.30 (2H , m) ₅ 3.53 (1H, in), 3.66 (3H, s), 4.10 (1H, m), 4.63 (2H, m), 7.21 (5H, m) (200) 7-(3-methoxycarbonylpropylthio) 1 2-(3 ct-hydroxy 1-4-methylthiooctyl) 1-cis 1, 2

- Jiazabishiku b [3 3.0.] Okuta 6 - E down one 3 - thione content folding value: as _{C 20 H 34 i / 2 0} 3 S 2

 Calculated values: C; 57.94, H; 8.27, N; 6.76

 Obtained: C; 57.57, H; 8.35, N; 6.74

MS: m / z 414 (M ⁺ )

P R (C D C £ 3 ZT M S) 6:

 0.88 (6H, m), 1.00-: 1.85 (11H, m), 1.02 (2H, m), 2.42 (2H, t, J = 7Hz), 2.89 (2H, m), 3.10 (2H, t, J = 7Hz), 3.33 (3H, m), 3.69 (3H, s), 4.60 (3H, m)

(201) 7- (3—Methoxycarbonylpropylthio) 1-2— (3 / 9—Hydroxy-4-metyloctyl) cis-1,2,6 diazabicyclo [3.3.0] oct 6— 3 — Thion content: C ₂₀ H ₃₄ N _z 0 ₃ S _z

 Calculated values: C; 57.94, H; 8.27, N; 6.76

 Obtained: C; 57.58, H; 8.40, N; 6.33

MS: m / z 414 (M ⁺ )

P M R (C D C £ 3 T M S) δ:

 0.88 (6H, m), 1.00 to 1.80 (11H, m), 2.02 (2H, m), 2.42 (2H, t, J = 7Hz), 2.90 (2H, m), 3.09 (2H, t, J = 7Hz) ), 3.50 (1H, m), 3.66 (3H, s), 4.10 (1H, m), 4.65 (2H, m)

(202) 7- (3—Methoxycarbonylpropylthio) 1-2— (3 or—N-hydroxy-5-phenylpentyl) cis-1,2,6 diazabicyclo [3.3.0] octa-6-ene One three—thion Min folding value: as _{C 22 H 30 N 2 0 3} S 2

 Calculated value: 60.63, H; 6.94, N; 6.34

 Found: C; 60.80, H; 6.96, N; 6.45

PMR (CDC £ ₃ / TMS) δ:

 1.70 (7Η, m), 2.00 (2H, m), 2.40 (2H, m), 2.69 (2Η, ra), 2.89 (2Η, m), 3.13 (2Η, t, J = 7Hz), 3.32 (2H, m) m), 3.67 (3H, s), 4.55 (3H, m), 7.21 (5H, br s)

 (203) 7- (3—Methoxycarbonylpropylthio) 1-2— [3 or—N-Droxy-l-41- (P—Cro-Mouth-Feninole) Butizole] 1-cis-1 2,6—Diazabicyclo [3 3.0] Octa 6 — Energy 3 — Thion

Analysis value: C ₂₁ H ₂₇ C1N ₂ 0 ₅ S

 Calculated: C; 55.44, H; 5.98, N; 6.16

 Obtained: C; 55.43, H; 5.98, N; 6.16

P M R (C D C £ 3 / T M S) δ:

 1.5 to 2.2 (4H, m), 2.45 (2H, t, J = 7Hz), 2.65 to 3.0 (5Η, m), 3.10 (2Η, m), 3.TO (3Η, s), 3.7 to 4.1 (5Η, m), 4.33 (1Η, m), 4.65 (1H, m), 6.85 (2H, d-like, J = 9Hz), 7.25 (5H, d-like, J = 9Hz)

M S: m / z 454 (M,)

 (204) 7 — (3 — methoxycarbonylpropylthio) 1 2 — (3 or — hydroxy 1 4 1-methyl 1 4 — phenoxyhexyl)

—Cis 1, 2,6 —diazabicyclo [3.3.0] oct 6 —en 3 —thion

Min folding value: as _{C 23 H 32 N 2 0 5} S * H 2 0 Calculated value: '59.21, H; 7.35, N; 6.00

 Obtained: C; 59.39, H; 7.26, N; 6.12

 P M R (C D C £ 3 / T M S) δ:

 1.20 (3Η, s), 1.26 (3H, s), 1.4 ~: 1.9 (2H, br), 1.99

 (2Η, q-like, J = 7Hz), 2,41 (2H, t, J = 7Hz), 2.60 to 2.90 (4H, m), 3.07 (2H, t, J = 7Hz), 3.35 to 3.70 (3H , br), 3.66 (3H, s), 4.30 (1H, m), 4.56 (1H, m), 6.90-7.40 (5H, m)

 (205) 7- (3—Methoxycarbonylpropylthio) 1-2— (3 ^ —Hydroxy-14-methyl-4-4-phenoxyhexyl)

—Cis 1, 6 — diazabicyclo [3.3.0] octa 6 — ene 3 — thion

Min folding values: the set to _{C 23 H 3 Z N 2 0} 5 S · H 2 0

 Calculated values: C; 59.21, H; 7.35, N; 6.00

 Obtained: C; 59.32, H; 7.38, N; 6.97

P R (C D C £ a / T M S) δ:

 1.22 (6Η, s), 1.50-1.85 (2H, br), 1.99 (2H, q-like, J = 7Hz), 2,43 (2Η, t, J = 7Hz), 2.60-2.90 (4Η, m) , 3.07 (2Η, t, J = 7Hz), 3.20-3.60 (3Η, ra), 3.67 (3Η, s), 4.30-4.70 (2Η, m), 6.90-7.40 (5Η, m)

 (206) 7 — (3 —Methoxycarbonylpropylthio) 1 2 — (3α-N-hydroxyl 4- 1-methyl 14-Phenoxyhexinole) 1cis 1,2,6-Diazabicyclo [3.3 [0] Octa 6 — Gene 3 — Thion

Analysis value: C ₂₃ H _3Z N ₂ 0 ₄ S _Z · H ₂₀ Calculated: C; 57.23, H; 7.10, N; 5.80

 Found: C; 57.62, H; 7.13, N; 5.65

PMR (CDCjg3 / TMS) δ:

1.23 (3H, s), 1.27 (3H, s), 1.55-: L.95, (2H, br), 2.00 (2H, q-like, J = 7¾), 2.42 (2H, t, J = 7Hz) _s 2.92 (2H, br s), 3.09 (2H, t, J = 7Hz), 3.30 (4H, br), 3.67 (3H, s), 3.60 (3H, br s), 6.90 to 7.40 (5H, m)

 (207) 7 — (3-methoxycarbonylpropylthio) 1 2 — (3 ^ — hydroxy 1 4 — methyl 1 4 — phenoxyhexyl) 1 cis 1 2, 6 — diazabicyclo [3.3. 0] Oct 6 — Energy 3 — Thion

Analysis value: C ₂₃ H ₃₂ N ₂ 0 ₄ S ₂ · ₂ · H ₂ 0

 Calculated: C; 54.20, H; 7.32, N; 5.50

 Found: C; 53.88, H; 6.95, N; 5.41

P M R (C D C £ a / T M S) δ:

1.22 (6Η, s), 1.50-1.85 (2Η, br) 1.99 (2H, q-like, J = 7Hz), 2.42 (2Η, t, J = 7Hz), 2.80-3320 (5 (, m), 3.30 (2Η, br s), 3.60 (1H, br) _s 3.67 (3H, s), 4.00 to 4.20 (1H, m), 4.70 (2H, br s), 6.90 to 7.40 (5H, m)

 (208) 7-(3 —Methoxycarbonylpropylthio) 1 2 —

C 4-(p-chlorophenoxy) 13 iS-hydroxybutyl] 1 -cis 2, 6-diazabicyclo [3.3.0] oct 6-en 3-on

Melting point: 66-67

Min folding value: as _{C 21 H 27 C1N 2 0 5} S Calculated: C; 55.44, H; 5.98, N; 6.16

 Obtained: C; 55.63, H; 6.06, N; 6.12

MS: m / z 455 (M + + 1), 436 (M + -H 2 0)

 (209) 7-(3-Methoxycarbonyl propylthio) 1 2-[4-(P-Chlorophenoxy) 1 3 or-Nodoxy butyl] 1 cis-1 2, 6-Diazabisik B [3.3.0] octa 6 — ene 3 — thion

 P M R (C D C £ a / T M S) δ:

 1.5 ~ 2.2 (4Η, m), 2.45 (2H, t-like, J = 7Hz), 2.8 ~ 3.0 (2H, m), 3.10 (2H, t-like, J = 7 Hz), 3.2 ~ 3.5 (3H , m), 3.70 (3H, s), 3.8 to 4.1 (3H, m), 4.2 to 4.7 (3H, m), 6.85 (2H, m), 7.25 (2H, m)

 MS: m / z 470 (M +)

