AU680512B2 - Amino acid derivative - Google Patents

Description

SPECIFICATION

AMINO ACID DERIVATIVE Field of the Invention The present invention relates to an amino acid derivative. More particularly, it relates to an amino acid derivative having excellent effects as a medicine.

Description of the Related Art Among heart diseases generally called heart failure, not only acute heart failure but also a disease requiring no immediate treatment such as chronic heart failure when it has progressed, is directly fatal to us. Accordingly studies on remedies for this disease have been actively made for a long time. As a result, there have been developed, up to the present, a number of medicines for heart failure with various action mechanisms.

For example, cardiac glycosides represented by digitalis have been used for a long time as ri medicine capable of improving cardiac contractile force and tolerance limit to exercise without elevating cardiac rate. However, these cardiac glycosides have such defects that they each has a narrow margin of safety and can administer to only limited patients. In addition, they exhibit some side effects of, for I example, causing severe arrhythmia, which makes them less useful.

To relieve hemostasis due to backward heart failure, diuretics such as furosemide and spironolactone are sometimes employed. Although these medicines have such advantages that they are also applicable to a mild case of heart failure and relieve subjective symptoms, they have such disadvantages that they exhibit side effects of, for example, electrolyte disturbance and dysglycemia and are not directly related to the improvement of tolerance limit to exercise and the so-called "quality of life".

As a vasodilaLor for improving blood flow in the coronary vessel, there have also been employed nitrates such as isosorbide nitrate and a-receptor blocking agents represented by bunazosin and prazosin.

Although the former has been widely used since it is characterized by relieving the preload and improving subjective symptoms and tolerance limit to exercise, exerting an immediate action and having no severe side effect, it has such a defect that it tends to be easily tolerated. On the other hand, the latter is characterized by relieving both of preload and postload and elevating the cardiac rate. However, it has been reported that these agents have no effect of 2 I I improving subjective symptoms or tolerance limit to exercise.

Furthermore, there have been known p-stimulating drugs such as dopamine and dobutamine, each having a potent effect of enhancing cardiac contractility, as the first choice in the emergency care for acute heart failure. However, these drugs are liable to be tolerant and sometimes cause arrhythmia, etc. It is also known that they exert some side effects of inducing, for example, myocardial disorders.

Accordingly care must be taken of the utilization of these drugs.

In recent years, atrial natriuretic peptide hydrolase (neutral endpeptidase: NEP 24, 11) inhibitors and angiotensin I-converting enzyme (hereinafter referred to simply as ACE) inhibitors have attracted attention as a novel remedy for heart failure.

The above-mentioned atrial natriuretic peptide (hereinafter referred to simply as ANP) is a hormone present in bionomics. In addition to a potent water diuretic/natriuret.c effect, a vasodilator effect and so on, it exerts a suppressive effect on the liberation of norepinephrine through the suppression of the sympathetic nerve, a suppressive effect on the 3 I secretion of renin from the kidney and a suppressive effect on the secretion of aldosterone from the adrenal gland, and, further, excerts also an inhibit, Y effect on perfusion through the enhancement of the wacer permeability in the vein, etc. With respect to the function of ANP in a patient suffering from the congestive heart failure with an increase in preload, for example, it is considered that the secretion of ANP is accelerated in proportion to atrial-stretch stimulation and the amount of the circulating body fluid is thus compensatingly controlled. In fact, by the administration of ANP to patients with heart failure, decrease of the pulmonary wedge pressure and a diuretic effect are observed, and the improvements of the cardiac index and the stroke volume are also attained. Further, it is reported that ANP suppresses the liberation of endogenous hormones promoting the vicious circle in heart failure, for example, aldosterone and norepinephrine to thereby relieve the pathological conditions of heart failure from various angles. It is considered that these effects of ANP are favorable in treating not only heart failure but also hypertension.

Because of being a peptide, however, ANP cannot be orally administered and has only a poor metabolic 4- 1 T i d stability, which brings about a problem that it can be clinically usable only in an acute stage at present.

Also it is reported that the effects of ANP would be deteriorated during prolonged administration. Thus it should be carefully used.

Under taking the above-mentioned characteristics of ANP into consideratin, much attention has been paid to the above-mentioned ANP hydrolase inhibitor (hereinafter referred to simply as NEP inhibitor) as an ANP-associated preparation for oral administration.

It is reported that the administration of the NEP inhibitor to a patient with heart failure increases the blood ANP level and exerts a natriuretic effect.

However, the existing NEP inhibitors only slightly affect the cardiovascular dynamics and cannot clearly exhibit the effect of relieving preload and postload.

On the other hand, there has been proved the usefulness of the ACE iihibitor which is one of vasodilators, because it suppresses the formation of angiotensin II (hereinafter referred to simply as AT-II) which is an increment factor of heart failure to thereby significantly improve the NYHA severity and enhance the tolerance limit to exercise in chronic heart failure, and thus exhibits life-prolongation effect. However, the effective ratio of the existing 5 c ACE inhibitors to the patients is not always high, and their efficacies widely vary from patient to patient.

In addition, it is pointed out such problem that the ACE Inhibitors have side effects of, for example, inducing hypotension, which restricts the administration thereof to those suffering from depression of renal function.

Disclosure of thA Tnvention As discussed above, the existing NEP inhibitors and ACE inhibitors are each limited in usefulness, though they have attracted public attention as novel remedies for heart failure. Therefore, it has been urgently desired to study a medicine having the advantages of both of the NEP inhibition activity and.

the ACE inhibition activity.

Under these circumstances, the present inventors have conducted studies with respect to a medicine which can be orally administered, has a h.igh metabolic stability and a high effective ratio and is also applicable widely to patients with complications. As a result, they have found that the desired object can be achieved by using an amino acid derivative or a pharmacologically acceptable salt thereof as will be shown hereinbelow, thus completing the present invention.

-r II I L I I The present invention relates to a medicinal composition comprising a therapeutically or prophylactically available dose of an amino acid derivative represented by the general formula or a pharmacologically acceptable salt thereof and a pharmacologically acceptable filler: 0

R'-(CHOM

2 m H

(I)

(CH

2

SR

wherein R 1 represents a hydrogen atom or an acyl group;

R

2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent; m and n represent each independently an integer of 0, 1 or 2; and J represents a cyclic group having an angiotensin I-converting enzyme inhibition activity.

The cyclic group having an ACE inhibition 7 activity as given in the definition of J in the above general formula involves every group each having an ACE inhibition activity and a saturated or unsaturated monocyclic or fused ring. Particular examples thereof include those represented by the following general formula, though the group is not restricted thereto: 0

Y

COOR

wherein R 3 represents a hydrogen atom or a carboxyl-protecting group;

Y

1 represents a group represented by the formula

-(CR

5

R

6 )p-Z-(CR 7 R)q- [wherein R 5

R

6

R

7 and R 8 are the same or different from one another and each represents a hydrogen atom, a lower alkyl group, an pryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent; Z represents a group represented by the formula -(CH 2 r (wherein r represents an integer of 0 or a group represented 8 by the formula a group represented by the formula a group represented by the formula -SO 2 a group represented by the formula or a group represented by the formula -NR 9 (wherein R 9 represents a hydrogen atom or a lowel alkyl group); and p and q represents each independently an integer of 0 or 1 to 4 and the sum of p and q is 6 or less; with the proviso that in R 5

R

6

R

7

R

8 and R 9 when two carbon atoms each having an arbitrary substituent selected from among R 5 to R 9 bonded thereto are adjacent to each other, said two carbon atoms and said two substituents bonded thereto may be combined together to form a benzene ring or a heteroaryl ring, which may have a substituent; and that when R 2 is an aryl group, p is 2, q is 2, Z represents a group represented by the formula (wherein r' is and two substituents arbitrary selected from among R 7 's and R 8 's which are bonded to two adjacent carbon atoms are combined together to form a benzene ring, said benzene ring must be substituted by an aryl group which may have a substituent]; and R4 represents a hydrogen atom, or a group used to form a 5- to 7-membered ring which may contain one -9sulfur or oxygen atom in combination with R 7 or R 8 To further promote the understanding of the present invention, particular examples of the compounds according to the present invention will be given herein'below, though the present invention is not restricted thereto: 0 03 (C )n NH R I(C 2 NH (0) (CH2) N

(CH

2 N 3/ 1 SRI SRRI C0R R1 9 y NHS0 2

R

1 0 R 2

-(CH

2 R 2

(CH

2 N H Y1NH (CH2) N (CHI). /j N 0I 1 0 4SRI SR'

COORP

CO OR'

R

2

'(CH

2 )m .N R 2(CH 2 )m N H Y)NH N (CHO N 1I H 0 CHOS COOPS COOR' R(c2CH)NmfH2),

N

SR /CD R3 i 00Ip COOR 3 wherein R 1 represents a hydrogen atom or an acyl group;

R

2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent;

R

3 represents a hydrogen atom or a carboxylprotecting group;

R

11 and R 12 are the same or different from each other and each represents a hydrogen atom or a lower alkyl group; u represents 0, 1 or 2;

R

19 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group or a halogen atom; m and n represent each independently 0, 1 or 2;

R

14 and R 15 represent each a hydrogen atom, a lower 1 1 1 I f 'i

-M

alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, an aryl group which may have a substituent or a heteroaryl group which may have a substituent; s and t represent each an integer of 0, 1 or 2;

Y

9 represents a group represented by the formula

-(CH

2 (wherein w represents an integer of 0 or a group represented by the formula a group represented by the formula a group represented by the formula -S02-, a group represented by the formula or a group represented by the formula

-NR

17 (wherein R 17 represents a hydrogen atom or a lower alkyl group);

R

10 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, an aryl group which may have a substituent or a heteroaryl group which may have a substituent; y 4 represents a group represented by the formula

-(CH

2 (wherein x represents an integer of 0 or a group represented by the formula a group represented by the formula a group represented by the formula -SO 2 a group represented by the' formula or a group represented by the formula

-NR

17 (wherein R 17 represents a hydrogen atom or a 12 iii lower alkyl group); and

R

18 represents a hydrogen atom, a lower alkyl group or an arylalkyl group which may have a substituent.

In the present invention, the lower alkyl group as given in the definition of R 2

R

5

R

6

R

7

R

8

R

9

R

10

R

13

R

14

R

15

R

16

R

17

R

18 and R 19 means a linear or branched alkyl group having 1 to 8, preferably 1 to 6, carbon atoms. Examples thereof include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-l-methylpropyl group, l-ethyl-2-methylpropyl group and so on.

Preferable examples thereof include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl 13 group, n-pentyl group and isopeptyl group. As R 2 particularly isobutyl group, still preferably S-isobutyl group, l(S)-methylpropyl group may be cited.

The lower alkoxy group as given in the definition of R 1 0

R

1 3

R

14 and R 15 means those derived from the above-mentioned lower alkyl groups, for example, methoxy, ethoxy, isopropoxy, n-butoxy, t-butoxy and so on.

In the aryl group which may have a substituent as given in the definition of R 2

R

5

R

6

R

7

R

8

R

1

R

14 and R 15 phenyl, 2-naphthyl, 3-naphthyl, anthracenyl and so on may be exampled as aryl.

The substituent in this case may mean a lower alkyl group such as methyl group, ethyl group, propyl group and isopropyl group, a lower alkoxy group such as methoxy group, ethoxy group, propyloxy group and isopropyloxy group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, nitro group, hydroxyl group, an amino group which may be mono- or di-substituted, an acyl group such as formyl group and acetyl group, a hydorxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, carbamoyl group, thiol group, an alkylthio group, sulfinyl group, sulfonyl group, an alkylsulfinyl group, an 14 lilI alkylsulfonyl group, a halogen atom, a carboxyl group which may be protected, a carboxylalkyl group which may be protected, an acylalkyl group which may be protected, and so on.

The heteroaryl group which may have a substituent as given in the definition of R 2

R

5

R

6

R

7

R

8

R

10

R

14 and R 1 5 means a 3- to 8-membered, preferably 5- to 6-membered, ring or fused ring containing at least one hetero atom such as oxygen atom, sulfur atom and nitrogen atom.

Particular examples thereof include thienyl, furanyl, pyranyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyrid'yl, pyrazinyl, pyrimidyl, pyridazinyl, isothiazolyl, isoxazolyl, furazanyl, benzothienyl, isobenzofuranyl, chromenyl, indolidinyl, isoindolyl, indolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, quinazolyl, carbazolyl, acridinyl, phenanthridinyl and so on.

In this case, the substituent has the same meaning as the one for the aryl as described above.

In the arylalkyl group which may have a substituent as given in the definition of R 2

R

5

R

6

R

7

R

8 and R 18 the aryl has the same meaning as the aryl as described above.

In this case, the alkyl has the same meaning as 15

II

the lower alkyl as described above. Further, the substituent in this case has the same meaning as the one for the aryl group as described above.

In the heteroarylalkyl group which may have a substituent as given in the definition of R 2

R

5

R

6

R

7 and R 8 it has' the same meaning as the heteroaryl as described above.

In this case, the alkyl has the same meaning as the lower alkyl as described above. Further, the substituent in this case has the same meaning as the one for the heteroaryl group as described.

The halogen atom as given in the definition of

R

10

R

13

R

14

R

15 and R 19 means fluorine atom, chlorine atom, bromine atom, iodine atom and so on.

The carboxyl-protecting group as given in the definition of R 3 means those which can be hydrolyzed into a carboxyl group in vivo. Examples thereof include lower alkyl groups such as methyl, ethyl and t-butyl; lower alkyl groups substituted with a phenyl group which may have a substituent, such as p-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; haloganated lower alkyl groups such as 2,2,2-trichloroethyl and 2-iodoethyl; lower alkanoyloxy lower alkyl groups such as pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryl- 16 oxymethyl, valeryloxymethyl, l-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and 2-pivaloyloxyethyl; higher alkanoyloxy lower alkyl groups such as palmitoyloxyethyl, heptadecanoyloxymethyl and l-palmitoyloxyethyl; lower alkoxycarbonyloxy lower alkyl groups such as methoxycarbonyloxymethyl, l-butoxycarbonyloxyethyl and 1-(isopropo;ycarbonyloxy)ethyl; carboxy lower alkyl groups such as carboxymethyl and 2-carboxyethyl; heterocyclic groups such as 3-phthalidyl; benzoyloxy lower alkyl groups which may have a substituent, such as 4-glycyloxybenzoyloxymethyl and 4-[N-(t-butoxycarbonyl)glycyloxy]benzoyloxymethyl; (substituted dioxolene) lower alkyl groups such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; cycloalkyl-substituted lower alkanoyloxy lower alkyl groups such as 1-cyclohexylacetyloxyethyl; and cycloalkyloxycarbonyloxy lower alkyl groups such as l-cyclohexyloxycarbonyloxyethyl.

The acyl group as given in the definition of R 1 includes aliphatic and aromatic acyl groups and those derived from heterocyclic groups, for examples, lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, valeryl group, isovaleryl group and pivaloyl group, aroyl groups such as benzoyl group, toluoyl group and naphthoyl group, -17-

-I

heteroaroyl groups such as furoyl group, nicotinoyl group and isonicotinoyl group, and so on. Among them, formyl group, acetyl group, benzoyl group and so on may be cited as particularly preferable ones.

As examples of the pharmacologically acceptable salt in the present invention, inorganic acid salts such as hydrochloride, sulfate, hydrobromide and phosphate and organic acid salts such as formate, acetate, trifluoroacetate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate may be cited.

The compounds of the present invention occur as various stereoisomers due to the structures thereof.

It is needless to say that they each falls within the scope of the present invention.

As preferable compounds an, .g compounds of the present invention, those represented by the following general formula (VII) may be cited:

CH

3 0

N

CHO (VII).

H

SR'

Although these compounds occur as op:ical isomers due to their structures as described above, the 18 compounds represented by the following general formula (VII') have preferable stereostructures: CH3 0 CH (VII').

H

SR'

eos The compounds of the present invention, in which

CHI

the side chain part: in common to the compounds represented by the general formula (VII) is bound to a cyclic group, can exert an enhanced effect as compared with other compounds being similar thereto Soo in structure. As a matter of course, they can exert remarkably improved effects as compared with compounds d* being similar in structure thereto when they are intravenously administered. Further, they can exert remarkably improved effects as compared with compounds oo*** being similar in structure thereto when they are orally administered, since they have improved bioavailabilities.

19

I

P:\PE\RM1M19366.94. 105- 16/4M 19A- Preferred moieties of J are selected from any one of the groups (iii), (iv) and

COOR

3 see" ae 00 0 000 00 00 *0 0 00 S*0 Co 9.

*e 00 0000 0 00 0e (iii) (iii) ;CH,)t (iv) 0 00 0 0 wherein R 3 represents a hydrogen atom ar a carboxyl-protecting group;

Y

3 represents a group represented by the formula -(CHOw- (wherein w represents 0 or a group represented by the formula a group represented by the formula a group represented by the formula a group represented by the formula or a group represented by the formula (wherein R 1 6 represents a hydrogen atom, a lower alkyl group); R' 0 represents ahydrogen atom, a lower alky! group, a lower alkoxy group, a hydroxyl group, a halogen atom, an aryl group which may have a substituent or a heteroaryl group which may have a substituent; R" and R" 1 are the same or different from each other and each represents a hydrogen atom or a lower alkyl group;

Y

4 represents a group represented by the formula (wherein x represents 0 or a group represented by the formula a group represented by the formula a group P;\OPER\TMH\69366.94,105 1614M 19B represented by the formula -SO 2 a group represented by the formula or a group represented by the formula -NR 1 7 (wherein R 1 7 represents a hydrogen atom or a lower alkyl group);

R

3 represents a group represented by the formula -V RIq (wherein R9 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group or a halogen atom) or a group represented by the formula -NHSO 2

R

8 B 10 (wherein R 1 8 represents a hydrogen atom, a lower alkyl group or an arylalkyl group which may have a substituent);

~R

1 4 and R" 5 represent each a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, an aryl group which may have a substituent or a heteroaryl group which may have a substituent; and s, t and u each independently represent an integer of 0, 1 or 2.

More preferred moieties of J are selected from any one of groups and 0) 7-OY r 0 R 0 O' CH{,) COOR' COOR' COOR' S"0 (iii') (iv') Rs O0R

I

II:OPI3R\RMI 1\69366-94.105-.1614W7 19C wherein W 3 R1 2 R1 3 R 14

R"

5 y 4 s, t and u each have the same meaning as defined above.

Most prefierably compounds of the present invention are as follows: 4.

S

4.

4 9* 45 4 0 o

SE,..

S 54 o S 4 95*4 cH 3

NH'

SH

CO OH

'S

1 5S *5 4,54 0 *4S~ 9' 5 44 9 Se. S

S

C OOR PAQ1'RR\RMII\6936940 -05 15/4/197 19D [S02CH 3

CH

3 CO OH 000 a..

0 .s a O 0 p e a

CH

3

COOH

Now, main processes for producing the compounds of the present invention will be given. Needless to say, the compounds of the present invention can be obtained by combining known reactions in addition to 2% 0 the production processes as will be given hereinafter.

Produntion procesq A-1

H

2 N N

(XX)

(CHOP)

COOR'O-

R

2 -(CH2)m COOH Stepi1

(CH

2

(XXI)

0 R 2 (CH).Y I HR1 (CHO. M XID) 1 0 SR I CL (OH2) 60OR3- Step 2 0

R

2

-(CH

2 )m H (CH2) N 7(XXIII) SH (CHOP~ COOl! wherein R 2 represents a hydrogen atom, a lower alkyl, group, a cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent; R0 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, an aryl group which may have a substituent or a heteroaryl group which may have a substituent;

R

l a represents an acyl group;

R

3 a represents a carboxyl-protecting group; p represents an integer of 1 or 2; and m and n represent each independently an integer of 0 to 2.

(Step 1) This step is one wherein a 3-amino-benzazepin- 2-one derivative (XX) is condensed with a carboxylic acid derivative (XXI) or an active derivative thereof such as an acid halide thereof to thereby give an amide derivative (XXII). The condensation is effected in the conventional manner. For example, the 3-aminobenzazepin-2-one derivative (XX) is reacted with the carboxylic acid derivative (XXI) in an inert solvent represented by methylene chloride, tetrahydrofuran and so on in the presence of a condensing reagent commonly employed in the art such as EEDQ (1-ethoxycarbonyl- -21- -0 I -1 2-ethoxy-l,2-dihydro-quinoline), DCC (1,3-dicyclohexylcarbodiimide), DEC [1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride] or diethyl cyanophosphonate to thereby give the amide derivative (XXII). When the condensation proceeds via an acid chloride of the carboxylic acid derivative (XXI), the carboxylic acid derivative (XXI) is converted into the acid chloride thereof in an appropriate inert solvent with the use of a chlorinating agent commonly employed in the art such as thionyl chloride and oxalyl chloride, followed by the reaction thereof with the 3-aminobenzazepin-2-one derivative (XX) to thereby give the compound (XXII).

(Step 2) This step is one wherein the ester group and acylthio group in the amide derivative (XXII) obtained in the step 1 are deprotocted by the conventional manner to thereby give the target compound (XXIII).

The deprotection is effected by a method commonly employed in the art. For example, it may be effected by hydrolyzing the amide derivative (XXII) in a dilute aqueous solution of an alkali such as sodium hydroxide and lithium hydroxide or in a dilute aqueous solution of a mineral acid.

-22 i"

I

Production process A-2 When RIO is an aryl group which may have a substituent, the compound can be synthesized by the following process: (XX IV) Step 1 f trif luoromethanesulfon ylation

OSO

2

CF

3

(XXV)

IR

4

"B(OH)

2 or Step 21R 4 %n(CH 3 )3 (XI) R1 Oct (XXV I) Step 3 rearrangement 23

I

(XXV II) /N z O H Step 4 jhalogenation X~ C XXVIII) X/ /N" O H Step 5 reduction x R0 (XXIX) O H Step 6 jazidation

N

3 R 0C (XXX) O H 24 Step 7 alkylation N3- R On (XXXI)

(CH

2 )p

COOR.

Step 8

H

2 N R (XX') (Ch 2 )p

COOR'

wherein R 3 a and p have each the same meaning as the one defined above;

R

10 a represents an aryl group which may have a substituent; and X represents a halogen atom.

(Step 1) This step is one wherein a hydroxytetralone 0 derivative (XXIV) is trifluoromethanesulfonylated to thereby give a trifluoromethanesulfonyloxy compound (XXV). The trifluoromethanesulfonylation is effected by reacting the derivative (XXIV) with trifluoro- 25 methanesulfonic anhydride or trifluoromethanesulfonyl chloride in an inert solvent represented by methylene chloride, tetrahydrofuran and so on in the presence of a base such as pyridine.

(Step 2) This step is one wherein the trifluoromethanesulfonyloxy compound (XXV) obtained in the step 1 is coupled with an arylboric acid compound or an aryltin compound (XI) to thereby give an aryltetralone derivative (XXVI). The coupling of the compound (XXV) with the compound or (XI) is effected in an appropriate solvent which would not inhibit this reaction in the presence of an appropriate base and a palladium catalyst. As examples of the solvent, hydrocarbons such as toluene and amides such as N,N'-dimethylformamide may be cited. As examples of the base, alkali or alkaline earth metal carbonates such as potassium carbonate and calcium carbonate and organic bases such as triethylamine and N-methylmorpholine may be cited. As an example of the palladium catalyst, tetrakis(triphenylphosphine)palladium may be cited.

(Step 3) This step is one wherein a benzazepine derivative (XXVII) is obtained from the aryltetralone derivative 26 (XXVI) obtained in the step 2 by a rearrangement reaction commonly employed in the art. The rearrangement can be carried out in accordance with a method commonly employed in the art, for example, the Beckmann rearrangement, the Schmidt rearrangement or the like. More particularly speaking, in the case of the Beckmann rearrangement, the benzazepine derivative (XXVII) can be obtained by treating the aryltetralone derivative (XXVI) with hydroxylamine hydrochloride to thereby give an oxime, and then, for example, heating the oxime in the presence of an appropriate acid. In the case of the Schmidt rearrangement, it is effected by, for example, a method which comprises reacting with hydrazoic acid or sodium azide in the presence of an appropriate acid. As the acid, every one commonly employed in the art may be used. Examples thereof include sulfuric acid, polyphosphoric acid, trichloroacetic acid, methanesulfonic acid and so on.

(Steps 4 and These steps are one wherein the benzazepine derivative (XXVII) obtained in the step 3 is halogenated and reduced to thereby give a 3-halo-benzazepine derivative (XXIX).

The dihalogenation and reduction can be proceeded each in accordance with a method commonly employed in 27 I the art. In particular, a preferable result can be achieved by carrying out these reactions in accordance with the method of Nagasawa et al. Med. Chem., 14, 501 (1979)].

Namely, first, the benzazepine derivative (XXVII) obtained in the step 3 is reacted with PX 5 (wherein X is Br or CJ) to thereby give a dihalogen-substituted benzazepine derivative (XXVIII), and next, the compound (XXVIII) is catalytically hydrogenated in the presence of a palladium catalyst to thereby give a 3-halo-benzazepine derivative (XXIX).

(Step 6) This step is one wherein the 3-halo-benzazepine derivative (XXIX) obtained in the step 5 is subjected to azidation to thereby give an azide (XXX).

The azidation is effected by a method commonly employed in the art. That is, it is effected by reacting the 3-halo-benzazepine derivative (XXIX) with sodium azide or lithium azide in an appropriate solvent, for example, ethanol, dimethylformamide or dimethyl sulfoxide.

(Step 7) This step is one wherein the azide (XXX) obtained in the step 6 is alkylated by the conventional manner to thereby give an N-alkylated compound (XXXI).

28 I -i u The alkylation can be effected by a method commonly employed in the art. For example, it is effected by reacting the azide (XXX) with an iodoalkyl ester in an appropriate solvent, for example, dimethylformamide or tetrahydrofuran in the presence of a strong base such as sodium hydride.

Alternatively, it is effected by reacting the azide (XXX) with an haloalkyl ester in tetrahydrofuran in the presence of a base such as potassium carbonate with the use of a phase transfer catalyst such as tetra n-butylammonium bromide and benzyltriethylammonium iodide.

(Step 8) This step is one wherein the N-alkylated compound (XXXI) obtained in the step 7 is reduced by the convectional manner to thereby give an amine The reduction can be effected by a method commonly employed in the art. It may be effected by catalytically hydrogenating the N-alkylated compound (XXXI) in an appropriate solvent, for example, methanol, ethanol or ethyl acetate in the presence of a catalyst such as palladium/carbon.

This amine is important as an intermediate for producing the compound of the general formula (II) wherein Y3 is a group represented by -CH 2 29 Production process B-1

H

2 N COOH MXL 1) step 1 phthal.imidation

COOH

(XLI 11)

H

2

N

Step 2 (X I I)

COOR

3 0 amidation (XL IV) Step 3 oxidation 30 R 14

(XLV)

,(CH

2 )~ClO COORc Step 4 (XLV I Step 4 Step (XLVII1) Step 6 31 (XLVI 11) Step 7

H

2

N

0 coo[ Step 8 MX I X) CH 2 0

Y-OH

(CH2

IR'

aridation (XL 11) 1 0

SR

2 Ni COOR IC

(L)

32 Step 9

R

2

<(CH

2 )n

YNH

0 CH 2 )t CO OH Step 10 1

R

2 ((CI2z) N

COOH

In a series of formulas, RI8 represents an acyl group; R 2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substitueit; R 3 a and R 3 a' represent carboxy -p rote ct ing groups; R 14 represents a hydrogen atom, a lower alkyl 33 group, a lower alkoxy group, a hydroxyl group, a halogen atom, an aryl group which may have a substituent or a heteroaryl group which may have a substituent; t represents an integer of 0, 1 or 2; m represents an integer of 0, 1 or 2; and n represents an integer of 0, 1 or 2.

(Step 1) This step is one wherein the amino group of a 2-thienylalanine derivative (XLVII) is protected through phthalimidation by the conventional manner to thereby give a phthalimide carboxylic acid derivative (XLIII). The compound (XLIII) can be obtained in accordance with a method for phthalimdation which is commonly employed in the art. For example, phthalic anhydride and the compound (XLII) are heated in an inert solvent, for example, dJ.methylformamide or aqueous dioxane or without using any solvent in the presence of a base such as triethylamine or without using any base to thereby give the phthalimide carboxylic acid derivative (XLIII). Alternately, a phthalimidating agent such as ethoxycarbonylphthalimide is reacted with the compound (XLII) in the presence of a base such as sodium carbonate and sodium hydrogencarbonate to thereby give the phthalimide carboxylic acid derivative (XLIII).

34

I

(Step 2) This step is one wherein the phthalimide carboxylic acid derivative (XLIII) obtained in the step 1 or an active derivative thereof, such as an acid halide thereof, is condensed with an amino acid ester derivative (XII) by the conventional manner to thereby give an amide derivative (XLIV).

The condensation is effected by a method commonly employed in the art. For example, the compound (XLIII) is reacted with the amino acid ester derivative (XII) in an irert solvent represented by methylene chloride, tetrahydrofuran and so on in the presence of a commonly employed condensli.g reagent such as EEDQ (l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), DEC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) or diethyl cyanophosphcnate to thereby give the compound (XLIV).

When the condensation is to be carried out via an acid chloride of the compound (XLIII), the compound (XLIII) is converted into an acid chloride thereof in an appropriate inert solvent with the use of a commonly employed chlorinating agent such as thionyl chloride and oxalyl chloride, and then the acid chloride thus obtained is reacted with the amino acid 35 L- L 0: ester derivative (XII) to thereby give the compound

(XLIV).

(Step 3) This step is one wherein the hydroxyl group of the amide derivative (XLIV) obtained in the step 2 is oxidized to thereby give an aldehyde derivative (XLV).

The compound (XLV) can be obtained by a method commonly used for the oxidation of alkyl alcohols.

For example, the aldehyde derivative (XLV) can be obtained by effecting the Swann oxidation with the use of oxalyl chloride and dimethyl sulfoxide or an oxidation with the use of manganese dioxide in an appropriate -protic solvent such as dichloromethane and chloroform.

(Step 4) This step is one wherein the aldehyde derivative (XLV) obtained in the step 3 is cyclized to thereby directly give, through an enamine derivative, an ester derivative (XLVI) or a carboxylic acid derivative (XLVII). For example, the ester derivative (XLVI) can be obtained by treating the compound (XLV) with trifluoroacetic acid in an appropriate aprotic solvent such as dichloromethane and chloroform.

Alternatively, the carboxylic acid derivative (XLVII) can be obtained by treating the compound (XLV) with a 36 mixture of trifluoromethanesulfonic acid and trifluoroacetic anhydride or trifluoromethanesulfonic acid alone in an appropriate aprotic solvent such as dichloromethane and chloroform.

(Step This step is one wherein the ester derivative (XLVI) directly obtained in the step 4 is subjected to deprotection by the conventional manner to thereby give a carboxylic acid derivative (XLVII). For example, the ester derivative (XLVI) is subjected to a protic strong acid treatment with trifluoromethanesulfonic acid in a protic solvent such as ethanol to thereby give the carboxylic acid derivative (XLVII).

(Step 6) This step is one wherin the functional carboxylic acid group of the carboxylic acid derivative (XLVII) obtained in the steps 4 and 5 is protected by esterification to thereby give an ester derivative (XLVIII). As the ester group, a general alkyl group, a branched alkyl group or a group which can be selectively deprotected under such reaction conditions that the acylthio group of the compound to be synthesized in the step 8 is not hydrolyzed is introduced. The esterification is effected by a method commonly employed in the art. For example, the 37 derivative (XLVII) is reacted with an alcohol in the presence of a mineral acid such as hydrochloric acid and sulfuric acid. Alternatively, the derivative (XLVII) is reacted with, for example, diphenylbromomethane, triphenylbromomethane or trimethylsilylethanol in an inert solvent such as dimethylformamide and tetrahydrofuran in the presence of a base such as cesium carbonate and potassium carbonate. Thus the ester derivative (XLVIII) can be obtained.

(Step 7) This step is one wherein the phthalimide group of the ester derivative (XLVIII) obtained in the step 6 is deprotected to thereby give an amine (XLIX). This method is one according to the conventional manner.

For example, the ester derivative (XLVIII) is treated with hydrazine in a solvent such as water, an alcohol and tetrahydrofuran to thereby deprotect the phthalimide. Thus, the amine (XLIX) can be obtained.

(Step 8) This step is one wherein the carboxylic acid derivative (XIII) or an active derivatine thereof, such as an acid halide thereof, is condensed with the amine (XLIX) obtained in the step 7 to thereby give an amide derivative This reaction is effected by a method commonly employed in the art. For example, the 38 carboxylic acid derivative (XIII) is reacted with the amine (XLIX) in an inert solvent such as methylene chloride and tetrehydrofuran in the presence of a commonly employed condensing reagent such as EEDQ, DCC, DEC or diethyl cyanophosphonate to thereby give the compound When the reaction is to be carried out via an acid chloride of the carboxylic acid derivative (XIII), the carboxylic acid derivative (XIII) is converted into an acid halogenide thereof in an appropriate inert solvent with a halogenating agent commonly employed in the art, such as thionyl chloride and oxalyl chloride, and then the obtained acid halogenide is reacted with the amine (XLIX) to thereby give the compound (Step 9) This step is one wherein either or both of the acylthio group and ester group of the amide derivative obtained in the step 8 is(are) deprotected by the conventional manner to thereby give a carboxylic acid derivative When the group(s) to be eliminated is(are) usual alkyl group(s), branched alkyl group(s) or the like, for example, the amide derivative is hydrolyzed in a dilute aqueous solution of an alkali such as sodium hydroxide and lithium hydroxide or in a dilute aqueous solution of a mineral acid to thereby 39

I

give a mercapto carboxylic acid derivative (LI) having Rla representing hydrogen. When the group(s} to be eliminated is(are) t-butyl group(s), an arylalkyl group(s), a branched arylalkyl group(s) or the like, the deprotection is effected under such reaction conditions that the acylthio group remains stable, for example, by catalytically hydrogenating, treating with triflioroacetic acid or the like, to thereby give an acylthio carboxylic acid derivative (LI).

(Step This step is one wherein the acylthio group, if contained, of the carboxylic acid derivative (LI) obtained in the step 9 is hydrolyzed to thereby give a mercapto carboxylic acid derivative (LII). The hydrolysis can be effected under conditions for hydrolysis commonly employed in the art, in a dilute aqueous solution of an alkali such as sodium hydroxide and lithium hydroxide or in a dilute aqueous solution of a mineral acid.

Production process R-2 When n is 0, the compound (LIV) can be also synthesized by the following process: 40 ,R14.

R

2

-(CH

2

COOH

OH

(X IV)

H

2

N

(XL IX) Step 1 auidation (LII11) Step 2 conversion into acyithic, derivative R 2

-(CH

2

(LIV)

COOR

In a series of formulas, R18, R 2

R

3 a, R 14 m and t have each the same meaning as the one defined above.

-41 (Step 1) This step is one wherein an a-hydroxy carboxylic acid derivative (XIV) is condensed with the amine (XLIX) obtained in the above-mentioned Production process B-1, step 7 by the conventional manner to thereby give an a-hydroxy carboxylic acid amide derivative (LIII). Similar to the Production process B-l, step 8, the compounds (LIII) and (XLIX) are reacted in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of a condensing reagent commonly employed in the art, for example, EEDQ, DCC, DEC, diethyl cyanophosphonate or the like.

Thus, the amide derivative (LIII) can be obtained.

(Step 2) This step is one wherein the hydroxyl group of the amide derivative (LIII) obtained in the step 1 is converted into an acylthio group by the conventional manner to thereby give an acylthio derivative (LIV).

The compound (LIV) can be synthesized in accordance with a method commonly employed for preparing an acylthio derivative. For example, the compound (LIII) is treated by a Mitsunobu type reaction in an inert solvent such as methylene chloride and tetrahydrofuran with the use of triphenylphosphine and an azodicarboxylic acid ester such as DIAD (diisopropyl 42 azodicarboxylate). Thus, the acylthio dexivative (LIV) can be obtained.

Prndiintinn process B-3 A compound represented by the general formula (VIb) can be produced by the following process:

S

(LV)

H

2 N COOH Sit.8p 1 phthaJlimidation

(LVOI

7 LV '"'OOH 0 Step 2 aznidation 2 0 H 1\1 OH 0 0 COOP~

OH

HO)

COOR'O

0

(XII')

(LVI 1) 43 Step 3 oxidation

R

0 H

N(CH

2

CHO

0 0 COOR3 Step 4 (LVII11) Step 4 Step (L IX)

(LX)

CO ON 44 step 6

N

o o X (CH 2) COOR' c Step?7 (LX IV)

H

2N f 0 0 H 2

COOR'-

Step 8 ami dation (LXII1) 0

R

2

-(CH

2

)M

OH

(XI 11) C 2 N I 0 V.) CO OR 3ci (LXI 11) 45 Step 9

R

R'-(CH

2

N

Y NH

(CH

2 )n N (Lla) 1 0 (CH 2 )s SH /i cH z

COOH

Step 0 R 2 -(CH 2

NHS

-YANH--1 (CH2), ,N (L l Ib) 1 0 (CH 2

)S

H 1 c 11

COOH

In a series of formulas, R la represents an acyl group; R 2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent; R 3 a represents a carboxyl-protecting group; R 15 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, an aryl group which may have a 46 substituent or a heteroaryl group which may have a substituent; s represents an integer of 0, 1 or 2 m represents an integer of 0, 1 or 2; and n represents an integer of 0, 1 or 2.

(Step 1) This step is one wherein the amino group of a 3-thienylalanine acid derivative (LV) is protected through phthalimidation to thereby give a phthalimide carboxylic acid derivative (LVI). The compound (LVI) can be obtained by a method commonly employed in the art. For example, the phthalimide carboxylic acid derivative (LVI) can be obtained by heating phthalic anhydride together with the compound (LV) in an inert solvent such as dimethylformamide and aqueous dioxane or without using any solvent in the presence of a base such as triethylamine or without using any base.

Alternatively, it can be obtained by heacting a phthallmidation agent such as ethoxycarbonylphthalimide together with the compound (LV) in the presence of a base such as sodium carbonate and sodium hydrogencarbonate.

(Step 2) This step is one wherein the phthalimide carboxylic acid derivative (LVI) obtained in the step 1 or an active derivative thereof, such as an acid 47 I halide thereof, is condensed with an amino acid ester derivative (XII') by the conventional manner to thereby give an amide derivative (LVII).

The condensation may be effected by a method commonly employed in the art. For example, the compound (LVI) is reacted with the amino acid ester derivative (XII') in an inert solvent represented by methylene chloride, tetrahydrofuran and so on in the presence of a commonly employed condensing reagent such as EEDQ (l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide),

DEC

(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) or diethyl cyanophosphonate. Thus, the compound (LVII) can be obtained. When the condensation is carried out via an acid chloride of the compound (LVI), the compound (LVI) is converted into an acid chloride in an appropriate inert solvenwith the use of a commonly employed chlorinating agent such as thionyl chloride and oxalyl chloride, anf then the acid chloride thus obtained is reacted with the amino acid ester derivative (XII') to thereby give the compound (LVII).

(Step 3) This step is one wherein the hydroxyl group of the amide derivative (LVII) obtained in the step 2 is 48 oxidized by the conventional manner to thereby give an aldehyde derivative (LVIII). The compound (LVIII) can be obtained by a method commonly used for the oxidation of alkyl alcohols. For example, the aldehyde derivative (LVIII) can be obtained by effecting the Swann oxidation with the use of oxalyl chloride and dimethyl sulfoxide or an oxidation with the use of manganese dioxide in an appropriate aprotic solvent such as dichloromethane and chloroform.

(Step 4) This step is one wherein the aldehyde derivative (LVIII) obtained in the step 3 is cyclized by the conventional manner to thereby give, through an enamine derivative, an ester derivative (LIX).

Alternatively, this step is also one wherein the aldehyde derivative (LVIII) is cyclized to thereby directly give, through an enamine derivative, a carboxylic acid derivative (LX).

For example, the ester derivative (LIX) can be obtained by treating the compound (LVIII) with trifluoroacetic acid in an appropriate aprotic solvent such as dichloromethane and chloroform.

Alternatively, the carboxylic acid derivative (LX) can be obtained by treating the compound (LVIII) with a mixture of trifluoromethanesulfonic acid and 49 trifluoroacetic anhydride or trifluoromethanesulfonic acid alone in an appropriate aprotic solvent such as dichloromethane and chloroform.

(Step This step is one wherein the ester derivative (LIX) obtained in the step 4 is deprotected to thereby give a carboxylic acid derivative For example, the ester derivative (LIX) is treated with a protic strong acid such as trifluoromethanesulfonic acid in a protic solvent such as ethanol. Thus, the carboxylic acid derivative (LX) can be obtained.

(Step 6) This step is one wherein the functional carboxylic acid group of the carboxylic acid derivative (LX) obtained in the steps 4 and 5 is protected by esterification to thereby give an ester derivative (LXIV).

As the protecting group, a general alky group, a branched alkyl group or a group which can be selectively deprotected under such reaction conditions that the acylthio group of the compound (LXIII) to be synthesized in the step 8 is not hydrolyzed may be introduced. The esterification is effected by a method commonly employed in the art. For example, the carboxylic acid derivative (LX) is reacted with an 50

I

O

alcohol in the presence of a mineral acid such as hydrochloric acid or sulfuric acid. Alternatively, the derivative (LX) is reacted with, for example, diphenylbromomethane, triphenylbromomethane or trimethylsilylethanol in an inert solvent such as dimethylformamide and tetrahydrofuran in the presence of a base such as cesium carbonate and potassium carbonate. Thus, the ester derivative (LXIV) can be obtained.

(Step 7) This step is one wherein the phthalimide group of the ester derivative (LXIV) obtained in the step 6 is deprotected to thereby give an amine (LXII). This reaction can be effected by the conventional manner.

For example, the compound (LXIV) is treated with hydrazine in a solvent such as water, an alcohol and tetrahydrofuran to thereby deprotect the phthalimide.

Thus, the amine (LXII) can be obtained.

(Step 8) This step is one wherein the carboxylic acid derivative (XIII) or an active derivative thereof, such as an acid halide thereof, is condensed with the amine (LXII) obtained in the step 7 to thereby give an amide derivative (LXIII). This reaction is effected by a method commonly employed in the art. For 51 I I example, the carboxylic acid derivative (XIII) is reacted with the amine (LXII) in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of a commonly employed condensing reagent such as EEDQ, DCC, DEC or diethyl cyanophosphonate.

Thus, the compound (LXIII) can be obtained. When the reaction is carried out via an acid chloride of the carboxylic acid derivative (XIII), for example, the carboxylic acid derivative (XIII) is converted into an acid halogenide in an appropriate inert solvent with a halogenating agent commonly employed in the art, for example, thionyl chloride, oxalyl chloride or the like, and then the obtained acid halogenide is reacted with the amine (LXII) to thereby give the compound

(LXIII).

(Step 9) This step is one wherein either or both of the acylthio group and ester group of the amide derivative (LXIII) obtained in the step 8 is(are) deprotected by the conventional manner to thereby give a carboxylic acid derivative (LIa). When the group(s) to be eliminated is(are) usual an alkyl group(s), a branched alkyl group(s) or the like, for example, the amide derivative (LXIII) is hydrolyzed in a dilute aqueous solution of an alkali such as sodium hydroxide and 52 lithium hydroxide or in a dilute aqueous solution of a mineral acid to thereby give a mercapto carboxylic acid derivative (LIa) which is a compound having R la representing hydrogen. When the group(s) to be eliminated is(are) t-butyl group(s), an allylalkyl group(s), a branched allylalkyl group(s) or the like, the deprotection is effected under such reaction conditions that the acylthio group remains stable, for example, by catalytically hydrogenating, treating with trifluoroacetic acid or the like, to thereby give an acylthio carboxylic acid derivative (LIa).

(Step This step is one wherein the acylthio group, if contained, of the carboxylic acid derivative (LIa) obtained in the step 9 is hydrolyzed to thereby give a mercapto carboxylic acid derivative (LIb). The hydrolysis can be effected under conditions for hydrolysis commonly employed in the art, in a dilute aqueous solution of an alkali such as sodium hydroxide and lithium hydroxide or in a dilute aqueous solution of a mineral acid.

Production process B-4 When n is 0, the compound (LVIa) can be also synthesized by the following process: 53

(CH

2 )v COOH Y+ H 2 N 1LI) OH

N

(XIV) 0

CH

2

)S

COOR"'

Step I amidation R S R/ N H2) M- N

(LXV)

O CHzOS COOR I-C Step 2 conversion into Iacylthio derivative

R

2

(CH

2 )m N z S LV a SR'O- 1 N (LV2a) CO OR in a series of formulas, R 1 a represents an acyl group; R 2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl. group which may 54 have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent; Ra represents a carboxyl-protecting group; R 15 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, an aryl group which may have a substituent or a heteroaryl group which may have a substituent; s represents an integer of 0, 1 or 2; and m represents an integer of 0, 1 or 2.

(Step 1) This step is one wherein an a-hydroxy carboxylic acid derivative (XIV) is condensed with the amine (LXII) obtained in the above-mentioned Production process B-3, step 7 by the conventional manner to thereby give an a-hydroxy carboxylic acid amide derivative (LXV). Similar to the Production process B-3, step 8, the compounds (XIV) and (LXII) are reacted in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of a condensing reagent commonly employed in the art, for example, EEDQ, DDC, DEC or diethyl cyanophosphonate. Thus, the amide derivative (LXV) can be obtained.

(Step 2) This step is one wherein the hydroxyl group of 55 tne amide derivative (LXV) obtained in the step 1 is converted into an acylthio group to thereby give an acylthio derivative (LVIa). The compound (LVIa) can be synthesized in accordance with a method commonly employed for converting a hydroxyl group into an acylthio group. For example, the compound (LXV) is treated by a Mitsunobu type reaction in an inert solvent such as methylene chloride and tetrahydrofuran with the use of triphenylphosphine and an azodicarboxylic acid es such as DIAD (diisopropyl azodicarboxylate). Thus, the acylthio derivative (LVIa) can be obtained.

Product-lon prones C-1 A compound represented by the general formula (VII) can be produced by the following process: CH3 CHX, COOH 0 ^(XXXII)

NHN

Step 1 CHa CH, 0H

(XXXIII)

Br 5613 Step 2

CHO

CH COOH CHH

(XXXIV)

SR

1 Step 3 H 2 N-J (XXXV)

CH

3 0 CHO J (VII)

SR'

In a series of formulas, R 1 represents a hydrogen atom or an acyl group; and J represents a cyclic group having an ACE inhibition activity.

