Peptide derivatives having thiazolyl-alanine residue

This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/JP97/02917 which has an International filing date of Aug. 22, 1997 which designated the United States of America.

1. Technical Field

This invention relates to a new peptide derivative having the residue of 3-(4-thiazolyl or 5-thiazolyl)-alanine and having an effect of activating the central nervous system. The compound of this invention is useful as a medicament.

2. Background Art

The compound of this invention is derived from L-pyroglutamyl-L-histidyl-L-prolineamide (p-Glu-His-Pro-NH

2

), known as TRH (thyrotropin releasing hormone) isolated from hypothalamus.

TRH is a hormone consisting of 3 amino acid residues isolated from hypothalamus, and seems to show the activities through a TRH receptor. It is known not only to promote the secretion of TSH (thyroid stimulating hormone) and prolactin, but also to have the following activity; brain nervous system activation such as motor stimulating activity etc., sympathetic activity such as blood pressure elevation, respiratory stimulation, etc., spinal activity such as spinal motor nerve stimulation etc., central nervous activity such as antidepression etc., and peripheral activity such as gastrin secretion suppression, glucagon secretion stimulation, etc. Because TRH has such various activity, it has been investigated on the clinical use, and is being used as an intravenous injection for treating spinocerebellar degeneration for purposes of improvement of motility disturbance and cognitive disturbance accompanied by brain functional disturbance (Sofue, Kanazawa, Ogawa, “Neuropeptide”'91, Medicalreview).

However, there are various problems barring the clinical application of TRH. Typical ones are described below:

1) TRH shows very short half-time in blood and is required to be administered frequently, because it is digested by enzymes such as pyroglutamyl peptidase, TRH amidase, etc. in a living body.

2) Excessive secretion of TSH is caused by repeated administration of TRH due to the activity of stimulating secretion of TSH.

3) A slight mount of TRH is transferred into brain by peripheral administration because of its low hydrophobicity.

In order to solve the above problems concerning TRH, the development of TRH derivatives which have more potent activity than TRH in view of activation of the central nervous system (for example, awaking stimulation, anti-reserpine activity (hyperthermia), locomotor increment, spinal reflex increase, dopamine action potentiation, anti-anesthetic action, etc.) and have long duration of action has been attempted. Such compounds reported at the present time are illustrated below.

For example, 1-methyl-L-4,5-dihydroorotyl-L-hystidlyl-L-prolineamide (JP-B 2-36574), 2,3,4,5-tetrahydro-2-oxo-L-5-furancarbonyl-L-histidyl-L,-prolineamide (JP-A 52-116465), (1S, 2R)-2-methyl-4-oxocyclolentylcarbonyl-L-histidyl-L-prolineamide (JP-B-3-236397), orotyl-L-histydyl-L-prolineamide (JP-B 59-36612), TRH-SR (Eur. J. Pharmacol., 271, 357 (1994)), etc. are known

However, the above TRH derivatives do not have enough continuous action. Additionally, intravenous injection of these compounds makes it difficult to improve the compliance to the periodical administration of them and QOL (Quality of Life) of patients having the motor disturbance.

DISCLOSURE OF INVENTION

In the above situation, the inventors of the present invention found the compounds having superior activity known TRH and its derivatives in view of the activation of the central nervous system, for example, sustained acetylcholine releasing action, anti-reserpine action and locomotor increment activity. The present invention relates to

a) A peptide derivative of the formula (I):

wherein A is 4-thiazolyl or 5-thiazolyl wherein the nitrogen in the thiazolyl ring may be quarternary nitrogen which is formed with optionally substituted alkyl or alkenyl, X is a bond, oxygen, or sulfur, m is an integer of 0 to 4, Y is optionally substituted alkyl, optionally substituted carboxy, cyano, or the substituent represented by the formula:

wherein R

1

and R

2

are independently hydrogen or optionally substituted alkyl, or R

1

and R

2

taken together with may form a non-aromatic heterocyclic ring the adjacent nitrogen which may contain oxygen, nitrogen, or sulfur and may be substituted, Z is the substituent represented by the formula:

wherein R

3

is hydrogen, optionally substituted alkyl, optionally substituted carboxy, or optionally substituted acyl, R

4

and R

5

are each independently hydrogen or optionally substituted alkyl, and W is —(CH

2

)n— wherein n is 0, 1, 2, or 3, oxygen, sulfur, or optionally substituted imino, or the substituent, represented by the formula:

its pharmaceutically acceptable salt, or hydrate thereof.

b) A peptide derivative of the formula (II):

wherein X, Y, Z, and m are as defined above, and the nitrogen in the thiazolyl ring may be quarternary nitrogen which is formed with optionally substituted alkyl or alkenyl, its pharmaceutically acceptable salt, or hydrate thereof.

c) A peptide derivative of the formula (III):

wherein W, X, Y, m, R

3

, R

4

, and R

5

are as defined above, its pharmaceutically acceptable salt, or hydrate thereof.

e) A peptide derivative of the formula (V):

wherein Y is as defined above, its pharmaceutically acceptable salt, or hydrate thereof.

f) A peptide derivative of the formula (VI):

wherein Y is as defined above, its pharmaceutically acceptable salt, or hydrate thereof.

g) A peptide derivative of any one of a) to d) wherein m is 1 or 2, provided that X is not a bond when m is 1, its pharmaceutically acceptable salt, or hydrate thereof.

h) A peptide derivative of any one of a) to d) wherein m is 1 and Y is optionally substituted alkyl, optionally substituted carboxy, or optionally substituted carbamoyl, its pharmaceutically acceptable salt, or hydrate thereof.

i) A peptide derivative of any one of a) to d) wherein m is 2 or 3 and Y is optionally substituted alkyl, optionally substituted carboxy, or optionally substituted carbamoyl, its pharmaceutically acceptable salt, or hydrate thereof.

j) A pharmaceutical composition which contains any one of the compounds a) to i) as an active ingredient.

k) A composition for activating the central nervous system which contains any one of the compounds a) to i) as an active ingredient.

l) A TRH derivative having such effect that the ratio represented by the blood glucose level of the active substance-administered group/the blood glucose level of the physiological saline-administered group is 0.7 to 1.3 in the rat to which an effective amount of it for exhibiting the main activity is intravenously administered.

All of the compounds represented by the above formula have superior activity of activating the central nervous system. Specifically, the compounds having the substituents shown below in the formula (IV) are preferable.

1) A peptide derivative wherein W is oxygen, X is oxygen or sulfur, Y is carbamoyl or optionally substituted alkyl, m is 1, R

3

is hydrogen, R

4

is optionally substituted alkyl, and R

5

is hydrogen, its pharmaceutically acceptable salt, or hydrate thereof.

2) A peptide derivative wherein W is oxygen, X is a bond, Y is carbamoyl or optionally substituted alkyl, m is 2, R

3

is hydrogen, R

4

is optionally substituted alkyl, and R

5

is hydrogen, its pharmaceutically acceptable salt, or hydrate thereof.

As further preferable compounds, the compounds having the substituents shown below in the formula (IV) are exemplified.

1′) A peptide derivative wherein W is oxygen, X is oxygen or sulfur, Y is carbamoyl or alkyl, m is 1, R

3

is hydrogen, R

4

is alkyl, and R

5

is hydrogen, its pharmaceutically acceptable salt, or hydrate thereof.

2′) A peptide derivative wherein W is oxygen, X is a bond, Y is carbamoyl or alkyl, m is 2, R

3

is hydrogen, R

4

is alkyl, and R

5

is hydrogen, its pharmaceutically acceptable salt, or hydrate thereof.

As further preferable compounds, the compounds having the substituents shown below in the formula (IV) are exemplified.

1″) A peptide derivative wherein W is oxygen, X is sulfur, Y is carbamoyl or C

1

-C

6

straight or branched chain alkyl, m is 1, R

3

is hydrogen, R

4

is C

1

-C

3

straight or branched chain alkyl, and R

5

is hydrogen, its pharmaceutically acceptable salt, or hydrate thereof.

2″) A peptide derivative wherein W is oxygen, X is a bond, Y is carbamoyl or C

1

-C

6

straight or branched chain alkyl, m is 2, R

3

is hydrogen, R

4

is C

1

-C

3

straight or branched chain alkyl, and R

5

is hydrogen, its pharmaceutically acceptable salt, or hydrate thereof.

As a preferable configuration, the configuration represented by the formula (IV′) for the formula (IV) (when one of R

4

and R

5

is hydrogen, the configuration shows the other one than shown in the formula)

The term “halogen” herein used means fluoro, chloro, bromo, and iodo.

The term “alkyl” herein used includes C

1

-C

6

straight or branched chain alkyl and C

3

-C

6

cyclic alkyl. Preferably, C

1

-C

6

straight or branched chain alkyl is exemplified. Further preferably, C

1

-C

3

straight, or branched chain alkyl is exemplified. Examples of alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The term “alkenyl” herein used includes C

2

-C

8

straight or branched chain alkenyl. Preferably, C

3

-C

6

straight or branched chain alkenyl is exemplified. Further preferably, C

2

-C

5

straight or branched chain alkenyl is exemplified. Examples of alkenyl are n-propenyl, n-butenyl, n-hexenyl, and the like.

The term “aryl” herein used includes monocyclic or condensed ring aromatic hydrocarbons. Preferably, monocyclic aromatic hydrocarbons are exemplified. Examples of aryl are phenyl, naphthyl, and the like.

The term “heteroaryl” includes a 5 to 6 membered aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, may be fused with a carbocyclic ring or an other heterocyclic ring, and may be substituted at any possible position. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl (e.g., 2-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g., 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolizinyl), pyridyl (e.g., 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyl (e.g., 2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzisoxazolyl (e.g., 4-benzisoxazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g., 2-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (e.g., 3-furyl), benzofuryl (e.g., 3-benzofuryl), thienyl (e.g., 2-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, and the like.

The term “non-aromatic heterocyclic group” herein used means a 5 to 7 membered non-aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, and may bind at any possible position. Examples of the non-aromatic heterocyclic group are morpholino, piperidino, 1-pyrrolidinyl, 2-pyrroline-3-yl, and the like.

The term “acyl” herein used includes alkanoyl of which alkyl part is the above mentioned “alkyl” and aroyl of which aryl part is the above mentioned “aryl”. Examples of acyl are acetyl, benzoyl, and the like.

The term “alkyloxy” herein used includes alkyloxy of which alkyl part is the above mentioned “optionally substituted alkyl”. Examples of alkyloxy are methyloxy, ethyloxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy, tert-butyloxy, and the like.

The term “optionally substituted alkyl” for R

1

and R

2

herein used includes the above mentioned “alkyl” which is optionally substituted at any possible position with one or more substituents, for example, hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, carbamoyl, C

1

-C

20

alkyloxycarbonyl (e.g., methoxycarbonyl, iso-propyloxycarbonyl, tetradecanyloxycarbonyl, and pentadecanyloxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, SO

p

R

A

(p is an integer of 1 to 3, and R

A

is hydrogen or alkyl), PO(OH)

2

or PO(O)OH which is optionally substituted with alkyl, substituted or unsubstituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), optionally substituted aryl (e.g., phenyl and tolyl), optionally substituted heteroaryl, an optionally substituted non-aromatic-heterocyclic group, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, arylcarbonyl, non-aromatic heterocyclic carbonyl, hydrazino, hydroxyamino, alkyloxyamino, and formyl. Examples of optionally substituted alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, iso-propyloxycarbonylmethyl, tetradecanyloxycarbonylmethyl, pentadecanyloxycarbonylmrthyl, and the like. As the preferred substituent, C

1

-C

20

alkyloxycarbonyl and phenyl are exemplified.

The term “optionally substituted alkyl” for Y, R

3

, R

4

, and R

5

herein used includes the above mentioned “alkyl” which is optionally substituted at any possible position with one or more substituents, for example, hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, carbamoyl, alkyloxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, SO

p

R

A

(p is an integer of 1 to 3, and R

A

is hydrogen or alkyl), PO(OH)

2

or PO(O)OH which is optionally substituted with alkyl, substituted or unsubstituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), optionally substituted aryl (e.g., phenyl and tolyl), optionally substituted heteroaryl, an optionally substituted non-aromatic-heterocyclic group, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, non-aromatic heterocyclic carbonyl, heterocyclic imino, hydrazino, hydroxyamino, alkyloxyamino, and formyl. For example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, hydroxymethyl, tert-butylcarbonyloxymethyl, morpholinomethyl, piperidinomethyl, N-methyl-1-piperazinylmethyl, ethylcarbonylmethyl, morpholinocarbonylmethyl, acetyloxymethyl, and the like are exemplified. As a preferable substituent, phenyl, hydroxy, alkylcarbonyloxy, morpholino, piperidino, N-alkyl-substituted piperazinyl, alkylcarbonyl, morpholinocarbonyl, acyloxy are exemplified.

The term “optionally substituted alkyl” for nitrogen in the thiazolyl ring herein used includes C

1

-C

3

straight or branched chain alkyl which is optionally substituted with phenyl optionally substituted with halogen or alkyl. For example, methyl, ethyl, n-propyl, n-butyl, benzyl, 4-methylbenzyl are exemplified.

The terms “optionally substituted aryl”, “optionally substituted heteroaryl”, and “an optionally substituted non-aromatic heterocyclic group” herein used include the above mentioned “aryl”, “heteroaryl”, and “a non-aromatic heterocyclic group”, respectively, which are optionally substituted with one or more substituents, for example, hydroxy, alkyloxy (e.g. methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy), substituted or unsubstituted amino (e.g., methylamino, dimethylamino, diethylamino, and bezylideneamino), guanizino, alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, cyclopropyl, cyclobutyl, and cyclopentyl), alkenyl (e.g., vinyl and propenyl), alkynyl (e.g., ethynyl and phenylethynyl), alkanoyl (e.g., formyl, acetyl and propionyl), acyloxy (e.g., acetyloxy) acylamino, alkylsulfonyl (e.g., methylsulfonyl), phenyl, benzyl, an azo group (e.g., phenylazo), optionally substituted heteroaryl (e.g., 3-pyridyl), optionally substituted ureido (e.g., ureido and phenylureido), and the like.

The substituents for “optionally substituted carboxy” of Y are, for example, straight or branched chain C

1

-C

20

alkyl, cyclic C

3

-C

8

alkyl, and aryl. Further, these alkyl and aryl are optionally substituted with one or more substituents which are exemplified as those for the above “optionally substituted alkyl” and “optionally substituted aryl”. Examples of the “optionally substituted carboxy” are carboxy, alkyloxycarbonyl and aryloxycarbonyl, for example, methoxycarbonyl, iso-propyloxycarbonyl, hexyloxycarbonyl, decyloxycarbonyl, phenyloxycarbonyl, tetradecyloxycarbonyl, icosanyloxycarbonyl, phenoxymethylcarbonyl, benzyloxycarbonyl, tolyloxycarbonyl, and the like. As a preferable substituent, straight or branched chain C

1

-C

20

alkyl and benzyl are exemplified.

The substituents for “optionally substituted carbamoyl” of Y are, for example, straight or branched chain C

1

-C

6

alkyl (e.g., methyl, ethyl, n-propyl, and iso-propyl). Further, this alkyl is optionally substituted with one or more substituents which are exemplified as those for the above “optionally substituted alkyl”. Examples of the “optionally substituted carbamoyl” are carbamoyl, methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, methylethylcarbamoyl, benzylcarbamoyl, iso-propyloxycarbonylmethylcarbamoyl, tetradecanyloxycarbonylmethylcarbamoyl, benzyloxycarbonylmethylcarbamoyl, acetyloxymethylcarbamoyl, acetylcarbamoyl, and the like. As a preferable substituent, C

1

-C

20

alkyloxycarbonylalkyl and acyloxyalkyl are exemplified.

The substituents for “optionally substituted carboxy” of R

3

are, for example, the above mentioned “optionally substituted alkyl” and “optionally substituted aryl”. Examples of the “optionally substituted carboxy” are carboxy, alkyloxycarbonyl, and aryloxycarbonyl, for example, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, phenyloxymethylcarbonyl, tolyloxycarbonyl, and the like.

The term “optionally substituted acyl” herein used includes alkanoyl of which alkyl part is the above mentioned “optionally substituted alkyl” and aroyl of which aryl part is the above mentioned “optionally substituted aryl”. Examples of the “optionally substituted acyl” are toluoyl and the like.

The term “optionally substituted imino” herein used includes the imino which is optionally substituted with the above mentioned “optionally substituted lower alkyl”, “optionally substituted aryl”, alkyloxycarbonyl, and the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1

shows the effect of releasing acetylcholine in cerebral cortex when the test compound is orally administered to rats (the horizontal axis shows time course and the vertical axis shows a concentration of acetylcholine in cerebral cortex.).

FIG. 2

shows the transition of the blood glucose level by intravenous injection to rats (the horizontal axis shows time course and the vertical axis shows the blood glucose level).

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds of this invention are able to be synthesized by means of the following methods A and B as a usual method of the peptide synthesis. The substituents, for example, Y and the like are able to be introduced by alkylation, acylation, esterification, etc. after the tripeptide was synthesized in the same manner as the method A or B.

The compound represented by the formula (VII):

wherein A and Z are as defined above, and the compound of the formula (VIII):

wherein A, X, Y, and m are as defined above, which are intermediates for the methods A and B, are novel.

wherein A, X, Y, Z and m are as defined above.

wherein A, X, Y, Z, and m are as defined above.

The methods A and B are to obtain the aimed compound of tripeptide (I) using the amino acid derivatives represented by the formulas (IX), (X), and (XI) as a starting material. In the method A the compound (IX) is reacted with the compound (X) to give the compound (VII), which is further reacted with the compound (XI). In the method B the compound (X) is reacted with the compound (XI) to give the compound (VIII), which is then reacted with t,he compound (IX). Each reaction is carried out in accordance with a usual peptide synthetic reaction, for example, the method described in “The peptide”. vol. 1, “Peptide Synthesis”, Nobuo Izumiya, Maruzen and the like.

As a usual peptide synthetic reaction, exemplified are the method of using a condensing agent such as N,N-dicyclohexylcarbodiimide (DCC) and the like, the azide method, the acid chloride method, the acid anhydride method, the activated ester method, and the like. When the starting material has a substituent interfering this peptide synthetic reaction, for example, amino, carboxy, hydroxy, etc., the substituent can previously be protected in accordance with the method of “Protective Groups in Organic Synthesis” Theodora W. Green (John Wiley & Sons), and then deprotected at an appropriate step.

Examples of an amino protective group are t-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phthaloyl, tritluoroacetyl, and the like.

Examples of a carboxy protective group are esters such as methyl ester, ethyl ester, benzyl ester, t-butyl ester, 2-(trimethylsilyl)ethyl ester, etc.

As the method to activate the carboxy concerning the reactions of the compounds (VII), (IX), and (X), the following methods are exemplified; 1) the method to give activated esters such as N-hydroxysuccinimide ester, N-hydroxybenzotriazole ester, p-nitrophenol ester, and the like, 2) the method to give acid chlorides using chlorination agents such as phosphorus oxychloride, phosphorous trichloride, thionyl chloride, oxalyl chloride, and the like, 3) the method to give azides, 4) the method to give acid anhydrides. These methods are able to be carried out in the presence or absence of a deoxidizer in an appropriate solvent such as N,N-dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, and the like at −50° C. to reflux.

The active derivatives of carboxylic acids which are produced by the above methods are isolated and are able to be reacted with the compounds (VIII), (X), and (XI) having an amino group concerning this reaction. Without isolating the active derivatives of carboxylic acids in the above methods, the compounds (VIII), (X), and (XI) having an amino group concerning this reaction may be added to the reaction solution of the above methods. 1-Hydroxybenzotriazole may be added to the reaction mixture to expedite these reactions.

In this way, the compounds of this invention are able to be synthesized from amino acid derivatives of the compounds (IX), (X), and (XI) by two peptide synthetic reactions. The starting material of the amino acid derivatives are able to be obtained as known natural compounds and to be synthesized from them easily. The compound (IX) is able to be synthesized in accordance with the methods described in J. Med. Chem., 33, 2130 (1990), Int. J. Peptide Protein Res., 14, 216 (1979), Chem. Lett., 1171 (1982), and Tetrahedron Lett., 36, 6569 (1995). The compound (X) is able to be synthesized in accordance with the methods described in Synthetic Commun., 20, 3507 (1990) and EP 417454. The compound (XI) is able to be synthesized in accordance with the method described in J. Med. Chem., 24, 692 (1981).

The term “the compounds of this invention” herein used includes pharmaceutically acceptable salts or hydrates of the compounds. For example, salts with alkali metals (e.g., lithium, sodium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid), or organic acids (e.g., acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, and p-toluenesulfonic acid) and hydrates of them are exemplified. These salts and hydrates can be formed by the usual method.

The compound of this invention is TRH derivative of which the histidine residue is converted into the residue of 3-(4-thiazolyl)alanine or 3-(5-thiazolyl)alanine and has strong, continuous, and selective action on the central nervous system. Administration of TRH and conventional TRH derivatives acutely raises up the blood glucose level and acutely let it fall down by the rebound, which are not observed in the compound of this invention. This fact may lead to the less side effect.

Since the compound of this invention has superior hyperthermia and locomotor increment effects caused by activation of the neurones such as dopamine system, norepinephrine system, and acetylcholine system in brain, it is useful for treatment of disorders accompanied with dysfunction of these nervous systems. Especially, as it remarkably activates the acetylcholine neurone system in cerebral cortex, it may be useful as a therapeutic agent of disorders such as motor disturbance, disturbance of consciousness, senile dementia, sopor, decline of concentration, speech dysfunction, and the like accompanied with the dysfunction of the acetylcholine neurone.

When the compound of this invention is administered to a person for treatment or prevention of the above diseases, it can be administered by oral administration such as powder, granules, tablets, capsules, pilulae, and liquid medicine, or by parenteral administration such as injections, suppository, percutaneous formulations, insufflation. or the like. An effective amount of the compound of this invention is formulated by being mixed with medicinal admixture such as excipient, binder penetrant, disintegrators, lubricant, and the like if necessary. When parenteral injection is prepared, the compound of this invention and an appropriate carrier are sterilized to prepare it.

An appropriate dosage varies with the conditions of the patients, an administration route, their age, and their body weight. In the case of oral administration to adult, a dosage can generally be between 0.1-100 mg/kg/day, preferably 1-20 mg/kg/day.

The following examples are provided to further illustrate the present invention and are not to be construed as limiting the scope thereof.

