ES2366641T3 - DERIVED FROM 4,4-DIFLUORO-1,2,3,4-TETRAHIDRO-5H-1-BENZAZEPINA OR SALT OF THE SAME. - Google Patents

Abstract

A 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by a formula (I) or a pharmaceutically acceptable salt thereof ** Formula ** [symbols of the formula mean the following, R 1: a group represented by a formula in which, Z 1: single bond, lower alkylene or-lower alkylene-C (= O) -, R 11: lower alkyl which may be substituted with one or more groups selected from the group consisting of -OH, -O-lower alkyl, -CO2H, -CO2-lower alkyl and carbamoyl which may be substituted with one or two lower alkyls, or -H, R 12: (1) when Z 1 represents a single bond or lower alkylene, -H, -OH, -O-lower alkyl, -CO2H, -CO2alkyl lower, carbamoyl which may be substituted with one or two lower alkyls, aryl which may be substituted with one or more selected groups among the substituent groups shown in the following (a) to (h), cycloalkyl which may be substituted with one or more g Ruples selected from the substituent groups shown in the following (a) to (h), hetero aromatic ring that may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h) or hetero ring aromatic which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), (2) when Z 1 represents-lower alkylene-C (= O) -, a group represented by the formula (III) or a formula (IV), ** Formula ** in which, Z 2: single bond or lower alkylene, R 15: -H, -OH, -O-lower alkyl, -CO2H, -CO2- lower alkyl, carbamoyl which may be substituted with one or two lower alkyls, aryl which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), cycloalkyl which may be substituted with one or more groups selected from the substituent groups shown in the s next (a) to (h), hetero aromatic ring that may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h) or non-aromatic hetero ring that may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), R 13, R 14: together with the non-adjacent nitrogen atom, non-aromatic cyclic amino group that may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), R 2: CF3 or halogen, R 3: H or halogen, a: a single bond, b: a double bond, -X-: -CH = CH-, -Y-: -CH-, -A-: -O- -S-, -NH- or -N (lower alkyl), B: lower alkyl, lower alkenyl or lower alkynyl, each of which is optionally substituted with one or more groups selected from the substituent groups shown in the following (a) to (g); or cycloalkyl or aryl, each of which is optionally substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), where the substituents (a) to (h) are as indicated by continued: (a) halogen, (b) -OH, -OR Z, -O-aryl, -OCO-R Z, oxo (= O), (c) -SH, -SR Z, -S-aryl, - SO-R Z, -SO-aryl, -SO2-R Z, -SO2-aryl, sulfamoyl which may be substituted with 1 or 2R Z, (d) amino which may be substituted with 1 or 2 RZ, -NHCO-R Z, -NHCO-aryl, -NHSO2-R Z, -NHSO2-aryl, nitro, (e) -CHO, -CO-R Z, -CO2H, -CO2-R Z, carbamoyl which may be substituted with 1 or 2 RZ, cyano, (f) aryl or cycloalkyl which may be substituted respectively with one or more groups selected from the class consisting of -OH, -O-lower alkyl, amino which may be substituted with 1 or 2 lower alkyl, carbamoyl which it may be substituted with 1 or 2 lower alkyl, aryl, hetero aromatic ring, halogen and RZ, (g) hetero aromatic ring or non-aromatic hetero ring which may be substituted respectively with one or more groups selected from the class consisting of -OH, -O-lower alkyl, amino which may be substituted with 1 or 2 lower alkyl, carbamoyl which may be substituted with 1 or 2 lower alkyl, aryl, hetero aromatic ring, halogen and RZ, (h) lower alkyl or lower alkenyl which may be substituted respectively with one or more groups selected from the substituent groups shown in the (a) a (g) mentioned above, and RZ: lower alkyl which may be substituted with one or more groups selected from the class consisting of -OH, -O-lower alkyl, amino which may be substituted with 1 or 2 lower alkyl, carbamoyl which may be substituted with 1 or 2 lower alkyl, aryl, hetero aromatic ring and halogen, and where the term "lower alkyl" refers to a monvalent group of C1-6 carbon chain linear or branched, the term "lower alkylene" refers to a linear or branched C1-6 carbon chain divalent group, the term "lower alkenyl" refers to a linear or branched C2-6 carbon chain monvalent group, having at least one double bond, the term "lower alkynyl" refers to a linear or branched C2-6 carbon chain monvalent group having at least one triple bond, the term "cycloalkyl" refers to a monvalent group of C3-8 non-aromatic hydrocarbon ring that can have a partially unsaturated bond, the term "aryl" refers to a monvalent group of aromatic hydrocarbon ring, from monocyclic to tricyclic, C6-14, the term "hetero aromatic ring" is refers to a monvalent monocyclic to tricyclic aromatic ring group having a hetero atom or atoms, the term "non-aromatic hetero ring" refers to a 5 to 7 membered monvalent ring group having an atom omo or hetero atoms, which may have a partially unsaturated bond and may be fused to an aryl or aromatic hetero ring, and the term "non-aromatic cyclic amino group" refers to a monvalent group of 3 to 10 membered non-aromatic cyclic amine , which optionally has nitrogen, oxygen or sulfur, which can have a partially unsaturated bond].

Description

5 Technical field

The present invention relates to a medicament, particularly a new derivative of 4,4-difluoro-1,2,3,4 tetrahydro-5H-1-Benzazepine or a salt thereof useful as a therapeutic agent for central diabetes insipidus and nocturia and a medicine that uses said compound as the active substance.

10

Background of the invention

Arginine vasopressin (AVP) is a peptide consisting of 9 amino acids that biosynthesize and secrete in the hypothalamus-pituitary system. The AVP receptor is classified into three subtypes V1a, V1b and V2, and a known

15 constriction action mediated by V1a receptor and an antidiuretic action mediated by V2 receptor as the main pharmacological actions of AVP in the peripheral system. As a selective sample of the V2 receptor, a peptide desmopressin has been synthesized (prepared by deleting the amino group of the cysteine from position 1 of AVP and converting the arginine from position 8 into form d) and used for the treatment of diabetes insipidus central (Reference No. of Patent 1). However, since the bioavailability of oral preparations of

20 desmopressin is considerably low, a high dose is necessary to obtain its effect. Therefore, desmopressin preparations are expensive and the generation of side effects based on the variation in absorption between individuals is observed in some cases. Consequently, interest has been directed towards the development of a non-peptide antidiuretic agent that selectively stimulates the V2 receptor and has high bioavailability.

25 On the other hand, accompanied by the diversification of medical treatment and advancing age, simple use of a drug has become uncommon and, in many cases, two or more drugs are administered simultaneously or intermittently. It is the same in the field of AVP receptor agonists. The drugs are inactivated and converted into metabolites undergoing the action of drug metabolizing enzymes and the most important

30 of these drug metabolizing enzymes is cytochrome P450 (CYP). There is a wide variety of molecular species in CYP and when two or more drugs that are metabolized by CYP of the same molecular species compete in the metabolizing enzyme, they are considered to experience a certain metabolic inhibition, although it varies depending on the affinity of the drugs for CYP. As a result, an increase in blood concentration, prolongation of blood half-life and similar drug interactions is expressed.

35 Such pharmacological interactions are undesirable actions except in the case where they are used for additive or synergistic action, because they sometimes cause unexpected side effects. Therefore, interest has been directed towards the creation of a drug that has a low affinity for CYP and a small possibility of causing drug interactions.

So far, tricyclic compounds represented by a general formula (A), a general formula (B) and a general formula (C) are known as non-peptide compounds that are selective agonists of the V2 receptor and show antidiuretic action (Reference of Patent 1, Patent Reference 2, Patent Reference 3)

image 1

Four. Five

(See these patent references for clues in the formulas.)

In addition, a condensed azepine derivative represented by a general formula (D) is known as a selective agonist of the V2 receptor (Patent Reference 4).

image 1

(See said patent reference for clues in the formula.)

In addition, benzazepine derivatives represented by a general formula (E) (Patent Reference 5, Patent Reference 6) and benzo-hetero ring compounds represented by a general formula (F) or a general formula (G) (Reference Patent 7, Patent Reference 8, Patent Reference 9) are known as selective agonists of the V2 receptor.

image 1

10

(See these patent references for clues in the formulas.)

However, there is no description of any of these patent references with respect to the derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine of the invention.

In addition, although the 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative that has antagonism to the AVP receptor or the oxytocin receptor is known, nothing is known about its relationship with the agonist action of the V2 receptor, central and nocturnal diabetes insipidus (Patent Reference 10, Patent Reference 20 11, Patent Reference 12). In this regard, Patent Reference 10 and Patent Reference 12 do not disclose the 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative of the invention in which CF3 or halogen it is substituted for the benzoyl of position 2 which replaces position 1 of benzazepine. In addition, Patent Reference 11 only discloses a compound in which an aromatic ring is directly attached to a heteroaryl group that is attached to the carbonyl that replaces the 1-position of benzazepine, but does not disclose the

4,4-Difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative of the invention in which the ring which is attached to the carbonyl that replaces the 1-position of the benzazepine has -O- , -S-, -NH- or a substituent group containing N (lower alkyl) -.

In this situation, great interest has been directed to the development of a non-peptide antidiuretic agent that has a high bioavailability, with the purpose of treating central diabetes insipidus and / or nocturia.

[Non-Patent Reference 1] Journal of Japan Endocrine Society, 54, 676-691, 1978 [Patent Reference 1] International Publication No. 99/06409 [Patent Reference 2] International Publication No. 99/06403

35 [Patent Reference 3] International Publication No. 00/46224 [Patent Reference 4] International Publication No. 01/49682 [Patent Reference 5] International Publication No. 97/22591 [Patent Reference 6] Japanese Patent No. 2926335 [Reference Patent 7] Japanese Patent No. 3215910

40 [Patent Reference 8] Japanese Patent Publication JP-A-11-349570 [Patent Reference 9] Japanese Patent Publication JP-A-2000-351768 [Patent Reference 10] International Publication No. 95/06035 [Reference Patent 11] International Publication No. 98/39325 [Patent Reference 12] Japanese Patent Publication JP-A-9-221475

Four. Five

Disclosure of the Invention

The present inventors have carried out intensive studies on a compound that has an agonist action of the V2 receptor, from which efficacy can be expected for central and / or nocturnal diabetes insipidus, and found that a

New derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine has such an excellent effect, so they carried out the invention. In addition, it was found that the compound of the invention has a remarkably low inhibitory activity after drug metabolization by CYP3A4 and CYP2C9 enzymes compared to conventionally known benzazepine derivatives that have V2 receptor agonist action.