(Step 1) That is, this step is one wherein the amino group of D-allo-isoleucine (XXXII) is brominated to thereby give a bromide (XXXIII). The bromide (XXXIII) can be obtained in accordance with a method commonly employed in the art for stereoselective bromination. For example, the compound (XXXII) is treated with a nitrite such as sodium nitrite and silver nitrite in an aqueou: solution of hydrogen bromide. Thus, the 57 bromide (XXXIII) can be obtained.

(Step 2) That is, this step is one wherein the bromine group of the bromide (XXXIII) obtained in the step 1 is converted into an acylthio group to thereby give an acylthiopentanoic acid derivative (XXXIV). This reaction is effected in accordance with the conventional manner. For example, the bromide (XXXIII) is reacted with a thiocarboxylate such as potassium thioacetate and sodium thioacetate in a polar solvent such as acetonitrile and acetone.

Alternatively, the bromide (XXXIII) is reacted with a thiocarboxylic acid such as thioacetic acid and thiobenzoic acid in the presence of a base such as potassium carbonate and cesium carbonate. Thus, the acylthiopentanoic acid derivative (XXXIV) can be obtained.

(Step 3) That is, this step is one wherein the acylthiopentanoic acid derivative (XXXIV) obtained in the step 2 or an active derivative thereof, such as an acid halide thereof, is condensed with an amino acid ester derivative (XXXV) to thereby give an amide derivative (VII). For example, the acylthiopentanoic acid derivative (XXXIV) is reacted with the amino acid 58 ester derivative (XXXV) in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of a commonly employed condensing reagent such as EEDQ (l-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline),

DCC

(1,3-dicyclohexylcarbodiimide), DEC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) or diethyl cyanophosphonate. Thus, the amide derivative (VII) can be obtained. When the condensation is carried out via an acid chloride of the acylthiopentanoic acid derivative (XXXIV), the acylthiopentanoic acid derivative (XXXIV) is converted into an acid chloride in an appropriate inert solvent with the use of a commonly employed chlorinating agent such as thionyl chloride and oxalyl chloride, and then the acid chloride thus obtained is reacted with the amino acid ester derivative (XXXV) to thereby give the target compound (VII).

Produ ci:on prces s 0-_2, A compound represented by the general formula (VII) can be also obtained by the following process: 59

CHJ

CH3 A COOH S(XXXI11) Br Step 1 H 2 N-J (XXXVII) CHa 0 CH, ,J (XXXVIII) S H Br Step 2 CHa 0 CH, J (VII) SR'

H

In a series of formulas, R 1 and J have each the same meaning as the one defined above.

(Step 1) That is, this step is one wherein the brominated carboxylic acid derivative (XXXIII) obtained in the Production process C-l, step 1 or an active derivative thereof, such as an acid halide thereof, is condensed with an amino ester derivative (XXXVII) to thereby give an amide derivative (XXXVIII). The amide 60

I

derivative (XXXVIII) can be obtained by the same treatment as the one in the Production process C-l, step 3.

(Step 2) That is, this step is one wherein the bromine group in the amide derivative (XXXVIII) obtained in the step 1 is converted into an acylthio group to thereby give an amide derivative (VII) which is the same one as the compound obtained in the Production process C-l, step.3. The amide derivative (VII) can be obtained by the same treatment as the one in the Production process C-l, step 2.

Production process 0-3 Among compounds represented by the general formula (VII), those wherein R 3 is a hydrogen atom can be also obtained by the following process: CH3I 0(

CH

2 Y R-

N

SR

1 0 COOR 3 a

(XL)

61 CH, 0 CHN y R 4

(XLI)

SR' H

COOH

In a series of formulas, R 1 represents a hydrogen atom or an acyl group; Ra represents a carboxylprotecting group; R 4 represents a hydrogen atom, a lower alkyl group or an arylalkyl group which may have a substituent; and Y 1 has the same meaning as the one defined above.

Namely, the ester alone or both of the ester Pnd acylthio group of the compounds (XL) obtained by the Production process C-1 and C-2 is(are) deprotected by the conventional manner to thereby give a carboxylic acid derivative (XLI). When the group(s) to be eliminated is(are) a usual alkyl or branched alkyl group or the like, the amide derivative (VII) is hydrolyzed in a dilute aqueous solution of an alkali such as sodium hydroxide and lithium hydroxide or in a dilute aqueous solution of a mineral acid to thereby give a carboxylic acid derivative (XLI) having R 1 representing hydrogen. When the group(s) to be eliminated is(are) t-butyl group(s), a branched allylalkyl group(s) such as benzhydryl group, a 62 silylethyl group(s) such as trimethylsilylethyl group, or the like, only the part of the ester group is deprotected under such reaction conditions that the thioacyl group remains stable, for example, by treating with trifluoroacetic acid or an alkylammonium fluoride, to thereby give an acylthio carboxylic acid derivative (XLI).

Production process DP A compound represented by the following general formula can be produced by the following process:

NHSO

2

R'

0 R-(CH) NHs R (D)

(CH

2 N I 0. s SR

COOR

3 wherein R 1

R

2 R, R 18 m and n have each the same meaning as the one defined above; 63 i' nitration

COGH

IStep 1 CODH 0I1) IStep 2 N0 2

COOH

esteri fication (111) (IV) COOR"" (V 64 I Step 3 reduction

COOR"

0 iStep 4

(VI)

sulfonyjlation (V 1I) I Step 5 deprotection (VI 11) 65 Step 6 amidation NHS0 2

R"

R -(CH 2 0 1 Y NH (IX) (CH2)

N

1 0

SR

1

M

COOR

3 Step 7 hydrolysis

NHSO

2

R"'

0 YNH (X) (CH2)

N

1 0

SH

COOH

In a series of formulas which represent the above Production process D-l, R 2

R

3 a, R 18 and n have each the same meaning as the one defined above; and R l a represents a group selected from those as given above in the definition of R 1 except a hydrogen atom.

(Step 1) Namely, this is a step which comprises nitrating a publicly known cyclic amino acid derivative or a cyclic amino acid derivative obtained by a publicly known method by a publicly known method.

66 The nitration described above is effected by the conventional manner. Usually, a method which comprises treating with a nitrating agent commonly employed in the art, for example, nitronium tetrafluoroborate or the like in an inert organic solvent, for example, chloroform, dichloromethane or the like to effect nitration, a method which comprises effecting nitration with fuming nitric acid or the like in the presence of acetic acid, acetic anhydride, sulfuric acid or the like, and other methods may be cited.

(Step 2) This is a step which comprises esterifying the functional carboxylic acid group of the nitro compound (II) obtained in the step 1.

As the above-mentioned ester, a lower alkyl group or a group which can be selectively deprotected under such reaction conditions that the thioacetyl group of the compound (IX) to be synthesized in the subsequent step 6 is not hydrolyzed, is introduced. The ester compound (IV) can be obtained by, for example, reacting the nitro compound (II) with an alcohol in the presence of a mineral acid such as hydrochloric acid and sulfuric acid or, alternatively, reacting the nitro compound (II) with diphenylbromomethane, triphenylbromomethane or trimethylsilylethanol in an inert solvent such as dimethyl- 67 I- formamide and tetrahydrofuran in the presence of a base such as cesium carbonate and potassium carbonate.

(Step 3) This is a step which comprises reducing the nitro group of the compound (IV) obtained in the step 2 by the conventional manner to thereby give an aniline compound

(VI).

The reduction described above may be effected by a method commonly employed in the art. For example, catalytic reduction with the use of palladium, platinum or the like as a catalyst, or reduction with the use of a metal such as zinc and iron under acidic conditions may usually be cited.

(Step 4) Namely, this is a step which comprises reacting the aniline compound (VI) obtained in the step 3 with a publicly known chlorosufonic acid derivative or a chlorosulfonic acid derivative obtained by a publicly known method to thereby give a sulfonylamide derivative

(VII).

For example, the sulfonylamide derivative (VII) can be obtained by reacting the aniline compound (VI) with the chlorosulfonic acid derivative with the use of an inert solvent such as acetonitrile, tetrahydrofuran, toluene and dichloromethane in the presence of a base 68 I such as pyridine, triethylamine and sodium carbonate.

(Step This is a step which comprises deprotecting the phthalimide group of the sulfonylamide derivative (VII) obtained in the step 4 to thereby give an amine compound

(VIII).

The deprotection described above may be effected by the conventional manner. The amine compouLd (VIII) can be usually obtained by, for example, treating the compound (VII) with hydrazine in a solvent such as water, an alcohol and tetrahydrofuran to thereby deprotect the phthalimide group.

(Step 6) This is a step which comprises condensing a publicly known carboxylic acid derivative or a carboxylic acid derivative obtained by a publicly known method or an active derivative thereof such as an acid halide thereof with the amine compound (VIII) obtained in the step 5 to thereby give an amide derivative (IX).

The condensation described above may be effected by the conventional manner. For example, the abovementioned carboxylic acid derivative is reacted with the amine compound (VIII) in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of a condensing reagent such as EEDQ (1-ethoxycarbonyl- 69

II

r -e 1_ 2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dichlorohexylcarbodiimide hydrochloride), DEC or diethyl cyanophosphonate. Thus, the amide derivative (IX) can be obtained. When the condensation is carried out via an acid chloride of the carboxylic acid derivative, the carboxylic acid derivative is converted into an acid chloride in an appropriate inert solvent with a chlorinating agent such as thionyl chloride and oxalyl chloride, and then the acid chloride thus obtained is reacted with the amine compound (VIII) to thereby give the amide derivative (IX).

(Step 7) This is a step which comprise deprotecting either or both of the ester group and thioacyl group of the amide derivative (IX) obtained in the above step 6 to thereby give the target compound When the ester group is a usual alkyl group, a branched alkyl group or the like, the amide derivative is hydrolyzed in a dilute aqueous solution of an alkali such as sodium hydroxide and lithium hydroxide or in a dilute aqueous solution of a mineral acid to thereby give a mercapto carboxylic acid derivative having R 1 representing hydrogen. When the ester group is t-butyl group, an allylalkyl group, a branched allylalkyl group or the like, the deprotection is effected under such reaction conditions that the 70 11~1 I thicacyl group remains stable, for example, by catalytically hydrogenating or using trifluoroacetic acid or the like, to -thereby give a thioacyl carboxylic acid

MX.

Production proness D_-9 Among compounds represented by the above general formula those wherein n is 0 can be also produced by the following process:

R-C

2 mY C O11 (VI 1)

(XI)

Step 1 ampidatiofl (XI 1) step 2 j thioesterificatiol 71 "NH NH (XIII) SR" N 000R

COOR'

Step 3 hydrolysis NHS0 2

R,

0H CHNH (XIV) SH

N

GOOH

In a series of formulas described above, R a

R

2

R

a

R

18 and m have each the same meaning as the one defined above.

(Step 1) This is a step which comprises condensing a publicly known a-hydroxy carboxylic acid derivative (XI) or an a-hydroxy carboxylic acid derivative (XI) obtained by a publicly known method with the amine compound (VIII) obtained in the above Production process D-l, step 5 to thereby give an amide derivative (XII).

72

I

c In the above condensation, similar to the above Production process D-1, step 6, the compounds (XI) and (VIII) are reacted in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of a condensing reagent such as EEDQ (1-ethoxycarbonyl- 2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dichlorohexylcarbodiimide hydrochloride), DEC or diethyl cyanophosphonate. Thus, the amide derivative (XII) can be obtained.

(Step 2) This is a process which comprises thioesterifying the hydroxyl group of the amide derivative (XII) obtained in the step 1 to thereby give an acetylthio derivative (XIII). The compound (XIII) can be synthesized in accordance with a method commonly employed for thioesterification of hydroxyl group. For examnle, the compound (XII) is treated by a Mitsunobu type reaction in an inert solvent such as methylene chloride and tetrahydrofuran with the use of triphenylphosphine and an azodicarboxylic acid ester such as DIAD (diisopropyl azodicarboxylate). Thus, the acetylthio derivative (XIII) can be obtained.

(Step 3) This is a step which comprises deprotecting either or both of the ester group and thioacyl group of the 73

I-

C -"'cLrn amide derivative (XIII) obtained in the above step 2 to thereby give a carboxylic acid derivative (XIV). The carboxylic acid derivative (XIV) can be synthesized by the same method as the one in the above Production process D-l, step 7.

Proihuction process g-1 A compound represented by the following general formula can be produced by the following process: 0

R'-(CH

2 )p T NH

(E)

(CH2)m /N

COOR

3 wherein R 1 represents a hydrogen atom or an acyl group;

R

2 represents a hydrogen atom, a lower alkyl group, a heteroaryl group which may be substituted or an arylalkyl group which may be substituted;

R

3 represents a hydrogen atom, a lower alkyl group or an arylalkyl group;

R

19 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group or a halogen atom; and 74 I L p, mn and n represent each independently an integer of 0, 1 or 2;

IV)

C2" "'OOH Step I1 phthaliiidatiofl

(V)

Off [2)n (VI) Step 2 amidatioi 75 m (VII1) cooP I C, oxidation Step 3 (V I11) Step 4 cyclization 76

IX)

step 5 j cyclization

(X)

Step 6 1 esterification 77 0 0 ,&CH2)n step 7 deprotection

RI

H 2 N

ICH

2 1 78

R

2

-(CH

2 )p COOH Step 8

(CH

2 amidation

(XIII)

R

1 9 0 R -(CH 2 )p A.

R NH (XIV)

(CH

2 N bl 0 (CH2)n COOR In a series of formulas described above, R 2

R

19 p, n and m have each the same meaning as the one defined above;

R

l a represents a group selected from among those given in the definition of R 1 except a hydrogen atom; and

R

3 a represents a group selected from among those given in the definition of R 3 except a hydrogen atom.

(Step 1) This step is one wherein the amino group of a biphenylamino acid derivative represented by the general formula (IV) is protected through phthalimidation to thereby give a phthalimide carboxylic acid derivative The phthalimidation 79 can be effected by a method commonly employed in the art. For example, the phthalimide carboxylic acid derivative can-be obtained by heating phthalic anhydride together with the compound (IV) in an inert solvent such as dimethylformamide and dioxane or without using any solvent. Alternatively, it can be obtained by reacting a phthalimidation agent such as ethoxycarbonylphthalimide with the compound (IV) in the presence of a base such as sodium carbonate and sodium hydrogencarbonate.

(Step 2) This step is one wherein the phthalimide carboxylic acid derivative obtained in the step 1 or an active derivative thereof such as an acid halide thereof is condensed with an amino acid ester derivative represented by the general formula (VI) by the conventional manner to thereby give an amide derivative (VII). The condensation may be effected by a method commonly employed in the art. For example, the compounds and (VI) are, reacted in an inert solvent represented by methylene chloride, tetrahydrofuran and so on in the presence of a commonly employed condensing reagent such as EEDQ (l-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiiMlide), DEC [1-(3-dimethyl- 80 aminopropyl)-3-ethylcarbodiimide hydrochloride] or diethyl cyanophosphonate. Thus, the compound (VII) can be obtained. When the condensation is carried out via an acid chloride of the compound the compound is converted into an acid chloride in an appropriate inert solvent with a commonly employed chlorinating agent such as thionyl chloride and oxalyl chloride, and then the acid chloride thus obtained is reacted with the amine compound (VI) to thereby give the compound (VII).

(Step 3) This step is one wherein the hydroxyl group of the amide derivative (VII) obtained in the step 2 is oxidized to thereby give an aldehyde derivative (VIII). The compound (VIII) can be obtained by a method commonly used for the oxidation of alkyl alcohols. For example, the aldehyde derivative (VIII) can be obtained by effecting the Swann oxidation with the use of oxalyl chloride and dimethyl sulfoxide or an oxidation with the use of pyridinium chlorochromate or manganese dioxide in an appropriate aprotic solvent such as dichloromethane and chloroform.

(Step 4) This step is one wherein the aldehyde derivative (VIII) obtained in the step 3 is cyclized by the 81 conventional manner to thereby give an enamine compound The enamine compound (IX) can be obtained by, for example, treating the aldehyde derivative (VIII) with trifluoroacetic acid in an appropriate aprotic solvent such as dichloromethane and chloroform.

(Step This step is one wherein the enamine compound (IX) obtained in the step 4 is subjected to the Friedel-Crafts reaction to thereby give the corresponding tricyclic derivative This reaction can be made to proceed in accordance with a method commonly employed in the art. For sxample, the tricyclic derivative can be obtained by treating the compound (IX) with a mixture of trifluoromethanesulfonic acid and trifluoroacetic anhydride or trifluoromethanesulfonic acid alone in an appropriate aprotic solvent such as dichloromethane and chloroform.

(Step 6) This step is one wherein the functional carbcxylic acid group of the tricyclic derivative (X) obtained in the step 5 is protected through esterification to thereby give an ester derivative As the ester group, a general alkyl group, a 82 branched alkyl group or a group which can be selectively deprotected under such reaction conditions that the acylthio group of the compound (XIV) to be synthesized in the step 8 is not hydrolyzed may be introduced. The esterification is effected by a method commonly employed in the art. For example, the compound is reacted with an alcohol in the presence of a mineral acid such as hydrochloric acid and sulfuric acid. Alternatively, the compound is reacted with, for example, diphenylbromomethane, triphenylbromomethane or trimethylsilylethanol in an inert solvent such as dimethylformamide and tetrahydrofuran in the presence of a base such as cesium carbonate and potassium carbonate. Thus, the ester derivative (XI) can be obtained.

(Step 7) This step Is one wherein the phthalimide group of the tricyclic derivative (XI) obtained in the step 6 is deprotected to thereby give an amine compound (XII). This reaction can be effected by the conventional manner. For example, the compound (XI) is treated with hydrazine in a solvent such as water, an alcohol and tetrahydrofuran to thereby deprotect the phthalimide. Thus, the amine compound (XII) can be obtained.

83 (Step 8) This step is one wherein the carboxylic acid derivative represented by the general formula (XIII) or an active derivative thereof, such as an acid halide thereof, is condensed with the amine derivative (XII) obtained in the step 7 to thereby give an amide derivativ.e (XIV). This reaction is effected by the conventional manner. For example, the carboxylic acid derivative (XIII) is reacted with the amine derivative (XII) in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of a commonly employed condensing reagent such as EEDQ, DCC, DEC or diethyl cyanophosphonate. Thus, the amide derivative (XIV) can be obtained. When the reaction is carried out via an acid chloride of the carboxylic acid derivative (XIII), the carboxylic acid derivative (XIII) is converted into an acid halogenide in an appropriate inert solvent with a halogenating agent commonly employed in the art, such as thionyl chloride and oxalyl chloride, and then the obtained acid halogenide is reacted with the amine derivative (XII) to thereby give the amide derivative (XIV).

Prod.uction process E-2 When R 3 in the above general formula is a hydrogen atom, the compound can be produced by the 84 following process: S-NH

(XIV')

cI s(CHO) SR 1

COOR

3O deprotection

R

1 9 R -NH

(XV)

(CH2)

-N

SR' 0 J CH2)

COOH

In a series of formulas, R 1

R

2

R

a

R

1 9 p, n and m have each the same meaning as the one defined above.

Namely, this is a method which comprises deprotecting an amide derivative represented by the general formula (XIV') by the conventional manner to thereby give a carboxylic acid derivative represented by the general formula (XV).

The deprotection is effected by a method commonly 85 I employed in the art. For example, when R 1 in the target carboxylic acid derivative (XV) is an acyl group, an acid derivative wherein R 2a is, for example, a t-butyl group or an arylalkyl group is selected as the starting compound, and then the starting compound is deprotected under such reaction conditions that the acrylthio group remains stable, for example, by catalytically hydrogenating or treating with trifluoroacetic acid. Thus, the target compound (XV) can be obtained.

When R 1 of the carboxylic acid derivative (XV), the target compound, is a hydrogen atom, an amide derivative wherein R 2a is a lower alkyl is selected as the starting compound and hydrolyzed in a dilute aqueous solution of an alkali such as sodium hydroxide and lithium hydroxide or in a dilute aqueous solution of a mineral acid to thereby give the target compound (XV).

Production process R-3 When R 1 and R 2 in the above general formula (E) are each a hydrogen atom, the compound can be also produced by the following process: 86 0

R

2 -(CHL)p K R'(NH-

(XIV)

(CH

2

N

I g 0 CH 2 )n SR' CH

COOR

3 deprotection 0R' R (NH (XV')

(CH

2

N

1 0 Z (CH 2

X

00

COOH

In a series of formulas, R la

R

2

R

3 a, R 19 p, n and m have each the same meaning as the one defined above.

Namely, this is a reaction which comprises hydrolyzing a carboxylic acid derivative represented by the general formula (XIV) by the conventional manner to thereby give a mercapto carboxylic acid derivative (XVI).

The hydrolysis can be effected by a method commonly employed in the art. For example, the 87 I starting compound may be hydrolyzed in a dilute aqueous solution of an alkali such as sodium hydroxide and lithium hydroxide or in a dilute aqueous solution of a mineral acid.

'roduction process F-4 When m in the above general formula is 0, the compound (XIV') can be also synthesized by the following process:

R"-(CH

2 COOH H2N

H

2

N

OH N (XVII) (CH)n

COOR

3

(XII)

Step 1 amidation 0 -R' R -(CH2)p O NH (XVIII) OH N 88

I

Step 2 thioesterification Rls 7 19 0 R CNH (XIV') SR' N 0

(CH

2 )n

COOR

3 In a series of formulas, Rla, R 2

R

3 a, R 19 p and n have each the same meaning as the one defined above.

(Step 1) This step is one wherein an a-hydroxy carboxylic acid derivative (XVII) is condensed with the amine compound (XII) obtained in the above Production process E-l, step 7 to thereby give an a-hydroxy carboxylic acid amide derivative (XVIII). Similar to the above Production process 1, step 8, the compounds (XII) and (XVII) are reacted in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of a condensing reagent commonly employed in the art, such as EEDQ, DCC, DEC o. diethyl cyanophosphonate. Thus, the amide derivative (XVIII) can be obtained.

89 (Step 2) This step is one wherein the hydroxyl group of the amide derivative (XVIII) obtained in the step 1 is converted into an acylthio group to thereby give an acylthio derivative The compound (XIV') can be synthesized in accordance with a method commonly employed for the conversion of a hydroxyl group into an acylthio group. For example, the compound (XVIII) is treated by a Mitsunobu type reaction in an inert solvent such as methylene chloride and tetrahydrofuran with the use of triphenylphosphine and an azodicarboxylic acid ester such as DIAD (diisopropyl azodicarboxylate). Thus, the acylthio derivative (XIV') can be obtained.

Production proess F-1 Among compounds represented by the following general formula compounds other than those wherein R 1 and R 3 are each a hydrogen atom can be produced by the following process: 0

RP-(CH

2

NH

SR'

COOR

90 I a, wherein R 1 represents a hydrogen atom or an acyl group;

R

2 represents a hydrogen atom, a lower alkyl group, an aryl group which may be substituted, a heteroaryl group which may be substituted, an arylalkyl group which may be substituted, a heteroarylalkyl group which may be substituted or a lower alkoxy group;

R

3 represents a hydrogen atom or a carboxylprotecting group; and m and n represent each independently an integer of 0, 1 or 2;

R'-(CH

2 COOH HN Y

H

2

N

(cH,)n S

COOR

3 I) (lI) amidation 91 0

R'-(CH

2

NH

(gg (III)

(CH

2

S

SR'

COOR

In a series of formulas, R 2 m and n have each the same meaning as the one defined above; R l a represents a group selected from among those given in the definition of R 1 except a hydrogen atom; and R 3 a represents a group selected from among those given in the definition of R 3 except a hydrogen atom.

Namely, this is a method wh'ch comprises condensing a carboxylic acid derivative represented by the general formula or an active derivative thereof, such as an acid halide thereof, with an amine derivative represented by the general formula (II) to thereby give an amide derivative (III).

The condensation may be effected by the conventional manner. For example, a condensation in the presence of a commonly employed condensing reagent such as l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (hereinafter referred to EEDQ), 1,3-dichlorohexylcarbodiimide hydrochloride (hereinafter referred to DEC) or diethyl cyanophosphonate may be usually cited.

92

I

As the reaction solvent, every organic solvent which remains inert during the reaction may be used.

Examples thereof include methylene chloride, tetrahydrofuran and so on.

When the condensation is carried out via ain acid chloride of the carboxylic acid derivative the carboxylic acid derivative is converted into an acid chloride in an appropriate inert solvent with a commonly employed chlorinating agent such as thionyl chloride and oxalyl chloride, and then the acid chloride thus obtained is reacted with the amine derivative (II) to thereby give the compound (III).

Production process F-2 Among compounds represented by the above general formula those wherein R 1 and R3 are each a hydrogen atom can be also produced by the following process: 0

R'-(CH

2 )m

NH

(CH2 N ([II) SR O 93 hydrolysis 0 R -(CH 2 1INH CH.

(IV)

SH

COOH

In a series of formulas, R 2 m, n, Ria and R 3 a have each the same meaning as the one defined above.

Namely, this is a reaction which comprises hydrolyzing an amide compound of the general formula (III) by the conventional manner to thereby give a mercapto carboxylic acid derivative To effect the hydrolysis, a method commonly employed in the art may be employed. For example, a method which comprises reating the amide compound (III) in a dilute aqueous solution of an alkali such as sodium hydroxide and lithium hydroxide or in a dilute aqueous solution of a mineral acid and others may be cited.

Production process F-3 Among compounds represented by the above general formula those wherein n is 0 can be also produced by the following process: 94

R

2

(CH

2 )m COOH 2

I

OH +x /N S 0P

COOR

30 MV0 1I) Step 1 amidation 0

RP-(CH

2 )m

IN

OH /N s 0VI) 0

COOR'

Step 2 Jthioesterification 0 Y NH ,al SR N S (VII1) 0P In a series of formulas, R 2 m, R1a and R 3 a have each the same meaning as the one defined above.

(Step 1) Namely, this is a step which comprises condensing 95 a lactic acid derivative represented by the general formula or a reactive derivative thereof, such as an acid halide thereof, with an amine derivative (II) to thereby give an amide derivative Similar to the above-mentioned Production process F-l, the compounds and (II) are reacted in an inert solvent such as methylene chloriae and tetrahydrofuran in the presence of a condensing reagent such as EEDQ or diethyl cyanophosphonate. Thus, the amide derivative (VI) can be obtained.

(Step 2) Namely, this is a step wherein the hydroxyl group of the amide derivative (VI) obtained in the step 1 is thioesterified in the conventional manner to thereby give an acetylthio derivative (VII).

An example of the method for thioesterifying the hydroxyl group includes one which comprises treating the compound (VI) by a Mitsunobu type reaction in an inert solvent such as methylene chloride and tetrahydrofuran with the use of triphenylphosphine and an azodicarboxylic acid ester such as diisopropyl azodicarboxylate (hereinafter referred to as DIAD) to thereby give the target compound (VII).

Further, among compounds represented by the general formula one wherein R 2 and R 3 are each 96 hydrogen can be obtained by effecting hydrolysis in the same manner as the one described in the Production process F-2.

Now, main methods for synthesizing the starting compounds used in the Production processes F-1 and F-3 will be described.

Production process F-4 Among compounds represented by the above general formula used in the Production process F-3 and the compounds represented by the above general formula (I) used in the Production process F-l, those wherein n is 0 can be synthesized by the following process:

R'-(CH

2 COOH

(VIII)

NH2 Ste. 1 hydroxylation R'-(CHz 2

COOH

Y (V)

OH

SStep 2 protection of ea:er

R

2 -(CH2) COOR 20 Y ix)

OH

97 Step 3 thioesterification

R

2

-(CH

2

COOR

20 Y (X)

SR

3 Step 4 deprotection of the ester

R

2

-(CH

2

COOH

Y

(XI)

SR

3 In a series of formulas, R 2 m and R 3a have each the same meaning as the one defined above; and R 20 represents a group represented by the formula: -CHPh 2 (wherein Ph represents a phenyl group), a group represented by the formula: -CPh 3 or a group represented by the formula: -(CH 2 2 -Si(CH 3 3 (Step 1) Namely, this is a step which comprises hydroxylating an amino acid derivative represented by S: the general formula (VIII) to thereby give a lactic acid derivative which is a starting material in the Production process F-3.

The above-mentioned lactic acid derivative (V) R can be synthesized through the hydroxylation for a l/B common amino acid. The lactic acid derivative can 98 o be synthesized by, for example, treating the amino acid derivative (VIII) and an azidating agent such as sodium nitrite and silver nitrite in an aqueous acidic solution such as dilute hydrochloric acid or dilute sulfuric acid.

(Step 2) Namely, this is a step which comprises protecting the functional carboxylic acid group of the lactic acid derivative obtained in the step 1 through esterification to thereby give an ester derivative

(IX).

As an appropriate protecting group, one which can be selectively deprotected under such reaction conditions that the acylthio group of the compound (X) to be synthesized in the subsequent step 3 is not hydrolyzed is introduced. For example, the lactic acid derivative is reacted with diphenylbromomethane, triphenylbromomethane or trimethylsilylethyl bromide in an inert solvent commonly employed in the art such as dimethylformamide and tetrahydrofuran in the presence of a base such as cesium carbonate and potassium carbonate. Thus, the lactate derivative (IX) can be obtained.

(Step 3) Namely, this is a step which comprises 99 thioesterifying the hydroxyl group of the lactate derivative (IX) obtained in the step 2.

This step can be effected in the same manner as the one described in the Production process F-3, step 2.

(Step 4) Namely, this is a step which comprises deprotecting the ester group of the acylthio derivative obtained in the step 3 to thereby give a carboxylic acid derivative When the esterprotecting group R 4 is an arylalkyl group such as diphenylmethyl and triphenylmethyl, the acylthio derivative is treated with trifluoroacetic acid and anisole to thereby give the carboxylic acid derivative When the ester-protecting group R 4 is a silylalkyl group such as trimethylsilylethyl, the acylthio derivative is treated with a fluorine compound such as potassium fluoride and tetrabutylammonium fluoride to thereby give the carboxylic acid derivative (XI).

The compounds according to the present invention can be obtained by processes commonly employed in the art or by combining these processes. Major production processes will now be described.

100 0 Production process 1 Among compounds represented by the general formula one wherein R 1 is a group other than a hydrogen atom can be obtained by the following process:

H

2 N-J (VIII)

R

2

-(CH

2

COOH

(IX)

(cH 2 )n

I

SR'

0

R

2

-(CH

2

)MX

N (X)

IH

(CH2)n

SR'

In a series of formulas, R l a represents an acyl group; R 2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an arylalkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent; m and n represent each independently an 101 integer of 0, 1 or 2; and J represents a cyclic group having an angiotensin I-converting enzyme inhibition activity.

Namely, this is a step which comprises condensing an amino acid derivative represented by the general formula (VIII) with a carboxylic acid derivative represented by the general formula (IX) or an active derivative thereof, such as an acid halide thereof, by the conventional manner to thereby give an amide derivative represented by the general formula The condensation may be effected by a method commonly employed in the art. For example, the amino acid derivative (VIII) is reacted with the carboxylic acid derivative (IX) in an inert solvent represented by methylene chloride or tetrahydrofuran in the presence of a commonly employed condensing reagent such as EEDQ (l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline), DCC (1,3-dJcyclohexylcarbodiimide), DEC (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) or diethyl cyanophosphonate. Thus, the amide derivative can be obtained.

When the condensation is carried out via an acid chloride of the carboxylic acid derivative the carboxylic acid derivative (IX) is converted into an acid chloride in an appropriate inert solvent with the 102 use of a commonly employed chlorinating agent such as thionyl chloride and oxalyl chloride, and then the acid chloride thus obtained is reacted with the amino acid derivative (VIII) to thereby give the amide acid derivative as the target compound.

Production process 2 When R 1 is a hydrogen atom, the compound (XI) can also be produced by the following precess; 0

R

2

-(CH

2 J

H

(CH

2 n

SR'

0 R -(CH 2 N (Xl)

(CH

2 )n

SH

In a series of formulas, R la

R

2 J, n and m have each the same meaning as the one defined above.

Namely, this is a process which comprises deprotecting the ester group and the acylthio group of 103 the amide derivative obtained by the Production process 1 by the conventional manner to thereby give an amino acid derivative, the target compound The deprotection may be effected by a method commonly employed in the art. Namely, it is effected by hydrolyzing the amide derivative in a dilute aqueous solution of an alkali such as sodium hydroxide and lithium hydroxide or in a dilute aqueous solution of a mineral acid.

Production process 3 Among compounds represented by the general formula one (XIV) wherein n is 0 can also be produced by the following method: R'-(CH2)y COOH Y+ H 2

N-J

OH (VIII)

(XII)

Step 1 amidation 104 0

R

2

-(CH

2 N z (X N (XIII) IO H Step 2 thioesterification 0 (N

(XIV)

I_

H

SR'a In a series of formulas, Ra, R 2 m and J have each the same meaning as the one defined above.

(Step 1) Namely, this is a step which comprises condensing a lactic acid derivative represented by the general formula (XII) or a reactive derivative thereof, such as an acid halide thereof, with an amine derivative represented by the general formula (VIII) to thereby give an amide derivative (XIII). Similar to the above-mentioned Production process 1, the compounds (XII) and (VIII) are reacted in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of a condensing reagent such as EEDQ or 105 diethyl cyanophosphonate. Thus, the amide derivative (XIII) can be obtained.

(Step 2) Namely, this is a step which comprises thioesterifying the hydroxyl group of the amide derivative (XIII) obtained in the step 1 in the conventional manner to thereby give the target compound represented by the general formula (XIV).

An example of the method for thioesterifying the hydroxyl group includes one which comprises treating the amide derivative (XIII) by a Mitsunobu type reaction in an inert solvent such as methylene chloride and tetrahydrofuran with the use of triphenylphosphine and an azodicarboxylic acid ester such as diisopropyl azodicarboxylate (hereinafter referred to as DIAD) to thereby give the target compound (XIV).

Production proces 4 The compound represented by the general formula (VII) can also be obtained by the following process:

CH

3 CH3@ COOH

S(XV)

NH

2 106 04"s Step 1

CH

3 CH,3 COOH

S(XVI)

Br Step 2 CH3 CH, COOH

CH

0 (XV I)

SR'

Step 3 H2N-J

CH

3 0 CH J (VII)

SR'

In a series of formulas, R 1 and J have each the same meaning as the one defined above.

(Step 1) Namely, this step is one which comprises brominating the amino group of D-allo-isoleucine (XV) to thereby give a bromide (XVI). The compound (XVI) 107 -e I can be obtained in accordance with a method commonly employed in the art for stereoselective bromination.

For example, the compound (XV) is treated with a nitrite such as sodium nitrite or silver nitrite in an aqueous hydrogen bromide. Thus, the bromide (XVI) can be obtained.

(Step 2) Namely, this step is one which comprises converting the bromine group of the bromide (XVI) obtained in the step 1 into an acylthio group to thereby give an acylthiopentanoic acid derivative (XVII', This reaction is effected in accordance with the conventional manner. For example, the bromide (XVI) is reacted with a thiocarboxylate such as potassium thioacetate and sodium thioacetate in a polar solvent such as acetonitrile and acetone.

Alternatively, the bromide (XVI) is reacted with a thiocarboxylic acid such as thioacetic acid and thiobenzoic acid in the presence of a base such as potassium carbonate and cesium carbonate. Thus, the acylthiopentanoic acid derivative (XVII) can be obtained.

(Step 3) Namely, this step is one which comprises condensing the acylthiopenatnoic acid derivative 108 (XVII) obtained in the step 2 or an active derivative thereof, such as an acid halide thereof, with an amino acid ester derivative, which is a publicly known compound or one obtained by a publicly known method, to thereby give the target compound (VII). For example, the acylthio derivative (XVII) is reacted with the amino acid ester derivative in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of a commonly employed condensing reagent such as EEDQ (l-ethoxycarbonyl-2-ethoxy-l,2dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), DEC [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride] or diethyl cyanophosphonate. Thus, the compound (VII) can be obtained. When the condensation is carried out via an acid chloride of jhe acylthio derivative (XVII), the acylthio derivative (XVII) is converted into an acid chloride in an appropriate inert solvent with the use of a chlorinating agent such as thionyl chloride and oxalyl chloride, and then the acid chloride thus obtained is reacted with the amino acid ester derivative to thereby give the target compound (VII).

Prodiition process S The compound represented by the general formula (VII) can also be obtained by the following process: 109 CH3 C 00C O

(XVI)

Br Step 1 H 2 N-J (XV I I) CH 0 CH, 7 J (XIX)

'N

H

Br Step 2 CH3 0

CH

3 ,J (VII) SR' H In a series of formulas, R 1 represents a hydrogen atom or an acyl group; and J has the same meaning as the one defined above.

(Step 1) Namely, this step is one which comprises condensing the bromo carboxylic acid derivative (XVI) obtained in the Production process 4, step 1 or an active derivative thereof, such as an acid halide thereof, with an amino acid ester derivative (XVIII) 110 by the conventional manner to thereby give an amide derivative (XIX). The amide derivative (XIX) can be obtained by the same treatment as the one described in the Production process 4, step 3.

(Step 2) Namely, this step is one which comprises converting the bromine group of the amide derivative (XIX) obtained in the step 1 into an acylthio group to thereby give the target compound. The target compound (VII) can be obtained by the same treatment as the one described in the Production process, step 2.

To illustrate the effects of the compounds according to the present invention, Pharmacological Experiment Examples will now be given.

PharmancologLical Experiment Example A-1 Determination of NEP inhibition activity of medicament by using rat renal cortex 1. Experimental method The NEP activity was determined by using a membrane fraction prepared from rat renal cortex in accordance with the method of Booth and Kenny (A Rapid Metod for the Purificaton of Microvilli from Rabbit Kidney., Andrew G. Booth and A. John Kenny, Biochem 1974, 142, 575-581.).

The NEP activity was determined by the following 111 manner in accordance with the method of Orlowsky and Wilk (Purification and Specificity of a Membrane-Bound Metalloendopeptidase from Bovine Pituitaries., Marian Orlowsky and Shrwin Wilk, Biochemistry, 1981, 4942-4950.).

As a substrate, benzoyl-glycyl-arginyl-arginyl-2naphthylamide (benzoyl-Gly-Arg-Arg-2-naphthylamide (Nova Biochem, Switzerland)) was used. In the presence of an NEP enzyme preparation and excessive leucine aminopeptidase (sigma chemical Co., the liberated naphthylamine was made to undergo color development with first garnet (Sigma chemical Co., followed by the measurement of the absorbance at a wavelength of 540 nm.

With respect to the NEP inhibition activity, the inhibitor was added to the reaction system as described above in such a manner as to give the final concentrations of 1, 3, 10, 30, 100, 300 and 1000 nM, an inhibition curve was prepared, and then the concentration at which 50% inhibition was achieved was taken as IC 50 2. Results of the experiment Table A-1 shows the results of the above experiment together with the results of the following Pharmacological Experiment Example A-2.

112 Pharmacologic1 Experiment Exnmnlp 6-2 Determination of ACE inhibition activity of medinaraent by using rat lurng 1. Experimental method The ACE inhibition activity was determined by using a membrane fraction prepared from rat lung in accordance with the method of Wu-Wong et al.

(Characterization of Endthelin Converting Enzyme in Rat Lung., Junshyum R. Wu-Wong, Gerald, P. Budzik, Edward M. Devine and Terry J. Opgenorth, Biochem.

Biophys. Res. Commun., 1990, 171, 1291-1296.).

The ACE activity was determined with the use of a modification (modified to a borate buffer, pH 8.3) of the method of Cushman and Cheung (Spectrophotometric Assay and Properties of the Angiotensin-Converting Enzyme of Rabbit Lung., Cushman, D.W. and Cheung H.S., 1971, 20, 1637-1648.).

In the presence of ACE, the hippurate liberated from hippuryl-histidyl-leucine (Hippuryl-His-Leu (Peptide Institute Inc., Japan)) was extracted with ethyl acetate and then the absorbance was measured at a wavelength of 228 nm.

With respect to the ACE inhibition activity, the inhibitor was added to the reaction system as described above in such a manner as to give the final 113

"I

concentrations of 1, 3, 10, 30, 100, 300 and 1000 nM, an inhibition curve was prepared, and then the concentration at which 50% inhibition was achieved was taken as ICoO.

2. Results of the experiment The following Table A-1 shows the results of the experiment effected according to the above-mentioned experimental method.

Table A-1 NEP inhibiticn ACE inhibition activity activity ICso (nM) IC 50 (nM) Cpd. of Ex. A-3 90 Cpd. of Ex. A-5 160 Cpd. of Ex. A-7 8.2 Cpd. of Ex. A-9 13 13 Cpd. of Ex. A-11 6.2 11 Pharmacological Rxpernment Example B-1 Determination of NEP inhibition activity of medicament by using rat renal cortex 1. Experimental method The NEP activity was determined by using a membrane fraction prepared from rat renal cortex in accordance with the method of Booth and Kenay (A Rapid Metod for the Purificaton of Microvilli from Rabbit Kidney., Andrew G. Booth and A. John Kenny, Biochem 114 1974, 142, 575-581.).

The NEP activity was determined by the following manner in accordance with the method of Orlowsky and Wilk (Purification and Specificity of a Membrane-Bound Metalloendpeptidase from Bovine Pituitaries., Marian Orlowsky and Shrwin Wilk, Biochemistry, 1981, 4942-4950.).

As a substrate, benzoyl-glycine-argininearginine-2-naphthylamide (benzoyl-Gly-Arg-Arg- 2-naphthylamide (Nova Biochem, Switzerland)) was used.

In the presence of an NEP enzyme preparation and excessive leucine aminopeptidase (sigma chemical Co., the liberated naphthylamine was made to undergo color development with first garnet (Sigma chemical Co., followed by the measurement of the absorbance at a wavelength of 540 nm.

With respect to the NEP inhibition activity, the inhibitor was added to the reaction system as described above in such a manner as to give the final concentrations of 1, 3, 10, 30, 100, 300 and 1000 nM, an inhibition curve was prepared, and then the concentration at which 50% inhibition was achieved was taken as ICc 0 2. R, sults of the experiment Table B-l, which will be described below, shows 115 lpr i-ri rr* the results of the above experiment together with the results of the following Pharmacological Experiment Example B-2.

Pharmaological Experiment Example B-2 Determination of ACE inhibition activity of medicrament by using rat lunge 1. Experimental method The ACE inhibition activity was determined by using a membrane fraction prepared from rat lung in accordance with the method of Wu-Wong et al.

(Characterization of Endthelin Converting Enzyme in Rat Lung., Junshyum R. Wu-Wong, Gerald, P. Budzik, Edward M. Devine and Terry J. Opgenorth, Biochem.

Biophys. Res. Commun., 1990, 171, 1291-1296.).

The ACE activity was determined with the use of a modification (modified to a borate buffer, pll 8.3) of the method of Cushman and Cheung (Spectrophotometric Assay and Properties of the Angiotensin-Converting Enzyme of Rabbit Lung., Cushmpi, D.W. and Cheung H.S., 1971, 20, 1637-1648.).

In the presence of ACE, the hippurate liberated from hippuryl-histidine-leucine (Hippuryl-His-Leu (Peptide Institute Inc., Japan)) was extracted with ethyl acetate and then the absorbance was measured at a wavelength of 228 nm.

116 I 1_1_ 1_ With respect to the ACE inhibition activity, the inhibitor was added to the reaction system as described above in such a manner as to give the final concentrations of 1, 3, 10, 30, 100, 300 and 1000 nM, an inhibition curve was prepared, and then the concentration at which 50% inhibition was achieved was taken as IC 50 2. Results of the experiment The following Table B-1 shows the results of the experiment effected according to the above-mentioned experimental method.

Table B-1 NEP inhibition ACE inhibition activity activity

IC

0 (nM) ICso (nM) Cpd. of Ex. B-3 8.6 16 Cpd. of Ex. B-7 55 Cpd. of Ex. B-8 72 Ph armacological Experiment Example C-1 1. Experimental method The NEP activity was determined by the following manner in accordance with the method of Orlowsky and Wilk (Purification and Specificity of a Membrane-Bound Metalloendpeptidase from Bovine Pituitaries., Marian Orlowsky and Shrwin Wilk, Biochemistry, 1981, 117 I Ir 4942-4950.).

As a substrate, benzoyl-glycyl-arginyl-arginyl-2naphthylamide (benzoyl-Gly-Arg-Arg-2-naphthylamide (Nova Biochem, Switzerland)) was used. In the presence of an NEP enzyme preparation and excessive leucine aminopeptidase (sigma chemical Co., the liberated naphthylamine was made to undergo color development with first garnet (Sigma chemical Co., followed by the measurement of the absorbance at a wavelength of 540 nm.

With respect to the NEP inhibition activity, the test compound was added to the reaction system as described above in such a minner as to give the final concentrations of 1, 3, 10, 30, 100, 300 and 1000 nM, an inhibition curve was prepared, and then the concentration at which 50% inhibition was achieved was taken as IC 50 As a comparative compound, [4S- [4a,7a(R*) :12bp (1-oxo-2-(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido- [2,1-a][2]benzazepine-4-carboxylic acid was used.

2. Results of the experiment Table C-l, which will be described below, shows the results of the above experiment together with the results of the Pharmacological Experiment Example C-2.

118 -II ~R Pharmacological Experiment Example C-2 Determ.nation of ACE inhibition activity of medicament by using rat lung 1. Experimental method The ACE inhibition activity was determined by using a membrane fraction prepared from rat lung in accordance with the method of Wu-Wong et al.

(Characterization of Endthelin Converting Enzyme in Rat Lung., Junshyum R. Wu-Wong, Gerald P. Budzik, Edward M. Devine and Terry J. Opgenorth, Biochem.

Biophys. Res. Commun., 1990, 171, 1291-1296.).

The ACE activity was determined with the use of a modification (modified to a borate buffer, pH 8.3) of the method of Cushman and Cheung (Spectrophotometric Assay and Properties of the Angiotensin-Converting Enzyme of Rabbit Lung., Cushman D.W. and Cheung H.S., 1971, 20, 1637-1648.).

In the presence of ACE, the hippurate liberated from hippuryl-histidyl-leucine (Hippuryl-His-Leu (Peptide Institute Inc., Japan)) was extracted with ethyl acetate and then the absorbance was measured at a wavelength of 228 nm.