 (210) 7-(3-Methoxycarbonylpropyl) 1 2-[4-(P-Chlorophenoxy) 13-?-Hydroxybutyl]

— Cis-1, 6 — diazabicyclo [3.3.0] octa 6 —ene 3 —thione

 P M R (C D C £ a T M S) δ:

 1.5 ~ 2.2 UH, ra), 2.43 (2H, t-like, J = 7Hz), 2.8 ~ 3.0 (2Η, m), 3.10 (2Η, t-like, J = 7Hz), 3.2 ~ 3.4 (2H, m ), 3.55 to 3.75 (1H, m), 3.68 (3H, s), 3.8 to 4.3 (5H, m), 4.55 to 4.8 (2H, m), 6.84C2H, m), 7.25 (2H, m)

(211) 7 — (3 — methoxycarbonylpropyl) 1 2 — (4,4 dimethyl-5 — ethoxy 3 α-dihydroxypropyl) 1 cis 1, 6 — diazabicyclo [3.3.0] 6—3

Analyzed value; C _z . As H ₃₄ N ₂ 0 ₅ S

 Calculated values: C; 57.95, H; 8.27, N; 6.76

 Obtained: C; 57.75, H; 8.27, N; 6.73

P MR (CDC £ ₃ / TM S) δ:

0.84 (3Η, s), 0.90 (3Η, s), 2.19 (3H, t, J = THz), 1.66 (2H, m), 2.00 (2H, m), 2.43 (3H, t, J = 7Hz), 2.73 (4H _S m), 3.09 (2H, t, J = 7Hz), 3.27 (2H, s), 3.47 (2H, q, J = 7Hz), 3.69 (3H, s), 3.8 (1H, m), 4.30 (1H _S ), 4.55 (1H, m)

 (212) 7- (3—Methoxycarbonylpropylthio) 1-2 — (, 4-Dimethyl-5-ethoxy3 / 9—Hydroxypentyl) cis-1,2,6-Diazabicyclo [3.3. 0] Oct 6

Minute fold value: C _2. H ₃₄ N ₂ 0 ₅ as S · ½H ₂ 0

 Min: C; 56.71, H; 8.32, N; 6.61

 Obtained: C; 56.33, H; 8.24, N; 6.65

PMR (CDC jg ₃ / TM S) δ:

1.90 (6Η, s), 2.20 (3H, t, J = 7Hz), 1.61 (2H, m), 2.00 (2H, m), 2.45 (2H, t, J = 7Hz), 2.70 (2H _S m), 2,80 (2H, m), 3.10 (2H, t, J = 7Hz), 3.30 (2H, s), 3.35 (2H, m), 3.49 (2H _S q, J = 7Hz), 3.70 (3H, s ), 3.81 (1H, m), 4.43 (1H, m), 4.63 (1H, m)

(213) 7— (3—Methoxycarbyl bromothio) 1 2— (, 4 Dimethyl 1-5—Ethoxy 1 3—Hydroxy pliers Le) 1cis 1, 2,6-diazabicyclo [3.3.0] oct 6-en 3-thion

Minute fold value: C _2. H _{3 <to} as the _{N 2 0 4 S 2 · Η} 2 0

 Calculated: C; 54.64, Η; 8.02, Ν; 6.37

 Found: C; 54.74, Η; 7.80, Ν; 6.33

 P M R (C D C £ a T M S) δ:

 0.88 (6Η, m), 1.18 (3H, t, J = 7Hz), 2.00 (4Η, m), 2.42 (2Η, t, J = 7Hz), 2.92 (2Η, m), 3.07 (2Η, t, J = 7Hz), 3.27 (6H, m), 3.46 (2H, q, J = 4Hz), 3.67 (3H, s), 4.20 (1H, m), 4.63 (2H, m)

 (214) 7-(3 —Methoxycarbonylpropylthio) 1 2 —

[3 or—Hydrochloride butyl (P—methylphenoxy) butyl] —cis 1,2,6—diazabicyclo [3.3.0] octa 6—ene 1—3—on

Melting point: 75-77

Min folding Value: C ₂₂ H _3. N ₂ 0 ₅ S

 Calculated values: C; 60.81, H; 6.96, N; 6.45

 Obtained: C; 60.65, H; 6.94, N; 6.37

MS: m / z 434 (Μ ⁺ ), 416 ( ⁺ -Η ₂₀ )

 (215) 7 — (3 —Methoxycarbonylpropylthio) 1 2 —

[3 9 -Nyldroxy 4-(Ρ-methyl phenoxy) butyl] -cis-1,2,6-diazabicyclo [3.3.0] octa 16 -en 3 -on

Melting point: 94-96

Min folding values: the set to _{C 22 H 3 O N 2 0} 5 S 6 2 Calculated: C; 60.81, H; 6.96, N; 6.45

 Obtained: C; 60.67, H; 7.05, N; 6.38

^{MS m / z 434 (M +} ), 416 (M + -H 2 0)

 (216) 7-(3 —Methoxycarbonylpropylthio) 1 2 —

[3—hydroxy-4— (一 -methylphenoxy) butyl] —cis-1,2,6-diazabicyclo [3,3.0] octa-6—ene-3—thion

Melting point: 79.5-80.5

Min圻値: as _{C 22 H 3O N 2 0 4} S 2

 Total: C; 58.64, H; 6.71,; 6.22

 Found: C; 58.53, H; 6.75, Nr 6.18

M S: m / z 450 (M "

 (217) 7- (3—Methoxycarbonylpropylthio) 1-2— [3 i8—Hydroxy-1-4 -— (P—Methylphenoxy) butyl]

—Cis-1,2,6—diazabicyclo [3.3.0] octa6—ene-3—thion

Min folding value: as _{C 22 H 3O N 2 0 4} S 2 · ½H 2 0

 Calculated values: C; 57.49, H; 6.80, Nr 6.09

 Obtained: C; 57.54, H; 6.85, N; 5.86

PMR (CDC £ ₃ / TM S) δ:

1.7 ~ 2.2 (4Η, m), 2.26 (3H, s), 2.40 (2H, t-like, J = 7Hz), 2.86 (2H, m), 3.06 (2H, t-like, J = 7Hz), 3.27 (4H _S m), 3.66 (3H, s), 3.89 (3H, ra), 4.30-76 (3H, m), 6.76 (2H, d-like, J = 9Hz), 7.06 (2H, d-1 ike , J = 9Hz) MS: m / z 450 (M +) (218) 7 — (3 —methoxycarbonylprovirthio) — 2 — (4 — (m-fluorophenoxy)) 1 3 1-doxycarbonyl 1) cis 1 2, 6 — diazabisik B [3.3.0] octor 6 — 1 3 — on

Minute value: C ₂₁ H ₂₇ FN ₂ 0 ₅ S · 3/4 H ₂ 0

 Total value: C; 55.80, H; 6.35, N; 6.20

 Obtained: C; 55.75, H; 6.39, N; 6.03

PMR (CDC £ 3 TMS) 6:

 1.5 ~ 2.2 (4Η, m), 2.42 (2H, t-like, J = 7Hz), 2.75 (4Η, m), 3.10 (3Η, m), 3.67 (3Η, s), 3.7 ~ 4.1 (5Η, m ), 4.3 (1H, m), 4.5 (1H, m), 6.65 (3H, m), 7.16 (1H, m)

MS: m / z 439 (M +), 420 (M + - H 2 0)

 (219) 7-(3-Methoxycarbonylprovirthio) 1 2-[4-(m-fluorophenoxy) 1 3 9-Hydroxybutyric] 1 cis-1, 2, 6-diazabicyclo [3.3.0] octa 1 — hen 1 — on

Min folding values: the set to _{C Z 1 H 27 FN 2 0} 5 S · 3/4 H 2 0

 Calculated values: C; 55.80, H; 6.35, N; 6.20

 Obtained: C; 55.68, H; 6.42, N; 6.08

PMR (CDC £ ₃ / TMS) δ:

1.5 to 2.2 (4Η, m), 2.42 (2Η, t-like, J = 7Hz), 2.75 (4H, m), 3.0 to 3.6 (5H, m), 3.66 (3H, s), 3.90 (3H , s-like), 4.4 (1H, m), 4.6 (1H, m), 6.63 (3H, ro), 7.17 (lfl, m) MS: m / z 439 (M + + 1), 420 (M +- H ₂ 0)

(220) 7 — (3 — methoxycarbonylpropyl) 1 2 — [3— (m-chlorophenyl) -13 α-didroxyprovir] —cis-1,2,6-diazabicyclo [3.3.0] octa-6—ene-1—one

Minute fold value: C _2. H ₂₅ C1N ₂ 0 ₄ as S · Η ₂ 0

 Calculated: C; 54.23, Η; 6.14, Ν; 6.32

 Found: C; 53.96, Η; 5.72, Ν; 23

PMR (CDC £ ₃ / TM S) 6:

1.63 (1H, s), 2,00 (4H, m), 2.43 (2H, t, J = 7Hz), 2.80 (4H S m), 3.10 (2H, t, J-7Hz), 3.69 (3H, s ), 3.99 (2H, ra), 4.36 (1H, m), 4.58 (2H, m), 7.25 (4H, m)

 (221) 7-(3-Methoxycarbonyl propylthio) 1 2-[3-(m-chlorophenyl) 1 3/9-Hydroxypropyl]

—Cis 1, 6 —diazabic π [3.3.0] octa 6 —en 3 —on

Analysis value: C ₂ oH ₂₅ N ₂ 0 ₄ SCl-½H ₂ 0

 Total value: C; 55.36, H; 6.04, N; 6.45

 Obtained: C; 55.27, H; 6.01, N; 6.42

 P M R (C D C £ 3 / T M S) δ:

1.93 (4Η, m), 2.43 (2H, t, J = 7Hz), 2.68 (2Η, m), 2.80 (2Η, m), 3.11 C2H, t, J = 7Hz), 3.43 (2H, m) ₅ 3.66 (3H ₅ s), 4.19 (1H, m), 4.30 (1H, m), 4.57 (2H, m)

(222) 7- (3—Methoxycarbonylpropylthio) -1-2— [3— (m-chlorophenyl) -1-3-dihydroxypropyl] cis-1,2,6-Diazabicyclo [3.3 [0] octor 6-en 3-zion Minute fold value: C _2. The as the _{H 25 C1N 2 0 3 S 2} · H 2 0

 Calculated values: C; 52.33, H; 5.93, N; 6.10

 Obtained: C; 52.42, H; 5.64, N; 5.81

P M R (C D C £ a Z T M S) δ:

 2.00 (4Η, m), 2.46 (2H, t, J = 7Hz), 3.00 (2Η, m), 3.19

(2Η, t, J = 7 Hz), 3.36 (2H, m), 3.66 (3H, s), 4.17 (2H, m), 4.70 (3H, m), 7.26 (4H, m)

(223) 7- (3-Methoxycarbonylpropylthio) 1-2- (3-Hydroxy-4-phenyloxybutyl) cis-1,2,6 diazabicyclo [3.3.0] octa-6-ene-3— Thion analysis: C ₂₁ H ₂₈ N _z 0 ₄ S ₂ · H ₂₀

 Calculated values: C; 56.61, H; 6.55, N; 6.29

 Obtained: C; 56.29, H; 6.42, N; 6.21

 1.65 (2H, m), 2.00 (2H, m), 2.43 (2H, t, J = 7Hz), 2.94 (2H, m), 3.10 (2H, t, J = 7Hz), 3.33 (2H, m), 3.70 (3H, s), 3.96 (3H, m), 4.66 (3H, m), 6.96 (3H, m), 7.25 (2H, m)

(224) 7 — (3 —Methoxycarbonylpropylthio) 1 2 — (3 / 9—Hydroxy-14-phenyloxybutyl) 1cis 1,2,6 —Diazahicyclo [3.3.0] 6-1-3-Thion Analysis: C ₂₁ H ₂₈ N ₂ 0 ₄ S ₂

 Calculated values: C; 57.77, H; 6.46, N; 6.42

 Obtained: C; 57.65, H; 6.52, N; 6.44

PMR (CDC £ ₃ / TMS) δ: 6 6

1.50 (2H, m), 2.00 (2H, m), 2.40 (2H, t, J = 7Hz), 2.90 (2H ₅ tn), 3.15 (2H, t ₃ J = 7Hz), 3.27 (2H, m), 3.66 (3H, s), 3.95 (2H, s), 4.15 (3H, m), 4.66 (2H, m), 6.96 (3H, m), 7.25 (2H, m)

 (225) 7 — (3 — methoxycarbonylpropylthio) 1 2 —

[4-1 (0-fluoropheninole) 1-3 or-hydroxybutyl]-cis-1, 2, 6-diazabicyclo [3.3.0] octa-6--3-on

Min folding values: the set to _{C 21 H 27 FN 2 0 5} S · H 2 0

 Min: C; 56.36, H; 6.31,; 6.26

 Found: C; 56.41, H; 6.30, N; 6.23

 P M R (C D C £ 3 / T M 3) 6:

 1.80 (2H, m), 2.00 (2H, m), 2.45 (2Η, t, J = 7Hz), 2.75 (2H, m), 2.90 (2H, in), 3.15 (2H, t, J = 7Hz), 3.69 (3H, s), 4.00 (5H, m), 4.40 (1H, m), 4.70 (1H, m), 7.00 (4H, m)

 (226) 7- (3-Methoxycarbonylpropylthio) 1-2- [4- (0-Fluorophenyl) -13-hydroxylbutyl]

—Sys 1, 6 —Zazabicyclo [3.3.0] Oct 6 —En 3 —On

Min folding values: the set to _{C 21 H 27 FN 2 0 5} S H 2 0.

 Calculated: C; 55.24, H; 6.40, N; 6.13

 Found: C; 54.65, H; 5.97, N; 6.00

PMR (CDC £ ₃ / TMS) δ:

2.00 (4Η, m), 2.45 (2Η, t, J = 7Hz) ₅ 2.71 (2H ₅ m), 2.86 (2H, m), 3.13 (2H, t, J = 7Hz), 3.46 (2H, m), 3.66 (3H, s), 4.00 (3H, br s), 4.42 (1H, m), 4.62 (1H, m), 7.00 (4H, m)

 (227) 7 — (3-methoxycarbonylpropyl) 1 2 —

(3α—Hide mouth 4,4—dimethynonyl) 1cis 1,2,6—diazabicyclo [3.3.0] October 6—en1 3—zhong

Analysis value: C ₂₂ H ₃₈ N ₂ 0 ₃ S ₂

 Calculated values: C; 59.69, H; 8.65, N; 6.33

 Obtained: C; 59.15, H; 8.66, N; 6.27

 P M R (C D C £ a / T M S) δ:

 0.86 (9Η, br.s), 1.23 (9H, br.s), 1.50 to 1.80 (1H, m), 2.03 (2H, ql ike, J = 7Hz), 2.43 (2Η, t, J = 7Hz), 2.88 (2H, br.s), 3.10 (2H, t, J = 7Hz), 3.15 to 3.50 (4H, m), 3.69 (3H, s), 4.40 to 4.80 (3H, m)

 (228) 7-(3 —Methoxycarbonylpropylthio) 1 2 —

(3 9—hydroxy-1,4,4—dimethynonyl) 1cis 1,2,6—diazabicyclo [3.3.0] octa 6—en-3

Analysis value: as a CwHaeNzi Sz · H ₂ 0

 Calculated values: C; 58.50, H; 8.70, N; 6.20

 Found: C; 58.74, H; 8.83, N; 6.29

P R (C D C £ 3 / T M S) 6:

0.82, 0.85 (6H, 2s), 0.86 (3H, t, J = 6 Hz), 1.22 (9H, br.s), 1 80 ~ 2,20 (3Η, m), 2.42 (2Η, t, J) = 7Hz), 2.91 (2H, br.s), 3.09 (2H, t, J = 7Hz), 3.30 (3H, br.s),

 3.50-3.80 m), 3.67 (3H, s), 4.10 (1H, m), 4.67

(2H, br.s)

 (229) 7 — (3 —Methoxycarbonylpropylthio) 1 2 —

(3 or—Hydrox 4, 4 —Dimethyltylononyl) 1 cis 1 2,

6 - Jiazabishiku b [3. 3.0] Okuta 6 - E down one 3 - one minute圻値: as _{C 2Z H 38 N 2 0 4} S

 Calculated: C; 61.94, H; 8.98, N; 6.57

 Found: C; 61.65, H; 8.79, N; 6.35

Melting point: 77-80'C

PMR (CDC £ ₃ / TM S) δ:

 0.83, 0.87 (6Η, 2s), 0.80 ~ 0.95 (3H, br.t), 1.22 (8H, br.s), 1.40 ~ 1.80 (2H, m), 2.05 (2Η, q-like, J = 7Hz) , 2.45 (2H, t, J = 7¾), 2.60-3.20 (8H, m), 3.68 (3H, s), 3.90 (1H, m), 4.28 (1H, m), 4.67C1H, m)

 (230) 7 — (3-Methoxycarbonylpropylthio) one 2 —

(3 i5—Hydroxoxy 4,4 dimethylinonyl) 1cis-1,2,6—diazabicyclo [3.3.0] octa6—en3—on Analytical value: C ₂₂ H ₃₈ N ₂ 0 ₄ S · H ₂ 0

 Min: C; 59.43, H; 9.07, N; 6.30

 Found: C; 59.02, H; 9.18, N; 6.39

PMR (CDC £ ₃ / TMS) δ:

0.82, 0.86 (6Η, 2s) , 0.88 (3H S t, J = 6Hz), 1.22 (8H, br.s), 1.40~: L.80 (2H, m), 2.05 (2H, q- like, J = 7Hz), 2.43 (2H, t, J = lBz), 2 to 2.9 (4H ₅ m), 3.12 (2H, t, J = 7Hz), 3.20 to 3.60 (3H, m), 3.68 (3H, s), 4.35 (1H, m), 4.60 (1H, m)