That is, according to the invention, a new 4,4-difluoro-1,2,3,4-tetrahydro-5H-1benzazepine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt of the which is useful as a therapeutic agent for central diabetes insipidus and / or nocturia; and a medicine that uses any one of these compounds as an active ingredient; particularly, the medicament mentioned above which is an arginine vasopressin V2 receptor agonist; and the medication mentioned above which is a

15 agent to treat nocturia or an agent to treat central diabetes insipidus.

image 1

R1: a group represented by a formula (II),

image 1

in which,

Z1: single bond, lower alkylene or-lower alkylene-C (= O) -, R11: lower alkyl which may be substituted with one or more groups selected from the group consisting of OH, -O-lower alkyl, -CO2H , -CO2-lower alkyl and carbamoyl which may be substituted with one or two lower alkyls, or -H, R12: (1) when Z1 represents a single bond or lower alkylene, -H, -OH, -O-lower alkyl, -CO2H, -CO2-alkyl

Lower, carbamoyl which may be substituted with one or two lower alkyls, aryl which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), cycloalkyl which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), hetero aromatic ring that may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h) or hetero ring non-aromatic that may be substituted

35 with one or more groups selected from the substituent groups shown in the following (a) to (h),

(2) when Z1 represents-lower alkylene-C (= O) -, a group represented by the formula (III) or a formula (IV),

image 1

in which, Z2: single bond or lower alkylene,

R15

: -H, -OH, -O-lower alkyl, -CO2H, -CO2-lower alkyl, carbamoyl which may be substituted with one or two lower alkyls, aryl which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), cycloalkyl which may be substituted with one or more groups selected from the substituent groups shown in the following

(a) to (h), hetero aromatic ring that may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h) or non-aromatic hetero ring that may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), R13, R14: together with the non-adjacent nitrogen atom, non-aromatic cyclic amino group that may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), R2: CF3 or halogen, R3: H or halogen,

a: a simple link,

b: a double bond, -X-: -CH = CH-, -Y-: -CH-, -A-: -O-, -S-, -NH-or -N (lower alkyl),

B: lower alkyl, lower alkenyl or lower alkynyl, each of which is optionally substituted with one or more groups selected from the substituent groups shown in the following (a) to (g); or cycloalkyl or aryl, each of which is optionally substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), where the substituents (a) to (h) are as indicated by continuation:

(to)

 halogen,

(b)

 -OH, -O-RZ, -O-aryl, -OCO-RZ, oxo (= O),

(C)

 -SH, -S-RZ, -S-aryl, -SO-RZ, -SO-aryl, -S42-RZ, -SO2-aryl, sulfamoyl which may be substituted with 1 or 2RZ,

(d)

 amino which may be substituted with 1 or 2 RZ, -NHCO-R2, -NHCO-aryl, -NHSO2-RZ, -NHSO2-aryl, nitro, (e) -CHO, -CO-RZ, -CO2H, -CO2- RZ, carbamoyl which may be substituted with 1 or 2 RZ, cyano,

(F)

 aryl or cycloalkyl which may be substituted respectively with one or more groups selected from the class consisting of -OH, -O-lower alkyl, amino which may be substituted with 1 or 2 lower alkyl, carbamoyl which may be substituted with 1 or 2 lower alkyl, aryl, hetero aromatic ring, halogen and RZ,

(g)

hetero aromatic ring or non-aromatic hetero ring that can be substituted respectively with one

or more groups selected from the class consisting of -OH, -O-lower alkyl, amino which may be substituted with 1 or 2 lower alkyl, carbamoyl which may be substituted with 1 or 2 lower alkyl, aryl, hetero aromatic ring, halogen and RZ,

(h) lower alkyl or lower alkenyl which may be substituted respectively with one or more groups selected from the substituent groups shown in the (a) to (g) mentioned above, and

RZ: lower alkyl which may be substituted with one or more groups selected from the class consisting of -OH, -O-lower alkyl, amino which may be substituted with 1 or 2 lower alkyl, carbamoyl which may be substituted with 1 or 2 lower alkyl, aryl, hetero aromatic ring and halogen.

The compound of the invention has a structural chemical characteristic in that it has a difluoro group on the carbon atom of the ring adjacent to the carbon atom of the benzazepine ring where a substituted methylidene group is substituted, which is completely different from the structures of selective agonists. of the conventionally known V2 receiver. In this sense, since the compound of the invention has a difluoro group, the double bond conjugated with the carbonyl group is not isomerized, so that it has sufficient stability within an organism.

A new derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine represented by the general formula (I) mentioned above, wherein -A-is -O-, is particularly desirable. or a pharmaceutically acceptable salt thereof.

Most desirable is a new 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by the general formula (I) mentioned above, in which -A-is -O- : and -B is lower alkyl which may be substituted with one or more groups shown in the (a) to (g) mentioned above, or a pharmaceutically acceptable salt thereof.

Among them, a new 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative in which R2 is trifluoromethyl is particularly desirable; and R3 is -H or -F, or a pharmaceutically acceptable salt thereof ,.

Particularly desirable compounds among these compounds are compounds selected from the group consisting of a group of compounds P and a group of compounds Q, or pharmaceutically acceptable salts thereof, and among them compounds selected from the group of compounds P are preferred , or pharmaceutically acceptable salts thereof.

In this case, the "group of compounds P" is a group consisting of

(2Z) -N- (2-amino-2-oxoethyl) -2- {4,4,7-trifluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4tetrahydro-5H-1-benzazepin-5-ylidene} acetamide, (2Z) -N- (2-hydroxyethyl) -2- {4,4,7-trifluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H1-benzazepin-5-ylidene} acetamide, (2Z) -N- (2 -hydroxyethyl) -2- {4,4,7-trifluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro -5H1-benzazepin-5-ylidene} acetamide, (2Z) -2- {4,4-difluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] - 1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N - [(2S) -2,3-dihydroxypropyl] acetamide, 3 - [((2Z) -2- {4,4,7 -trifluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1benzazepin-5-ylidene} acetyl) amino ] propanamide, and (2Z) -N - [(2R) -2,3-dihydroxypropyl] -2- {4,4,7-trifluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4tetrahydro-5H-1-benzazepin-5-ylidene} acetamide, and the "group of compounds Q" is a gru po consisting of (2Z) -N- (2-amino-2-oxoethyl) -2- {4,4,7-trifluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2 - (trifluoromethyl) benzoyl] -1,2,3,4 tetrahydro-5H-1-benzazepin-5-ylidene} acetamide, (2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- ( trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N- (2-hydroxyethyl) acetamide, (2Z) -2- {4,4- difluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene} -N- ( 2-hydroxyethyl) acetamide, (2Z) -2- {4,4-difluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3 , 4-tetrahydro-5H-1-benzazepin-5ylidene} -N- (2-hydroxyethyl) acetamide, (2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoyl] -4,4,7-trifluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N- (2-hydroxyethyl) acetamide, (2Z) -N - [(2R) -2, 3-dihydroxypropyl] -2- {4,4,7-trifluoro-1- [4-propoxy-2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1benzazepin-5-ylidene} acetamide , (2Z) -2- {4,4-difluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2- (trifluoromet il) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N - [(2S) -2,3-dihydroxypropyl] acetamide, (2Z) -2- {4,4- difluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N- [ (2R) -2,3-dihydroxypropyl] acetamide, 3 - [((2Z) -2- {4,4,7-trifluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2 - (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1benzazepin-5-ylidene} acetyl) amino] propanamide, (2Z) -N - [(2R) -2,3-dihydroxypropyl] -2 - {4,4,7-Trifluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin- 5-ylidene} acetamide, 3 - [((2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoyl] -4,4,7-trifluoro-1,2, 3,4-tetrahydro-5H-1-benzazepin-5ylidene} acetyl) amino] propanamide, (2Z) -2- {4,4-difluoro-1- [4-propoxy-2- (trifluoromethyl) benzoyl] -1, 2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene} -N - [(2R) 2,3-dihydroxypropyl] acetamide, and (2Z) -2- {4,4-difluoro-1 - [4-Propoxy-2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene} -N - [(2S) 2 , 3-dihydroxypropyl] acetamide.

In this regard, with respect to R1, the group represented by the formula (II) mentioned above is desirable

or the formula (III) mentioned above; the group represented by the formula (U) mentioned above, in which Z1 is a single bond, R12 is -H and R11 is lower alkyl which may be substituted with a group selected from the group consisting of -OH, is more desirable. -O-lower alkyl, -CO2H -CO2-lower alkyl and carbamoyl which may be substituted with one or two lower alkyls; and the group represented by the formula (II) mentioned above is particularly desirable, in which Z1 is a single bond, R12 is -H and R11 is lower alkyl which may be substituted with one or more substituent groups selected from a group consisting of in -OH and carbamoyl.

Furthermore, with respect to R2, trifluoromethyl or chlorine is desirable; and trifluoromethyl is particularly desirable.

Furthermore, with respect to R3, it is desirable -H or fluorine; and it is particularly desirable -H or 7-fluoro.

Furthermore, with respect to a, b, -X-and -Y-, it is desirable that a single link be, b be a double link, -X-be CH-CH-, and Y be CH.

In addition, -O-is desirable as A-.

Further, with respect to -B, lower alkyl is desirable which may be substituted with one or more groups shown in the (a) to (g) mentioned above; and lower alkyl which may be substituted with F. is particularly desirable.

The following further describes the compound of the invention.

According to the invention, "lower alkyl" refers to a monovalent linear C1-6 carbon chain group

or branched, and its illustrative examples include methyl, ethyl, propyl, butyl, pentyl and hexyl, and isopropyl, tert-butyl and their structural isomers of this type, preferably a C1-4 alkyl, methyl, ethyl, propyl, butyl and isobutyl.

"Lower alkylene" refers to a straight or branched C1-6 carbon chain divalent group, and its illustrative examples include methylene, ethylene, trimethylene, methylmethylene, methylethylene, dimethylmethylene and the like.

"Lower alkenyl" means a linear or branched C2-6 carbon chain monovalent group having at least one double bond, and its illustrative examples include vinyl, allyl, 1-butenyl, 2-butenyl, 1-hexenyl and 3hexenyl, 2-Methylalkyl and its structural isomers of this type, of which allyl and 2-methyl-1-propen3-yl are preferable.

"Lower alkynyl" refers to a linear or branched C2-6 carbon chain monovalent group having at least one triple bond, and its illustrative examples include ethynyl, propargyl, 1-butynyl, 3-butynyl, 1-hexinyl, and 3hexinyl, 3-methyl-1-butynyl and their structural isomers of this type, of which propargyl and 1-butin-4yl are preferable.

"Cycloalkyl" refers to a monovalent C3-8 non-aromatic hydrocarbon ring group which may have a partially unsaturated bond, and its illustrative examples include cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclohexenyl, cyclooctanedionyl, and the like.

The "aryl" refers to a monovalent aromatic hydrocarbon ring group, C6-14, from monocyclic to tricyclic, and its illustrative examples include phenyl, naphthyl and the like, of which phenyl is preferred.

The "hetero aromatic ring" refers to a monovalent monocyclic to tricyclic aromatic ring group having a heteroatom or heteroatoms such as nitrogen, oxygen, sulfur or the like, and their illustrative examples include pyridyl, thienyl, furyl, pyrazinyl, pyridazinyl, thiazolyl, pyrimidinyl, pyrazolyl, pyrrolyl, oxazolyl, isothiazolyl, isooxazolyl, imidazolyl and the like, of which pyridyl is preferred.

The "nonheteroaromatic ring" refers to a monovalent 5 to 7 membered ring group having a heteroatom or heteroatoms such as nitrogen, oxygen, sulfur or the like, which can have a partially unsaturated bond and can be fused to a hetero ring aryl or aromatic, and its illustrative examples include pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepinyl, morphonyl, thiomorphonyl, tetrahydrofuryl, tetrahydrothienyl and the like, of which pyrrolidinyl, piperidinyl and morphonyl are preferred.

The "non-aromatic cyclic amino group" refers to a monovalent group of 3 to 10 membered non-aromatic cyclic amine, preferably 5 to 7 membered non-aromatic cyclic amine, which optionally has nitrogen, oxygen or sulfur, and which may have a partially unsaturated bond, and its illustrative examples include pyrrolidinyl, piperidinyl, azepinyl, morphonyl, thiomorphonyl, piperazinyl, pyrazolidinyl, dihydropyrrolyl and the like, of which pyrrolidinyl, piperidinyl, piperazinyl and morphonyl are preferred.