With respect to the ACE inhibition activity, the test compound was added to the reaction system as described above in such a manner as to give the final 119 dl concentrations of 1, 3, 10, 30, 100, 300 and 1000 nM, an inhibition curve was prepared, and then the concentration at which 50% inhibition was achieved was taken as IC 50 As a comparative compound, [4S- [4a,7a(R*),12bp]]-7-[(l-oxo-2-(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido- [2,1-a][2]benzazepine-4-carboxylic acid was used.

2. Results of the experiment The following Table C-1 shows the results of the experiment effected according to the above-mentioned experimental method.

Table C-1 NEP inhibition ACE inhibiticn Test compound activity activity ___ICg (nM) ICS 0 (nM) Ex. C-8 13.4 5.3 (n=3) Ex. C-10 12.5 13.0 (n=2) Ex. C-1 6.2 11.0 (n=l) Ex. C-12 15.1 12.5 (n=2) Ex. C-14 17.8 12.3 (n=6) Ex. C-15 6.6 12.5 (n=2) Comparative Cpd. 27.0 9.0 (n=4) 120 Pharmacological Experiment Fxample C-3 Hvpotensive effect on 2K,1C-Goldblatt hypertensive rat 1. Experimental method A silver clip with a slit of 0.25 mm in width was fitted into the left renal artery.of each of male Sprague Dawley rats (aged 6 to 7 weeks) and, after three weeks, rats showing a systolic blood pressure of 180 mmHg or above were employed. One to several drops of a 1 N aqueous solution of sodium hydroxide were dropped into purified water and each test compound was dissolved or emulsified therein to prepare it at a dose of 5 ml/kg, followed by orally administration.

After keeping the rats in an incubator at 45 0 C for to 10 minutes, the systolic blood pressure was measured by the indirect method of tail artery plethysmography. As a comparative compound, [4S- [4a,7a(R*),12bp]]-7-[(1-oxo-2-(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid was used.

2. Results of the experiment The following Table C-2 shows the results of the experiment effected according to the above-mentioned method.

121

LI

Table C-2 Compound Decrease in Decrease in examined blood pressure blood pressure (dose) after 1 3 hrs. after 6 hrs.

Ex. C-8 28.4 25.3 (1 mg/kg) (after 2 hrs) Ex. C-10 17.3 20.8 (1 mg/kg) (after 2 hrs) Ex. C-14 13.4 1 (1 mg/kg) (after 3 hrs) Ex. C-14 25.9 2 (3 mg/kg) (after 3 hrs) Comp. compound 15.4 1 (3 mg/kg) (after 1 hr) Comp. compound 14.2 1 mg/kg) (after 1 hr) As described above, the hypotensive effect according to the present invention was excellent about three or more times that of the comparative compound.

Pharmacological Experiment Example C-4 Dinretic effect on ANP-treated SHR 1. Experimental method ng/kg/min of rat Atrial natriuretic peptide (r-ANP) was intravenously injected into Spontaneously hypertensive male rats (aged 14 to 16 weeks). When the hematogenic dynamics and the blood r-ANP level became stable 1 hour after the injection, the diuretic effect of each test compound was examined. The diuretic effect was determined by intravenously 7 122- Zi injecting the test compound and measuring an increase rate of change) in urinary accumulation within minutes. As a comparative compound, [4S- [4a,7a(R*),12bp]]-7-[(l-oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a]- [2]benzazepine-4-carboxylic acid was used.

2. Results of the experiment The following Table C-3 shows the results obtained by the above experiment.

Table C-3 Test 0.01 mg/kg 0.03 mg/kg 0.1 mg/kg 0.3 mg/kg cpd. i.v. i.v. i.v. i.v.

Ex.

200% 280% 340% C-8 Ex. 220% 390% 460% C-11 Ex.

Ex. 240% 420% 470% C-14 Comp. -220% 370% 360% cpd.

As these results show, the activities of the test compounds in the diuretic effects were about three times that of the comparative compound.

Pharmacological Experimen. Rxample Hypotensive effect on SHR SHRs aged 15 to 20 weeks were anesthetized by intraperitoneally administering thiopental sodium 123

I

mg/kg). The depth of anesthesia was maintained by optionally effecting supplemental anesthesia (5 mg/kg, Catheters were inserted into the left common carotid artery and the vein respectively for the measurement of blood pressure and for the administration of a medicament. The cardiac rate was counted by using blood pressure as a trigger.

When the blood pressure became stable after the completion of the operation, the comparative compound was intravenously administered in 0.1, 0.3 and mg/kg and changes in blood, pressure and cardiac rate were measured. Following the administration, the measurement was effected for 10 minutes in the cases of 0.1 and 0.3 mg/kg or for 30 minutes in the case of mg/kg. The invention compound was intravenously administered in 0.03, 0.1 and 0.3 mg/kg and the measurement was effected for 10 minutes after the administratic, .n the cases of 0.03 and 0.1 mg/kg or for 30 minutes after the administration in the case of 0.3 mg/kg.

The comparative compound showed a continuous decrease in blood pressure of 3 to 4% at the dose of 0.3 mg/kg or above, and 12 to 13% in the case of mg/kg, and the blood pressure did not return within minutes after the administration. The cardiac rate 124 I tended to gradually decrease.

The compound of the present invention showed an obvious hypotensive effect of about 8% at the dose of 0.03 mg/kg or above, and further showed a continuous hypotensive effect of 13 to 15% at the dose of 0.1 mg/kg and 23% at the dose of 0.3 mg/kg. The cardiac rate showed no change.

Thus, it is considered that the compound of the present invention is about 10 times as active as the comparative compound in the hypotensive effect on SHR.

Pharmacological Rxperiment Example C-6 Hypotensive effect by oral administration on SHR By using Spontaneously hypertensive male rats (aged 16 to 17 weeks), the compound of Example C-8 and a comparative compound [S-(R',R*)]-2,3,4,5-tetrahydro- 3-[(2-mercapto-l-oxohexyl)amino]-2-oxo-iH-benzazepine- 1-acetic acid having the following structure each dissolved in 0.5% methylcellulose were orally administered thereto. Hypotensive effects were measured by the tail cuff method and data obtained before the oral administration and 2, 4 and 8 hours after the administration were compared. The hypotensive effect achieved by 1.0 mg/kg of the compound of Example C-8 was comparable to the one achieved by 10 mg/kg of the above comparative 125 compound. Accordingly, the compound of Example C-8 has an activity about 10 times as high as that of the comparative compound.

Comparative compound 0 CH3

NHI

1 J SH

N

COOH

Pharmacolial Experiment Example D-1 Determination of NEP and ACE Inhibition activitles 1. Experimental method As a source of the enzyme NEP, a membrane fraction prepared from rat renal cortex in accordance with the method of Booth and Kenny (A Rapid Method for the Purification of Microvilli from Rabbit Kidney., Andrew G. Booth and A. John Kenny, Biochem. 1974, 142, 575-581.) was employed. The NEP activity was determined in accordance with the method of Orlowsky and Wilk (Purification and Specificity of a Membrane- Bound Metalloendpeptidase from Bovine Pituitaries., Marian Orlowsky and Shrwin Wilk, Biochemistry, 1981, 4942-4950.). Now the procedure will be briefly described.

126 _now As a substrate, benzoyl-glycine-argininearginine-2-naphthylamide benzoyl-Gly-Arg-Arg- 2-naphthylamide (Nova Biochem, Switzerland)) was used.

In the presence of an NEP enzyme preparation and excessive leucine aminopeptidase (sigma chemical Co., the liberated naphthylamine was made to undergo color development with first garnet (Sigma chemical Co., followed by the measurement of the absorbance at a wavelength of 540 nm.

As a source of the enzyme ACE, a membrane fraction prepared from rat lung in accordance with the method of Wu-Wong et al. (Characterization of Endthelin Converting Enzyme in Rat Lung., Junshyum R.

Wu-Wong, Gerald, P. Budzik, Edward M. Devine and Terry J. Opgenorth, Biochem. Biophys. Res. Commun., 1990, 171, 1291-1296.) was used. The ACE activity was determined with the use of a modification (modified to a borate buffer, pH 8.3) of the method of Cushman and Cheung (Spectrophotometric Assay and Properties of the Angiotensin-Converting Enzyme of Rabbit Lung., Cushman D.W. and Cheung 1971, 20, 1637-1648.). Now the procedure will be briefly described.

In the presence of ACE, the hippurate liberated from hippuryl-histidine-leucine (Hippuryl-His-Leu (Peptide Institute Inc., Japan)) was extracted with 127 ethyl acetate and then the absorbance was measured at a wavelength of 228 nm.

To determine the NEP inhibition activity and the ACE inhibition activity, the inhibitor was added to the assay systems of both enzyme activities as described above in such a manner as to give the final concentrations of 1, 3, 10, 30, 100, 300 and 1000 nM and inhibition curves were prepared. Then the concentration at which 50% inhibition was achieved was taken as ICs0.

2. Results of the experiment The following Table D-1 shows the results of the above Experimental Example D-1.

Table D-l NEP inhibition ACE inhibition activity IC5 (nM) activity ICgp (nM) Ex. D-5 33 17 Ex. D-6 38 12 Comp. cpd. l 14 11 Note) *1 Comparative compound: 5(S)-[2-mercapto-3-(4methoxyphenyl)propylamino]-4-oxo-2,3,4,5,6,lOb(R)hexahydro-l-thia-3a-azabenzo[e]azuleno-3(S)-carboxylic acid.

128 PhEarmacoloicR -Experiment Example D-2 1. Experimental method Spontaneously hypertensive rats (SHR) aged 15 to weeks were anesthetized by intraperitoneally administering thiopental sodium (50 mg/kg). The depth of anesthesia was maintained by optionally effecting supplemental anesthesia (5 mg/kg, Catheters were inserted into the left common carotid artery and the vein respectively for the measurement of blood pressure and for the administration of a medicament.

The cardiac rate was counted by using blood pressure as a trigger.

When the blood pressure became stable after the completion of the operation, the comparative compound or the compound of Example 9 was intravenously administered in doses of 0.1, 0.3 and 1.0 mg/kg and changes in blood pressure and cardiac rate were measured. Following the administration, the measurement was effected for 10 minutes in the cases of 0.1 and 0.3 mg/kg or for 30 minutes in the case of mg/kg.

2. Results of the experiment The comparative compound showed a continuous decrease in blood pressure of 3 to 4% at the dose of 0.3 mg/kg or above, and 12 to 13% in the case of 129 mg/kg, and the blood pressure did not return within minutes after the administration. ov.ile, the cardiac rate tended to gradually decrease.

On the other hand, the compound of Example D-6 showed an obvious hypotensive effect (3 to at the dose of 0.1 mg/kg orr above, and showed a continuous hypotensive effect of 10 to 13% at the dose of 0.3 mg/kg and 25% at the dose of 1.0 mg/kg. While, the cardiac rate tended to gradually decrease.

Accordingly, on the basis of the results of the Experimental Example D-2 described above, it was confirmed that the hypotensive effect of the compound of Example D-6 on SHR was about th'ree times that of the comparative compound.

Pharmaolongical Experiment Examnle -1 (Determination of NEP and ACE inhibition activities) 1. Experimental method As a source of the enzyme NEP, a membrane fraction prepared from rat renal cortex in accordance with the method of Booth and Kenny (A Rapid Method for the Purification of Microvilli from Rabbit Kidney., Andrew G. Booth and A. John Kenny, Biochem. 1974, 142, 575-581.) was employed. The NEP activity was determined in accordance with the method of Orlowsky and Wilk (Purification and Specificity of a Membrane- 130 Bound Metalloendpeptidase from Bovine Pituitaries., Marian Orlowsky and Shrwin Wilk, Biochemistry, 1981, 4942-4950.). Now the procedure will be briefly described.

As a substrate, benzoyl-glycyl-arginyl-arginyl-2naphthylamide (benzoyl-Gly-Arg-Arg-2-naphthylamide (Nova Biochem, Switzerland)) was used. In the presence of an NEP enzyme preparation and excessive leucine aminopeptidase (sigma chemical Co., the liberated naphthylamine was made to undergo color development with first garnet (Sigma chemical Co., followed by the measurement of the absorbance at a wavelength of 540 nm.

As a source of the enzyme ACE, a membrane fraction prepared from rat lung in accordance with the method of Wu-Wong et al. (Characterization of Endthelin Converting Enzyme in Rut Lung Jinshyum R.

Wu-Wong, Gerald, P. Budzik, Edward M. Devine and Terry J. Opgenorth, Biochum. Biophys. Res. Commun., 1990, 171, 1291-1296.) was used. The ACE activity was determined with the use of a modification (modified to a borate buffer pH 8.3) of the method of Cushman and Cheung (Spectrophotometric Assay and Properties of the Angiotensin-Converting Enzyme of Rabbit Lung., Cushman D.W. and Cheung 1971, 20, 1637-1648.). Now the 131 procedure will be briefly described.

In the presence of ACE, the hippurate liberated from hippuryl-histidyl-leucine (Hippuryl-His-Leu (Peptide Institute Inc., Japan)) was extracted with ethyl acetate and then the absorbance was measured at a wavelength of 228 nm.

To determine the NEP inhibition activity and the ACE inhibition activity, the inhibitor was added to the assay systems of both enzyme activities as described above in such a manner as to give the final concentrations of 1, 3, 10, 30, 100, 300 and 1000 nM and inhibition curves were prepared. Then the concentration at which 50% inhibition was achieved was taken as IC 50 2. Results of the experiment The following Table E-l shows the results of the experiment effected according to the above experimental method.

132 Table E-1 NEP inhibition ACE inhibition activity activity

IC

50 (riM) 1C 50 p (riM) cpd. of Ex. E-6 28 10 cpd. of Ex. E-7 45 11 (n=3) cpd. of Ex. E-10 8.2 10 (n=3) cpd. of Ex. E-13 14 11 (n=4) Comp. cpd. E-l' 1 27 9 (n=4) Note) *1 Comparative compound 1: [4S- [4,aR)1b]17[loo2S-ho3peypo~) amino]-l,2,3,4,6,7,8,12b--octahydro-6-oxopyrido[12,1-a]- [2]benzazepine-4-carboxylic acid (compound name: MDL-100,173).

Pharmacological Experiment Exnrnple F-2 To male Wistar rats aged 11 to 13 weeks was sob.#*intravenously injected (1 mg/kg) and orally administered (10 mg/kg, 30 mg/kg) the compound of Example E-6 or the comparative compound E-1. Then changes in the blood level of each medicament were monitored with the lapse of time by using liquid chromatography. In the case of the compound of Example E-B, the blood level. of the medicament was determined by measuring the UV (257 nm) absorbance.

While in the case of the comparative compound E1-1, the 133 the blood level of the medicament was determined by the fluorescent labeling method with the use of ABD-F.

The bioavailabilities of the compound of Example E-6 calculated from the AUC of the oral administration and the AUC of the intravenous administration were respectively 24.6% (30 mg/kg, and 18.8% mg/kg, On the other hand, the dynamics in vivo of the comparative compound E-l were measured by the same method. As a result, the bioavailabilities thereof were 7.8% (30 mg/kg, and 4.3% (10 mg/kg, Accordingly, the compound of Example E-6 is superior in oral absorbability to the comparative compound E-1.

Pharmacological Experiment Example E-3 V1 and V2 receptor binding assay Membrane specimens of rat liver (Vl) and rat kidney (V2) were used. 100,000 counts (3.69 nM) of 3 H]-Arg-vasopressin, 25 #g (1 mg protein/ml) of each membrane specimen and a test medicament to 10-5 M) were incubated in a total volume of 250 41 of an assay buffer (pH=7.4) containing 10 mM of MgC1 2 2 mM of EGTA and 20 mM of HEPES at 4 0 C over day and night. Then, the incubation was washed with 5-ml portions of the buffer 5 times to thereby separate the membrane specimen binding to vasopressin followed by filtration 134 with the use of a glass filter This glass filter was dried for about 3 hours and mixed with a cocktail for liquid scintillation (10 ml, ACSII).

After allowing to stand overnight, the amount of the 3 H]-Arg-vasopressin binding to the membrane was determined with a liquid scintillation counter and the inhibition ratio was calculated in accordance with the following formula: Inhibition ratio 100 [(Cl Bl)/(CO Bl)] x 100 wherein Bl; the amount of 3 H]-Arg-vasopressin binding to the membrane in the presence of excessive vasopressin o* (10 MM) S S CO; the amount of [3H]-Arg-vasopressin binding to the membrane in the absence of the test medicament and Cl; the amount of 3 H]-Arg-vasopressin binding to the membrane in the presence of both the test medicament in a known amount and 3 H]-Arg-vasopressin.

The amount of the test medicament giving an inhibition ratio as calculated in accordance with the above formula of 50% was determined and taken as IC 50 The IC 50 of the compound of Example determined by the above-mentioned method for the 135 vasopressin (VI) receptor was 10 uM or above, while that for the vasopressin (V2) receptor was 4.49 iM.

Pharmacological Experiment Example F-1 (Determination of NEP and ACE inhibition activities) 1. Experimental method As a source of the enzyme NEP, a membrane fraction prepared from rat renal cortex in accordance with the method of Booth and Kenny (A Rapid Method for the Purification of Microvilli from Rabbit Kidney., Andrew G. Booth and A. John Kenny, Biochem. 1974, 142, 575-581.) was employed. The NEP activity was determined in accordance with the method of Orlowsky and Wilk (Purification and Specificity of a Membrane- Bound Metalloendpeptidase from Bovine Pituitaries., Marian Orlowsky and Shrwin Wilk, Biochemistry, 1981, 20, 4942-4950.). Now the procedure will be briefly described.

As a substrate, benzoyl-glycyl-arginyl-arginyl-2naphthylamide (benzoyl-Gly-Arg-Arg-2-naphthylamide (Nova Biochem, Switzerland)) was used. In the presence of an NEP enzyme preparation and excessive leucine aminopeptidase (sigma chemical Co., the liberated naphthylamine was made to undergo color development with first garnet (Sigma chemical Co., followed by the measurement of the absorbance 136 at a wavelength of 540 nm.

As a source of the enzyme ACE, a membrane fraction prepared from rat lung in accordance with the method of Wu-Wong et al. (Characterizition of Endthelin Converting Enzyme in Rat Lung., Jinshyum R.

Wu-Wong, Gerald P. Budzik, Edward M. Devine and Terry J. Opgenorth, Biochem. Biophys. Res. Commun., 1990, 171, 1291-1296.) was used. The ACE activity was determined with the use of a modification (modified to a borate buffer pH 8.3) of the method of Cushman and Cheung (Spectrophotometric Assay and Properties of the Angiotensin-Converting Enzyme of Rabbit Lung., Cushman D.W. and Cheung 1971, 20, 1637-1648.). Now the procedure will be briefly described.

In the presence of ACE, the hippurate liberated from hippuryl-histidyl-leucine (Hippuryl-His-Leu (Peptide Institute Inc., Japan)) was extracted with ethyl acetate and then the absorbance was measured at a wavelength of 228 nm.

With respect to the NEP inhibition activity and the ACE inhibition activity, the inhibitor was added to the assay systems of both enzyme activities as described above in such a manner as to give the final concentrations of 1, 3, 10, 30, 100, 300 and ±000 nM, inhibition curves were prepared, and then the 137 concentration at which 50% inhibition was achieved was taken as IC 50 2. Results of the experiment The following Table 1 shows the results of the experiment effected according to the above experimental method..

Table F-i NEP inhibition ACE inhibition activity activity (case no.) 1 JriMnM) (case no.) Ex. F-14 22.5 7.7 (3) Ex. F-15- 9.2 5.2 (1) Ex. F-17 11.1 13.4 (2) Ex. F-18 5.6 7.0 (3) Ex. F-19 104 13.5 (2) Ex. F-20 56.5 16.0 (2) Ex. F-22 9.0 13 (1) Ex. F-23 120 (1) Ex. F-24 8.0 13.0 (1) Ex. F-25 265 9.0 (2) Comp.

1 cpd. 17.1 48.0 (7) F-1 Comp.

cpd. 13.5 10.6 (2) F Note) *1 Comparative compound F-i: Glycoprilat N- [1-oxo-2 CS) -mercaptomfethyl-3-(3, 4-methiylenedioxy- 138 phenyl)propyl]glycine *2 Comparative compound F-2: [4S- [4a,7a(R*),12bp]]-7-[(1-oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a]- [2]benzazepine-4-carboxylic acid.

Pharmacologecal Experiment Example F-2 V1 and V2 receptor binding assay Membrane specimens of rat liver (VI) and rat kidney (V2) were used. 100,000 counts (3.69 nM) of 3 vasopressin, 25 gg (1 mg protein/ml) of each membrane specimen and a test medicament (10' 7 to 10 5

M)

were incubated in 250 1l in total of an assay buffer (pH=7.4) containing 10 mM of MgC12, 2 mM of EGTA and mM of HEPES at 4 0 C over day and night. Then, the incubation was washed with 5-ml portions of the buffer times to thereby separate the membrane specimen binding to vasopressin followed by filtration with the use of a glass filter This glass filter was dried for about 3 hours and mixed with a cocktail for liquid scintillation (10 ml, ACSII). After allowing to stand overnight, the amount of the 3 H]-Argvasopressin binding to the membrane was determined with a liquid scintillation counter and the inhibition ratio was calculated in accordance with the following formula: 139 Inhibition ratio 100 [(Cl B1)/(CO 31)] x 100 wherein Bl; the amount of 3 HJ-Arg-vasopressin binding to the membrane in the presence of excessive vasopressin jM) CO; the amount of 3 H]-Arg-vasopressin binding to the membrane in the absence of the test medicament 0* and Cl; the amount of 3 H]-Arg-vasopressin binding to the membrane in the presence of both the test medicament in a known amount and 3 H]-Arg-vasopressin.

The amount of the test medicament giving an inhibition ratio as calculated in accordance with the above formula of 50% was determined and taken as IC 5 0 se' The IC 50 of the compound of Example F-17 determined by the above-mentioned method for the 9' vasopressin (VI) receptor was 10 M or above, while that for the vasopressin (V2) receptor was 1.39 pM.

140 P:\OP'ER\RMI\69366.94.105 106/4/9 0 000, O 0 0 0 140A Further comparative tests have been conducted. Table I shows the superiority of the compound of Example 148 of the present invention over that of the compound of Example 8 in EP-A 481522 in respect to both NEP inhibiting activity and ACE inhibiting acitvity.

Table 1: NEP inhibiting activity and ACE inhibiting activity Compounds Chemical Structure NEP*' ACE* 2 IC,, (nM) ICso (nM)

H

0 1 Example 8 0 N in N 27.0 EP-A 481522 \H COOH 2 Example 148 in the present C H 3 5.1 5.3 application HaC-Y H O SH

COOH

SH

oa 0000 00* 00* 0 0 0 IO0 0 a 2 Same experiments as described hereinbefore Table 2 shows the superiority of the compounds at Example C-8 and Example A-11 over representative compounds of the citation JP-A 6-56790 in respect to reducing blood pressure in rats.

i 11 oI'flR11\MlI\693669M 105 20/5/97 -140B Table 2: Anithypertensive effect in SH~s Compounds Chemnical Structure Antihypertensive effect* mg/kg, iv Ex. 6 in JP-A 6-56790 (n 3) Compounds in prior art 0 0 6 6 00 0 2 Ex. 50in 0 JP-A 6-56790 N (n 3) H N

COOH

3 Ex. 59 in 0 JP-A 6-56790 I(n =3) H N SH 0

COOH

E3x. 11I in iP-A 6-56790 o ;Ny 0 COOH SH H0 (n 3)

I

P:\OPR\RMIl\9366.94,105. 16/4/97 140C *r a.

4I 000e a a 44 0 a.

0 0 a.

a, *00 a.

S

94 ar Dose which caused 10% reduction of initial blood pressure in SHRs; numbers of experiment) Experimental Method: Male spontaneously hypersensitve rats (SHRs) were anaesthetized with thiopental sodium. A catheter was inserted into the left carotid artery of each rat to measure the mean blood pressure and heart rate and another catheter was inserted into the left jugular vein of each rat for the adminsitration of the compounds. Three doses of each compound were administered to the rats cumulatively.

The results of the pharmacological experiments as described above have clearly indicated that the invention compounds have ACE inhibition effects, NEP inhibition effects or vasopressin antagonist effects.

Accordingly, the compounds of the present invention suppress the formation of AT-II. which is an increment factor of heart failure, simultaneously with the enhancement of the action of ANP, which is a compensation mechanism for symptoms of heart failure, and, therefore, are expected to have various therapeutic effects on heart failure, for example, reducing body fluids, relieving preload, relieving postload or the like. In addition, these compounds are usable as an antihypertensive diuretic.

Furthermore, the compounds of the present invention are efficacious to diseases which might be therapeutically treated with the use of NEP inhibition action or ACE inhibition action, in particular, cardiovascular disorders such as acute or chronic heart failure, angina pectoris and hypertension, renal failure, edema, salt retention, pulmonary edema, pain, treatment of a specific mental state such as depression, angina, premenstrual syndrome, Meniere diE -se, hyperaldosteronism, hypercalcinuria, ascites, glaucoma, asthma, gastrointestinal disorders such as diarrhea, irritative intestinal syndrome and hyperacidity, cyclosporin-induced renal failure and the like.

Further, the above Pharmacological Experiment Examples have clearly indicated that the c"opounds of the present invention are comparable or uven superior *f

S

r 5,55 *5*5*5 S S C

C..

*SSS9i~

CSC

S

S W *CI S~ 141 to the existing and representative ACE- and NEP-double inhibitors in the ACE and NEP inhibition effects and apparently superior thereto in the hypotensive and diuretic effects. In addition to the above-mentioned Pharmacological Experiment Examples, an experiment was separately effected with the use of SHR for examining hypotensive effects through intravenous administration. As the result, in the comparison of the conventionally known double inhibitors [S- (R*,R*)]-2,3,4,5-tetrahydro-3-[(2-mercapto-l-oxohexyl- 3-phenylpropyl)amino]-2-oxo-iH-benzazepine-l-acetic acid and [S-(R*,R*)]-2,3,4,5-tetrahydro-3-[(2mercapto-l-oxo-4-methylpentyl)amino]-2-oxo-lH-benzazepine-1-acetic acid with the compounds of the present invention, Example C-8 and Example C-10, the inhibitors and should be administered each in a dose of 1.0 mg/kg to decrease the blood pressure by whereas the administration of 0.03 to 0.1 mg/kg of the compound of Example C-8 and the administration of 0.1 to 0.3 mg/kg of the compound of Example each achieved the same effect.

It has been also clarified that the compounds of the present invention have such an advantage that they are excellent in an efficacy in oral administration.

This characteristic of being excel3ent in oral 142 LI Il efficacy is a highly preferable one from a viewpoint that the diseases to which the compounds of the present invention are applied generally require prolonged administration.

The present inventors have also clarified that among the compounds of the present invention, those having a (2S,3S)-3-iiethyl-2-thiopentanoic acid moiety in the side chain are particularly excellent in oral efficacy.

Since the invention compounds have natures that they are little toxic but highly safe, they are substances each having an extremely excellent value as a medicament.

In addition, the compounds of the present invention also have antagonistic effects on vasopressin receptors. It is considered that vasopressin is one of increment factors in heart failure, hypertension or the like. It is believed that these actions further enhance the efficacy of the compounds of the present invention on the above-mentioned diseases.

When the compound of the present invention is employed as a preventive or thrapeutic medicament against the above-mentioned diseases, it can be administered either orally or parenterally. The dose 143 Irll L thereof is not p'-ticularly restricted but varies depending on, for example, the levels of the conditions, age, sex and sensitivity to medicaments of a patient, administration route, administration time, administration intervals, properties of the medicinal preparation, type of the medicinal preparation and kind of the active ingredient. It is generally appropriate to administer from about 0.1 to 1000 mg/day to an adult once to several times.

The compounds of the present invention can be formulated into a medicinal preparation in the convectional manner with the use of fillers for medicinal preparations commonly employed in the art.

Namely when a solid oral preparation is prepared, fillers for the principal agent and, if necessary, binders, disintegrating agents, lubricants, coloring agents, corrigents, antioxidants, etc., are added thereto, and then the mixture is formulated into tablets, coated tablets, granules, powders, capsules, etc., by the conventional manner.

As the above-mentioned fillers, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide are usable.

As the binders, for example, polyvinyl alcohol, polyvinyl ether, ethylcellulose, mothycellulose, gum 144 rL I I arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, pectin and the like are usable. As the lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oils and the like are usable.

As the coloring agents, those which are approved to add to medicines may be used. As the corrigents, cocoa powder, mentha herb, aromatic powders, mentha oil, borneol, powdered cinnamon bark and the like are usable. As the antioxidants, those which are approved to added to medicines, such as ascorbic acid (vitamin C) and a-tocopherc) (vitamin may be used. As a matter of course, these tablets and granules may be subjected to an appropriate coating treatment, such as sugar coating, gelatin coating and others, at need.

On the other hand, when an injection is prepared, pH regulators, buffers, suspending agents, dissolution aids, stabilizers, isotonic agents, antioxidants, preservatives and the like are added to the principal agent at need. Thus, an intravenous, subcutaneous or intramuscular injection can be prepared. The injection may also be formulated into a freeze-dried preparation, at need.

Examples of the above-mentioned suspending agent 145 ,I I b sPIP I include methylcellulose, Polysorbate 80, hydroxyethylcellulose, gum arabic, tragacanth powder, carboxymethylcellulose sodium, polyoxyethylene sorbitan monolaurate and the like.

Examples of the dissolution aids include polyoxyethylene hardened castor oil, Polysorbate nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol, castor oil fatty acid ethyl ester and the like.

As the stabilizers, for examples, sodium sulfite, sodium metasulfite, ether and the like are usable.

Examples of the preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like.

Examples To further promote the understanding of the present invention, Examples will be given hereinafter.

However it is needless to say that the present invention is not restricted to them only.

Synthesis examples for the starting compounds in the present invention will also be described hereinafter, prior to Examples.

146 I -rr Ir~e r~ Synthesis Example A-1 7-Triflluoromethanesuilfonvloxy-3.4-dihvriro-1 (2H)naphthl enone Q >OSO 2 CFj 0 Into 100 ml of a solution of 9.94 g (61.29 mmol) of 7-hydroxy-3,4-dihydro-1(2H)-naphthalenone and 24.8 ml (306 mmol) of pyridine in dichloromethane being stirred at 0°C was dropped 11.86 ml of trifluoromethanesulfonic anhydride in portions while maintaining the temperature so as not to exceed 5 0

C.

After stirring at the same temperature for 10 minutes and then at room temperature for 30 minutes, water was added to the reaction mixture. The dichloromethane layer was collected, washed with 1 N hydrochloric acid, water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.

After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. After successively eluting with hexane ethyl acetate in a ratio ranging from 1 to 8 1 15.33 g of the title compound was obtained as a pale yellow, oily product.

147

I

Yield 1 11-NMVR (400 MHz, CDC1 3 )8: 3.00(2H1, t, J=611z) 2.70(1W d, J=6Hz) 2-68(1H, d, 3=6Hz) 2.18(2H1, quint, J=6Hz) Snthesis Exa~mple A-2, 7-Phenyl -3.4-dihvdrn-1 (214) -naphthBaLenDon~ While stirring a mixture comprising 15.32 g (52.06 mmol) of 7-trifluoromethanesulfonyloxy- 3,4-dihydro-1(2H)-naphthalenone obtained in the Synthesis Example A-1, 12.7 g (104.12 mmol) of phenylbcric acid, 10.8 g (78.09 mmol) of potassium carbonate and 450 ml of toluene at room temperature, nitrogen gas was bubbled thr-reinto for 30 minutes.

Next, 1.81 g (1.57 mmol) of tetrakistriphenylphosphine palladium was added thereto. The mixture was slowly heated to thereby maintain the bulk temperature at about 900 C. After stirring at this temperature for minutes, the reaction mixture was cooled and water was added thereto. The insoluble matters were filtered through celite and thoroughly washed with ethyl 148 acetate. The organic phase was collected, washed successively with a saturated aqueous solution of sodium hydrogencarbonate, water, 1 N hydrochloric acid, water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.

After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. After successively eluting with hexane ethyl acetate in a ratio ranging from 1 to 12 1 9.53 g of the title compound was obtained as white crystals. Yield 82%.

1H-NMR (400 MHz, CDC1 3 8.28(1H, d, J=2Hz) 7.72(2H, dd, J=8.2Hz) 7.64-7.33(8H, m) 3.01(2H, t, J=6Hz) 2.71(11H, d, J=6Hz' 2.69(1H, d, J=61z) 2.18(2H, quint, J=6Hz) Synthesis Example A-3 8-Phenvl-2.3.4.5-ttrahvydro-1H-ri 1 -h-nzaepin- 2-one 0 H A mixture of 9.19 g (41.34 mmol) of 7-phenyl-3,4- 149 dihydro-l(2H)flaphthalenone obtained in the Synthesis Example A-2 with 150 g of polyphosphoric acid was stirred-at 50 to 60 0 C and 2.96 g (45.47 inmol) of sodium azide was added in portions thereto in the form of a solid as such. After stirring at this temperature for additional 90 minutes, the reaction mixture was added to ice water. The crystals thus precipitated were collected. by filtration, washed with water and n-hexane and hot-air dried at 70 0

C

overnight. Thus, 9.3 g of the title compound was obtained. Yield IH-NMR (400 MHz, DMSO-d 6 9.60(11, s) 7.58(2H1, d, J=8Hz) 7.44(2H, t, J=8Hz) 7.35-7.29(3H1, m) 7.22(111, d, J=211z) 2.69(211, t, J=7Hz) 2.17(2H1, t, J=7Hz) 2.09(2H1, quint, J=7Hz) Synth~i~ ~mp A-4 Cl To a mixture of 8.94 g (37.67 mmol) of 8-phenyl- 2 3 4 ,5-tetrahydro1~1]benzazepin 2 one obtained In 1.50 the Synthesis Example A-3 with 180 ml of xylene was added 23.53 g (113 mmol) of phosphorus pentachloride and the mixture was slowly heated. After stirring at about 90C for 30 minutes, water was added to the reaction mixture, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate. After extracting with dichloromethane, the dichloromethane phase was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the oily residue was crystallized by adding ethyl acetate thereto. Thus, 2.60 g of the title compound was obtained. The mother liquor was subjected to silica gel column chromatography. After successively eluting with hexane ethyl acetate in a ratio ranging up to 20 1 0.38 g of the title compound was further obtained. By combining with the one obtained above, 2.98 g of the title compound was obtained in total.

Yield 26%.

1H-NMR (400 MHz, CDCl 3 )8: 7.70(1H, d, J=2Hz) 7.61-7.35(6H, m) 7.21(1H, d, J=8Hz) 3.09-3.01(4H, m) 151 Synthesis Fxampe A- 3-Chl oro-8-phenvl -2.3.4.5-t-etrah-rrro-1 H- 1 Zhenazepi n-2-onn Cl O H A mixture comprising 2.88 g (9.4 mmol) of 3,3dichloro-8-phenyl-2,3,4,5-tetrahydro-lH-[1]benzazepin- 2-one obtained in the Synthesis Example A-4, 0.89 g (11.89 mmol) of sodium acetate, 0.2 g of palladium-carbon and 40 ml of acetic acid was catalytically hydrogenated at room temperature under 3 atm for 2 hours. After filtering off the insoluble matters, the filtrate was concentrated. Then, dichloromethane was added to the residue, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate. The dichloromethane phase was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, a small amount of dichloromethane was added to the residue, followed by collection of crystals by filtration. Thus, 0.53 g of the title compound was obtained. The mother liquor 152 was subjected to silica gel column chromatography.

After successively eluting with hexane ethyl acetate in a ratio ranging from 6 1 to 3 1 and then with a dichloromethane methanol in a ratio of 200 1 0.4 g of the title compound was further obtained. By combining with the one obtained above, 0.93 g of the title compound was obtained in total.

Yield 36%.

IH-NMR (400 MHz, CDCl 3 )6: 7.55-7.21(8H, m) 4.55(1H, dd, J=11.7Hz) 3.09-2.51(4H, m) Synthesis Example A-9 3-Azi do-8-phenvy 5-tetrahydro-1 H- [11]benzazepin-2-one

N

3 0

H

A mixture comprising 0.93 g (3.42 mmol) of 3-chloro-8-phenyl-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-one obtained in the Synthesis Example 0.27 g (4.18 mmol) of sodium azide and 15 ml of dimethyl sulfoxide was stirred at 80 0 C for 3 hours.

After further adding 0.05 g of sodium azide and stirring for 30 minutes, the reaction mixture was 153 added to ice water. The crystals were collected by filtration and dried under reduced pressure 'to thereby give 0.77 g of the title compound. Yield 81%.

IH-NMR (400 MHz, DMS0-d 6 6: 7.60-7.33(7H1, m) 7.24(111, d, J=2Hz) 2.40(111, m) 2.10(111, m) Synthesis E~xampe A-7 3-Azi do-1 -Pthoxycblrbonyl methyl -R-npny -2 3. I-etrahvdrQ-1{L-L1h]enzazepJ n-2-one

N

3

COOC

2 While stirring 30 ml of a mixture of 0.75 g (2.70 mmol) of 3-azido-8-phenyl-2,3,4,5-tetrahydo-l-- [l1benzazepin-2-one obtained in the Synthesis Example A-6, 0.093 g (0.288 mmol) of tetralhbutylafnmonium bromide, 0.17 g (3.03 mmol) of powdery potassium carbonate and tetrahydrofuran at room temperature, 0.35 ml (3.16 mmol) of ethy. bromoacetate was added thereto, followed by stirring for 2 hours. After adding ethyl acetate to the reaction mixture, the obtained mixture was washed with water and a saturated 154 aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. After eluting with hexane :ethyl acetate in a ratio of 1 0.8 g of the title compound was obtained as a pale yellow, oily product. Yield 81%.

1 I-NMR (400 MHz, CDCl 3 6: 4.u'If d, J=l7Hz) 4-47(11, d, J=l7Hz) 4.20(2H1, dq, J=7.3Hz) 3.87(111, brt, J=9Hz) 3.40(111, m) 2.74(111, m) 2.52-2.33(214, m) 1.26(3H1, t, J=711z) Syn1:hesiq Exnmnle B-1 (S)-2-(1.3-Dihydrp-1.3-dipxp-2T4-jgoindol-2-yl)-3- (2-thienvI )propanoic acid 0

S

N OOH 0 To 29.3 g (171 mmol) of L-(S)-3-(2-thienyl)alanAne were added 257 ml of dioxane, 86 ml of water, 25.9 g (175 mmol) T~ phthalic anhydride and 23.9 ml (171 mmol) of triethylamine. While stirring the 155 mixture at room temperature for 1 hour, 23.9 ml of triethylamine was slowly added thereto. 342 ml of dioxane was added and the mixture was heated under reflux. When the pH of the liquid distilled off showed no basicity any more, heating was ceased and the reaction mixture was concentrated under reduced pressure. 10 ml of diethyl ether and 684 ml of 0.5 N hydrochloric acid were added thereto and the mixture was vigorously stirred. The crystals thus precipitated were collected by filtration, washed with a small amount of water and dried by passing a dry nitrogen gas therethrough. 40.7 g of the title compound was obtained as yellow crystals (yield 79%).

MASS m/e (FAB); 302(MH 172-173 0

C

IH-NMR (400 MHz, CDC13, Me 4 Si)6; 3.76(1H, dd, J=4.8, 15.3Hz) 3.89(1H, dd, J=11.6, 15.3Hz) 5.19(1H, dd, J=4.8, 11.6Hz) 6.81-6.84(2H, m) 7.08(1H, dd, J=1.6, 4.8Hz) 7.70-7.74(2H, in) 7.80-7.85(2H, m) 156 L L I I Synthesis Example B-2 N-f 1 3-Dibhydro-1 .3-dioxo-2H-isoindoI- 2-v 2-thienvl ~)propanovl 1-i-hydroxvnorleuciine ethyl ester o H N 0 0 0 COOC 2 Hi To 21.8 g (102.9 mmol) of 6-hydroxy-DL-norleucine ethyl ester hydrochloride were added 686 ml of dichloromethane and 17.0 ml (154 mmol) of N-methylmorpholine at 0°C to thereby give a homogeneous solution. Then, 31.0 g (102.9 mmol) of the compound obtained in the Synthesis Example B-l and 38.2 g (154 mmol) of EEDQ were added thereto and the obtained mixture was stirred overnight while slowly heating to room temperature. The reaction mixture was washed with 1000 ml of 1 N hydrochloric acid, an aqueous sodium hydrogencarbonate and an aqueous sodium chloride and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (dichloromethane/ 157 L I I ethyl acetate 3 Thus, 22.8 g of the title compound was obtained as a pale yellow solid (yield 48%).

MASS in/e (FAB); 459(MH*) Mn.P.; 102-104 0

C

1 1-NMR (400 MHz, CDCl 3 Me 4 Si)8; 1.22-1.27(31, in) 1.28-1.96(7H1, mn) 3.57-3.65(2H1, in) 3.74-3.87(2H1, in) 4.09-4.20(2H1, in) 4.58-4.66(lH, in) 5.07-5.13(11, mn) 6.60-6.71(total 1H1, each brd) 6.78-6.83(21, in) 7.05-7.09111, in) 7.70-7.75(21, in) 7.81-7.85(2H1, in) Synthesis Rxainple B-.i-

N

N

COOC

2 Under a nitrogen gas stream, 93 ml of dichloromethane was cooleQ to -65 0 C and 1.71 ml (19.6 minol) of oxalyl chloride was added thereto. After dropping 158 1.53 ml (21.3 mmol) of dimethyl sulfoxide thereinto, the mixture was stirred for 30 minutes. A solution of 3.00 g (6.54 mmol) of the compound obtained in the Synthesis Example B-2 in dichloromethane (24 ml) was dropped thereinto and the resulting mixture was stirred for 30 minutes. Further, 9.1 ml (65 mmol) of triethylamine was dropped thereinto and the mixture was slowly heated to 0°C. Three hours thereafter, a solution of 12.2 g of potassium peroxymonophosphate (OXONER) in water (50 ml) was dropped thereinto at 0 0

C

and the mixture was vigorously stirred. After minutes, the organic phase was separated, washed with a saturated aqueous solution of sodium chloride.

After drying over magnesium sulfate, the solution was concentrated to a volume of about 65 ml at 20 0 C or below. 6.5 ml of trifluoroacetic acid was dropped thereinto at 0 C and the obtained mixture was heated to room temperature and stirred for 14 hours. The reaction mixture was concentrated under reduced pressure at a low temperature and 100 ml of ethyl acetate was added. At 0°C, a saturated aqueous sodium hydrogencarbonate and solid sodium hydrogencarbonate were slowly added thereto and the mixture was vigorously stirred. The organic phase was separated, washed with water and a saturated aqueous sodium 159 I ichloride, dried over magnesium sulfate, and then concentrated. The crude product (3.27 g) was purified by silica gel column chromatography (hexane/ethyl acetate 3) to thereby give 540 mng (yield: 19%) of the title compound as white crystals.

140-1500C.

1 H-NMR (400 MHz, CD-l 3 Mve 4 Si)6; 0.94(3H1, t, J=7.2Hz) 1.62-1.953H, m) 2.1.4-2.20(2H, m) 2.41-2.49(111, m) 3.44(111, ddd, J=1.6, 4.0, 16.8Hz) 3.72-3.80(111, in) 3.87-3.95(111, m) 4.58(111, m like t) 5.32(111, dd, J=1.6, 7.6Hz) 5.36(111, brt) 6.06(111, dd, J=4.0, 13.6Hz) 6.83(111, d, J=5.411z) 7.09(111, d, J=5.4Hz) 7.70-7.76(2H1, m) 7.86-7.92(2H1, m) S v n Ih e s s Ex axnplJ-3z-A 2-fl .3-Dihvdro- 3-dioxo)-2H--isoindiol -2-v 0 N

COOH

56.0 g (269.6 mmol) of DL-3--(3-thienyl)alanine 160 was reacted in the same manner as that of the Synthesis Example B-i. Thus, 68.4 g of the title compound was obtained as pale yellow crystals (yield 84%).

MASS m/e (FAB); 302(MH") 162-165'C IH-NMR (400 MHz, CDCl 3 Me 4 Si)8; 3.55(111, dd, J=4.8, 15.0Hz) 3.72(111, dd, J=11.6, 15.0Hz) 5.21(111, dd, J=4.8, 11.6Hz) 6.91-6.93(11, m) 6.97(111, m like brs) 7.18(1W, dd, J=3.2, 4.8Hz) 7.69-7.72(21, m) 7.78-7.81(2H1, m) SynthPes Example N-F 2-(1.3-dihydro-1.3-diox-2---cnindol-2-vlY-3- (3-thienvi )propanovl 1-6-hvdroxynorleuecinea ethyl cie

H

0 COOC 2

H

23.0 g (108.7 nimol) of 6-hydroxy-DL-norleucine ethyl ester hydrochloride and 32.74 g (108.7 mmol) of the compound obtained in the Synthesis Example B-4 were reacted in the same manner as that of the 161 Synthesis Example B-2. Thus, 25.9 g of the title compound was obtained as pale yellow crystals (yield 52%).

MASS rn/c (FAB); 458(MH+) 80-85 0

C

IH-NMR (400 MHz, CDCl 3 Me 4 Si)6; 1.23-1.30(3H1, in) 1.31-1.96(6H1, m) 3.54-3.67(4H1, m) 4.09-4.24(21, m) 4.58-4.68(11, mn) 5.11-5.17(11, m) 6.68-6.77(total 111, each brd) 6.93-7.01(2H, in) 7.17-7.22(111, mn) 7.70-7.74(2H1, m) 7.79-7.84(2H1, m) Synthesis FExample 3-f6 Ethyl .5-hi.3-dihydro-- 3-clipxp-214-isindpnl-2-vl )-63oxo-4,5.9.P -9A.11 11l-oetahydrojnyjdorl.2-anjjjeion-

N

0

COOC

2

HS

2 g (4.36 mmol) of the compound obtained in the Synthesis Example B-5 was reacted in the same manner as that of the Synthesis Example B-3. Thus, the title 162 compound was obtained as white crystals and as a mixture of two diastereomers (1.25 g, 67%).