Abbreviations described below are used in the following examples.

c-: cyclo

Me: methyl

Et: ethyl

Pr: propyl

Bu: butyl

Pen: pentyl

Hex: hexyl

Ph: phenyl

Ac: acetyl

BOC: tert-butyloxycarbonyl

Bzl: benzyl

Cbz: benzyloxycarbonyl

p-TsOH: p-toluenesulfonic acid

DCC: N,N-dicyclohexylcarbodiimide

HOBT: 1-hydroxybezotriazole

EXAMPLE

Example 1

Process 1

Preparation of N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl-L-prolineamide (1)

N-(tert-butyloxycarbonyl)-3-(4-thiazolyl)-L-alanine (8.17 g, 30 mmol) which was synthesized in accordance with the method described in the literature (Synthetic Commun., 20, 3507 (1990)) and L-prolineamide (3.42 g, 30 mmol) were dissolved in N, N-dimethylformamide (100 ml). To this solution was added the solution of dicyclohexylcarbodiimide (DCC, 6.81 g, 33 mmol) in N,N-dimethylformamide (10 ml) and 1-hydroxybenzotriazole (405 mg, 3 mmol) under ice-cooling with stirring and the resulting mixture was stirred overnight, at room temperature. To the reaction mixture was added ethyl acetate (200 ml) and the precipitation which appeared was filtered off. The filtrate was concentrated in vacuo. The residue (15.98 g) was subjected to silica gel column chromatography (chloroform: methanol=98:2 to 97:3) to give the compound (1) (10.01 g. 90.6%).

The compounds (2) an(d (3) were synthesized in a manner similar to that described in the above method. The results were shown in Table 1.

TABLE 1

melting

Example

Compound

point

No.

No.

A

X

[α]D

(° C.)

NMR

1-1

1

4-thiazolyl

CH

2

−57.1°

(CD

3

OD) 1.38(9H, s), 1.8-2.3

(c = 1.004,

(4H, m), 3.19(2H, ddd), 3.47

CHCl

3

,

(1H, m), 3.76(1H, m), 4.44

23.5° C.)

(1H, dd), 4.68(1H, dd, J=6.2,

7.4Hz), 7.33, 7.40(total 1H,

d, J=1.6Hz), 8.93(1H, d,

J=1.6Hz)

2-1

2

4-thiazolyl

S

−81.8°

(CD

3

OD) 8.95(bs, 1H), 7.40

(c = 0.501,

(bs, 1H), 4.6-5.0(3H), 4.44

MeOH,

(d, J=8.6Hz, 1H), 3.0-3.4

23° C.)

(4H), 1.39(s, 9H)

3-1

3

5-thiazolyl

CH

2

−53.5°

216-218

(CDCl

3

) 8.88(1H, s), 7.70

(c = 1.000,

and 7.73 (total 1H, s), 4.57

MeOH,

(1H, dd, J=4.4, 9.9Hz), 4.43

23.5° C.)

(1H, dd, J=4.2, 8.2Hz), 3.72

(2H, m), 3.40(1H, dd, J=4.4,

15.2Hz), 3.12(1H, dd,

J=9.8, 15.2Hz), 2.40-1.80

(4H, m), 1.38(9H, s)

Example 1

Process 2

Preparation of 3-(4-thiazolyl)-L-alanyl-L-prolineamide dihydrochloride (4)

To a solution of the compound (1,5.53 g. 15 mmol) in ethyl acetate (30 ml) was added a solution of 4N-hydrochloride in ethyl acetate (75 ml, 300 mmol) under ice-cooling and the resulting mixture was stirred for 2.5 h at the same temperature. To the reaction mixture was added diethyl ether (400 ml) and the precipitation which appeared was filtered off. The precipitation was washed with diethyl ether and dried in vacuo with vacuum pump to give 6.67 g of the compound (4). This compound was used in the next reaction without purification.

The compounds (5) and (6) were synthesized in a manner similar to that described in the above method. The results were shown in Table 2.

TABLE 2

Example

Compound

No.

No.

A

X

[α]D

NMR

1-2

4

4-thiazolyl

CH

2

−29.0°

(D

2

O) 9.53(1H, d, J=2.1Hz), 7.89

(c = 1.006,

(1H, d, J=2.1Hz), 4.66(1H, t,

MeOH,

J=5.7Hz), 4.53(1H, dd, J=5.4, 8.4

26° C.)

Hz), 3.50-3.7(4H, m), 2.5-1.8(4H, m)

2-2

5

4-thiazolyl

S

(D

2

O) 9.12 and 9.10(total 1H, s),

7.61 and 7.56(total 1H, s), 4.9-4.7

(3H, m), 4.41(1H, d, J=9.6Hz),

3.4-3.6(3H, m), 3.20(1H, dd,

J=5.8, 12.6Hz)

3-2

6

5-thiazolyl

CH

2

(CD

3

OD) 8.40 and 8.23(total 1H,

s), 4.72(1H, t, J=5.4Hz), 4.51(1H,

dd, J=5.4, 8.6Hz), 4.20-3.40(4H,

m), 2.5-1.8(4H, m)

Example 1

Process 3

Preparation of L-pyroglutamyl-3-(4-thiazolyl)-L-alanyl-L-prolineamide dihydrochloride (I-1)

L-Pyroglutamic acid (1.76 g, 13.64 mmol) and N-hydroxysuccinimide (1.73 g, 15 mmol) were dissolved in N,N-dimethylformamide (50 ml). To this solution was added the solution of DCC (3.09 g, 15 mmol) in N,N-dimethylformamide (10 ml) under ice-cooling and the resulting mixture was stirred for 2 h at, the same temperature. 3-(4-thiazolyl)-L-alanyl-L-prolineamide dihydrochloride (4) (6.67 g, 15 mmol) and triethylamine (4.6 ml. 33 mmol) were added successively to the solution and the reaction mixture was stirred overnight. After the precipitation which appeared was filtered off, to the filtrate was added sodium hydrogencarbonate aq. to adjust pH 8. The reaction mixture was subjected to gel filtration column chromatography (MCI gel CHP-20P, 200 ml, aq. MeOH) to give the compound (I-1) (2.54 g, 49%).

The compounds (I-2) to (I-12) were synthesized in a manner similar to that described in the above method. The results were shown in Tables 3 to 6.

TABLE 3

Example

Compound

IR

No.

No.

A

X

[α]D

(cm

−1

)

NMR

1-3

I-1

4-thiazolyl

CH

2

−42.9°

(KBr)

(CD

3

OD) 8.95(1H, d, J=2

(c = 1.003,

3294,

Hz), 7.43 and 7.34(total 1H,

MeOH,

1683,

d, J=2Hz), 4.95(1H, t, J=7

24° C.)

1639,

Hz), 4.42 and 4.34(total 1H,

1541,

m), 4.17(1H, m), 3.80(1H,

1518,

m), 3.1-3.6(3H, m), 1.8-2.5

1444,

(8H, m).

1263

2-3

I-2

4-thiazolyl

S

−87.6°

(KBr)

(CD

3

OD) 8.95(1H, d, J=1.8

(c = 1.012,

3301,

Hz), 7.43 and 7.37(total 1H,

H

2

O,

2936,

d, J=1.8Hz), 5.05(1H, t,

23° C.)

1685,

J=6.8Hz), 4.99(1H, d, J=8.6

1518,

Hz), 4.86(1H, m), 4.45(1H,

1419,

d, J=8.6Hz), 4.18(1H, dd,

1330,

J=5, 8.6Hz), 3.1-3.5(4H, m),

1262

1.9-2.5(4H, m)

3-3

I-3

5-thiazolyl

CH

2

−53.6°

(KBr)

(CD

3

OD) 8.86(1H, s), 7.75

(c = 1.002,

3393,

and 7.71(total 1H, d, J=0.6

MeOH,

3081,

Hz), 4.90(1H, m), 4.42(1H,

23° C.)

1684,

dd, J=4.5, 8.4Hz), 4.18(1H,

1639,

dd, J=4.8, 8.7Hz), 3.95-3.60

1540,

(2H, m), 3.50(1H, dd, J=4.5,

1443,

15.3Hz), 3.24(1H, dd,

1247

J=9.3, 15.3Hz), 2.60-1.80

(8H, m).

TABLE 4

Example

Compound

IR

No.

No.

A

X

[α]D

(cm

−1

)

NMR

4-3

I-4

4-thiazolyl

CH

2

−10.4°

(KBr)

(D

2

O) 8.93(1H, s), 7.35 and

(c = 1.005,

3397,

7.29(1H, s), 5.03(1H, m),

H

2

O,

2954,

4.39(1H, m), 4.21(1H, m),

24° C.)

1719,

3.76(1H, m), 3.57(1H, m),

1676,

2.7-3.4(4H, m), 3.04 and 3.4

1542(w),

(4H, m), 3.04 and 3.01(total

1519(w),

3H, s), 1.8-2.4(4H, m).

1448

5-3

I-5

4-thiazolyl

S

−37.3°

(KBr)

(CD

3

OD) 8.93(1H, d, J=1.8

(c = 1.005,

3313,

Hz), 7.39 and 7.33(total 1H,

H

2

O,

2931,

d, J=1.8Hz), 5.02(1H, t,

23° C.)

1720,

J=6.8Hz), 4.95(1H, d, J=8.8

1675,

Hz), 4.86(1H, m), 4.46(1H,

1517,

d, J=8.8Hz), 4.09(1H, dd,

1468,

J=4.4, 7.2Hz), 3.1-3.5(4H,

1435,

m), 3.06(3H, s), 2.97(1H,

1305,

dd, J=7.2, 16.6Hz), 2.78

1125.

(1H, dd, J=4.2, 16.6Hz)

6-3

I-6

5-thiazolyl

CH

2

−12°

(KBr)

(CD

3

OD) 8.87(1H, s), 7.67

(c = 1.011,

3318,

and 7.73(total 1H, s), 4.90

MeOH,

1720,

(1H, m), 4.42(1H, dd, J=4.4,

23° C.)

1675,

8.2Hz), 4.09(1H, dd, J=3.6,

1523,

7Hz), 3.70(2H, m), 3.49

1448,

(1H, dd, J=4.2, 15.4Hz),

1356,

3.21(1H, dd, J=9.2, 15.4

1304,

Hz), 3.08 and 3.05(total 3H,

1270.

s), 2.92(1H, dd, J=7, 12.6

Hz), 2.78(1H, dd, J=3.6,

12.6Hz), 2.4-1.8(4H, m).

TABLE 5

Example

Compound

IR

No.

No.

A

X

[α]D

(cm

−1

)

NMR

7-3

I-7

4-thiazolyl

CH

2

−30.3°

(KBr)

(CD

3

OD) 8.95(1H, d, J=2

(c = 1.003,

3398,

Hz), 7.43 and 7.33(1H, d,

H

2

O,

1752,

J=2Hz), 4.97(1H, t, J=7

25° C.)

1677,

Hz), 4.3-4.6(2H, m), 3.93

1641,

(1H, d, J=5.4Hz), 3.78(1H,

1517,

m), 3.1-3.6(3H, m), 1.7-2.3

1445,

(4H, m), 1.45(3H, d, J=6.6

1229.

Hz).

8-3

I-8

4-thiazolyl

S

−58.8°

(KBr)

(CD

3

OD) 8.95(1H, d, J=1.8

(c = 1.010,

3397,

Hz), 7.43 and 7.36(1H, d,

H

2

O,

2980,

J=1.8Hz), 5.07(1H, t, J=6.6

23° C.)

2932,

Hz), 4.98(1H, d, J=8.6Hz),

1752,

4.86(1H, m), 4.4-4.6(1H,

1677,

m), 4.45(1H, d, J=8.6Hz),

1649,

3.95(1H, d, J=5Hz), 3.1-3.5

1519,

(4H, m), 1.46(3H, d, J=6.2

1413,

Hz).

1227

9-3

I-9

5-thiazolyl

CH

2

−25.8°

(KBr)

(CD

3

OD) 8.89(1H, s), 7.76

(c = 1.009,

3397,

and 7.71(total 1H, s), 4.90

H

2

O,

1753,

(2H, m), 4.43(1H, dd, J=5.4,

23° C.)

1677,

6.3Hz), 3.93(1H, d, J=5.4

1639,

Hz), 4.1-3.6(2H, m), 3.50

1527,

(1H, dd, J=4.2, 15Hz), 3.25

1446,

(1H, dd, J=9.3, 15Hz), 2.4-

1403,

1.8(4H, m), 1.44(3H, d,

1301,

J=6.3Hz).

1230

TABLE 6

Example

Compound

IR

No.

No.

A

X

[α]D

(cm

−1

)

NMR

10-3

I-10

4-thiazolyl

CH

2

−52.1°

(KBr)

(CD

3

OD) 8.95(1H, d, J=1.8

(c = 1.006,

3392,

Hz), 7.43 and 7.35(total 1H,

H

2

O,

1751,

d, J=1.8Hz), 5.02(1H, t,

26° C.)

1676,

J=7.1Hz, 1H), 4.90(1H, m),

1638,

4.38(1H, m), 4.33(1H, d,

1542,

J=8.6Hz), 3.88(1H, m), 3.1-

1519,

3.6(3H, m), 1.9-2.3(4H, m),

1446,

1.26 and 1.20(total 3H, d,

1407,

J=6.6Hz).

1235,

1097

11-3

I-11

4-thiazolyl

S

−80.3°

(KBr)

(CD

3

OD) 8.99 and 8.95(total

(c = 1.010,

3308,

1H, d, J=2Hz), 7.43 and

H

2

O,

2985,

7.39(total 1H, d, J=2Hz,),

23° C.)

2936,

5.11(1H, t, J=6.5Hz), 5.10

1752,

(1H, d, J=8.6Hz), 4.7-5.0

1678,

(2H, m), 4.48(1H, d, J=8.6

1651,

Hz), 4.34(1H, d, J=8.8Hz),

1518,

3.1-3.5(4H, m), 1.22(3H, d,

1414,

J=6.6Hz)

1333,

1231,

1096

12-3

I-12

5-thiazolyl

CH

2

−46.2°

(KBr)

(CD

3

OD) 8.89 and 8.80(total

(c = 1.002,

3406,

1H, s), 7.73 and 7.77(total

MeOH,

1752,

1H, s), 4.90(1H, m), 4.90

23° C.)

1677,

(1H, m), 4.41(1H, dd, J=5.2

1638,

and 9Hz), 4.35(1H, d, J=8.7

1542,

Hz), 3.90(1H, m), 3.71(1H,

1447,

m), 3.50(1H, dd, J=4.2, 15.3

1404,

Hz), 3.25(1H, dd, J=9.6,

1343,

15.3Hz), 2.4-1.8(4H, m),

1300,

1.26 and 1.18(total 3H, d,

1237

J=6.3Hz).

Example 13

Preparation of L-2-oxo-oxazolidine4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-prolineamide (I-13)

The compound (I-13) was obtained in a manner similar to that described in the method of Example 1-3.

Example 14

Preparation of trans-L-N-benzyl-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-prolineamide (I-14).

(1) trans-L-5-Methyl-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (706 mg, 3 mmol) which was synthesized in accordance with the method described in Tetrahedron Lett., 36, 6569 (1995) was dissolved in N, N-dimethylformamide (8 ml). After benzyl bromide (0.39 ml, 3.28 mmol) was added to the solution, 60% sodium hydride (120 mg, 3 mmol) was added to the mixture over 5 min. with stirring. The mixture was stirred for 3 h at room temperature. The reaction mixture was partitioned between ice-water and ethyl acetate. The organic layer was washed with water, dried over magnesium sulphate, and concentrated in vacuo. The residue was subjected to Lobar® column B (Merck inc.) and the fractions eluting with toluene:acetone=30:1 were collected to yield trans-L-N-benzyl-5-methyl-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (859 mg. 88%) as colorless oil.

NMR (CDCl

3

): 7.1-7.5 (10H, m), 5.17 (2H, s),4.92 (1H, d, J=14.6 Hz),4.56 (1H, m),4.14(1H, d, J=14.6 Hz), 3.63 (1H, d, J=5.2 Hz), 1.39 (3H, d, J=6.4 Hz).

The compound (860 mg, 2.61 mmol) obtained in the above process was dissolved in mixed solvents of tetrahydrofuran (18 ml) and 1,2-dimethoxyethane (2.7 ml). To the mixture was added the solution of lithium hydroxide monohydrate (548 mg, 13.1 mmol) in water (10 ml) and the resulting mixture was stirred for 30 min. at room temperature. The reaction mixture was poured into ice-water and extracted with diethyl ether three times. To the alkali layer was added 5N hydrochloric acid (3 ml) for adjusting pH 1 and the mixture was extracted with ethyl acetate twice. The organic layer was washed with water, dried over magnesium sulphate, and concentrated in vacuo. The residue (574 mg. 93.5%) was recrystallized from acetone-hexane to give trans-L-N-benzyl-5-methyl-2-oxo-oxazolidine-4-carboxylic acid (493 mg, 80.3%).

mp: 127° C.

[α]

D

=−7.8° (c=1.003, CHCl

3

, 24° C.)

IR (KBr) cm

−1

: 2716, 2601, 1740, 1692, 1497, 1442, 1421, 1369, 1248, 1201, 1186, 1078.

IR (CHCl

3

) cm

−1

: 1758, 1496, 1455, 1415, 1227, 1223, 1212, 1205.

NMR (DMSO-d6): 7.2-7.5 (5H, m), 4.69 (1H, d, J=15.4 Hz), 4.62 (1H, m),4.15 (1H, d, J=15.4 Hz), 3.71 (1H, d, J=4.4 Hz), 1.32 (3H, d, J=6.2 Hz).

Elemental analysis (C

12

H

13

NO

4

) Calcd.: C,61.27; H,5.57; N,5.96. Found: C,61.30; H,5.61; N,5.91.

Compound (I-14) was obtained in a manner similar to that described in the Example 1-3.

Example 15

Preparation of trans-L-N,5-dimethyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-prolineamide (I-15)

To a solution of trans-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (488 mg, 2.075 mmol) in N, N-dimethylformamide (6 ml) was added iodomethane (0.17 ml, 2.73 mmol) under ice-cooling in nitrogen atmosphere with stirring. Subsequently, 60% sodium hydride (83 mg, 2.075 mmol) was added to the mixture over 10 min. The reaction mixture was stirred for 3 h at the same temperature. The reaction mixture was partitioned between ice-water and ethyl acetate. The organic layer was washed with water, dried over magnesium sulphate, and concentrated in vacuo. The residue (503 mg) was subjected to Lobar® column B (Merck inc.) and the fractions eluting with toluene:acetone=30:1 were collected to yield trans-L-N,5-dimithyl-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (444 mg. 85.8%) as colorless oil.

NMR(CDCl

3

): 7.37 (5H, m), 5.27 (1H, d, J=12.2 Hz), 5.20 (1H, d, J=12.2 Hz), 4.51 (1H, m), 3.86 (1H, d, J=5.4 Hz), 2.92(3H, s), 1.50 (3H, d, J=6.2 Hz).

A solution of the compound (551 mg, 2.21 mmol) which was obtained the above process in mixed solvents of methanol (10 ml)-water (1 ml) was hydrogenated using 5% Pd/C (150 mg) for 1 h at room temperature. The catalyst, was filtered off and the filtrate was concentrated in vacuo to obtain trans-L-N,5-dimethyl-2-oxo-oxazolidine-4-carboxylic acid (345 mg, 98%).

mp: 125-127° C.

[α]

D

=−11.1° (c=1.005, MeOH, 24° C.)

IR(KBr)cm

−1

: 3433, 2585, 1743, 1697, 1483, 1443, 1408, 1227, 1034.

NMR(DMSO-d6): 4.51 (1H,m), 3.99 (1H, d J=5.4 Hz), 2.79 (3H, s), 1.38 (3H, d, J=6.2 Hz).

Elemental analysis (C

6

H

9

NO

4

) Calcd.: C,45.28; H,5.70; N,8.80. Found: C,45.40; H,5.63; N,8.74.

The compound (I-15) was obtained in a manner similar to that described in the method of Example 1-3. The results were shown in Table 7.

TABLE 7

Example

Compound

IR

No.

No.

Z

[α]D

(cm

−1

)

NMR

13

I-13

−53.0° (c = 1.009, H

2

O, 25° C.)

(KBr) 3294, 1752, 1676, 1637, 1542, 1519, 1446, 1407, 1237

(CD

3

OD) 8.95(1H, d, J=2 Hz), 7.43 and 7.33(total 1H, d, J=2Hz), 4.96(1H, t, J=7.1Hz), 4.2-4.6(4H, m), 3.80(1H, m),

# 3.1-3.6 (3H, m), 1.9-2.3(4H, m)

14

I-14

−43.7° (c = 1.008, H

2

O, 24.5° C.)

(KBr) 3412, 1752, 1679, 1644, 1543, 1516, 1442, 1415, 1227, 1206, 1092, 1066.

(CD

3

OD) 8.99(1H, d, J=2 Hz), 7.41(1H, d, J=2.1 Hz), 7.1-7.5(5H, m), 4.95 (1H, m), 4.73(1H,

# d, J=15.2Hz), 4.42(2H, m), 3.87(2H, d, J=15.2Hz), 3.78(1H, m), 3.68(1H, d, J=5.1Hz), 3.0-3.6(3H, m), 1.8-2.3(4H, m), 1.35 (3H, d, J=6.4Hz).

15

I-15

−31.9° (c = 1.000, H

2

O, 23° C.)

(KBr) 3412, 1751, 1678, 1519, 1544, 1519, 1437, 1401, 1237.

(CD

3

OD) 8.96(1H, d, J=2 Hz), 7.44 and 7.35(total 1H, d, J=2Hz), 5.04(1H, dd, J=6.2, 7.8Hz), 4.40 (2H, m), 3.88(1H,

# d, J=5.4Hz), 3.80(1H, m), 3.1-3.6(3H, m), 2.67(3H, s), 1.8-2.3(4H, m), 1.43 (3H, d, J=6.4Hz)

Example 16

Preparation of 4-[2-L-pyroglutamyl-2-{(S)-2-carbamoylpyrrolidine-1-ylcarbonyl}ethyl]-3-methylthiazolium iodide (I-16)

To a solution of the compound (I-1)(5 g, 13.18 mmol) in acetonitrile (500 ml) was added iodomethane (67 ml, 1.07 mol) and the resulting mixture was heated at reflux on oil bath (80° C.) for 20 h. After the reaction mixture was cooled at 0° C., the supernatant liquid was removed by decanting. The precipitate was washed with cold acetonitrile and was added diethyl ether. The crystal powder was collected by filtration to give 6.64 g of compound (I-16) as yellow powder. Using a procedure analogous to that described above, the compounds (I-17) to (I-27) were synthesized. The results were shown in Table 8 to Table 10.

TABLE 8

Example

Compound

No.

No.