"Halogen" refers to a monvalent group of halogen atom, and its illustrative examples include fluorine, chlorine, bromine, iodine and the like.

Depending on the type of substituent groups, the compounds of the invention represented by the general formula

(I) sometimes contain an asymmetric carbon atom, and optical isomers based on them may be present. All mixtures and isolates of these optical isomers are included in the invention. In addition, in some cases tautomers are present in the compounds of the invention, and isolates or mixtures of these isomers are included in the invention.

In addition, the compounds of the invention in some cases form salts, and said salts are included in the invention with the proviso that they are pharmaceutically acceptable salts. Its illustrative examples include acid addition salts with hydrochloric acid, hydrobromic acid, iodide, sulfuric acid, nitric acid, acid

5

10

fifteen

twenty

25

30

35

40

Four. Five

phosphoric and the like, inorganic or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and the like, organic acids, salts with inorganic bases including sodium, potassium, calcium, magnesium and similar metals or with methylamine, ethylamine, ethanolamine, lysine, ornithine and similar organic bases, ammonium salts and the like In addition, various hydrates, solvates and substances having polymorphism of the compounds of the invention and pharmaceutically acceptable salts thereof are also included in the invention.

(Production methods)

The compounds of the invention and pharmaceutically acceptable salts thereof can be produced using various commonly known synthesis methods, making use of features based on their basic nuclei or the type of substituted groups. Typical production methods are exemplified below. In this sense, depending on the type of functional group, it is sometimes effective, in view of production techniques, to replace said functional group with an appropriate protective group, specifically a group that easily converts into said functional group, at a stage from materials to intermediates. After that, the compound of interest can be obtained by removing the protective group as the occasion demands. Examples of said functional group include a hydroxyl group, carboxy group, amino group and the like, and the protective groups described in "Protective Groups in Organic Synthesis (3rd Edition)" edited by Greene and Wuts, which can be exemplified as their protecting groups which they can optionally be used in response to the reaction conditions.

<Intermediate production method>

image 1

(In the reaction scheme, R2, a, b, X, Y and A are as defined above; Lv represents a leaving group; B1 represents the B mentioned above or a protecting group of the hydroxyl group, amino group or sulfanyl group ; Ra represents a carboxyl group, a lower alkyl-oxycarbonyl group or a cyano group. The same will be applied hereinafter.)

This production method is a method in which the compound (c) is produced by replacing the leaving group Lv of the compound (a) with the compound (b), and then the compound (d) is produced from it by performing hydrolysis of the same as the occasion demands.

(First stage)

Examples of the leaving group Lv in compound (a) include fluorine, chlorine, methanesulfonyloxy, p-toluenesulfonyloxy and trifluoromethanesulfonyloxy, of which fluorine, chlorine and methanesulfonyloxy are preferred.

The reaction can be carried out from room temperature to reflux heating using the compound (a) and the compound (b) in equimolar amounts or one of them in an excess amount, without solvent or in a reaction inert solvent such as benzene, toluene, xylene or the like, such as aromatic hydrocarbons; diethyl ether, tetrahydrofuran (THF), dioxane or similar ethers; dichloromethane, 1,2-dichloroethane, chloroform or similar halogenated hydrocarbons; N, N-dimethylformamide (DMF); dimethylacetamide (DMA); N-methylpyrrolidone; dimethylsulfoxide (DMSO); ethyl acetate (EtOAc) or similar esters; acetonitrile or the like, or in methanol (MeOH), ethanol (EtOH), 2-propanol (iPrOH) or similar alcohols. Depending on the compound, in some cases it is advantageous to carry out the reaction in the presence of an organic base (preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or 4- (N, N-dimethylamino) pyridine) or a metal salt base (preferably carbonate

potassium, cesium carbonate, sodium hydroxide or sodium hydride).

(Second stage)

The reaction can be carried out by treating the compound (c) with cooling under reflux heating, in a solvent inert to the reaction, such as an aromatic hydrocarbon, an ether, a halogenated hydrocarbon, an alcoholic solvent, DMF, DMA, DMSO, pyridine , water or the like in the presence of sulfuric acid, hydrochloric acid, hydrobromic acid or similar mineral acids, formic acid, acetic acid or similar organic acids or sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, ammonia or a base Similary.

10 <First production method>

image 1

15 (In the reaction scheme, R1 is as defined above, and Rb represents a lower alkyl. The same will be applied hereinafter.)

This production method is a method in which a compound (1 b) is produced by condensation of the compound

(d) produced in the intermediate production method mentioned above with a compound (1a), a

Compound (1c) is produced by hydrolysis of the above and then the product is condensed with a compound (1d), thereby producing the compound (I) of the invention in which B1 is B or a compound (1 e) in which B1 is a hydroxyl group, an amino group or a sulfanyl group.

(First stage)

The compound (d) can be used in the reaction as a free acid, but its reactive derivative can also be used in the reaction. Examples of the reactive derivative of compound (d) include methyl ester, ethyl ester, tert-butyl ester or similar general esters; acid chloride, acid bromide or similar acid halide; acid azide; active ester with N-hydroxybenzotriazole, p-nitrophenol, N-hydroxysuccinimide or the like; acid anhydride

30 symmetric; mixed acid anhydride with alkyl carbonate halide or a similar alkyl ester of halocarboxylic acid, pivaloyl halide, p-toluenesulfonic acid chloride or the like; mixed acid anhydride such as a phosphoric acid system mixed with acid anhydride obtained by reaction with diphenylphosphoryl chloride and Nmethylmorpholine and the like.

When the compound (d) is allowed to undergo the reaction as a free acid, or an active ester is allowed to undergo the reaction without isolation, it is desirable to use a condensing agent such as dicyclohexylcarbodiimide (DCC), 1,1'- carbonylbis-1H-imidazole (CDI), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide, 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide hydrochloride (WSCD) or the like.

In accordance with the invention, an acid chloride method, a method in which the reaction is carried out in coexistence of an active esterifying agent and a condensing agent and a method in which a general ester is treated with amine, because the compound of the invention can be obtained in a conventional and simple way.

Although it varies depending on the reactive derivative and the condensing agent used, the reaction is carried out with refrigeration, with cooling at room temperature or under ambient temperature conditions under heating, in a reaction inert solvent such as a halogenated hydrocarbon, a aromatic hydrocarbon, an ether, an ester, acetonitrile, DMF, DMSO or the like.

In this sense, in some cases it is advantageous that the reaction proceeds smoothly to use the compound (1a) in an excess amount at the time of carrying out the reaction, or performing the reaction in the presence of a base such as N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, N, N-dimethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, picoline, rutidine or the like. In addition, a salt consisting of pyridine hydrochloride, pyridine p-toluenesulfonate, N, N-dimethylaniline hydrochloride or a similar weak base and a strong acid can be used. Pyridine can also be used as solvent.

Particularly, it is suitable to carry out the reaction in acetonitrile, DMF or a similar solvent in the presence of pyridine, N, N-dimethylaniline or a similar base or pyridine hydrochloride or a similar salt.

(Second stage)

The reaction can be carried out according to the second stage of the intermediate production method.

(Third stage)

The reaction can be carried out according to the first stage of the first production method.

The compound (1e) can be prepared in the compound (I) of the invention by removing the protective group as the occasion demands or by additionally introducing a necessary side chain according to a general method. The introduction of the necessary side chain can also be carried out in accordance with the third stage of the next second production method.

<Second production method>

image 1

5 (In the reaction scheme, B2 is a protecting group of the hydroxyl group, amino group or sulfanyl group. The same will be applied hereinafter.)

This production method is a method in which a compound (2a) is produced by condensation of a compound (dd) produced by the intermediate production method mentioned above, in which B2 does not

10 is B, with a compound (1a), a compound (2b) is produced by removing the protective group B2, a compound (2f) is produced by condensation with a compound (2c) or (2d), a compound (2f) is produced by hydrolyzing it and then the compound (I) of the invention is produced by condensation with a compound (1d).

(First stage) 15 This reaction can be carried out according to the first stage of the first production method.

(Second stage)

As the protecting group of the hydroxyl group, amino group or sulfanyl group, the protecting groups described in "Protective Groups in Organic Synthesis (3rd Edition)" mentioned above may be mentioned. The reaction can be carried out according to the method described in "Protective Groups in Organic Synthesis (3rd Edition)".

Particularly, when a benzyl group is used as the protecting group of the hydroxyl group, a method can also be used in which the benzyl group is removed by allowing pentamethylbenzene to react with it in a strongly acidic solution such as trifluoroacetic acid or the like.

(Third stage)

As the leaving group Lv in the compound (2c), there may be mentioned, for example, chlorine, bromine, iodine, methanesulfonyloxy, ptoluenesulfonyloxy and trifluoromethanesulfonyloxy, of which bromine, methanesulfonyloxy and ptoluenesulfonyloxy are preferred.

With respect to the reaction using the compound (2c), a general alkylation reaction can be used, and preferably, it can be performed using the compound (2b) and the compound (2c) with cooling, with room temperature or temperature cooling ambient to heating in equimolar amounts, or one of them in an excess amount in a reaction inert solvent such as acetonitrile, DMF, DMSO, an ether or the like, in the presence of potassium carbonate, sodium carbonate, cesium carbonate, hydroxide sodium, potassium hydroxide or a similar base.

The reaction using compound (2d) can be carried out under Mitsunobu reaction conditions in an aprotic solvent inert to the reaction, such as an ether, DMF, N-methylpyrrolidone or the like, in the presence of triphenylphosphine or similar organic phosphine and azodicarboxylate of diethyl, diisopropyl azodicarboxylate or a similar dialkyl azodicarboxylate (Synthesis, 1981, p. 1).

(Fourth stage)

This reaction can be carried out according to the second stage of the first production method.

(Fifth stage)

This reaction can be performed according to the first stage of the first production method.

In addition, some of the compounds of the invention represented by the formula (I) can be produced from the compounds of the invention obtained by the first production method or the second production method, optionally conventionally combining an alkylation reaction, known acylation or substitution, oxidation, reduction, hydrolysis and similar steps, which can generally be employed by those skilled in the art. Illustratively, one can cite, for example, oxidation of the sulfur atom with metachloroperbenzoic acid or a similar oxidation agent, and the like, and such reactions are performed using, or in accordance with, the methods described in "Jikken Kagaku Koza (Experimental Chemistry Course) 4th edition "(Maruzen, 1990-1992). In addition, these steps that can generally be employed by those skilled in the art are not limited to the application to the compounds of the invention, but can also be applied to production intermediates. Illustratively, they can be applied, for example, to the compound obtained by the third stage of the second production method, and thereafter, the next stage can be performed.

The compounds of the invention produced in this way are isolated and purified in the form of free compounds or salts thereof by performing the salt formation treatment in the usual manner. The isolation and purification are performed using usual chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography and the like.

Various isomers can be isolated in the usual manner making use of the differences in physicochemical properties between isomers. For example, a racemic mixture can be converted into optically pure isomers, for example, by a general racemic body resolution method such as a method in which they are converted into diastereomeric salts with tartaric acid or a similar general optically active acid and then subject to optical resolution. In addition, a diastereomeric mixture can be separated, for example, by fractional crystallization.

or various types of chromatography. In addition, an optically active compound can also be produced using an appropriate optically active material.