I-NMR (400 MHz, CDCl 3 M~e 4 Si) 6; 0.92 and l.25(total 3H, each t, each J=7.2Hz) 1.65-2.50(6H, m) 3.20 and 3.30(total lH, each ddd, each J=1.6, 4.0, 16.8Hz) 3.76-7.23(total 2H, m) 4.28-4.45(total 11H, m) d 5.30(total 1H, each m) 5.54-5.61(total 1H, m) 5.83 and 6.03(total 1H, each dd, each J=4.0, 13.6Hz, 14.0Hz) 6.84 and 6.87(total lI-I, each d, each J=5.2Hz and J=5.6Hz) 7,13-7.16(total 1H, m) 7.72-7.75(2H, m) 7.85-7.90(2H1, m) Synthesjs PFxrnnle (2-1 (2R.3S)-2-Bromo-3-methvlpent-anoic acid CH 3

CH

3

"COOH

Br 1.50 g (11.43 mmol) of D-allo-lsoleucine [(2R,3S)-2-ainino-3-methylpentanoic acid] was dissolved in a mixed solution of 12.7 ml of a, 47% aqueous solution of hydrogen bromide with 12.7 ml of water, followed by cooling to 0 0 C. A solution of 1.20 g of sodium nitrite in 3.0 ml of water was slowly dropped 163 thereinto at such a rate that the reaction temperature did not exceed 5 0 C. Next, the mixture was stirred at 0°C for 30 minutes and then at room temperature for 3 hours. After distilling off the excessive nitric acid gas under reduced pressure, ether extraction was effected. The organic phase was washed with water and a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. Thus, 2.11 g of the title compound was obtained as a yellow oil. Yield 1 H-NMR (400 MHz, CDC1 3 )6; 4.29(1H, d, J=7Hz) 2.01(1H, m) 1.52(1H, m) 1.33(1H, m) 1.08(3H, d, J=7Hz) 0.95(3H, t, J=7Hz) Synthesis Example C-2 2RL.3j -2-Aceytv thi o-3-methvl pentanoi anied CH3

CH

3

COOH

SCOCH3 2.11 g (10.8 mmol) of (2R,3S)-2-bromo-3-methylpentanoic acid obtained in the Synthesis Example C-1 was dissolved in 43 ml of acetonitrile and 1.42 g of potassium thioacetate was added thereto at 0°C. The mixture was stirred at 0°C for 30 minutes and then at 184 I I--I is s room temperature for 5 hours. After filtering off the insoluble matters, the filtrate was concentrated. To the resi~due were added ether and a saturated aqueous solution of sodium hydrogencairbonate, followed by separation. The aqueous phase was acidified by adding a 2 N aqueous solution of hydrochloric acid at a low temperature and then extracted with ether. The ether phase was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. Thus, 1.68 g of the title compound was obtained as a colorless oil (yield 82%).

IH-NMR (400 MHz, CDCl 3 6; 4.21(lH, d, J=7H-z) 2.39(3H, s) 2.02(lH, m) 1.58(111, m) 1.22(111, m) 1.03(0H, d, J=711z) 0.9203H, t, J=7Hz) Synthesis ct- (1 .3-Dihvydro-1 3-dioxo-2--i soinriol -2.y.l (1 -1'-bphevijy)-4-propnToicn acid 0 43.70 g (181.3 minol) of c-amino-(1,l'-biphenyl)- 165 4-propanoic acid and 26.80 g (181.3 mmol) of anhydrous fumaric acid were suspended i~n 100 mi. of dimethylforinamide, followed by heating at 120 0 C for 2 hours and half. Then, the transparent solution thus obtained was poured into 1.2 1 of ice water, followed by vigorously stirring. Thus, white crystals were precipitated. These crystals were collected by filtration, washed with water and hexane and hot-air dried. Thus, 65.5 g of the title compound was obtained as white crystals (yield 73%).

IH-NMR (400 MHz, DMSO-d 6 8; 7.83(411, s) 7.58(2H, d, J=811z) 7.51(2H1, d, J=8Hz) 7.40(2H, t, J=8Hz) 7.31(111, t, J=8Hz) 7.26(2H1, d, J=8Hz) 5.16(lH, dd) Syntbesis Examrnpe C-4 £Sz-Nzja(1 3-Dihydro- .3-dioxo-2H-iqoindol- 2,-yi '-hiphenvi )-4-propionv1 -8-hvdirnxyvnorle.lae 0 nIzo0H 166 To a mixed solution of 28.53 g (76.90 mmol) of a- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)- (l,l'-biphenyl)-4-propanoic acid obtained in the Synthesis Example C-3 and 19.10 g (96.70 mmol) of (S)-6-hydroxynorleucine methyl ester hydrochloride in 600 ml of dichloromethane was added 42.47 ml of N-methylmorpholine. After preparing a homogeneous solution therefrom, l-hydroxybenztriazole hydrate and 28.92 g (150.87 mmol) of l-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride were added thereto at 0°C. The reaction mixture was stirred at 0°C for minutes and then at room temperature overnight and washed with a 2 N aqueous solution of hydrochloric acid, water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous sodium chloride. The dichloromethane phase was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent; chloroform methanol 99 Thus, 24.80 g of the title compound was obtained as a colorless amorphous product (yield 63%).

1 H-NMR (400 MHz, CDC1 3 )6; 7.79(2H, m) 7.69(2H, m) 7.52-7.22(9H, m) 6.77 and 6.68(total 1H, each brd, J=8Hz) 5.19(1H, m) 4.63(11 m) 167 I I- 3.72 arnd 3.71(total 3H, each s) 3.68-3.52(4H, m) l.97-l.30(6fH, m) Synthesis Fxample (S)-N-[a-(1.3-Djhydro-1.3-dioxo-2H-jsoindol- 2-v '-hi phenvi -4-prop ionyi 1-R-oxonorl eiici ne methyl ester 0

CHO

NHN

00O CODC H3 A solution of 9.82 ml (115.35 mmol) of oxalyl :chloride in 330 ml of d"Ichloromethane was cooled to and a solution of 8.18 ml (1L15.35 mmol) of dimethyl sulfoxide in dichloromethane (70 ml) was slowly dropped thereinto within 15 minutes. This reaction mixture was stirred at -700C for 15 minutes.

Then, a solution of 24.80 g (48.20 mmol) of 3-dihydro- 3-dioxo-2H-isoindol-2-yl) bipheniyl)-4-propionyl]-6-hydroxynorleucine methyl RA, ester obtained in the Synthesis Example C-4 in dichloromethane (130 ml) was slowly dropped thereinto at -70 0 C to -60 0 C within about 40 minutes. After 168 I stirring the reaction mixture at -70 C for 20 minutes, 52.66 ml of triethylamine was slowly dropped thereinto within 20 minutes. The reaction mixture was stirred at 0°C for 1 hour and a solution of 70.18 g of.

potassium peroxymonosulfate (OXONER) in water (830 ml) was dropped thereinto at 0 to 5 0 C, followed by extraction with dichlorome:hane. The dichloromethane phase was washed with water and a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. Thus, the title compound was obtained as a brown oil. This aldehyde was not purified but employed in the subsequent reaction (Synthesis Example C-6).

H: 1 -NMR (400 MHz, CDC1 3 6; **3 9.71 and 9.70 (total 1H, m) 7.78(2H, m) 7.68(2H, m) 7.50-7.20(9H, m) 6.82 and 6.78 (total 1H, each brd, J=8Hz) 5.20(1H, m) 4.61(1H, m) 3.91(3H, s) 3.75-3.52(4H, m) 2.50-1.30(total 6H, m) 4* i.

Po 169 Ip 1 -4*1 CI _1 Synthesis Example C -6 Methyl .3-dihyro-1 .3-dioxo-2Hisoindol-2-yl .1'-biphenvl )-4-propionyvl 1-1 .2.3.4tetrahydro-2-pyridinecarboxyl ate 0 00 COOCH3 To (S)-N-[a-(1,3-dihydro-l,3-dioxo-2H-isoindol- 2 yl)-(1,1'-biphenyl)-4-propionyl]-6-oxonorleucine methyl ester obtained in the Synthesis Example (crude product, 48.2 mmol) was added 60 ml of trifluoroacetic acid at once at 0°C. The solution thus formed was stirred at room temperature for 2 hours. The mixture was concentrated and the residual oil was subjected to azeotropic distillation with benzene. The brown, oily residue was partitioned into dichloromethane and water and washed with a saturated aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous sodium chloride. The dichloromethane phase was dried over magnesium sulfate and then concentrated. The residual oil was purified 170 lll~ by silica gel column chromatography (eluent; dichloromethanE). Thus, 8.70 g of the title compound was obtained as a colorless amorphous product (Yield from the Synthesis Example C-4 37%).

IH-NMR (400 MHz, CDCl 3 7.84-7.74(2H1, m) 7.69(2H1, m) 7.53-7.20(91, m) 6.73 and 6.51(total 1H1, each brd, J=811z) 5.52 and 5.42(total 111, each dd, J=12.7Hz) 5.29 and 5.24(total lIH, each dtlike) 5.03 and 4.88(total li-, each m) 3.87-3.47(2H1, in) 3.75 and 3.65(total 3H1, each s) 2.39(111, m) 2.10-1.75(3H1, m) Synthes~is Example C-7 r4S-r4.7et(R*)12ll7-(13Dihydro-1.3-dioxooetabydropyridro2.l-alr2lbenzazepine-4-carhoxvlin Pnid 0 0 0 A solution. of methyl (S)-l.-[a-(1,3-dihydro-1,3dioxo-2H-isoindol-2-yl) -biphenyl) -4-propionyl] 171

M

1,2,3,4-tetrahydro-2-pyridinecarboxylate (8.70 g, 17.61 mmol, a 1 1 mixture of diastereomers) obtained in the Synthesis Example C-6 in dichloromethane (58 ml) was dropped into a mixed solution of 10.82 ml (2 mmol) of trifluoromethanesulfonic acid and trifluoroacetic anhydride (TFAA, 2.75 ml, 19.51 mmol) at 0°C.

After the mixture was stirred under a nitrogen atmosphere at room temperature for 30 hours, the mixture was poured into ice water, followed by extraction with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous sodium chloride dried over magnesium sulfate and concentrated. The amorphous residue was purified by silica gel column chromatography (eluent; trichloromethane methanol 99 Thus, 1.80 g of the title compound was obtained as an amorphous product (yield 42%).

1 IH-NMR (400 MHz, CDC13)8; 7.78(2H, dd, J=8.4Hz) 7.66(2H, dd, J=8.4Hz) 7.49(2H, dd, J=8.2Hz) 7.43(1H, d, J=2Hz) 7.37(3H, m) 7.28(1H, tt, J=7.2Hz) 7.14(1H, d, J=8Hz) 5.78(1H, dd, J=10.6Hz) 5.30(1H, t, J=6Hz) 5.14(1H, dd, J=8.4Hz) 4.05(1H, dd, J=16.10Hz) 3.44(1H, dd, J=16.6Hz) 2.52-2.32(2H, m) 2.10-1.97(21 m) 172 1.88-1.66(2H1, m) Synrthesis Example C-9 fliphenyIv rnethyl. f4-~ c R1 19h 17( dihvdro-1 3-di oxo-2I4-T -aindol -2-yl )-9-oxo-1 I-nphenyl 1 .2.39.4.6.7.8.12b-octahvdirnpvridor2.1-qir21be-nzazepjne-4-cpnrboxyl ate 0 04 To a solution of 1.80 g (375 mmol) of [4S- [4a, 7a J2bP]I-7- 3-dihydro-1, 3-dioxo-2Hisoindol-2-yl) -6-oxo-11-phenyl-1 12boctahydropyridol2,1-a] [2lbenzazepine-4-carboxylic acid obtained in the Synthesis Example C-7 in dimethylfornainide (40 ml) was added 1.34 g (4.21 minol) of cesium carbonate. The obtained mixture was stirred for 30 minutes. 1.30 g (5.25 mmol) of promodiphenylmethane was added thereto and the mixture was stirred 173 at room temperature for 5 hours. It was partitioned into ethyl acetate and water. The ethyl acetate phase was washed with water and a saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The amorphous residue was purified by silica gel column chromatography (eluent; chloroform hexane 4 Thus, 2.03 g of the title compound was obtained as a colorless amorphous product (yield 84%).

1 11-NMVR (400 MHz, CDCl 3 )8; 7.85(2H, brs) 7.69(2H1, dd, J=8.4Hz) 7.44-6.98(7H1, m) 6.58(111, d, J=811z) 6.18(1H, s) 6.03(111, dd, J=10.611z) 5.42(111, t, J=6Hz) 5.14(lH, dd, J=8.41iz) 4.35(111, dd, J=16.lOHz) 3.22(111, dd, J=16.6Hz) 2.37(2H1, m) 2.05(lH, m) 1.80-1.63(3H1, m) 174 Di phenyl meth3:1 14,q- r4.7a HP) .12hpfIl-7-ami no- 6-oxo-I 1-phenyl -1 2 -S.4...Ahotvdpir2,1-al1r21henzazepinR-4-carhoxylate

H

2 N

N

0' 2.03 g (314 mmol) of diphenylmethyl [4S- [4z, 7a ,12b 1-7- (l,3-dihydro-l, 3-diox--2Hisoindol-2-yl) -6-oxo-li--phenylil ,2,3 ,4,6,7,8,12boctahydropyrido [2lbenzazepine-4-carboxylate obtained in the Synthesis Example C-8 was dissolved in a mixed solution of 40 ml of methanol. with 20 ml of tetrahydrofuran. 0.34 ml (7.10 mmol) of hydrazine monohydrate was added thereto, followed by heating under reflux for 3 hours. The reaction mixture was concentrated, the residual solid was dissolved in dichloromethane and the insoluble solid matters were 175 removed by filteration. The filtrate was concentrated, and the sticky residue was purified by silica gel column chromatography (eluent; chloroform methanol :aqueous ammonia 98 :2 Thus, 1 .20 g of the title compound was obtained as a colorless amorphous product (yield 74%).

IH-NMR (400 MHz, CDCl1 3 8; 7.40(4H1, m) 7.31(111, tt, 3=7.2Hz) 7.24(111, d, 3=2Hz) 7.15(111, dd, 3=8.2Hz) 6.99(211, dd, 3=8.4Hz) 6.87(2H1, dd, 3=8.2Hz) 6.63(111, d, 3=8Hz) 6.20(111, s) 5.42-5.33(2H1, m) 4.53(111, dd, 3=10.6Hz) 3.17(1H, dd, 3=16.6Hz) 2.58(111, dd, 3=1,6.10Hz) 2.40(2H1, m) 1.94(111, m) 1.85-1.58(31, m) Synthesis Example C-1 isoi ndo-2-v1)--firOXl 3.4. 6 -78.J.2h-ntn- 8. 30 g (20. 5 mmol) of 4S- [4a, 7a 12b3] 7- 3-dioxo-l, 3-dihydroisoindol-2-y1) -6-oxo- 1 ,2,3,4,6,7,8,12b-octahydropyrido[2,1-al[2]benzazepine-4-carboxylic acid was dissolved in 110 ml of 176 methylene chloride, followed by cooling to -600C.

Next, a solution obtained by dissolving nitronium tetrafluoroborate (0.5 M solution in sulfolane 148 ml, 74 mmol) in 90 ml of methylene chlorine was dropped thereinto. Then the mixture was slowly heated to within 10 hours and then stirred at 20C for 5 hours.

Then, it was partitioned into 500 ml of methylene chloride and 1200 ml of water. Further, after the organic phase separated was washed with a saturated aqueous sodium chloride, it was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue thus obtained was purified by flash silica gel chromatography (1 1 ethyl acetate/hexane ethyl acetate containing 5% of acetic acid added). Thus, a mixture of the title S)mpounds was obtained.

Synthesis Example C-11 Methyl 4,S-14 .7afR*)I.12411-7- (1 .3 -d i oxo -1 3d1hvdrnisnindol-2-vy l-9-nitro-6-nx octahydrovrido2 1-alL2enansenpine-4-rboxvlate and metbhyl r4S-.:ic7a(Lr *)l12l2bi1-7-(1.P-dioxo-1 .3i c hYvd rois or p d 9- -ni o--xo- 1.2.3.4.6.7-3.12b-oeta hydronvyido2.1 -a.1 21- Le nzazseD N-4-a. nrbhox1 ylate !7 g (12.2 mmol) of a mixture of [4S- 177

_I

[4a,7a(R*),12bp]]-7-(1,3-dioxo-l,3-dihydroisoindol-2yl)-9-nitro-6-oxo-l,2,3,4,6,7,8,12b-octahydropyrido- [2,1-a][2]benzazepine-4-carboxylic acid and [4S- [4a,7a(R*),12bp]]-7-(1,3-dioxo-1,3-dihydroisoindol- 2-yl.)-ll-nitro-6-oxo-l,2,3,4,6,7,8,12b-octahydropyrido[2,l-a][2]benzazepine-4-carboxylic acid obtained in the above Synthesis Example C-10 was dissolved in ml of dimethylformamide. To this solution was added 4.76 g (14.6 mmol) of cesium carbonate at room temperature. The mixture thus obtained was stirred under a nitrogen atmosphere for 30 minutes and then 2.42 g (17.0 mmol) of methyl iodide was added thereto.

The resulting mixture was stirred for 11 hours. Next, the solution stirred was partitioned into 300 ml of water and two 250-ml portions of ethyl acetate.

Further, after the organic phase separated was washed with a saturated aqueous sodium chloride, it was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. After the completion of the concentration, the residue thus obtained was purified and separated by flash silica gel chromatography (1 1 ethyl acetate/hexane).

Thus, 1.62 g (yield: 29%) of the title compound having a nitro group at the 11-position and 1.78 g (yield: 31%) of the title compound having a nitro group at the 178

-M

9-position were obtained.

dioxo-1 r3-dhdi-osoIn 12- )LLz.-IXOz I 4 8,1-2b-oc-t~ivd rnnvr do r2. 1 -a 1 2henaziaDRinp-4-ecirhoxylste ,s NH 2 0 C00CH 3 1.62 g (32.5 mmol) of methyl [4S- [4,c(*,2p17(,-doo13dhdosidl 2-yl)-11-nitro-6-oxo-i,2, 3,4,6,7,8 ,12b-octahydropyridolj2,1-a] 12]benzazepine-4--carboxyiate obtained in the above Synthesis Example C-li was dissolved in 5 nil of acetic acid and 60 mil of dimethylformamide. Then, 230 g of 10% palladium/carbon was added to this solution, followed by shaking at room temperature for 2 hours. 150 mil of methanol was further added to the solution s'iaken, followed by filtration. The filtrate was concentrated under reduced pressure to thereby give 1.50 g of the title compound.

179 'H-NMR (400 MHz, CDC.

3 Me 4 Si) 8; 1.70-2.45(6H1, in) 3.20(3H, s) 3.30(1H, dd, J=16.6, 6.7Hz) 4.26(lH, dd, 12.1Hz) 5.19(1H, mn) 5.34(111, in) 5.98(1H, dd, J=12.1, 6.7Hz) 6.56(211, mn) 6.98(111, d, J=8.SHz) 7.70-7.90(4H1, mn) S yn t r- It'YPmp In f- 13 Me thyl r4 7 b 1-1-eh lq foy amn~o-7-(l. 3-djoxc-1 .3-dihyciroisoindol-2-yl ')-F-oxo- 1. .7.8.1 2h-no-1tahyvcIrny Ir9.[. I-&I 2jbEnZ,a zep)-meBzA-.carhoxv1 I te y NHSO 2 CHa

N

o 0 COOCH3 1.50 g (3.5 inmol) of methyl [4S-[4z,7U~(R*),12b~311- 11-amino-7- 3-dioxo-1, 3-dihydroisoindol-2-yl) -6-oxo- 1, 2,3, 4,6, 7, 8,12b-octahydropyr ido 12, 1-al 12 Ibenzazepine-4-carboxylate obtained in the above Synthesis Example C-12 was dissolved in 50 ml of methylene chloride. Next, to this soluition were added 3 ml of pyridine and 440 rug (3.8 mmoi.) of iethanesulfonyl chloride under cooling with ice. Then, the mixture 180 was stirred at room temperature under a nitrogen atmosphere for 2 hours. After 100 ml of a 1 N aqueous solution of hydrochloric acid was further added to the solution stirred under cooling with ice, it was extracted with methylene chloride. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure. Next, the residue was purified by silica gel column chromatography (3 1 methylene chloride/ethyl acetate). Thus, 1.14 g of the title compound was obtained (yield: 64%): IH-NMR (400 MHz, CDCl 3 Me 4 Si)8; 1.60-2.46(6H, m) 3.00(3H, s) 3.23(3H, s) 3.42(1H, dd, J=17.1, 4.46(1H, dd, J=17.1, 11.9Hz) 5.21(1H, m) 5.44(LH, m) 6.04(1H, dd, J=11.9, 6.65(1H, s) 7.05(1H, dd, J=8.2, 2.2Hz) 7.19(1H, d, J=8.2Hz) 7.24(1H, d, J=2.2Hz) 7.74-7.90(4H, m) 181 Synthesis~ Example-14J MethYl- r4S-r4a. l2hall-ll-methvlqil-Pnylamino-7-amino-g3-oxo-l .3.4.A.7.8 l2h-ocntAhvdropvrldo_ r2.1-Fflr2Tenzzepine-4-carhoxvlate

SNHSO

2 CH3 Ii 2

N

/N

D

COOCH

3 1.1.4 g (2'.23 mmol) of methyl [4S- [4a, 7a ,12b P I] -1l-methylsulf onylanino-7- 3-dioxo-1l, 3-dihydroisoindol-2-yl) -6--oxol,2,3,4,6,7,8,12b-octahydropyridol2,1 a] benzazepine-4-carboxylate obtained in the above Synthesis Example C-1l3 was dissolved in 49 ml of methanol. Next, to this solution was added 12"k mg (2.46 mmol) of hydrazine hydrate. Then, the mixture was stirred under an argon atmosphere at room temperature for 66 hours. The solution, stirred was concentratea under reduced pressure. Further, methylene chloride was added to the concentrate.

After removing out the insoluble matters by filtration, ethyl acetate was added to the filtrate.

Thus, 0.50 g (yield: 59%6) of the title compound was 182

-M

obtained as white crystals.

1 H-NMR (400 MHz, CD 3 OD/CDCl 3 Me 4 Si)6; 1.60-2.45(6H1, m) 2.87(111, dd, J=17.6, 12.7Hz) 2.94(3H1, s) 3.13(3H, s) 3.40(111, dd, J=17.6, 4.65(111, dd, J=12.7, 6.0Hz) 5.30(111, m) 5.43(111, mn) 7.02(111, dd, J=8.2, 2.2Hz) 7.11(111, d, J=8.2Hz) 7.1.6(111, d, J=2.4Hz) r 4.s- r 4a 7a 1 9.hR11-17- (1 -3-Ph oxo-1 I. 3-d J hydr-oisoindol-2- 1)-q-nitro-R-oo-1. 234.7..8,2-o.ta-.

bydropyridor2.1-alr21hen~azepine-4-carboxylic, acid and hvclropyridof2.1-alr2lbenzazepine-4-carhoxvlic acild isoindol-2-yl) -6-oxo-1,2,3,4,6,7,8, 12b-octahydropyrido[2,1-a] [2]benizazepine-4-carboxylic acid (8.30 g, 20.5 mmol) was dissolved in methylene chloride (110 ml), followed by cooling to -60*C. Next, a solution obtained by dissolving nitronium tetrafluoroborate MI solution in sulfolane 148 ml, 74 mmol) in methylene chloride (90 ml) was dropped thereinto.

Thereafter, the mixture was slowly heated to 2'C within 10 hours and then stirred at 2 0 C for 5 hours.

183 Next, it was partitioned into methylene chloride (500 ml) and water (1200 ml). Further, after the organic phase separated was washed with a saturated aqueous sodium chloride, it was dried over (MgS0 4 was used) and the solvent was concentrated under reduced pressure.

The residue thus obtained was purified by flash silica gel chromatography (1 :1 ethyl acetate/hexane ethyl acetate containing 5% of acetic acid added). Thus, a mixture of the title compounds was obtained.

Syntheqiq Fxnimpln D-2 Methyl 1*S r i. a( 1 b l l- i x q dihyvdrnisoindlol-2-fl)--9-nit-ro-6-oxo-1.2.3.4 .7.8.12hontahvrroprio.1,-alf2bnapin--4-~jrhoxylte and metvl 4S-r4.7(R*) 2hfll-7-(l.3-dioxo-%3-dIhYdrohydropyri 9f2A-,qlr92benzizepine-4-ent-boxy-Lta A mixture (5.47 g, 12.2 mmol) of [4S- [4,aR)1bl--13doo13dhdosidl 2-yl) -9-nitro-6--oxo-l,2,3,4, 6,7,8, 12b-octahydropyrido- [2]benzazepine-4-carboxylic acid and [4Spyrido[2,l-a] [2]benzazepine-4-carboxylic acid obtained in the above Synthesis Example D-1 was dissolved in dimethylformamide (80 ml). To this solution was added 184 cesium carbonate (4.76 g, 14.6 mmol) at room temperature. The mixture thus obtained was stirred under a nitrogen atmosphere for 30 minutes and then 2.42 g (17.0 mmol) of methyl iodide was added thereto.

The resulting mixture was stirred for 11 hours. Next, the solution stirred was partitioned into water (300 ml) and ethyl acetate (250 ml x Further, after the organic phase separated was washed with a saturated aqueous sodium chloride, it was dried over (MgS0 4 was used) and the solvent was concentrated under reduced pressure. After the completion of concentration, the residue thus obtained was purified and separated by flash silica gel chromatography (1 1 ethyl acetate/hexane). Thus, the title 11-nitro compound (1.62 g, 29%) and the title 9-nitro compound (1.78 g, 31%) were obtained.

185 c- II Fx~pleD-3 Methyl r 4S- [4a 7eH*) .1 h R 1 1 -ami no-7- 1 2 4, 6_7,_;12-octahdroprido21-ar2hfl9,azepi ne-4-carhcxyja-ta

NH

2 0 0 COOCH3 Methyl [4S-[47u(R),12bpM7-(l,3-dioxo-1,3 dihydroisoindol-2-yl) -11-nitro-G3-oxo- 1,2,3,4,6,7,8,12b-octahydropyrido[2,l-a][2]belzazepine-4-carboxylate (1.62 g, 3.5 minol) obtained in the above Synthesis Example D-2 was dissolved in acetic acid (5 ml) and diiethylformamide (60 ml).

Next, 10% palladium/carbon (230 mg) was added to this solution, followed by shaking at room temperature for 2 hours. After methanol (150 ml) was further added to the solution shaken, it was filtered and the filtrate was concentrated under reduced pressure. Thus, the title compound (1.50 g) was obtained.

186 H-NNIR (400 MHz, CDCl 3 Me 4 Si)8; 1.70-2.45(6H1, in), 3.20(3H, s), 3.30(111, dd, J=16.6, 6.7Hz), 4.26(1H, dd, J=16.6, 12.1Hz), 5.19(1H, mn), 5.34(1H, in), 5.98(1H, dd, J=12.1, 6.7Hz), 7.70-7.90(4H1, mn) Synthesis Example F-1 hip'henyi Y4-propanoin anid N COO a-Ainno-(l,1'-bipheflyl)-4-propafloic acid (43.70 g, 181.3 inmol) and anhydrous fumaric acid (26.80 g, 181.3 inmol) were suspended in 100 ml of diinethylforinamide (DMF), followed by heating at 120 0 C for 2 hours and half. Next, the transparent solution thus obtained was poured into ice water (1.2 followed by vigorously stirring. Thus, white crystals were precipitated. These crystals were collected by filtration, (washed with water and. hexane) and hot-air 187 dried. Thus, the title compound was obtained as white crystals (65.5 g, yield 73%).

IH-NMR (400 MHz, DMSO-d 6 )8; 7.83(4H1, 7.58(2H1, d, J=8Hz), 7.51(2H, d, J=8Hz), 7.40(211, t, J=8Hz), 7.31(111, t, J=8Hz), Synthesis Example E-2 (1 .1'-hi phenv -4-p2ropionvi 1-8-hvcdroxynorl eii nemethyl ester 0 OHl

N

11: O

/-NH'

0v

GOOCH

3 To a mixed solutioni of c-(1,3-dihydro-1,3-dioxo- 2H--isoindol-2-yl)-(l,l'-biphenyl)-4-propanoic acid (28.53 g, 76.90 mmol) obtained in Synthesis Example E-1 with (S)-6-hydroxynorleucine methyl ester hydrochloride (19.10 g, 96.70 mnmol) in 600 ml of dichloromethane (CH 2 Cl 2 was added 42.47 ml of N-methylmorpholine (NMNI). After preparing a homogeneous solution therefrom, l-hydroxybenztriazole 188 hydrate (HOBT) and 1-(3-dimethylaminopropyl)- 3 -ethylcarbodl.imide hydrochloride (DEC) (28.92 g, 150.87 mmol) were added thereto at 0 C. After the reaction mixture was stirred at 0°C for 30 minutes and then at room temperature overnight, it was washed with a 2 N aqueous solution of hydrochloric acid, water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous sodium chloride. The CH 2 Cl 2 phase was dried over anhydrous magnesium sulfate and concentrated. The residual oil was purified by silica gel column chromatography (eluent; chloroform (CHCI 3 methanol (MeOH) 99 Thus, the title compound was obtained as a colorless amorphous product (24.80 g, yield 63%).

o 1 H-NMR (400 MHz, CDC 3 )6; 7.79(2H, 7.69(2H, 7.52-7.22(9

H

m), 6.77 and 6.68 (total 1H, each brd, J=8Hz), 5.19(1H, 4.63(1, m), 3.72 and 3.71(total 3H, each s), 3.68-3.52(4H, 1.97-1.30(6H, m) 189 I -e c rlpC~-- ll Syntheqi~q Example F-3 (1.1 '-biphenvl)-4-propionyll-R-oxonnrleicine methyl 0 I CHO N NH 0 0

COOCH

3 A solution of oxalyl chloride (9.82 ml, 115.35 mmol) in CH 2 Cl 2 (330 ml) was cooled to -70* C and a solution of dimethyl sulfoxide (DMVSO, 8.18 ml, 115.35 mmol) in CH 2 Cl 2 (70 ml) was slowly dropped thereinto to within 15 minutes. This reaction mixture was stirred at -70 0 C for 15 minutes. Then, a solution of too* *a.*[c-(,3-dihydro-1,3-dioxo-2H-isoifldol-2-yl)-(i,l'biphenyl)-4-propionyl]-6-hydroxynorleucile methyl ester (24.80 g, 48.20 mmol) obtained in the Synthesis *:too. Example E-2 in CH 2 Cl 2 (130 ml) was slowly dropped krA4,thereinto at -70*C to -60 0 C within about 40 minutes.

:5 After stirring the reaction mixture at -70O C for minutes, triethylamine (TEA, 52.66 mil) was slowly dropped thereinto within 20 mrinutes. The reaction 4s~N 190w

TO

mixture was stirred at 0 0 C for 1 hour and then a solution of potassium peroxymonosulfate (OXONE, 70.18 g) in water (830 ml) was dropped thereinto at 0 to 0 C, followed by extraction with CH 2 Cl 2 The CH 2 C1 2 layer was washed with water and a saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated. Thus, the title compound was obtained as a brown oil. This aldehyde was not purified but employed in the subsequent reaction (Synthesis Example E-4).

0 YH-NMR (400 MHz, CDC1 3 )8; 9.71 arid 9.70(total 1Hi, in), 7.78(2H, mn), 7.68(2H, in), 7.50-7.20(91-, in), :6.82 and 6.78(total 1H, each brd, J=8Hz), 00 5.20(lH, in), 4.61(lH, in). 3.91(3W s), 0 .1 3.75-3.52(4H, in), 2.50-l.30(total 6H, in) a..

a 191

I

Synthesis Example R-4 lm hyl 3-dihydro-1 .3d i no- 2 H-isoind l-2 Yl .1 '-hinphenvl -4-pronpionyl 1-1 2,3.4-tetrahydro-2nyvridinecarboxvyl ate 0 0 COOCH3 To (S)-N-[a-(1,3-dihydro-l,3-dioxo-2H-isoindol-2yl)-(1,1'-biphenyl)-4-propionyl]-6-oxonorleucine methyl ester obtained in the Synthesis Example E-3 (crude product, 48.2 mmol) was added to trifluoroacetic acid (TFA, 60 ml) at once at 0°C. The solution thus formed was stirred at room temperature for 2 hours. The mixture was concentrated and the residual oil was subjected to azeotropic distillation with benzene. The brown, oily residue was partitioned into

CH

2 C12 and water, and the CH2C12 phase was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous sodium chloride. The CH 2 C12 phase was dried over magnesium sulfate and then concentrated. The residual oil was 192 cpurified by silica gel column chromatography (eluerit; dichioromethane). Thus, the title compound was obtained as a colorless amorphous product (8.70 g, yield from Synthesis Example E-2 37%).

1 J1-NNIR (400 MHz, CDCl 3 6; 7.84-7.74(2H, in), 7.69(2H1, in), 7.53-7.20(9H, in), 6.73 and 6.51(total 1H, each brd, J=811z), 5.52 and 5.42(total 1H, each dd, J=12, 7Hz), 5.29 and 5.24(total 1H, each dt like), 5.03 and 4.88(total 1H1, each in), 3.87-3.47(2H1, m), 3.75 and 3.65(total 3H1, each 2.39(111, m), 2.10-1.75(3H1, in) Synthesi~s Fxnmple 17-5 f4 i7f]*,2 o l7 (l ivio 1 3 d o o 2f j oridlol-92-y )-6-oxo-1 1-phenyl -1 2 3. 4. S.7, 82bncta hydrnpyrjdo[21-a f1ezrepin(e-4-carboxvlle aicid 07 Q 04 SR 00 s

COON

A solution of methyl (S)-1-[a-(1,3-dihydro-1,3- 193 dioxo-2H-isoindol-2-yl)-(1,1'-biphenyl)-4-propionyl]- 1,2,3,4-tetrahydro-2-pyridinecarboxylate (8.70 g, 17.61 mmol, a 1 1 mixture of diastereomers) obtained in the Synthesis Example E-4 in CH 2 C1 2 (58 ml) was dropped into a mixed solution of trifluoromethanesulfonic acid (10.82 ml, 122 mmol) and trifluoroacetic anhydride (TFAA, 2.75 ml, 19.51 mmol) at 0°C. The mixture was stirred under a nitrogen atmosphere at room temperature for 30 hours, and then poured into ice water. The mixture thus obtained was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The amorphous residue was purified by silica gel column chromatography (eluent; CHC13 MeOH 99 Thus, the title compound was obtained as an amorphous product (1.80 g, yield 42%).

1H-NMR (400 MHz, CDC1 3 )6; 7.78(2H, dd, J=8, 4Hz), 7.66(2H, dd, J=8, 4Hz), 7.49(2H, dd, J=8, 2Hz), 7.43(1H, d, J=2Hz), 7.37(3H, 7.28(1H, tt, J=7, 2Hz), 7.14(111, d, J=8Hz), 5.78(1H, dd, J=10, 6Hz), 5.30(1H, t, J=6Hz), 5.14(1H, dd, J=8, 4Hz), 4.05(1H, dd, J=16, 3.14(1H, dd, J=16, 6Hz), 2.52-2.32(2H, m), 194 LI II -L ii 2.10-1.97(2H, in), 1.88-1.66(2H, m) Evntb.ja-, Fx.amn Ie F- 9 Dipbenvlmethyl r4-~e7(* bl 3dbdo 1,3-dioxo-2T-i qoindo1 -9-v1 -g3-oxo-1 1-phenvi 1 .7.8.12h-octa,,hvdiropvrido2.-1-a1[21be-n2- 00 To a solution of [4S- [4a, 7a 2bP j 3dihydro- 3-dioxo--2H-isoindol-2-yl) -6-oxo-li-plhenyl- 1, 2, 3,4, 6,7,8,12b-octahydropyrido[2, l-aI[2]benzazepine-4-carboxylic acid (1.80 g, 375 minol) obtained in the Synthesis Example E-5 in DMVF (40 ml) was added cesium carbonate (1.34 g, 4.21 mmol). The mixture was stirred for 30 minutes. Bromodiphenyimethane (1.30 g, 5.25 inmol) was added to the obtained mixture and the mixture was stirred at room temperature for 5 hours.

195 The obtained reaction mixture was partitioned into ethyl acetate and water. After the ethyl acetate phase was washed witfl water and a saturated aqueous sodium chloride, it was dried over magnesium sulfate and concentrated. The amorphous residue was purified by silica gel column chromatography (eluent; CHC1 3 hexane (Hex) =4 Thus, the title compound was obtained as a colorless amorphous product (2.03 g, yield 84%).

1 1-N'vR (400 MHz, CDC13)6; 7.85(2H1, brs), 7.69(2H1, dd, J=8, 4Hz), 7.44-6.98(7H1, in), 6.58(111, d, J=8Hz), 6.18(1W, 6.03(11, dd, J=10, 6Hz), 5.42(1H1, t, J=6Hz), 5.14(111, dd, J=8, 4Hz), 4.35(111, dd, J=16, 3.22(111, dd, J=16, 6Hz), 2.37(2H, in), 2.05(111, mn), 1.80-1.63(3H1, in) Synthesis Examnpe F-1 Pr~jLt'jn of diphenviinethyl 3-(4--fluorophenyI Iacl~a-ta 196 g_ To 4-fluorophenylalanine (4.99 g, 27.2 mmol) was added a 0.5 N aqueous solution of HC1 (123 ml). The obtained mixture was cooled to 0°C under cooling with ice and silver nitrite (5.6 g, 36.2 mmol) was further added thereto in several portions within 1 hour under vigorous stirring. Six hours thereafter, the obtained mixture was heated to room temperature and further stirred for 1 day. The silver chloride thus precipitated was removed out by filtration and the filtrate was extracted with diethyl ether (200 ml x The diethyl ether phase was dried over (MgSO 4 was used). The diethyl ether phase filtered was concentrated under reduced pressure. Thus, a crude product (4.69 g) of 3-(4-fluorophenyl)lactic acid was obtained. Next, this crude product (4.69 g) was dissolved in dry dimethylformamide (80 ml) and cesium carbonate (8.58 g, 26.3 mmol) was added thereto. The mixture thus obtained was stirred at room temperature for 40 minutes and subsequently bromodiphenylmethane (11.8 g, 47.8 mmol) was added thereto. The resulting mixture was stirred at room temperature for a day and water (300 ml) was then added thereto. The mixture .o -thus obtained was extracted with ethyl acetate (100 ml x Next, the organic phase was washed with a y j saturated aqueous solution of sodium hydrogencarbonate 197 -u 0 ml) and a saturated aqueous sodium chloride (100 ml) and dried over magnesium sulfate. Afte~r filtering thereof, the residue (13.4 which was obtained by concentrating the filtrate under reduced pressure, was purified by silica gel column chromatography (hexane ethyl acetate =90 As a result, the title compound (4.2 g, we~s obtained as white crystals.

1 H- NMR (400 MHz, CDCl 3 )6; 2.98(lH, dd, J=6.2, 14.1Hz), 3.13(iH, dd, J=4.8, 14.1Hz), 4.55(iH, q, J=5.4Hz), 6.85(2H1, t, J=8.4Hz), 6.94,eLH, 6.99(2H, dd, J=5.6, 8.4Hz), 7.28-7.38(10H1, m) MASS m/e (FAB); 373(MNa+) 52-54 0

C

Erepgrnti on OT di phenvimethbyl 2-aneetl hio--3- (4fluoropherivi nropionnte coo J SAc

F

Triphenylphosphine (3.99 g, 15.2 mmol) was 198 dissolved in dry tetrahydrofuran (78 ml), followed by cooling to 0°C under cooling with ice. Further, diisopropyl azodicarboxylate (DIAD (2.99 ml, 15.2 mmol)) was dropped thereinto under stirring. Thirty minutes thereafter, a solution of a mixture of thioacetic acid (1.25 ml, 17.6 mmol) with diphenylmethyl 3-(4-fluorophenyl)lactate (4.0 g, 11.4 mmol) obtained in the Synthesis Example F-l in dry tetrahydrofuran (45 ml) was dropped thereinto. The mixture was allowed to react at 0 C for 3 hours. Then the ice bath was removed and the reaction mixture was warmed to room temperature and allowed to react at this temperature overnight. Next, this reaction mixture was concentrated under reduced pressure. The residue thus obtained was separated by silica gel column chromatography (hexane ethyl acetate 6 1) to thereby give a crude product (4.7 This crude product was recrystallized from diisopropyl ether and hexane (20 ml 30 ml). The solid thus precipitated was removed by filtration and the filtrate was concentrated under reduced pressure to thereby give the title compound (3.54 g, 76%) as an oily product.

1 H-NMR (400 MHz, CDC1 3 )6; 2.33(3H, 3.01(1H, dd, J=6.6, 14.0Hz), 3.19(1H, dd, J=8.8, 14.0Hz), 199 II 4.52(1H, t, J=8.2Hz), 6.81(1H, s), 6.85(2H, t, J=8.6Hz), 7.05(2H, dd, J=5.8, 7.8Hz), 7.14~7.17(2H, 7.26-7.36(8H, m) Synthesis Example F-3 Preparation of 2-acetylthio-3-(4-fliioropeny1)-.

propionic acid S\ COOH SAc

F

Diphenylmethyl 2-acetylthio-3-(4-fluorophenyl)propionate (3.38 g, 8.27 mmol) was dissolved in anisole (9.0 ml), followed by cooling to -10 0 C. Into this solution was further droppei trifluoroacetic acid (51.0 ml). Next, this solution vas heated to 0°C.

About 1 hour thereafter, it was concentrated under reduced pressure. To the concentrate was added diethyl ether (80 ml) and the resulting solution was extracted with a saturated aqueous solution of sodium hydrogencarbonate (100 ml x To the alkaline aqueous solution thus obtained was added a 2 N aqueous solution of hydrochloric acid until the solution became acidic. Further, it was extracted with methylene chloride (100 ml x The organic phase was washed with a saturated aqueous sodium chloride 200

II

(100 ml) and dried over magnesium sulfate. After drying, the filtrate obtained by filtering thereof was concentrated under reduced pressure. Thus, the title compound (1.96 g, 98%) was obtained as colorless crystals.

I H-NMR (400 MHz, CDCl 3 6; 2.35(3H, 3.0Q0lH, dd, J=7.4, 14.2Hz), 3,26(1H, dd, J=7.8, 14.2Hz), 4.40(1H, t, J=7.6Hz), 6.99(2H, t, J=8.6Hz), 7.20(2H, dd, J=5.6, 8.4Hz) MASS in/e (FAB); 243(N1H+) rn.p.; 44-46"C Synthp~iq Ryamples F-4t In accordance with -the processes of the Synthesis Examples F-1 to F-3, the following compounds were obtained.

Pxample P-4 (Ff-2-Aetvlil-3-npnvlpropio)nic acld

SAC"

By using D-phenylalanine as the starting material, it was synthesized in accordance with the processes of the Synthesis Examples F-1 to F-3.

201 'H-NMYR (400 MHz, CDC1 3 )8; 2.34(3H, 3.02(114, dd, J=7.6, 14.0Hiz), 3.30(114, dd, J=7.6, 14.0Hz), 4.44(111, t, J=7.61Jz), 7.21-7.33(514, m) MASS m/e (FAB); 225(MH+) 59-61"C Syn theh P is-xamnle-E.

2-Acetvlthio-3-(1 .4-biphenyl~nropnhonic nnid SAc 1 H-NMR (400 MHz, CDC1 3 6; 2.36(3H1, 3.07(114, dd, J=7.6, 14.4Hz), 3.34(11, dd, J=7.6, 14.4Hz), 4.48(11, t, 7.29-7.59(9H4, m) MASS m/e (FAB); 301(MH+) 122-123 0

C

Syvnthes-is Examnple F-S (S)-2-Acetylthio-3-(4-meatboxyvphonvl nrnnintic CH3 yiCOOH 202 IH-NMR (400 MHz, 2.34(3H, 2.97(11, dd, J=7.6, 14.4Hz), 3.23(11, dd, J=7.6, 14.4Hz), 3.79(31, s), 4.39(111, t, 6.81-6.86(211, in), 7.12-7.17(2H1, m) MASS m/e (FAB3); 255(MH+) 95-98*G S-Amino-i -lthoxyvronylrne-thv1-8-nhenv ttrahydro-1fl-f 1 hen'zaz.pi--2,nne

H

2

N

N 7 0

K

COOC

2 Hs A mixture comprising 0.785 g (2.15 mmol) of 3-azido-l-ethoxycarbonylmethyl-8-phenyl-2,3,4,5tetrahydro-H-1j1]benzazepin-2-one obtained in the Synthesis Example A-7, 0.05 g of 10% palladium-carbon and 20 ml of ethanol was catalytically hydrogenated at room temperature under 4 atm for 1 hour. After filterin off the catalyst, the filtrate was concentrated. Thus, 0.73 g of the title compound was obtained as a pale yellow oily product. Yield 100%.

203 IH-NMR (400 MHz, CDC1 3 8: 7.56-7.35(6H1, m) 7.33(11, d, J=2Hz) 7.30(111, d, J=8Hz) 4.69(111, d, J=17H-z) 4.51(11, d, J=1711z) 4.21(211, dq, J=7.1Hz) 3.53(1H, dd, J=11.81z) 3.28(1H, dt, J=13.8Hz) 2.65(11, dd, J=14.7Hz) 2.46(111, m) 1.96(11, m) Fxnmple A-? -Ance.tylthi o-.9-pbenyl nrplony aino] -1 ethboxvcarbonvlmet-hvl-8-npnyl-lH-f1 ]henzaz'epin-2-one

CH

3COS CONH

N

COOC

2

H

341 mng (1 mmol) of 3-amino-1-ethoxycarbonyl.methyl-8S-phenyl-2,3,4,5-tetrahydro-1i1-[llbenza7l-pin- 2-one obtained in the Example A-1 and 247 mg (1.1 mmol) of (S)-2-acetylthio-3-phenylpropionic acid were dissolved in 20 ml of dichloromethane. 300 mg (1.21 mmol) of EEDQ was added thereto and the obtained mixed solution was stirred overnight. The reaction mixture was washed with 1 N hydrochloric acid, water and a saturated aqueous sodium chloride and dried over 204 anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.

After successively eluting with hexane :ethyl acetate in a ratio ranging from 15 :1 to 3 :1 329 mg of the title compound was obtained as a colorless amorphous product. Yield 72%.