B

D

NMR (CD

3

OD)

16-3

I-16

Me

I

8.03 and 7.96(total 1H, s), 5.13(1H, t, J=7

Hz), 4.58 and 4.42(total 1H, m), 4.31 and 4.26

(total 3H, s), 4.20(1H, m), 3.66(2H, m), 3.50

(1H, dd, J=6.6 and 15.6 Hz), 3.25(1H, dd,

J=7.4, 15.6Hz), 1.8-2.5(8H, m)

17-3

I-17

Et

I

10.08(1H, s), 8.04 and 7.97(total 1H, s), 5.12

(1H, t, J=7.6Hz), 4.62(2H, q, J=7.2Hz), 4.42

(1H, m), 4.19(1H, m), 3.2-3.7(4H, m), 2.32

(4H, m), 1.98(4H, m), 1.66(3H, t, J=7.2Hz).

18-3

I-18

n-Pr

I

10.08(1H, d, J=2.6Hz), 8.06 and 8.00(total

1H, d, J=2.6Hz), 5.12 and 4.98(total 1H, t,

J=7.0Hz), 4.56(2H, t, J=7.8Hz), 4.43(1H, m),

4.20(1H, m), 3.2-3.9(4H, m), 2.34(4H, m),

2.02(6H, m), 1.18 and 1.07(total 3H, t, J=7.4

Hz).

19

I-19

n-Bu

I

10.07(1H, d, J=2.6Hz), 8.06 and 7.99(total

1H, d, J=2.6Hz), 5.12 and 4.99(total 1H, t,

J=7.0Hz), 4.59(2H, t, J=7.8Hz), 4.43(1H, m),

4.20(1H, m), 3.2-3.9(4H, m), 2.34(4H, m),

2.02(6H, m), 1.49(2H, m), 1.04(3H, t, J=7.0

Hz).

TABLE 9

Example

Compound

No.

No.

A

X

[α]

D

NMR (CD

3

OD)

20

I-20

allyl

Br

8.65 (1H, d, J=9.3 Hz), 8.08

(1H, d, J=2.7 Hz), 6.17 (1H,

m), 5.47 (2H, m), 5.25 (2H,

m), 5.11 (1H, m), 4.41 (1H,

dd, J=4.2, 8.8 Hz), 4.19 (1H,

dd, J=4.8, 8.8 Hz), 3.66 (2H,

m), 3.50 (1H, dd, J=7.2, 15

Hz), 3.25 (1H, m), 1.8-2.5

(8H, m).

21

I-21

Br

−70.5° (c = 1.005, H

2

O, 24° C.)

9.90 and 9.86 (total 1H, d, J=2.4 Hz), 8.12 and 8.03 (total 1H, d, J=2.4 Hz), 7.47 (5H, m), 5.89 (1H, d, J=15.2 Hz), 5.80 (1H, d, J=15.2 Hz), 5.04 (1H, t, J=7 Hz), 4.40 (1H, m), 4.20 (1H, m), 3.1- 3.7 (4H, m), 2.35 (4H, m), 1.97 (4H, m).

22

I-22

Br

−65.4° (c = 1.001, H

2

O, 24° C.)

9.12 and 8.02 (total 1H, d, J=2.4 Hz), 7.32 (4H, m), 5.82 (1H, d, J=15 Hz), 5.73 (1H, d, J=15 Hz), 5.02 (1H, t, J=7 Hz), 4.40 (1H, m), 4.20 (1H, m), 3.1-3.7 (4H, m), 2.37 (3H, s), 2.34 (4H, m), 1.97 (4H, m).

23

I-23

Br

9.71 (1H, d, J=2.4 Hz), 7.02 (1H, d, J=2.7 Hz), 5.62 (2H, d, J=4.2), 5.04 (1H, m), 4.42 (1H, m), 4.19 (1H, dd, J=4.2, 8.5 Hz,) ,3.66 (2H, m), 3.50 (1H, m), 3.25 (1H, m), 2.22 (6H, s), 1.8-2.5 (8H, m).

TABLE 10

Example

Compound

No.

No.

Z

[α]

D

NMR (CD

3

OD)

24

I-24

−26.9° (c = 1.001, H

2

O, 22.5° C.)

7.91 and 7.88 (total 1H, s), 5.12 (1H, dd, J=5.1 and 9.9 Hz), 4.44 and 4.55 (total 1H, m), 4.13 and 4.26 (total 1H, m), 4.23 (3H, s), 3.63 (2H, m), 3.48 (1H, dd, J=4.5 and 15.6 Hz), 3.31 (1H, dd, J=9.6 and 15.6 Hz), 3.11 (1H, dd, J=6.9, 16.8 Hz), 3.05 (3H, s), 2.76

# (1H, dd), 1.8-2.4 (4H, m).

25

I-25

−42.9° (c = 1.013, H

2

O, 24.5° C.)

8.04 and 7.94 (total 1H, s), 5.16 (1H, dd, J=6.4, 7.8 Hz), 4.4-4.6 (2H, m), 4.30 and 4.26 (total 3H, s), 3.98 and 3.90 (total 1H, d, J=5.4 Hz), 3.66 (2H, m), 3.52 (1H, dd, J=6.6, 16.0 Hz), 3.27 (1H, dd, J=8.2, 16 Hz), 1.8-2.4 (4H, m), 1.46 (3H, d, J=6.2 Hz).

26

I-26

−50.0° (c = 1.006, H

2

O, 24.5° C.)

8.09 and 8.02 (total 1H, s), 5.19 (1H, t, J=7 Hz), 4.8-5.0 (1H, m), 4.3-4.5 (2H, m), 4.30 and 4.24 (total 3H, s), 3.82 (1H, m), 3.64 (1H, m), 3.53 (1H, dd, J=7, 15.6 Hz), 3.26 (1H, m), 1.8- 2.4 (4H, m), 1.27 (3H, d, J=6.4 Hz).

27

I-27

−59.2° (c = 1.006, H

2

O, 24.5° C.)

8.03 and 7.95 (total 1H, s), 5.15 (1H, dd, J=6.4, 7.8 Hz), 4.58 (1H, dd, J=8.4, 9 Hz), 4.42 (1H, dd, J=4.6, 9 Hz), 4.2-4.5 (2 H, m), 4.30 and 4.26 (total 3H, s), 3.67 (2H, m), 3.52 (1H, dd, J=7.4, 15.8 Hz), 3.27 (1H, dd, J=8, 15.8 Hz), 1.8-2.4 (4H, m).

Example 28

Preparation of 5-[2-L-pyroglutamylamino-2-{(S)-2-carbamoylpyrrolidine-1-ylcarbonyl}ethyl]-3-methylthiazolium iodide (I-28)

The compound (I-28) was obtained 56.4% yield in a manner similar to that, described in the method of Example 16 using the compound (I-3) as a starting material.

[α]

D

=−40.6° (c=1.001, MeOH, 21° C.)

IR(KBr)cm

−1

: 3412, 1677, 16:39, 15:3:3, 14:39, 1262.

NMR(CD

3

OD): 8.20 and 8.21 (total 1H, s), 502 (1H, dd, J=6,7 Hz), 4.41 (1H, dd, J=4,8.4 Hz), 4.25 (1H, dd, J=3, 5.8 Hz), 4.22 (3H, s), 3.68 (2H, m), 3.53 (1H, dd, J=7, 15 Hz), 3.34 (1H, dd, J=6, 15 Hz), 1.8-2.4 (4H, m), 2.02 (4H, m).

Elemental analysis (C

17

H

24

N

5

O

4

IS 3H

2

O) Calcd.: C,35.48; H,5.25; N,12.17; I,22.05; S,5.57. Found: C,35.36; H,5.15; N,12.43; I,21.97; S,5.75. Found: C,35.36; H,5.15; N,12.43; I,21.97; S,5.75.

Example 29

Process 1

Preparation of tetradecyl L-prolyl-glycinate (10)

(i) To a solution of N-benzyloxycarbonyl glycine (3 g, 14.3 mmol), tetradecylalcohol (3.07 g, 14.3 mmol) an N,N-dimethylaminopyridine (87 mg, 10.3 mmol) in ethyl acetate (100 ml) was added DCC (2.98 g, 2.34 mmol) and the resulting mixture was stirred for 2 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue was washed with ethanol to give N-benzyloxycarbonylglycine tetradecyl ester (7) (3.46 g, 59.5%) as crystal.

mp: 57-58° C.

NMR(CDCl

3

): 7.36 (5H, s), 5.22 (1H, m), 5.13 (2H, s), 4.14 (2H, t, J=6.6 Hz), 3.84 (2H, d, J=5.4 Hz), 1.60 (2H, m), 1.26 (22H, br.s), 0.88 (3H, t, J=6.6 Hz).

Elemental analysis (C

24

H

39

NO

4

) Calcd.: C,71.07; H,9.69; N,3.45. Found: C,70.94; H,9.60; N,3.74.

(ii) A solution of the compound (7) and p-toluenesulfonic acid hydrate (1.4 g, 7.39 mmol) in mixed solvents of water (2 ml)-methanol (70 ml) was hydrogenated using 5% pd/C (500 mg) for 3 h at room temperature. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was recrystallized from ethyl acetate to give tetradecanylglycinate p-toluensulfonate (8) (2.76 g, 84%).

mp: 85.5-86.56° C.

NMR(CD

3

OD): 7.70 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.2 Hz), 4.23 (2H, d, J=6.6 Hz), 3.82 (2H, s), 2.37 (3H, s), 1.65 (2H, m), 1.29 (22H, m), 0.90 (3H, t, J=6.6 Hz).

Elemental analysis (C

23

H

41

NSO

5

) Calcd.: C,62.12; H,9.29; N,3.15; S,7.21. Found: C,61.90; H,9.15; N,3.18; S,7.72.

(iii) To a solution of the compound (8) (2.06 g, 4.64 mmol), N-(tert-butyloxycarbonyl)-L-proline (1 g, 4.64 mmol), N-hydroxybenzotriazole (18 mg, 0.139 mmol), and triethylamine (0.71 ml) in N,N-dimethylformamide (30 ml) was added DCC (1 g, 4.87 mmol) and the resulting mixture was stirred for 18 h at room temperature. After the precipitation which appeared was filtered off. the filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water, dried over magnesium sulphate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (toluene: ethyl acetate=3:1) to give tetradecyl N-(tert-butyloxycarbonyl)-L-prolyl-glycinate (9) (1.94 g, 89.4%).

[α]

D

=−54.4° (c=1.008, CHCl

3

, 23° C.)

NMR(CDCl

3

): 4.31 (1H, m), 4.13 (2H, t, J=6.6 Hz), 4.05 (2H, dd, J=5.8, 7.7 Hz), 3.45 (2H, m), 1.90 (2H, m), 1.47 (9H, s), 1.26 (22H, br.s), 0.88 (3H, t, J=7 Hz).

Elemental analysis (C

26

H

48

N

2

O

5

) Calcd.: C,66.63; H,10.32; N,5.98. Found: C,66.62; H, 10.24; N,6.05.

(iv) A suspension of the compound (9) (1.47 g, 3.02 mmol) in trifluoroacetic acid (14 ml) was stirred for 2 h under ice-cooling. The reaction mixture was diluted with toluene and the resulting mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and sodium hydrogencarbonate aq. The organic layer was washed with water and concentrated in vacuo to give 1.08 g of tetradecyl L-prolyl-glycinate (10) as powder.

The compounds (11) and (12) were synthesized in a manner similar to that described in the above method. The results were shown in Table 11.

TABLE 11

Example

Compound

No.

No.

R

6

[α]

D

NMR

29-1

10

(CH

2

)

13

CH

3

−45.7°

(CDCl

3

) 8.10 (1H, m), 4.13 (2H, t,

(c = 1.004,

J=6.6 Hz), 4.03 (2H, d, J=5.6 Hz),

MeOH,

3.79 (1H, dd, J=5.4, 9 Hz), 3.00 (2H,

23° C.)

m), 1.8-2.2 (2H, m), 1.70 (4H, m),

1.26 (22H, m), 0.88 (3H, t, J=6.8

Hz).

30-1

11

CH (CH

3

)

2

(CD

3

OD) 7.36 (5H, s), 5.18 (1H, d,

J=7 Hz), 4.31 (1H, m), 4.08 (2H, m),

3.35 (2H, m), 2.44 (1H, m), 2.05 (3H,

m)

31-1

12

CH

2

Ph

(CD

3

OD) 5.03 (1H, m), 4.33 (1H, m),

4.00 (2H, m), 3.35 (2H, m), 2.48 (1H,

m), 2.06 (3H, m), 1.24 (6H, d, J=6

Hz)

Example 29

Process 2

Preparation of tetradecyl N-(tert-butyloxycarbonyl)-3-(4-thiazolyl)-L-alanyl-L-prolyl-glycinate (13)

To a solution of N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine (1, 480 mg, 1.76 mmol) which was synthesized in accordance with the method described in the literature (Synthtic Commun., 20, 3507, (1990)), the compound (10) (650 mg, 1.76 mmol), and N-hydroxybenzotriazole (70 mg, 0.528 mmol) in N,N-dimethylformamide (20 ml) was added DCC (380 mg, 1.848 mmol) and the resulting mixture was stirred overnight at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the precipitation which appeared was filtered off again. The filtrate was concentrated in vacuo. The residue was subjected to silica gel column chromatography (ethyl acetate:toluene=9:1) to give 1.02 g of the compound (13).

The compounds (14) and (15) were synthesized in a manner similar to that described in the above method. The results were shown in Table 12.

TABLE 12

Example

Compound

No.

No.

R

6

[α]

D

NMR (CDCl

3

)

29-2

13

(CH

2

)

13

CH

3

−44.9°

8.78 (1H, d, J=1.8 Hz), 7.22 (1H, d,

(c = 1.012,

J=2 Hz), 5.54 (1H, d, J=8.2 Hz), 4.67

CHCl

3

,

(2H, m), 4.41 (1H, dd, J=7.4, 17.6

23° C.)

Hz), 4.14 (2H, t, J=7 Hz), 3.74 (1H,

dd, J=5.5, 17.6 Hz), 3.50 (1H, m),

3.30 (2H, m), 2.97 (1H, m), 1.45 (9H,

s), 2.30 (1H, m), 1.95 (3H, m), 1.27

(22H, m), 0.89 (3H, t, J=6.6 Hz).

30-2

14

CH (CH

3

)

2

−43.2°

8.80 (1H, s), 8.60 (1H, m), 7.22 (1H,

(c = 1.012,

s), 5.78 (1H, m), 5.07 (1H, m,

CHCl

3

,

COOCH), 4.64 (2H, m), 1.45 (9H, s),

23° C.)

1.29 (3H, d, J=6 Hz), 1.27 (3H, d,

J=6Hz)

31-2

15

CH

2

Ph

−49.4°

8.58 (1H, d, J=2 Hz), 7.36 (5H, s),

(c = 1.01,

7.18 (1H, d, J=1.8 Hz), 5.50 (1H, d,

CHCl

3

,

J=6.8 Hz), 4.64 (2H, m), 4.47 (1H,

23° C.)

dd, J=6.8, 17.5 Hz), 3.77 (1H, dd,

J=5, 17.5 Hz), 3.50 (1H, m), 3.30

(2H, m), 2.95 (1H, m), 2.2-1.7 (4H,

m), 1.44 (9H, s)

Example 29

Process 3

Preparation of tetradecyl 3-(4-thiazolyl)-L-alanyl-L-prolyl-glycinate hydrochloride (16)

To a solution of the compound (13) (1.2 g, 1.92 mmol) in ethyl acetate (20 ml) was added the solution of 4N-hydrogen chloride in ethyl acetate (20 ml) under ice-cooling and the resulting mixture was stirred for 2 h at the same temperature. The reaction mixture was concentrated in vacuo to give the compound (16) (1.27 g, quantitative). This compound used in the next, reaction without purification.

Example 30

Process 3

Preparation of isopropyl 3-(4-thiazolyl)-L-alanyl-L-prolyl-glycinate hydrochloride (17)

In a manner similar to that described in the method of Example 29-3, the compound (17) (590 mg, quantitative) was obtained by de-tert-butoxycarbonylation of compound (14) (580 mg, 1.24 mmol). This compound was used in the next reaction without purification.

Example 31

Process 3

Preparation of benzyl 3-(4-thiazolyl)-L-alanyl-L-prolyl-glycinate hydrochloride (18)

In a manner similar to that described in the method of Example 29-3, the compound (18) (700 mg, quantitative) was obtained by de-tert-butoxycarbonylation of the compound (15) (750 mg, 1.45 mmol). This compound was used in the next, reaction without purification.

Example 29

Process 4

Preparation of tetradecyl cis-L-5-methyl-2-oxo-oxazolidine-4-ylcarbonyl-3-(4-thiazolyl)-L-alanyl-L-prolyl-glycinate (I-29)

Cis-5-methyl-2-oxazolidine-4-yl carboxylic acid (139 mg, 0.96 mmol), which was synthesized in accordance with the method described in Chem. Lett., 1982. 1171. and N-hydroxysuccinimide (110 mg, 0.96 mmol) were dissolved in N, N-dimethylformamide (2 ml). To this solution was added DCC (200 mg, 0.97 mmol) and the resulting mixture was stirred for 2 h at, room temperature. To the reaction mixture was added the free base of the compound (16) prepared by filtering off the salt which was precipitated by adding triethylamine (0.53 ml, 3.8 mmol) to the solution of the compound (16) (635 mg, 0.96 mmol) in N,N-dimethylformamide (15 ml) under ice-cooling. The reaction mixture was stirred for 72 h at room temperature. After the precipitation which appeared was filtered off and the filtrate was concentrated in vacuo. Mixed solvents of methanol:water=3:1 was added to the residue and the precipitation which appeared was filtered off. The filtrate was subjected to gel filtration column chromatography (MCI Gel CHP 20P 200 ml, methanol-water) and successively to silica gel column chromatography (chloroform:methanol=7:1) to give 381 mg of the compound (I-29).

The compounds (I-30) and (I-31) was synthesized in a manner similar to that described in the above method. The results were shown in Table 13.

Example 32

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-ylcarbonyl-3-(4-thiazolyl)-L-alanyl-L-prolyl-glycine (I-32)

To a solution of the compound (I-31) (500 mg, 0.919 mmol) in mixed solvents of methanol (20 ml)-water (20 ml) was added lithium hydroxide (193 mg, 4.56 mmol) and the resulting mixture was stirred for 30 min at room temperature. After the reaction mixture was neutralized by adding the diluted hydrochloric acid, the mixture was concentrated in vacuo. The residue was subjected to gel filtration column chromatography (MCI Gel CHP 20P, 200 ml, methanol-water) and further lyophilized to give 218 mg of the compound (I-32). The result was shown in Table 13.

TABLE 13

Example

Compound

No.

No.

R

6

[α]

D

NMR (CD

3

OD)

29-4

I-29

(CH

2

)

13

CH

3

−54.7°

8.95 (1H, d, J=1.2 Hz), 8.58 (2H, m),

(c = 0.505,

7.45 (1H, s), 4.90 (2H, m), 4.49 (1H,

MeOH,

m), 4.34 (1H, d, J=8.6 Hz), 4.14 (2H,

23° C.)

t, J=6.6 Hz), 3.96 (2H, d), 3.87 (1H,

m), 3.30 (3H, m), 1.28 (3H, d, J=6.6

Hz), 0.89 (3H, t, J=6.6 Hz).

30-4

I-30

CH (CH

3

)

2

−68.7°

8.78 (1H, d, J=1.8 Hz), 7.22 (1H, d,

(c = 0.504,

J=2 Hz), 5.54 (1H, d, J=8.2 Hz), 4.67

MeOH,

(2H, m), 4.41 (1H, dd, J=7.4, 17.6

25° C.)

Hz), 4.14 (2H, t, J=7 Hz), 3.74 (1H,

dd, J=5.5, 17.6 Hz), 3.50 (1H, m),

3.30 (2H, m), 2.97 (1H, m), 1.45 (9H,

s), 2.30 (1H, m), 1.95 (3H, m), 1.27

(22H, m), 0.89 (3H, t, J=6.6 Hz).

31-4

I-31

CH

2

Ph

−61.8°

8.88 (1H, s), 7.42 (1H, s), 7.35 (5H,

(c = 0.508,

m), 5.18 (2H, s), 4.95 (2H, m), 4.47

MeOH,

(1H, dd, J=4.2, 8.6 Hz), 4.33 (1H, d,

23° C.)

J=8.7 Hz), 4.07 (1H, d, J=17.7 Hz),

3.99 (1H, d, J=17.7 Hz), 3.80 (1H,

m), 3.60 (1H, dd, J=6.9, 14 Hz), 3.35

(1H, m), 3.22 (1H, m), 2.2-1.9 (4H,

m), 1.21 (3H, d, J=6.6 Hz)

32

I-32

H

−69.2°

8.99 (1H, d, J=1.4 Hz), 7.44 (1H, d,

(c = 0.507,

J=1.4 Hz), 4.95 (2H, m), 4.47 (1H, t,

H

2

O,

J=5.4 Hz), 4.34 (1H, d, J=8.8 Hz),

22.5° C.)

3.87 (1H, d, J=17.2 Hz), 3.67 (1H, d,

J=17.2 Hz), 3.80-3.20 (4H, m), 2.2-

1.8 (4H, m), 1.21 (3H, d, J=6.2 Hz)

Example 33

Preparation of tetradecyl L-pyroglutamyl-3-(4-thiazolyl)-L-alanyl-L-prolyl-glycinate (I-33)

In a manner similar to that described in the method of Example 29-4, N-hydroxysuccinimide ester of L-pyroglutamic acid which are prepared by the reaction of L-pyroglutamic acid (124 mg, 0.96 mmol), N-hydroxysuccinimide (110 mg, 0.96 mmol), and DCC (200 mg, 0.97 mmol) was reacted with the free base of the compound (16) which was prepared by the compound (16) (635 mg, 0.96 mmol) and triethylamine (0.53 ml, 3.84 mmol) to give 497 mg (81.7%) of the compound (I-33).

[α]

D

=−52.4° (c=0.508, MeOH, 23° C.)

NMR(CD

3

OD): 8.95 (1H, d, J=2.1 Hz), 7.44 (1H, d, J=2.1 Hz), 4.92 (1H, t, J=6.9 Hz), 4.49 (1H, dd, J=3.6, 8.5 Hz), 4.14 (3H, m), 3.97 (2H, s), 3.75 (1H, m), 3.40 (1H, m), 3.20 (2H, m), 2.4-1.8 (8H, m), 1.62 (2H, m), 1.32 (22H, m), 0.89 (3H, t, J=6.9 Hz).

Elemental analysis (C

32

H

51

N

5

O

6

S 0.4H

2

O)

Calcd.: C,59.96; H,8.14; N,10.92; S,5.00. Found: C,59.97; H,8.18; N,11.02; S,5.07.