 (231) 7- (3—Methoxycarbonylpropylthio) 1-2— [4— (2,4—difluorophenyloxy) 13-3hydroxylbutyl] cis-12,6—diabicyclo [3.3. 0] Quarter 6 — Energy 3 — On

Min folding value: as _{C 21 H 26 F z N 2} 0 5 S

 Calculated values: C; 55.25, H; 5.74, N; 6.14

 Obtained: C; 55.11, H; 5.91,; 6.05

PMR (CDC £ ₃ TMS) δ:

 1.5 to 2.2 (4Η, m), 2.42 (2H, t-like, J = 7Hz), 2.76 (4H, m), 2.9 to 3.2 (3H, m), 3.66 (3H, s), 3.7 to 4.1 (5H , ra), 4.32 (1H, m), 4.65 (1H, m), 6.7-7.1 (311, m)

 M S: / z 457 (M ++ 1)

 (232) 7 — (3 — methoxycarbonylpropylthio) 1 2 — [4 1 (2,4 — difluorophenoxy) — 3 β — hydroxoxybutyl] 1cis 1, 2, 6 — diazabicyclo [3 . 3.0] Oct 6-3-On

_Analysis value: C _zl H ₂₆ F ₂ N ₂ 0 ₅ S

 Calculated values: C; 55.25, H; 5.74, N; 6.14

 Obtained: C; 55.07, H; 5.90, N; 6.21

 P M R (C D C £ 3 / T M S) δ:

1.6-2.2 (4Η, m), 2.42 (2H, t-like, J = 7Hz), 2.76 (4Η, m), 3.11 (2Η, t, J = 7Hz), 3.43 (2H, t, J = 7Hz) , 3.66 (3H, s), 3.93 (3H, m), 4.36 (1H, m), 4.61 (1H, m), 6,70〜 7.05 (3H, m)

MS: m / z 457 (M ⁺ + l)

 (233) 7- (3-Methoxycarbonylpropylthio) 1-2-(-(2,4-difluorophenoxy) -13α-Hydroxybutyl] cis-1,2,6-Diazabicyclo [3.3 [0] Oct 1 6-3-Zion

Melting point: 102.5 to 103.5

Minute value: as C _2t H ₂₆ F ₂ N ₂ 0 ₄ S ₂

 Calculated: C; 53.37, H; 5.55, N; 5.93

 Found: C; 53.73, H; 5.57, N; 5.95

M S: m / z 472 (M +)

 (234) 7- (3—Methoxycarbonylpropylthio) -1-2— [4— (2,4-Difluorophenoxy) -13 / 5—Hydroxybutyl] cis-1,2,6—Diazabicyclo [3 3.0] Oct 6 — 1 3 — Zion

Minute value: C ₂₁ H ₂₆ F ₂ N ₂ 0 ₄ S ₂ · 3/4 Η ₂₀

 Total value: C; 51.89, Η; 5.70, Ν; 5.76

 Found: C; 51.84, Η; 5.64, Ν; 5.71

 P M R (C D C £ 3 ZT M S) δ:

 1.6 ~ 2 (4Η, m), 2.41 (2Η, t-Iike, J = 7Hz), 2.8 ~ 3.2

(4H ₅ ra), 3.31 (2H _S ra), 3.66 (3H, s), 3.5 ~ 3 (5H, m),

4.68 (2H, br.s), 6.65 to 710 (3H, m)

M S: m / z 472 (M +)

(235) 7- (3—Methoxycarbonylpropylthio) -1-2— [4— (3—chloro-1--4—fluorophenoxy) -1 3 i8—high 1-cis-1,2,6-diazabicyclo [3.3.0] octa 6-en-3—on

Min folding values: the set to _{C Z 1 H 26 C1FN 2 0} 5 S · H 2 0

 Calculated: C; 52.33, H; 5.65, N; 5.81

 Obtained: C; 52.29, H; 5.67, N; 5.83

 P M R (C D C £ 3 T M S) δ:

 1.6 to 2.2 (4Η, m), 2.42 (2H, t-like, J = 7Hz), 2.76 (4H, m), 3.10 (2H, t, J = 7Hz), 3.46 (2H, t, J = 7Hz) , 3.66 (3H, s), 3.89 (3H, br.s), 4.38 (1H, m), 4.60 (1H, m), 6.65 to 7.17 (3H, m)

MS: m / z 472 (M ⁺ )

 (236) 7- (3—Methoxycarbonylpropyl) 1 2— [4— (3—Chloro-4-funenolelophenoxy) 1 3 or—Nodidroxybutyl] 1cis 1 2, 6 — JAZABI CYCRO [3.3.0] octor 6 — ONE 3 — ON

Analysis value: C ₂₁ H ₂₆ C1FN ₂ 0 ₅ S · ZH _Z 0

 Calculated value: C; 52.83, H; 5.59, N; 5.87

 Obtained: C; 52.73, H; 5.74, N; 5.74

MS: m / z 472 (M ⁺ )

 (237) 7 — (3 — methoxycarbonylpropylthio) -2 — [3α-hydroxyl 4 — (Ρ — methoxyphenoxy) butyl) 1 cis 1 2, 6 — JAZABI CYCLO [3.3.0] octa 6 1-3-on

(238) 7 — (3-Methoxycarbonylpropyl) 1 2 — [3 or Hydroxy 1 4- (3-Chenyloxy) butyl] —Cis 1 2, 6 — diaza bicyclo [3.3.0] oct 1 6 — 1 3 — on

 (239) 7-(3 —methoxycarbonylpropyl) 1 2 —

(3α-hydroxy-14-phenylthiobutyl) cis-1,2,6-diazabicyclo [3.3.0] octa 6-en-3—one

(240) 7 — (3-Methoxycarbonylpropyl) 1 2 — [3α-hydroxyl 5 — (2-Chenyl) pentyl] — Sisu2,6 — Diazabicyclo [3.3.0] Octa 6 — En 3 — On

 (241) 7- (3—Methoxycarbonylpropylthio) 1-2— (3—Hydroxyl-3—Methyloctyl) 1cis-1,2,6—Diazabicyclo [3,3.0] octa -6-1 3-ON

(242) 7 — (3-Methoxycarbonylpropylthio) 1 2 —

[2— (1-Hydrocyclohexane 1-yl) ethyl] —cis 1,2,6-diazabicyclo [3.3.0] octa 6—en-3—on

 (243) 7- (3—Methoxycarbonylpropyl) 1 2 — (4—Isopropylpyramino 1 3 —Hydroxybutyl) 1cis 1,2,6 —Diazabicyclo [3.3.0] 6-3-on

 (244) Ί — (3 —methoxycarbonylpropylthio) 1 2 — (3 —hydroxyl 4 — morpholinobutyl) 1 cis 1, 6

-Jazavish mouth [3.3.0] octa 1 6-1 3-on

(245) 7 — (3 — methoxycarbonylpropyl) 1 2 — [3 — hydroxy 1 4 — (4-methyltylbiperazino) butyl] 1 cis 1 2, 6 — diazabicyclo [3. 3. 0] octa 1 6 — energy 3 1 on

 (246) 7-(3-methoxycarbonylpropyl) 1 2-(, 4 dimethyl 1 3 or-nitrodoxy 1 6-heptur)

— Cis 1 2, 6 — aza bicyclo [3.3.0] octor 6 — yan 3 1 on

 (247) 7 — (3 — methoxycarbonyl propylthio) 1 2 — (5, 9 — dimethyl 1 3 or — hydroxy 1 8 — decenyl) 1 cis 1, 2, 6 — diazabicyclo [3. 3.0) Octa 1 6 — En 1 3 — On

 (248) 7- (3—Methoxycarbonylpropyl) —2— [3— (N-propylpyridinine-1 4-—yl) -1 3—N-doxypropylpropyl] 1-cis-1 2, 6 — JAZABI CYCRO [3.3.0] octa 6 — 3 3 — ON

 (249) 7-(3-Methoxycarbonylpropyl) 1 2-[3-(4-Probicyclocyclohexyl)-1-3-Ndoxyl mouth pill]-cis-1, 2, 6- Jazabicyclo [3.3.0] octa — 6 — 1 3 — On

 (250) 7 — (3 —methoxycarbonylpropyl) 1 2 — (5 —ethylthio 3 —dihydroxylopentyl) 1 cis 2,

6—Jabisicuro [3. 3.0) Oct. 6 — 1 3 — On

(251) 7 — (3 —methoxycarbonylpropyl) 1 2 —

[3— (m-fluorophenyl) -1 3—nydroxoxypropyl] cis 1,2,6 — diazabicyclo [3.3.0] octa 1 6—en-3—on (252) 7-(3 -Methoxycarbonylpropylthio) 1 2-(3 -Hydroxy- 1-4-phenylthiobutyl) 1 -cis 1, 2-6-diazabicyclo [3.3.0] Oct 6-1-3 -on