Industrial Applicability

The compounds of the invention have excellent agonist activity at the V2 receptor of arginine vasopressin. Consequently, the compounds of the invention have an antidiuretic action of a profile based on this action and are effective in preventing and / or treating urinary frequency, urinary incontinence, enuresis, central diabetes insipidus, nocturia and nocturnal enuresis. Also, in addition to these, since they have the action of releasing blood coagulation factor VIII and von Willebrand factor based on the agonist activity of the V2 receptor, they are useful for various bleeding conditions and useful in the diagnosis, prevention and treatment of spontaneous haemorrhage, hemophilia, von Willebrand disease, uremia, congenital or acquired platelet dysfunction, traumatic or operative haemorrhage, liver cirrhosis and the like.

In addition, the compounds of the invention have a remarkably low inhibitory activity in the CYP3A4 and CYP2C9 drug metabolising enzymes, possibility of provoking pharmacological interaction with other drugs that are metabolized by CYP3A4 or CYP2C9 compared to the commonly known Benzazepine derivatives that have activity arginine vasopressin V2 receptor agonist, so that they are excellent from the point of view that they can be used safely in therapy combined with other medications.

Examples of drugs that are metabolized by CYP3A4 include simvastatin, lovastatin, fluvastatin, midazolam, nifedipine, amlodipine, nicardipine and the like and examples of drugs that are metabolized by CYP2C9 include diclofenac, ibuprofen, indomethacin, tolbutamide, glibenclamide, glibenclamide, glibenclamide, glibenclamide, glibenclamide similar (Sogo Rinsho (General Clinics), 48 (6), 1427-1431, 1999).

The pharmacological actions of the compounds of the invention were verified by the following test methods.

(1) V2 receptor binding assay

A sample of CHO cell membrane with human V2 expression was prepared according to the method of Tahara et al. (British Journal of Pharmacology, Vol. 125, p. 1463-1470, 1998). A 2 μg part of the membrane sample was incubated together with [3H] -arginine vasopressin (simply referred to as "[3H] -vasopressin" hereinafter) (0.5 nM, specific activity = 75 Ci / mmol ) and each compound to be tested (10-10 to 10-5 M) at 25 ° C for 60 minutes in 250 µl total volume of 50 mM Tris-HCl buffer (pH = 7.4) containing 10 mM MgCl2 and albumin of 0.1% bovine serum (BSA). Next, the free [3H] -vasopressin and the [3H] receptor-linked vasopressin were separated using a cell collector and the [3H] -vasopressin bound to the receptor was attached to a uni-filter plate GF / B glass filter . After sufficient drying, this was mixed with a microplate scintillation cocktail, the amount of the receptor-bound [3 H] -vasopressin was measured using top count and the inhibition ratio was calculated by the following formula.

Inhibition ratio (%) = 100 - (C1 -B1) / (C0 -B1) x 100

C1: Amount of [3H] -vasopressin bound to the membrane sample when the [3H] -vasopressin and the membrane sample with receptor are treated in coexistence with the test compound having known concentration.

C0: Amount of [3H] -vasopressin bound to the membrane sample when [3H] -vasopressin and the membrane sample are treated with receptor in the absence of test compound.

B1: Amount of [3H] -vasopressin bound to the membrane sample when [3H] -vasopressin and the membrane sample with coexisting receptor are treated with excess amount of vasopressin (10-6).

The concentration of each test compound for which the inhibition ratio is 50% (IC50 value) was calculated by the aforementioned formula and the affinity of the test compound for the receptor was calculated, namely the dissociation constant (Ki ), from this by the following formula.

Dissociation constant (Ki) = IC50 / (1 + [L] / Kd]

[L]: Concentration of [3H] -vasopressin

Kd: Dissociation constant of [3H] -vasopressin against the receptor obtained by a saturation binding assay

(Table 1)

Affinity for the V2 receiver

Compounds

Ki (nM)  Compounds Ki (nm)

Example 3

eleven Example 31 10

Example 9

19 Example 54 17

Example 14

18 Example 55 16

Example 24

4.3 Example 134 12

Example 46

5.8 Example 136 eleven

Example 98

6.2 Comparative Compound 68

In this regard, the comparative compound is the compound of Example 32 described in International Publication WO 97/22591 (compound name: 2 - [(5R) -1- (2-chloro-4-pyrrolidin-1-ylbenzoyl) - 2,3,4,5-tetrahydrobenzazepin-5-yl] -N5 isopropylacetamide).

As shown in Table 1, it was confirmed that the compounds of the invention have high affinity for the V2 receptor.

10 (2) Antidiuretic test (intravenous administration)

Five animals per group of male Wistar rats (10 to 12 weeks old) were used in the trial. The compound of Example 3 was administered intravenously to group A at a dose of 0.3 mg / kg and the compound of Example 9 to group B at a dose of 0.3 mg / kg, both after dissolving in a solvent. (physiological saline solution containing DMSO) and the solvent only at a dose of 1 ml / kg to group C as a control and then 30 ml / kg distilled water was administered orally by force 15 minutes later (water loading ). Urine samples were collected up to 2 hours after water loading using a metabolism cage and the amount of urine when the amount of water loading was defined as 100% was calculated as the urine excretion ratio. In this regard, the average value of the urine excretion ratio up to 1 hour later and the excretion ratio

20 urine up to 2 hours later in each group was used in the evaluation. Results are shown in table 2.

Efectos antidiuréticos (administración intravenosa)

Compuestos

Relación de excreción de orina ( %)

Después de 1 hora

Después de 2 horas

Grupo A

Ejemplo 3 1,3 6,2

Grupo B

Ejemplo 9 0 5,3

Grupo C

Disolvente 64,0 80,0

(Tabla 2)

Antidiuretic effects (intravenous administration)

Compounds

Urine excretion ratio (%)

After 1 hour

After 2 hours

Group A

Example 3 1.3 6.2

B Group

Example 9 0 5.3

Group C

Solvent 64.0 80.0

(Table 2)

As shown in Table 2, it was revealed that the compounds of the invention have excellent antidiuretic effects.

(3) Antidiuretic test (oral administration)

Male Wistar rats (10 to 12 weeks old) were used in the trial. Each compound to be tested is

30 administered orally and then distilled water was orally administered 30 ml / kg 15 minutes later (water loading). Urine samples were collected up to 4 hours after the water load using a metabolism cage and the amount of urine was calculated when the water load was defined as 100% as the urine excretion ratio. In this regard, the dose of each test compound needed to reduce 50% of the urine excretion ratio (ED50) in the evaluation was used. As a result, it was revealed that

35 compounds of the invention show excellent antidiuretic action not only by intravenous administration but also by oral administration.

(4) Enzyme inhibition assay by cytochrome P450 (3A4)

40 This test was carried out according to the method of Crespi et al. (Analytical Biochemistry, 248, 188-190, 1997).

Using a 96-well plate, 7-benzyloxy-4- (trifluoromethyl) coumarin as the substrate (5 x 10-5 M), each test compound (4.9 x 10-8 at 5 x 10-5) was incubated M) and the enzyme (5 x 10-9) at 37 ° C for 30 minutes in 200 μl of total volume of 200 mM phosphate buffer (pH = 7.4) containing NADP +, 8.2 μM, glucose-6-phosphate 0.41 mM, MgCl2 0.41 mM and glucose-6-phosphate dehydrogenase 0.4 units / ml. Then, the reaction was stopped by adding

5 0.5M aqueous 2-amino-2-hydroxymethyl-1,3-propanediol solution containing 80% acetonitrile and fluorescence intensity was measured (excitation wavelength 409 nm, fluorescence wavelength 530 nm) using a fluorescence plate reader. The inhibition ratio was calculated based on the following formula and the concentration of each test compound was obtained whereby the inhibition ratio is 50% (IC50). The results are shown in Table 3.

10

Inhibition ratio (%) = 100 - (C1 -B1) / (C0 -B1) x 100

C1: Fluorescence intensity in the presence of test compound having known concentration, enzyme and substrate.

C0: Fluorescence intensity in the absence of the test compound and in the presence of enzyme and substrate.

B1: White well fluorescence intensity.

20 (5) Enzyme inhibition assay by cytochrome P450 (2C9)

This test was carried out according to the method of Crespi et al. (Analytical Biochemistry, 248, 188-190, 1997).

Using a 96-well plate, 7-methoxy-4- (trifluoromethyl) coumarin as the substrate (7.5 x 105 M), each test compound (4.9 x 10-8 at 5 x 10-) was incubated 5 M) and the enzyme (10-8 M) at 37 ° C for 45 minutes in 200 μl of total volume of 200 mM phosphate buffer (pH = 7.4) containing NADP +, 8.2 μM, glucose-6-phosphate 0.41 mM, MgCl2 0.41 mM and glucose-6-phosphate dehydrogenase 0.4 units / ml. Then, the reaction was stopped by adding 0.5M 2-amino-2-hydroxymethyl-1,3-propanediol aqueous solution containing 80% acetonitrile and the

30 fluorescence intensity (excitation wavelength 409 nm, fluorescence wavelength 530 nm) using a fluorescence plate reader. The inhibition ratio was calculated based on the same formula of the

(4) mentioned above and the concentration of each test compound was obtained whereby the inhibition ratio is 50% (IC50). The results are shown in Table 3.

35 (Table 3)

CYP inhibitory activity (3A4 and 2C9)

Compounds

IC50 (μM)

CYP3A4

CYP2C9

Example 3

> 50 > 50

Example 9

13 eleven

Example 51

> 50 3. 4

Example 54

> 50 43

Example 130

> 50 > 50

Example 136

> 50 > 50

Comparative compound

<0.091 <0.091

As shown in Table 3, the compounds of the invention showed a remarkably low inhibitory action on the CYP3A4 and CYP2C9 drug metabolising enzymes. In this regard, the comparative compound is the same comparative compound shown in Table 1.

The medicament of the invention can be prepared by a method generally used that employs one or more of the compounds of the invention represented by the general formula (1) and vehicles for drug, fillers and other additive agents that are generally used in the preparation of medicines Its administration may be oral administration in the form of tablets, pills, capsules, granules, powders, solutions and the like or

45 parenteral administration in the form of intravenous injections, intramuscular injections or similar injections

or suppositories, transnasal preparations, transmucosal preparations, percutaneous preparations and the like.

The solid composition for use in oral administration according to the present invention is used in the form of tablets, powders, granules and the like. In such a solid composition, one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum magnesium silicate or the like. In the usual way, the composition may contain other additives other than the inert diluent, such as magnesium stearate or similar lubricants, calcium cellulose glycolate or similar disintegrating agents, lactose or similar stabilizing agents and glutamic acid, aspartic acid or agents that aid the similar solubilization. As the occasion demands, the tablets or pills may be coated with a sugar coating, a film of a gastric or enteric substance, such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate or the like.

The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert diluent such as purified water or ethanol. In addition to the inert diluent, this composition may also contain a wetting agent, a suspending agent and similar auxiliary agents, as well as sweeteners, flavorings, aromatics and antiseptics.

Injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the diluent for use in aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of the diluent for use in non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, olive oil or similar vegetable oils, EtOH

or similar alcohols, polysorbate 80 and the like. Such a composition may additionally contain additive agents that include an antiseptic, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent such as lactose and an agent that helps solubilization such as glutamic acid or aspartic acid. These are sterilized, for example, by filtration through a filter that retains bacteria, a germicidal mixture or irradiation. Alternatively, they can also be used by first preparing them in sterile solid compositions and dissolving them in sterile water or a sterile solvent for injection before use.