Example 34

Process 1

Preparation of benzyl cis-L-3-ethoxycarbonyl-5-methyl-2-oxo-oxazolidine-4-carboxylate (19)

A solution of cis-5-methyl-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (706 mg, 3 mmol) which was synthesized in accordance with the method described in Chem. Lett., 1982, 1171 in tetrahydrofuran (12 ml) was cooled in a dry ice-acetone bath (−50° C.) under nitrogen atmosphere. To the solution was added potassium tert-butoxide (337 mg, 3 mmol) and the resulting mixture was stirred for 20 min. at the same temperature. To the mixture was added dropwise a solution of ethyl chlorocarbonate (0.46 ml, 4.83 mmol) in tetrahydrofuran (2 ml) over 10 min. The reaction mixture was stirred for 3 h at −50 to −14° C.(bath temperature). The reaction mixture was partitioned between ice-water and ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to Lober® column (Merck inc.) and recrystallized from diethyl ether-hexane to give 847 mg of the compound (19) as colorless needle crystal.

Example 34

Process 2

preparation of cis-L-3-ethoxycarbonyl-5-methyl-2-oxo-oxazolidine-4-carboxylic acid (20)

A solution of the compound (19) (718 mg, 2.34 mmol) in 50% aqueous methanol (3 ml) was hydrogenated using 5% Pd/C (200 mg) for 2 h at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to give 516 mg of compound (20) as powder.

Example 35

Process 1

Preparation of benzyl cis-L-3-pivaloyloxymethyl-5-methyl-2-oxo-oxazolidine-4-carboxylate (21)

In a manner similar to that described in the method of Example 34-1, cis-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (706 mg, 3 mmol) was pivaloyloxymethylatied with pivalic acid iodomethyl (1.19 g, 4.92 mmol) in the presence of potassium tert-butoxide (337 mg, 3 mmol) in tetrahydrofuran (12 ml) to give 893 mg of the compound (21) as colorless needle crystal.

Example 35

Process 2

Preparation of benzyl cis-L-3-pivaloyloxymethyl-5-methyl-2-oxo-oxazolidine-4-carboxylic acid (22)

In a manner similar to that described in the method of Example 34-2, the compound (21) (892 mg, 2.55 mmol) was de-benzylesterificated by hydrogenating in the presence of 5% Pd/C (250 mg) in aqueous methanol to give 642 mg of the compound (22) as colorless needle crystal.

Example 36

Process 1

Preparation of cis-L-5-methyl-N-(4-morpholinylcarbonylmethyl)-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (23)

In a manner similar to that described in the method of Example 34-1, to a solution of cis-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (706 mg, 3 mmol) in THF (14 ml) was added potassium tert-butoxide (337 mg, 3 mmol) at −53° C. in nitrogen atmosphere and the resulting mixture was stirred for 20 min. at the same temperature. To the reaction mixture was added a solution of N-iodoacetylmorpholine (1.15 g, 4.51 mmol) in THF (1 ml) and the resulting mixture was stirred for 4 h at −53° C. to −15° C. The reaction mixture was partitioned between ethyl acetate and cooled sodium thiosulfate aq. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to Lobar® column (Merck inc.) and the fractions eluting with toluene:acetone=5:1 were collected to yield the compound (23) (873 mg) as crystal.

Example 36

Process 2

Preparation of cis-L-5-methyl-N-(4-morpholinylcarbonylmethyl)-2-oxo-oxazolidine-4-carboxylic acid (24)

In a manner similar to that, described in the method of Example 34-2, the compound (23) (846 mg, 2.33 mmol) was de-benzylesterificated by hydrogenating in the presence of 5% Pd/C (250 mg) in aqueous methanol to give 740 mg of the compound (24) as colorless needle crystal.

Example 37

Process 1

Preparation of cis-L-5-methyl-N-(4-morpholinocarbonyl)-2-oxo-oxazolidine-4-carboxylic acid benzylester (25)

In a manner similar to that described in the method of Example 34-1, cis-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (470 mg, 2 mmol) was reacted with 4-morpholine-carbonylchloride (0.35 ml, 3 mmol) in the presence of potassium tert-butoxide (224 mg, 2 mmol) in THF to give 630 mg of the compound (25).

Example 37

Process 2

Preparation of cis-L-5-methyl-N-(4-morpholinocarbonyl)-2-oxo-oxazolidine-4-carboxylic acid (26)

In a manner similar to that described in the method of Example 34-2, the compound (25) (1.08 g, 3.10 mmol) was de-benzylesterificated by hydrogenating in the presence of 5% Pd/C (200 mg) in aqueous methanol to give 706 mg of the compound (26).

Example 38

Process 1

Preparation of cis-L-5-methyl-N-(4-oxo-butyl)-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (27)

In a manner similar to that described in the method of Example 34-1, cis-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid benzyl ester (3 g, 12.9 mmol) was reacted with 1-iodo-2-butanone (3.83 g, 19.3 mmol) in the presence of potassium tert-butoxide (1.45 g, 12.9 mmol) in THF to give 2.15 g of the compound (27).

Example 38

Process 2

Preparation of cis-L-5-methyl-N-(2-oxo-butyl)-2-oxo-oxazolidine-4-carboxylic acid (28)

In a manner similar to that described in the method of Example 34-2, the compound (27) (1.67 g, 5.47 mmol) was de-benzylesterificated by hydrogenating in the presence of 5% Pd/C (480 mg) in aqueous methanol to give 0.65 g of the compound (28). The above results were shown in Tables 14 and 15.

TABLE 14

Example

Compound

No.

No.

R

3

R

7

[α]

D

NMR

34-1

19

COOEt

Bzl

−63.1°

(CDCl

3

): 7.37 (5H, bs), 5.29

(c = 1.015,

(1H, d, J=12 Hz), 5.22 (1H, d,

CHCl

3

,

J=12 Hz), 4.79 (2H, m), 4.26

23° C.)

and 4.25 (2H, q, J=7.2 Hz), 1.30

(3H, d, J=6 Hz), 1.25 (3H, t,

J=7.2 Hz).

34-2

20

COOEt

H

(DMSO-d

6

): 4.93 (1H, m), 4.76

(1H, d, J=8.4 Hz), 4.21 (2H, m),

1.30 (3H, d, J=6.3 Hz), 1.22

(3H, t, J=7.2 Hz).

35-1

21

CH

2

OC (O)—CMe

3

Bzl

−41.1°

(CDCl

3

): 7.38 (5H, s), 5.43 (1H,

(c = 1.003,

d, J=11.2 Hz), 5.30 (1H, d, J=12

CHCl

3

,

Hz), 5.24 (1H, d, J=11,2 Hz),

22° C.)

5.20 (1H, d, J=12 Hz), 4.79 (1H,

m), 4.58 (1H, d, J=8.8 Hz), 1.23

(3H, d, J=6.4 Hz), 1.20 (9H, s).

35-2

22

CH

2

OC (O)—CMe

3

H

−32.0°

(DMSO-d

6

): 5.31 (1H, d,J=11

(c = 1.007,

Hz, 5.17 (1H, d, J=11 Hz), 4.89

MeOH,

(1H, dq, J=8.6, 6.8 Hz), 4.48

22° C.)

(1H, d, J=8.6 Hz), 1.26 (3H, d,

J=6.8 Hz), 1.14 (9H, s).

36-1

23

Bzl

−112.1° (c = 1.009, MeOH, 25° C.)

(CDCl

3

): 7.38 (SH, s), 5.29 (1H, d, J=12 Hz), 5.15 (1H, d, J=12 Hz), 4.90 (2H, m), 4.55 (1H, d), 3.74 (1H, d) 3.3-3.7 (8H, m), 1.26 (3H, m)

TABLE 15

Example

Compound

No.

No.

R

3

R

7

[α]

D

NMR

36-2

24

Bzl

(CDCl

3

): 5.01 (1H, dq, J=6.4, 9.0 Hz), 4.62 (1H, d, J=9 Hz), 4.46 (1H, d, J=17.2 Hz), 3.95 (1H, d, J=17.2 Hz), 3.4-3.8 (8H, m), 1.39 (3H, d, J=6.4 Hz)

37-1

25

Bzl

−68.4° (c = 1.012, CHCl

3

, 25° C.)

(CDCl

3

): 7.37 (5H, s), 5.30 (1H, d, J=11.6 Hz), 5.15 (1H, d, J=11.6 Hz), 5.00 (1H, d, J=8.6 Hz), 4.89 (1H, m), 3.8-3.4 (8H, m), 1.26 (3H, d, J=6.4 Hz)

37-2

26

H

−48.8° (c = 0.510, MeOH, 26° C.)

(CD

3

OD): 4.99 (1H, m), 4.87 (1H, d, J=6 Hz), 3.72 (4H, m), 3.54 (4H, m), 1.38 (3H, d, J=6 Hz)

38-1

27

Bzl

−129.5° (c = 1.018, CHCl

3

, 26° C.)

(CDCl

3

): 7.37 (5H, s), 5.20 (2H, dd, J=11.6 Hz), 4.91 (1H, m), 4.73 (1H, d, J=9 Hz), 4.54 (1H, d, J=19.2 Hz), 3.79 (1H, d, J=19.2 Hz), 2.41 (2H, dq, J=2, 7.4 Hz), 1.06 (3H, t, J=7.4 Hz)

38-2

28

H

−110.3° (c = 1.006, MeOH, 26° C.)

(CDCl

3

): 4.98 (1H, m), 4.70 (1H, J=9 Hz), 4.52 (1H, d, J=18.8 Hz), 3.91 (1H, d, J=18.8 Hz), 2.47 (2H, q, J=7.4 Hz), 1.44 (3H, d, J=6.6 Hz), 1.09 (3H, t, J=7.4 Hz)

Example 34

Process 3

Preparation of cis-L-3-ethoxycarbonyl-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-prolineamide (I-34)

To the compound (20) (236 mg, 1.08 mmol) was added oxalyl chloride (0.15 ml, 1.72 mmol) and N,N-dimethylformamide (2 drops) and the resulting mixture was stirred for 2.5 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (3 ml) and to the solution was added a solution of 3-(4-thiazolyl)-L-alanyl-L-prolineamide (6,688 mg, 1.2 mmol) and triethylamine (0.61 ml, 4.35 mmol) in N,N-dimethylformamide (9 ml) under ice-cooling with stirring. The reaction mixture was stirred overnight at room temperature. After the percipitation was filtered off, the filtrate was concentrated in vacuo. After the residue was dissolved in water and the solution was subjected to gel filtration column chromatography (MCI Gel CHP-20P, 200 ml, methanol-water) to give the crude compound (248 mg). The crude compound was subjected to silica gel column chromatography (chloroform:methanol=9:1) to give 188 mg of the compound (I-34).

The compound (I-35) to (I-39) were synthesized in a manner similar to that described in the above method. The results were shown in Tables 16 and 17. When the compounds I-36, 38, and 39 were synthesized, DCC was used instead of oxalyl chloride as an activating agent.

TABLE 16

Example

Compound

No.

No.

R

3

mp (° C.)

[α]

D

NMR

34-3

I-34

COOEt

126-130

−94.5°

(CD

3

OD): 8.97 and 8.96 (total

(c = 0.511,

1H, d, J=2.1 Hz), 7.45 and

H

2

O,

7.38 (total 1H, d, J=2.1 Hz),

23° C.)

5.01 (1H, t, J=6.9 Hz), 4.84

(1H, m), 4.78 (1H, d, J=8.4

Hz), 4.41 (1H, dd, J=4.2, 8.7

Hz), 4.20 (2H, q, J=7.2 Hz),

3.88 (1H, m), 3.48 (1H, m),

3.40 (1H, dd, J=6.9, 14.7 Hz),

3.20 (1H, dd, J=7.2, 14.7 Hz),

2.19 (1H, m), 1.99 (3H, m),

1.37 and 1.30 (total 3H, d,

J=6.3 Hz), 1.25 and 1.20 (total

3H, t, J=7.2 Hz).

35-3

I-35

CH

2

OC(O)—CMe

3

212-213

−66.3°

(CD

3

OD): 8.97 and 8.94 (total

(c = 0.514,

1H, d, J=2.1 Hz), 7.48 and

MeOH,

7.40 (total 1H, d, J=2.1 Hz),

22.5° C.)

5.33 and 5.31 (total 1H, d,

J=11.1 Hz), 5.03 (1H, t, J=6.9

Hz), 5.01 and 4.96 (total 1H,

d, J=11.1 Hz), 4.84 (1H, m),

4.58 and 4.54 (total 1H, d,

J=8.7 Hz), 4.41 and 4.32 (1H,

dd, J=3.9, 8.1 Hz), 3.89 (1H,

m), 3.52 (1H, m), 3.41 (1H, dd,

J=6.6, 14.7 Hz), 3.22 (total

1H, dd, J=7.2, 14.7 Hz), 2.29

(1H, m), 2.00 (3H, m), 1.30

and 1.25 (total 3H, d, J=6.6

Hz), 1.21 and 1.96 (total 9H,

s).

TABLE 17

Example

Compound

No.

No.

R

3

X

[α]

D

NMR

36-3

I-36

CH

2

−79.1° (c = 1.004, H

2

O, 25° C.)

(CD

3

OD): 8.98 and 8.96 (total 1H, d, J=2 Hz), 7.46 and 7.37 (total 1H, d, J=2 Hz),4.9-5.1 (2H, m), 4.53 and 4.52 (total 1H, d, J=9 Hz), 4.40 (1H, 4.36 (1H, d, J17.2 Hz), 3.86 (1H, m), 3.86 (1H, d, J17.2 Hz), 3.3-3.7 (10H, m), 3.18(1H, dd, J=7.8, 14.4

# Hz), 1.8-2.3 (4H, m), 12.4 and 1.17 (total 3H, d, J=6.4Hz)

37-3

I-37

CH

2

−69.7° (c = 0.505, MeOH, 26° C.)

(CD

3

OD): 8.93 and 8.72 (total 1H, d, J=1.8 Hz), 7.48 and 7.39 (total 1H, d, J=1.8 Hz), 4.9-5.1 (3H, m), 4.42 (1H, dd, J=4.4, 8.4 Hz), 3.85 (1H, m), 3.70 (4H, m), 3.50 (4H, m), 1.8- 2.3 (4H, m) 1.28 (3H, d, J=5.8 Hz)

38-3

I-38

CH

2

−80.4° (c = 1.012, MeOH, 26° C.)

(CD

3

OD): 8.96 and 8.98 (total 1H, d, J=2.1 Hz), 7.35 and 7.43 (total 1H, d, J=2.1 Hz), 5.02 (1H, dd, J=6.6 Hz), 4.92 (1H, m), 4.48 and 4.49 (toal 1H, d, J=4.4, 8.4 Hz), 4.40 (1H, dd, J=4.2, 8.4 Hz), 4.34 (1H, d, J=18.6 Hz), 3.76 (1H, d, J=18.6 Hz), 3.85

# (1H, m), 3.51 (1H, m), 3.38 (1H, dd, J=6.6, 14.9 Hz), 3.17 (1H, dd, J=6.6, 14.9 Hz), 2.48 (2H, m), 1.80- 2.30 (4H, m), 1.26 (3H, d, J=6.9 Hz), 1.21 (3H, d, J=6.9 Hz), 1.06 (3H, t, J=1.78 Hz), 1.05 (3H, t, J=4.8 Hz)

39-3

I-39

S

−103.9° (c = 1.004, H

2

O, 25° C.)

(CD

3

OD): 8.97 (1H, d, J=2 Hz), 7.47 and 7.42 (total 1H, d, J=2 Hz), 4.8- 5.2 (4H, m), 4.4-4.62 (4H, m), 437(1H, d, J=17.2 Hz), 3.86 (1H, d, J17.2 Hz), 3.67 (4H, m), 3.50 (4H, m), 3.1-3.4 (4H, m), 1.19 (3H, d, J=6.6 Hz)

Example 40

Preparation of cis-L-3-morpholinomethyl-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-prolineamide (I-40)

To a ethanol (3.6 ml) solution of the compound (I-10) (237 mg, 0.6 mmol) was added morpholine (180 mg, 2.07 mmol) and 37% formalin (0.22 ml) and the resulting mixture was stirred for 3 h on oil bath (60° C.). The reaction mixture was concentrated in vacuo. The residue was dissolved in a mixed solvents of chloroform and methanol and the solution was subjected to alumina column chromatography (chloroform:methanol=973) to give the fractions containing the aimed compound (258 mg). The fractions were dissolved in methanol and a large amount of diethyl ether was added to the solution. The precipitation which appeared was filtered off to give 195 mg of the compound (I-40).

The compound (I-41) was synthesized in a manner similar to that described in the above method. The results were shown in Table 18.

Example 42

Preparation of cis-L-3-(N-methylpiperazinyl)methyl-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-prolineamide hydrochrolide (I-43)

i) In a manner similar to that described in the method of Example 40, the compound (I-10) (395 mg, 1 mmol) was treated with N-methylpiperazine (0.2 ml, 2.34 mmol) and 37% formalin (0.24 ml) in ethanol (10 ml) to form Mannich base, giving 350 mg of the compound (I-42) which was free base of the compound (I-43).

The detailed date was shown in Table 18.

ii) After the compound (I-42) (120 mg, 0.244 mmol) was dissolved in methanol (1 ml), to this solution was added a solution 4N hydrogen chloride in ethyl acetate (0.15 ml). Subsequently, to the mixture was added diethyl ether and the precipitation which appeared was filtered off to give 138 mg of the compound (I-43).

[α]

D

=−82° (c=0.51, H

2

O, 23° C.)

IR(KBr)cm

−1

: 3412, 1764, 1677, 1647, 1544, 1446, 1342, 1298, 1221.

Elemental analysis (C

22

H

32

N

6

O

5

S 1.8HCl 0.3Et

2

O 1.2H

2

O) Calcd.: C,46.28; H,6.56; N,13.96; Cl,10.60; S,5.33. Found: C,46.08; H,6.38; N,14.27; Cl,10.88; S,5.37.

TABLE 18

Example

Compound

No.

No.

R

3

[α]

D

NMR

40

I-40

−61° (c = 0.503, H

2

O, 23.5° C.)

(CD

3

OD): 8.98 and 8.96 (total 1H, d, J=1.8 Hz), 7.43 and 7.36 (total 1H, d, J=1.8 Hz), 5.08 (1H, dd, J=6.0, 7.8 Hz), 4.84 (1H, m), 4.46 (1H, d, J=8.4 Hz), 4.42 (1H, dd, J=3.9, 8.4 Hz), 4.07 (1H, d, J=12.6 Hz), 3.91 (1H, m), 3.63 (5H, m), 3.56 (1H, d, J=12.6 Hz), 3.41

# (1H, dd, J=6.0, 14.4 Hz), 2.47 (4H, m), 2.21 (1H, m), 2.01 (2H, m), 1.30 and 1.24 (total 3H, d, J=6.9 Hz).

41

I-41

−69.1° (c = 0.966, H

2

O, 23.5° C.)

(CD

3

OD): 8.98 and 8.96 (total 1H, d, J=2 Hz), 7.43 and 7.36 (total 1H, d, J=2 Hz), 5.07 (1H, dd, J=6.4, 8.2 Hz), 4.80 (1H, m), 4.44 (1H, d, J=8.6 Hz), 4.41 (1H, dd, J=48.2 Hz), 4.11 and 4.10 (total 1H, d, J=13 Hz), 3.90 (1H, m), 3.40 (1H, dd, J=6.4, 14.4 Hz),

# 2.3-2.6 (8H, m), 2.27 and 2.15 (total 3H, s), 2.20 (1H, m), 2.01 (2H, m), 1.29 and 1.24 (total 3H, d, J=6.2 Hz)

42

I-42

−62.3° (c = 0.514, H

2

O, 23.5° C.)

(DMSO-d

6

): 9.06 and 9.02 (total 1H, d, J=2 Hz), 8.81 and 8.59 (total 1H, d, J=8 Hz), 7.43 (1H, d, J=2 Hz), 7.34 (1H, br. s), 7.16 and 6.90 (1H, br.s), 4.96 (1H, m), 4.74 (1H, m), 4.50 and 4.37 (total 1H, d, J=8.2 Hz), 4.22 (1H, m), 3.95 (1H, d, J=12.8 Hz), 3.72 (1H,

# m), 3.60 (1H, m), 3.26 (1H, d, J=12.8 Hz), 3.20 (1H, dd, J=5.14 Hz), 3.04 (1H, dd, J=9.8, 14 Hz), 2.31 (4H, m), 1.6-2.1 (4H, m), 1.40 (6H, m), 1.16 and 1.09 (total 3H, d, J=6.4 Hz).

Example 44 and 45

Process 1

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanine (29)

A solution of cis-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid (1.08 g, 7.5 mmol) in N,N-dimethylformamide (30 ml) was added N-hydroxysuccinimide (650 mg, 8.25 mmol) and DCC (1.70 g, 8.25 mmol) and the resulting mixture was stirred for 3 h at room temperature. After the precipitation which appeared was filtered off, to the filtrate was added 3-(4-thiazolyl)-L-alanine trifluoroacetate (4.64 g, 7.5 mmol) and triethylamine (5.23 ml, 37.5 mmol). The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated in vacuo. The residue was subjected to gel filtration column chromatography (MCI GEL CHP-20P, 200 ml, aq. MeOH) and to silica gel column chromatography (chloroform:methanol=10:1) to give 890 mg (39.7%) of the compound (29).

NMR(CD

3

OD): 9.02 (1H, J=1.8 Hz), 8.46 (1H, d, J=7.8 Hz), 7.74 (1H, s), 7.38 (1H, d, J=1.8 Hz), 4.77 (1H, dq, J=8.7, 6.6 Hz), 4.66 (1H, m), 4.21 (1H, d, J=8.7 Hz), 3.24 (1H, dd, J=5.1, 15 Hz), 3.13 (1H, dd, J=8.4, 15 Hz), 1.13 (3H, d, J=6.6 Hz).

Elemental analysis (C

11

H

13

N

3

O

5

S 0.2H

2

O) Calcd.: C,43.62; H,4.46; N,13.87; S,10.59. Found: C,43.66; H,4.45; N,13.73; S,10.39.

Example 44 and 45

Process 2

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-prolineamide (I-10)

To a solution of the compound (29) (150 mg, 0.5 mmol) and N-hydroxysuccinimide (63 mg, 0.55 mmol) in N, N-dimethylformamide (5 ml) was added DCC (114 mg, 0.55 mmol) under ice-cooling and the resulting mixture was stirred for 60 min. Subsequently, to the mixture was added L-prolineamide (63 mg, 0.55 mmol) and the resulting mixture was stirred for additional 16 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue was dissolved in water and was subjected to gel filtration column chromatography (MCL GEL CHP-20P, 200 ml, aq. MeOH) to give 164 mg (82.8%) of the same compound which are synthesized in Example 10-3.