(253) 7- (3-Methoxycarbonyl-1-2-propylthio) — 2- [3—hydroxy-3— (3-pyridyl) propyl] cis-1,2,6-diazabicyclo [3.3.0] octa One 6—en 3—on

 (254) 7- (3-Methoxycarbonylpropylthio) -1-2- (5- (5-Imidazolyl) -13-Hydroxypentyl) -cis-1,2,6-Diazabicyclo [3.3.0] octa-1 6 — No — 3 — On

 (255) 7-(3 -Methoxycarbonyl-1-2-propynylthio) — 2 — (3 —Hydroxygtyl) 1 cis-1,2,6 —Diazabicyclo [3.3.0] Factor 6 —En 3 —On

 (256) 7- (3—Methoxycarbonylbutylthio) 1-2— (3—Hydroxy-1-4-phenoxybutyl) cis-1,2,6-Diazabicyclo [3.3.0] octane 6—3—one

(257) 7- (3-Methoxycarbonylpropylthio) 1-2- (4-methyl-14-hydroxyl-octyl) cis-1,2,6-diazabicyclo [3.3.0] octa-1-ene-3—one

(258) 7 — (3 — methoxycarbonylpropylthio) 1 2 — (2 —hydroxyl-octyl) 1cis 1, 2, 6 — diazabisik mouth [3.3.0] octa 1 6 — 3 — on

(259) 7-(3-Carboxypropylthio) 1 2-(4,4-Dimethyl-5-Ethoxy 1 3-Hydroxypentiples) 1 2, 6 — Jazabicyclo [3.3.0] Oct 1 6 — En 1 3 — On

 (260) 7 — (3 — Carboxyprovirthio) 1 2 — (3 — Hydroxy 4 — Metyl 4 — Phenoxicopentyl) 1 cis 1, 2 — 6 — Diazabicyclo [3.3.0] ] Oct. 6 — En 3 — On

 (261) 7- (3—Methoxycarbonylpropylthio) 1 2— [41 (m-fluorophenoxy) 1 3 or—N-doxyloxybuty!] 1 cis 1 2,6 — Diazabicyclo [3.3.0] octa-one

 (262) 7- (3—Methoxycarbonylpropyl) 1-2- [3— (m-cyclophenyl) -13—N-dioxypropyl] cis-1 2,6—Diazabicyclo 3.3.0] octa 6 —ene 3 —thion

 (263) 7- (3-Methoxycarbonylpropyl) 1 2— [31-N-doxy-l-41- (3-Chenyloxy) butyl]

— Cis 1, 6 — diazabicyclo [3.3.0] octa 6 — ene 3 — thion

 (264) 7 — (3 —methoxycarbonylpropylthio) 1 2 —

(3o-hydroxy-4-phenylthiobutyl) cis-1,2,6-diazabicyclo [3.3.0] octa 6-en-3 -thione

(265) 7 — (3-Methoxycarbonylpropyl) 1 2 — [3α-hydroxyl 5 — (2-Chenyl) pentyl] 1 2, 6 — diazabicyclo [3.3 [0] Quarter 6 3—Thion

 (266) 7-(3-methoxycarboninolef * mouth virthio) 1 2-(3-hydroxy 1 3-methylocyl) 1 cis-1, 2-6-diazabicyclo [3.3.0] —Yen 1 —Thion

(267) 7- (3-Methoxycarbonylpropylthio) -1-2- [2- (1-Hydroxycyclohexane-1-yl) ethyl]

—Cis 1, 6 — diazabicyclo [3.3.0] octa 6 — ene 3 — thion

 (268) 7- (3—Methoxycarbonylpropyl) 1 2— (4—Isoproviramine 3—Hydroxybutyl) cis

— 2, 6 — diazabicyclo [3.3.0] octa 6 — 3 — thion

 (269) 7- (3—Methoxycarbonylpropylthio) 1-2— (3—hydroxy-4-morpholinobutyl) cis-1,2,6 diazabicyclo [3.3.0] octa 16— 3 — Thion

(270) 7-(3-methoxycarbonylpropyl) 1 2-[3-hydroxy 4-(4-methylbiperazino) butyl]

—Cis 1, 6 — diazabicyclo [3.3.0] octa 6 — ene 3 — thion

 (271) 7- (3—Methoxycarbonylpropyl) 1 2— (4,4—Dimethyl 13—Hydroxie 6 ^ Ptul) 1cis 1,2,6—Diazabisik mouth [3.3.0] 6-3-Thion

(272) 7- (3-Methoxycarbonylpropylthio) 1 2 — (5—Methyl 1 3 —Hydroxynonyl) 1 cis 1 2, 6—Di Azabicyclo [3.3.0] octa 6-ene 3-thion

(273) 7 — (3 — methoxycarbonylpropyl) 1 2 — (3 — nitrodoxyl 3 — (4 — propylinolecyclohexyl) pu) 1 cis 1, 6 — Diazabicyclo [3.3.0] octa — 6 — 3 — Thion

 (274) 7 — (3 — methoxycarbonylpropyl) 1 2 — [3 — hydroxy1 3 — (N— propylpyridin 1 4 — yl) propyl] 1 cis 1, 6-diazabicyclo [3.3.0] octa 6-en 3-thion

 (275) 7 — (3 —Methoxycarbonylpropyl) 1 2 — (5 —Techtylthio 3 —Hydroxycypentyl) 1 cis 1,

6 — Jizabicyclo [3.3.0] octor 6 — 1 3 — Zhong

 (276) 7 — (3 — methoxycarbonylpropyl) — 2 — [3 — hydroxy 1 5 — (2 — phenyl) pentyl] cis

— 2, 6 — diazabicyclo [3. 3. 0] octa 6

 (277) 7- (3-Methoxycarbonylpropyl) 1 2— [3—Hydroxy 1 3— (2—Chenyl) propyl] 1cis

— 2, 6 — Diazabicyclo [3.3.0] Octa 1-6

(278) 7- (3—Methoxycarbonylpropyl) 1 2— [3—Hide mouth 3— (2—pyridyl) propyl] 1cis 1 2,6—Diazabicyclo [3 3.0] Octa 1-6 — ene 3 — Thion (279) 7-(3 —methoxycarbonylpropyl) 1 2 —

[3—hydroxy-4— (p-methylphenylthio) butyl] 1-cis-1,2,6-diazabicyclo [3.3.0] octa 16-ene-3—thione

 (280) 7 — (3 — methoxycarbonylpropyl) 1 2 — [5 — (5 — imidazolyl) 1 3 — hydroxyoxypentyl] 1 cis 1 2, 6 — diazabicyclo [3.3.0] Octer 6 — ene — 3 — zion

 (281) 7- (3—Methoxycarbonylpropyl) 1 2— [41 (P-fluorophenoxy) 13 α-Hydroxybutyl] 1 1,5—Dimethyl-1-cis 1,2,6 -JAZABI CYCLO [3.3.0) Occasion 1 6-En 1 3-ON

 (282) 7-(3-methoxycarbonylpropylthio) 1 2-(3-hydroxy 1-4-methyl-1-4-phenoxypentyl)

— 1, 5 — Dimethyl cis 1, 2, 6 — Diazabicyclo [3.3.0] octor 6 — Energy 3 — On

 (283) 7 — (3 — methoxycarbonylpropyl) 1 2 — (, 4 — dimethyl 3 — hydrated octyl) 1, 5 — dimethyl thyrus 1, 2, 6 — diazabicyclo [3.3] [0] 1-6-3-ON

 (284) 7-(3-methoxycarbonylpropyl) 1 2-[3-hydroxy3-(4-probicyclocyclo) pill] 1 1, 5-dimethylthyrus 1 2, 6 — Diazabicyclo [3.3.0] Octa 1 6 — Energy 3 — On

(285) 7- (3—methoxycarbonylpropyl) 1 2— (3 — Hydroxy 4 — Phenyl oxybutyl) 1, 5 — Dimethyl 1 cis 1, 2, 6 — Diazabicyclo [3.3.0] Oct 6-En 1 31

 (286) 7 — (3 —methoxycarbonylpropyl) 1 2 — [4 — (p —fluorophenoxy) 1 3 —hydroxylbutyl] 1 1, 5 —dimethyl-2-cis 1, 6 — diazabicyclo [3.3.0] octa 6 — ene-3 — thion

 (287) 7- (3—Methoxycarbonylprovirthio) 1 2— (3—Hydroxy 4—Methyl 1 4 1-Phenoxypentyl)

— 1, 5 — Dimethyl cis 1 2, 6 — Diazabicyclo [3, 3.0] octa 6 — En 3 — Thion

 (288) 7 — (3 — methoxycarbonylprovirthio) 1 2 — (4,4 dimethyl-5) —ethoxy 3 — hydroxypentyl) 1-1,5 — dimethyl-1 cis-1 2 , 6-diazabicyclo [3.3.0] octa 1-3-thion