IH-NMR (400 MHz, CDCl 3 6: 7.55-7.15(13H1, m) 7.04 and 6.88(total 1H, each br) 4.82 and 4.78(total 1H1, each d, J=l7Hz) 4.50(111, m) 4.39 and 4.34(total 1H1, each d, J=l7Hz) 4.27-4.123M, m) 3.42-3.22(2H1, m) 2.94(111, mn) 2.77-2.49(2H1, im) 2.34 and 2.33(total 311, each s) 1.24(3H1, q, J=7Hz) FxaimpIe A-3 1 -~roxvetv1 q.r ~~--rnrciiio-3-henv1 nrnnvnin--h-y-IT1rlbez-zpn2Dl 205 To a mixture of 358 mg (0.657 mmol) of acetylthio-3-phenylpropionylamino]-1-ethoxycarbonylmethyl-8-phenyl-1H-[l]benzazepin-2-one obtained in the Example A-2 with 10 ml of degassed ethanol was added 3.3 ml of a degassed 1 N aqueous solution of sodium hydroxide at 0°C under a nitrogen atmosphere under stirring. The mixture thus obtained was stirred at room temperature for 2 hours and half. The reaction mixture was cooled and acidified with 1 N hydrochloric acid and water was further added thereto. The white crystals thus precipitated were collected by filtration, washed with water and n-hexane and dried under reduced pressure. Thus, 267 mg of the title compound was obtained. Yield 86%.

1 H-NMR (400 MHz, CDC1 3 )6: 7.54-7.14(13H, m) 4.74 and 4.73(total 111, each d, J=17Hz) 4.54(1H, m) 4.47 and 4.45(total 1H, each d, J=17Hz) 3.56 and 3.42(total 1H, each m) 3.3-3.16(2H, m) 3.06(1H, dd, J=14.71z) 2.98(1H, dd, J=14.7Hz) 2.74-2.52(2H, m) 2.08 and 1.97(total 1H, each d, J=9Hz) 206 I 1xamplP A-4 3- F(S) Act~y tIn .9-~mB±thv1 hiitvrv I im Inn I -12tDy n arhony'imethyl -8 -ph enyl -111 1 L1 b(-n7zneP.i n-9-onP CHCOS

CONF

COOC

2

H

352 mg (1.04 mmol) of 3-amino-1-ethoxycarbonylmethyl-8-phienyl-2,3,4, 5-tatrahydro-ll- Il benzazepin- 2-one obtained in the Example A-i and 202 mg (1.14 mmol) of (S)-2-acetylthio-3-methylbutanoic acid were reacted in the same manner as that of Example A-2.

Thus, 396 mg of the title compound was obtained as a colorless amorphous product. Yield 77%.

IH-NMR (400 MI.1z, CDCl1 3 8: 7.55-7.29(8H, in) 7.10 and 7.03 (total 111, each brd, J=7Hz) 4.86 and 4.83 (total 1H1, each d, J=1711z) 4.61-4.54(11, m) 4.39 and 4.37(Itotal 11.1, each d, J=17fIz) 4.24-4.13(3H, in) 3.85 and 3.84(total, 1H1, each d, J=71.lz) 3.40(111, in) 2.80-2.60(211, mn) 2.37(31, s) 207 2.26 and 2.95(total l1H, each m) 1.25(3H, q, J=7Hz) 0.99 and 0.96(total 6H, each d, dd, each J=T'z, J=7.21z) FExgmpl e IzICarbnxyiethvl-s-r (S)-2-mercpto-3-me 4 hbYlz HS CONH

COOH

347 mg (0.7 mmol) of 3-[(S)-2-acetylthio-3methylbutyrylamino] -l-ethoxycarbonylmethyl-8-phenyl- 1H-[1]benzazepin-2-one obtained in the Example A-4 was hydrolyzed in the same manner as that of Example A-3.

Thus, 243 mg of the title compound was obtained as white crystals. Yield 81%.

IH-NMR (400 MHz, CDCl 3 )8: 7.55-7.29(8H, m) 4.80 and 4.78(total 1H1, each d, J=1711z) 4.60(111, m) 4.48 and 4.46(total 1,11, each d, J=l7Hz) 3.33(111, m) 3.11(111, m) 2.78-2-62(211, m) 208

I

2.18(111, m) 2.01(11, m) 1.84 and 1.83(total 11-1, each d, J=911z) 0.99-C-94(61, m) TEXample A-63 3- f(S-Aretythi h(nvl rni nv-Iqini noLzj se±bnxvcarbonv1 methyl-i-I-Fl1 benzazepij-2- ae

CH

3 COS CONK

COOC

2 Ht To a mixed solution comprising 0.76 g (2.9 mmol) of 3-amino-1-ethoxycarbonylmethyl-1- [1]benzazepin- 2-one, 0.65 g (2.9 mmol) of (S)-2-acetylthio-3-phenylpropionic acid and 30 ml of tetrahydrofuran were added 0.61 g (3.18 mmol) of DEC, 0.35 ml (3.18 mimol) of N-methylmorpholine and 0.43 g (3.18 mnmol) of 1hydroxybenztriazole. The mixture thus obtained was stirred at room temperature for 5 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic phase was washed with water, 1 N hydrochloric acid and water and dried over anhydrous magnesium sulfate. The solvent of the 209 organic phase was distilled off' under reduced pressure, and the ;r-sidue was subjected to silica gel column chromatography. After eluting with toluene ethyl acetate in a ratio of 7 1. 0.95 g of the title compound was obtained as a colorless amorphous product. Yield IH-NMR (400 MHz, CDCl 3 )6: 7.30-7.08(9H, m) 7.04 and 6.88(total 1H, each brd, J=7Hz) 4.77 and 4.72(total 1H1, each d, J=l7Hz) 4.42(lH, m) 4.33 and 4.28(total IH, each d, J=l7Hz) 4.24-4.38('VJ, m) 3.38-3.21(2H1, m) 2.93(lH, m) 2.75-2.46(21, m) 2.33 and 2.32(total 3H1, each s) 1.83 and l.66(total 1H1, each m) E~xample A-7 1 -Carboxvm~ fhyl -2-mereapto-3-obpnY1 pxoda~_aJDJ1 naoin2=n

COOH

210 To a mixed solution of 0.65 mg (1.39 mmol) of 3-[(S)-2-acetylthio-3-phenylpropionylamino]-1-ethoxycarbonylmethyl-lH-[l]benzazepin-2-one obtained in the Example A-6 with 10 ml of degassed ethanol was added 7 ml of a degassed 1 N aqueous solution of sodium hydroxide at 0°C under a nitrogen atmosphere with stirring. The mixture thus obtained was stirred at room temperature for 3 hours. After the reaction mixture was cooled and acidified with 1 N hydrochloric acid, it was extracted with dichloromethane. The dichloromethane phase was washed with a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent of the organic phase was distilled off under reduced pressure. Thus, 0.53 g of the title compound was obtained as a colorless amorphous product. Yield 96%.

1 1H-NMR (400 MHz, CDC1 3 )6: 7.31-7.11(9H, m) 4.68 and 4.65(total 1H, each d, J=17Hz) 4.51-4.38(2H, m) 3.55 and 3.42(total 1H, each m) 3.28-3.14(2H, m) 3.05 and 2.97(total 1H, each dd, J=14.7Hz) 2.72-2.48(2H, m) 2.07 and 1.96(total 1H, each d, J=9Hz) 1.88 and 1.64(total 1H, each m) 211 E~xample A-B etboxyc.arhonvrmethv1-l-H-f1 1henzazepin-2--one NHa

SOCCH

3 0 7C

H

0.525 g (2 mmol) of 3-amii.n-l-ethoxycarbonylmethyl-1H-II1]benzazepin-2-one and 0.418 g (2.2 mmol) of (2S,3S)-2-acetylthio-3-methylvaleric acid were reacted in the same manner as that of Example A-2.

Thus, 0.42 g of the title compound was obtained as a colorless amorphous product. Yield 48%.

IH-NMR (400 MlHz, CDCl 3 8: 7.31-7.00(5H, m) 4.81 and 4.78(total 1H, each d, J=1711z) 4.53-4.45(111, m) 4.33 and 4.31(total 1H1, each d, J=l7Hz) 4.22-4.12(2H1, m) 3.91 and 3.89(total 1H1, each d, J=7Hz) 3.44-3.33(111, m) 2.78-2.56(2H1, m) 2.37(31, s) 2.07-1.87(2H1, m) 1.59-1.50(11, in) 1.28-1.22(3H, m) 212 0.6ad09(oa 3,ec ,J7z 0.8aO.5(total 3H, each d, J=7Hz) Example A-9R 1 -farboxymethyl (2S 3S) -2-=trn~capto-3methyl vare yl and noi -1 T- r 1 henzazppi n-2.-onae CH3 o CH3

NH

SH

/N

(CONH

A mixed solution of 0.385 g (0.89 mmol) of (2S,3S)-2-acetylthio-3--methylvalerylamino]l-ethoxycarbonylmethyl-1H-Iillbenzazepin-2-one obtained in the Example A-B with 15 ml of degassed ethanol was acidified with degassed 1 N hydrochloric acid under stirring at O 0 C under a nitrogen atmosphere. It was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous magnesium sulfate. The solvent of the organic phase was distilled off under reduced pressure. Thus, 0.34 g of the title compound was obtained as a colorless amorphous product (yield quantitative).

1 H-NMR (400 MHz, CDCl 3 6: 7.39-7.14(5H, m) 213 4.74 and 4.71(total 1H-, each d, J=l7Hz) 4.57-4.50(1H, m) 4.44 and 4.43(total 1H1, each d, J=1711z) 3.34-3.10(2H1, m) 2.77-2.58(2H, m) 2.03-1,87(2H1, m) 1.85 and 1.84(total 11-, each d, J=9Hz) 1.64-1.50(11, m) 1.22-1.15(11, m) 0.95(3H1, d, J=711z) 0.86(3H1, t, J=7Hz) Example A-bO (S)-i-j12S3S)-2-Aeetlthio-3mel~hvi3Lr.lylr am! no I -1 -PthobvrjyQrbonvl met:hvI 3.4, S-tetrahvriro-l 14- 1 benzepin-2-one CH 3 0N NiH

SCOCH

3 COO 0.55 g (2.1 mmol) of (S)-3-amino-1-ethoxycarbonylmethyl-2, 3,4, 5-tetrahydro-1H- [1]benzazepin- 2-one and 0.434 g (2.3 mmol) of (2S,3S)-2-acetylthio- 3-methylvaleric acid were reacted in the same manner as that of Example A-2. Thus, 0.614 g of the title compound was obtained as a colorless amorphous product. Yield 67%.

214 a- IH-NMR (400 MHz, CDC1 3 6: 7.31-7.17(3H, m) 7.12(111, dd, J=8.lHz) 4.49(111, dt, J=11.8Hz) 4.33(111, d, J=1711z) 4.24-4.12(2H1, m) 3.89(11, d, J=711z) 3.38(111, m) 2.74-2.56(2H1, m) 2.37(3H1, s) 2.04-1.87(2H1, m) 1.56(111, m) 1.25(31, t, J=711z) 1.14(111, m) Fxamplp A-11 aminol-1-cajroxmeth 1-2..4.9t.eZraydroz11I ri 1berzaepn-2-one

CH

3 a Cila

NH

S H CO O

H

0.6 g (1.38 mmnol) of (S)-3-[(2S,3S)-2-acetylthio- 3-methylvarelylamino]-1l-ethoxycarbonylnethyl-2, 3,4,5tetrahydro-111-[1]benzazepin-2-one obtained in the Example A-10 was hydrolyzed in the same manner as that of Example A-9. Thus, 0.49 g of the title compound was obtained as a colorless amorphous product. Yield 97%.

215 1 H-NN R (400 MHz, CDCl 3 8: 7.40(111, brd, J=711z) 7.33-7.14(4H1, m) 4.71(111, J=1711z) 4.54(lHi, dt, J=11, 7Hz) 3.17(111, dd, J=9.7Hz) 2.74-2.59(2H1, m) 2.04-1.89(21, m) 1.84(11, d, J=9Hz) 1.55(111, m) 1.17(111, m) 0.95(31, d, J=7Wz 0.86(3H1, t, J=7Hz) Examp~lp B-1 4~..8.,1011 11 a-ocj-,qhvrnroi(InI*r1 -ri] thiP enf3-2-clazepine-Bcarhoxyite

H

2

N

0N

COOC

2

H

540 mg (1.23 mmcl) of the compound obtained in the Synthesis Example B-3 was dissolved in 31 ml of ethanol and 0.072 ml (1.48 mnmol) of hydrazine monohydrate was added thereto. The mixture thus obtained was stirred at room temperature for a Nvee1k.

The reaction mixture was concentrated as such under reduced pressure and dichloromethane was added thereto. The filtrate obtained by filtering it was 216 concentrated again. The residue was purified by silica gel column chromatozraphy (dichioromethane/ methanol/aqueous ammonia 98/2/0.3) to thereby give 332 mg of the title ,Zompound (yield 88%).

MASS in/e (FAB); 309(MH") 92-97 0

C

1 H-NNIR (400 MHz, CDCl 3 Me 4 Si)b; 0.881(3H1, t, J=7.2Hz) 1.57-1.94(5H1, m) 2.03-2.21(2H1, in) 2.40-2.47(11, m) 2.95(lH, m like t) 3.32(111, ddd, J=1.6, 4.8, 16.8Hz) 3.67-3.75(11, m) 3.81-3.88(111, in) 4.61lH,'dd, J=4.8, 13.21-z) 5.1(111, brt, J=6.4Hz) 5.30(111, dd, J=1.6, 8.0Hz) 6.78(111, d, J=5.O1-z) 7.04(111, d, Fxample Bl-2 .thyl r5ss- r. .A 1 1Tp- r(S) ntvl t i ooctZahydrorpyarin.lI.>ih eno[3, 2-C l17epinn-8- -carboxy ate, 217 150 mg (0.49 mmol) of the compound obtained in the Example B-i was dissolved in 12 ml of dichioromethane, 120 mg (0.54 mmol) of 2(S)-acetylthio-3phenylpropionic acid and 1.44 mg (0.58 mmol) of EEDQ were added thereto at 0 0 C. The mixture thus obtainaed was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 3) to thereby give 168 mng (yield: 67%) of the title compound as an amorphous product.

IH-NMR (400 MHz, CDCl 3 Me 4 Si)6; 0.87(3H1, t, J=7.2Hz) 1.60-1.91(3H1, m) 2.01-2.20(2H1, m) 2.36(311, s) 2.39-2.48(11, m) 2.81(111, m like dd) 3.04(111, dd, J=7.6, 14.0Hz) 3.34(111, dd, J=7.6, 14.0Hz) 3.51(111, m like dd) 3.68-3.88(2H1, m) 4.33(111, t, J=7.6Hz) 5.19-5.25(21, m) 5.50-5.57(11, m) 8.75(111, d, J=5.211z) 7.04(111, d, J=5.21z) 7.21-7.33(5H1, m) 7.50(111, brd) 218 Example B-3 a. a 1 1 i l 1I-5-r f (S)-2-Mlercapto-1-oxo- 3-phefiylpropy ami no] -fi-oxo-4. fi 8.8. 3 10.1 1 a-onta_hydropyridol .2-a]thieno[3.2-]aazpine-8-carboxylic acid 0 S SSH 0

COOH

To 163 mg (0.32 mmol) of the compound obtained in the Example B-2 was added 12.7 ml of degassed methanol. Further, 3.8 ml of degassed 1 N sodium hydroxide was added thereto. The mixture thus obtained was stirred at 40°C. Suven hours thereafter, Jt was cooled to 0°C. To the reaction mixture was added 5.7 ml of 2 N hydrochloric acid. Then, the mixture was concentrated to a certain extent under reduced pressure. The crystals precipitated by adding a small amount of water thereto were collected by filtration and dried over phosphorus pentaoxide under reduced pressure. Thus, 92 mg of a mixture of the title compound with its epimer at a ratio of 4 3 was obtained (yield 219 1 I-NMR (400 MHz, CDC1 3 Me 4 Si)6; 1.63-2.43(6H1, m) 2.54-4.30(5H1, m) 5.16 and 5.24(total IH, each m) 5.31 and 5.40(total 1H1, each m) 5.62 and 5.79(total 1H1, each m) 6.73-6.78(total 111, m) 6.90-7.04(total 111, m) 7.19-7.91(total 6H1, m) Exaplp B-4 Fthyl rs-ja- rRHT .lp]sf[(S) -2-Ficetv1-l hi n- 3-rethyl-l-pxohbutyllmino--oo--4t.5A8....1Iaoct.ahyjdropyridof 1 2-althienf3.2--e1.zeine-8carhoxyl a-iie CH3 0

S

CH

3 l NH scocHi3 0 NS

COOC

2 Ib 170 ml (0.55 mmol) of the compound obtained in the Example B-i and (S)-2-acetylthio-3-methylbutanoic acid (107 ing, 0.61 inmol) were reacted in the same manner as that of Example B-2. Thus, 203 ing of a stereoisomeric mixture of the title compound with its epimer was obtained (yield 79%).

220

I

1 14-NNIR (400 MHz, CDC1 3 Me 4 SI)a; 0.88 and 0.89(total 31-1, each t, each J=7.2Hz) 1.00 and 1.01(total 314, each d, each J=6.8Hz) 1.05 and 1.06(total 3H1, each d, each J=6.4Hz) 1.59-2.24(total 51H, in) 2.32-2.48(total 2H1, mn) 2.40 and 2.42(total 3H4, each s) 2.84-2.98(total 111, mn) 3.49-3.58(totai 1H4, m) 3.68-3.96(total 3H4, mn) 5.23-5.29(total 2H4, in) 5.58-5.66(total 1H1, mn) 6.76(totai 1H4, m) 7.04(total 114, mn) 7.52-7.59(total 1H4, mn) 8-carboXylic acid CH IA NH 0/K0

COOH

200 mg of ethyl acetylthio-3-inethyl-1-oxobutyl] amino]I-6-oxo- 4,5,6,8,9,10,11, lla-octahiydropyrido[1, 2-aithiieno- [3,2-c]azepine-8.-carboxylate obtained in the Example 221 B-4 was reacted in the same manner as that of Example 1-3. Thus, a stereolsomeric mixture of the title compound was obtained as a white solid (127 mng, 74%).

1 11-NMR (400 MHz, CDC1 3 Me 4

SO

4 6; 1.01-'1.06(total 6H, m) 1.66-2.42(total 8H, m) 2.85-3.60(total 3H1, m) 5.19-5.24(total lIH, m) 5.32-5.40(total 111, m) 5.64-5.79(total 1H1, m) 6.74-6.79(total 1H, m) 7.00-7.05(total 1H1, m) 7.37-8.23(total 1H, m) Example B-6 Ethyl -mn--x-.AA.1.1.a.

01a,,hvIropvridnf 1 .2-g~theno2.3cjn 8~

H

2

N

0 1.28 g (2.92 minol) of the conipound obtained in the Synthiesis Example B-6 was reacted in the same manner as that of Example B3-1. Thus, 581 ing of a mixture of two diastereomers of the title compound was obtained as a racemic modification MASS In/c (FAB); 3. 09 (MH 4 222 IH-NMR (400 MHz, CDCl 3 IMe 4 Si) 8; 0.87 and 1.30(total 311, each t, each J=7.2Hz) l.60-2.48(total 8H1, m) 2.77(total H, m like q) 3.13-3.21(total 1H1, m) 3.71-3.91 and 4.24(total 2H1, each m and q, each J=7.2Hz) 4.47 and 4.57(total 1H1, each dd, each J=4.8, 12.8Hz) 4.76 and 5,28(total 111, each t and dd, each J=5.OHz and J=1.6, 7.6Hz) 5.43 and 5.49(total 1H1, each brt and brs) 6.77-6.81(total 1H1, m) 7.07-7.ll(total 1H1, mn) Example B-7 Rthyl q-f hp- -xo-3-ph envl prnpyl Iai no-8-oxo-4.c 5.R. R- 1 0. 11 1la-optahydropvido- 01

NH

sc o c H 3 0

COOC

2

H

581 ml (1.88 mmol) of the compound obtained in the Example B-4 and (S)-2-acetylthio-3-phenylpropionic acid (423 mg, 1.88 mmol) were reacted in the same manner as that of Example B-2. After purifying by silica gel column chromatography (hexane/ethyl acetate 223 232 mg (yield 24%) of a mixture of two diastereomers was obtained from the former fraction.

Further, from the latter fraction, 324 mng (yield 33%) of a 1 :1 mixture of two diastereomers different from those contained in the former fraction was obtained.

Former fraccion 1 1-NMR (400 MHz, CDC]- 3 NMe 4 Si)8; 0.86 and 1.29(total 311, each t, each J=7.2Hz) 1.62-2.48(total 6H1, m) 2.34 and 2.36(total 3H1, each s) 2.58-2.70(total 111, mn like q) 2.96-3.06(total 111, m) 3.30-3.42(total 2H1, m) 3.72-3.88 and 4.23(total 211, each mn and q, each J=7.2Hz) 4.28-4.35(total 1H1, in) 4.80 and 5.19-5.23(total 1ii, each brt and m) 5.34-5.54(total 211, mn) 6.74-6.77(total 111, in) 7.06--7.10(total 111, mn) 7.20-7.47(total 6H, mn) Latter fraction IH-NMR (400 MHz, CDCl 3 Me 4 Si)8,; 0.85 and 1.29(total 31-1, each t, each J=7.211z) l.60-2.44(total 6H, m) 2.34 and 2.40(total 3H1, each s) 2.44-3.37(tota. 411, i) 3.69-3.88 and 4.18-4.30(total 3H1, mn) 4.78 and 5.22(totai 111, each brt and mn) 224 5.35-5.55(total 2H, m) 6.71(total 1H, t, J=5.2Hz) 7.08(total l1H, dd, J=5.2, 8.4Hz) 7.21- 7.36(total 6H, m) ExaniPie B-8 5.-f(S)-2-Merrnnapto-l-oxo-S.-ihenvlpropy'llamino- 9-xo-~4.5,6.8.9.10.11 .1a-oc-tahvdr-F1 .2-althienor2.3f azPPIne--rroa'v1I~c.acijj 0

S

NN

SH

N

COOH

227 mg (0.44 mmol) of the compound obtained from the former fraction in the Exaimple B-7 was reacted in the same manner as that of Synthesis Example B-3.

Thus, 1.43 mg of the title compound, which was a mixture of two diastereomers at a ratio of 7 was obtained as white crystals (yield 67%).

IH-NMR C(400 MHz, GDCl 3 Me 4 Si)6; 1.72-2.48(total. 711, m) 2.64-2.78(total lH, m like q) 3.06-3.15(total 111, m) 3.25-3.41"total 21H, m) 3.58-3.65(total 1H1, m) 4.80 and 5.20(total 1H1, each dd arnd m like d, each J=3.8, 225 5.40-5.63(total 2H, mn) 6.71-6.79(tota'- lH, in) 7.05-7.14(total 1H, mn) 7.21-7.61(total 6H, m) 'Fxamlp B3-9 0

NH

NH

K SHN CO OH 320 mg (0.62 mmol) of the compound obtained from the latter fraction in the Example B-7 was reacted in the same manner as that of Synthesis Example B-3.

Thus, 189 mg of the title compound, which was a mixture of two diastereomers at a ratio of I1 1, was obtained as white crystals (yield 63%).

IH-NMvR (400 MHz, CDCl 3 Me 4 Si) 8; l.B8-2.52(total 7H, m) 2.64-3.63(total 5H, mn) 4.76 and 5.17-5.21(total 1H, each brt and mn like brd, each J=4.6llz) 5.39-5,63(total 2H, m) 6.67 and 6.71(total 1H, each d and d, each J=5.2Hz and J=5.2Hz) 7.03 and 7.ll(total li-, each d, and d, each J=5.2Hz and J=4.8Hz) 7.20- 7.33(total 6H, mn) 'H-NMR (400 MHz, CDCl 3 Me 4 Si) 6; 1.60-2.42(6H1, in) 2.15(111, d, J=9.2Hz) 226 2.61(1H, m like dd, J=12-8, 16.01-z) 3.07(11, dd, J=6.4, 13.6Hz) 3.24-3.32(2H1, m) 3.45-3.51(11, mf) 5.21(lH, dd, J=2.0, 7.6Hz) 5.29-5.34(lH, m) 5.59-5.66(1H, m) 6.76(111, d, J=5.2Hz) 7.01(111, d, J=5.2Hz) 7.20-7.34(6H, m) FX a Mpi Me thyl q A- 2,3)2BcJyt i o-3-meth1-1z o.oppntvl tbjrqznLa2-Qheie3cahxl

CH

3 H3C

NH

SCOCH

3 0 CH3000 A solution of 225 mg (0.92 mmol) of methyl [3R- [3ca,6c(S*) ,9aP]]I-6-aminooctahydro-5-oxothiazoll3,2-a]azepine-3--carboxylate in nmethylene chloride (17 ml) was cooled to 0 0 C under cooling with ice. Next, to this solution were continuously added a solution of 193 mig (1.01 mrnol) of (2S,3S)-2-acetylthio-3-methylpentanoic acid in methylene chloride (6 ml) and 296 mg (1.20 mmol) of EEDQ. Then, the ice bath was removed, and the obtained mixture was stirred at room 227 temperature overnight under nitrogen. Then, it was concentrated on an evaporator to a ceratin extent.

Next, this residue was dissolved in ethyl acetate.

The mixture thus obtained was successively washed with a 1 N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The residue, which was obtained by filtering it and concentrating the filtrate under reduced pressure, was purified by a column chromatography (hexane ethyl acetate 3).

Thus, 206 mg of the title compound was obtained as an &iorphous product (yield: 54%).

IH-NMR (400 MHz, CDC1 3 )8; 0.88(3H, t, J=7.6Hz) 0.99(3H, d, J=6.8Hz) 1.10-1.22(1H, m) 1.51-1.70(2H, m) 1.82-2.14(6H, m) 2.38(3H, s) 3.20(1H, dd, J=6.4, 11.8Hz) 3.28(1H, dd, J=2.4, 11.8Hz) 3.79(3H, s) 3.98(1H, d, J=6.8Hz) 4.54(1H, dd, J=6.4, 10.4Hz) 5.02(1H, d, J=8.8Hz) 5.28(1H, dd, J=2.4, 6.4Hz) 7.41(1H, d, 228 I LC Example 0=2 Methyl f 3R-f3a.6eh Da116fF(Sq--ytl octabydrothi azo1 M3.2--21.q9zepjne-3-enirbov1 te CH3 0

H

3

C

NH

SCOCH

3 IN I CHAOOC -CH 3 In the same manner as that of' Example C-1 and starting with 170 mg (0.62 mmcl) of methyl [3R- [3a,6 ,9ap I] -6-amino-2,2- dime thiazoltI3,2-alazepine--3-carboxylate and 131 mg (0.69 mmol) of' (2S,3S) -2-acetylthio-3-methylpentanoic acid obtained in the Synthesis Example C-2, 136 mg of the title compound was obtained as a colorless amorphous product (yield: 49%).

1 H-NMR (400 MHz, CDCl 3 )8; 0.8803H, t, J=7Hz) 0.99(3H, d, J=7Hz) 1.10-1.21(11, m) 1.41(31, s) 1.55(31, s) 1.50-1.62(211, m) 1.84-2.32(6H1, m) 2.38(3H, s) 3.79(3H1, s) 3.98(111, d, J=711z) 4.52-4.57(11, m) 4.77(111, s) 5.11(11, d, J=1011z) 7.43(11, d, J=6Hz) 229 Example f-3 3-f r (2S SI;) Acetyl th i -S-me thy] -1 -OxO- 2,.4.5-tetrabydro-lT4-[llhenzrnzenin-2-on~e

CH

3 o NH

SCOCH

3

N

COOC

2

H

By using 0.525 g (2.00 nimol) of 3-amino-iethoxycarbonylmethyl-2,3,4 ,5-tetrahydro-ill- benzazepin-2-one and 0.418 g (2.20 mmol) of (2S,3S)-2-acetylthio-3-methylpentanoic acid obtained in the Synthesis Example C-2, the treatment of Example C-1 was repeated. Thus, 0.420 g of the title compound was obtained as a colorless amorphous product (yield 48%).

1 1-NMR (400 MHz, CDC1 3 )8; 7.31-7.00(5H1, m) 4.81 and 4.78(total 1H1, each d, J=17Hz) 4.53-4.45(111, m) 4.33 and 4.31(total 1H1, each d, J=17Hz) 4.22-4.12(2H1, m) 3.91 and 3.89(total 111, each d, J=7Hz)

RA(>

LU- 230 T~rO 3.44-3.33(111, in) 2.78-2.56(2H1, mn) 2.37(3H1, s) 2.07-1.87(2H, mn) 1.59-1.50(11, mn) 1.28-1.22(3H1, mn) 0.96 and 0.95(total 3H1, each d, J=711z) 0.85(total 3H-, each t, J=711z) ExampleC-4 DQxnnpntv1lq 1~Inno1-P-thnoynarbonylmelhv1 2,.3...A.5-tetraihdro-l 11-Fl 1henzazpiuz2n9-on

H

3

C

(COOC

2

H%

0.550 g (2.10 mmol) of (S)-3-amino-1-ethoxycarbonylmethyl-2, 3,4, 5-tetrahydro-1H- [1]benzazepin-2one and 0.434 mng (2.30 mmol) of (2S,3S)-2--acetylthio- 3-methylpentanoic acid were treated in the same manner as that of Example C-i. Thus, 0.614 g of the title compound was obtained as a colorless amorphous product 1 1-NMR (400 MHz, CDC1 3 )6; 7.31-7.17(3H1, 7.12(1H1, dd, J=8.lHZ) 231 0 7.01(111, brd, J=711z) 4.78(111, d, J=l7Hz) 4.24-4.12(2H1, m) 3.89(111, d, J=7Hz) 3.38(11, m) 2.74-2.56(2H1, m) 2.37(3H1, s) 2.04-1.87(2H1, m) 1.56(111, m) 1.25(3H1, t, J=611z) 1.14(111, m) 0.96(3H, d, J=711z) 0.86(3H1, t, J=81Hz) Example oxoipntvl bnmino1-5-ethoxvecirhonylmethy1- 2.3-dlhvrn-3

H

3 C~ N S C O C H 3 Q x H 0.208 g (2.74 mmol) of carbonylmethyl-2, 3-dihydro-1 4(511)-one and 0.166 g (0.872 mmol) of (2S,3S)-2-' acetylthio-3-inethylpentanoic acid obtained in the Synthesis Example C-2 were treated in the same manner as -that of Example C-1. Thus, 0.200 g of the title compound was obtained as a colorless amorphous product (yield 232 1 1-NMR (400 MHz, CDCl 3 )8; 7.64(11, dd, J=8.2Hz) 7.43(111, dt, J=8.2Hz) 7.33(111, dd, J=8.2Hz) 7.25(114, dt, J=8.21z) 4.67(111, dt, J=11.711z) 4.25(2H1, q, J=711z) 4.15(111, d, J=1711z) 3.87(111, d, J=8Hz) 2.37(3H1, s) 2.00(111, m) 1.54(111, m) 0.85(3H. t, J=7Hz) Di phnnvl mpthyl r 4S r41y,7tx .12h1)01-7.- f (2S,,aS.L.

2-aeetvlthio-3-methvyl-l-oxolnntvl ]armnQIn-(-oxo-ll- ]2hpnyl-1 .2 3..fi,7,8.12b-ontabydrapyri dor2 1 -P1 r2,1.

benzazopjn.e-4-narhoxy1'~a HCH3

SCOCH

3

X/

233 In the same manner as that of Example C-i and starting. with 1.23 g (2.38 mmol of diphenylmethyl [4S- 4a~,7a 1l2b] P] -7-amino-6--oxo-1I--phenyl- 1,2,3,4,6,7,8,12b-octahydropyrido[2,l-a] 1211benzazepine-4-carboxylate obtained in the Synthesis Example C-9 and 0.52 g (2.74 mmol) of (2S,3S)-2acetylthio-3-methylpentanoic acid obtained in the Synthesis Example C-2, 1.22 g of the title corwpound was obtained as a colorless amorphous product (yield 74%).

1 11-NMvR (400 MHz, CDCl 3 6; 7.55-.6.91(17H, m) 6.67(IH, d, J=8Hz) 6.27(111, s) 5.65(111, quint, J=BHz) 5.47(111, d like) 5.41(111, d like) 4.05(11, d, J=7Hz) 3.42(lHi, dd, J=16, 6Hz) 2.61-2.40(2H1, m) 2.14(11, m) 2.00(111, m) 1.92-1 .58(51, m) 234 Fample Cl-7 njthyi r4S-r4c.7(RP1J2hp1 1-1 1-methylsuI -Pornyl amino -7-r r (29. 2 S)-2-avotyRl-th I o-b 03 -me h l -oxo s pn 3 .y I 1 ]1 Fminal-13-nn-1 .2.3.4..7.8,.12b-octahyd=4LyXJtor2,1-alr 21 hen zazepin e rboxyvljE31 H3 NHI NHS0 2 CH3 H3C

NHN

SCOCH

3

N

COOCH

3 140 mg (0.367 mmo) o' methyl [4S-[4a,7(R*) 12bp]l-ll-methyisulfonylamino-7-aino-6-oxo- 1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate obtained in the Synthesis Example C-14 and 77 mg (0.405 mmol) of (2S,3S)-2acetylthio-3-methylpentanoic acid were dissolved in ml of methylene chloride and 10 ml of ethanol. To this solution was added 118 mg (0.477 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) at room temperature. Then, the mixture thus obtained was stirred for 19 hours under a nitrogen atmosphere and concentrated under reduced pressure. 1 N hydrochloric acid was added to the residue, followed by extraction with dichioromethan. The organic phase -235 was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (2 98, ethanol :dichloromethane) to thereby give 198 mg (yield: 98%) of the title compound.

11--NMvR (400 MHz, CDCl 3 Me 4 Si)6; 0.920H1, t, J=811z) 1.04(0H, d, J=711z) 1.10-1.15(211, m) 1.60-2.12(6H, m) 2.39(311, m) 2.41(3H1, s) 2.81.(111. dd, J=17.2, 12.8Hz) 2.93(3H1, s) 3.09(3H, s) 5.26(111, m) 5.36(111, m) 5.68(111, m) 6.94-7.68(511, m) FPxmnpe fl-8 C R y iy(4 a rrm~s 3mty oD 2-tLhiop(-ntyllamrnro-oct,.hydlro-5-oxobhian..LU2-nJ.

B",piDP-3-carboxyv1( in ~jd 236 200 mg (0.48 mmol) of methyl [3R-[3a,6a(S*),9ap]]- 6-[[(2S,3S)-2-acetylthio-3-methyl-l-oxopentyl]amlio]octahydro-5-oxothiazol[3,2-a]azepine-3-carboxylate obtained in the Example C-1 N'as introduced into a flask and 8 ml of degassed ethanol was added thereto, followed by cooling to 0°C under a nitrogen atmosphere. 3.8 ml of a degassed 1 N aqueous solution of lithium hydroxide was added thereto, and the obtained mixture was stirred at room temperature for minutes. The reaction mixture thus obtained was acidified by adding 2.9 ml of a 2 N aqueous solution of hydrochloric acid at 0°C and then extracted with dichloromethane. After the organic phase was washed with a saturated aqueous sodium chloride, it was dried over anhydrous ma. .sium sulfate and concentrated.

The solid residue was recrystallized from hexanedichloromethane. Thus, 150 mg of the title compound was obtained as white crystals 1 H-NMR (400 MHz, CDC1 3 )6; 0.90(3H, t, J=7Hz) 1.00(3H, d, J=7Hz) 1.24(1H, m) 1.55-1.74(2H, m) 1.87(1H, d, J-8Hz) 1.90-2.10(6H, m) 3.20(1H, dd, J=6, 12Hz) 3.24(1H, d, J=7Hz) 3.36(1H, d, J=2, 12Hz) 4.62(1H, dd, J=6, 10Hz) 5.07(1H, t like, J=6Hz) 5.29(1H, dd, J=2, 6Hz) 7.69(1H, d, J=6Hz) 237 Examrpl e C-9 3R- r3. c(a g I1 r r( 2S 'IS) -3-Mothyvl-1 -oxo)-2thiopentvllamino1-2.2-dimetv1-S-oxo-otihvdrothiaza1r3,2-aflavepjne-3-carhoxvyIj acd HaG

NHOL

SH 0'

CH

3 130 mg 29 minol) of methyl 3R- 3a,6Bee(S*) 9aP]I]I 6-l[(2S,3S)-2-acetylthio-3-methyl-1-oxopentyllaminol-- 2 ,2-dimethyl-5--oxooctahydrothiazol[13 ,2-alazepine- 3-carboxylate obtained in the Example C-2 was introduced into a flask and 5.8 ml of degassed methanol was added thereto. To the obtained mixture was added a degassed 1 N aqueous solution of sodium hydroxide (2.3 ml) under a nitrogen atmosphere. The obtained mixture was stirred at 45 0 C for 8 hours. To the -eaction mixture thus obtained was added 1.8 ml of 2 N hydrochloric acid, and it was concentrated under reduced pressure to a certain extent. Water (50 ml) was added to the concentrate. The crystals thus precipitated were collected by filtration and air-dried for a while. Thus, 80 mg of the title -238compound was obtained (yield: 71%).

1 H-NMR (400 MHz, GDC1 3 )6 0.90(3H1, t, J=7Hz) 1.01(3H1, d, J=7Hz) 1.17-1.29(11, m) 1.53(3H4, s) 1.56(3H, s) 1.52-1.683(2H, m) l.86(lH, d, J=9Hz) 1.88-2.28(6H. m) 3.27(lH, dd, J=6, 9Hz) 4.58-4.66(lH, m) 4.79(1H, s) 5.15(lH, d, J=lOHz) 7.84(lH, d, J=6Hz) Example 1 -Carhoxyme-thyl -3-rrF(2S .3S) -3-methyl-i -oxo-2thiopentvllaminol-2.3.4.5-tetrahydro-lH-rllhenzazepin- Z2flJe *6 6 6 0 606* S S 0 05 00 66 60 0 6 a

S

CH

3 0

K

3

C

NH-

S 0 0 *000 *5 0 6 6 0 50@5 69

S

S

6 -v o~4~O~ To a mixed solution of 0.385 g (0.89 mmoi) of 3-[[(2S,3S)-2-acetylthio-3-methyl-l-oxopentyl]amino]-l-ethoxycarbonyl-lH-ri ]benzazepin-2-one obtained in the Example C-3 with 15 ml of degassed ethanol was added 4.4 ml of a degassed 1. N aqueous solution of sodium hydroxide at 0 0 C under a nitrogen atmosphere with stirring. The mixture thus obtained 239 was stirred at room temperature for 1 hour. The reaction mixture was cooled, acidified with 1 N hydrochloric acid and extracted with ethyl acetate.

The organi- phase was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent of the organic phase, 0.34 g of the title compound was obtained as a colorless amorphous product (quantitative).

IH-NMR (400 MHz, CDCl 3 6 7.39-7.14(5H, m) 4.7 and 4.71(total 1H, each d, J=l7Hz) 4.57-4.50(lH, m) 4.44 and 4.43(total 1H, each d, J=l7Hz) 3.34-3.10(2H, m) 2.77-2.58(211, m) 2.03-l.87(2H, m) 1.85 and l.84(total 1Hl, each d, J=9Hz) a l.64-l.50(lH, m) i.22-l.15(lH, m) 0.95(3H, d, J=7Hz) 0.86(3H, t, J=7Hz)

~SEC

N'T 240- -farboxvmethyl-3'-rFF(25.3S) -3-methyl-i -oxo-2thiopentyjLamixhoI-2.3,4-5-tetrabydro-l-r-llbenznpnin- 2-n CH3 o

H

3 C

NH

SHN

SCOOH

0.600 g (1.38 mir. of (S)-3-[[(2S,3S)-2-acetylthio-3-methyl-l-oxop~ntyl] amino] -1-ethoxycarbonylmethyl-2,3,4, 5-tetrrihydro-1H- Ill]benzazepin-2-one obtained in the Example C-4 was hydrolyzed in the same manner as that of Example C-10. Thus, 0.490 g of the title compound was obtained as a colorless amorphous product (yield 97%).

IH-NMR (400 MHz, CDCl 3 )6; 7.40(lH, brd, J=7Hz) 7.33-7.14(4H, m) 4.71(111, d, J=l7Hz) 4.54(111, dt, J=11, 7Hz) 4.44(111, d, J=l7Hz) 3.29(111, m) 3.17(111, dd, J=9, 7Hz) 2.74-2.59(2H1, m) 2.04-1.89(21, m) 1.84(111, d, J=9Hz) 1.55(11, m) 1.17(111, m) 0.95(31, d, J=7Hz) 0.86(3H1, t, J=7Hz) 241 Fxample C-12 (R'-3-rr(2.s-.,--3-methy -J-oxo-2-tbiopentlamino]-5-carhoxymethyl-2,3-dihvdro-l thi azepln-4(5H) -one

CH

3 o

H

3 C Hf J 0,187 g (0.43 mniol) of 1 3S)-2-acetylthio-.3-methyl-1-oxopentyllamino] methyl-2 ,3-dihydro-l 5-benzothiazepin-4(5H) -one obtained in the Example C-5 was treated in the same manner as that of Example C-10. Thus, 126 mg of the title compound was obtained as white crystals (yield IH-NMR (400 MHz, CT)C1 3 7.67(1H1, dd, J=8.lHz) 7.53(111, d, J=7Hz) 7.46(111, dt, J=8, 2Hz) 7.36(111, dt, J=8, 21Iz) 7.29(lH, dt, J=8, 1Hz) 4.91(lH, d, J=l8Hz) 4.72(1H, dt, J=11, 7Hz) 4.16(111, d, J=l8Hz) 3.83(lH, dd, J=1ll, 7Hz) 3.19(111, dd, J=9, 6Hz) 2.88(111, t, J=llHz) 1.94(lH, m) 1.85(lH, d, J=9Hz) 1.54(111, m) 1.20(1-, m) 242 0.95(3H, d, J=7Hz) 0.86(3H, t, J=7Hz) Exampl P C-1 3 r4-,-r4,Y,7NP*) 12hbI1 1-7-r R -2-AePtylthio-3methv1-l-eoxopentyl-lmino1--6-oxo-11-pheny1-1 .2.3.4.6-7 8.12h-oc-tahvdropyridor2 1-alr2lbenzazpnine-4carbnxvylica qrj(

H

3 C NH /e scocH 3 0" CO OH Into a mixed solution of 1.22 g (1.773 minol) of diphenylmethyl [4-4,aR)1bol7[(S3) 2-acetylthio-3-methyl-l-oxopentyl]amino] -6-oxo-liphenyl-l,2,3,4,6,7,8,12b-octahydropyrido[2,l-a] benzazepine-4--carboxylate obtained in the Example C-6 with 1.92 ml of anisole was dropped 11.01 mJ of trifluoromethanesulfonic acid at 0 0 C. After stirring the reaction mixture at O 0 C for 40 minutes. it was concentrated at a temperature not exceeding 40*C. The residual oil was subjected to azeotropic distillation with toluene twvice. The residual oil was purified by silica gel column chromatography (eluent; chloroform 243 hexane 4 :1 and chloroform :methanol 98.5 successively). Thus, the title compound was obtained as a colorless amorphous product (0.897 g, yield 97%), IH-NMR (400 M4Hz, CDCl 3 8; 7.52-7.31(8H, mn) 7.04(111, d, J=8Hz) 5.69(11, quint, J=6Hz) 5.48(111, m) 5.18(111, mn) 4.02(111, d, J=7Hz) 3.54(111, m) 2.86(111, dd, J=16, 12Hz) 2.51(111, in) 2.40(3H1, s) 2.28(111, in) 2.11(11, in) 2.04-1.56(5H1, in) 1.20(11, in) 1.02(3H1, d, J=7Hz) 0.91(3H1, t, J=7Hz) Fxmple C-14 [4-ra h 17. 21 S 3Mty 1 -oxo-2-thiopentvl laminol-6-oxo-llzpiiayL- 1 .,234.R.7-8,12h-octnhvdrnnvrjdar21-ar2Ibenyvpinp-4-carboxyv1in areid

OH

3 0 H3C \ZY ~NH

N

SH0

COOH

0.780 g (1.492 mmol) of [4S-[4a,7a(R*),l2bP]]-7oxo-ll-phenyl-l 12b-octahydropyrido- 244 [2,1-al [2ibenzazepine-4-carboxylic acid obtained in the Example C-13 was dissolved in 20 ml of degassed ethanol and 4.48 ml of a 1.0 N aqueous solution of lithium hydroxide was added thereto at 000. The mixed solution was stirred under a nitrogen atmosphere for minutes.

The reaction mixture was acidified by adding 20.0 ml of water and 2.0 N hydrochloric acid. The white solid thus precipitated was collected by filtration and washed with water. Thus, 0.622 g of the title compound was obtained (yield: 87%).

IH-NMR (400 MHz, CDCl1 3 )c3; 7.66(lH, d, J=7Hz) 7.53-7.32(7H, m) 7.08(lH, d, J=8Hz) 5.72(lH, qunit, J=6Hz) 5.52(111, m) 5.25(111, m) 3.60(lH, dd, J=17.611z) 3.23(111, dd, J=9, 7Hz) 2.93(lH, dd, J=17, 13Hz) 2.55(111, m) 2.34(111, m) 2.00(2H, m) 1.92(111, d, J=8Hz) 1.98-1.61(41, m) 1.25(111, m) 1.0303H, d, J=7Hz) 0.93(3H, t, J=7Hz) 245 Example [4S-r4tN.7a(R*) 12hR 11--11-Metb ii1*fnnv1nminO-7- Lr(2S.3S)-3-methv1-1-oxo-2-thiopentv laminol-g-oxo- L 17 8 2b-octahvdropvridor2.1-a121 benzaepine-4-earboxv1c ac idi

CH~

0

NHSO

2

CH

3 CH3 0 H3N S H 0

I

COOH

198 mg (0.158 mmol) of methyl [4S- [4c,7c(R*),l2bo]]-11-methylsulfonylamino-7- [[(2S,3S)-2-acetylthio-3-methyl-l-oxopentyl amino]- 6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,i-a][2]benzazepine-4-carboxylate obtained in the above Example C-7 was introduced into a flask, followed by sufficient purging with nitrogen. Next, 5 ml of degassed ethanol was added thereto and the flask was cooled in an ice bath. Then, 3.6 ml of a degassed 1 N aqueous solution of sodium hydroxide was added thereto. After removing the flask from the ice bath, it was slowly warmed to room temperature and the contents thereof were stirred for 1 hour and minutes. 10 ml of a 1 N aqueous solution of 246 hydrochloric acid was added to the reaction system, and then it was extracted with dichioromethane. The organic phase was dried over anhydrous magnesium sulfate. The organic phase dried was concentrated under reduced pressure and the residue was crystallized from dichloromethane. Thus, 84 mg (yield: 47%) of the tilkQle compound was obtained.