Example 44 and 45

Process 3

Preparation of cis-L-3-acetoxymethyl-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-N-(acetoxymethyl)-L-prolineamide (I-44) and cis-L-3-acetoxymethyl-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-prolineamlde (I-45)

A solution of the compound (I-10) (198 mg, 0.5 mmol) in ethanol (1 ml) was added 0.1 ml of the solution of triethylamine (0.5 ml) in ethanol (10 ml) and 37% formalin (0.13 ml, 1.6 mmol) and the resulting mixture was heated at reflux on oil bath (105° C.) for 2 h. The reaction mixture was concentrated in vacuo. After the residue was dissolved in pyridine (9 ml) to the mixture was added acetic anhydride (0.9 ml) and was stood for 1 h at room temperature. After toluene was added to the reaction mixture, the resulting mixture was concentrated in vacuo. The residue was subjected to silica gel column chromatography (chloroform:methanol=19:1) to give 143 mg of the compound (I-44) and 71 mg of the compound (I-45).

Example 46

Preparation of cis-L-3-acetyl-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)L-alanyl-L-prolineamide (I-46)

After the compound (I-10) (125 mg, 0.316 mmol) was dissolved in pyridine (5 ml), to the mixture was added acetic anhydride (0.6 ml) and the resulting mixture was stood for 16 h at room temperature. Additionally, to the mixture was added acetic anhydride (0.6 ml) and the resulting mixture was stood for 2 days at room temperature. After toluene was added to the reaction mixture, the mixture was concentrated in vacuo. The residue was subjected to silica gel column chromatography (chloroform:methanol=19:1) to give 94 mg of the compound (I-46).

Example 47

Preparation of cis-L-3-acetoxy-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-thaiazolidine-4-carboxyamide (I-47)

In a manner similar to that described in the method of Example 44 and 45-3, after the compound (I-11) (210 mg, 0.5 mmol) was hydroxymethylated by treating with 37% formalin (0.13 ml) and triethylamine (0.05 ml), the resulting compound was acetylated by treating with acetic anhydride - pyridine to give 140 mg of the compound (I-47). The above results were shown in Table 19.

TABLE 19

Example

Compound

No.

No.

R

3

R

8

X

NMR

44-3

I-44

CH

2

OAc

CH

2

OAc

CH

2

(CDCl

3

): 9.02 and 8.97 (total 1H, d, J=2.1

Hz), 7.47 and 7.36 (1H, d, J=2.1 Hz), 5.31 (1H,

d, J=11.4 Hz) 5.24 (1H, d, J=10.2 Hz), 5.20

(1H, d, J=10.2 Hz), 5.01 (1H, d, J=11.4 Hz),

5.00 (1H, t, J=6.9 Hz), 4.80 (1H, m), 4.57 and

4.55 (total 1H, d, J=8.4 Hz), 4.31 (1H, dd,

J=4.2, 8.4 Hz), 3.86 (1H, m), 3,42 (1H, m),

3,35 (1H, m), 3,20 (1H, dd, J=6.9, 14.7 Hz),

1.8-2.3 (4H, m), 2.05 (3H, s), 2.04 (3H, s), 1.29

and 1.24 (total 3H, d, J=6.6 Hz).

45-3

I-45

CH

2

OAc

H

CH

2

(CD

3

OD): 8.97 and 8.94 (1H, d, J=1.8 Hz),

7.47 and 7.39 (total 1H, d, J=1.8 Hz), 5.31

and 5.29 (total 1H, d, J=11.2 Hz), 5.04 (1H, t,

J=6.9 Hz), 5.01 and 4.98 (total 1H, d, J=11.1

Hz), 4.80 (1H, m), 4.59 and 4.56 (1H, d, J=8.7

Hz), 4.41 and 4.30 (1H, dd, J=3.9, 8.4 Hz),

3.87 (1H, m), 3.50 (1H, m), 3.40 (1H, dd,

J=14.1, 6.6 Hz), 3.22 (1H, dd, J=6.9, 14.1 Hz),

1.7-2.3 (4H, m), 2.05 (3H, s), 1.30 and 1.24

(total 3H, d, J=6.6 Hz).

46

I-46

Ac

H

CH

2

(CD

3

OD): 8.94 and 8.93 (total 1H, d, J=1.8

Hz), 7.47 and 7.38 (total 1H, d, J=1.8 Hz),

4.97 (1H, t, J6.9 Hz), 4.8-4.9 (2H, m), 4.41 and

4.25 (total 1H, dd, J=3.9, 8.7 Hz), 3.85 (1H,

m), 3.44 (1H, m), 3,39 (1H, dd, J=7.2, 15 Hz),

3.23 (1H, dd, J=6.9, 15 hz), 2.46 (3H, s), 1.8-

2.3 (4H, m), 1.2-1.4 (3H, m).

47

I-47

CH

2

OAc

H

S

(CD

3

OD): 8.94 and 8.99 (total 1H, d, J=2.1

Hz), 7.42 and 7.48 (total 1H, d, J=2.1 Hz),

5.32 (1H, d, J=11.4 Hz), 5.13 (1H, t, J=6.9

Hz), 5.09 (1H, d, J=8.7 Hz), 5.03 (1H, d,

J=11.4 Hz), 4.70-4.90 (2H, m), 4.57 (1H, d,

J=8.7 Hz), 4.48 (1H, d, J=8.7 Hz), 3.43 (1H,

dd, J=6.9, 14.4 Hz), 3.10-3.40 (3H, m), 2.05

(3H, s), 1.25 and 1.32 (total 3H, d, J=6.6 Hz)

Example 48

Process 1

Preparation of N-(tert-butyloxycarbonyl)-3-(4-thiazolyl)-L-alanyl-L-proline benzyl ester (30)

A solution of N-(tert-butyloxycarbonyl)-3-(4-thiazolyl)-L-alanine (2.72 g, 10 mmol), L-proline benzyl ester hydrochloric acid (2.42 g, 10 mmol), and HOBT (135 mg, 1 mmol) in tetrahydrofuran (60 ml) was added triethylamine (1.4 ml, 10 mmol) and DCC (2.43 g, 11.8 mmol) and the resulting mixture was stirred for 18 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue (5.5 g) was subjected to silica gel column chromatography with Lobar® column C (Merck inc.) (toluene:acetone=9:1) to give 4.16 g of the compound (30).

Example 48

Process 2

Preparation of 3-(4-thiazolyl)-L-alanyl-L-proline benzyl ester hydrochloride (32)

To a solution of the compound (30) (3 g, 6.528 mmol) in ethyl acetate (10 ml) was added a solution of 4N hydrogen chloride in ethyl acetate (33 ml) under ice-cooling and the resulting mixture was stirred for 3 h. To the reaction mixture was added diethyl ether and the precipitation which apl)eare(d was filtered off to give 2.77 g of compound (32). This compound was used in the next reaction without purification.

The compounds (31) and (33) are synthesized in a manner similar to that described in the above method. The results were shown in Table 20.

TABLE 20

Example

Compound

No.

No.

R

9

R

10

salt

[α]

D

NMR

48-1

30

BOC

Bzl

—

−55.6°

(CDCl

3

): 8.75 and 8.72 (total

(c = 1.03,

1H, d, J=1.8 Hz), 7.35 (5H, m,

MeOH,

Ph), 7.10 and 7.08 (total 1H, d,

23° C.)

J=1.8 Hz), 5.39 (1H, d, J=9 Hz),

5.19 (1H, d, J=12.4 Hz), 5.27

(1H, d, J=12.3 Hz), 4.81 (1H,

m), 4.58 (1H, dd, J=3.9, 8.4 Hz),

3.73 and 3.51 (total 2H, m),

3.26 (1H, dd, J=5.7 Hz, 14.1

Hz), 3.02 (1H, dd, J=7.5, 14.1

Hz), 2.19 (1H, m), 1.97 (3H, m),

1.37 (9H, s).

48-2

32

H

Bzl

HCl

(CD

3

OD): 9.41 (1H, d, J=1.8

Hz), 7.68 (1H, d, J=1.8 Hz),

5.17 (1H, s), 4.60 (2H, m), 3.75

(1H, m), 3.45 (3H, m), 2.30 (1H,

m), 2.00 (3H, m).

49-1

31

BOC

iso-Pr

—

−40.8°

(CDCl

3

): 8.77 (1H, d, J=2 Hz),

(c = 1.015,

7.19 (1H, s), 5.40 (1H, d, J=8.6

CHCl

3

,

Hz), 5.03 (1H, q, J=6.2 Hz),

26° C.)

4.83 (1H, m), 4.48 (1H, m), 3.73

(1H, m), 3.59 (1H, m), 3.32 (1H,

dd, J=5.2 Hz, 14.4 Hz), 3.04

(1H, dd, J=7.8, 14.4 Hz), 2.20

(1H, m), 1.97 (3H, m), 1.36 (9H,

s), 1.26 (3H, d, J=6.4 Hz), 1.22

(3H, d, J=6.4 Hz).

49-2

33

H

iso-Pr

HCl

Example 48

Process 3

Preparation of cis-L-5-metyhyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-proline benzyl ester (I-48)

A solution of cis-L-5-methyl-2-oxo-oxazoline-4-carboxylic acid (316 mg, 2.17 mmol) and N-hydroxysuccinimide (249 mg, 2.17 mmol) in N, N-dimethylformamide (5 ml) was added DCC (448 mg, 2.17 mmol) and the resulting mixture was stirred for 4 h at room temperature. After the precipitation which appeared was filtered off, to the filtrate was added 865 mg (2.17 mmol) of the compound (32) and triethylamine (1.21 ml, 8.7 mmol). The reaction mixture was stirred for 16 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue was subjected to gel filtration column chromatography (MCL GEL CHP-20P, 200 ml, aq. MeOH) and to silica gel column chromatography to give 496 mg of the compound (I-48).

The compound (I-49) was synthesized in a manner similar to that described in the above method. The results were shown in Table 21.

Example 50

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-proline (I-50)

A solution of the compound (I-48) (1.99 g, 4.09 mmol) in 50% aqueous methanol was added lithium hydroxide (858 mg, 20.45 mmol) and the resulting mixture was stirred for 35 min. at room temperature. After the reaction mixture was neutralized by adding 1N hydrochloric acid (20.4 ml), the resulting mixture was concentrated in vacuo to about half volume. The aqueous solution was washed with ethyl acetate twice. The aqueous layer was subjected to gel filtration column chromatography (MCI GEL CHP-20P, 200 ml, aq. MeOH) to give 1.29 g of the compound (I-50). The result was shown in Table 21.

TABLE 21

Example

Compound

No.

No.

R

11

[α]

D

IR (cm

−1

)

NMR

48-3

I-48

Bzl

−55.9°

(CD

3

OD): 8.93 (1H, d, J=2 Hz),

(c = 0.508,

7.35 (5H, m, Ph), 7.30 (1H, d, J=2

MeOH,

Hz), 5.15 (12H, s), 5.11 (1H, m),

26° C.)

4.90 (1H, m), 4.49 (1H, m), 4.31

(1H, d, J=8.6 Hz), 3.90 (1H, m),

3.60 (1H, m), 3.17 (2H, m), 2.25

(1H, m), 1.97 (3H, m), 1.17 (3H,

d, J=6.6 Hz).

49-3

I-49

iso-Pr

−53.7°

(CD

3

OD): 8.99 (1H, d, J=2 Hz),

(c = 0.501,

7.44 (1H, d, J=2 Hz), 5.00 (3H,

MeOH,

m), 4.40 (1H, m), 4.34 (1H, d,

25° C.)

J=8.6 Hz), 3.93 (1H, m), 3.66

(1H, m), 2.30 (1H, m), 2.00 (3H,

m), 1.28 (6H, t, J=6.2 Hz), 1.20

(3H, d, J=6.6 Hz).

50

I-50

H

−52.0°

(KBr)

(CD

3

OD): 8.95 (1H, d, J=2.1 Hz),

(c = 1.01,

3398, 3299,

7.40 and 7.33 (total 1H, d, J=2.1

H

2

O

1749, 1636,

Hz), 5.09 (1H, dd, J=5.4, 8.4 Hz),

23° C.)

1523, 1450,

4.90 (1H, m), 4.42 (1H, dd, J=3.6,

1230.

8.1 Hz), 4.37 and 4.32 (total 1H,

d, J=8.7 Hz), 3.91 (1H, m), 3.61

(1H, m), 3.30 (1H, m), 3.17 (1H,

dd, J=8.4, 14.7 Hz), 2.25 (1H, m),

2.01 and 1.83 (total 3H, m), 1.25

and 1.18 (total 3H, d, J=6.9 Hz).

Example 51

Process 1

Preparation of 4-(N-benzyloxycarbonyl-L-prolyl)morpholine (34)

A solution of N-benzyloxycarbonyl-L-proline (5 g, 20.06 mmol), morpholine (1.92 ml, 20.06 mmol), and N-hydroxysuccinimide (2.31 g, 20.06 mmol) in N, N-dimethylformamide (100 ml) was added DCC (4.14 g, 20.06 mmol) and the resulting mixture was stirred for 4 h at room temperature. After the precipitation was filtered off, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the resulting precipitation was filtered off. After the filtrate was washed with dilute hydrochloric acid, saturated sodium hydrogencarbonate aq., and water, the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from the mixed solvents of ethyl acetate-hexane to give the compound (34) (4.44 g, 69.5%).

mp: 142-143° C.

[α]

D

=−18.0° (c=1, CHCl

3

, 23° C.)

IR(CHCl

3

)cm−1: 1700, 1660, 1420.

NMR(CDCl

3

): 7.35 (5H, m), 5.12 (2H, m), 4.59 and 4.70 (total 1H, dd, J=3.6, 8.4 Hz), 3.20-3.90 (10H, m), 1.80-2.30 (4H, m).

Elemental analysis (C

l7

H

22

N

2

O

4

) Calcd.: C,64.13; H,6.96; N,8.80. Found: C,53.99; H,6.94; N,8.81.

Example 51

Process 2

Preparation of 4-L-prolyl-morpholine p-toluenesulfonate (35)

A solution of the compound (35) (3.6 g, 11.31 mmol) in methanol (50 ml)-water (10 ml) was hydrogenated using 5% Pd/C (1.6 g) and p-toluenesulfonic acid (2.15 g, 11.31 mmol) for 3 h at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to obtain the compound (35) (4.31 g, 100%).

mp: 130-131° C.

NMR(CD

3

OD): 7.70 (2H, m), 7.24 (2H, m), 4.65 (1H, dd, J=6.2, 8.4 Hz), 3.20-3.80 (10H, m), 1.80-2.60 (4H, m), 2.37 (3H, s).

Elemental analysis (C

16

H

24

N

2

O

5

S) Calcd.: C,53.92; H,6.79: N,7.86: S,9.00. Found: C,53.91; H,6.73; N,7.97; S,8.99.

Example 51

Process 3

Preparation of 4-[N-{N-(tert-butoxycarbonyl)-3-(4-theiazolyl)-L-alanyl}-L- prolyl]morpholine (36)

In a manner similar to that described in the method of synthesis of the compound (34), the compound (35) (2.7 g, 7.57 mmol) was condensed with N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine (2.03 g, 7.57 mmol) in the presence of HOBT (200 mg, 1.498 mmol), triethylamine (2.1 ml, 14.98 mmol), and DCC (1.55 g, 7.49 mmol) in N,N-dimethylformamide. The product was subjected to silica gel column chromatography (chloroform:methanol=50:1) to give the compound (36) (2.23 g, 67.1%).

[α]

D

=−23.1° (c=0.91, CHCl

3

, 25° C.)

IR(CHCl

3

)cm

−1

: 3433, 1707, 1644, 1501, 1441, 1232, 1167, 1115.

NMR(CDCl

3

): 8.76 (1H, d, J=2 Hz), 7.21 (1H, d, J=2 Hz), 5.46 (1H, d, J=9 Hz), 4.83 (2H, m), 3.40-4.00 (10H, m), 3.35 (1H, dd, J=5, 14.6 Hz), 3.08 (1H, dd, J=7.8, 14.6 Hz), 1.70-2.30 (4H, m), 1.37 (9H, s).

Elemental analysis (C

20

H

30

N

4

O

5

S 0.5H

2

O) Calcd.: C,53.67; H,6.98; N,12.52; S,7.16. Found: C,53.71; H,7.07; N,12.34; S,7.17.

Example 51

Process 4

Preparation of 4-[N-{3-(4-thiazolyl-L-alanyl}-L-prolyl]morpholine hydrochloride (37)

To a solution of the compound (36) (1.5 g, 3.42 mmol) in ethyl acetate (17 ml) was added a solution of 4N hydrochloric acid in ethyl acetate (17 ml) under ice-cooling and the resulting mixture was stirred for 3 h at the same temperature with stirring. The precipitation which appeared was filtered off and washed with ethyl acetate to give the compound (37) (1.33 g, 94.4%).

[α]

D

=−39.1° (c=1, MeOH, 25° C.)

IR(CHCl

3

)cm

−1

: 3429, 1741, 1654, 1610, 1465, 1370, 1238, 1111.

NMR(CD

3

OD): 9.86 (1H, d, J=2 Hz), 8.06 (1H, d, J=2 Hz), 4.98 (1H, dd, J=6.0, 8.4 Hz), 4.76 (1H, t, J=5.4 Hz), 3.40-4.00 (12H, m), 1.80-2.40 (4H, m).

Example 51

Process 5

Preparation of 4-[N-{N-(cis-L-5-methyl-2-oxo-oaxzolidine-4-yl-carbonyl)-3-(4-thiazolyl)-L-alanyl}-L-prolyl]morpholine (I-51)

In a manner similar to that described in the method of synthesis of the compound (34), cis-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid (300 mg, 2.07 mmol) was condensed with the compound (37) (850 mg, 2.07 mmol) in the presence of N-hydroxysuccinimide (240 mg, 2.07 mmol), DCC (470 mg, 2.28 mmol), and triethylamine (1.16 ml, 8.28 mmol) in N,N-dimethylformamide to give 560 mg of the compound (I-51).

The result was shown in Table 22.

Example 52

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-N-(tert-butyl)-L-prolineamide (I-52)

In a manner similar to that described in the method of synthesis of the compound (34), the compound (I-50) (300 mg, 0.76 mmol) was condensed with tert-butylamine (110 mg, 1.52 mmol) in the presence of N-hydroxysuccinimide (87 mg, 0.76 mmol) and DCC (170 mg, 0.84 mmol) in N, N-dimethylformamide to give 210 mg of the compound (I-52).

In the manner to that described in the above method, the compound (I-53) was synthesized.

The above results were shown in Table 22.

TABLE 22

Example

Compound

No.

No.

R

13

[α]

D

NMR

51-5

I-51

−55.9° (c = 0.508, MeOH, 26° C.)

(CD

3

OD): 8.94 and 8.98 (total 1H, d, J2 Hz), 7.32 and 7.42 (total 1H, d, J=2 Hz), 5.09 (1H, dd, J=4.6, 9.4 Hz), 4.70-5.00 (2H, m), 4.30 and 4.33 (total 1H, d, J=8.6 Hz), 3.50- 4.10 (10H, m), 3.38 (1H, dd, J=4.6, 15 Hz), 3.15 (1H, dd, J=9.4, 15 Hz), 1.60-2.40

# (4H, m), 1.17 and 1.21 (total 3H, d, J=6.6 Hz).

52

I-52

t-BuNH

−53.7°

(CD

3

OD): 8.95 and 8.97 (total 1H, d,

(c = 0.501,

J=1.8 Hz), 7.57 and 7.71 (total 1H,

MeOH,

s), 7.34 and 7.42 (total 1H, d, J=1.8

25° C.)

Hz), 5.06 (1H, dd, J=5.4, 8.1 Hz),

4.90 (1H, m), 4.34 (1H, t, J=8.7 Hz),

4.31 (1H, d, J=8.7 Hz), 3.60-3.91

(2H, m), 3.37 (1H dd, J=5.4, 15.3

Hz), 3.19 (1H, dd, J=8.1, 15.3 Hz),

1.70-2.30 (4H, m), 1.33 (9H, s), 1.18

and 1.25 (total 3H, d, J6.3 Hz)

53

I-53

n-PenNH

−52.0°

(CD

3

OD): 8.97 (1H, d, J=2.1 Hz),

(c = 1.01,

7.35 and 7.44 (total 1H, d, J=2.1

H

2

O, 23° C.)

Hz), 5.00 (1H, t, J=6.9 Hz), 4.91

(1H, m), 4.37 (1H, dd, J=4.2, 10.5

Hz), 4.33 and 4.35 (total 1H, d, J=9

Hz), 3.87 (1H, m), 3.30-3.60 (5H, m),

1.70-2.30 (4H, m), 1.51 (2H, m), 1.31

(4H, m), 1.20 and 1.25 (total 3H, d,

J=6.6 Hz), 0.90 (3H, t, J=6.9 Hz).

Example 54

Process 1

Preparation of N-(tert-butoxycarbonyl)-L-proline 5-methyl-2-oxo-1,3-dioxolene-4-ylmethyl ester (38)

A solution of 4-hydroxymethyl-5-methyl-2-oxo-1,3-dioxolene (651 mg, 5 mmol) which was synthesized in accordance with the method described in Synthetic Commun., 22, 1277 (1992), tert-butyloxycarbonyl-L-proline (1.07 g, 5 mmol), and 4-dimethylaminopyridine (61 mg, 0.5 mmol) in THF (20 ml) was added DCC (1.14 g, 5.5 mmol) and the resulting mixture was stirred for 16 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue was subjected to silica gel column chromatography (hexane:acetone=4:1) to give the compound (38) (1.33 g, 81.2%).

NMR(CDCl

3

): 4.8-5.0 (2H, m), 4.2-4.4 (1H, m), 3.3-3.6 (2H, m), 2.19 and 2.17 (total 3H, s), 1.93 (2H, m), 1.66 (2H, m), 1.45-1.39 (9H, s).

Example 54

Process 2

Preparation of L-proline 5-methyl-2-oxo-1,3-dioxolene-4-ylmethyl ester trifuluoroacetate (39)

Trifluoroacetic acid (2.5 ml) was added to the compound (38) (360 mg, 1.1 mmol) under ice-cooling and the resulting mixture was stood for 45 min. To the reaction mixture was added toluene and the mixture was concentrated in vacuo to give 490 mg of the compound (39). This compound was used in the next reaction without purification.

NMR(CDCl

3

): 5.03 (1H, d, J=14.1 Hz), 4.97 (1H, d, J=14.1 Hz), 4.53 (1H, m), 3.52 (2H, m), 2.51 (1H, m), 2.18 (3H, s), 2.18 (3H, s).