 (289) 7 — (3 —methoxycarbonylpropyl) 1 2 — (3 —hydroxyl 4-phenoxycyptyl) 1, 5 — dimethyl 1 cis 1, 2,6 — diazabicyclo [3. 3.0] Octa 1-6

 (290) 7 — (3 —methoxycarbonylpropyl) 1 2 — (3 —hydroxyl 4-phenylthiobutyl) 1, 5 —dimethyl 1 cis 1 2, 6 —diazabicyclo [3.3.0] octa 6-ene 3 -thion

(291) 7-(3-methoxycarbonylpropylthio) 1 2-[3-hydroxy3-(N-propylpyridin 1-4- Propyl) 1, 5 —dimethyl-cis 1, 2,6 — diazabicyclo [3.3.0] octa 1 6 —en-3 —thione

 (292) 7-(3-methoxycarbonylpropyl) 1 2-[3-(in-phenyl) 1-3-hydroxypropyl]

— 1, 5 — Dimethyl cis 1, 2, 6 — Diazabicyclo [3.3.0] Oct. 6 — Energy 3 — Thion

 (293) 7- (3-Methoxycarbonylpropylthio) 1 2 — (3—Hydroxyl 4-morpholinobutyl) 1, 5—Dimethyl-1-cis 1,2,6 —Diazabicyclo [3. 3.0] Octa 1 6 1 3

 (294) 7 — (3 —Methoxy carbonyl propylthio) 1 2 — [3 — Hydroxy 1 5 — (2 — Chenyl) pentyl] 1, 5 — Dimethyl lysis 1, 6 — Diazabicyclo [3 [3.0] Octa-one 6-en-thion

 (295) 7 — (3 —methoxycarbonylpropyl) 1 2 — (, 4 —dimethyl 3 —hydroxy 6 «putur) 1

1, 5 —Dimethysis 1, 2, 6 —Diazabicyclo [3.3.0] octa 6 —Zen 3 —Thion

 (296) 7- (3—Methoxycarbonylpropylthio) 1-2— (4-hydroxyl-octyl) -cis-1,2,6-diazabic mouth [3.3.0] octa-6—ene-1 3— ON

 (297) 7- (3—Methoxycarbonylpropyl) 1 2— (4Hydroxy 1—4 1Buroctyl) 1 cis—1,2,6—Diazabicyclo [3.3.0] Octa 1 6 —Yen 3 —On

(298) 7 — (3 — methoxycarbonyl 2 — bronil)- 2 — (3 — Hydroxy 4 — methyl 4 — phenoxypentyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octa

6—Yen 3—On

 (299) 7 — (4 — methoxycarbonylbutylthio) 1 2 — (

3 — nitrodoxy 1-4-phenoxybutyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octa 1 6 — gen 3 — on

(300) 7- (4-methoxycarbonyl) Mouth-hexylthio) — 2 — (41- (P-fluorophenyl) 1 3 —Hydroxy butyl) 1 cis 1 2, 6 — JAZABI CYCLO [3.3.0] octa 1 — Jen 3 — ON

 (301) 7- (3—Methoxycarbonylpropyl) —2— [3α-Dynoxydroxyl 4— (0—Fluorohydroxy) butyl] 1 cis-1 2, 6—Diazabicyclo [3.3.0] octa 6 — ene 3 — on

 (302) 7 — (3 — methoxycarbonylpropyl) 1 2 — [3 i9 — hydroxy 4 — (0 — fluorenoxy) butyric) 1 cis 1 2, 6 — diazabisik B [3.3.0] octa 6 —en 1 3 —on

 (303) 7 — (3 —methoxycarbonylpropyl) 1 2 —

[3 α-Hide mouth x 4 1 (2, 4 — difluorophenoxy) butyl) 1 cis 1 2, 6 — diazabicyclo [3.3, 0] octa — 6 — 1 3 —Thion

 (304) 7 — (3 —methoxycarbonylpropyl) 1 2 —

[3 5—Hide mouth x 4 (2,4 difluorene) butyl] 1 cis 1 2, 6—Zyabi cyclo [3.3.0] octa One 6 — one three — thion

 (305) 7- (3-Methoxycarbonylpropylthio) 1-2- [3-N-hydroxyl-4-1- (3-chloro-14-Fluorophenoxy) butyl] 1-cis-1 2 , 6 — Jahabicyclo [3, 3.0] octor 6 — General 3 — Thion

 (306) 7- (3-Methoxycarbonylpropylthio) 1-2- [3α-Hydroxy-141- (4-methoxycarbonylcarbonyl) butyl] cis-1,2,6-Diazabicyclo [3. 3.0] Octane 6 — ene — 3 — thion

 (307) 7-(3-methoxycarbonylprovirthio) 1 2-[3 or-hydroxy 4-(4-nitrophenoxy) butinole]

— Cis-1, 6 — diazabicyclo [3.3.0] octa 6 — ene 3 — thion

 (308) 7 — (3-methoxycarbonyl propylthio) 1 2 — [3 or-hydroxy 1-4 (4-dimethylaminophenol) butyl] 1 cis-1, 2, 6-diazabicyclo [3.3.0] octa — 6 — 1 3 — Thion

 (309) 7- (3—Methoxycarbonylpropyl) 1 2— [3 or—N-doxyloxy 4- (1—4—dimethylmethylaminocarbonylphenoxy) butyl] 1cis 1,2,6—Diazabisik B [3.3.0] octa 6 — ene 3 — thion

 (310) 7- (3-Methoxycarbonylprovirthio) 1-2- (3α-N-dirodoxy-6-phenylhexyl) -cis-1,2,6-Diazabicyclo [3.3.0] Oct. 6 — 1 — 3 — Thion

(311) 7-(3 —methoxycarbonylpropyl) 1 2 — (4 1-hydroxy-5-phenoxypentyl) 1-cis-1,2,6 diazabicyclo [3.3.0] oct 6-en-3 -thione

(312) 7 — (3 -Methoxycarbonylpropylthio) 1 2 — [3α-Hydroxy 1 -41- (4-methoxyphenoxy) butyl] 1 -cis 1, 2,6-diazabicyclo (3.3. 0) Oct 6 1 3 — Thion

 (313) 7 — (3-methoxycarbonylpropyl) 1 2 — [3-1-hydroxyl 4- 1 (3-trifluorometylphenoxy) butyl] 1 -cis 1, 2, 6-diazabicyclo [3. 3.0] Octa 6 — Energy 3 — Thion

 (314) 7-(3 —Methoxycarbonylpropylthio) 1 2 —

[3α-hydroxy-4 butyl (4-cyanophenoxy) butyl]-cis-1,2,6-diazabicyclo [3.3.0]

 (315) 7 — (3 — methoxycarbonylpropylthio) 1 2 — [3 or hydroxy 1 4 — (3 — cyclopentoxy) butyl] 1 cis 1 2, 6 — diazabicyclo [3. 3.0] Oct. 6 — En 3 — Thion

 (316) 7- (3—Methoxycarbonylpropylthio) 1-2— [3ατ—Hydroxoxy 4— (3,5—Dichlorophenoxy) butyl) 1cis-1 2,6—Diazabicyclo [3 . 3.0] Octa — 6 — 3 — Thion

(317) 7 — (3 —Methoxycarbonylpropylthio) 1 2 — [3α-Hydrox xy 4 1 (3 — (Ν, Ν-dimethylmethylaminophenoxy)) butyl] 1cis 1 2 , 6-Jazabicyclo [3. 3.0) Octa 1-6

 (318) 7- (3—Methoxycarbonylpropyl) 1 2— [3 or—N-Droxy 1-14 (4—Methylcarboylphenoxy) butyl) 1cis 1 2,6—Diazabisik B [3.3.0] Octa 6 -en-3 -thione

 (319) 7- (3—Methoxycarbonylpropylthio) —2— [3α-Hydroxoxy 4— (4—Aminocarboylphenoxy) butyl) -1 cis-1 2,6— Diazabicyclo [3.3.0] octa 6 -en 3 -thion

 (320) 7 — (3 — methoxycarbonylpiruthio) 1 2-[3ατ-hydroxy 1 4-(4-amino sulfoylphenoxy) butyl] 1 cis-1, 2, 6-diazabicyclo [3. 3.0) Octa 6-ene-3-thione

 (321) 7-(3 —methoxycarbonylpropyl) 1 2 —

[3 or—Nylodoxy 1-4-1 (2,4—Difluoro phenoxy) butyl] 1-cis 1-, 2,6-Diazabicyclo [3.3.0] Octa 6- ON

 (322) 7-(3 —methoxycarbonylpropyl) 1 2 —

[3 ^ —Hydroxy 4— (2,4—difluorophenoxy) butyl) 1cis-1,2,6—diazabicyclo [3.3.0] octa 16—en1 3—o N