In the case of oral administration, the appropriate daily dose is generally about 0.0001 to 50 mg / kg, preferably about 0.001 to 10 mg / kg, more preferably 0.01 to 1 mg / kg, per body weight, and this is administered once a day or dividing it into 2 to 4 doses. In the case of intravenous administration, the appropriate daily dose is generally about 0.0001 to 1 mg / kg, preferably about 0.0001 to 0.1 mg / kg, per body weight and this is administered once a day or dividing it into two or more doses. The dose is optionally decided in response to individual cases considering symptoms, age, sex and the like. However, since the dose varies under various conditions, a dose smaller than the previous interval may be sufficient in some cases.

Best Way to Carry Out the Invention

The invention is described below in an illustrative manner based on examples, but the invention is not restricted to these examples. In this regard, since new substances are included in the material compounds to be used in the examples, methods for producing such material compounds from substances conventionally known as reference examples are described.

Reference Example 1

A 5.2 g portion of 60% dispersion of sodium hydride was suspended in 50 ml of DMF and 6.73 ml of benzyl alcohol was added with ice cooling. After heating to room temperature, 12.3 g of 4-fluoro-2-trifluoromethylbenzoic acid was added and stirred at room temperature for 6 hours. A 1M aqueous solution of hydrochloric acid was added to the reaction mixture, and the crystals precipitated in this manner were collected by filtration to obtain 16.39 g of 4- (benzyloxy) -2- (trifluoromethyl) benzoic acid. MS (+); 297

In the same manner as in Reference Example 1, Reference Examples 2 to 4 shown in Table 4 were produced using the corresponding respective materials.

In this sense, the symbols in the table show the following meanings (the same will be applied hereinafter).

Rf: Reference Example number, Data: physicochemical data (NMR: use (CH3) 4If as an internal standard, and unless otherwise indicated, shows δ peaks (ppm) per 1 H NMR using DMSO-d6 as the measuring solvent, MS (+): FAB-MS [M + H] + MS (-): FAB-MS [M-H] +, EMS (+): ESI-MS [M + H] + EMS (-): ESI-MS [M-H] + RA, RB: substituent groups in the general formula,

nPr: normal propyl, cPr: cyclopropyl.

In this regard, with respect to NMR data, there is a case in which a compound gives complex data due to the presence of two or more conformers, but among them, only one peak was described that corresponds to a conformer considered as The mainly present. In addition, these peaks were convergent on a peak, which shows a type of compound, by measurement with heating.

(Table 4)

Rf

RA RB Data

2

CF3 cPr-CH2O EMS (-): 259

3

Cl nPr-S MS (+): 231

4

CF3 nPr-S MS (-): 263

10 Reference Example 5

A portion of 4.44 g of methyl 4-fluoro-2-trifluorobenzoate was dissolved in 40 ml of DMF, 3.32 g of potassium carbonate and 4.10 ml of N-methyl-N-propylamine were added and the mixture stirred at 80 ° C for 14 hours. After cooling the reaction mixture, a phase separation operation was performed by adding water and EtOAc.

The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the crude product obtained by evaporation of the solvent was subjected to column chromatography on silica gel, eluting with hexane-EtOAc (4: 1) and concentrated under reduced pressure to obtain 4.79 g of methyl 4- [methyl (propyl) amino] -2 (trifluoromethyl) benzoate. MS (+): 276

20 Reference Example 6

A 4.78 g portion of the compound of Reference Example 5 was dissolved in 20 ml of MeOH and 6.94 g of a 5 M aqueous solution of sodium hydroxide was added and stirred at 70 ° C for 5 hours. The reaction mixture is

25 cooled and then concentrated under reduced pressure. The residue obtained in this manner was neutralized with a 1M aqueous solution of hydrochloric acid and the precipitated crystals were collected by filtration to obtain 4.36 g of 4- [methyl (propyl) amino] -2- (trifluoromethyl) benzoic acid. MS (+): 262.

30 Reference Example 7

A 8.0 g portion of the compound of Reference Example 1 was dissolved in 80 ml of THF, 8 ml of thionyl chloride and 3 drops of DMF were added with ice cooling and then stirred at room temperature for 3 hours. Evaporating the reaction solvent and then drying, an acid chloride compound was obtained. This was mixed with 6.84 g of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene) (Z) -methyl acetate, mixed with 50 ml of pyridine with ice cooling and then stirred at room temperature for 12 hours. After the reaction was completed, the solvent was evaluated and the layers were separated by adding a 1M aqueous solution of hydrochloric acid and EtOAc. The organic layer was washed with water and saturated brine and dried with anhydrous sodium sulfate. The solvent was evaporated and and the residue obtained from this

This was recrystallized from EtOH to obtain 9.12 g of (2Z) - {1- [4- (benzyloxy) -2- (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro acetate -5H-1-benzazepin-5-ylidene} methyl. EMS (+): 532

In the same manner as in Reference Example 7, Reference Examples 8 to 11 shown in Table 5 were produced using the corresponding respective materials.

In this sense, the symbol in the table represents the following meaning (this will be applied hereinafter in this document).

50 Me: methyl.

5

10

fifteen

twenty

25

30

35

40

45 (Table 5)

Rf

RA RB Data

8

CF3 cPr-CH2O EMS (+): 49 6

9

Cl nPr-S MS (+): 466

10

CF3 nPr-S MS (+): 500

eleven

CF3 nPr-N (Me) MS (+): 497

Reference Example 12

A 9.1 g portion of the compound of Reference Example 7 was dissolved in 100 ml of trifluoroacetic acid, 5.1 g of pentamethylbenzene was added and stirred at room temperature for 12 hours. The insoluble matter was filtered and then the filtrate was concentrated under reduced pressure. To the residue obtained in this way was added diethyl ether and the precipitated crystals were collected by filtration to obtain 6.22 g of (2Z) - {4,4-difluoro-1 [4- (benzyloxy) -2- ( methyl trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}. EMS (+): 442

Reference Example 13

A 3.89 g portion of the compound of Reference Example 12 was dissolved in 20 ml of DMSO, 2.06 g of tert-butyl bromoacetate and 1.46 g of potassium carbonate were added and stirred at room temperature for 2 hours. After filtration of the insoluble matter, the layers were separated by the addition of water and EtOAc. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was evaporated and the residue obtained in this way was subjected to column chromatography on silica gel to obtain 3.55 g of (2Z) - {1- [4- (2-tert-butoxy-2-oxoethoxy acetate) ) -2- (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene} methyl from the chloroform-MeOH eluate (80: 1). EMS (+): 556

Reference Example 14

A 3.75 g portion of the compound of Reference Example 13 was dissolved in 20 ml of trifluoroacetic acid and stirred at room temperature for 30 minutes. By evaporation of the solvent under reduced pressure, 3.25 g of [4 - {[(5Z) -4,4-difluoro-5- (2-methoxy-2-oxoethylidene) -2,3,4,5 acid were obtained -tetrahydro-1H-1-benzazepin-1yl] carbonyl} -3- (trifluoromethyl) phenoxyacetic. MS (+): 450

Reference Example 15

A 1.09 g portion of the compound of Reference Example 14 was dissolved in 10 ml of DMF, 324 mg of HOBt, 460 mg of WSCD, 1.20 ml of dimethylamine (2.0 M solution in THF) were added. and 0.335 ml of triethylamine and then stirred at room temperature for 6 hours. An aqueous solution of sodium bicarbonate was added to the reaction liquid, the precipitate formed in this way was collected by filtration and the crude product obtained in this way was washed with water and then dried under reduced pressure to obtain 1.14 g (2Z) - {1- [4- (2-dimethylamino-2-oxoethoxy) -2- (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1 acetate -benzazepin-5ylidene} methyl. MS (+): 527

Reference Example 16

A 1.00 g portion of the compound of Reference Example 12 was dissolved in 15 ml of THF, 0.415 ml of 1-butanol, 1.19 g of triphenylphosphine and 2.08 ml of diethyl azodicarboxylate were added and then stirred at room temperature for 17 hours. Water and EtOAc were added to the reaction mixture to separate the layers. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue thus obtained was subjected to column chromatography on silica gel, eluting with chloroform-MeOH (50: 1) and then concentrated under reduced pressure to obtain 1.41 g of acetate (22 ) - {1- [4-Butoxy-2- (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene} crude methyl.

The compound obtained above was dissolved in 5 ml of MeOH-10 ml of THF, mixed with a 1 M aqueous solution of sodium hydroxide and then stirred at room temperature for 2 hours. After evaporation of the solvent, 1M hydrochloric acid and chloroform-iPrOH (mixed solvent 3: 1) were added to separate the layers. The organic layer was washed with saturated brine and dried over sodium sulfate.

10 anhydrous By evaporation of the solvent, 1.01 g of (2Z) - {1- [4-butoxy-2 (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H acid were obtained -1-benzazepin-5-ylidene} acetic. MS (+): 484

In the same manner as in Reference Example 16, Reference Examples 17 to 19 15 shown in Table 6 were produced using the corresponding respective materials.

In this sense, the symbol in the table represents the following meaning (this will be applied hereinafter in this document).

20 iBu: isobutyl.

(Table 6)

Rf

RA RB Data

17

CF3 nPr-O MS (+): 470

18

CF3 iBu-O MS (+): 483

19

Cl iBu-O MS (+): 450

Reference Example 20

A 1.43 g portion of the compound of Reference Example 7 was dissolved in a mixed solvent of 15 ml of MeOH-25 ml of THF, mixed with a 1 M aqueous solution of sodium hydroxide and stirred at room temperature for 2 hours. After evaporation of the solvent, the liquid part was changed to acidic by the addition of 1M hydrochloric acid and then the white solid precipitated in this way was collected by filtration and was

30 dried under reduced pressure to obtain 1.39 g of (2Z) - {1- [4- (benzyloxy) -2- (trifluoromethyl) benzoyl] -4,4-difluoro1,2,3,4-tetrahydro-5H acid -1-benzazepin-5-ylidene} acetic. MS (+): 518

In the same manner as in Reference Example 20, Reference Examples 21 to 25 shown in Table 7 were produced using the corresponding respective materials.

(Table 7)

 image 1

Rf

RA RB Data

twenty-one

CF3 cPr-CH2O EMS (+): 482

22

Cl nPr-S MS (+): 452

2. 3

CF3 nPr-S MS (+): 486

24

CF3 nPr-N (Me) MS (+): 483

25

CF3 Me2NOCCH2-O MS (+): 513

Reference Example 26

5 Concentrated sulfuric acid was added to a MeOH solution of the compound of Reference Example 1 and refluxing was performed for 3 days. The reaction mixture was poured into ice-cold water to perform the ether extraction operation. After evaporation of the solvent, the residue obtained in this way was dissolved in EtOH, mixed with 10% palladium on carbon and, under a hydrogen atmosphere, stirred at room temperature for 24 hours to obtain 4-hydroxy-2. - methyl trifluoromethyl benzoate.

10 MS (+): 221

Reference Example 27

Bromoacetone and potassium carbonate were added to an acetonitrile solution of the compound of Reference Example 26 and stirred at 60 ° C for 1 hour to obtain methyl 4- (2-oxopropoxy) -2- (trifluoromethyl) benzoate. ESI-MS (+): 299 [M + 23] +.

Reference Example 28

20 (Diethylamino) sulfur trifluoride was added at -78 ° C to a solution in methylene chloride of the compound of Reference Example 27, and stirred at room temperature for 24 hours to obtain 4- (2,2-difluoropropoxy) 2- methyl (trifluoromethyl) benzoate. EI-MS: 298 [M] +

25 Reference Example 29

A 5M aqueous solution of sodium hydroxide was added to a MeOH solution of the compound of Reference Example 28, and stirred at 90 ° C for 2.5 hours to obtain 4- (2,2-difluoropropoxy) -2 (trifluoromethyl) )benzoic.