Example 54

Process 3

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-proline 5-methyl-L-proline 5-methyl-2-oxo-1,3-dioxolene-4-ylmethyl ester (I-54)

In a manner similar to that described in the synthetic method of the compound (34), the compound (29) (299 mg, 1 mmol) was condensed with the compound (39) (130 mg, 0.76 mmol) in the presence of N-hydroxysuccinimide (127 mg, 1.1 mmol), DCC (227 mg, 1.1 mmol), and triethylamine (0.56 ml, 4 mmol) in N,N-dimethylformamide to give 162 mg (30%) of the compound (I-54). The chemical formula was shown below.

[α]

D

=−56.2° (c=0.502, H

2

O, 26° C.).

NMR(CD

3

OD): 8.97 and 8.96 (total 1H, d, J=2.1 Hz), 7.39 and 7.32 (total 1H, d, J=2.1 Hz), 5.09 (1H, m), 4.96 (2H, s), 4.90 (1H, m), 4.46 (t 1H, m), 4.31(1H, t, J=8.7 Hz), 3.92 (1H, m), 3.61 (1H, m), 3.29 (1H, dd, J=5.4, 14.7 Hz), 3.16 (1H, dd, J=8.4, 14.7 Hz), 2.27 (1H, m), 2.17 (3H, s), 2.00 (3H, m), 1.23 and 1.18 (total 3H, d, J=6.6 Hz).

Elemental analysis (C

21

H

24

N

4

O

9

S 1.1H

2

O) Calcd.: C,47.74; H,5.00; N,10.60; S,6.07. Found: C,47.78; H,5.04; N,10.67; S,5.97.

Example 55

Process 1

Preparation of N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl-2S-cyanopyrrolidine (40)

2S-Cyanopyrrolidine p-toluenesulfonate (440 mg, 1.62 mmol) which was synthesized in accordance with Bioorg, Med. Chem. Lett., 6, 1163 (1996) was condensed with N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine (440 mg, 1.62 mmol) in the presence of N-hydroxysuccinimide (190 mg, 1.62 mmol), DCC (370 mg, 1.78 mmol), and triethylamine (0.46 ml, 3.24 mmol) to give 180 mg (31.5%) of the compound (40).

[α]

D

=−37.2° (c=0.503, CHCl

3

, 26° C.)

IR(Nujol)cm

−1

: 2246, 1697, 1645, 1162.

NMR(CDCl

3

): 8.79 (1H, d, J=2 Hz), 7.15 (1H, d, J=2 Hz), 5.41 (1H, d, J=8.2 Hz), 4.79 (1H, dd, J=7, 8.2 Hz), 4.72 (1H, dd, J=3.6, 6.9 Hz), 3.62 (1H, m), 3.35 (1H, m), 3.22 (2H, d, J=7 Hz), 1.90-2.3 (4H, m), 1.40(9H, s).

Elemental analysis (C

16

H

22

N

4

O

3

S) Calcd.: C,54.84; H,6.33; N,15.99: S,9.15. Found: C,54.64; H,6.30; N,15.80; S,8.95.

Example 55

Process 2

Preparation of 3-(4-thiazolyl)-L-alanyl-2(S)-cyanopyrrolidine trifluoroacetate (41)

Trifluoroacetic acid (5 ml) was added to the compound (40) (500 mg, 1.43 mmol) under ice-cooling and the resulting mixture was stirred for 90 min. Toluene was added to the reaction mixture and the mixture was concentrated in vacuo to give 970 mg of the compound (41). This compound was used in the next reaction without purification.

NMR(CDCl

3

): 8.85 (1H, d, J=2 Hz), 7.31 (1H, d, J=2 Hz), 4.78 (1H, dd, J=4.8, 6.6 Hz), 4.62 (1H, t, J=6.6 Hz), 3.10-3.70 (4H, m), 1.80-2.3 (4H, m).

Example 55

Process 3

Preparation of Cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-2(S)-cyanopyrrolidine (I-55)

In a manner similar to that described in the synthetic method of the compound (34), cis-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid (210 mg, 1.43 mmol) was condensed with the compound (41) (970 mg, 1.43 mmol) in the presence of N-hydroxysuccinimide (160 mg, 1.43 mmol), DCC (320 mg, 1.57 mmol), and triethylamine (0.6 ml, 4.29 mmol) in N,N-dimethylformamide to 330 mg of compound (I-55). The result was shown in Table 23.

Example 56

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-L-prolinol (I-56)

In a manner similar to that described in the synthetic method of the compound of (34), the compound of (29) (299 mg, 1 mmol) was condensed with L-prolinol (101 mg, 1 mmol) in the presence of N-hydroxysuccinimide (127 mg, 1.1 mmol), DCC (227 mg, 1.1 mmol), and triethylamine (0.15 ml, 1.1 mmol) in N, N-dimethylformamide to give 162 mg of the compound (I-56). The result was shown in Table 23.

TABLE 23

Example

Compound

No.

No.

R

14

[α]

D

NMR

55-3

I-55

—CN

−35.0°

(CD

3

OD): 8.98 (1H, d, J=2 Hz), 7.35 (1H,

(c = 1.007,

d, J=2.1 Hz), 4.90-5.00 (2H, m), 4.70 (1H,

MeOH,

dd, J=8, 3.6 Hz), 4.34 (1H, d, J=8.4 Hz),

25° C.)

3.77 (1H, m), 3.43 (1H, m), 3.30 (1H, m),

3.24 (1H, dd, J=7.2, 14.1 Hz), 2.10 (4H,

m), 1.23 (3H, d, J=6.3 Hz).

56

I-56

—CH

2

OH

−10.7°

(CD

3

OD): 8.98 and 8.95 (total 1H, d, J=2.1

(c = 0.506,

Hz), 7.36 and 7.35 (1H, d, J=2.1 Hz), 5.21

H

2

O, 26° C.)

and 5.06 (1H, t, J=7.5 Hz), 4.91 (1H, m),

4.37 and 4.35 (total 1H, d, J=8.7 Hz), 4.06

(1H, m), 3.7-3.9 (1H, m), 3.51 (1H, dd,

J=3.9, 10.8 Hz), 3.43 (1H, dd, J=6.3, 10.8

Hz), 3.40 (1H, m), 3.25 (2H, m), 1.6-2.0

(4H, m), 1.25 and 1.22 (total 3H, d, J=6.3

Hz).

Example 57

Process 1

Preparation of 3-(4-thiazolyl)-L-alanine p-toluenesulfonate (43)

Trifluoroacetic acid (80 ml) was added to N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine (42, 21.79 g, 80 mmol) which was synthesized in accordance with the method described in the literature (Synth. Commun., 20, 3507 (1990)) and the resulting mixture was stirred for 2 h under ice-cooling, Subsequently, to the mixture was added p-toluenesulfonic acid hydrate (15.22 g, 80 mmol) and the resulting mixture was stirred for 30 min. at room temperature. The reaction mixture was concentrated in vacuo. To the residue was added water and methanol, and excess trifluoroacetic acid was removed by concentrating in vacuo. To the residue was added diethyl ether and the precipitation which appeared was filtered off to give 29.8 g (quantitative) of the compound (43).

NMR(CD

3

OD): 9.01 (1H, d, J=1.8 Hz), 7.70 (2H, m), 7.46 (1H, d, J=1.8 Hz), 7.23 (2H, m), 4.38 (1H, dd, J=4.8 and 7.6 Hz), 3.45 (2H, m), 2.37 (3H, s).

Example 57

Process 2

Preparation of 3-(4-thiazolyl)-L-alanine diphenylmethylester p-toluenesulfonate (44)

To a solution of 38.85 g of the compound (43) (112.8 mmol) in ethanol (200 ml)-THF (600 ml) was added diphenyldiazomethane (39 g, 201 mmol) little, by little over 30 min. at room temperature with stirring. After the reaction mixture was stirred for 1 h at room temperature, to the mixture was added diphenyldiazomethane (10 g, 51.5 mmol) and the resulting mixture was stirred for 1 h. To the reaction mixture was added acetic acid (0.1 ml) for quenching the excess reagent and the mixture was concentrated in vacuo. The residue (92 g) was crystallized by adding ether (1 L) to give 49.05 g (96.1%) of the compound (44).

mp: 139-140° C.

[α]

D

=−34.7° (c=1.006, CHCl

3

, 23° C.)

IR(KBr)cm

−1

: 1753, 1602, 1512, 1496, 1260, 1224, 1171, 1124, 1036, 1012.

NMR(CD

3

OD): 8.92 (1H, d, J=2 Hz), 7.70 (2H, m), 7.2-7.4 (13H, m), 6.91 (1H, s), 4.62 (1H, t, J=5.8 Hz), 3.47 (2H, d, J=5.8 Hz), 2.36 (3H, s).

Elemental analysis (C

26

H

26

N

2

O

5

S

2

) Calcd.: C,61.16; H,5.13; N,5.49; S,12.56. Found: C,61.14; H,5.32; N,5.41; S,12.46.

Example 57

Process 3

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanine diphenylmethyl ester (45)

A solution of 13.95 g (96.14 mmol) of cis-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid, 49.09 g (96.14 mmol) of the compound (44), 2.6 g (19.23 mmol) of N-hydroxybenzotriazole, and 14.1 ml (101 mmol) of triethylamine in THF (1 L) was added DCC (20.83 g, 101 mmol) under ice-cooling. After the mixture was stirred for 10 min. at the same temperature, the ice-cooling bath was removed and the reaction mixture was stirred for 20 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo to give oily residue (82.7 g). The reside was dissolved in ethyl acetate (700 ml) with heating and the precipitation which appeared was filtered off. The filtrate was washed with sodium carbonate aq. and water. After methanol (20 ml) was added to the organic layer, the organic layer was dried over magnesium sulfate and concentrated in vacuo. The precipitated crystal was filtered off and washed with ethyl acetate-ether (2:3) to give 35.69 g (79.8%) of the compound (45). After the mother liquor was concentrated in vacuo, the residue was crystallized from ethyl acetate-ether to give 2.62 g (5.9%) of the compound (45).

mp: 176-177° C.

[α]

D

=−39.2° (c=1.007, CHCl

3

, 24° C.)

IR(KBr)cm

−1

: 1739, 1681, 1508, 1453, 1386, 1237, 1193, 1089.

NMR(CDCl

3

): 8.71(1H, d, J=1.8 Hz), 8.18 (1H, d, J=7.8 Hz), 7.2-7.4 (10H, m), 6.82 (1H, s), 6.66 (1H, d, J=1.8 Hz), 5.79 (1H, s), 5.12 (1H, m), 4.94 (1H, m), 4.35 (1H, dd, J=1.8 and 9.0 Hz), 3.40 (1H, dd, J=5.7 and 15 Hz), 3.29 (1H, dd, J=4.5 and 15 Hz), 1.27 (3H, d, J=6.3 Hz).

Elemental analysis (C

24

H

23

N

3

O

5

S) Calcd.: C,61.92; H,4.98; N,9.03; S,6.89. Found: C,61.95; H,5.01; N,8.94; S,6.62.

Example 57

Process 4

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanine(46)

Anisole (240 ml) and trifluoroacetic acid (120 ml) was added to 41.24 g (88.59 mmol) of the compound (45) under ice-cooling and the resulting mixture was stirred for 15 min. After the cooling bath was removed, the mixture was stirred for 2.5 h at room temperature. The reaction mixture was concentrated in vacuo to give oily residue. To the residue was added ether (500 ml) and the precipitation which appeared was filtered off as powder. The powder was dissolved in water (50 ml)—methanol (300 ml) with heating and the precipitation which appeared was filtered off. The filtrate was concentrated in vacuo. To the residue was added the seed crystal and methanol and the resulting mixture was stood for 3 days at room temperature. The precipitated crystal was filtered off to give 14.89 g (56.1%) of the compound (46). The mother liquor was concentrated in vacuo and the residue was crystallized from methanol-ether to give 10.3 g (38%) of the compound (46).

mp: 214-215° C.

IR(KBr)cm

−1

: 1753, 1707, 1655, 1548, 1529, 1409, 1343, 1264, 1236, 1102, 1092.

NMR(DMSO-d6): 9.02 (1H, d, J=1.8 Hz), 8.46 (1H, d, J=7.8 Hz), 7.74 (1H, s), 7.38 (1H, d, J=1.8 Hz), 4.77 (1H, dq, J=6.6 and 8.7 Hz), 4.66 (1H, m), 4.21 (1H, d, J=8.7 Hz), 3.24 (1H, dd, J=5.1 and 15 Hz), 3.13 (1H, dd, J=8.4 and 15 Hz), 1.13 (3H, d, J=6.6 Hz).

Elemental analysis (C

11

H

13

N

3

O

5

S) Calcd.: C,44.14; H,4.38; N,14.04; S,10.71. Found: C,43.94; H,4.478; N,14.09; S,110.58.

Example 57

Process 5

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanyl-2(R)-methylpyrrolidine (I-57)

(Method A) To a suspension of 12.1 (40.48 mM) of the compound (46) and N-hydroxysuccinimide (4.66 g, 40.48 mM) in THF (242 ml) was added DCC (8.35 g, 40.48 mM) under ice-cooling and the resulting mixture was stirred for 30 min. The cooling bath was removed and the reaction mixture was stirred for 2 h at room temperature additionally. To a suspension of (R)-(+)-2-methylpyrrolidine hydrochloride (5.42 g) which was synthesized in accordance with the method described in the literature (Tetrahedron, 27, 2599 (1971)) and triethylamine (8.46 ml, 60.72 mM) in THF (121 ml) was added the solution containing N-hydroxysuccinimide ester of the compound (46) at room temperature. The reaction mixture was stirred for additional 15 h. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue (24.6 g) was subjected to gel filtration column chromatography (MCI Gel CHP-20P, 600 ml). The fractions eluting with 40% aqueous methanol were collected to give 8.87 g of the crude compound (I-57). After the crude compound was subjected to silica gel column chromatography (chloroform-methanol), the purified compound was freeze-dried to give 5.37 g (35.7%) of the compound (I-57).

mp: 192-194° C.

[α]

D

=−1.9° (c=1.005, H

2

O, 25° C.)

IR(KBr)cm

−1

: 1755, 1675, 1625, 1541, 1516, 1448, 1232, 1097.

NMR(CD

3

OD): 8.97 (1H, t, J=2.1 Hz), 7.34 (1H, t, J=2.1 Hz), 5.19 and 5.04 (total 1H, each t, J=7.5 Hz), 4.92 (1H, dq, J=6.6 and 8.7 Hz), 4.36 and 4.35 (1H, d, J=8.7 Hz), 4.07 and 3.92 (total 1H, each m), 3.78 (1H, m), 3.42 (1H, m), 3.22 (2H, m), 1.5-2.0 (4H, m), 1.28 and 1.22 (total 3H, each d, J=6.6 Hz), 1.21 and 1.02 (total 3H, each d, J=6.6 Hz).

Elemental analysis (C

16

H

22

N

4

O

4

S H

2

O) Calcd.: C,49.99; H,6.29; N,14.57; S,8.34. Found: C,49.99; H,6.29: N,14.79: S,8.36.

(Method B) To a solution of 10 g (33.41 mol) of the compound (46) and N-hydroxysuccinimide (4.04 g, 35.08 mM) in DMF (45 ml)-THF (360 ml) was added DCC (7.24 g, 35.08 mM) under ice-cooling and the resulting mixture was stirred for 4 h. To this reaction mixture was added a solution of (R)-(+)-2-methylpyrrolidine p-toluenesulfonate (8.6 g) which was synthesized in accordance with the method described in the literature (Helv. Chim. Acta, 34, 2202 (1951)) and triethylamine (9.32 mL 66.82 mmol) in THF (11 ml) under ice-cooling. After the mixture was stirred for 4 h at the same temperature, the cooling bath was removed and the mixture was stirred for 48 h. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue (38 g) was dissolved in water (220 ml) and the precipitation which appeared was filtered off. The filtrate was subjected to gel column chromatography (MCI Gel CHP-20P, 600 ml). The fractions eluting with 40% aqueous methanol were collected and crystallized from water to give 6.94 g (56.7%) of the same compound (I-56) that the compound had been synthesized in Method A.

Example 58

Process 1

Preparation of 3-(4-thiazolyl)-DL-alanine p-toluenesulfonate (48)

17.16 g (70 mmol) of 3-(4-Thiazolyl)-DL-alanine hydrochloride (47) was dissolved in purified water (100 ml) and the resulting mixture was adsorbed on ion exchange resin Amberlite IR-120 B (Organo inc.) (120 ml, Type-H) column. The column was washed with water and the fractions eluting with ammonia water to yield the free base of the compound (47) (11.04 g).

NMR(D

2

O): 8.98(1H, d, J=1.8 Hz), 7.42 (1H, d, J=1.8 Hz), 4.08(1H, dd, J=4.8 and 7.8 Hz), 3.45 (1H, dd, J=4.8 and 15.3 Hz), 3.33 (1H, dd, J=7.8 and 15.3 Hz).

After the free base (11.04 g) was suspended in water (50 ml), to the suspension was added a solution of p-toluenesulfonic acid hydrate (12.19 g) in water (50 ml). The mixture was concentrated in vacuo to give syrupy residue (24.43 g). To the residue was added methanol (10 ml) and ether (300 ml) and the precipitated crystal was filtered off to give 21.84 g (98.9%) of the compound (48).

NMR(CD

3

OD): 9.00 (1H, d, J=2.1 Hz), 7.71 (2H, m), 7.46 (1H, J=2.1 Hz), 7.23 (2H, m), 4.37 (1H, dd, J=4.5 and 7.5 Hz), 3.50 (1H, dd, J=4.5 and 15.9 Hz), 3.38 (1H, dd, J=7.5 and 15.9 Hz), 2.36 (3H, s).

Example 58

Process 2

Preparation of 3-(4-thiazolyl)-DL-alanine diphenylmethyl ester p-toluenesulfonate (49)

After 21.84 g (123.6 mmol) of the compound (48) was dissolved in ethanol (200 ml) and THF (100 ml) with heating to the solution was added diphenyldiazomethane (24 g, 123.6 mmol) under ice-cooling over 35 min. little by little. The cooling bath was removed and the mixture was stirred for 1 h at room temperature. To the reaction mixture was added acetic acid (0.1 ml) for quenching the excess reagent, and the mixture was concentrated in vacuo. The residue was crystallized from ether and ethanol to yield 31.63 g (97.7%) of the compound (49).

mp: 148-149° C.

IR(KBr)cm

−1

: 1755, 1607, 1516, 1493, 1216, 1202, 1181, 1125, 1088, 1066, 1036, 1011.

NMR(CD

3

OD): 8.92 (1H, d, J=2.1 Hz), 7.70 (2H, m), 7.2-7.4 (13H, m), 6.91 (1H, s), 4.62 (1H, t, J=6 Hz), 3.47 (2H, d, J=6 Hz), 2.36 (3H, s).

Elemental analysis (C

26

H

26

N

2

O

5

S

2

) Calcd.: C,61.16; H,5.13; N,5.49; S,12.56. Found: C,60.98; H,5.06; N,5.45; S,12.40.

Example 58

Process 3

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-L-alanine diphenylmethyl ester (45) and cis-L-5-methyl-2-oxo-oxazolidine-4-carbonyl-3-(4-thiazolyl)-D-alanine diphenylmethyl ester (50)

In a manner similar to that described in the above process 3, cis-L-5-methyl-2-oxo-oxazoline-4-carboxylic acid (8.14 g, 56.07 mmol) was condensed with 28.63 g (56.07 mmol) of the compound (49) using DCC (12.15 g, 68.87 mmol) in the presence of N-hydroxybenzotriazole (1.52 g, 11.21 mmol) and triethylamine (8.21 ml, 58.87 mmol) in the mixed solvents of DMF (100 ml)-THF (680 ml). After the precipitation which appeared was filtered off the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (400 ml) with heating and the precipitation which appeared was filtered off. The filtrate was washed with sodium carbonate aq. and water. After the ethyl acetate layer was stood overnight and the precipitated crystal was filtered off, the crystal was recrystallized from ethyl acetate-methanol to give 4.6 g (17.6%) of the compound (50).

mp: 203-204° C.

[α]

D

=+27.5° (c=1, DMF, 22° C.) IR(KBr)cm

−1

: 1754, 1738, 1664, 1523, 1381, 1228, 1207, 1171, 1100.

NMR(DMSO-d6): 9.02 (1H, d, J=1.8 Hz), 8.67 (1H, d, J=7.8 Hz), 7.82 (1H, s) 7.2-7.4 (1H, m), 6.79 (1H, s), 5.00 (1H, m), 4.68 (1H, m), 4.19 (1H, d, J=8.4 Hz), 3.2-3.4 (1H, M), 3.16 (1H, dd, J=9.3 and 14.4 Hz), 0.81 (3H, d, J=6.3 Hz).

Elemental analysis (C

24

H

23

N

3

O

5

S) Calcd.: C,61.92; H,4.98; N,9.03: S,6.89. Found: C,61.60; H,5.04; N,9.22; S,6.96.

The mother liquor which was obtained by collecting the crystals was concentrated in vacuo, the precipitated crystal was filtered off to give 17.26 g (76.1%) of the mixture of the compounds (50) and (45). The mixture was crystallized from methanol-ethyl acetate to yield 3.92 g (15%) of the compound (50). After the mother liquor was concentrated in vacuo, the residue was crystallized from acetone-ether to give 6.21 g (23.7%) of the same compound (45) that the compound had been synthesized in Example 57—process 3.

Example 58

Process 4

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-D-alanine (51)

In a manner similar to that described in the method of Example 57—process 4, 4.1 g (8.81 mmol) of the compound (50) was de-diphenylmethylesterificated by treating with tritluoroacetic acid-anisole to give 206 g (78.3%) of the compound (51).

mp: 214° C.

[α]

D

=+6.9° (c=0.5, DMF, 22° C.) IR(KBr)cm

−1

: 1753, 1708, 1657, 1560, 1413, 1343, 1280, 1241, 1175, 1095.

NMR(DMSO-d6): 9.02 (1H, d, J=2.1 Hz), 8.46 (1H, d, J=8.1 Hz), 7.78 (1H, s), 7.40 (1H, d, J=8.4 Hz), 4.6-4.8 (2H, m), 4.18 (1H, d, J=8.4 Hz), 3.25 (1H, dd, J=4.2 and 15 Hz), 3.10 (1H, dd, J=9.9 Hz and 15 Hz), 0.80 (3H, d, J=6.6 Hz).

Elemental analysis (C

11

H

13

N

3

O

5

S) Calcd.: C,44.14; H,4.38; N,14.04; S,10.71. Found: C,44.08; H,4.39; N,14.04; S,10.71.

Example 58

Process 5

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-yl-carbonyl-3-(4-thiazolyl)-D-alanyl-2(R)-methylpyrrolidine (I-58)

In a manner similar to that described in the method of Example 57—process 5, the compound (51) was condensed with 2(R)-methylpyrrolidine p-toluenesulfonate in the presence of N-hydroxysuccinimide, DCC, and triethylamine in DMF-THF to give the compound (I-58).

mp: 170-172° C.