(323) 7- (3—Methoxycarbonylpropylthio) 1-2— [3 or—hydroxy-14— (3—chloro-4—fluorophenoxy) butyl] 1cis-1,2,6—diazabisik B [3.3.0] octor 6-1 3-on (324) 7 — (3 —methoxycarbonylpropyl) 1 2 — [3 or—hydroxyl 4- (4—methoxycarboyfenoxyl) butyl] 1 cis 1 2, 6 — diazabicyclo [3.3.0] octa 1 6—en 1 3—on

 (325) 7- (3—Methoxycarbonylpropyl) 1 2— [3 or—Hydroxyxy 4- (412-trophenoxy) butyl] 1-cis-12,6—Diazabicyclo 3.3.0] octor 6 —en 3 —on

 (326) 7- (3—Methoxycarbonylpropyl) —2— [3α-hydroxyl 4-((4-dimethylaminophenol) butyl) -cis-1,2— Jazabicyclo [3.3.0] octa 6 —en 3 —on

 (327) 7 — (3 — methoxycarbonylpropyl) 1 2 — [3α-hydroxyl 4 — (4 — dimethylaminocarbonylphenoxy) butyl) 1 cis 1, 6 — JAZABI CYCLO [3.3.0] October 6 — En 1 3 — ON

 (328) 7 — (3 —methoxycarbonylpropyl) 1 2 — (3α-dihydroxy) 6 — phenylhexyl) cis 1, 2, 6 — diazabicyclo [3.3 [0] octa 6 — ene 1 3 — on

(329) 7 — (3 — methoxycarbonylpropyl) 1 2 — (4 1-doxy 1-5 — phenoxy pentyl) cis 1 2,

6 — Jazabicyclo [3.3.0] octa 6 — 3-on

(330) 7- (3—Methoxycarbonylpropyl) 1 2— [3o—Hydroxy 1—4— (4—Methoxy hex) butyl] 1—cis 1,2—6— Jabi Sikkuro [3.3,0] Oct. 1 6 — 1 3 — ON

 (331) 7- (3-Methoxycarbonylpropylthio) -1-2— [3 / S—Hydroxoxy-41- (3—trifluorometylphenoxy) butyl) -cis-1 2,6—Diazabicyclo [3.3.0] octa 6-ene 3 -thione

 (332) 7-(3 —methoxycarbonylpropyl) 1 2 —

[3 or—Hide mouth 4 — (4 — phenoxy) butyl] 1 cis 1, 2, 6 — diazabicyclo [3. 3 0] octa 1 6 — en 1 3 — on

 (333) 7 — (3-methoxycarbonylpropyl) 1 2 — [3οτ—Hydroxoxy 1-4-(3-chlorophenoxy) butyl] 1 -cis 1, 2, 6-diazabicyclo [3. 3.0) octor 6—en 3—on

 (334) 7- (3—Methoxycarbonyldibutylthio) 1-2— [3α-Hydroxy-1-4 (3,5—dichloroenoxy) butyl) 1cis-1,2,6—Diazabicyclo [3.3.0] octa 6-en 3 — on

 (335) 7 — (3 —methoxycarbonylpropylthio) 1 2 — [3 α-hydroxyl 4- 1 (3 — ((, Ν-dimethylmethylaminophen)) butyl] 2, 6 — diaza bicyclo [3.3.0] octor 6 — 1 3 — on

(336) p- (3-Methoxycarbonylpropylthio) 1 2— [3-hydroxyl 4- (4-methylcarbonylphenoxy) butyl] 1-cis 1,2,6-diazabicyclo [ 3.3.0] Octa 1 6 — En 1 3 — On (337) 7 — (3 — methoxycarboxy cyrpirthio) 1 2 — [3o — hydroxy 1 4-1 (4-aminocarboninolef enoxy) butyl) 1cis 1, 2 — 6 — diazabisik B [3.3.0] octa 1 6-en 1 3-on

 (338) 7-(3-methoxycarboxycypirthio) 1 2-[3 or-hydroxyl 4- 1 (4-amino sulphoyulfenoxy) butyl] 1 cis-1, 2, 6-diazabicyclo [ 3.3.0] Octa 1 — 3 — On

Example 3 3 9

 (+) — 7 — (3 — methoxycarbonylpropylthio) 1-2-(3 α-hydridoxy 4-1-phenyloxybutyl) 1-cis-1,2, 6-diazabicyclo [3.3. 0] Octa 6-ene-3-one and (1-)-17- (3-methoxycarbonylpropylthio) 1-2- (3-hydroxy-4-phenyloxybutyl) -cis — 2, 6 — JAZABI CYCLO [3.3.0] octor 6 — 3 — ON

 (i) 7 — (3 — methoxycarbonylpropyl) 1 2 — (3 or — hydroxy 4 — phenoxybutyl) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] 1.6 g-benzene-3 -one 3.1 g of methylene chloride in 200 fflfi solution under ice-cooling 2.7 g of dimethylaminoviridine and (1S)-(-)-ka Add 1.9 g of sulfonic acid chloride and stir at room temperature for 30 minutes.

After the reaction, water is added to the reaction solution, and the mixture is extracted with black-mouthed form. After washing with 5% hydrochloric acid and water and drying over sodium sulfate, the solvent is distilled off, and the residue obtained is purified by silica gel chromatography. 8 8

Hexane / Ethyl acetate Z ethanol = 4: 4: 1)

Next, thin-layer chromatography using a solvent of the same composition as the developing solvent

Compound (a) with an R f value of 0.38 (1.9 g) and R f value

(B) of 0.30 are obtained.

Compound (a)

P MR (CDC £ ₃ ZT MS) δ:

 0.95 (3Η, s), 1.06 (3H, s), 1.11 (3H, s), 2.07 (8H,

 m), 2.43 (2H, t, J = 7Hz), 4.70 (4H, m), 3.10 (2H, t,

 J = 7Hz), 3.70 (3H, s), 3.83 (2H, m), 4.12 (2H, d,

 J = 6Hz), 4.35 (1H, m), 4.62 (1H, m), 5.32 (1H, m),

 6.92 (3H, m), 7.29 (2H, m)

Compound )

 P M R (C D C £ a / T M S) δ:

 0.97 (3H, s), 2.05 (3H, s), 2.10 (3H, s), 2.02 (8H,

 m), 2.42 (2H, t, J = 7¾), 2.66 (4H, m), 3.06 (2H, t,

J = 7Hz), 3.66 (3H, s), 3.95 (2H, m), 4.09 (2H ₅ d,

 J = 6Hz), 4.30 (1H, m), 4.58 (1H, m), 5.30 (1H, m),

6.92 (3H, m), 7.29 (2H ₅ ra)

 (ii) Compound (a) Sodium in 1.9 g of methanol 50 solution

Add 170 ig of methoxide and stir at room temperature for 3 hours. After the reaction,

The reaction solution is poured into ice water and extracted with black-mouthed form. Wash with water,

After drying over sodium sulfate, the solvent is distilled off, and the residue is silica gel.

 -Column Chromatography 1

 : Purification in 1) yields (+)-7- (3—Methoxycarbonitrile)

Luprovirthio) 1 2 — (3 — Hydroxy 4 1 (Cisbutyl) 1, cis-1,2,6-diazabicyclo [3.3.0] octa 6-en-3-on 1.2 g is obtained.

ί) _D = tens 9 1. 3 8 ° (c = l, CHC1 3)

Minute value: C ₂ , H _2B N ₂ 0 ₅ S · H ₂ 0

 Calculated values: C; 57.51, H; 6.89, N; 6.39

 Found: C; 57.40, H; 6.34, N; 6.30

 P M R (C D C £ 3 ZT M S) δ:

 1.76 (2Η, m), 2.00 (2H, m), 2.42 (2H, t, J = 7Hz), 2.73 (4H, m), 3.19 (2H, t, J = 7Hz), 3.66 (3H, s), 4.92 (5H, m), 4.36 (1H, m), 4.64 (1H, m), 6.95 (3H, m), 7.26 (2H, m)

 (iii) When 1.3 g of compound (b) is treated in the same manner as in (ii), (1) — 7 — (3 — methoxycarbonylpropylthio) 12 — (3 — hydroxy-14 — phenoxybutyl) One system one, two, six-diaza bicyclo [3.3.0] one six-one-three-on, seven hundred nines.

 [Α] D = — 9 2.3 2 ° (c = l, CHCls)

Analysis value: C ₂₁ H ₂₈ N ₂ 0 ₅ S · H ₂ 0

 Calculated values: C; 57.51, H; 6.89, N; 6.39

 Obtained: C; 57.48, H; 6.39, N; 6.36

P R (C D C £ 3 / T M S) δ:

1.76 (2Η, ra), 2.00 (2H, in), 2.42 (2H, t, J = 7Hz), 2.73 (4H, m), 3.19 (2H, t, J = 7Hz), 3.66 (3H, s), 4.92 (5H, m), 4.36 (1H, m), 4.64 (1H, m), 6.95 (3H, m), 7.26 (2H, m) 90 According to the above Example 33 39, the following compounds are similarly prepared.