30 MS (-): 283

Reference Example 30

Triethylamine was added to a solution in methylene chloride of (2S) -propane-1,2-diol and then a

35 solution in methylene chloride of p-toluenesulfonyl chloride at -20 ° C and stirred at room temperature for 18 hours to obtain (2S) -2-hydroxypropyl-4-methylbenzenesulfonate. MS (+): 231

Reference Example 30A

N, N-Dimethylaniline and acetic anhydride were added to a THF solution of the compound of Reference Example 30 and stirred at 0 ° C for 1 hour to obtain (1S) -1-methyl-2 - {[(4 -methylphenyl) sulfonyl] oxy} ethyl. MS (+): 273

45 Reference Example 30B

The compound of Reference Example 26 and potassium carbonate were added to a DMF solution of the

compound of Reference Example 30A and stirred at 70 ° C for 17 hours to obtain methyl 4 - {[(2S) -2 (acetyloxy) propyl] oxy} -2- (trifluoromethyl) benzoate. MS (+): 321

Reference Example 31

A 1 M solution of potassium hydroxide-MeOH at 0 ° C was added to a MeOH solution of the compound of Example Reference 30B and stirred at room temperature for 1 hour to obtain methyl 4 - {[(2S) -2-hydroxypropyl] oxy} -2 (trifluoromethyl) benzoate. MS (+): 279

Reference Example 32

(Diethylamino) sulfur trifluoride was added at -78 ° C to a methylene chloride solution of the compound of the Reference Example 31 and stirred at room temperature for 15 hours to obtain methyl 4 - {[(2R) -2fluoropropyl] oxy} -2- (trifluoromethyl) benzoate. FAB-MS (+): 280 [M] +

Reference Example 33

A 5 M aqueous solution of sodium hydroxide was added to a MeOH solution of the compound of the Example of Reference 32 and stirred at 70 ° C for 6 hours to obtain 4 - {[(2R) -2-fluoropropyl] oxy} -2 (trifluoromethyl) benzoic acid. MS (+): 267

Reference Example 34

Sodium borohydride at 0 ° C was added to a solution in EtOH of the compound of Reference Example 27 and stirred at room temperature for 1 hour to obtain methyl 4- (2-hydroxypropoxy) -2- (trifluoromethyl) benzoate. ESI-MS (+): 301 [M + 23] +

Reference Example 35

In the same manner as in Reference Example 30, (2R) -2-hydroxypropyl-4-methylbenzenesulfonate was produced using (2R) -propane-1,2-diol. MS (+): 231

Reference Example 35A

In the same manner as in Reference Example 30A, (1R) -1-methyl-2 - {[(4-methylphenyl) sulfonyl] oxy} ethyl acetate was produced using the compound of Reference Example 35, MS (+): 273

Reference Example 35B

In the same manner as in Reference Example 30B, methyl 4 - {[(2R) -2- (acetyloxy) propyl] oxy} -2 (trifluoromethyl) benzoate was produced using the compound of Reference Example 35A. MS (+): 321

Reference Example 36

In the same manner as in Reference Example 31, methyl 4 - {[(2R) -2-hydroxypropyl] oxy} -2 (trifluoromethyl) benzoate was produced using the compound of Reference Example 35B. MS (+): 279

Reference Example 37

In the same manner as in Reference Example 32, methyl 4 - {[(2S) -2-fluoropropyl] oxy} -2 (trifluoromethyl) benzoate was produced using the compound of Reference Example 36. MS (+): 281

Reference Example 38

In the same manner as in Reference Example 33, 4 - {[(2S) -2-fluoropropyl] oxy} -2 (trifluoromethyl) benzoic acid was produced using the compound of Reference Example 37. MS (+): 267

In the same manner as in Reference Example 7, Reference Examples 39 to 41 shown in Table 8 were produced using the corresponding respective materials.

(Table 8)

 image 1

Rf

RB RD Data

39

(S) -O-CH2CHFCH3 H EMS (+): 502

39A

(R) -O-CH2CHFCH3 H H EMS (+): 502

40

(S) -O-CH2CHFCH3 F MS (+): F MS (+): 520

40A

(R) -O-CH2CHFCH3 F MS (+): 520

41

-O-CH2CF2CH3 MS (+): H MS (+): 520

In the same manner as in Reference Example 20, Reference Examples 42 to 46 shown in Table 9 were produced using the corresponding respective materials.

(Table 9)

Rf

RB RD Data

42

(S) -O-CH2CHFCH3 H MS (+): 488

43

(R) -O-CH2CHFCH3 H MS (+): 488

44

(S) -O-CH2CHFCH3 F MS (+): 506

Four. Five

(R) -O-CH2CHFCH3 F MS (+): 506

46

-O-CH2CF2CH3 H MS (+): 506

10 Example 1

A 150 mg portion of the compound of Reference Example 20 was dissolved in 5 ml of DMF, mixed with 43 mg of HOBt, 61 mg of WSCD, 35 mg of glycine amide hydrochloride and 0.045 ml of triethylamine and then

15 stirred at room temperature for 4 hours. An aqueous solution of sodium bicarbonate and EtOAc was added to the reaction mixture to separate the layers. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue thus obtained was recrystallized from EtOH to obtain 139 mg of (2Z) -N- (2-amino-2-oxoethyl) -2- {1- [4- (benzyloxy) -2 (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene} acetamide.

In the same manner as in Example 1, Examples 2 to 16 shown in Table 10 were produced using the corresponding respective materials.

Example 17

A 150 mg portion of the compound of Example 20 was dissolved in 3.5 ml of THF, mixed with 0.3 ml of thionyl chloride and 2 to 3 drops of DMF and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and thionyl chloride was further removed by azeotropic evaporation using toluene. The residue obtained in this way was dissolved in THF and this solution was added dropwise to aqueous ammonia. The layers were separated by adding EtOAc to the reaction mixture. The organic layer was washed with saturated brine and then dried with anhydrous magnesium sulfate. The crude product obtained in this manner was recrystallized from a mixed solvent of iPrOH-diisopropyl ether to obtain 126 mg of (2Z) -2- {1- [4 (benzyloxy) -2- (trifluoromethyl) benzoyl] -4.4 -difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene} acetamide.

In the same manner as in Example 17, Example 18 shown in Table 10 was produced using the corresponding respective materials. In addition, in the same manner as in Reference Example 12, Examples 19 and 20 which are shown in Table 10 were produced using the corresponding respective materials.

Example 21

A 325 mg portion of the compound of Example 6 was dissolved in 5 ml of 1,2-dichloroethane, mixed with 148 mg of m-chlorobenzoic acid with ice cooling and stirred at room temperature for 4 hours. The reaction mixture was mixed with a 10% (w / v) aqueous solution of Na2S2O3-5 H2O, water and chloroform to perform layer separation. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and dried with anhydrous sodium sulfate, the solvent was evaporated, and then the crude product obtained in this way was subjected to a column chromatography on silica gel, eluting with chloroform-MeOH (23: 2) and concentrated under reduced pressure to obtain 121 mg of (2Z) -N- (2-amino-2-oxoethyl) -2- {4,4-difluoro-1- [4 (propylsulfinyl ) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene} acetamide.

In the same manner as in Example 21, Example 22 was produced which is shown in Table 10 using the corresponding respective starting materials. In addition, Examples 23 to 147 shown in Tables 11 to 18 were produced using the corresponding respective starting materials, by the production methods mentioned above or the methods described in the Examples, or methods obvious to those skilled in the art. or modified methods thereof.

In this sense, the symbols in the tables represent the following meanings (this will be applied hereinafter in this document).

Ex .: example number, Rc: substituent group in the general formula, Et: ethyl, nBu: normal butyl, Ph: phenyl, Py: pyridyl, Bn: benzyl, Gly: carbamoylmethylamino (-NHCH2CONH2), Etha: 2-hydroxyethylamino (-NHCH2CH2OH), Car: amino (-NH2). In this sense, the number before each substituent group represents the substitution position. Illustratively, for example, -NHPh (2-OH) means 2-hydroxyphenylamino, and -NHCH2 (2-Py) means pyridin-2-ylmethylamino.

(Table 10)

image 1

image 1

image 1

image 1

(Table 14) (Table 15) (Table 16) (Table 17) (Table 18)

image 1

image 1

image 1

image 1

image 1

In the following, the NMR data of some Example compounds is shown in the Table (Table 19)

Ex

NMR

one

2.35-2.55 (1H, a), 2.60-2.80 (1H, a), 3.00-3.15 (1H, a), 3.76 (2H, s), 4, 75-4.90 (1H, a), 5.09 (2H, s), 6.45 (1H, s), 6.73 (1H, d, J = 7.8 Hz), 6.87 (1H , d, J = 7.8 Hz), 7.03 (1H, dd, J = 7.8, 4 Hz), 7.1 0-7.19 (2H, m), 7.247.40 (9H, m ), 8.68 (1H, t, J = 5.7 Hz).

2

2.55-2.55 (1H, a), 2.60-2.80 (1H, a), 3.20-3.25 (2H, m), 3.42-3.50 (2H, m ), 4.72 (1H, t, J = 5.4 Hz), 4.75-4.90 (1H, a), 5.09 (2H, s), 6.39 (1H, s), 6 , 72 (1H, d, J = 7.8 Hz), 6.87 (1H, d, J = 73 Hz), 7.04 (1H, d, J = 2.0.8.3 Hz), 7 , 1 6 (1H, t, J = 7.6 Hz), 7.22-7.42 (8H, m), 8.46 (1H, t, J = 5.4 Hz).

3

0.24-0.30 (2H, m), 0.49-0.58 (2H, m), 1.08-1.20 (1H, m), 2.33-2.45 (1H, a ), 2.60-2.97 (1H, a), 3.02-3.29 (1H, a), 3.68-3.88 (4H, m), 4.60-5.05 (1H , a), 6.44 (1H, s), 6.71 (1H, d, J = 8.8 Hz), 6.85 (1H, d, J = 8.8 Hz), 6.93 (1H , dd, J = 2.0.8.8 Hz), 7.11-7.38 (6H, m), 8.48 (1H, t, J = 5.4 Hz).

4

0.24-0.31 (2H, m), 0.48-0.56 (2H, m), 1.09-1.21 (1H, m), 2.27-2.46 (1H, a ), 2.65-2.90 (1H, a), 3.00-3.26 (3H, m), 3.43-3.52 (2H, m), 3.80 (2H, d, J = 6.8 Hz), 4.73 (1H, d, J = 53 Hz), 4.75-4.92 (1H, a), 6.39 (1H, s), 6.71 (1H, d , J = 73 Hz), 6.84 (1H, d, J = 8.8 Hz), 6.93 (1H, dd, J = 25.8.8 Hz), 7.13-7.18 (2H , m), 7.24 (1H, t, J = 7.3 Hz), 7.30-7.34 (1H, m), 8.48 (1H, t, J = 53 Hz).

5

0.92 (3H, t, J = 7.6 Hz), 1.46-1.55 (2H, m), 2.24-2.50 (1H, a), 2.65-2.84 ( 1H, a), 2.89-2.93 (2H, m), 3.04-3.22 (1H, a), 3.75 (2H, s), 4.70-4.92 (1H, a), 6.37 (1H, s), 6.87 (1H, s), 6.94 (1H, d, J = 7.6 Hz), 7.01 (1H, d, J = 8.0 Hz), 7.14-7.53 (6H, m), 8.62 (1H, s).