1 H-NMR (400 MHz, CDCl 3 /cD 3 OD, Me 4 Si)8; 0.93(3H, t, J=8Hz) 1.04(3H, d, J=7Hz) 2.90(111, m) 2.91(3H, s) 3.23(111, d, J=8Hz) 3.56(lHi. dd, J=17.3, 6.1Hz) 5.23(111, m) 5.48(1H, m) 5.71(lH, m) 7.01-7.16(3H1, m) Preparat-Ion of methyl r 4S- f Au J-2b 01 1 1-mPthvl qifl f onyi ami S-cP n-x-1 i bvropyri do[ .1 r2 qnz~y PjnP-4-r.,rhn~cylat(-

NHSO

2

CH

3 0

COOCH

3 247 Methyl [4S-[4a,Ta(R*),12bp]]-ll-amino-7- (1,3-dioxo-l,3-dihydroisoindol-2-yl)-6-oxo- 1,2,3,4,6,7,8,12b-octahydropyrido[2,l-a][2]benzazepine-4-carboxylate (1.50 g, 3.5 mmol) obtained in the above Synthesis Example D-3 was dissolved in methylene chloride (50 ml). Next, to this solution were added pyridine (3 ml) and methanesulfonyl chloride (440 mg, 3.8 mmol) under cooling with ice.

The obtained mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. Further, a 1 N aqueous solution of hydrochloric acid (100 ml) was added to the solution stirred under cooling with ice, followed by extraction with methylene chloride.

The methylene chloride phase was dried over (MgS0 4 was used) and then concentrated under reduced pressure.

Next, the residue was purified by silica gel column chromatography (3 1 methylene chloride/ethyl acetate) to thereby give the title compound (1.14 g, 64%).

1 H-NMR (400 MHz, CDC13, Me 4 Si)6; 1.60-2.46(6H, 3.00(3H, 3.23(3H, s) 3.42(11 dd, J=17.1, 4.46(1H, dd, J=17.1, 11.9Hz), 5.21(1H, m), 5.44(1H, 6.04(1H, dd, J=11.9, 6.65(1H, 7.05(1H, dd, J=8.2, 2.2Hz), 248 7.74-7.90(4H, m) Example Dl-2 MethYl r 4S- 14a 71Y j 2jb 0 11 1 1 -ejhyl~si If nyl .2.3.4rR.7.8,12b-oetaphwlropvrijdof2rl,-a1F2lhen7,zZepine-4-cFarhoxvlate

NHSO

2

CH

3

/N'

0 2

SS

COOCH

3 Methyl 4S- (4a~,7a ,12bp3]-l1-methylsulf onylamino-7- 3-dioxo- 3-dihydroisoindol-2-yl) -6-oxol,2,3,4,6,7,8,12b-octahydropyrido[2,l-a][2]benzazepine-4-carboxylate (1.14 g, 2.23 mmol) obtained in the above Example D-1 was dissolved in methanol (49 ml). Next, to this solution was added hydrazine hydrate (123 mg, 2.46 mmol). Then, the obtained mixture was stirred at room temperature under an argon atmosphere for 66 hours. The solution stirred was concentrated under reduced pressure. Further, methylene chloride was added to the concentrate and the insoluble matters were removed out by filtration.

249 Then, ethyl acetate was added to the filtrate. Thus, the title compound was obtained as white crystals (0.50 g, 59%).

IH-NMR (400 MHz, CD 3 0D/CDC] 3 Me 4 Si)8; 1.60-2.45(6H1, mn), 2.87(111, dd, J=17.6 12.7Hz), 2.94(311, 3.13(31, s), 3.40(111, dd, J=17.6, 5.43(111, in), 7.02(111, dd, J=8.2, 2.2Hz), 7.11(lH, d, J=8.2Hz), 7.16(111, d, J=2.4Hz) Examnple D-3 Methy1l f447a(1Th.12hP11-ll-methvlRulfonnyL.

Fmn-7-rf L)-2-a etyl thio-3--phenvl -1-oxopropyvl1amino-8-oxo-1,2.3,4.6,7.8.12b-octahvrdropyridor2.l-a1r2lhenzavzepi-- aroxyat

NHSO

2

CH

3 0 I ~cNH S R CO OCH3 Methyl [4S-[4a,7a(R*) ,12bo] ]-11-iethylsulfonylainino-7-amino-6-oxo-1 12b-octahydropyridol2lbenzazepine-4-carboxylate (310 ing, 0.81 250 mmol) obtained in the above Example D-2 and acetylthio-3-phenyljropionic acid (183 mg, 0.81 mmol) were dissolved in methylene chloride (16 ml) and tetrahydrofuran (32 ml). Next, to this solution was added N-ethox.carbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ, 221 mg, 0.89 mmol). Then, the mixture thus obtained was stirred under a nitrogen atmosphere for hours and the solution stirred was concentrated under reduced pressure. Further, a 1 N aqueous solution of hydrochloric acid was added to the concentrate, followed by extraction with methylene chloride. Next, after the organic phase was washed with a 1 N aqueous solution of hydrochloric acid, water and a saturated aqueous sodium chloride, it was dried over (MgS04 was used) and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (1 1 hexane/ethyl acetate) to thereby give the title compound (240 mg, 1 H-NMR (400 MHz, CDC1 3 Me 4 Si)8; 1.66-2.40(6H, 2.36(3H, s), 2.72(1H, dd, J=17.4, 12.7Hz) 2.93(3H, 3.06(1H, dd, J=14.1, 7.9Hz), 3.10(3H, 3.35(1H, dd, J=14.1, 7.1Hz), 3.46(1H, 4.36(1H, t, J=7.4Hz), 5.23(1H, m), 251 5.33(111, in), 5.58(1H, in), 6.93-7.56(10H1,m MyJLv 4SL4a. 7 (B1) 1 9h R 1- 1 1-methyvqii If ony amino-7-(fr(S)-2-actvl thio-3-(4-methoxvphenvl -OX0.

)r-opv1Amjn1-R-nyrn-1 -2.3,4,.7,8.12b-ontnhvdropvridxxOr2.1-alr2]beinzazpine--4-cnirhoxyate,

NHSO

2

CH

3 NH S R C~aOSAC

COOCH

3 Methyl [4S-[4a,7a(R*) ,12bp] ]-ll-methylsulfonylamino-7-amino-6-oxo-1 6 8 ,12b-octahydropyrido- [2,1-a][2lbenzazepine-4-carboxylate (188 mng, 0.49 mmol) obtained in the above Example D-2 and 2(S)acetylthio-3- (4-methoxyphenyl)-propionic acid (125 mng, 0.49 mmol) were dissolved in methylene chloride ml), tetrahYdrofuran (20 ml) and ethanol (40 ml).

Next, to this solution was added 405 mg (1.64 inmol) of EEDQ at room temperature. Then, the mixture thus obtained was stirred unider a nitrogen atmosphere for hours and the solution stirred was concentrated under reduced pressure. Further, a 1 N aqueous solution of 252 hydrochloric acid was added -to the concentrate, followed by extraction with methylene chloride. Next, the organic phase was washed with a 1 N aqueous solution of hydrochloric acid, water and a saturated aqueous sodium chloride, and then it was dried over (MgSO 4 was used) and concentrated under reduced pressur., The obtained residue was purified by silica gel chromatography (1 :1 hexane/ethyl acetate) to thereby give the title compound (133 mg, 44%).

IH-NMR (400 MHz, CDCl 3 Me 4 Si)8; 1.66-2.05(6H1, in), 2.37(3H1, s), 2.72(lH, dd, J=17.3, 12.7Hz), 2.94(31, s), 3.00(1H, dd, J=14.3, 7.7Hz), 3.11(3H1, s), 3.28(111, dd, J=14.3, 7.7Hz), 3.48(111, dd, J=17.3, 5.7Hz), 3.79(3H1, s), 4.30(1H, t, J=7.7Hz), 5.23(111, brd), 5.33(lH, brd), 5.57(lH, quint, J=6.2Hz), 6.83(2H1, d, J=8.7Hz), 6.97(111, d, J=8.211z), 7.01lH, dd, J=8.2, 2.0Hz), 7.24(111, s), 253 ExamPL I 4t 4 1 'I -hMethvI cilfonvlaqmino- 7-f F(S)-2-mercap2to-3-Pbenvl-l-oxopropyl )pminol-fg-oxo-- 1.2,3.4.6.7.8.1,2b-oc'.tahydropyridoi2.1-alf2lenzazepine-4-carboxvlic acid

NHSO

2

CH

3 7 0 N H S SH 14, N

S

COOH

Methyl [4S- 4a, 7a(R*) ,12b P I -11-methylsulfonylamino-7-[[(S)-2-acetylthio--3-phenyl-l-oxopropyl]amino]-6-oxo-l,2,3,4,6,7,8,12b-octahydropyrido- [2,l-a][2]benzazepine-4-cerboxyiate (228 mg, 0.39 mmol) obtained in the above Example D-3 was introduced into a flask, followed by sufficient purging with nitrogen. Next, degassed tetrahydrofuran (1 ml) and methanol (6.2 ml) were added in the flask, and the flask was cooled in an ice bath. A degassed 1 N lithium hydroxide solution (3.3 ml) was added to the 4 robtained solution. After removing the flask from the ii ice bath, the flask was slowly warmed to room l" temperature and the obtained mixture was stirred for a~f4~O41P~~' IP- 254 Mr hours. Next, the solution stirred was concentrated under reduced pressure and the concentrate was extracted with methylene chloride. Then, the aqueous phase was separated and the pH thereof was adjusted to 1 with a 1 N aqueous solution of hydrochloric acid.

The concentrate was extracted with methylene chloride.

Next, the organic phase was dried over (MgSO 4 was used) and then concentrated under reduced pressure. To the concentrate, diisopropyl ether was added, followed by trituration. Thus, the title compound (110 mg, 53%) was obtained.

S

1 H-NMR (400 MHz, CDC1 3 /CD30D, Me 4 Si)6 1.70-2.50(6H, 2.85(1H, dd, J=17.4, 1I .7Hz), 2.90(3H, 3.12(1H, dd, J=13.8, 3.29(1H, dd, J=13.8, 6.6Hz), 3.52(1H, m), 3.67(1H, 5.19(11 5.47(1H, m), 5.65(1H, 7.03-7.80(10H, m) *o a 0**0oo 0 0* 0 *e 255 Example D-ES fA4a J2pl1lmtbl su Ifonylam in7 i1JL) 2ziersiapto-3-- (4-methoxyphennl -oxopropyl Iamino-6-oxo-l .2.3.4-A.7.8-12b-octabydropvrido- [2.1-al f2lbenzazepine-4-carhoxvlin acid

NHSO

2

CH

3 0 7 NH S R

N

S 0 S

COOH

Methyl 4S- [4a, 7a ,12b ]-ll-methylsulfonylamino-7-[ (S)-2-acetylthio-3-(4-methoxyphenyl)-l-oxopropy. ]amino] -6-oxo-1,2,3,4,6,7,8, 12b-octahydropyrido- [2]benzazepine-4-carboxylate (133 mg, 0.22 mmol) obtained in the above Example D-4 was introduced into a flask, followed by sufficient purging with nitrogen. Next, degassed ethanol (20 ml) was added into the flask and then a degassed 1 N aqueous solution of sodium hydroxide (5 ml) was further added into the flask. The obtained mixture was stirred at room temperature for 3 hours. Next, a 1 N aqueous solution of hydrocbloric acid (10 ml) was added to the solution stirred, followed by concentration under 256 reduced pressure. To the concentrate were added methylene chloride and water, followed by extraction with methylene chloride. Further, the organic phase separated was dried over (MgSO 4 was used) and concentrated under reduced pressure to thereby give the title compound (80 mg, 1 H-NMR (400 MHz, CDC1 3

/CD

3 0D, Me 4 1.74-1.86(3H, in), 1.92-2.07(11, in), 2.37-2.49(2H1, in), 2.83(3H1, 2.83(11, in), 3.ll(1H, dd, J=14.0, 6.9Hz), 3.23(111, dd, J=13.8, 6.5Hz), 3.55-3.66(2H, in), 3.80(3H1, 5.26(lH, brd), 5.43(iH, brd), 5.62(lH, quint, J=6.0Hz), 6.57(1H, d, J=6.lHz), 6.86(21, d, J=8.7Hz), 6.96(111, d, J=6.iHz), 7.13-7.19(3H1, mn), 7.54(lH, s), 257 Fxarnplp F-1 D! ph enylmethyl 12PI17,mI xphenvl-l .2-3.4.R.7-8.2-otahvdropvriof2l-azl 21benvazenine-4-carhn V1wqte

H

2 N S R dihydro-1 ,3-dioxo--2i-isoindol-2-yl) -6-oxo-1-il phenyl-1,2,3,4,6,7,8,12b-octahydropyrido[2,l-a][2]benzazepine-4-carboxylate (2.03 g, 3.14 mmol) obtained in the Synthesis Exampl.e E-6 was dissolved in a mixed solution of methanol (40 nil) with tetrahydrofuran (THF, 20 mil), followed by addition thereto of hydrazine monohydrate (0.34 mil, 7.10 mmol). The mixture thus obtained was heated under reflux for 3 hours. The reaction mixture was concentrated and the residue was dissolved in CH 2 C1 2 and the insoluble 258 matters were removed out by filtration. The filtrate was concentrated and the sticky residue was purified by silica gel column chromatography (eluent; CHC1 3 MeOH aqueous ammonia (NH 4 OH) 98 :2 Thus, the title compound was obtained as a colorless amorphous product (1.20 g, yield 74%).

IH-NMR (400 MHz, CDCl 3 )6; 7.40(4H, in), 7.31(111, tt, J=7, 2Hz), 7.24(111, d, J'=2Hz), 7.15(lH, dd, J1=8, 2Hz), 6.99(2H1, dd, J=S, 4Hz), 6.87(2H1, dd, J1=8, 2Hz), 6.63(111, d, J=811z), 6.20(111, s), 5.42-5.33(2H, in), 4.53(111, dd, J=10, 6Hz), 3.17(111, dd, J1=16, 6Hz), 2.58(111, dd, J1=16, 10Hz), 2.40(21, in), 1.94(lH, in), 1.85-1.58(3H1, mn) 259 Example F-2 Dipheny1methyl r40-~f7tR)1hl--(')2 ac'etltio-3-phenlpropionlm-inol-B-oxo-11phenyl-1 .2.3.4,6.7.8,12-otaiivclropvriclor2.l-a]r21benzazepine-4-nnarhnxy1ntP SAc Ox/N coo Diphenylmethyl [4S-[4a,7ThIR*) ,l2bpMl-7-ainino- 6-oxo-1l-phenyl-1 ,2,3,4,6 ,7,8 ,1lzb-octahydropyrido- [2,l-a][2]benzazepine-4--carboxylate (0.59 g, 1.14 mmol) obtained in the Example E-1 and (S)-2-acetylthio-3-phenylpropionic acid (0.27 g, 1.20 mmol) were dissolved in CH 2 01 2 (30 ml), and EEDQ (0.37 g, 1-,48 mmol) was added thereto. The mixed solution stirred at room temperature overnight. The reaction mixture was partitioned into CH 2 Cl 2 and wi.er, and the

CH

2

CI

2 phase was washed with water,a saturated aqueous 260 solution of' sodium hydrogencarbonate and a saturated aqueous sodium chloride. The CH 2 C1 2 phase was dried over magnesium sulfate and then concentrated. Thus, the title compound was obtained as a colorless amorphous product (0.89 g, yield 109%). This product was not purified but used in the subsequent reaction as such.

I H-NMR (400 MHz, CDC1 3 )8; 7.52-7.41(4H, in), 7.40-7.12(15H, in), 7.04(2H1, dd, J=8.4Hz), 6.93(2H1, dcl, J=8, 2Hz), 6.67(lH, d, J=8Hz), 6.26(111, s), 5.59(111, quint, J=6Hz), 5.44(11, in), 3.41(111, dcl, J=16, 6Hz), 3.36(111, dcl, J=14, 7Hz), 3.07(lH, dd, J=14, 7Hz), 2.54(111, dcl, J=16, 10Hz), 2.47(2H, in), 2.40(3H1, 2.00(111, in), 1.87-1.70(3H1, in) 261 Example F-3 D I ph enviuethyl r41-4.r(*).2BI17f()2- nv :thi 0-3-Umt vnev~riovlmn)IBoo I-L-phenvl--1 2,3.4-L-7-31Zb-n.da9hvdrnvrJ Ido2_I 1L [21benzazepinp-4-Caroxi.'ite 0

CH

3 0 SAc N 7 In the same manner as that of Example E-2 and starting with of diphenylmethyl 4S- [4a, 7a 12b P] 7-amino--6-oxo-1l-phenyl-1, 2,3, 4,6,7, 8, l2b-octahydropyridoli2,1-a] [2]benzazepine-4-carboxylate (0.59 g, 1.14 mmol) obtained in the Example E-1 and acetylthio-3-(4.-methoxyphenyl)propionic acid (0.31 g, 1.20 mmol), the title compound was obtained as a colorless amorphous product (0.81 g, yield 95%6).

1 1--NMR (400 MHz, CDCl 3 8; 7.42-7.34(4H1, in), 7.31(111, in), 7.24-7,04(10H1, in), 262 6.96(2H, dd, J=8, 4Hz), 6.86(2H1, dd, J=8, 2Hz), 6.77(2H1, d, J=8Hz), 6.59(1H, d, J=8Hz), 6.19(111, 5.51(11, quint, J=6Hz), 5.37(1H, in), 5.31(11, d, J=611z), 4.31(111, t, J=7Hz), 3.72(3H, 3.34(111, dd, J=16, 6Hz), 3.20(111, dd, J=14, 7Hz), 2.94(111, dd, J=14, 7Hz), 2.47(111, dd, J=16, 10Hz), 2.40(2H1, m), 2.33(3H, 1.92(111, mn), 1.81-1.62(3H, mn) .xamni 7-4 nropi onvi mi no] -g-oxo-ll1-pnvi -1 2.3.4. .7.8.1 2hoctaby rop ndf 1 112bel!Zpni e-4-cIarbo yllC anid SAC 0' N

COOH

Into a mixed solution off diphenylinethyl [.4S- [4a,7adR*) ,12bpl]-7-[(S)-2-acetylthio-3-phenlylpropionylainino] -6-oxo-11-pheflyl-1 12boctahydropyrido[2,1-a] [2]benzazepine-4-carboxylate (0.89 g, about 1.14 minol) obtained in the Example E-2 with anisole (1.24 ml) was dropped trifluoromethane- 263 sulfonic acid (TFA, 7.08 ml) at 0°C. After stirring the reaction mixture at 0C for 20 minutes, it was concentrated at a temperature not exceeding 40 0 C. The residual oil was subjected to azeotropic distillation with benzene twice. The residual oil was purified by silica gel column chromatography (eluent; CH 2 C12 Hex 1 2 and CHZCl 2 MeOH 99 1, successively).

Thus, the title compound was obtained as a colorless amorphous product (0.64 g, yield 100% 2 steps from Example E-l).

H-NMR (400 MHz, CDC1 3 )6; 7.38-7.14(12H, 7.00(1H, d, J=8Hz), 5.57(1H, quint, J=6Hz), 5.41(lH, m), 5.14(1H, d, J=6Hz), 4.29(1H, t, J=7Hz), 3.51(1H, dd, J=16, 6Hz), 3.28(1H, dd, J=14, 7Hz), 2.99(1H, dd, J=14, 7Hz), 2.73(1H, dd, J=16, 10Hz), 2.46(111, m), 2.29(3H, 2.26(1H, 2.00-l.60(4H, m) 264 pheny1)prnnjnn n minn1 -R-nxn-1 1 -phenv.

1.2.3,4-R.7 .f.12h-octabdroprido2--ar2beflz.

apnine-4-carboxvl in acjO~ 0 7 NH

N

XY SAc 0

COOH

In the same manner as that of Example E-4 and starting with diphenylmethy. [4S- [4a, 7a ,12b 0 [(S)-2-acetylthiio-3-(4-methoxyphenyl)propioflylamifl> 6-oxo-11--phenyl-1 ,2,3 12b-octahydropyrido- [2]benzazepine-4-carboxylate (0.81 g, 1.08 mmcl) obtained in the Example E-3, the title compound was obtained as a colorless amori~hous product (0.52 g, yield 81%).

1 H-NMR (400 MHz, CDCl 3 8; 7.45-7.32(SH, in), 7.29-7.24(3H, in), 7.08(2H, d, J=8z), 6.96(1H, d, J=8Hz), 6.76(2H1, d, J=811z), 5.53(111, quint, J=611z), 5.38(11, brd), 5.09(111, brd, J=SHz), 265 4. 22 (1H, 3. 47 (1H, 2. 92 (1H, 2. 71(1H1, 2. 28 OH31 Fxample F,-9 rA-(-FAtN 7Ny(P'* t, J=7Hz), 3.72(3H1, s), dd, J=16, 6Hz), 3.19(111, dd, J=14, 7Hz), dd, J=14, 7Hz), dd, J=16, 10Hz), 2.43(11, in), 2.22(111, in), 1.97-1..59(41, in), 129hRl 1-7-F (S-2-Me.rr'nt-2-nhenvlpropi onyi mi no] -g-oxo-ll1-phenvi -1 L1 2bocavrTvio2larlbnaeie4nroyi- noid [4S-[4a, 7c(R),12bo 1-7- -2-acetylthio- 3 phenylpropionylamino] -6-oxo-li-phenyl- 1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]beflzazepine-4-carboxylic acid (0.55 g, 1.00 mmol) obtained in the Example E-4 was dissolved in degassed T11F ml) and methanol (10 ml). To this solution was added a 1.0 N aqueous solution of lithium hydroxide (4.00 ml). The mixture was stirred at room temperature under a nitrogen atmosphere for 45 minutes. A 2.0 N 266 aqueous solution of hydrochloric acid (3.00 ml) was dropped into the mixture, and then water was added thereto The obtained mixture was vigorously stirred.

The white crystals thus precipitated were collected by filtration, washed with water and dried under reduced pressure. Thus, the title compound was obtained (0.45 g, yield 87%).

1 H-NMR (400 MHz, CDCl 3 7.75(l1, d, .Th7Hz), 7.66(2H1, d, J=8Hz), 7.59(2H1, t, J=8Hz), 7.55-7.37(7H, in), 7.22(111, d, .1=8Hz), 5.81.(lH, quint, .1=6Hz), 5.65(11, mn), 5.36(11, d, .1=6Hz), 3.82-3.68(2H, in), 3.45(111, dd, J=14, 7Hz), 3.30(111, dd, .1=14, 7Hz), 2.99(111, dd, .1=17, 12Hz), 2.70(11, in), 267 Rxa~mple F-7 f4a. 7a(R*) .12bo 11-7- r(R) -9-M~rnnt-- (4-nethnxvyz mhenyl )ipropi onylami nol oxo-1 I pnhenv1 1,2.3.4.6.7.R.12h- octahvdropvridL21-aij2lbLenz az~PinP-4-eAr-bocv11 anid 0

NH

COOH

In the same manner as that of Example E-6 and starting with [4-4,aR)1bll7[S--ctl thio-3- (4-methoxyphenyl)propionylamino] -6-oxo-1-il phenyl-l,2, 3,4,6, 7, 8,12b-octahydropyridol2, -a112]benzazepine-4-carboxylie acid (0.42 g, 0.708 mmol) obtained in the Example E-5, the title compound was obtained as white crystals (0.37 g, yield 1 11-NMVR (400 MHz, CDCl 3 )8; 7.36(2H1, t, J=8Hz), 7.28(2H, in), 6.78(2H1, d, J=8Hz), 5.57(111, quint, J=6FHz), 5.42(lH, mn), 5.13(11, d like, J=6H-z), 268 3.73(31, 3.50(2H, in), 3.14(111, dd, J=14, 7Hz), 3.03(11, dd, J=14, 7Hz), 2.76(111, dcl, J=17, 12Hz), 2.47(11, in), 2.28(111, in), 1.97(11, d, J=9Hz), 2.00-.1.63(4H, mn) Example F-8 D I 2bheny meby FAS r4a 7a j 2bh01 f(SIR a2zeyl tbio-3-rnethvlbhutvrylaminol-6-oxo-11-phpnyl,- 1 .23.4A7.812b-octabydropyridof2.1-fl1en7,azea2inp-4-narhnxyl ate

CH

3 0 CI% NH 0 SAc /0 In the same manner as that of Example E-2 and starting with diphenylmethyl [4S-[4a,7a(R*) ,l2bP]]-7amino-6-oxo-11-pheiyl-1, 2, 3, 4,6 12b-octahydropyridoll2,1-a] 12]benzazepine-4-carboxylate (0.4 g, 0.774 inmol) obtained in the Example E-1 and (S)-2-acetylthio-3-methylbutanoic acid (0.136 g, 0.774 269 mmol), the title compound was obtained as a colorless amorphous product (0.36 g, yield 69%).

IH-NMR (400 MHz, CDCl 3 )8; 7.54-6.92(17H1, in), 6.68(lH, d, J=8-z), 6.28(lH, 5.65(111, quint, J=6Hz), 5.49-5.40(2H1, in), 4.00(111, d, J=7Hz), 3.42(lH, dd, J=16, 6Hz), 2.60-2.37(7H, in), 2.02(111, in), 1.88-1.72(3H, in), 1.08(3H1, d, J=7Hz), 1.04(3H1, d, J=711z) Example F-9 CH3, 0 CH, T N H 0'

COOH

In the same manner as that of Exanrle E-4 and starting with diphenylinethyl ,l2bP] [(S)-2-acetylthio--3-methylbutyrylainflO--oxo11phienyl-,2,3,4,6,7,8,12b-octahydropyrido[2,1-l 2

I

benzazepine-4-carboxylate (0.36 g, 0.533 inmol) 270 obtained in the Example E-8, the title compound was obta~ined as a colorless amorphous product (0.157 g, yield 58%).

H-NMR (400 MHz, CDCl 3 )8; 7.55-7.28(8H, in), 7.03(111, brs), 5.69(11, quint, J=6Hz), 5.46(111, in), 3.97(111, d, J=711z), 3.51(111, in), 2.96-2.82(2H, in), 2.56-2.20(7H, in), 2.00-1.60(4H1, in), 1.05(3H1, d, J=711z), hvdrnvrildnr2.j--ajr21enzsa~eplne-4-carboxylic aCid

CH

3 0

CH

3

INH

COOH

4 S- 4a 7 a(R) ,12 b 1]-7 ac e ty 1th o 3-mnethylbutyrylamino I-6-oxo-li-phenyl- 1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid (0.147 g, 0.289 inmol) 271 obtained in the Example E-9 was dissolved in degassed ethanol (5 ml). To this solution was added a 1.0 N aqueous solution of lithium hydroxide (0.9 ml). The mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The reaction mixture was acidified by adding a 1.0 N aqueous solution of hydrochloric acid under cooling with ice and stirring, followed by extraction with dichloromethane. The organic phase was washed with a saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent of the organic phase, the obtained residue was crystallized from dichloromethane-hexane. Further, the mother liquor was evaporated to dryness and then treated with isopropyl ether-hexane. Thus, 0.103 g (yield 76%) o.

the title compound was obtained.

IH-NMR (400 MHz, CDC1 3 )6; 7.68(1H, d, J=7Hz), 7.51(2H, d, J=8Hz), 7.44(2H, d, J=8Hz), 7.39-7.33(3H, m), 7.08(1H, d, J=8Hz), 5.73(1H, quint, J=6Hz), 5.53(1H, 5.26(1H, m), 3.61(1H, dd, J=17, 6Hz), 3.19(1H, dd, J=9, 7Hz), 2.93(1H, dd, J=17, 13Hz), 2.60-2.22(3H, m), 2.08-1.70(41 1.05(6H, d, J=7Hz) 272

LI

Example FP-11 Dihenylmthvl [4.S-f4.r R lb~l7U83)2 ac.-ty1 thi o-3-methyv3l 1ryl gmi nol -R--ox-1 enyl azepine-4-o.arhoxyla-te

CH

3 0 SH s NH-, 'f

SCOCH

3 0 In the same manner as that of Example E-2 and starting with diphenylmethyl 14S-[4a,7a(R*), l2bp]]- 7-ainino-6-oxo-l1-phenyl-1,2,3,4, 6,7,8, 12b-octahydropyridolj2,1-a] [2]benzazepine-4-carboxylate (1.23 g, 2.38 minol) obtained in the Example E-1 and (2S,3S)-2-acetylt"hio-3-methylvaleric acid (0.52 g, 2.74 mniol), the title compound was obtained as a colorless amorphous product (1.22 g, yield 74%).

IH11-NMR (400 MHz, CDC1 3 )6; 7.55-6.91(17H, in), 6.67(111, d, J=811z), 273 6.27(111, 5.65(11, quint, J=8Hz), 5.47(111, di like), 5.41(111, di like), 4.05(111, d, J=711z), 3.42(111, dci, J=16, 6Hz), 2.61-2.40(2H1, in), 2.45(3H1, s), 2.14(11, in), 2.00(11, in), 1.92-1.58(5H, in), l.24(lH, in), 1.05(31, ci, J=7Hz), 0.94(< H, t, J=7Hz) Ex2ample P-19 .Ls3-i4a-.7.---R)L2b4ijj -7-f 3S I-2-Acet- iao.- 1,2.39.4.9.7.,?L12h-oc-tahydroprid2. 1 I r F2nz.

azepine-4-Ciarhoxylic acid Lils 0 S NH- s R

SCOCH

3 0 fN

S

HOO C In the same manner as that of Example E-4 and starting with diphenylmethyl 4S- [4a, 7a(R*) ,19b [(2S ,3S) -2-acetylthio-3-methylvalerylamino II-6-oxo- 11-phenyl-1,2,3,4,6,7,8,12b-octahydropyridoll2,1-a112]benzazepine-4-carboxylate (1.22 g, 1.773 mmol) obtained in the Example E-11, 'the title compound was 274 obtained as a colorless amorphous product (0.897 g, yield 97%).

I H-NMVR (400 [M/Hz, CDCl 3 )6; 7.52-7.31(8H1, mn), 7.04(111, d, J=811z), 5.69(111, quint, J=6Hz), 5.48(1I), 5.18(11, in), 2.86(1H, dd, J=16, 12Hz), 2.51(11, in), 2.40(3H1, 2.28(111, in), 2.11(11, in), 2.04-1.56(5H, 1.20(11, in), 1.02(31, d, J=71z), 0.91(3H1, t, J=711z) TExFarn1e F-12 val Pryl a inol -63-oxo-1 1-phpuyl -1 8,12b-otaib~dropvri dorf2 .±-ajl2Jlenznzeni ne-4-carboxxL_L.c

CH

3 0

CH

3 S

NH

SH 0N

HOOC

3-methylvalerylanino]-6-oxo-11-phnyl- 1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid (0.780 g, 1.429 minol) 275 obtained in the Example E-12 was dissolved in degassed ethanol (20 ml). To this solution was added a 1.0 N aqueous solution of' lithium hydroxide (4.48 ml) at 0 0 C. The mixed solution thus obtained was stirred under a nitrogen atmosphere for 40 minutes.

The mixed solution was acidified by adding water (20.0 ml) and a 2.0 N aqueous hydrochloric acid. The white solid thus precipitated was collected by filtration (washed with 1120) to thereby give the title compound (0.622 g, yield 87%).

1 HI-NNIR (400 MHz, CDC1 3 7.66(lH, d, J=7Hz), 7.53-7.32(711, in), 7.08(1W. d, J=8Hz), 5.72(111, quint, J=6H-z), 5.52(111, in), 5.25(lH, in), 3.60(lH, dd, J=17, 6Hz), 3.23(111, dd. J=9, 7H-z), 2.93(lH, dd, J=17, 13H-z), 2.55(1-1 mn) 2.34(lH, in), 2.00(211, m), 1.92(111, d, J=8H-z) 1 .98 61(411, in), *'1.25(lH, mn). 1.03(311, d, J=7H-z), 0.93(3WI t, J=7Hz) 6 6 T6 0 276 Examplo F-1 Methyl 3rs-F3aE(S* qaoi rS)-1 -oxo-2aceytho-3-(4-fhlorophenyI )-njyinl 1Tnjnn1-nctahydro-5-oxothiazolr3.2-alaepinle-3-carhoxylate.

0 NH S

R

SAc N S CH3000 To methyl [3-3,aS)9p mn-ca hydro-5-oxothiazoli3,2-ailazePifle-3-Carboxylate (681 mg, 2.79 mmol) was added a solution of 2-acetylthio- 3-(4-fluorophenyl)propionic acid (743 mg, 3.07 mmol) obtained in the Synthesis Example F-3 in methylene chloride (28 ml). The obtained mixture was cooled to 000 under cooling with ice. After adding N-ethoxycar-boniyl-2-cthoxr-1,2-diiydroquilife (EEDQ, 793 Rig, 3.21 mmol) thereto, the ice bath was taken away. The obtained mixture was stirred under a nitrogen atmosphere at room temperature for 3 hours. The obtained mixture was washed with a 0.5 N aqueous solution of hydrochloric acid (15 ml x water ml), a saturated aqueous solution of sodium hydrogencarbonate (15 ml x 2) and a saturated aqueous sodium 277 chloride (15 ml), afied over magnesium sulfate and filtered. Next, the filtrate was conc-atrated under re'luced pressure to thereby give a crude product mixture of epimers (1.39 This crude product mixture was separated and purified by silica gel column chromatography (hexane :ethyl acetate =3 As a result, the title compound (500 mg, 38%) was obtained as a first epimer from the first fraction.

H-NMR (400 MHz, GDCl 3 6; 1.55-2.02(6H, in), 2.34(3H, s), 2.97(1-, dd, J=7.2, 14.2Hz), 3.18(lH, dd, J=6.6, 11.6Hz), 3.27(1W, dd, J=2.4, 11.6Hz), 3.27(lHi, dd, J=7.6, 14.2Hz), 3.78(3H1, s), 4.24(111, t, J=7.4Hz), 4.44(111, dd, J=6.0, 11.2Hz), 4.99(111, d, J=9.2Hz), 5.25(111, dd, J=2.4, 6.6Hz), 6.0,5(2H, t, J=8.6Hz), 7.18(2H1 dd, J=5.2, 8.4Hz), 7.31(1H, d, J=3.2Hz) MASS m/e (FAB) 469(MH") in.p.; 53-570C 278 Exampie P-2 Methyl [3R-r3a .qR11f-R-fF(R)-3-oxo-2acety~tbjo-3-(4-f'lioropheny1 )propvyl 'Iminnloetahydr S-oxothiazal F3-2-lapine-3-nnr nyvltA 0 Sc NH' S/

R

CH

3 00C/- Following the first epimer obtained in the Example F-i, the title compound (486 mg, 37%) was obtained from the column as a second epimer.

H-NNIR (400 MHz, 'CDCl 3 )8; 1.45-2.02(611, in), 2.3303H, s), 2.93(111, dd, J=6.8, 13.6Hz), 3.16(111, dd, J=6.8, 12.0Hz), 3.26(111, dcl 1 J=2.4, 12.0Hz), 3.28(111, dd, J=8.8, 13.6Hz), 3.77(3H1, s), 4.19(111, dd, J=6.8, 8.8Hz), 4.45(111, dd, J=6.2, 11.2Hz), 4.97(lH, J=8.8Hz), 5.26(111, dd, J=.4 6.8Hz), 6.96(211. t, J=8.811z), 7.19(21, dd, J=5.6, 7.32(111, d, J=5.6Hz) 4b MASS in/c (FAB); 469(MH+) 55-60 0

C

-279- Exa~mple F-3 Methyi thiazol F3.2-Fflazepine-3-cairboxylate 0 Ss NH S

R

SAc N S CHAfOC4- A solution bf methyl 3R- [3a, 6a(S*) ,9ap I -6-aminoazepine-3-carboxylate (430 mg, 1.76 mmol) in methylene chloride (17.6 ml) was cooled to 0 8 C under cooling with ice. Next, to this solution were successively added (S)-2-acetylthio-3-phenylpropionic acid (395 mg, 1.76 mmol) obtained in the Synthesis Example F-4 and N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ, 479 img, 1.94 mmol). Then, the ice bath was taked away, and the mix.ture thus obtained was stirred under a nitrogen atmosphere at room temperature for 6 hours. Then, the mixture was washed with a 0.5 N aqueous solution of hydrochloric acid (10 ml x water (10 ml), a saturated aqueous solution of sodium hydrogencarbonate ml x 2) and a saturated aqueous sodium chloride 280 ml), and dried over magnesium sulfate. Next, the filtrate, which was obtained by filtering it, was concentrated under reduced pressure. The residue thus obtained was purified by column chromatography (methylene chloride ethyl acetate 20 Thus, the title compound as an amorphous product (563 mg, 71%) was obtained.

1 H-NMR (400 MHz, CDC1 3 )6; 1.50-2.03(6H, 2.32(3H, s), 2.99(1H, dd, J=7.6, 14.0Hz), 3.17(1H, dd, J=6.4, 12.0Hz), 3.26(1H, dd, J=2.4, 12.0Hz), 3.31(1H, dd, J=7.6, 14.0Hz), 3.78(3H s), 4.29(1H, t, J=7.6Hz), 4.46(1H, dd, J=6.4, 10.4Hz), 4.99(1H, d, J=8.8Hz), 5.24(1H, dd, J=2.4, 6.4Hz), 7.18-7.36(6H, m) MASS m/e (FAB); 451(MH') indeterminable owing to the amorphous form.

281 I I Example F-4 Methyl r3-a~r(S)AOI]-6f(() oo2 acetyl thiomiethyl -3-np nvlron llamnoMl-octcahy~xrn.

5-oxotbiqzo1 3.2-alazepine-3-carhoxvlnte AcS0 CH3 OOC;-- A solution of' methyl [3R-[3ca,6a(S*) ,9aP]]-6-aminooctahydro-5-oxothiazol[3,'Z-a]azepine-3-carboxylate (375 mg, 1.53 mmol) in methylerne chloride (15.3 ml) was cooled to 0 0 C under cooling with ice. Next, (S)-2-acetylthiomethyl-3-phenylpropionic acid (365.8 mg, 1.54 rn'-l) and N-ethoxycarbonyl-2-ethoxy- 1.,2-dihydroquinoline (EEDQ, 418 mg, 1.69 mmol) were successively added to this solution. Then, the ice bath was taken away, and the mixture thus obtained was stirred under a nitrogen atmosphere at room temperature for 6 hours. Then, it was washed with a N aqueous 1101 solution (10 ml x water (10 ml), a saturated aqueous NaHCO 3 solution (10 ml x 2) and a saturated aqueous sodium chloride (10 ml), and dried 282 over (MgS0 4 was used). Next, the filtrate, which was obtained by filtering it, was concentrated under reduced pressure. The residue thus obtained was purified by column chromatography (methylene chloride ethyl acetate =20 Thus, 'the title compound as a sticky solid (435 mg, 61%) was obtained.

H-NMR (400 MHz, CDCl 3 6; 1.55-2.11(6H, in), 2.3203H, 2.62-2.70(1-, mn), 2.82(lH, dd, J=6.8, 14.0Hz), 2.97(lH, dd, 14.0Hz), 3.03(11, dd, J=8.8, 13.6Hz), 3.11(111, dd, 13.6Hz), 3.17(IH, dd, J1=6.8, 11.6Hz), 3.27(lH, dd, J1=2.8, 11.6Hz), 3.78(3H1, s), 4.40-4.44(11, m like 4.98(111, d, .1=8.8Hz), 5.20(lH, dd, J=2.8, 6.8Hz), 6,79(111, d, J=6.OHz), 7.15-7.28(11, m) MASS m/e (FAB) 465 (MH-I) indeterminable owing to the amorphous form.

283 Example methyi rAP-('Srt. S 9 0p 11-ra-f F 2S, 3S)-1 -oxo-2acetyltbio-3-methylpentyll 1,nmn1nntabdro-5-oxothi zol f 3. 2-alazepinep3.c-hioxyl ate

OH

3 o CHa S s NH S R SAc

S

0/

CH

3 00C~i A solution of methyl (3R-[3z,6c(S*) ,9aP]]-6-amino- 2-alazepine-3-carboxylate (225 mng, 0.92 mmol) in methylene chloride (17 nil) was cooled to 0 0 C under cooling with ice. Next, a solution of (2S S) -2-acetylthio-3-miethylpentanoic acid (193 mng, 1.01 mmol) in mnethylene chloride (6 mil) and EEDQ (296 mg, 1.20 mmol) were successively added to this solution. Then, the ice bath was taken away, and the mixture thus obtained was further stirred under a nitrogen atmosphere at room temperature overnight. Then, the mixture was concentrated to a certain extent with an evaporator. Next, the residue was dissolved in ethyl acetate, and the resulting solution was washed with a 1 N aqueous HCl solution, a saturated aqueous NaHCO 3 solution and a saturated 284 aqueous sodium chloride and then dried over (MgSO 4 was used). The filtrate, which was obtained by filtering it, was concentrated under reduced pressure. The residue thus obtained was purified by column chromatography (hexane :ethyl acetate 3 Thus, the title compound as an amorphous product (206 mg, 54%) was obtained.

I H-NMR (400 MHz, CDC1 3 )8; 0.88(3H, t, J=7.6Hz), 0.99(3H1, d, J=6.8Hz), 1.10-1.22(111, in), 1.51-1.70(2H, in), 1.82-2.14(6H1, mn), 2.38(3H1, s), 3.20(111, dd, J=6.4, 11.8Hz), 3.28(111, dd, J=2.4, 11.8Hz), 3.79(3H1, s), 4.54(111, dd, J=6.4, 10.4Hz), 5.02(lH, d, J=8.811z), 5.28(111, dd, J=2.4, 6.4Hz), 7.41(111, d, Rxamps PR-R to 7-12a Compounds of Examples F-6 to F-13 as will be shown hereinafter were obtained by the same procedures as those of Examples F-l to 285 Exaiple F-R acetylthlo-.9-(4-methnxvphenvl )nropvII PmInOntahr..z_ 5-oxothiazo1 r329-;qlaepin-3-earhoxylatp 0 s NH -S

R

CH0SAc /S N S

CH

3 00C 1 H-NMR (400 MHz, CDC1 3 1.55-2.04(6H1, in), 2.33(3H, s), 2.-94(1U, dd, J=7.6, 14.4Hz), 3.18(111, dd, J=6.8, 11.61Hz), 3.24('H, dd, J=7.2, 14.4Hz), 3.27(111, dd, 3=2.4, 11.6Hz), 3.78(6H1, s), 4.24(111, t, J=7.6Hz), 4.45(111, dd, J=6.0, 10.8Hz), 4.99(d, J=8.8Hz), 5.24(111, dd, J=2.4, 6.8Hz), 6.80(2H, d, 3=8.8Hz), 7.13(2H1, d, J=8.4Hz), 7.32(111, d, 3=6.4Hz) *MASS m/e (FAB); 481(MH') M indeterminable owing to the qt1;orphous form.