 (340) (+) -7-(3 -Methoxycarbonylpropylthio) — 2 — [3 or —Hydroxy- 1-4- (P -fluorophenoxy) butyl] 1-cis 1, 2,6 — Diazabicyclo [3. 3.0] Octa 1 6 — 1 3 — Thion

ί) _Ώ : +4 _5.9 ° (c = 3.0, CHCI ₃ )

Analysis value: C ₂₁ H ₂₇ FN ₂ 0 ₄ S _z · の as H ₂ 0

 Calculated: 54.94, H; 5.98, N; 6.10

 Obtained: C; 54.89, H; 6.00, N; 5.91

 (341) (-)-7- (3-Methoxycarbonylpropylthio) 1-2- [3 or-hydroxy-14- (P-fluorophenoxy) butyl] cis-1,2,6-Diazabicyclo [3. 3.0] Octa — 6 — 1 3 — Thion

 [N: 1D: _ 46.1 ° (c = 6.3, CHCls)

Analytical value: C _{2 l} H _Z7 Ffi ₂ 0 ₄ S _z

 Total value: C; 55.49, H; 5.99, N; 6.16

 Found: C; 55.20, H; 6.07, N; 5.96

 (342) (D) 1 7 — (3 —Methoxycarbonylpropylthio) — 2 — [3/8 —Hydroxy-1 4 — (P —Fluorophenoxy) butyl] 1cis 1, 2, 6 — Diazabicyclo [3 . 3.0] Octa 1-3-Thion

[Or] D: 10 2.4 ° (c = 1.0 ₅ CHCI ₃ )

 Melting point: 8 1 to 8 6

(343) (1) 1 7 — (3 — methoxycarbonylpropylthio) — 2 — [3 ^ —hydroxy-1 4 — (P —fluorophenoxy) [Putil] 1 cis 1 2, 6-diazabicyclo [3. 3. 0] octa 1-6-3-thione

[Or] D: — 85.9. (C = 1.0, CHC1 ₃₎

 Melting point: 75 ~ 80 0

 (344) (+)-7-(3-methoxycarbonylpropylthio)-3-[3 ar-nitrodroxy-41 (P-fluorophenoxy) butyl] cis-1,2, 6-diazabicyclo [3. 3.0] Octa 1 6

[Do] D: + 5 4. 9 6 ° (c = 1.2, CHC1 3)

Formulation Example 1

 Example 1 Microcrystalline cellulose was added to 5 mg of the compound of 98, 100 ng of magnesium stearate, 100 ng of lactose, 20 mg of talc, 1 nig of talc and 150 mg of corn starch, and mixed well until uniform, followed by a conventional method. To give tablets containing 5 mg of active ingredient per tablet.

Formulation Example 2

 Example 10 Compound 10m of 98 and lactose 30a were dissolved in distilled water for injection, sterile-filtered by a conventional method, filled in an ampoule, freeze-dried and sealed, and 1 ampoule was added. A lyophilized preparation for injection having 10 mg of active ingredient in it is obtained.

Claims

Claim aspects

 (1 set

 [Wherein the symbols mean the following.

 X represents oxygen, sulfur, one NH or N.

 X, represents alkylene or alkenylene, and the alkylene or alkenylene may form a ring together with the 1N when X is 1N.

 Y represents alkylene.

Y, represents hydrogen, alkyl or alkenyl, and the alkyl may form a cycloalkyl with Y ₂ , and the cycloalkyl may be substituted with alkyl.

Υ2 may be hydrogen, anoalkyl, alkenyl, alkynyl, or alkyl-substituted alkyl; alkyl-substituted aminoalkyl; alkoxyalkyl; Aryl, Ararquinole, Aryloxyalkyl, Arylthioalkyl (However, in the above definitions, the aryl or aryl part is norocene, triphenylenelomethizole, azolequinole, anorecoxy, nitole, nitro, etc. De σ-xyl, amino, alkylamino, alkoxy force It may be substituted with a group selected from luponyl, carboxyl and cyano. ), Heterocyclic-substituted alkyl, heterocyclic-substituted oxyalkyl, and heterocyclic-substituted thioalkyl.

 A represents hydrogen or hydroxyl optionally having a protecting group.

R, R, and R ₂ each represent hydrogen or alkyl.

Z represents oxygen or sulfur. ]

Cis-1,2,6-diazabicyclo [3.3.0] octane derivative, salt or ester thereof represented by

 Equation (2)

[Wherein the symbols mean the following.

 Y represents alkylene.

Y, represents hydrogen, alkyl or alkenyl, and the alkyl may form a cycloalkyl with Y ₂ , and the cycloalkyl may be substituted with alkyl.

Y ₂ is hydrogen, alkyl, alkenyl, alkynyl, alkyl optionally substituted with alkyl, alkyl-substituted aminophenol, anorecoxyalkyl, anorecenyloxyalkyl, alkynyloxyalkyl, alkylthioalkyl, aryl. Aralkyl quinole, aryloxyalkyl, arylthioalkyl (however, in the above definitions, aryl or aryl refers to norogen, trifluormethinole, alkyl, alkoxy, nitrite, nitrodoxyl, amino, May be substituted with a group selected from alkylamino, alkoxycarbonyl, carboxy, and cyano.), Heterocyclic, heterocyclic-substituted alkyl, heterocyclic-substituted oxyalkyl, and heterocyclic-substituted thioalkyl.

 A represents hydrogen or hydroxyl which may have a protecting group.

 R and R! Each represents hydrogen or alkyl.

R ₄ represents a hydrogen or nitrogen protecting group.

 Z and W each represent oxygen or sulfur. ]

A compound represented by the formula:

 Equation (3)

[Wherein the symbols mean the following.

R ₃ is a hydrogen or nitrogen protecting group or group (B)

 A

 I

One Y— C one Y ₂ (Β)

 Υ I

(In the formula, each symbol means the following. Y represents alkylene.

Upsilon, is hydrogen, alkyl or alkenyl, also the alkyl rather it may also be formed a consequent Russia alkyl with Upsilon _zeta, the a cycloalkyl may be substituted with alkyl.

 Υ2 is hydrogen, alkyl, alkenyl, alkynyl, alkyl optionally substituted with alkyl, alkyl-substituted amino aminoalkyl, anoreco xylene, arakeninoreoki cyanolecicle, anolequininoleoxy cyanolequinole, anorezole Anolequinole, aryl mono, aralkyl, aryloxyalkyl, arylthioalkyl

(However, in each of the above definitions, aryl or aryl is replaced with norogen, trifluorene, anorecre, acrekoxy, nitrite, nitrodoxyl, amino, anorequinoleami And may be substituted with a group selected from the group consisting of propyl, carboxy and cyano.), Heterocyclic-substituted alkyl, heterocyclic-substituted oxyalkyl and heterocyclic-substituted thioalkyl.

 Α represents hydrogen or hydroxyl optionally having a protecting group. )

Represents a group which can lead to

 R and R, each represent hydrogen or alkyl.

 R 4 represents a hydrogen or nitrogen protecting group. (However, R and

When R 1 and R 2 are both alkyl, R ₃ and R ₄ are groups other than hydrogen. )]

A compound represented by the formula:

 (4) 7 — (3—methoxycarbonylpropyl) 1 2 — (

3 o — hide mouth 1 cis 1 2> 6 — jazabisik Mouth [3.3.0] octa 6-en 3 -one, 7-(3-methoxycarbonylpropyl) 1 2-(3o-nitro, hydroxy-4- 1-cis-1,2,6-diazabicyclo [3.3.0] octa 6-en-3- (one) 7- (3-methoxycarbonylcarbonylthio) 1 2- (3α-high (4-D-hydroxybutyl) 1-cis-1,2,6-diazabicyclo [3.3.0] octa 6-en-3—one, 7— (3—methoxycarbonylpropylpropylthio ) 1 2 — (3 α—Hide mouth 4, 1, 4) 1 cis 1, 2, 6 — diazabicyclo [3.3.0] octa 1 6 — en 1 3 — On, Ί — (3 — methoxycarbonylpropylthio) 1 2 — [4-(ρ — fluorophenyl) 1 — 3 or — 1 cis 1 2, 6 — diazabicyclo

[3.3.0] octa-6-phen-3-on, 7- (3-methoxycarbonylpropylthio) 1-2- [4- (P-fluorophenyl) 13 1-Hydroxybutyl] 1-cis-1,2,6-diazabicyclo [3.3.0] octa-6-ene-3—thion and Ί— (3—methoxycarbonylpropylthio) 2 — C 4-

(p-fluorophenyl) 13 ^ -hydroxybutyl) 1-cis 2, 6- diazabicyclo [3.3.0] octa 1 6-en 1 3 The compound according to (1), a salt thereof or an ester thereof.

 (5) A pharmaceutical composition comprising the compound according to claim (1), a salt thereof or an ester thereof as an active ingredient.