[α]

D

=−16.2° (c=1.014, MeOH, 25° C.)

IR(KBr)cm

−1

: 1749, 1661, 1637, 1538, 1441, 1381, 1264.

NMR(CD

3

OD): 8.97 (1H, t, J=2.1 Hz), 7.34 (1H, t, J=2.1 Hz), 5.19 and 5.04 (total 1H, each t, J=7.5 Hz), 4.92 (1H, dq, J=6.6 and 8.7 Hz), 4.36 and 4.35 (1H, d, J=8.7 Hz), 4.07 and 3.92 (total 1H, each m), 3.78 (1H, m), 3.42 (1H, m), 3.22 (2H, m), 1.5-2.0 (4H, m), 1.28 and 1.22 (total 3H, each d, J=6.6 Hz), 1.21 and 1.02 (total 3H, each d, J=6.6 Hz).

Elemental analysis (C

16

H

22

N

4

O

4

S H

2

O) Calcd.: C,49.99; H,6.29; N,14.57; S,8.34. Found: C,52.40; H,5.98; N,15.19; S,8.77.

In a manner similar to that, described in the method of the above, the compounds below may be able to be synthesized.

TABLE 24

Example No.

Y

Example No.

Y

59

Et

83

—CONHMe

60

n-Pr

84

—CON(Me)

2

61

i-Pr

85

—CON(Me)(Et)

62

c-Pr

86

—CON(Et)

2

63

n-Bu

87

—CH

2

-(c-Pr)

64

sec-Bu

88

—CH

2

-(c-Bu)

65

i-Bu

89

—CH

2

-(c-Pen)

66

t-Bu

90

—CH

2

-(c-Hex)

67

c-Bu

91

—CH

2

CN

68

n-Pen

92

—CH

2

CHO

69

c-Pen

93

—CH

2

COOH

70

n-Hex

94

—CH

2

COOMe

71

c-Hex

95

—CH

2

COOEt

72

—COOMe

96

—CH

2

COO(n-Pr)

73

—COOEt

97

—CH

2

COO(i-Pr)

74

—COO(n-Pr)

98

—CH

2

COO(c-Pr)

75

—COO(c-Pr)

99

—CH

2

CF

3

76

—COO(n-Bu)

100

—CH

2

CONH

2

77

—COO(c-Bu)

101

—CH

2

C(O)CH

3

78

—COO(c-Pen)

102

—CH

2

C(O)Et

79

—COO(c-Hex)

103

—CH

2

C(O)Pr

80

—COO(n-Dec)

104

—CH

2

Ph

81

—COO(4-Me-Ph)

105

—CH

2

(4-Me-Ph)

82

—COOPh

106

—CH

2

SH

TABLE 25

Example No.

Y

Example No.

Y

107

—CH

2

SMe

131

—CH

2

PO(OH)

2

108

—CH

2

NO

2

132

—CH

2

PO(OH)

109

—CH

2

NH

2

133

—CH

2

PO(OMe)

2

110

—CH

2

NHMe

134

—CH

2

CH

2

OH

111

—CH

2

N(Me)

2

135

—CH

2

CH

2

OMe

112

—CH

2

N(Me)(Et)

136

—CH

2

CH

2

CN

113

—CH

2

OC(O)CH

3

137

—CH

2

CH

2

CHO

114

—CH

2

OC(O)Et

138

—CH

2

CH

2

COOH

115

—CH

2

OC(O)Ph

139

—CH

2

CH

2

COOMe

116

—CH

2

OMe

140

—CH

2

CH

2

CONH

2

117

—CH

2

OEt

141

—CH

2

CH

2

NO

2

118

—CH

2

O(n-Pr)

142

—(CH

2

)

3

CN

119

—CH

2

O(c-Pr)

143

—(CH

2

)

3

CHO

120

—CH

2

O(n-Bu)

144

—(CH

2

)

3

COOH

121

—CH

2

O(t-Bu)

145

—(CH

2

)

3

COOMe

122

—CH

2

O(c-Pen)

146

—(CH

2

)

3

CONH

2

123

—CH

2

O(c-Hex)

147

—(CH

2

)

3

NO

2

124

—CH

2

OPh

148

—CH

2

-(1-Pyrrolidinyl)

125

—CH

2

SO

3

H

149

—CO-(1-Piperidyl)

126

—CH

2

SO

3

Me

150

—CO-(1-Piperazinyl)

127

—CH

2

SO

2

Me

151

—CO-(1-Pyrrolyl)

128

—CH

2

SO

2

Ph

152

—CO-(1-Imidazolizinyl)

129

—CH

2

SOMe

153

—CO-(1-Indolyl)

130

—CH

2

SOEt

154

—CO-(1-Imidazolyl)

TABLE 26

Example No.

Y

Example No.

Y

155

Me

179

—CH

2

CN

156

Et

180

—CH

2

CHO

157

n-Pr

181

—CH

2

COOH

158

i-Pr

182

—CH

2

COOMe

159

c-Pr

183

—CH

2

COOEt

160

n-Bu

184

—CH

2

COO(n-Pr)

161

i-Bu

185

—CH

2

COO(i-Pr)

162

sec-Bu

186

—CH

2

COO(c-Pr)

163

c-Bu

187

—CH

2

COOPh

164

n-Pen

188

—CH

2

CONH

2

165

c-Pen

189

—CH

2

C(O)CH

3

166

n-Hex

190

—CH

2

C(O)Et

167

c-Hex

191

—CH

2

C(O)Pr

168

—COOMe

192

—CH

2

SH

169

—COOEt

193

—CH

2

SMe

170

—COO(n-Pr)

194

—CH

2

NO

2

171

—COO(c-Pr)

195

—CH

2

NH

2

172

—COO(n-Bu)

196

—CH

2

NHMe

173

—COO(c-Bu)

197

—CH

2

N(Me)

2

174

—COO(c-Pen)

198

—CH

2

OC(O)CH

3

175

—COO(c-Hex)

199

—CH

2

OC(O)Et

176

—CONHMe

200

—CH

2

OC(O)Ph

177

—CON(Me)

2

201

—CH

2

-(1-Pyrrolidinyl)

178

—CON(Me)(Et)

202

—CO-(1-Piperidyl)

TABLE 27

Example

Example

No.

R

3

Y

No.

R

3

Y

203

H

Me

227

Me

Me

204

H

Et

228

Me

Et

205

H

n-Pr

229

Me

n-Pr

206

H

i-Pr

230

Me

i-Pr

207

H

c-Pr

231

Me

c-Pr

208

H

n-Bu

232

Me

n-Bu

209

H

i-Bu

233

Me

i-Bu

210

H

sec-Bu

234

Me

sec-Bu

211

H

t-Bu

235

Me

t-Bu

212

H

—COOH

236

Me

—COOH

213

H

—COOMe

237

Me

—COOMe

214

H

—CONH

2

238

Me

—CONH

2

215

H

—CONHMe

239

Me

—CONHMe

216

H

—CN

240

Me

—CN

217

H

—CH

2

OH

241

Me

—CH

2

OH

218

H

—CH

2

OMe

242

Me

—CH

2

OMe

219

H

—CH

2

COOH

243

Me

—CH

2

COOH

220

H

—CH

2

COOMe

244

Me

—CH

2

COOMe

221

H

—CH

2

COPh

245

Me

—CH

2

COPh

222

H

—CH

2

CONH

2

246

Me

—CH

2

CONH

2

223

H

—CH

2

CN

247

Me

—CH

2

CN

224

H

—CH

2

CHO

248

Me

—CH

2

CHO

225

H

—CH

2

CF

3

249

Me

—CH

2

CF

3

226

H

—CH

2

SH

250

Me

—CH

2

SH

TABLE 28

Example

Example

No.

R

3

Y

No.

R

3

Y

251

H

Me

275

Me

Me

252

H

Et

276

Me

Et

253

H

n-Pr

277

Me

n-Pr

254

H

i-Pr

278

Me

i-Pr

255

H

c-Pr

279

Me

c-Pr

256

H

n-Bu

280

Me

n-Bu

257

H

i-Bu

281

Me

i-Bu

258

H

sec-Bu

282

Me

sec-Bu

259

H

t-Bu

283

Me

t-Bu

260

H

—COOH

284

Me

—COOH

261

H

—COOMe

285

Me

—COOMe

262

H

—CONH

2

286

Me

—CONH

2

263

H

—CONHMe

287

Me

—CONHMe

264

H

—CN

288

Me

—CN

265

H

—CH

2

OH

289

Me

—CH

2

OH

266

H

—CH

2

OMe

290

Me

—CH

2

OMe

267

H

—CH

2

COOH

291

Me

—CH

2

COOH

268

H

—CH

2

COOMe

292

Me

—CH

2

COOMe

269

H

—CH

2

COPh

293

Me

—CH

2

COPh

270

H

—CH

2

CONH

2

294

Me

—CH

2

CONH

2

271

H

—CH

2

CN

295

Me

—CH

2

CN

272

H

—CH

2

CHO

296

Me

—CH

2

CHO

273

H

—CH

2

CF

3

297

Me

—CH

2

CF

3

274

H

—CH

2

SH

298

Me

—CH

2

SH

TABLE 29

Example

Example

No.

R

3

Y

No.

R

3

Y

299

H

Me

323

Me

Me

300

H

Et

324

Me

Et

301

H

n-Pr

325

Me

n-Pr

302

H

i-Pr

326

Me

i-Pr

303

H

c-Pr

327

Me

c-Pr

304

H

n-Bu

328

Me

n-Bu

305

H

i-Bu

329

Me

i-Bu

306

H

sec-Bu

330

Me

sec-Bu

307

H

t-Bu

331

Me

t-Bu

308

H

—COOH

332

Me

—COOH

309

H

—COOMe

333

Me

—COOMe

310

H

—CONH

2

334

Me

—CONH

2

311

H

—CONHMe

335

Me

—CONHMe

312

H

—CN

336

Me

—CN

313

H

—CH

2

OH

337

Me

—CH

2

OH

314

H

—CH

2

OMe

338

Me

—CH

2

OMe

315

H

—CH

2

COOH

339

Me

—CH

2

COOH

316

H

—CH

2

COOMe

340

Me

—CH

2

COOMe

317

H

—CH

2

COPh

341

Me

—CH

2

COPh

318

H

—CH

2

CONH

2

342

Me

—CH

2

CONH

2

319

H

—CH

2

CN

343

Me

—CH

2

CN

320

H

—CH

2

CHO

345

Me

—CH

2

CHO

321

H

—CH

2

CF

3

346

Me

—CH

2

CF

3

322

H

—CH

2

SH

347

Me

—CH

2

SH

TABLE 30

Example

Example

No.

R

3

Y

No.

R

3

Y

348

H

Me

372

Me

Me

349

H

Et

373

Me

Et

350

H

n-Pr

374

Me

n-Pr

351

H

i-Pr

375

Me

i-Pr

352

H

c-Pr

376

Me

c-Pr

353

H

n-Bu

377

Me

n-Bu

354

H

i-Bu

378

Me

i-Bu

355

H

sec-Bu

379

Me

sec-Bu

356

H

t-Bu

380

Me

t-Bu

357

H

—COOH

381

Me

—COOH

358

H

—COOMe

382

Me

—COOMe

359

H

—CONH

2

383

Me

—CONH

2

360

H

—CONHMe

384

Me

—CONHMe

361

H

—CN

385

Me

—CN

362

H

—CH

2

OH

386

Me

—CH

2

OH

363

H

—CH

2

OMe

387

Me

—CH

2

OMe

364

H

—CH

2

COOH

388

Me

—CH

2

COOH

365

H

—CH

2

COOMe

389

Me

—CH

2

COOMe

366

H

—CH

2

COPh

390

Me

—CH

2

COPh

367

H

—CH

2

CONH

2

391

Me

—CH

2

CONH

2

368

H

—CH

2

CN

392

Me

—CH

2

CN

369

H

—CH

2

CHO

393

Me

—CH

2

CHO

370

H

—CH

2

CF

3

394

Me

—CH

2

CF

3

371

H

—CH

2

SH

395

Me

—CH

2

SH

TABLE 31

Example

Example

No.

R

3

Y

No.

R

3

Y

396

H

Me

420

Me

Me

397

H

Et

421

Me

Et

398

H

n-Pr

422

Me

n-Pr

399

H

i-Pr

423

Me

i-Pr

400

H

c-Pr

424

Me

c-Pr

401

H

n-Bu

425

Me

n-Bu

402

H

i-Bu

426

Me

i-Bu

403

H

sec-Bu

427

Me

sec-Bu

404

H

t-Bu

428

Me

t-Bu

405

H

—COOH

429

Me

—COOH

406

H

—COOMe

430

Me

—COOMe

407

H

—CONH

2

431

Me

—CONH

2

408

H

—CONHMe

432

Me

—CONHMe

409

H

—CN

433

Me

—CN

410

H

—CH

2

OH

434

Me

—CH

2

OH

411

H

—CH

2

OMe

435

Me

—CH

2

OMe

412

H

—CH

2

COOH

436

Me

—CH

2

COOH

413

H

—CH

2

COOMe

437

Me

—CH

2

COOMe

414

H

—CH

2

COPh

438

Me

—CH

2

COPh

415

H

—CH

2

CONH

2

439

Me

—CH

2

CONH

2

416

H

—CH

2

CN

440

Me

—CH

2

CN

417

H

—CH

2

CHO

441

Me

—CH

2

CHO

418

H

—CH

2

CF

3

442

Me

—CH

2

CF

3

419

H

—CH

2

SH

443

Me

—CH

2

SH

TABLE 32

Example

Example

No.

R

3

Y

No.

R

3

Y

444

H

Me

468

Me

Me

445

H

Et

469

Me

Et

446

H

n-Pr

470

Me

n-Pr

447

H

i-Pr

471

Me

i-Pr

448

H

c-Pr

472

Me

c-Pr

449

H

n-Bu

473

Me

n-Bu

450

H

i-Bu

474

Me

i-Bu

451

H

sec-Bu

475

Me

sec-Bu

452

H

t-Bu

476

Me

t-Bu

453

H

—COOH

477

Me

—COOH

454

H

—COOMe

478

Me

—COOMe

455

H

—CONH

2

479

Me

—CONH

2

456

H

—CONHMe

480

Me

—CONHMe

457

H

—CN

481

Me

—CN

458

H

—CH

2

OH

482

Me

—CH

2

OH

459

H

—CH

2

OMe

483

Me

—CH

2

OMe

460

H

—CH

2

COOH

484

Me

—CH

2

COOH

461

H

—CH

2

COOMe

485

Me

—CH

2

COOMe

462

H

—CH

2

COPh

486

Me

—CH

2

COPh

463

H

—CH

2

CONH

2

487

Me

—CH

2

CONH

2

464

H

—CH

2

CN

488

Me

—CH

2

CN

465

H

—CH

2

CHO

489

Me

—CH

2

CHO

466

H

—CH

2

CF

3

490

Me

—CH

2

CF

3

467

H

—CH

2

SH

491

Me

—CH

2

SH

TABLE 33

Example

Example

No.

R

3

Y

No.

R

3

Y

492

H

Me

516

Me

Me

493

H

Et

517

Me

Et

494

H

n-Pr

518

Me

n-Pr

495

H

i-Pr

519

Me

i-Pr

496

H

c-Pr

520

Me

c-Pr

497

H

n-Bu

521

Me

n-Bu

498

H

i-Bu

522

Me

i-Bu

499

H

sec-Bu

523

Me

sec-Bu

500

H

t-Bu

524

Me

t-Bu

501

H

—COOH

525

Me

—COOH

502

H

—COOMe

526

Me

—COOMe

503

H

—CONH

2

527

Me

—CONH

2

504

H

—CONHMe

528

Me

—CONHMe

505

H

—CN

529

Me

—CN

506

H

—CH

2

OH

530

Me

—CH

2

OH

507

H

—CH

2

OMe

531

Me

—CH

2

OMe

508

H

—CH

2

COOH

532

Me

—CH

2

COOH

509

H

—CH

2

COOMe

533

Me

—CH

2

COOMe

510

H

—CH

2

COPh

534

Me

—CH

2

COPh

511

H

—CH

2

CONH

2

535

Me

—CH

2

CONH

2

512

H

—CH

2

CN

536

Me

—CH

2

CN

513

H

—CH

2

CHO

537

Me

—CH

2

CHO

514

H

—CH

2

CF

3

538

Me

—CH

2

CF

3

515

H

—CH

2

SH

539

Me

—CH

2

SH

TABLE 34

Example

Example

No.

R

3

Y

No.

R

3

Y

540

H

Me

564

Me

Me

541

H

Et

565

Me

Et

542

H

n-Pr

566

Me

n-Pr

543

H

i-Pr

567

Me

i-Pr

544

H

c-Pr

568

Me

c-Pr

545

H

n-Bu

569

Me

n-Bu

546

H

i-Bu

570

Me

i-Bu

547

H

sec-Bu

571

Me

sec-Bu

548

H

t-Bu

572

Me

t-Bu

549

H

—COOH

573

Me

—COOH

550

H

—COOMe

574

Me

—COOMe

551

H

—CONH

2

575

Me

—CONH

2

552

H

—CONHMe

576

Me

—CONHMe

553

H

—CN

577

Me

—CN

554

H

—CH

2

OH

578

Me

—CH

2

OH

555

H

—CH

2

OMe

579

Me

—CH

2

OMe

556

H

—CH

2

COOH

580

Me

—CH

2

COOH

557

H

—CH

2

COOMe

581

Me

—CH

2

COOMe

558

H

—CH

2

COPh

582

Me

—CH

2

COPh

559

H

—CH

2

CONH

2

583

Me

—CH

2

CONH

2

560

H

—CH

2

CN

584

Me

—CH

2

CN

561

H

—CH

2

CHO

585

Me

—CH

2

CHO

562

H

—CH

2

CF

3

586

Me

—CH

2

CF

3

563

H

—CH

2

SH

587

Me

—CH

2

SH

TABLE 35

Example

Example

No.

R

3

Y

No.

R

3

Y

588

H

Me

612

Me

Me

589

H

Et

613

Me

Et

590

H

n-Pr

614

Me

n-Pr

591

H

i-Pr

615

Me

i-Pr

592

H

c-Pr

616

Me

c-Pr

593

H

n-Bu

617

Me

n-Bu

594

H

i-Bu

618

Me

i-Bu

595

H

sec-Bu

619

Me

sec-Bu

596

H

t-Bu

620

Me

t-Bu

597

H

—COOH

621

Me

—COOH

598

H

—COOMe

622

Me

—COOMe

599

H

—CONH

2

623

Me

—CONH

2

600

H

—CONHMe

624

Me

—CONHMe

601

H

—CN

625

Me

—CN

602

H

—CH

2

OH

626

Me

—CH

2

OH

603

H

—CH

2

OMe

627

Me

—CH

2

OMe

604

H

—CH

2

COOH

628

Me

—CH

2

COOH

605

H

—CH

2

COOMe

629

Me

—CH

2

COOMe

606

H

—CH

2

COPh

630

Me

—CH

2

COPh

607

H

—CH

2

CONH

2

631

Me

—CH

2

CONH

2

608

H

—CH

2

CN

632

Me

—CH

2

CN

609

H

—CH

2

CHO

633

Me

—CH

2

CHO

610

H

—CH

2

CF

3

634

Me

—CH

2

CF

3

611

H

—CH

2

SH

635

Me

—CH

2

SH

TABLE 36

Example

Example

No.

R

3

Y

No.

R

3

Y

636

H

Me

661

Me

Me

637

H

Et

662

Me

Et

638

H

n-Pr

663

Me

n-Pr

639

H

i-Pr

664

Me

i-Pr

640

H

c-Pr

665

Me

c-Pr

641

H

n-Bu

666

Me

n-Pu

642

H

i-Bu

667

Me

i-Bu

643

H

sec-Bu

668

Me

sec-Bu

645

H

t-Bu

669

Me

t-Bu

646

H

—COOH

670

Me

—COOH

647

H

—COOMe

671

Me

—COOMe

648

H

—CONH

2

672

Me

—CONH

2

649

H

—CONHMe

673

Me

—CONHMe

650

H

—CN

674

Me

—CN

651

H

—CH

2

OH

675

Me

—CH

2

OH

652

H

—CH

2

OMe

676

Me

—CH

2

OMe

653

H

—CH

2

COOH

677

Me

—CH

2

COOH

654

H

—CH

2

COOMe

678

Me

—CH

2

COOMe

655

H

—CH

2

COPh

679

Me

—CH

2

COPh

656

H

—CH

2

CONH

2

680

Me

—CH

2

CONH

2

657

H

—CH

2

CN

681

Me

—CH

2

CN

658

H

—CH

2

CHO

682

Me

—CH

2

CHO

659

H

—CH

2

CF

3

683

Me

—CH

2

CF

3

660

H

—CH

2

SH

684

Me

—CH

2

SH

TABLE 37

Example

Example

No.

R

3

Y

No.

R

3

Y

685

H

Me

709

Me

Me

686

H

Et

710

Me

Et

687

H

n-Pr

711

Me

n-Pr

688

H

i-Pr

712

Me

i-Pr

689

H

c-Pr

713

Me

c-Pr

690

H

n-Bu

714

Me

n-Bu

691

H

i-Bu

715

Me

i-Bu

692

H

sec-Bu

716

Me

sec-Bu

693

H

t-Bu

717

Me

t-Bu

694

H

—COOH

718

Me

—COOH

695

H

—COOMe

719

Me

—COOMe

696

H

—CONH

2

720

Me

—CONH

2

697

H

—CONHMe

721

Me

—CONHMe

698

H

—CN

722

Me

—CN

699

H

—CH

2

OH

723

Me

—CH

2

OH

700

H

—CH

2

OMe

724

Me

—CH

2

OMe

701

H

—CH

2

COOH

725

Me

—CH

2

COOH

702

H

—CH

2

COOMe

726

Me

—CH

2

COOMe

703

H

—CH

2

COPh

727

Me

—CH

2

COPh

704

H

—CH

2

CONH

2

728

Me

—CH

2

CONH

2

705

H

—CH

2

CN

729

Me

—CH

2

CN

706

H

—CH

2

CHO

730

Me

—CH

2

CHO

707

H

—CH

2

CF

3

731

Me

—CH

2

CF

3

708

H

—CH

2

SH

732

Me

—CH

2

SH

TABLE 38

Example

Example

No.

R

3

Y

No.