286 acetylthio-3-(1 .4-blpheanyv 1)propy 1 Iaminnl-octahydro- 5-oxotbiao'F3.2-1.,97Epine-3-t.-rboxylate, H-NMR (400 MHz, CDC1 3 )8; 3.05(1H, dd, J=7.6, 14.4Hz), 3.11(111, dd, J=6.6, 12.0Hz), 3.23(111, dd, J=2.4, 12.0Hz), 3.34(111, dd, J=7.6, 14.4Hz), 3 4.32(111, t, J=7.6Hz), 4.45(111, dd, J=6.4, I' '3Hz), 4.98(1H, d, J=8.4Hz), .21(111, 7.26-7.60(101, in) *MASS m/e (FAB); 527(MH") 68-720C .77(3OH, s) dd, J=2.4, 6.6Hz), 287 methyl r3R-r~ix's' -aoi--rR~loo2 acetylthlo-3-(l .4-bJihhe~nypropyllamjnol-on ~VcIror3'.2-Ala~enine-3-carboxylate 0

R

A NH S R A Sc N S N ~0/

CH

3 00C; 1 1-NMR (400 MHz, CDCl 3 )6; 1.46-2.00(6H1, in), 2.34(31, s), 3.01(1H, dd, J=7.2, 14.0Hz), 3.15(111, dd, J=6.4, 12.0Hz), 3.25(111, dd 3=2.4, 12.0Hz), 3.36(111, dd, J=8.8, 14.0Hz), 3.76(3H1, s), 4.28(111, dd, J=7.2, 8.8Hz), 4.45-4.49(11, m like 4.97-4.99(111, mn like d), 5.26(111, dcl, J=2.4, 6.4Hz), 7.29-7.59(10H1, in) MASS in/e 527(MH in.p.; 77-800C 288 Pxnmpe E-9 methy, nr r3Pf3s, l r f(S' -oxo-2aetyl th io-3- (2-th Ienvl nronyl Ianno oxothia~zolr(3.2-R 17.ein--arhxylatLe, 0 Sc NH

S

H-NMR (400 MHz, CDCl 8 6; 1.50-1.70(2H1, in), 1.86-2.08(4H1, mn), 2.36(3H1, s), 3.18(111, dd, J1=6, 12Hz), 3.27(111, dd, J=2, 12Hz), 3.29(111, dd, J=7, 14H1z), 3.49(111, dd, 14Hz), 3.78(3H, 4.30(11, d, .1=7Hz), 4.49(111, dd, J1=6, 10Hz), 5.00(1H, d, .1=9Hz), 5.26(111, dd, J=2, 6HZ), 6.86(111, brd, .1=4Hz), 6.90(111, dd, J1=3, 5Hz), 7.14(111, dd, J=2, 7.40(111, d, J=6Hz) 289 R~ample Methyl f 3R-f 3-a.E( 9a I l-B-r r (2S 3R) -1.

nyo-2-aetv~thi--ethvyInJotyami[np1-oethydr-- 5-oxothiazolr3.2-alazepine-3-earhovlaqje

CH

3 0 C s N H S R SAc 0/N S CH 3 00C/- H-NMVR (400 MHz, CDC1 3 )6; 0.91(311. t, J=7Hz), 0.92(3Wl d, J=7Hz), 1.27(1H, in), 1.44(1H, mn), 1.64(111, mn), 1.88-2 06(5H, mn), 2.07(111, quint, J=7Hlz), 2.40(3H, 3.19(111, dd, J=6, 12Hlz), *3.28(1W, dd, J=2, 12Hz), 3.80(3H, s), 4.07(111. d, J=7Hz) 4.53(111, dd, J=G, 5.02(111, d, J=9Hz), 5.28(111, dd, J=2, 6Hfz), 7.51(11-, d, J=6Hz) S S

*SSS

290 Exa~mple P-1l ace-tyl thli hutl 1ami not-oct-.hydr--oxothiagzo1 La. 2- a I q,(pi-nt-.--o-qrboxyl t e 0

CH

3

NH

SAc I//N S 04>~ Cl{ 3 0O0 H-NMR (400 MHz, CDC1 3 6; 1.86-2.06(6H1, in), 2.37(3H1, s), 3.19(111, dd, J=6, 12Hz), 3.27(111, dd, J=2, 12Hz), 3.79(3H1, 3.96(111, t, J=611z), 5.28(111, dd, J=2, 6Hz), 7.35(111, d, J=6Hz), 291 Example P-12 Methyl [3-r3a. qa) .Rpl-n-r r -nxn-2ac Lthjoz3-rn etihvl hitvl laminol-oJtaJJyXInZro.Q-xo

CH

3 0 CH 3 1 NH SAc /N S 0) I C~H3 0C 1 1--NMR (400 0 97(3OH, 1. 65 (1H, 2.39(3OH, 3. 28 (1H, 3. 91 (1H, 02 (1H, 7. 40 (1H, MHz, CDC1 3 8; d, J=7Hz), 1.02(31, d, J=7Hz), mn), 1.88-2.06(4H1, in), 2.35(11, mn), 3.20(111, dd, J=6, 12Hlz), dd, J=2, 12Hz), 3.80(3H1, s), d, J=7Hz), 4.54(1IH, dd, J=6, d, J=911z), 5.28(111, dd, J=2, 6,Hz), d, J=611z) 292 Exaimple F-13 Methyl r,3 -3 .1I S

CH

3 GH3 0

CH

3 y NH SAc N S 041

CH

3 00C; H-NNIR (400 1.02(9H1, 2. 17 (3H, 3. 28(1H1, 3. 80(3H1, 03 (1H, 7. 20(1H1, Mliz, CDC1 3 8; 1.63(111, mn), 1.88-2.09(5H1, Mn), 3.20(11, dd, J=6, 12Hz), dd, J=2, 12Hz), 3.77(311, s), d, J=9Hz), 5.28(IH, dd, J=2, 6Hz), d, J=6Hz) 293 Example F-14 3SR- rf 3 .6f ,.9flp11--f[ -l-Ono-2-thlo-3- (4-f1lorophenyv )p ropyvl aminol-ontalhydro- -oxothi azol- S SH N RS

HOOC

Methyl [3R-[3a,6a(S*),9ap]]-6-[(S)-l-oxo-2-acetylthio-3-(4-fluorophenyl)propyl]amino]-octahydro-5-oxotbiazol[3,2-a]azepine-3-carboxylate (384 mg, 0.82 mmol) obtained in the Example F-I was introduced into a flask, followed by sufficient purging with nitrogen, After adding degassed tetrahydrofuran (1.95 ml) and methanol (11.7 ml) thereto, the flask was cooled to 0 0 C. To the mixture thus obtained was added a degassed 1 N aqueous solution of lithium hydroxide (6.6 ml). The obtained mixture was returned to room temperature and stirred for 2 hours. After cooling the mixture to 0°C again, a 1 N aqueous solution of hydrochloric acid (10 ml) was added thereto. The obtained mixture was extracted with chloroform (50 ml x The organic phase was washed with a saturated 294 S~SP~Pl~a~bdl--cl- -,el -r aqueous sodium chloride (30 ml) and then dried over magnesium sulfate. Then, the organic phase was filtered and the filtrate was concentrated under reduced pressure to a certain extent. Toluene (50 ml) was added to the concentrate, followed by concentration, again. Further, the residue was dissolved in a small amount (about 1 ml) of chloroform and diisopropyl ether (about 1 ml) and recrystallized.

To the crystals thus obtained was added hexane (3 ml).

After grinding and filtering, the solid was dried under reduced pressure. Thus, the title compound (362 mg, 107%) was obtained as white crystals.

S1H-NMR (400 MHz, CDC13)6; 1.55-1.68(1H, 1.90-2.06(6H, m), 3.09(1H, dd, J=6.8, 14.0Hz), 3 .18-3.25(2H, n), 3.34(1H, dd, J=2.4, 12.0Hz), 3.51-3.56(1, m like q), 4.52(1H, dd, J=6,4, 11.2Hz), 5.03(1H, t, J=5.2Hz), 5.26(1H, dd, J=2.4, 6.4Hz), 6.97(2H, t, J=8.8Hz), 7.17(2H, dd, J=5.8, 8.2Hz), 7.52(1H, d, MASS m/e (FAB); 413(MH') 2 09-211"C 295 -1 R 1 c~ r Example [3R-[Uy, 6 t(S S 9apl 1-6-F [(S.3S)-1-Oyo-2-thjo-3methylpentylv Jnino]oetahydro-5-oxothiayzol 3.2-alaepi ne-3-earboxylic acid

CH

3 0

CH

3 S 00C S

HOOC

Methyl [3R-[3a,6a(S*),9ap]]-6-[(2S,3S)-l-oxo-2thiazol[3,2-a]azepine-3-carboxylate (200 mg, 0.48 mmol) obtained in the Example F-5 was introduced into a flask, followed by addition of degassed ethanol (8 ml). The flask was cooled to 0°C under a nitrogen atmosphere. A degassed 1 N aqueous solution of lithium hydroxide (3.8 ml) was added to the obtained mixture. The resulting mixture was stirred at room temperature for 50 minutes. The obtained mixture was acidified by adding a 2 N aqueous solution of hydrochloric acid (2.9 ml) at 0°C. The obtained mixture was extracted with methylene chloride. After the organic phase was washed with a saturated aqueous sodium chloride, it was dried over magnesium sulfate 296 I-I 1'IL and concentrated. The residual solid was recrystallized from hexane-methylene chloride. Thus, the title compound (150 mg, 87%) was obtained as white crystals.

IH-NMR (400 MHz, CDCl 3 8; 0.90(31, t, J=7Hz), 1.00(31, d, J=7Hz), 1.24(lH-, in), 1.55-1.74(2H, in), 3.20(111, dd, J=B, 12Hz), 3.24(111, d, J=7Hz), 3.36(111, dd, J=2, 12Hz), 4.62(111, dd, J=6, 5.07(11, t like, J=6Hz), 5.29(111, dd, J=2, 6Hz), Example F-16 .LSR- 3a. SL&LLqDaU 1 -6-r r -1 -nxo-2-thi o-3- (4fliiorophenyl ~oroov1 1mino1-nocIt-abydcro-5-oxothia7.nIr3 ,2-a 1azenint--c-(arboxy1llc arcJ 0 NH S R F 0O;/J

HOOC

The compound of Example F-2 was treated in the same manner as that of Example F-14 to thereby give the title compound.

297 1 H-NMR (400 MHz, CDCl 3 6; 1.44-1.56(1H, mn), 1.82-2.03(51, 3.03(111, dd, J=6.8, 14.0Hz), 3.20(111, dd, J=6.8, 11.6Hz), 3.25(111, dd, J=8.0, 14.0Hz), 3.34(111, dd, J=2.0, 11.6Hz), 3.45(111, q, J=8.OHz), 5.27(111, dd, J=2.0, 6.8Hz), 6.97(2H1, J=8.6Hz), MASS in/e (FAB); 413(MH") 98-105 0

C

Fxamples P-17 to F-26 .Compounds of Examples F'-17 to F-26 as will be shown hereinafter were obtained by the same procedures as those of Examples F-14 and F-15 using the compounds of Examples F-3, F-4 and F-6 to F-13.

298 Examle F-17 phenvi propyl laminol- -octhvdrn-5-oxothi nizol 3.2-ql azepine-2-carboxylic acirl 0 SsNH S

R

SH oN S 100 H-NMR (400 MHz, CDC1 2 1.53-1.68(11, in), 1.88-2.07(6H, in), 3.10(111, dd, J=6.8, 13.6Hz), 3.19(111, dd, J=6.6, 12.0Hz), 3.27(111, ad, J=h6.8, 13.6HIz), 3.34(11, dd, J=2.4, 12.011z), 3.59(111, q, J=6.81Iz), 4.51-4.56(11, m ike1 dd), 5.02-5.04(11, m like t), 5.26(111, dd, J=2.4, 6.6Hz), 7.17-7.30(511, in), 7.53(111, d, J=6.OHz) 0 MASS rn/c (FAB); 395(MH+) 0 Mn.P." 232-235 0

C

299 m Example~ F-19 phenylpropylla o-caylr--ytiq~nr*.,,l aappine-3-carboxylic acid s NH S

R

HS 0~

HOOC

*'H-NMR (400 MHz, CDC1 3 )6; 1.46(31H, t, J=8.4Hz), 1.59-1.70(11, in), 1.84-2.14(5Y:, mn), 2.55-2.68(2H1, mn), 2.76-2.83(2H1, in), 2.97(111, dd, J=7.0, 13.4Hz), 3.21(111, dd, J=6.8, 12.0Hz), 3.35(111, dd, J=2.4, 12.0H1z), 4.54-4.59(11, in like 5.02-5.05(11, in like t), 7.12-7.30(5H1, mn) MASS rn/c (FAB); 409(M1+) 210-212 0

C

300 E3~ampe F-19 metbojjnval lronv1 ]aminol-octabdro--o11i&ZL.Qv~z r3,2-alaepine-3-carhoxylic acid 0 7NH S R SH 0/N

S

HOOC4R H-NMR (400 MHz, CDC1 3 1.55-1.68(1H, mn), 1.88-2.09(6H, in), 3.08(lH, dd, J=6.8, 14.4Hz), 3.20(111, dcl, J=6.8, 12.0Hz), 3.34(111, dcl, J=2.4, 12.0Hz), 3.55(111, dt, J=8.8, 6.8Hz), 3.79(3H1, s), 4.52-4.56(11, in like dd), 5.02-5.05(11, in like t), 5.25(111, dcl, J=2.4, 6.8Hlz), 6.82(2H1, d, J=8.4Hz), *MASS in/e (FAB); 425(MH+) 182-183 0

C

301 Fxamp~e biphpenyl )Tpronvl laminol-ontahvdro-s-oxothinvo F3.2-A1azepine-S-cinrboxylir arid 0 NH S R "N

NSH

1 H-NMR (400 MtHz, CDCl 3 1.55-1.67(111, in), 1.88-2.08(51, in), 2.06(111, d, J=8.811z), 3.12(111, dd, J=6.8, 12.0Hz), 3.16(1H, dd, J=6.8, 14.0Hiz), 3.26-3.31(2H1,i) 3.60(11, q, J=6.8Hz), 4.50-4.54(11, in like q), 5.00-5.03(1H, in), 5.20(1H, dd, J=2,4, 6.8Hz), 7.28 -7.59(10H, mn) MASS in/e (FAB); 471 (M1 4 106-1170C 302 hibIpaenyl )ipropvl ]aio !nayr--xo~iz~3,2-~.7 azepine-3-carboxylic aeid 0

R

NH R 2

HOOC

1 11-NMIR (400 MHz, CDC.1 3 1.44-1.56(11, in), 1.84-2.00(511, mn), 2.12(111, d, J=9.G11z), 3.08(111, dd, J=6.4, 14.0Hz), 3.16(111, dd, J=6.8, 12.0Hz), 3.29-3.50(2H1, 3.50-3.55(11, m like q), 4.52-4.57(11, in like dd), 5.01-5.04(11, m), 5.25(111, dd, J=2.4, 6.8Hz), 7.26-7.58(0.1, in) MASS in/e (FAB); 471(MH+) 109-116'C 303 Exaniple P22 Fa 2-alazepine-3-carhoxylic aid H-NNIR (400 1. 64(1H1, 9(1H1, 3. 34(111, 3. 58 (11, 5(1H1, 6. 87 (1H, 7. 17(1H1, MHz, CDC13) 6; in), 1.90-2.12(5H, in), d, J=8Hz), 3.20(111, dd, J=6.1211z), dd, J=2, 12Hz), 3.44(2H!, d, J=611z), in), 4.57(111, dd, J=6, 1011z), mn), 5.26(111, dd, J=2, 6Hz), brd, J=4Hz), 6.93(1H, dd, J=3, dd, J=2, 5Hz), 7.65(111, d, J=6Hz) /0 LRA W C 304 Example F-23 [3.9-alnzpinp-n-cnrboxv1 atea

CH

3 0 RH /Y NH S

OOCG;

1 11-NMIR (400 MHz, CDCl 3 )6: 1.30(111, mn), 1.49(111, mn), 1.70(111, m), 1.76(11, d, J=811z), 1.90-2.14(61, m), 3.22(111, dd, J=6, 1211z), 3.32-3.42(2H, in), 4.62(111 dd, J=6, 10Ilz), 5.06(111, in), 5.30(111, dd, J=2, 611z), 7.94(11, d, J=6Hz) Examnple P-24

CU

3 NHP S R SH 0 N S

HOOC

305 I H-NNIR (400 MvHz, CDC1 3 8; 1.90-2.10(7H1, mn), 3.19-3.30(2H1, m), 3.35(111, ad, J=2, 12Hz), 4.62(111, dd, J=3, 5.06(111, in), 5.29(111, dd, J=2, 6Hz), FxnMple F7-2S azepirie-3-nnrboxvljn acid

CH

3 0 CH("'i<NH S R SH 7//1a

HOOC;

1 1-NMVR (400 M11z, CDC1 3 6; 0.99(3H1, dl, J=7Hz), 1.03(311, dl, J=711z), 1.69(11, mn), 1.85(111, dl, J=9Hz), 1,90-2.10(5H1, in), 2.25(111, septet, J=7Hz), 3.16-3.26(211, in), 3.35(111, dd, J=2, 3.1Hz), 4.61(111, dd, J=6, 1011z), 5.06(111, t like, .1=6H1z), 5.30(111, dd, J=2, 8Hz), 7.67(111, d, .1=6Hz) 306 Rxamnri P-2s a7pirj'n-3-arho-,xylp avid CH3 CH 3 0 CH3 s NH S R 38 1

S

HOOG

*'H-NMR (400 MHz, .l.06(9H, 1.74(111, rn), 1.85-2.10(5H, in), 3.25-3.35(3H1, in), 4.58(1H1, mn), 5.17-5.25(2H1, mn) EXaI2mP 101 thn- otxo-Is~h 307 fa) (4S--3-r (3R)-1-oxo-3-phenvlbutvl 1-4-phenvlmethvl- 2-oxazol dinone

CH

3 0 0 N- O 5.96 g of (R)-3-phenylbutanoic acid was dissolved in 90 ml of dichloromethane and several drops of dimethylformamide were added thereinto. Into the mixture thus obtained was dropped 9.5 ml of oxalyl chloride. The obtained mixture was stirred at room temperature for 0.5 hour and then concentrated. The residue was dissolved in 60 ml of tetrahydrofuran.

Next, 6.44 g of (S)-4-phenylmethyl-2-oxazolidinone was dissolved in 120 ml of tetrahydrofuran. Into the obtained solution was dropped 14.5 ml of a 2.5 M solution of n-butyllithium in hexane under a nitrogen atmosphere at -70°C. The obtained mixture was stirred at the same temperature for 20 minutes and then the solution of the acid chloride in tetrahydrofuran which had been prepared was added thereto. Further, the mixture thus obtained was stirred at -70"C for minutes and then heated to room temperature. The -308reaction mixture was concentrated. Ethyl acetate and water were added thereto and the target compound was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride, and then it was dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to thereby give 9.7 g of the title compound (yield 83%).

1 H-NMVR (400 MHz, CDC1 3 )6; 7.33-7.18(81, m) 7.07(2H, dd, J=2, 8Hz) 4.63(1H, m) 4.18(111, dd, J=8, 8Hz) 4.11(111, dd, J=9, 3Hz) 3.45(2H1, mn) 3.08(2H1, m) 2.59(lH, 1H1, dd, J=14, 9Hz) 1.3603H, d, J=7Hz) (4SY-3-[(2,3S)-2-hromo-l-oxo-3-phenylb1tv~l-]4- 3.25 g of (4S)-3-((3R)-1-oxo-3-phenylbutyl-4phenylmetb.yl]-2-oxazolidinone was dissolved in 50 ml of dichloromethane. To the solution were added 10 ml 309 of diisopropylethylaiine and 1" 5 ml of di-n-butylborotrifluoromethanesulfonic acid under a nitrogen atmosphere at -70 0 C. The mixture thus obtained was stirred at the same temperature for 15 minutes and then at 0 C for 1 hour. The reaction mixture was coolod to -70 0 C. The one obtained by suspending 3.64 g of N-bromosuccinimide in 20 ml of dichloromethane was prepared in another container and the above-mentioned reaction mixture was added thereto under a nitrogen atmosphere at -70 0 C. The mixture thus obtained was stirred at the same temperature for 1.25 hours and then poured into a solution comprising N sodium sulfate and a saturated aqueous sodium chloride. The resulting mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography. Thus, 3.43 g of the target compound was obtained (yield 1 H-NMR (400 MHz, CDC1 3 )6; 7.38-7.24(10H, m) 5.96(1H, d, J=10Hz) 4.76(1H, m) 4.23(2H, m) 3.57(1H, dd, J=10, 7Hz) 3.34(1H, dd, J=14, 3Hz) 2.81(lh, dd, J=14, 1.38(3H, d, J=7Hz) 310 -1 I r (4Sl-3-r(2R.3R)-2-azido-1-onxo-3-phpenyv1butyL]v-4phenvymethvy -2-oxazo1 idinone

CH

3 o N 3 6.43 g of (4S)-3-[(2S,3S)-2-bromo-l-oxo- 3-phenylbutyl]-4-phenylmethyl-2-oxazolidinone was dissolved in 80 ml of dichloromethane. To the obtained solution was added a solution of 7.58 g of tetramethylguanidinium azide in 20 ml of dichloromethane at 0 C. The mixture thus obtained was stirred at the same temperature for 1 hour and then at room temperature for 2.5 days. Further, it was heated under reflux for 8 hours. To the reaction mixture thus obtained was added a saturated aqueous solution of sodium hydrogencarbonate. The resulting mixture was extracted with dichloromethane. The organic phase was washed with a saturated aqueous sodium chloride, and then it was dried over anhydrous sodium sulfate and concentrated. After purifying by silica gel column chromatography, 4.33 g of the target compound 311 was obtained (yield 74%).

IH-NMR (400 MHz, CDC1 3 )8; 7.37-7.22(8H, m) 6.99(2H, dd, J=8, 2Hz) 5.37(1H, d, J=9Hz) 4.60(1H, m) 4.12(1H, dd, J=9, 9Hz) 3.45(1H, m) 2.80(1H, dd, J=14, 4Hz) 1.98(1H, dd, J=14, 1.50(3H, d, J=7Hz) (2R.3S-2-azido-3-phenv1hultanoic acid CH3 0

NH

2

OH

4.32 g of (4S)-3-[(2R,3S)-2-azido-l-oxo-3phenylbutyl]-4-phenylmethyl-2-oxazolidinone was dissolved in 60 ml of tetrahydrofuran-water (4 1).

To the solution thus obtained were added 7.75 ml of a aqueous hydrogen peroxide and an aqueous solution (38 ml) containing 0.73 g of lithium hydroxide at 0°C.

The obtained mixture was stirred at 0°C for 1 hour and then an aqueous solution (57 ml) containing 9.58 g of sodium sulfite was added thereto. The tetrahydrofuran was distilled off from the reaction mixture under reduced pressure. The aqueous phase was washed with dichloromethane, and then the pH thereof was adjusted to 1 with cone. hydrochloric acid, followed by 312 extraction with ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride, and then it was dried over anhydrous sodium sulfate and concentrated. Thus, 2.30 g of the target compound was obtained (yield 1 H-NMR (400 MHz, CDC1 3 )8; 7:37-7.27(5H, m) 4.09(11, d, J=6Hz) 3.39(1H, dq, J=7, 7Hz) 1.39(3H, d, J=7Hz) (2R.3S)-2-amino-3-phenyl1htanoie qac-i

CH

3 0

OH

NH

2 2.20 g of (2R,3S)-2-azido-3-phenylbutanoic acid was dissolved in 40 ml of methanol. To the obtained solution were added 2.71 g of ammonium formate and 0.36 g of 10% palladium carbon (a water-containing preparation), followed by reacting at room temperature for 1.5 hours. After removing out the catalyst by filtration and concentrating the filtrate, 300 ml of a mixed solvent comprising methanol and dichloromethane (1 9) was added to the residue, followed by extraction. After concentrating the extract, 2.43 g of the target compound was obtained (crude product).

313 1 H-NMR (400 MHz, CDC1 3 )8; 7.32-7.16(5H, m) 3.78(1H, d, J=5Hz) 3.38(1H, m) 1.23(3H, d, J=7Hz) (2R.3S)-2-bromo-3-phenylbitanoic acid 0 3

AOH

Br 1.70 g of (2R,3S)-2-amino-3-phenylbutanoic acid was dissolved in a mixed solvent comprising 7.2 ml of water and 10.5 ml of 47% hydrobromic acid. To the obtained solution was added 0.98 g of sodium hypochlorite at -10°C. The resulting mixture was stirred at 0"C for 30 minutes and then at room temperature for 2 hours. Next, water and diethyl ether were added thereto, followed by extraction. The ether phase was washed with water and a saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated. Thus, 1.84 g of the target compound was obtained as a crude product.

1 H-NMR (400 MHz, CDC1 3 )6; 7.38-7.18(5H, m) 4.35(111, d, J=10Hz) 3.36(1H, m) 1.23(3H, d, J=7Hz) 314 -I I 2.(23S) -2-aetv!Plitho-3-phenv1hbutanoic acid

CH

3 0 A

OH

\N SCOCH 3 1.80 g (7.35 mmol) of (2R,3S)-2-bromo-3-phenylbutanoic acid was dissolved in 40 ml of acetonitrile.

To the obtained solution was added 1.01 g (88.2 mmol) of potassium thioacetate at -10°C. The resulting mixture was stirred at 0°C for 30 minutes and then at room temperature overnight. The insoluble matters were removed by filtration and the solution was concentrated. Diethyl ether and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue obtained by the concentration, followed by extraction the target compound into the aqueous phase.

The pH of the aqueous phase was adjusted to 1 with dilute hydrochloric acid, followed by extraction with diethyl ether. The organic phase was washed with a saturated aqueous sodium chloride, and then it was dried over anhydrous sodium sulfate and concentrated, Thus, 1.52 g of the target crude product was obtained.

IH-NMR (400 MHz, CDC13)6; 7.40-7.18(5H, m) 4.42(1H, d, J=10Hz) 3.33(1H, m) 2.25(31 s) 1.43(3H, d, J=7Hz) 315 methy-I .Y g3te(os* Pap i ir f2S..9,q) -2acelIvl fbi p-1-i -ox~3zIrjeny butyl 1nmi oxothiiazo? f3.2-aln7epine-31-rarboxv1alte

CH

3 0

(YYCOH

3 0O~ 0.3 g (1.23 mmol) of methyl-{3R-[3a,6a(S*), 9ap]}-6-aminooctahydro-5-oxothiazol[3,2-a]azepine-3-carboxylate was dissolved in 10 ml of dichloromethane. To the obtained solution were successively added a solution of 0.32 g (1.35 inmol) of (2S,3S)-2-acetylthio-3-phenylbutanioic acid in 10 ml of dichloromethane and 0.43 g (1.6 mmol) of EEDQ at 0 0

C

under a nitrogen atmosphere. The mixture thus obtained was stirred at room temperature overnight.

Then, it was successively washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography. Thus, 0.27 g of the target compound was obtained.

316 1 H-NMR (400 MHz, CDC1 3 )6; 7.34-7.15(5H1, m) 5.28(1H, dd, J=6, 2Hz) 5.02(111, d, J=9Hz) 4.56(1H, dd, J=11, 7Hz) 4.22(111, d, J=lOHz) 3.79(3H1, s) 3.45(111, mn) 3.28(111, dd, J=12, 3Hz) 3.19(111, dd, J=12, 7Hz) 2.23(3H1, s) 2.04-1.88(6H1, m) 1.37(3H1, d, D=7Hz) Exaqmnp 1J02 _L3BSJzL[ (2S -2-Anetyl th -I o-oxo-S-nPhnvl Ibty1 1- A -ino-l-ethoxvearbonvmthvl-2.3,4.5-tetrihvdro- 1 H-rl1benziiznpIn-2--nja

COOC

2

H

0.40 g (1.53 mmol) of (3S)-amino-1-ethoxycarbonylinethyl-2, 3,4, 5-tetrahydro-l-l-(] benzazepin- 2-one and 0.40 g (1.68 mmol) of' (2S,3S)-2-acetylthio- 3-phenylbutanoic acid obtained in the Example 101 (g) were treated in the same manner as that of' Example 101 Thus, 0.37 g of the title compound was obtained, IH-NMR (400 MHz, CDCl 3 )6; 4.77(111, d, J=1711z) 4.50(111, in) 4.34(111, d, J=17iHz) -317 4.22-4.13(3H1, m) 3.42-3.30(2H, mn) 2.71-2.54(211, m) 2.22(3H1, s) 1.81(111, mn) 1.33(3H1, d, J=7Hz) 1.25(3H, t, J=71iz) Fxaimpl e 103 thiobiityllaminoloctahydro-5-oxopthipzp1r~ F.-alaepine- S-carhoxylic acid

CH

3 o

NHO

sc\oc- YSOC3/ N S HOo -J 0.25 g (0.539 minol) of methyl-{3R- [3a 1 6ca(S),9af]-6-{[(2S,3S)-2-acetylthio-1-oxo-3phenylbutyllamnino}octahydro-5-oxothiazol[13,2-a]azepine-3-carboxylate obtained in the Example 101 was dissolved in 10 ml of ethanol. To the obtained solution was added 10 ml of a 1 N aqueous solution of lithium hydroxide under a nitrogen atmosphere at 0 0

C.

The mixture thus obtained was stirred at room temperature for 1 hour and then cooled to 0 0 C again, followed by adjusting the p11 thereof to 1 with dilute hydrochloric acid. Ethanol was distilled off from the reaction mixture under reduced pressure. Water and 318 dichioromethane were added to the residue, followed by extraction. After the organic phase was washed with a saturated aqueous sodium chloride and dried over anhydride sodium sulfate, it was concentrated. Thus, 0.15 g of the target compound was obtained.

1H-NIVR (400 Mfz, CDC1 3 )8; 7.61(111, d, J=6Hz) 7.34-7.3.8(5H1, m) 5.29(lh, dd, J=7, 2Hz) 5.06(111, m) 4.62(111, dd, J=11, 7H-z) 3.51(lh, dd, J=8, 711z) 3,45(111, m) 3.35(111, dd, J=12, 2Hz) 3.21(111, dd, J=12, 7Hz) 2.10-1.90(611, m) Example 104 1..CarDX.Yxmetv1 -2-f f (2S.3S')-1 -nxn-AlznhinyLL-2z

COOH.

0.35 g (0.726 mmol) of (3S)-{K(2S,3S)-2-acetylthio-i-oxo-3-phienylbutYl Iaminol -ethioxycarbonylmethyl-2,3,4, 5-tetrahydIro-1H- -[1]benzazepin-2-onie obtained in the Example 102 was dissolved in 10 ml of 319 ethanol. To the obtained solution was added 10 ml of a 1 N aqueous solution of sodium hydroxide under a nitrogen atmosphere at 0 0 C. The mixture thus obtained was stirred at room temperatare for J hour and then the pH thereof was adjusted to 1 by adding hydrochloric acid at 0 0 C. Water was added thereto and the crystals thus precipitated were collected by filtration. Thus, 0.25 g of the target compound was obtained.

IH-NMR (400 MHz, CDCl 3 )8; 7.34-7.13(9H1, m) 4.68(lh, d, J=17Hz) 4.52(lH, mn) 4.45(111, d, J=1711z) 3.47(111, dd, J=8, 8Hz) 3.41(111, dq, J=8, 7Hz) 3.23(111, m) Pxamnpe 105 MethIYl r.R3P-r3 Art s'q) 9aoI 1-6- r(2S, 3S) -2-ncnety'ith Io- I-Oxo-2.4-di methvlpnon tyI a~m ino I-ontahvdro-5 -oxot b Ia 7, o1 Ia2 a I a z e p Ina3-crkQxyI-a~a CHa 0 320 (2S.3S)-2-acetylthio-34-linthlpentanc<jjacid- CH3 o

H

3

C

OH

C8 3 SCOCH3 Using 3.70 g (28.2 mmol) of (R)-3,4-dimethylpentanoic acid as the starting material and in the same procedures as those of Example 101 to 1.2 g of (2S,3S)-2-acetylthio-3,4-di' ',th'.lpentanoic acid was obtained.

1 11-NNIR (400 MHz, CDC1 3 )6; 4.21(111, d, J=8Hz) 2.38(3H1, s) 1.87(111, m) l.63(1H, m) 0.97(31, d, J=7Hz) 0.93(3H1, d. J=7Hz) 0.80(3H, d, J=711z) methv' P.9 3I t~aS6a 9aR I I-A- I r(2. 3S) -2acpxil thio-l-Qxo-34-dimethylpentvl 1amino1-oetaihvdro-5-oxotlhiazolF3.2-alaepine-3-carhoyvlnte Y

NH

CI% SCOCH 3 0~ N S 0.275 g (1.35 mmol) of (2S,3S)-2-acetyltho-3,4dimethylpentanoic acid obtained by the above 321 procedures and 0.300 g (1.23 mmol) of methyl- {3R 3a, 6a(S*) ,9apI [3,2-alazepine-3-carboxylate used were treated by the same method as that of Example 101 Thus, 0.260 g of the target compound was obtained.

IH-NMNR (400 MHz, CDC1 3 6; 5.28(111, dd, J=6, 2Hz) 5.02(111, d, J=9Hz) 4.54(111, m) 3.95(111, d, J=9Hz) 3.79(3H1, s) 3.28(111, dd, J=12, 2Hz) 3.20(111, dd, J=132, 7Hz) 2.36(3H1, s) 2.10-1.87(6H, m) 1.72-1.60(2H, m) 0.94(3H1, d, J=7Hz) 0.89(3H1, d, J=7Hz) 0.75(3H, d, J=7Y~z) Fxample 106 1 -oxoppntyl 1Inmi nno-1 -Pthoxv~arhonvI me-thvl 2.3,.5-tetrahydrO-il-r1I n7nzenin-2-one CH3 o

H

3 C N NH- t0/

CH

3 SCOCH N

COOC

2 Ht 0.500 g (1.91 mmol) of (3S)-amino-i-ethoxycarbonylmethyl-2, 3,4, 5-tetrahydro-1H- [llbenzazepin- 2-one and 0.430 g (2.1 mmol) of (2S,3S)-2-acetylthio- 322

I

3,4-dimethylpentanoic acid were treated by the same metho.

1 as that of Example 101 Thus, 0.420 g of the title compound was obtained.

IH-NMR (400 Mflz, CDCl 3 )8; 7.32-7.10(41, m) 4.78(111, d, J=l7Hz) 4.50(1H, m) 4.34(111, d, J=i7H-z) 4.22-4.14(3H1, mn) 3.87(111, d, J=l0Hz) 3.42-3.32(11, in) 2.75-2.63(1H, in) 2.35(31, s) 2.02-1.86(3H1, in) 1.25(3H, t, J=711z) 0.91(3H1, d, J=7Hz) 0.85(3H, d, J=7Hz) 0.72(3H1, d, J=7Hz) 1--oxo-2-thiopentyll arinoloctahvrdro-5-oxothiazo1-

CH

3 0

H

3

C

Y=Y' NH- CH3 SH 0 /N S 0Y~

HOOC

In the same manner as that of Example 104 and starting with 0.200 g (0.465 minol) of methyl [3R- 3,4-dimethylpentyl]ainino]-octahydro-5-oxothiazol- [3,2-alazepinie-3-carboxylate obtained in the Example 323 105, 0.150 g of the title compound was obtained.

1 H-NMR (400 MHz, CDCl 3 )6; 7.42(lH, d, J=6Hz) 5.29(111, dd, J=6, 2Hz) 5.07(111, m) 4.65(111, dd, J=10, 6Hz) 3.35(111, dd, J=12, 2Hz) 3.23(111, dd, J=12, 7Hz) 3.14(111, dd, J=9, 8Hz) 2.25-1.92(6H1, m) 1.93(111, d, J=9Hz) 1.82-1.62(2H1, m) 0.95(3H1, d, J=7Hz) 0.84(3H1, d, J=7Hz) 0.77(3H1, d, J=7Hz) -ximplIe 108 1-Garhovvmet1hv" ns-rr(2S.3S)-3.4-dimPthvl -1oxo-2-thinnentvl qm, 1-.34.-tetrahdro-1T4-1jhenvanzeni n-2-one CH3 o H3NH

CH

3 SH 0 N

COOH

In the same manner as that of Example 104 and starting with 0.300 g (0.67 mmol) of acetylthio-3,4-dimethyl-l-oxopentyl]amino]-1--ethoxycarbonylmethyl-2,3,4, 5-tetrahydro-lH- [1]benzazepin- 2-one obtained in the Example 106, 0.200 g of the title compound was obtained.

-0 -324 1 H-NMR (400 MHz, CDC1 3 8; 7.36-7.13(4H, m) 7.06(111, d, J=711z) 4.72(11, di, J=1711z) 4.53(11, m) 4.43(111, d, J=1711z) 3.28(111, m) 3.07(111, t, J=9Hz) 2.70(111, m) 2.61(111, m) 2.15(111, m) 1.99(111, m) l.90(1H, d, J=811z) 1.72(1H, m) 0.91(3H1, d, J=711z) 0.79(3H1, d, J=711z) 0.72(3H1, d, J=711z) FxamplpR 109 to 138 Compounds which will be described in the Examples 109 to 138 were synthesized in accordance with the processes of the Examples 101 to 108 with the ubc~ of appropriate starting materials corresponding thereto.

ExampIe- 0 J4S-r4a. 7 .12bp 1-7- rr (2S) -1-Oxn-91-thio- ,hvcdropror2j-aI12hen7zz7pinp.-4-c-arboxvl-ic acid 0

CH"SJ

HOOC

325 1 H-NMR (400 MHz, CDC1 3 )8; 7.65(1H, d, J=7Hz) 7.50(21, d, J=8Hz) 7.43(111, t like, J=8Hz) 7.38.-7.33(3H1, m) 7.05(11, d, J=8Hz) 5.68(111, quint, J=611z) 5.50(lH, brd) 5.23(111, brd) 3.56(111, dd, J=17, 6Hz) 3.46(111, quint, J=7Hz) 2.90(111, dd, J.=17, 13Hz) 2.53(1H, m) 2.32(11, m) 1.46(31, d, J=7Hz) tbJopenZt 1 ami nol oxo-1 1-phenvi -1 .7.8.1 2Woctahvdropyridor2.l-aJ2lbenzaizepine-4-caqrboxvlilc ncid 0 CH3 s*

'N(

y ~NH- s

R

CH

3 Sjj N

HOOC

1 H-NMR (400 MHz, CDCl 3 6; 7.51(3H1, m) 7.44(2H1, t like, J=8Hz) 7.39-7.32(3H1, mn) 7.08(111, d, J=8Hz) 5.71(111, quint, Jz6,Hz) 5.52(111, in) 5.25(111, in) 3.60(111, dd, J=17, 6Hz) 3.37(111, oi like, J=7Hz) 326 2.91(11H, cid, J=17, 13Hz) 2.55(111, m) 2.36(111, in) 2.05-1.72(6H, m) 2.03(1H, di, J=811z) 1.60(111, mn) 0.96(3H1, d, J=7Hz) 0.92(31, d, J=7Hz) Fxaimple 111 12b I1-7-fF (2S)-1pxo2hiobtvI I aminol-EB-oxo-11-pbenyl-1 .2,.3.4.6-.8.2b-otavcronvridor2.1-aIF21henzazepine-4-ca)-boxylic acid 0 NH] s R

SH

O s

HOOC

'H-NMR (400 MHz, CDC1 3 )6; 7.59(1-, di, J=8Hz) 7.51(2H, di, J=8Hz) 7.44(2H, t like, J=8Hz) 7.39-7.32(3H1, m) 5.54(1H, in) 5.26(11, mn) 3.62(111, dd, J=17, 6Hz) 3.27(111, q like, J=7Hz) 2.94(111, dd, J=17, 13Hz) 2.56(111, m) 2.37(111, in) 2.08-1.72(6H1, m) 2.04(111, d, J=8H-z) 1.04(3H1, t, J=711z) 327 Fxaimplp 112 r4tfc:7aR* ).mnol6-oo-1hn1--1 .2A.4.Ephp7.8.12hohvydropyridor2,1-ar2lhenzr.,zepine-4-envrhoxvlifc avid (isomer A) A:B 2:1 07 K 1r NH s R SH N O's

HOOC

1 1--NNIR (400 MvHz, CD3OD)8; 7.57-7.26(13H, m) 7.19(1H, d, J=8) 5.78(111, dd, J=9, 6Hz) 5.67(1H, m) 5.16(11, d like) 3.50(111, dd, J=17, 61Hz) 3.12(11, dd, J=17, 13Hz) 2.58(1H, m) 2.40(111, m) 2.15-1.76(41, m) 328 Example 13 e-thyl) qminol--Oxo-1--pbeny1-1 .2,3,4.9.7.8.12h-octbI~d=j idof2.1-alr2lhenzazepine-4-carhoxlicI .aci-d A:B =1:2 NH-, s f SH N

HOOC

1 H-NMR (400 MHz, CD3OD)8: 7.57-7.27(13H1, m) 7.08(11, d, J=8Hz) 5.77(1H, dcl, J=9, 6Hz) 5.67(111, in) 5.20(1H, d like) 3.49(1H, dd, J=17, 6Hz) 3.06(1H, dcl, J=17, 13Hz) 2.60(111, in) 2.42(111, mn) 2.17-1.75(4H1, mn) 329 Fxamnpe 114 FAS- f4o: .7a(R -1 2bp 11-7-[Frf(2RP)-3-MetbYv1-I -OXOthiohnityllaminol-R-oxo-11-nhe-nvl-i .2.3.4A.-7.8.12boctI-.hvcropyridor2.1-a1f21benzazepine-4-cnrhnxylic acid Cf! 3 0 CH3 NHb R SH dI N

HOOG

1 H-NMR (400 MHz, CDC1 3 )6; 7.51(11, d, J=8H1z) 7.47-7.24(7H1, m) 7.03(111, d, J=8Hz) 5.67(1H, quint, J=6Hz) 5.47(111, m) 5.20(111, d like) 3.57(111, dd, J=17, 6Hz) 3.09(1H, t, J=7Hz) 2.89(111, dd, J=17, 13Hz) 2.50(1H, m) 2.31(1H, m) 2.20(111, sextet, J=7H-z) 2.02-i..50(41, in) 1.85(111, d, J=8Hz) 1.01(311, d, J=7Hz) 0.98(3H1, d, J=7Hz) 330 Examnp 115 propvl 1aminol-2.2--dimethv-5-oxootabydro',bii~olr3.--lazepine-3 carboxylic anid

CH

3 0

CH

3 iANH s R SH 7xN S HOOC CH 3 1 1-NMR (400 MHz, CDC1 3 )8; 7.61(1H, d, J=6Hz) 7.31-7.19(5H, m) 5.12(111, d, J=1011z) 4.74(1H, s) 4.53(1H, dd like, J=12, 6Hz) 3.60(1H, dt, J=9, 7Hz) 3.26(111, dd, J=14, 6Hz) 3.12(111, dd, J=14, 7Hz) 2.25-2.13(1H, m) 1.99(111, d, J=9Hz) 2.07-1.84(4H1, m) 1..60-1.50(11, m) 1.55(3H1, s) 1.51(3H, s) 331 Example 16 £r~g *r~tp11(SE.aol-r rr3ethyl-1pxo-(s1; thiohltyl lam in01-2r- -rIm.th I-5-oxooctahydrothj azo Ir3.2-alazepinp-2 enrhoxvlic acid CHa D

CH

3 I-,NH s SH

S

0 HOOC CH 3 'H-NMR (400 MHz, CDC1 3 J6; 7.81(lH, d, J=6Hz) 5.15(1H, d, J=lOHz) 4.79(1H, s) 4.61(1H, m) 3.21(111, dt, 6Hz) 2.33-1.88(6H, mn) 1.83(1H, d, J=911z) 1.69-1.57(11, m) 1.56(3H1, s) 1.52(3H1, s) 332 Pxa~mple 117 [4S- F4a-.7ae(Pu. 12bho_ 11-7-rf[ (2S 3R'-3 -Me thy]-i -oxoz 2-hi opentl Iam ino--oxo- 1 -hnvlI-2.

3

A

4

E.