6

0.93 (3H, t, J = 7.2 Hz), 1.48-1.57 (2H, m), 2.28-2.52 (1H, a), 2.63-2.87 ( 1H, a), 2.94-2.97 (2H, m), 3.08-3.20 (1H, a), 3.73-3.76 (2H, m), 4.73-4, 88 (1H, a), 6.48 (1H, s), 6.73 (1H, d, J = 8.0 Hz), 6.84 (1H, d, J = 8.0 Hz), 7, 14-7.76 (7H, m), 8.69 (1H, t, J = 52 Hz).

7

0.92 (3H, t, J = 3 Hz), 1.62-1.72 (2H, m), 2.30-2.50 (1H, a), 2.60-2.80 (1H, a), 3.00-3.10 (1H, a), 3.76 (2H, s), 3.90 (2H, t, J = 6.6 Hz), 4.70-4.90 (1H , a), 6.45 (1H, s), 6.72 (1H, d, J = 7.8 Hz), 6.85 (1H, d, J = 7.8 Hz), 6.85 (1H , dd, J = 2,1,7,6 Hz), 7,10-7,38 (6H, m), 8,68 (1H, t, J = 5,4 Hz).

8

0.92 (3H, t, J = 7.3 Hz), 1.62-1.72 (2H, m), 2.30-2.50 (1H, a), 2.60-2.80 ( 1H, a), 3.00-3.20 (1H, a), 3.23 (2H, t, J = 59 Hz), 3.44-3.50 (2H, m), 3.90 (2H , t, J = 6.6 Hz), 4.72 (1H, t, J = 5.4 Hz), 4.75-4.86 (1H, a), 6.40 (1H, s), 6 , 71 (1H, d, J = 7.8 Hz), 6.85 (1H, d, J = 8.3 Hz), 6.95 (1H, dd, J = 2.5.8.8 Hz) , 7.10-7.18 (2H, m), 7.25 (1H, t, J = 7.1 Hz), 7.30-7.34 (1 Hm), 8.46 (1H, t, J = 5.6 Hz).

0.89 (3H, t, J = 7.3 Hz), 1.31-1.42 (2H, m), 1.57-1.67 (2H, m), 2.30-2.50 ( 1H, a), 3.70-2.85 (1H, a), 3.00-9 3.20 (1H, a), 3.76 (2H, s), 3.94 (1H, t, J = 6.6 Hz), 4.65-4.95 (1H, a), 6.45 (1H, s), 6.72 (1H, d, J = 7.8 Hz), 6.85 (1H , d, J = 8.8 Hz), 6.94 (1H, dd, J = 2.4.8.8 Hz), 7.10-7.20 (3H, m), 7.22-7, 32 (1H, m), 7.33-7.37 (1H, m), 8.68 (1H, t, J = 53 Hz).

10

0.89 (3H, t, J = 7.4 Hz), 1.32-1.42 (2H, m), 1.58-1.67 (2H, m), 2.25-2.45 ( 1H, a), 2.60-2.80 (1H, a), 3.00-3.15 (1H, a), 3.20-3.30 (2H, m), 3.44-3, 50 (2H, m), 3.94 (2H, t, J = 6.4 Hz), 4.73 (1H, t, J = 5.2 Hz), 4.75-4.87 (1H, a ), 6.39 (1H, s), 6.71 (1H, d, J = 7.8 Hz), 6.84 (1H, d, J = 8.8 Hz), 6.95 (1H, dd , J = 2,5,8,8 Hz), 7,12-7,18 (2H, m), 7.21-7.26 (1H, m), 7.30-7.33 (1H, m ), 8.46 (1H, t, J = 5.6 Hz).

eleven

0.92 (6H, d, J = 6.8 Hz), 1.89-2.00 (1H, m), 2.30-2.50 (1H, a), 2.60-2.80 ( 1H, a), 3.00-3.20 (1H, a), 3.70-3.82 (4H, m), 4.75-4.85 (1H, a), 6.45 (1H, s), 6.72 (1H, d, J = 7.9 Hz), 6.86 (1H, d, J = 8.8 Hz), 6.95 (1H, dd, J = 2.4.8 , 3 Hz), 7.12-7.19 (3H, m), 7.23-7.30 (2H, m), 7.36 (1H, dd, J = 7.8 Hz, 1.5 Hz ), 8.68 (1H, t, J = 5.6 Hz).

12

0.92 (6H, d, J = 6.4 Hz), 1.89-2.00 (1H, m), 2.30-2.50 (1H, a), 2.60-2.80 ( 1H, a), 3.00.3-15 (1H, a), 3.19-3.25 (2H, m), 3.44-3.50 (2H, m), 3.72 (2H, d, J = 63 Hz), 4.73 (1H, t, J = 51 Hz), 4.76-4.88 (1H, a), 6.40 (1H, s), 6.71 (1H, d, J = 73 Hz), 6.85 (1H, d, J = 8.8 Hz), 6.96 (1H, dd, J = 25.83 Hz), 7.13-7.18 (2H, m), 7.22-7.27 (1H, m), 7.32 (1H, dd, J = 7.8 Hz, 5 Hz), 8.46 (1H, J = 5.6 Hz).

13

0.91 (6H, d, J = 6.8 Hz), 1.86-1.98 (1H, m), 2.25-2.50 (1H, a), 2.60-2.80 ( 1H, a), 3.00 3.15 (1H, a), 3.67 (2H, d, J = 6.3 Hz), 3.70-3.78 (2H, a), 4.73- 4.90 (1H, a), 6.35 (1H, s), 6.63-6.69 (1H, m), 6.89-6.96 (3H, m), 7.117.20 (2H, m), 7.22-7.33 (3H, m), 8.62 (1H, s)

14

0.80 (2H, t, J = 7.2 Hz), 1.40-1.45 (2H, m), 2.27-25.3 (1H, a), 2.53-2.77 ( 1H, a), 2.55-2.77 (3H, s), 2.92-3.15 (1H, a), 3.24 (2H, s), 3.7S (2H, s), 4 , 71-5.05 (1H, a), 6.44 (1H, s), 6.58 (1H, d, J = 8.4 Hz), 6.67 (1H, d, J = 8.4 Hz), 6.71 (1H, d, J = 7.6 Hz), 6.77 (1H, s), 7.14-7.36 (5H, m), 8.64 (1H, s).

fifteen

2.30 (1H, a), 2.65-2.85 (1H, a), 2.80 (3H, s), 2.92 (3H, s), 3.00-3.20 (1H, a), 3.70-3.82 (2H, m), 4.75-4.90 (1H, a), 4.86 (2H, s), 6.44 (1H, s), 6.73 (1H, d, J = 7.8 Hz), 6.83 (1H, d, J = 83 Hz), 6.90 (1H, dd, J = 2.4.8.33 Hz), 7.1 1-7.20 (3H, m), 7.24-7.30 (2H, m), 7.36 (1H, dd, J = 7.3 Hz, 1.4 Hz), 8.68 (1H , t, J = 5.7 Hz).

16

0.92 (3H, t, J = 7.8 Hz), 1.61-1.71 (2H, m), 2.35-2.55 (1H, a), 2.60-2.80 ( 1H, a), 3.00-3.20 (1H, a), 3.90 (2H, t, J = 6.4 Hz), 4.70-4.90 (1H, a), 6.38 (1H, s), 6.72 (1H, d, J = 7.8 Hz), 6.84 (1H, d, J = 8.7 Hz), 6.96 (1H, dd, J = 2, 5.8.6 Hz), 7.10-7.18 (2H, m), 7.22-7.27 (1H, m), 7.28-7.31 (1H, m), 7.35 (1H, s), 7.87 (1H, s).

17

2.30-2.55 (1H, a), 2.60-2.80 (1H, a), 3.05-3.25 (1H, a), 4.75-4.95 (1H, a ), 5.09 (2H, s), 6.38 (1H, s), 6.73 (1H, d, J = 7.8 Hz), 6.86 (1H, d, J = 8.7 Hz ), 7.05 (1H, dd, J = 2.4.8.4 Hz), 7.1 3-7.18 (1H, m), 7.22-7.42 (9H, m), 7 , 88 (1H, s).

18

0.81 (3H, t, J = 7.2 Hz), 1.40-1.46 (2H, m), 2.24-2.52 (1H, a), 2.57-2.78 ( 1H, a), 2.85 (3H, s), 2.95-3.17 (1H, a), 3.23 (2H, s), 4.70-5.02 (1H, a), 6 , 36 (1H, s), 6.62-6.76 (4H, m), 7.16-7.34 (4H, m), 7.84 (1H, s)

19

2.30-2.50 (1H, a), 2.55-2.80 (1H, a), 3.00-3.20 (H, a), 3.75 (2H, s), 4, 70-4.90 (1H, a), 6.47 (1H, s), 6.66-6.76 (3H, m), 7.00 (1H, d, J = 1.5 Hz), 7 , 10-7.19 (1H, m), 7.22-7.30 (2H, m), 7.35 (1H, d, J = 7.8 Hz), 8.65 (1H, t, J = 5.6 Hz), 10.3 (1H, s).

twenty

2.30-2.50 (1H, a), 2.55-2.80 (1H, a), 3.00-3.20 (1H, a), 4.70-4.90 (1H, a ), 6.41 (1H, s), 6.67-6.74 (3H, m), 7.00 (1H, s), 7.15 (1H, td, J = 1,4,7,8 Hz), 7.24 (1H, t, J = 7.6 Hz), 7.27-7.32 (1H, m), 7.34 (1H, s), 7.85 (1H, s), 1.03 (1H, s).

twenty-one

0.87 (1H, t, J = 7.2 Hz), 1.19-1.27 (1H, m), 1.45-1.58 (1H, m), 2.18-2.52 ( 1H, a), 2.65-2.78 (1H, a), 2.93-3.00 (2H, m), 3.06-3.25 (1H, a), 3.74-3, 76 (2H, m), 4.75-4.92 (1H, a), 6.55 (1H, s), 6.73 (1H, d, J = 7.6 Hz), 7.127.15 (1H , m), 7.24-7.33 (2H, m), 7.36 (1H, dd, J = 1.6.7.2 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.98 (1H, s), 8.70 (1H, s).

22

0.84 (3H, t, J = 7.6 Hz), 1.38-1.47 (2H, m), 2.15-2.54 (1H, a), 2.67-2.90 ( 1H, a), 3.15-3.30 (1H, a), 3.34-3.52 (2H, m), 3.75-3.77 (2H, m), 4.75-4, 90 (1H, a), 6.61 (1H, s), 6.74 (1H, d, J = 8.0 Hz), 7.13-7.17 (3H, m), 7.267.39 (2H , m), 7.37-7.39 (1H, m), 7.97 (1H, d, J = 8.4 Hz), 8.16 (1H, s), 8.71 (1H, s) .

30

1.32 (3H, dd, J = 6.4.29 2 Hz), 2.31-2.43 (1H, a), 2.60-2.80 (1H, a), 3.18-3 , 27 (1H, a), 3.20-3.34 (2H, m), 4.00-4.37 (2H, m), 4.64-5.10 (2H, m), 6.56 (1H, s), 6.73-6.80 (1H, m), 6.87 (1H, d, J = 8.8Hz), 7.02-7.08 (2H, m), 7, 14 (1H, s), 7.24-7.26 (2H, m), 7.32 (1H, s), 8.64-8.64 (1H, a).