R

3

Y

733

H

Me

757

Me

Me

734

H

Et

758

Me

Et

735

H

n-Pr

759

Me

n-Pr

736

H

i-Pr

760

Me

i-Pr

737

H

c-Pr

761

Me

c-Pr

738

H

n-Bu

762

Me

n-Bu

739

H

i-Bu

763

Me

i-Bu

740

H

sec-Bu

764

Me

sec-Bu

741

H

t-Bu

765

Me

t-Bu

742

H

—COOH

766

Me

—COOH

743

H

—COOMe

767

Me

—COOMe

744

H

—CONH

2

768

Me

—CONH

2

745

H

—CONHMe

769

Me

—CONHMe

746

H

—CN

770

Me

—CN

747

H

—CH

2

OH

771

Me

—CH

2

OH

748

H

—CH

2

OMe

772

Me

—CH

2

OMe

749

H

—CH

2

COOH

773

Me

—CH

2

COOH

750

H

—CH

2

COOMe

774

Me

—CH

2

COOMe

751

H

—CH

2

COPh

775

Me

—CH

2

COPh

752

H

—CH

2

CONH

2

776

Me

—CH

2

CONH

2

753

H

—CH

2

CN

777

Me

—CH

2

CN

754

H

—CH

2

CHO

778

Me

—CH

2

CHO

755

H

—CH

2

CF

3

779

Me

—CH

2

CF

3

756

H

—CH

2

SH

780

Me

—CH

2

SH

TABLE 39

Example

Example

No.

R

3

Y

No.

R

3

Y

781

H

Me

805

Me

Me

782

H

Et

806

Me

Et

783

H

n-Pr

807

Me

n-Pr

784

H

i-Pr

808

Me

i-Pr

785

H

c-Pr

809

Me

c-Pr

786

H

n-Bu

810

Me

n-Bu

787

H

i-Bu

811

Me

i-Bu

788

H

sec-Bu

812

Me

sec-Bu

789

H

t-Bu

813

Me

t-Bu

790

H

—COOH

814

Me

—COOH

791

H

—COOMe

815

Me

—COOMe

792

H

—CONH

2

816

Me

—CONH

2

793

H

—CONHMe

817

Me

—CONHMe

794

H

—CN

818

Me

—CN

795

H

—CH

2

OH

819

Me

—CH

2

OH

796

H

—CH

2

OMe

820

Me

—CH

2

OMe

797

H

—CH

2

COOH

821

Me

—CH

2

COOH

798

H

—CH

2

COOMe

822

Me

—CH

2

COOMe

799

H

—CH

2

COPh

823

Me

—CH

2

COPh

800

H

—CH

2

CONH

2

824

Me

—CH

2

CONH

2

801

H

—CH

2

CN

825

Me

—CH

2

CN

802

H

—CH

2

CHO

826

Me

—CH

2

CHO

803

H

—CH

2

CF

3

827

Me

—CH

2

CF

3

804

H

—CH

2

SH

828

Me

—CH

2

SH

TABLE 40

Example

Example

No.

R

3

Y

No.

R

3

Y

829

H

Me

853

Me

Me

830

H

Et

854

Me

Et

831

H

n-Pr

855

Me

n-Pr

832

H

i-Pr

856

Me

i-Pr

833

H

c-Pr

857

Me

c-Pr

834

H

n-Bu

858

Me

n-Bu

835

H

i-Bu

859

Me

i-Bu

836

H

sec-Bu

860

Me

sec-Bu

837

H

t-Bu

861

Me

t-Bu

838

H

—COOH

862

Me

—COOH

839

H

—COOMe

863

Me

—COOMe

840

H

—CONH

2

864

Me

—CONH

2

841

H

—CONHMe

865

Me

—CONHMe

842

H

—CN

866

Me

—CN

843

H

—CH

2

OH

867

Me

—CH

2

OH

844

H

—CH

2

OMe

868

Me

—CH

2

OMe

845

H

—CH

2

COOH

869

Me

—CH

2

COOH

846

H

—CH

2

COOMe

870

Me

—CH

2

COOMe

847

H

—CH

2

COPh

871

Me

—CH

2

COPh

848

H

—CH

2

CONH

2

872

Me

—CH

2

CONH

2

849

H

—CH

2

CN

873

Me

—CH

2

CN

850

H

—CH

2

CHO

874

Me

—CH

2

CHO

851

H

—CH

2

CF

3

875

Me

—CH

2

CF

3

852

H

—CH

2

SH

876

Me

—CH

2

SH

TABLE 41

Example

Example

No.

R

3

Y

No.

R

3

Y

877

H

Me

901

Me

Me

878

H

Et

902

Me

Et

879

H

n-Pr

903

Me

n-Pr

880

H

i-Pr

904

Me

i-Pr

881

H

c-Pr

905

Me

c-Pr

882

H

n-Bu

906

Me

n-Bu

883

H

i-Bu

907

Me

i-Bu

884

H

sec-Bu

908

Me

sec-Bu

885

H

t-Bu

909

Me

t-Bu

886

H

—COOH

910

Me

—COOH

887

H

—COOMe

911

Me

—COOMe

888

H

—CONH

2

912

Me

—CONH

2

889

H

—CONHMe

913

Me

—CONHMe

890

H

—CN

914

Me

—CN

891

H

—CH

2

OH

915

Me

—CH

2

OH

892

H

—CH

2

OMe

916

Me

—CH

2

OMe

893

H

—CH

2

COOH

917

Me

—CH

2

COOH

894

H

—CH

2

COOMe

918

Me

—CH

2

COOMe

895

H

—CH

2

COPh

919

Me

—CH

2

COPh

896

H

—CH

2

CONH

2

920

Me

—CH

2

CONH

2

897

H

—CH

2

CN

921

Me

—CH

2

CN

898

H

—CH

2

CHO

922

Me

—CH

2

CHO

899

H

—CH

2

CF

3

923

Me

—CH

2

CF

3

900

H

—CH

2

SH

924

Me

—CH

2

SH

TABLE 42

Example

Example

No.

R

3

Y

No.

R

3

Y

925

H

Me

949

Me

Me

926

H

Et

950

Me

Et

927

H

n-Pr

951

Me

n-Pr

928

H

i-Pr

952

Me

i-Pr

929

H

c-Pr

953

Me

c-Pr

930

H

n-Bu

954

Me

n-Bu

931

H

i-Bu

955

Me

i-Bu

932

H

sec-Bu

956

Me

sec-Bu

933

H

t-Bu

957

Me

t-Bu

934

H

—COOH

958

Me

—COOH

935

H

—COOMe

959

Me

—COOMe

936

H

—CONH

2

960

Me

—CONH

2

937

H

—CONHMe

961

Me

—CONHMe

938

H

—CN

962

Me

—CN

939

H

—CH

2

OH

963

Me

—CH

2

OH

940

H

—CH

2

OMe

964

Me

—CH

2

OMe

941

H

—CH

2

COOH

965

Me

—CH

2

COOH

942

H

—CH

2

COOMe

966

Me

—CH

2

COOMe

943

H

—CH

2

COPh

967

Me

—CH

2

COPh

944

H

—CH

2

CONH

2

968

Me

—CH

2

CONH

2

945

H

—CH

2

CN

969

Me

—CH

2

CN

946

H

—CH

2

CHO

970

Me

—CH

2

CHO

947

H

—CH

2

CF

3

971

Me

—CH

2

CF

3

948

H

—CH

2

SH

972

Me

—CH

2

SH

Referential Example

Preparation of cis-L-5-methyl-2-oxo-oxazolidine-4-carbonyl-L-hystidyl-L-prolineamide (52)

In a manner similar to that described in the method of Example 1-3, N-hydroxysuccinimide ester of cis-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid which was synthesized by reacting cis-L-5-methyl-2-oxo-oxazolidine-4-carboxylic acid (226 mg, 1.56 mmol), N-hydroxysuccinimide (179 mg, 1.56 mmol), and DCC (338 mg, 1.63 mmol) in N, N-dimethylformamide (5 ml) was condensed with L-hystidyl-L-prolineamide hydrobromide (870 mg, 1.56 mmol), which was synthesized in accordance with the method described in Bull. Chem. Soc. Jpn. 44, 1689 (1971), in the presence of triethylamine (0.87 ml, 6.24 mmol) to give the referential compound (42) (223 mg, 38%). The chemical formula was shown below.

[α]

D

=−49.9° (c=0.505, MeOH, 24° C.).

NMR(CD

3

OD): 7.60 (1H, s), 6.97 (1H, s), 4.90 (2H, m), 4.41 (1H, dd, J=3.3, 8.5 Hz), 4.35 (1H, d, J=8.4 Hz), 3.85 (1H, m), 3.43 (1H, m), 3.13 (1H, dd, J=6.6, 14.7 Hz), 2.98 (1H, m), 2.29 (1H, m), 2.00 (3H, m), 1.22 and 1.29 (total 3H, d, J=6.3 Hz).

Elemental analysis (C

16

H

22

N

6

O

5

2H

2

O) Calcd.: C,46.37; H,6.32; N,20.28. Found: C,46.30; H,6.27; N,20.54.

Test Example 1

Anti-recerpine Action After Oral Administration of Test Compounds

Reserpine-induced hypothemia mice (ddY, male, body weight: 30 to 40 g) were prepared by the subcutaneous administration of reserpine in back side of the rat (3 mg/kg) at 18 hours before test compounds administration. Mice with their body temperature about 25° C. were used in the experiment. Test compounds were solubilized in saline and 0.2 ml (10 μmol/kg) of them were administered by sonde for oral administration. After the administration, rectal temperature was measured at, 30, 60, 120, 180, 240, 300, and 360 min. The area under curve (AUC) of the body temperature-time profile was calculated by the general trapezoidal method. In the control experiment, vehicle (saline) was administered to mice and the rectal temperature was measured by the same protocol. The effective dose, which can increase the average of body temperature at 1° C. for 420 min in reserpine-induced hypothermia mice after oral administration of the test compounds, is calculated by the following equation:

Effective dose = \frac{Orally administered dose}{AUC(test compounds) - AUC(vehicle)/420}

Effective dose: Dose which can increase the average of body temperatures at 1° C. for 420 min in reserpine-induced hypothermia mice.

AUC (test compounds): The area under curve (AUC) of the body temperature-time profile for 420 min after oral administration of test compounds was calculated by the general trapezoidal method.

AUC (vehicle): The area under curve (AUC) of the body temperature-time profile for 420 min after oral administration of saline was calculated by the general trapezoidal method.

The results were shown in Table 43.

TABLE 43

Dose which can increase the average of

body temperatures at 1° C. for 420 min in

reserpine-induced hypothermia mice by

oral) (μmol / kg)

TRH

42.68

I-4

0.86

I-5

1.22

I-10

1.14

I-11

2.03

I-30

2.59

I-40

1.65

Test Example 2

Anti Recerpine Action After Intravenous and Intracerebroventicular Administration of Test Compounds

Recerpine-induced hypothermia mice (ddY, male) were prepared by the administration of reserpine (3 mg/kg) at 18 hours before test compounds administration. Mice with their body temperature about 25° C. were used in the experiment. Test compounds were solubilized in saline and 0.1 ml (1 μmol/kg) of them were administered intravenously and 0.005 ml (0.21 μmol/kg) of them were administered intracerebroventicularly, respectively. After the administration, rectal temperature was measured at 30, 60, 120, and 180 min. The area under curve (AUC) of the body temperature-time profile was calculated by the general trapezoidal method. In the control experiment, vehicle (saline) was administered to mice intravenously or intracerebroventicularly and the rectal temperature was measured by the same protocol. The effective dose, which can increase the average of body temperatures at 1° C. for 180 min in reserpine-induced hypothermia mice after intravenous or intracerebroventicular administration of the test compounds, is calculated by the following equation:

Effective dose = \frac{Orally administered dose}{AUC(test compounds) - AUC(vehicle)}

Effective dose = \frac{Orally administered dose}{AUC(test compounds) - AUC(vehicle)/180}

Effective dose: Dose which can increase the average of body temperatures at 1° C. for 180 min in reserpine-induced hypothermia mice.

AUC (test compounds): The area under curve (AUC) of the body temperature-time profile for 180 min after intravenous or intracerebroventicular administration of test, compounds was calculated by the general trapezoidal method.

AUC (vehicle): The area under curve (AUC) of the body temperature-time profile for 180 min after intravenous or intracerebroventicular administration of saline was calculated by the general trapezoidal method.

The results were shown in Table 44.

TABLE 44

Dose which can increase the average of body

temperatures at 1° C. for 180 min in reserpine-

induced hypothermia mice (μmol / kg)

administered

administered

intracerebroventicularly

intravenously

TRH

0.033

9.84

I-10

0.025

0.11

Test Example 3

Effect on Acetylcholine Release

Male Wister rats (body weight: 250 to 300 g) which were fasted over night and anesthetized with uretane were placed in stereotaxic frame for rats. After the skin of scalp was incised and the skull was exposed, the cortex of frontal lobe was drilled (A 3.7, L 3.0, H 4.0). The dialysis probe used in the present experiment was I-shaped with a 3 mm long polycarbonate membrane tubing (CMA-12, BAS Co., LTD). Body temperature of rats were kept at 37° C. by a hot blanket. Perfusion was performed at a constant rate of 2 μl/min with Ringer's solution containing 10 μM physostigmine. Perfusate were collected every 30 min. After the perfusion for 2 hours, test compounds (24 μmol/kg) solubilized in saline were administered orally to rats and then perfusion was continued for 6 hours. The concentrations of acetylcholine in perfusate were determined by a HPLC/ECD. The acetylcholine level before the administration of test compound was defined as the average baseline level (100%). Data represent the increase of acetylcholine content of each fraction, expressed as a percentage compared to the average baseline level. The result was shown in FIG.

1

.

Test Example 4

The Change of Blood Glucose Levels After the Duodenal Administration of the Test Compounds to Rats

Fasted male Wistar rats (250-350 g) were anesthetized with urethane. Test compounds were solubilized in saline and administered intravenously (50 μmol/kg). Body temperature of rats were kept at 37° C. by a hot blanket. After the administration, blood was collected from jugular vein at 5, 15, 30, 60, 120, 180, 240, 300, 360, 420, and 480 min and blood glucose levels were measured (BM Test blood sugar, Wako Chemical Indus.) The blood glucose levels at each sampling time in vehicle (saline)-treated rats were defined as the baseline level (100%). Data represent the changes of blood glucose levels after the duodenal administration of test compounds to rats, expressed as a percentage compared to the baseline level. The results was shown in FIG.

2

. The date was shown in Table 45.

TABLE 45

Time (min)

TRU

Compound (I-10)

0

116.3

107.7

5

114.6

119.9

15

123.3

104.3

30

137.9

109.1

60

153.5

112.1

120

139.1

126.5

180

119.1

105.3

240

112.6

110.9

300

113.2

104.0

360

103.5

100.4

420

102.6

102.6

480

97.1

111.8

Formulation Example

Formulation Example 1

Granules are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

10

mg

Lactose

700

mg

Corn Starch

274

mg

HPC-L

16

mg

1000

mg

The compound represented by the formula (I) and lactose were made pass through a 60 mesh sieve. Corn starch was made pass through a 120 mesh sieve. They were mixed by a twin shell blender. An aqueous solution of HPC-L (low mucosity hydroxypropylcellulose) was added to the mixture and the resulting mixture was kneaded, granulated (by the extrusion with pore size 0.5 to 1 mm mesh), and dried. The dried granules thus obtained were sieved by a swing sieve (12/60 mesh) to yield the granules.

Formulation 2

Powders for filling capsules are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

10

mg

Lactose

79

mg

Corn starch

10

mg

Magnesium stearate

10

mg

100

mg

The compound represented by the formula (I) and lactose were made pass through a 60 mesh sieve. Corn starch was made pass through a 120 mesh sieve. These ingredients and magnesium stearate were mixed by a twin shell blender. 100 mg of the 10-fold trituration was filled into a No. 5 hard gelatin capsule.

Formulation 3

Granules for filling capsules are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

15

mg

Lactose

90

mg

Corn starch

42

mg

HPC-L

3

mg

150

mg

The compound represented by the formula (I) and lactose were made pass through a 60 mesh sieve. Corn starch was made pass through a 120 mesh sieve. After mixing them, an aqueous solution of HPC-L was added to the mixture and the resulting mixture was kneaded, granulated, and dried. After the dried granules were lubricated, 150 mg of that, were filled into a No. 4 hard gelatin capsule.

Formulation 4

Tablets are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

10

mg

Lactose

90

mg

Microcrystal cellulose

30

mg

CMC-Na

15

mg

Magnesium stearate

5

mg

150

mg

The compound represented by the formula (I), lactose, microcrystal cellulose, and CMC-Na (carboxymethylcellulose sodium salt) were made pass through a 60 mesh sieve and then mixed. The resulting mixture was mixed with magnesium stearate to obtain the mixed powder for the tablet formulation. The mixed powder was compressed to yield tablets of 150 mg.

Formulation Example 5

Sustained release tablets are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

15

mg

Lactose

20

mg

Microcrystal cellulose

100

mg

Magnesium stearate

5

mg

Lovely wax-120 H

110

mg

250

mg

The compound represented by the formula (I), lactose, and microcrystal cellulose were made pass through a 60 mesh sieve and were mixed. Mixpowders were heated and solubilized with lovely wax-120 H (Froint Inds.) and then granulated. Magnesium stearate previously made pass through a 60 mesh sieve was added to the obtained granules and the resulting granules were compressed to yield sustained-release tablets.

Formulation Example 6

Sustained release double layered tablet are prepared using the following ingredients.

Ingredients

Immediately release layer

The compound represented by the formula (I)

15

mg

Lactose

25

mg

Microcrystal cellulose

100

mg

Methylcellulose

5

mg

Magnesium stearate

5

mg

150

mg

Sustained layer

The compound represented by the formula (I)

15

mg

Lactose

25

mg

Microcrystal cellulose

90

mg

Stearic acid

10

mg

Methylcellulose

5

mg

Magnesium stearate

5

mg

150

mg

Immediately release layer: The compound represented by the formula (I), lactose, and microcrystal cellulose were made pass through a 60 mesh sieve and were mixed. A solution of methylcellulose was added to the mixture and the resulting mixture was kneaded, granulated and dried to yield the granules.

Sustained release layer: The compound represented by the formula (I) lactose, and microcrystal cellulose were made pass through a 60 mesh sieve and were mixed. Stearic acid was added to the mixture and the resulting mixture was heated and dissolved. They were kneaded, were granulated, and were dried to yield the granules.

Double layered tablet formation: Magnesium stearate was added to the granules of immediately release layer and the resulting mixture was compressed. Subsequently, magnesium stearate was added to the granules of immediately release layer and the resulting mixture was compressed on to yield sustained release double layered tablets.

Formulation Example 7

Enteric coated granules are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

30

mg

Microcrystal cellulose

125

mg

Corn starch

50

mg

CMC-Na

25

mg

HPC or MC

10

mg

240

mg

(Coating solution)

HP-55

10.5

mg

Fatty acid ester of glycerin

2.0

mg

Ethanol

41.0

mg

Dichloromethane

46.5

mg

Talc

4

mg

The active ingredient, microcrystal cellulose, corn starch, and CMC-Na were made pass through a 20 mesh sieve and mixed thoroughly. A solution of HPC (hydroxypropyhlcellulose) or MC (methylcellulose) was added to the mixture and the kneading was made pass through a 16 mesh sieve. The obtained granules were dried at 50 to 60° C. The dried granules were spray-coated with a solution of HP-55 (hydroxypropylmethylcellulose phthalate, Shinetsu Kagaku inc.) in fatty acid ester of glycerin, ethanol, dichloromethane, and talc to yield the enteric coated granules.

Formulation 8

Enteric coated granules are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

30

mg

Microcrystal cellulose

155

mg

Corn starch

60

mg

CMC-Na

25

mg

HPC or MC

5

mg

275

mg

(Coating solution)

Eudragit L30D-55

46.8

mg

Polysolvate 80

0.7

mg

PEG 6000

1.4

mg

Talc

4.2

mg

Purified water

46.8

mg

The granules which are prepared in a manner similar to that described in the method of Formulation example 7 was coated with the coating solution comprising the solution of Eudragit L30D-55 (Röhm Pharma) in polysolvate 80 (polyoxyethylenesorbitan monooleate, Kao inc.), PEG 6000, talc, and purified water. After the obtained granules were dried, the resulting granules were made pass through a 16 mesh sieve to yield the enteric coated granules.

Formulation Example 9

Sublingual tablets are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

10

mg

Lactose

70

mg

Corn starch

12

mg

Methylcellulose

5

mg

Talc

2

mg

Magnesium stearate

1

mg

100

mg

The compound represented by the formula (I), lactose, and corn starch were made pass through a 80 mesh sieve and mixed. Mixpowder was kneaded with methylcellulose solution and granulated, dried, then the granules were lubricated.

Formulation Example 10

Injections are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

1

mg

Glucose

2

mg

Water for injection

997

mg

1000

mg

The above ingredients were filled into ampoules.

Formulation 11

Freeze-dried injections are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

1

mg

D-mannitol

200

mg

Water for injection

779

mg

1000

mg

The above ingredients were filled into ampoules for freeze-drying and the ampoules were freeze-dried to yield the freeze-dried injections.

Formulation 12

Suppositories are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

30

mg

Witepsol

1470

mg

1500

mg

The compound represented by the formula (I) was made pass through a 60 mesh sieve. The compound was dispersed in the solution of the melted witepsol (higher fatty acid triglyceride) at 50 to 60° C. The solution was cooled to 38 to 40° C. with stirring to yield the medical fluid. The medical fluid was filled into a container of aluminum foil, sealed, and then cooled to yield the suppositories.

Formulation Example 13

Nasals are prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

2

mg

Carboxyvinylpolymer

5

mg

L-Arginine

10

mg

Sodium chloride

0.6

mg

Purified water

84.2

mg

100

mg

After the compound represented by the formula (I) was dissolved in carboxyvinylpolymer, L-arginine and sodium chloride was added to the solution. The solution's pH was adjusted and the mucosity was adjusted by adding purified water to yield the objective medical fluid.

Formation Example 14

Endermatic formulation was prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

10

mg

Iso-propyl myristate

990

mg

1000

mg

After the compound represented by the formula (I) was dispersed in iso-propyl myristate, the mixture was mixed with acrylic adhesive formulation and was attached plastered to a support to yield endermatic formulation.

Formulation Example 15

Ointment was prepared using the following ingredients.

Ingredients

The compound represented by the formula (I)

10

mg

Liquidparaffin

7.5

mg

Glycerol

82.5

mg

100

mg

The compound represented by the formula (I) was dispersed in liquid paraffin and kneaded to yield the ointment.

Industrial Applicability

The novel peptide derivatives having 3-(4-thiazolyl or 5-thiazolyl)-alanine residue and having an effect of activating the central nervous system were provided.

Peptide derivatives having thiazolyl-alanine residue

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

PCT Information

Foreign Referenced Citations (1)

Non-Patent Literature Citations (4)