7 .1 12lm octahvdropyrido2.1-mi]I2lbenzazepife-4-carhoxylic aCid

CM

3 0 )NH'S R CH3 sH /N

HOOC

I-H-NMR (400 MHz, CDC1 3 )8; 7.91(111, d, J=8Hz) 7.51(2H1, d, J=8Hz) 7.44(2H1, t like, J=8Hz) 7.38-7.32(31, m) 7.06(1H, d, J=8Hz) 5.71(111, quint, J=BHz) 5.52(111, brd) 5.23(111, mn) 3.58(1H, dd, J=17, 6Hz) 3.39(1H, dd, J=9, 7Hz) 2.91(111, dd, J=17, 13Hz) 2.54(1H, In) 2.32(111, m) 2.12(111, septet, J=7Hz) 2.00(111, In) 1.87(111, m) 1,80(11, d, J=8Hz) 1.82-1.70(2H1, m) 1..51(11, m) 1.34(111, m) 0.97(3H, d, J=7Hz) 0.93(31, t, J=711z) 333 PFuampl P 118 OXO-2(')-thiopropyl laminol-2. 2-dilmethvl hydrothiazolr3.2-alazepine-3-cairboxvli- ci-d 0 sK -'NH s R

CH

3 811 /N HOOC CH 3 1 1-NMR (400 MHz, CDC1 3 )6; 7.63(111, di, J=611z) 7.12(2H1, di, J=8Hz) 6.82(2H1, d, J=8Hz) 5.12(111, di, J=lOHz) 4.74(1H, s) 4.54(lh, dci, J=11, 6Hz) 3.78(31, s) 3.57(111, cit, J=9, 7Hz) 3.18(111, dci, J=14, 6Hz) 3.07(111, cid, J=14, 7Hz) 2.25-2.14(111, m) 1.98(111, di, J=9Hz) 2.07-1.84(4H, m) 1.60-1.50(111, m) 1.55(3H1, s) 1.51(3H, s) 334 Exampl P 119 [4S-r4ce 7a(R*) 1 2bol1 -7-r r(2S) (4-P111oropliem~l)-1-oxo-2-tbiopr-opyll minol-S-oxo-l 1-phenvi 1 12b-COetqliydropyrido[2 I-a~r2bepnaepine-4-narboxylic anid s0 NH S R K SH F O/si

HOOC

1 H-NMR (400 MHz, DMSO-d6)6; 8.37(1, d, J=7Hz) 7,62(2H, d, J=8Hz) 7.46(3H, t, J=8Hz) 7.41(1H, s) 7.35(lH, t, J=8Hz) 7.29(2H1, dd, J=8, 6Hz) 7.19(111, d, J=8Hz) 7.12(2H1, t, J=8Hz) 5.62-5.71.(2H1, m) 5.05(111, m) 3.94(114, m) 3.87(111, m) 3.19(111, dd, J=14, 7Hz) 2.95(111, dd, J=17, 13Hz) 2.88-2.80(2H1, m) 2.52(111, m) 2.22(1H, m) 1.96(111, m) 1.65-1.80(3H1, iii) 335

I

F amp I p12-0 1 -oxo-2-thi opropyl hm~i ol -S-oxo-1 1-ph envi 1.2.3,4-9, 7.8, 12h-ro-tahvdlropyri do r2.1I-pa-Ir21benz-, aepine-4-carhoxylin Ae-id R0 SNH

R

S

N

F O s

HOOG

1 1-NMR (400 MHz, DMSO-d6)6; 8.31(111, d, J=7Hz) 7.61(2H1, d, J=811z) 7.46(31, t, J=811z) 7.39(111, s) 7.35(111, t, J=811z) 7.30(2H1, dd, J=8, 6Hz) 7.16(21, t, J=811z) 7.03(1H, d, J=8Hz) 5.58-5.70(2H1, in) 5.06(111, mn) 3.94(lH, mn) 3.10(111, dcl, J=14, 9Hz) 2.98-2.88(21, mn) 2.63(111, dd, J=17, 12Hz) 2.49(11, m) 2.23(111, mn) 1.97(111, in) 1.78-1.63(3H1, in) 336 FxamI2le 121 1-oxo-2-thiopropyll]nmino-R-Qxo-11-phenyl- 1.,3.4.FL7.8.12h-oc-tahvdronvridor2.1-a][r2lbenzazelpine-4-can-boxylin acid 0 Br s s NH s R SH Nf O s

HOOC

1 H-NMR (400 MHz, CDCl 3 )6; 7.67(lH, d, J=8Hz) 7.51(2H1, d, J=8Hz) 7.43(2H, t like, J=8Hz) 7.39-7.32(3H1, m) 7.07(111, d, J=8Hz) 6.89(1H, d, J=4Hz) 6.66(111, d, J=411z) 5.66(111, quint, J=6Hz) 5.50(111, brd) 5.22(111, m) 3.62-3.49(2H1, m) 3.36(2H1, d, '=6Hz) 2.86(1H, dd, J=17, 13Hz) 2.54(111, m) 2.34(111, m) 2.15(111, d, JlO~z) 2.10- 1.71(4f1, m) 337 Fxample 122 r4S-r4t .1 2b1I1-7-r r(2S)-3-Ph(-nyl-1 -oxo-2thiometbvlpropyl 1aminio]-f-oxo-ll-nhe.nv azepjne-4-naiJ-oxv~Ie acid 7NH S R KSH 0 s

HOOC

1 H-NMR (400 MHz, DMSO-d6)6; 8.29(111, d, J=711z) 7.62(2H, d, J=8Hz) 7.46(3H, t, J=8Hz) 7.41(11, s) 7.38-7.17(7H1, m) 5.77-5.66(2H1, mn) 5.04(111, d like) 3.07-2.96(2H1, m) 2.90(iH, m) 2.73-2.64(2H1, mn) 2.55(111, mn) 2.43(1H, in) 2,.29(111, mn) 2.24(iH, in) 1.99(11, mn) 1.78-1.67(3H1, in) 338 Examal~aeJ2, amiol-s--oxo-11-phenvI-1 .2,3AG7.8-12h-o(,tq'hvdrQpyrirdo[2.1-;-'r2benznzeoine-4-cnrboxylie acid 0 Cf1 NH VRe

HOOC

1 H-NMR (400 MHZ, CDC1 3 )6; 7.55(111, d, J=7Hz) 7.51(2H1, d, J=8Hz) 7.42(111, t like, J=811z) 7.40-7.28(3H1, m) 7.09(111, d, J=811z) 5.71(111, quint, J=6Hz) 5.52(111, brd) 5.23(111, brd) 3.61(111, dd, J=17, 6Hz) 3.30(111, q, J=7Hz) 2.92(111, dd, J=17. 13Hz) 2.57(111, m) 2.37(111, m) 2.02(111, d, J=1I-Iz) 2,05-1.70(6H1, m) 1.50-1.20(4H1, m) 0.91(3H1, s) 339

I

0 ExainP-e 194 L4S.-L4n: 7a 1 2bf 11-7-fr r(9S) (2-Thlenvl I-oxo-2-thinprnnvllaminol-6-oxo-11-phenyl- 1.2-3-4.E67812b-octahdropyridoU21i-a1[~21hezazepJne-4arhxyIIc aniA 1 H-NMR (400 MHz, CDCl 3 )8: 7.67(111, d, J=611z) 7.51(2H1, d, J=8Hz) 7.43(2H, t like, J=8Hz) 7.38-7.32(3H1, m) 7.19(111, d, J=411z) 7.06(111, d, J=811z) 6.95(111, d, J=411z) 6.90(111, d, J=4H-z) 5.66(111, quint, J=6Hz) 5.49(111, brd) 5.2 3.64-3.54(2H1, mn) 3.50-3.40(2H1, mn) 2.84(111, dd, J=17, 1311z) 2.54(111, mn) 2.3 2.15(11, d, J=lOHz) 2.10-1.70(41, m) 1(1H1, in) 3 (1H1, m) 340 Exape 125 hvdropyridor2l-air2lhnazepi-ne-4-carhoxyllcI acid 0 NHs

R

SH

./N

O s

HOOC

1 1-NMR (400 MHz, CDC1 3 )8; 7.57(111, d, J=7Hz) 7.51(21, d, J=811z) 7.44(111 t like, J=8Hz) 7.38-7.32(3H1, m) 7.07(111, d, J=8Hz) 5.71(111, quint, J=611z) 5.52(111, brd) 5.23(1H, brd) 3.58(111, dcl, J=17, 6Hz) 3.32(111, q, J=7Hz) 2.81(111, dd, J=17, 13Hz) 2.54(111, m) 2.33(111, m) 2.09(111, d, J=10Hz) 2.10-1.67(6H, mn) 1.55-1.35(2H1, m) 0.94(3H, t, J=7Hz) 341 sul -Pony] aminophpnv1 -ox 2-thionrnp-,71a minoi- R-oxo-ll-phenv-1 2..4.A.7.8.12b-octaihvdropvridor2.1-alr2lbeu7pzepine-4-earhoxvlie acid

[L

3

CSO

2 NH sNH S

R

N SH 0,N

HOOC

IH-NMR (400 MHz, CDC1 3 6; 7.71(111, d, J=7Hz) 7.61(lH, brs) 7.47(2H1, d, J=8H-z) 7.40(2H1, t like, J=8Hz) 7.36-7.28(3H1, m) 7.22(111, d, J=811z) 7.16(11, d, J=811z) 7.03-6.98(3H1, m) 5.88(111, quint, J=811z) 5.45(111, brd) 5.06(11, d like) 3.63(111, m) 3.44(111, dd, J=17, 6Hz) 3.24-3.06(2H1, m) 2.90(3H, s) 2.82(111, dd, J=17, 13Hz) 2.51(11, m) 2.32(111, m) 2.20(11, d, J=lOHz) 2.05-1.70(4H1, m) 342 Fxaimp 127 I-o A--hropvlR* 2bomIn1-73-r r(2S-11-(3nv-bI 1-.2.3.4,6.7.8.12b-otadrprrcdo f2. 1 2herizniZe2i ne-4-carhnxv~I j _cid.

0 NH s R

SH

HOOC

1 11-NNIR (400 MHz, CDC1 3 )8: 7.64(111, d, J=711z) 7.50(2H1, d, J=811z) 7.43(2H1, t like, J=811z) 7.37-7.32(3H1, m) 7.26(111, d, J=8Hz) m) 7.03(111) d, J=8-z) 6.96(1H, d, J=5Hz) 5.64(111, quint, J=611z) 5.47(111, brd) 5.18(111, d like) 3.62-3.45(2H1,m 3.30-3.16(2H1, m) 2.80(111, dd, J=17, 13Hz) 2.04-1.67(4H1, m) 34,q Example 128 r4S-r4iy ,7ty(R) j 2b Il1-7-F (2-Mptbl v-oxo-2--thiopropyl)aminol-A-oxo-11-pllenvl-1.2.3.4.-7.8,12b-ocItahvdronvridoF2.1-alr21henzazepinel-4-crhoxin acid.

1 1-NMR (400 MHz, CDCi 3 )8; 8.11(111, d, J=7Hz) 7.50(2H, d, J=81Iz) 7.43(11, t like, J=8Hz) 7.38-7.32(3H1, mn) 7.08(1H, d, J=8Hz) 5.65(1H, quint, J=6Hz) 5.52(111, brd) 5.23(111, brd) 3.59(111, dd, J=17, 6Hz) 2.81(111, dd, J=17, 2.53(111, mn) 2.32(111, in) 2.32(111, s) 2.06-1.70(41, mn) 1.63(3H, s) 1.64(3H, s) Exam- I a1 99 r4S-r4ct7a(R*) o2boI 1-7rr(2)3(4-MetL 13Hz) 11-phenyl-1 2.3.4.9,7.8.-12b---otahviropvridof2.1-,-il,2[n n~pninp-4-arhoxvil acid 344 1 H-NMR (400 MHz, CDC13)6; 7.83 and 7.53(total 1H1, each brs) 7.60-7.02(total 12H1, m) 6.89 and 6.80(total 1H1, each d, J=8Hz) 5.66 and 5.64(total 1H1, ea-h quint, J=6Hz) 5.44(total 1H, m) 5.08 and 4.97(total 1H1, each brd) 3.54-3.00(4H1, m) 2.83 and 2.82(total 3H1, each s 2.72 and 2.20(total 2H1, m) 2.21 and 2.19(total 1H1, each d, J=1011z) 2.04-1.90(total 4H, m) Example 130 rAI-Ay7~* 2ll-7r (vjhxjloo2 3) oc tahvdropyri dor2. 1 -a l r21befzaze-pi11e--c~BnxJ)y J c aeJd (isomnerA) NfleS

R

0Os

HOOC

1 1-NMR (400 MHz, CDC1 3 )6; 345 7.44(iIi, t like, J=8Hz) 7.38-7.32(3H1, m) 7.07(111, d, J=:8Hz) 5.62(i.H, quint, J=6Hz) 5.43(1IH, brd) 5.24(111, brd) 3.59(111, dd, J=17, 6Hz) 3.35(111, q, J=7Hz) 2.80(111, dcl, J=17, 13Hz) 2.53(111, m) 2.33(111, m) 2.06-1.63(9H1, m) 1.91(1H, d, J=l0Hz) 1.34-1.96(6H1, m) Exampe 131 F4S-r4cx7ty(R*) 1 2hp1-7-F Iohxy-1 -oxo-2.- _hi nt'hyl )amino I-6-oxo-1 1-1henyl -1 .2 .34-!L7. 1h octahydropyrjdor2.1-a1[2'Ib nzazopine-4-carboxylinc q(-iA 0

HOOC

1 H-NMR (400 MHz, CDCl 3 )6; 7.53(111, d, J=711z) 7.51(2H1, d, J=811z) 7.05(111, d, J=8Hz) 5.61(111, quint, J=6H-z) 5.51(111, brd) 5.21(11, brd) 3.57(111, dd, J=17, 6Hz) 3.42(111, dcl, J=7, 6Hz) 346

I

2.90(111, dd, J=1.7, 13Hz) 2.52(111, m) 2.31(111, m) 2.04-1.64(11, m) 1.90(111, d, J=1011z) 1.36-1.95(6H1, m) ExampleI 139 2-thioel .7yl 12-h-ox-1-U2n-Cv1on2nv--.7.2octahydropyridoF2.1-aJI21lhenz7,zeppine-4-Carboxylic acid 0 -y NH- s R SH if-N O s

HOOC

1 H-NMR (400 MHz, CDC1 3 )6; 7.45(2H1, d, J=8Hz) 7.40-7.25(611, m) 7.02(111, d, J=8Hz) 5.66(111, quint, J=6Hz) 5.47(111, m) 5.17(111, d like) 3.54(111, dd, J=17, 6Hz) 3.13(111, t, J=7Hz) 2.85(111, dd, J=17, 13Hz) 2.49(111, m) 2.33-2.20(2H1, m) 2.00-1.46(10H1, m) 1.97(111, d, J=811z) 1,37-1.23(2H1, m) 347 th loethyl)qmi no] -g-oxo-1 1-phbenvi -1 ,2.3 .7 .8,2boctahvrpvio2-12bnzeie4crxvc R)i iNH s R SH 0/

NS

HOOC

1 H-NMR (400 MHz, CDC1 3 )8; 7.45(2H, d, J=8Hz) 7.40-7.24(11, m) 7.03(111, d, .1=8Hz) 5.67(111, quint, J=6Iiz) 5.47(111, m) 5.19(111, di like) 3.57(1H, dci, .1=17, 6Hz) 3.31(lH, t, J=7Hz) 2.88(111, cid, J=17, 13Hz) 2.50(111, m) 2.36-2.22(2H1, m) 1.98(111, d, .1=8Hz) 2.02-1.18(12H, m) 348 00 NH~p~ 134 rSs-r4 N i~xn.2-tiopopv1h~mno1 ~-ox-1 -phn~d 1 .234.fL.8.12-oetHvoio21a][1~z 'H-pNMR 400 MHz, CD13 8;i 7.9(11 =8z 7432 lk =/z 7.39-732(4Hm) 7. 7- m)'N (l ,bdJ8z 7.2- .9 (2 .6 (l ui tJ=0z 2I{NMR (00 M~d,CD~l 3 20-16(4,m 349 Fxarp 135 f4Sr(4u.7(R*) 12ho I I7f(3-Pt 11-o~xo-thiObydropvi-ido[2.1-alfi21benzaZepine-4.-carhoxylie iicid

CH

3 0 CHa 3J RSA NHs H S R

N

HOOC

1 H1-NMIR (400 MHz, DMSO-dB)8; 8.42 and 8.38(total 1H1, each d, J=7Hz) 7.62(2H1, d, J=8Hz) 7.46(3H1, t, J=8Hz) 7.41(1H, s) 7.35(111, t, J=8Hz) 7.18(total 1H1, each d, J=8Hz) 5.77-5.65(total 211, m) 5.06(total 1H-, d like) 3.58 and 3.54(total 1H1, each t, J=711z) 3.30-3.17(total 111, in) 2.58-2.47(total 1Hi, mn) 2.23(111, in) 1.98(111, in) 1.80-.l.601,BH, in) 0.7(HtJ=Hz 0-23Ht0- =Hz E-XampIp 1a6 thiobutV jarninQl-6-oxn--1-phenyl-1.2.3.4A.7.8,12b- 1 H-NMR (400 MHz, CDC1 3 )6; 7.56-7.92(11, m) 7.52-7.30(7H1, m) 7.10-6.94(11, m) 5.81-5.66(11, m) 5.56-5.48(11, m) 5.26-5.19(11, m) 3.68-2.85(3Hi, m) 2.53(111, brd) 2.34(111, brd) 2.08-1.70(5H1, m) 2.17(total 1H1, each d, J=811z) 2.05 and 2.17(total 1H1, each d, J=811z) 1.40 and 1.96(total 3H-, each d, J=7Hz) 351 2-thioiltyv1smi no I-B3--oxn-1 1 -pnvl-1.92.4 G. 4 7.1 2oe-ayr~v-dr--i~bn7.,,zie4(,lb-vi- acid

CH

3 0 K S NH S R SH /N

HOOC

'H-NMR (400 MHz, CDC1 3 Y8; 7.84(111, d, J=7Hz) 7.51(2H1, d, J=8Hz) 7.43(2H1, t, J=8Hz) 7.38-7.31(3H1, mn) 5.53(111, mn) 5.25(111, in) 3.70(111, quint, J=711z) 3.62(1H, dd, J=17, 6Hz) 3.40(3H1, s) 3.39(1H, t, J=711z) 2.94(111, dd, J=17, 13Hz) 2.55(111, mn) 2.36(111, in) 2.27(111, d, J=81{z) 2.08-1.72(4H1, in) 1.30(3H1, d, J=7Hz) 352 Fxample 138 hexyl-) ami no]I -9-oxo-1 1 -phe-.nvl -1 .7 -8 .1 2bh-oentahvdropyrido[2.1-alr21henzazepine-4-earboxylic- acid

CH

3 0

H

3 C ^'NH s R SH

/N

HOOC

1 H-NMR (400 MHz, CDCl 3 )6; 7.70 and 7.61(tota. 1H1, each d, 3=7Hz) 7.50(21, d, 3=8Hz) 7.43(2H, t, J=8Hz) 7.40- 7.30(3H1, m) 7.07 and 7.O6(total. 1H1, each d, J=8Hz) 5.71(111, quint, 3=6Hz) 5.52(1H, m) 5.23(1H, m) 3.59(111, m) 3.29(1H, dd, J=17, 12Hz) 2.92(lH, ad, J=17, 12Hz) 2.54(111, m) 2.34(111, m) 2.10-1.94(2H1, m) 1.94-1.82(11, m) 1.80-1.70(11, m) 1.56(111, m) 1.41(111, m) 1.35-1.14(2H1, m) 1.03 and 1.02(total 311, each d, 3=7Hz) 0.92 and 0.91(total 311, each t, 3=7Hz) 353 E~xample 139 (4-mornhbo Iinvyl )actvlthio-.i.,-oxopentyv1 minlaI26zn-Dxaz-1.

phenyl-1 .2.3.4.6r,7.8.12b-octabyrropvridor2Ai--,1 21henzazepine-4-c.arhoxylin nicid trifluDorDA-ce±,apte

H

3 C \S YNH. f R

CF

3

COOH

o 0 HOOC jphenylnethyl F4S-F4.g.7H*)~.12bpll-7-r(L2s ,3-methyl-i -oxo-2-thi onpntvl 11 mi nol -r-oxo-1 1-Tphenyi 1.2.3 &,6.7.8-12b-oetabvdrnpyridor2-l-aF2-3hzl azepi ne-4-carboxylata, 354 0 0.500 g (0.730 mmol) of diphenylmethyl [4S- 1l2bP]]-7-[ [K2S,3S)-2-acetylthio-3-methyl-loxopentyl Iaminio]-6-6-oxo-11-phenyl- 2,3,4,6,7,8, 12boctahydropyridol2,1-a] 12]benzazepine-4-carboxylate obtained in the Example C-6 was dissolved in 10 ml of dry ethanol. To the solution thus obtained was added ml of a 12% ammonia-ethanol solution under cooling with ice. The resulting mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure and diluted with dichloromethane. It was washed with water and a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. Thus, 0.468 g of the title compound was obtained as white crystals (yield 99%).

IH-NMR (400 M Hz, CDCl 3 )6; 7.72(111, d, J=6Hz) 7.50-6.92(17H, mn) 6.70(111, d, J=81iz) 6.30(11H, s) 5.67(111, dt, J=13, 6Hz) 5.49(lH, in) 5.42(111, d like, J=4Hz) 3.45(111, dd, J=18, 61-z) 3.28(111, dd, J=8, 7Hz) 2.61(11, dd, J=18, 13Hz) 1.62-2.08(6H1, mn) 1.37-1.25(111, mn) 1.06(0H, d, J=7Hz) 0.96(311, t, J=7Hz) 355 3-methvl-2.-(4-morphol invl Paeetylthlio-l-ooopnt-v1 Ia~mino1-6-oxo-1 1-phenvi -1.2.3.4.R.7.&J-L2ocaab3dro pyrido.l-a1F2lbenz.azepine-4-carboxylate

CH

3 0

H

3 C ~s \Y NH s R 0 0 0~ 0.262 mg (1.44 mmol) of 4-morpholinylacetic acid hydrochloride was dissolved in 7.2 ml of degassed dry dimethylformamide. To the solution thus obtained was added 0.176 g (1.08 mmol) of carbodinylimidazole under cooling with ice. The resulting mixture was stirred -t room temperature for 1.5 hours. The obtained mixture was cooled with ice again and a solution of 0.467 g (0.72 mmol) of diphenylmethyl [4S-II4c,7a(R*), l2bp] F (2S, 3S)-3-methyl-l-oxo-2-thiopentyllamino]- 6-oxo-1l-phenyl-l, 2,3,4,6,7, 8, 12b-octahydropyrido- [2,l-aI [2]henzazepine-4-carboxylate obtained in the 356

I

above in degassed dry tetrahydrofuran (7.2 ml) was dropped thereinto. The obtained mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure until the volume of the liquid was reduced to about one-half. Ethyl acetate was added thereto and the resulting mixture was washed with a sa 4 urated aqueous solution of sodium hydrogencarbonate and a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. Thus, 0.500 g of the target morpholino compound was obtained (yield H-NMR (400 MHz, CDC1 3 )6; 7.54(1H, d, J=6Hz) 7.49-6.92(17H, m) 6.67(1H, d, J=8Hz) 6,29(1H, s) 5.64(1H, dt, J=13, 6Hz) 5.44-5.49(1H, m) 5.40-5.36(1H, m) 3.99(1H, d, J=7Hz) 3.80(4H, t, J=5Hz) 3.41(1H, dd, J=16, 7Hz) 3.35(2H, s) 2.71-2.60(4H, m) 2.60-2.44(2H, m) 2.21-1.59(7H, m) 1.31-1.91(1H, m) 1.06(3H, d, J=7Hz) 0.94(3H, t, J=7Hz) 357 (c r45-r4 .1 2 hp11-7-r 3 )-3-mthvl marrnhnlinv ace tylth i o- 1- oxopenn ttyll.qm Inoll -6 -oxo-1 1 p.Lenyl-1 4. R. 7 .8R. -oc-tahvcropyridior9.1-a] henzazpi ne-A-earboxyllc, acid trifuoraace-tate CH3g 0

H

3 C s S NH s R CF 3

COOH

S N 03 0 HOOC Into a solution of 0.500 g (0.65 mmol) of diphenyimethyl 4S- [4a, a R 12bo3-7- (S,3S)methyl-2-(4-morpholinyl)acetylthio-l-oxopentylaminol- 6-oxo-l1-phenyl-l,2,3,4,6,7,8,12b-octahydropyrido- [2,1-a][2]benzazepine-4-carboxylate obtained in the above and 0.54 ml (5.00 mmoi) of anisole in dichloromethane (6.2 ml) was dropped 0.95 ml 12.00 mmol) of trifluoroacetic acid at -50 0 C. The mixture thus obtained was heated to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was recrystallized from diethyl ether-hexane. Thus, 0.414 g of the title compound was obtained (yield 89%).

358

I

'H-NMvR (400 MHz, CDC1 3 )6; 7.59-7.30(8H, in) 7.09(111, d, J=9Iiz) 5.74-5.65(14, mn) 5.54-5.47011H, in) 5.20-5.14(14, in) 4.06(1H, d, J=7Hz) 3.81(4H4, in) 3.67(211, s) 3.54(111, dd, J=17, 6Hz) 3.52-3.30(211, br) 3.02-2.90(1-, mn) 2.55(114, brd) 2,36(1H, brd) 2.17-1.74(5H, in) 1.66-1.55(14, in) 1.26-1.14(114, in) 1.03(3H4, d, J=714z) 0.92(3H1, t, J=714z) rxY~mp1P 140 .4S.-fr4.7iR) 1h I1-7-1r (2R..3s)-2-(Diethy1jno)n acet~y Ithio-S-me±thv1--1J-oxopenJt1 I am ino I -A-oxaz.I1t.

pbenyl-1 .7.8.12h-oci:ahydropvyridor2.--1 r21bnzaz2J2.jne-4-(carhoxylic acid trji1=naro -et~a

CH

3 o S NH s R CF 3 000H s 0

/N

HC 0

HOOC

In the same method as that of Example 139 except that 0.526 g (3.34 mmiol) of N,N-dlethylailnoacetic acid hydrochloride was used in place of 4-morpholinyl- 359 acetic acid hydrochloride, and starting with 1.1 g (1.-57 mmol) of' diphenylmethyl 4S- 4a~,7a 1l2b P] L-7- [iE(2S,3S)-3-methyl-1-oxo-2--thiopentyl]aminol-6-oxo- 11-phenyl-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a] benzazepine-4-carboxylate, 0.89B g of the title compound was obtained at a yield of 81% through two steps.

IH-NNIR (400 MHz, CDC1 3 8; 7.79(111, d, J=7H-z) 7.50-7.03(8H1, m) 5.75(111, dt, J=13, 6Hz) 5.55-5.48(11, m) 5.18-5.16(11, m) 4.22(111, d, J=7Hz) 4.14-4.04(2H1, m) 3.46(111, dd, J=17, 6Hz) 3.30-3.20(41, m) 2.98(111, dd, J=17, 13Hz) 2.57(111, brd, J=l2Hz) 2.40(11, brd, J=12Hz) 2.17-1.74(5H1, m) 1.67-1.56(11, mn) 1.25(6H1, t, J=7Iiz) 1.28-1.16(11, m) 1.050H1, d, J=7Hz) 0.92(3H, t, J=7Hz) 360 RExampnp 141 L1.zj-mazolinn I antylth I methyl- I-nxopentv1 1nmjno (6-oxo-1 1 -npnvl -1 S 7.8 R012-octa~hydrppyrj dnr2.1-alr2lbhenzaepinea-4-crboxvn~y-ic acid

CH

3 o H SA NH s R -CF3COOH 0 HOOC In the same method as that of Example 139 except that 0.287 g (1.76 mmol) of l-inuidazolylacetic acid hydrochloride was used in place of the 4-morpholinylacetic acid hydrochloride, and starting with 0.570 g (0.88 mmol) of diphenylmethyl 4S-[4a,7a(R*),l2bP]]-7- [[(2S,3S)-3-.methyl-l-oxo-2-thiopentyllamino]-6-oxo-llphenyl-l,2,3,4,6,7,8,12b-octahydropyrido[2,l-aj benzazepine-4-carboxylate, 0.355 g of the title compound was obtained as a white amorphous product at a yield of 57% through two steps.

1 1-NMR (400 MHz, GA)Cl 3 )8; 8.37(111, brs) 7.69(lH, d, J=7Hz) 7.53-7.25(7H1, m) 361 7.09(11, brs) 7.03-6.98(21, in) 5.65(111, dt, J=13, 6Hz) 5.48-5.42(11, mn) 5.10-5.04(111, mn) 5.01(111, d, J=18Hz) 4.92(111, d, J=18Hz) 4.16(11, d, J=6Hz) 3.41(-H, dd, J=17, 6Hz) 2.92(111, dd, J=17, 13Hz) 2.55(111, brd) 2.320iH, brd) 2.16-2.07(11, in) 2.04-1.86(21, mn) 1.83-1.72(2H1, mn) 1.67-1.55(111, mn) 1.23-1.10(1H1, in) 1.03(3H1, d J=711z) 0.92(3H1, t, J=711z) Fxample 142 pentvllmino-2345-tetrahdr-1T-rllenza~zepin- 2-one1

OH

3 o

H

3 C s' NH*

S

0>

GOOH

In accordance with the Example 117, 'fle title compound was synthesized.

1 1-NMR (400 MHz, CDC13)8; 7.60(11, brd, J=711z) 7.33-7.14(4H1, mn) 4.70(11, d, J-17Hz) 4.53(111, dt, J=11, 7Hz) 4.44(111, d, J=17Hz) 3,35-3.24(2H, m) 362 2.74-2.59(2H, mn) 2.06-1.96(2H1, m) 1.74(111, d, J=911z) 1.44(11, m) 1.26(111, m) 0.87(6H1, m) FXarnple 143 Fthyl (3S)-rr(2S.3S)-2-acetvlthin--metbyl-l-oxoberizoxaizepi

CH

3 o

H

3 C 1 0

SCOH

COOC

2

H

528 mg of ethyl (3S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate and 419 mg (1.1 eq.) of (2S,3S)-2-acetylthio-3-methylpentanoic acid were dissolved in 40.ml of methylene chloride. To the solution thus obtained was added 544 mg (1.1 eq.) of EEDQ under cooling with ice. The resulting mixture was -,"urther stirred at room temperature for 21 hours.

The reaction mixture was made weekly acidic by adding 1 N hydrochloric acid under cooling with ice, and the methylene chloride phase was separated. After the methylene chloride phase was washed with an aqueous sodium chloride twice, it was dried over anhydrous 363 magnesium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (ethanol :chloroform 1.5 :98.5 4 Thus, 370 mg of the title compound was obtained.

IH-NMR (400 MHz, CDCl 3 8: 7.14-7.25(41, m) 7.04(111, d, J=7Hz) 4.94(111, dd, J=10, 7Hz) 4.69(11, dd, J=10, 7Hz) 4.68(11, d, J=l8Hz) 4.33(111, d, J=l8Hz) 4.25(2H1, q, J=7Hz) 4.13(111, t, J=l0Hz) 3.92(111, d, J=7Hz) 2.37(3H1, s) 2.02(111, m) 1.56(11, m) 1.2603h, t, J=711z) 1.14(111, m) Exa~mple 144 (3s)-rr(2sq..s4-3-Methv1-l-oxo-2-thiopentyl1aminol-4-oxo-2.3.4.5-teti-r~hvdiro-1

CH

3 o H \C S

NH

SH 0N

COOH

360 mg of ethyl (3S)-[[(2S,3S)-2-acet~v'lthio-3methyl-l-oxopentyl~amino] -4-oxo-2,3,4, 1,5-benzoxazepine-5-acetate obtained in the Example 364 143 was dissolved in 6 ml of degassed ethanol. To the obtained solution was added a degassed 1 N aqueous solution of sodium hydroxide under cooling with ice.

The obtained mixture was stirred at room temperature for 30 minutes and then made weakly acidic by adding 1 N hydrochloric acid, followed by extraction with chloroform (15 ml x The organic phase was washed with water and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 250 mg (yield 83%) of the title compound was obtained.

IH-NMR (400 MHz, CDC1 3 )8: 7.47(12, d, J=7Hz) 7.18-7.29(4H, m) 4.90(1H, dt, J=10, 7Hz) 4.78(1H, d, J=18Hz) 4.69(1H, dd, J=10, 7Hz) 4.30(1H, d, J=18Hz) 4.22(1H, t, J=O1Hz) 3.23(1H, dd, J=9, 6Hz) 1.94(1H, m) 1.88(1H, d, J=9Hz) 1.53(1H, m) 1.22(1H, m) 0.96(3H, d, J=6Hz) 0.87(3H, t, J=7Hz) 365 Example 145 r3T?-r3tL. 6 1 yas*) anni i-E-r r(9,R3S1)-3-Mg-thv1 -1 -oxo-2azepn--crhoxyvli c id CHI o

H

3 C, *jR S. NH S R SH 0N S

HOOCR

In accordance with Example 144, the title compound was synthesized.

1 1-NMR (400 MHz, CDCl 3 )8; 7.80(111, d, J=6Hz) 5.30(111, dd, J=7, 2Hz) 5.08-5.06(11, m) 4.63(11, dd, J=11, 6Hz) 3.37-3.33(2H1, m) 3.22(111, dd, J=12, 7Hz) 2.14-1.90(611, m) 1.79(111, d, J=9Hz) 1.75-1.64(11, m) 1.55-1.43(11, m) 1.36-1.22(1H, m) 0.92(3H1, d, J=7Hz) 0.92(3H, t, J=7Hz) 366 Exa~mple 146 r~ x-6a n-q t -n rr(,.q )2 ~v thi omethyl -3-methyl-i -oxonPtv 11amino 1 -nnithvdio-Sox()thlazolr39.2-qlazenlne-3-carboxvlfro acid CHa o

H

3 C S N S N R SCO CH 3 0' N

S

HO OC; 0.200 g (0.550 mmol) of [3R-[3a,6a(S*) 9ap] [[(2S,3S)-3-methyl-l-oxo-2-thiopentyl]amino]octahydro-5-oxothiazolll3,2-alazepine-3-carboxylic acid obtained in the Example C-8 and 0.058 nil (0.610 mmol) of acetic anhydride were dissolved In 6 ml. of acetonitrile-tetrahydrofuran (1 The obtained solution was dropped into a solution of 0.022 g (0.170 mmol) of cobalt (II) chloride in 5 ml of acetonitrile.

After the mixture thus obtained was stirred for 7 hours, it was concentrated under reduced pressure, and water was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residual solid was 367 recrystallized from ethyl acetate-diethyl etherhexane. Thus, 0.180 g of the title compound was obtained as white crystals (yield IH-NMR (400 MHz, CDC1 3 6: 7.44(111, d, J=6Hz) 5.30(111, dd, J=7, 2Hz) 5.05(111, t like, J=5Hz) 4.60(111, dcl, J=11, 6Hz) 3.97(111, d, J=7Hz) 3.35(11, dd, J=12, 2Hz) 3.21(111, dd, J=12, 7Hz) 2.38(0H, s) 2.14-1.86(6H, m) 1.72-1.52(2H1, m) 1.24-1.10(11, m) 1.00(3H, d, J=7Hz) 0.88(31, t, J=7Hz) Example 147 t sR r (29. SR) -9,-Ace(-tyl thi n-.3-rmetbyl -1 -oxopnty] I ami nol S-tetjrahvdror-11I- r 1 1benzzep~jn- 2-ni CFL o

H

3 C s" S NH S Ot/ SCOCH3 C OOH 0.547 g (1.5 mmol) of (S)-l-carboxymethyl-3- 2,3,4,5-tetrahydro-1H-[1)benzazepin-2-onie obtained in the Example C-1l and 0.168 ml (1.650 mmol) of acetic 368 anhydride were dissolved in 7 ml of acetonitrile. The obtained solution was dropped into a solution of 0.075 g (0.577 mmol) of cobalt (II) chloride in 10 ml of acetonitrile. After the mixture thus obtained was stirred for 2 hours, it was concentrated under reduced pressure, and water was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Thus, 0.43 g of the title compound was obtained as a colorless amorphous product.

1 H-NMR (400 MHz, CDC1 3 )6; 7.30-7.09(5H, m) 4.76(1H, d, J=17Hz) 4.49(11, dt, J=1l, 7Hz) 4.39(1H, d, J=17Hz) 3.88(1H, d, J=7Hz) 3.30(1H, m) 2.70-2.50(2H, in) 2.35(3H, s) 2.02-1.82(2H, m) 1.53(1H, m) 1.11(1H, m) 0.93(3H, d, J=7Hz) 0.84(3H, t, J=7Hz) Examples 148 to 152 In accordance with the processes of the above Examples 101 to 108, compounds of Examples 148 to 152 were obtained.

369 Fxamplp 148 -LASilF4a.h(P3* .32h I1-7-r r( US-'S) -3-Nethvl -1 -oxo-2,pyri do[ 2.1-,q i 2henzazepine-4-yarboxylin acid

H

3 C ,yJk NH s R

N

COOH

1 H-NMR (400 MHz, CD30D)6; 7.69(21-1, d, J=811z) 7.17-7.05(3H1, m) 7.02(111, d, J=811z) 5.69(111, quint, J=811z) 5.48(111, brd, J=6Hz) 5.20(111, m) 3.52(111, dd, J=17, 6Hz) 3.21(111, dcl, J=9, 7 Hz) 2.90(111, dcl, J=17, 13Hz) 2.50(111, m) 2.35(111 m) 1.92-2.03(2H1, mn) 1.92(111, d, J=811z) 1.27(111, mn) 1.02(3H1, d, J=711z) 0 -1311, J=711z) 370 Exaiple 149 rs 2-alazepi ne-3-carboJljn nni

H

3

C

S NH R 'R0 SH N S HO OC4 1 1-NMR (400 MHz, CDC1 3 )8; 7.78 and 7.84Ctota. 1H1, each d, J=7Hz) 5.56-4.58(3H, m) 3.82-2.92(3H, in) 2.34-1.45(9H1, m) 1.30-1.18(11, m) 0.88-1.00(61J. im) T~xmnl(-e 150 Ln-rae~.a-ai -R-frr(S)-4-Methvl -jD2 1Jabionpentyll 1aminol-octahdro-5-oxothla,,io1 FS 2-a]aZepine-S-nsrhoxvljn acidj 0 Y^ NH s

O

3 SH IQ fN HOOC4 -371 'H-NMR (400 MHz, CDC1 3 )6; 7.56-7.60(1H, t like) 5.29(1H, dd, J=7, 3Hz) 5.08-5.06(lH, m) 4.65-4.61(111, m) 3.40-3.33(2H1, m) 3.23(111, dd, J=12, 7Hz) 2.08-1.90(6H1, m) 1.88-1.64(3H1, m) 1.60-1.52(11, mn) 0.94(3H1, d, J=6Hz) 0.90(3H1, d, J=711z) Example 151 aminol-octavriro--5-oxothi~izo1 [3.2-,ilag~pine-- 0 H3C NH S R SH /N S HO0C 1 H-NMR (400 MHz, CDCI.

3 7.58(111, d, J=6Hz) 5.30(111, dd, J=7, 2Hz) 5.07(111, t like, J=511z) 4.59-4.64(11, m) 3.36(111, dd, J=12, 31-z) 3.30(11, dt, J=8, 7Hz) 3.22(111, dd, J=12, 7Hz) 2.10-1.90(6H1, m) 2.00(111, d, J=8Hz) 1.76-1.64(2H1, in) 1.46-1.24(4H1, m) 0.90(3H1, t, J=71Hz) 372 EXample 152 3-methyl -1-oopentyl lqmlno -Octahdro--oxth jj7nl r3,2-ai]zepine-3-narboxv1ic acid

CH

3 0 H3C S S NH

R

S /N S 0 HOOC4 In the same procedure as that of Example 146 except that benzoyl chloride was used In place of the acetic anhydride, the title compound was obtained as a white product (147 mg, yield 51%).

1 1-NMR (400 MHz, CDCl 3 8, 0,92(3H1, t, J=7Hz) 1.06(3H1, d, J=6Hz) 1.20-1.30(11, m) 1.58-1.72(2H1, mn) 1.90-2.03(5H1, m) 2.13-2.23(11, mn) 3.19(111, dd, J=7, 12H-z) 3.33(1H, dd, J-2, 12Hz) 5.02-5.08(11, m) 5.28(11, dd, J=2, 71Hz) 7.43-7.61(4H, m) 7.97-7.99(2H1, m) 373

Claims (19)

1. An amino acid derivative of the formula (VII) or a pharmaceutically acceptable salt thereof: CH, 0 N"J H (VII) e see@ 0 0 0000 so *eO* 00 S 0e V 00 0* eq S *S I wherein R' represents a hydrogen atom or an acyl group; and J represents a cyclic group having an angiotensin I-converting enzyme inhibition activity selected from any one of the groups (iii), (iv) and COR COOR' R14 0 O c 0 e COOR' wherein R 3 represents a hydrogen atom or a carboxyl-protecting group; Y 3 represents a group represented by the formula -(CH 2 (wherein w represents 0 or a group represented by the formula a group represented by the formula a group represented by the formula -SO 2 a group represented by the formula or a group represented by the formula -NR 6 (wherein R 6 represents a hydrogen atom, a lower alkyl 7 group); R' 0 represents ahydrogen atom, a lower alkyl group, a lower alkoxy group, a -I P'\OPBHIRMM I 1\69366.341 1/4/97 -375 hydroxyl group, a halogen atom, an aryl group which may have a substituent or a heteroaryl group which may have a substituent; R" and R' 2 are the same or different from each other and each represents a hydrogen atom or a lower alkyl group; Y' represents a group represented by the formula (wherein x represents 0 or a group represented by the formula a group represented by the formula a group represented by the formula -SO 2 a group represented by the formula or a group represented by the formula -NR 1 7 (wherein R' 7 represents a hydrogen atom or a lower alkyl group); R 1 3 represents a group represented by the formula (wherein R 1 9 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group or a halogen atom) or a group represented by the formula -NHS0 2 R 1 8 (wherein R 1 8 represents a hydrogen atom, a lower alkyl group or an arylalkyl group which may have a substituent); R 1 4 and R 1 5 represent each a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, an aryl group which may have a substituent or a heteroaryl group which may have a substituent; and s, t and u each independently represent **ct an integer of 0, 1 or 2.

2. An amino acid derivative according to claim 1, wherein the compound of the formula a* (VII) is represented by the formula (VII'): CH 3 0 SR' wherein R' and J each have the same meaning as defined in claim 1. -I, 11 \OI'ER\RMI 1\6936( 6 4 341 14/4/-77 376

3. An amino acid derivative according to claim 2, wherein J in the formula (VII') is selected from any one of the groups and *0 50 o we 5 0 0*ge S. S. 5 4 0G oc S 3 Si S 04 4* *6 S S.. S* 54 0.n 4* 0 (ii') (iii') (iv') 44 a e a. S S wherein RW, R1 2 R 1 3, R1 4 R15, y4, S, t and u each have the same meaning as defined in claim 1.

4. An amino acid derivative of the following formula or a pharmaceutically acceptable salt thereof. 0 CHcoolH 11 \OPIRHM11\69366-. '1 14/41VI -377 An amino acid derivative of the following formula or a pharmaceutically acceptable salt thereof. OH 3 0 SH NH COOH .6 6 6 i.e. e* 6 0666 @6 6. 0 '~666 .0 *6 6 6E C deOi S. .id CO 6 .6 6 3666 *960

6. An amino acid derivative of the following formula or a pharmaceutically acceptable salt thereof. CI{3 0 s1{ 0 P COBH P \I'2t\J~IIi\6366)I3411 14,4/1 378

7. An amino acid derivative of the following formula or a pharmaceutically acceptable salt thereof. CH3 0 CH 3 1H SH 00011 00*~ Ia 0. a 0* ye 06 I 6e* I. CG 't 6 '~a4

8. An amino acid derivative of the following formula or a pharmaceutically acceptable salt thereof. 2Cl' 3 COOl'

9. An amino acid derivative of the following formula or a pharmaceutically acceptable salt thereof. COGH I l'\OI' R\RMIMH\69366 9 3. 14/4/i 379 An amino acid derivative of the following formula or a pharmaceutically acceptable salt thereof. CH 3 N N NH SH 0/ COOH

11. A pharmaceutical composition comprising an amino acid derivative, or a pharmaceutically acceptable salt thereof, according to any preceding claim and a So,, pharmaceutically acceptable carrier or diluent. °O

12. A method for treating or preventing diseases which comprises administering a therapeutically or prophylatically available dose of an amino acid derivative or a pharmacologically acceptable salt thereof according to any one of claims I to 10 or a composition according to claim 11 to a patient with a disease against which an angiotensin I- converting enzyme inhibition activity is efficacious. 0o 0

13. A method for treating or preventing diseases which comprises administering a therapeutically or prophylactically available dose of an amino acid derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10 or a composition according to claim 11 to a patient with a disease against which a vasopressin antagonism is efficacious. 0

14. A method for treating or preventing diseases which comprises administering a therapeutically or prophylactically available dose of an amino acid derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10 or a composition according to claim 11 to a patient with a disease against which an atrial natriuretic peptide hydrolase inhibition acitivity is efficacious. P:\OPR\RMH\69366.4.341 16419 -380- A method for treating or preventing diseases which comprises administering a therapeutically or prophylactically available dose of an amino acid derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10 or a composition according to claim 11 to a patient with heart failure.

16. A method for treating or preventing diseases which comprises administering a therapeutically or prophylactically available dose of an amino acid derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10 or a composition according to claim 11 to a patient with hypertension.

17. A method for treating or preventing diseases which comprises administering a therapeutically or prophylactically available dose of an amino acid derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10 or a composition according to claim 11 to a patient with a disease against which a diuretic activity is efficacious,

18. An amino acid derivative according to any one of claims 1 to 10 substantially as hereinbefore described with reference to the Examples (excluding the comparative Examples). S

19. A pharmaceutical composition according to claim 11 substantially as hereinbefore described with reference to the Examples (excluding the comparative Examples).

20. A method for treating or preventing diseases according to any one of claims 12 to 17 *S substantially as hereinbefore described with reference to the Examples (excluding the comparative Examples). DATED this 16th day of APRIL, 1997 Eisai Co., Ltd. by DAVIES COLLISON CAVE i Patent Attorneys for the Applicant(s) -I I- _I~ INTERNATIONAL SEARCH REPORT International application No. PCT/JP94/00947 AI CLASSIFICATION OF SUB!ECT'MATI R Int. C15 A61K31/47, A61K31/55, A61K37/02 According to International Patent Classification (1PC) or to both national classification and IPC B. FIELDS SEARCHED A. CLASSIFICATION OF SUBJECT MATTER Int. C1 5 A61K31/47, A61K31/55, A61K37/02 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Int. C1 5 A61K31/47, A61K31/55, A61K37/02, C07D215/00, C07D223/16, Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) CAS ONLINE C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. P, X US, A, 5238932 (Merrell Dow Pharmaceuticals, 1-55 Inc.), August 24, 1993 (24. 08. 93) WO, A, 9323397 P, X J. Med. Chem. 36 2420-2423 1-55 (1993 August) X EP, A, 533084 (Schering Corp.), 1-55 March 24, 1993 (24. 03. 93), AU, A, 9226506 X EP, A, 481522 (Merrell Dow Pharmaceuticals 1-55 Inc.) April 22, 1992 (22. 04. 92) JP, A, 4-282382 P, X JP, A, 6-56790 Squibb Sons, Inc.), 1-55 March 1, 1994 (01. 03. 94), AU, A, 9338627 Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: laterdocumentpublishedaftertheinternational filngdateorpriority Sgodate and not in conflict with the application but cited to understand document defining the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance earlier document but published on or after the international filing date document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) document of particular relevance; the claimed nvention cannot be Si i iiconsidered to involve an inventive step when the document is document referrig to an oral disclosure, use, exhibition or other combinedwithoneormoreothersuchdocuments,suchcombination means being obvious to a person skilled in the art document published prior to the international filing date but later than the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report July 6, 1994 (06. 07. 94) July 26, 1994 (26. 07. 94) Name and mailing address of the ISA/ Authorized officer Japanese Patent Office Facsimile No. Telephone No. Form PCT/ISA/210 (second sheet) (July 1992) ~I I 'I INTERNATIONAL SEARCH REPORT International application No. PCT/JP94/00947 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANTI Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. P, A JP, A, 5-294963 (Merrell Dow Pharmaceuticals 1-55 Inc November 9, 1993 (09. 11. 93) EP, A, 534363 Form PCTI/ISA/21O (continuation of second sheet) (July 1992) WNTRNATIONAL SEARCHI REPORT International application No. PCT/JP94/00947 B (Continuation). FIELDS SEARCLHD C07D267/OO, C07D281/OO, CO7D47.1/OO, C07D487/OO, C07D495/OO, C07D498/OO, C07D513/OO, C07D521/OO, C07K5/OO I- Form PCr/ISAfl1O (extra sheet) (July 1992) 1MWIv PC/J 94/00947 A. c}1 (I PC)) Int.CUs A6 1K3 1/4 7, A6 1K3 1/5 5, A61IK3 7/0 2 B. rnt-f (I PC)) In t.CUs A61IK3 1/47, A61IK3 1/5 5, A61IK3 7/0 2, C07D21 5/00, C07D223/1 6, CAS ONLINE C. M1;59G~t63r P, X U S, A, 5 2389 3 2(Merrell Dow Pharmaceuticals, 1-55 Inc. )v

24. 8,9. 19 93 24. 08S. 93) &WO, A, 9323397 P, X J. Mod. Chem. 36( 16 2420-2423 1-55 (1 993 August X EP, A, 5 3 30 8 4Schering Corp. ),1-55 rAE I±45fP, V)TIVSt RU O)MR119O)40 r Lj Brx i 0 6. 0 7. 94

26.07.94 6 rT- S/J P) 4 79 3 4 S03-3581-1 101 r 3450 I "FALB i4 PCT/JP 9 4 0 0 9 4 7 CUI~4 MELJ*9/094 x P, x P, A 2 4. 3.9. 19 9 3( 24. 0 3. 9 3) &AU, A, 9226506 EP', A, 48 15 2 2(Merrell Dow Pharmaceuticals Inc. 2 2. 4)1. 1 99 2 22. 0 4. 92) &JP, A, 4-282382 J P, A, 6 5 6 7 9O(- 0.f.Y' &AU, A, 9338627 &EP, A, 534363 1-55 1-5 1-55 to~pcr/ ,SA/2 1 0 (Z-tVOV 1 99 2417A) I MWHV PCT/JP 94'/ 0 094 7 I PC) I nt. Cz, CO 7D2 67/00, Co 7D4 71/00, Co 7 D49 5/0 0, CO 7D 1 3/00, Co 7K5/0 0 Co 7D2 81/00. CO 7D48 7/00, CO 7D4 98/00, Co0 7 D 5 2 1/0 0, MAP C T/ I S A/ 2 1 0 V) 1 9 9 2 Irl 7 n)