31

1.33 (3H, dd, J = 6.3.29.3 Hz), 2.33-2.47 (1H, a), 2.59-2.83 (1H, a), 3.03- 3.25 (1H, a), 3.72-3.85 (2H, m), 4.02-4.24 (2H, m), 4.72-4.84 (1H, a), 4, 86-5.07 (1H, m), 6.56 (1H, s), 6.74-6.80 (1H, m), 6.88 (1H, d, J = 8.8 Hz), 7 , 00-7.08 (2H, m), 7.14 (1H, s), 7.21-7.26 (2H, m), 7.32 (1H, s), 8.65 (1H, t , J = 5.4 Hz).

51

1.67 (3H, t, J = 19.5 Hz), 2.30-2.48 (1H, a), 2.46-2.90 (1H, a), 3.08-3.34 ( 3H, m), 3.39-4.00 (2H, m), 4.32 (2H, t, J = 12.7 Hz), 4.70-4.78 (2H, m), 6.38 (1H, s), 6.71 (1H, d, J = 7.8 Hz), 6.89 (1H, d, J = 8.8 Hz), 7.04 (1H, dd, J = 2, 4.8.8 Hz), 7.15 (1H, d, t, J = 1, 5.7.8 Hz), 7.22-7.34 (3H, m), 8.47 (1H, t , J = 5.3 Hz).

52

1.32 (3H, dd, J = 6.4.23.5 Hz), 2.36-2.47 (1H, a), 2.65-2.76 (1H, a), 3.18- 3.30 (3H, m); 3.43-3.49 (2H, m), 4.00-4.20 (2H, m), 4.68-5.06 (3H, m), 6.39 (1H, s), 6, 72 (1H, d, J = 8.8 Hz), 6.87 (1H, d, J = 8.8 Hz), 6.98 (1H, dd, J = 2.4.8.8 Hz), 7.15 (1H, dt, J = 1, 4.8.8 Hz), 7.21-7.27 (2H, m), 7.32 (1H, dd, J = 1.4.8.8 Hz), 8.46 (1H, t, J = 5.8 Hz).

53

1.32 (3H, dd, J = 6.8.23.9 Hz), 2.37-2.46 (1H, a), 2.65-2.83 (1H, a), 3.19- 3.28 (3H, m), 3.44-3.50 (2H, m), 4.00-4.20 (2H, m), 4.69-5.05 (3H, m), 6, 39 (1H, s), 6.73 (1H, d, J = 8.8 Hz), 6.87 (1H, d, J = 8.8 Hz), 6.99 (1H, dd, J = 2 , 4.8.8 Hz), 7.15 (1H, dt, J = 1, 4.8.8 Hz), 7.21-7.27 (2H, m), 7.32 (1H, dd, J = 1.4.8.8 Hz), 8.46 (1H, t, J = 5.4 Hz).

54

1.33 (3H, dd, J = 5.9.29.8 Hz), 2.31-2.46 (1H, a), 2.61-2.84 (1H, a), 3.18- 3.26 (2H, m), 3.44-3.50 (2H, m), 4.01-4.22 (2H, m), 4.74 (1H, t, J = 53 Hz), 4 , 76-4.85 (1H, a), 4.96-5.06 (1H, m), 6.51 (1H, s), 6.70-6.77 (1H, m), 6.86 (1H, d, J = 8.8 Hz), 7.01-7.08 (1H, m), 7.19 (2H, dd, J = 2.9.8.8 Hz), 7.25 ( 1H, d, J = 2.9 Hz), 7.66 (1H, d, J = 8.8 Hz), 8.46 (1H, t, J = 5.9 Hz).

55

1.32 (3H, dd, J = 5.9.29.8 Hz), 2.32-2.46 (1H, a), 2.61-2.84 (1H, a), 3.03- 3.27 (2H, m), 3.44-3.51 (2H, m), 4.02-4.22 (2H, m), 4.74 (1H, t, J = 5.3 Hz) , 4.76-4.85 (1H, a), 4.87-5.06 (1H, m), 6.52 (1H, s), 6.70-6.78 (1H, m), 6 , 87 (1H, d, J = 8.8 Hz), 7.00-7.08 (1H, m), 7.19 (2H, dd, J = 2.9.8.8 Hz), 7, 24 (1H, d, J = 2.9 Hz), 7.67 (1H, d, J = 8.8 Hz), 8.47 (1H, t, J = 5.4 Hz).

56

1.69 (3H, t, J = 19.6 Hz), 2.31-2.46 (1H, a), 2.61-2.83 (1H, a), 3.05-3.27 ( 3H, m), 3.43-3.50 (2H, m), 4.34 (2H, t, J = 12.7 Hz), 4.68-4.86 (2H, m), 6.50 (1H, s), 6.73-6.78 (1H, m), 6.89 (1H, d, J = 8.8 Hz), 7.01-7.13 (2H, m), 7, 20 (1H, dd, J = 2.9,8.8 Hz), 7.31 (1H, d, J = 29 Hz), 8.43 (1H, t, J = 5.4 Hz).

84

0.97 (3H, t, J = 7.3 Hz), 1.61-1.72 (2H, m), 2.31-2.47 (1H, a), 2.65-2.81 ( 1H, a), 2.99-3.17 (3H, m), 3.32-3.40 (2H, m), 3.52-3.61 (1H, m), 3.90 (2H, t, J = 7.3 Hz), 4.54 (1H, t, J = 5.9 Hz), 4.75-4.87 (2H, m), 6.40 (1H, s), 6, 71 (1H, d, J = 8.8 Hz), 6.85 (1H, d, J = 8.8 Hz), 6.95 (1H, dd, J = 2.5.8.8 Hz), 7.12-7.19 (2H, m), 7.24 (1H, t, J = 8.8 Hz), 7.34 (1H, dd, J = 1.4.8.8 Hz), 8 , 45 (1H, t, J = 5.4 Hz).

85

0.98 (3H, t, J = 7.3 Hz), 1.61-1.71 (2H, m), 2.30-2.46 (1H, a), 2.65-2.80 ( 1H, a), 2.99-3.20 (1H, m), 3.32-3.39 (2H, m), 3.51-3.62 (1H, m), 3.90 (2H, t, J = 7.3 Hz), 4.54 (1H, t, J = 5.9 Hz), 4.76-4.90 (2H, m), 6.40 (1H, s), 6, 71 (1H, d, J = 8.8 Hz), 6.86 (1H, d, J = 8.8 Hz), 6.94 (1H, dd, J = 2.5.8.8 Hz), 7.12-7.19 (2H, m), 7.24 (1H, t, J = 8.8 Hz), 7.34 (1H, dd, J = 1.4.8.8 Hz), 8 , 45 (1H, t, J = 5.4 Hz).

86

0.93 (3H, t, J = 6.8 Hz), 1.61-1.72 (2H, m), 2.31-2.46 (1H, a), 2.61-2.83 ( 1H, a), 3.00-3.21 (3H, m), 3.31-3.39 (2H, m), 3.52-3.63 (1H, m), 3.92 (2H, t, J = 6.8 Hz), 4.56 (1H, t, J = 5.9 Hz), 4.52-4.86 (2H, m), 6.53 (1H, s), 6, 71-6.77 (1H, m), 6.85 (1H, 8 Hz), 6.99 (1H, dd, J = 2.0, 8.5 Hz), 7.04 (1H, dt, J = 2,0,8,8 Hz), 7,17 (1H, d, J = 2,0 Hz), 7, 21 (1H, dd, J = 2,0,8,8 Hz), 8,42 (1H, t, J = 53 Hz).

129

1.32 (3H, dd, J = 6.3.23.4 Hz), 2.34-2.46 (1H, a), 2.25-2.83 (1H, a), 3.20- 3.32 (3H, m), 3.35-3.40 (2H, m), 3.52-3.60 (1H, m), 4.00-4.20 (2H, m), 4, 50 (1H, m), 4.73, 5.05 (3H, m), 6.39 (1H, s), 6.72 (1H, d, J = 8.8 Hz), 6.67 (1H , d, J = 8.8 Hz), 6.9 (1H, d, J = 2.5.8.8 Hz), 7.15 (1H, dt, J = 2.5.8.8 Hz) , 7.19-7-27 (2H, m), 7.34 (1H, dd, J = 1.4.8.8 Hz), 7.47 (1H, t, J = 5.4 Hz).

130

1.31 (3H, dd, J = 6.3.23.4 Hz), 2.26-2.47 (1H, a), 2.62-2.47 (1H, a), 3.00- 3.23 (3H, m), 3.32-3.38 (2H, m), 3.53-3.62 (1H, m), 4.00-4.20 (2H, m), 4, 45 (1H, t, J = 5.4 Hz), 4.76-5.05 (3H, m), 6.40 (1H, s), 6.72 (1H, d, J = 7.8 Hz ), 6.88 (1H, d, J = 8.8 Hz), 6.99 (1H, dd, J = 2.5.8.8 Hz), 7.15 (1H, dt, J = 1, 4.7.8 Hz), 7.20-7.28 (2H, m), 7.34 (1H, dd, J = 1.4.7.8 Hz), 8.47 (1H, t, J = 5.9 Hz).

132

1.31 (3H, dd, J = 6.4.23.4 Hz), 2.30-2.46 (1H, a), 2.54-2.80 (1H, a), 3.00- 3.32 (3H, m), 3.34-3.40 (2H, m), 3.52-3.61 (1H, m), 4.00-4.20 (2H, m), 4, 51-4.6 (1H, m), 4.72-5.05 (3H, m), 6.40 (1H, s), 6.12 (1H, d, J = 8.8 Hz), 6 , 87 (1H, d, J = 8.8 Hz), 6.99 (1H, dd, J = 2.5.8.8 Hz), 7.15 (1H, dd, J = 2.5, 8 , 8 Hz), 7.19-7.29 (2H, m), 7.31-7.36 (1H, m), 8.46 (1H, t, J = 5.4 Hz)

133

(3H, dd, J = 6.3.23.9 Hz), 2.27-2.46 (3H, m), 2.60-2.84 (1H, a), 3.22-3.34 (1H, a), 3.34-3.402 (H, m), 4.004.22 (2H, m), 4.70-5.06 (2H, m), 6.44 (1H, s), 6, 71-6.76 (1H, m), 6.81-6.89 (2H, m), 7.01-7.07 (2H, m), 7.19 (1H, dd, J = 2.9 , 8.8 Hz), 7.24 (1 Hz), 7.33-7.38 (1H, a), 8.45-8.52 (1H, a).

134

1.33 (3H, dd, J = 6.4.29.8 Hz), 2.26-2.46 (3H, m), 2.64-2.87 (1H, a), 3.00- 3.23 (1H, a), 3.27-3.42 (2H, m), 4.01-4.22 (2H, m), 4.66-5.07 (2H, m), 6, 49 (1H, s), 6.71-6.78 (1H, m), 6.87 (2H, d, J = 8.8 Hz), 7.00-7.08 (2H, m), 7 , 19 (1H, dd, J = 2.9.8.8 Hz), 7.24 (1H, d, J = 2.9), 7.33-7.39 (1H, a), 8.50 (1H, t, J = 5.4 Hz).

135

1.32 (3H, dd, J = 6.3.23.9 Hz), 2.32-2.46 (1H, a), 2.63-2.84 (1H, a), 3.00- 3.24 (3H, m), 3.33-3.40 (2H, m), 3.52-3.61 (1H, m), 4.01-4.21 (2H, m), 4, 57 (1H, t, J = 53 Hz), 4.73-5.06 (3H, m), 6.52 (1H, s), 6.72-6.78 (1H, m), 6.87 (1H, d, J = 8.8 Hz), 7.00-7.08 (2H, m), 7.18-7.26 (2H, m), 8.38-8.48 (1H, m ).

136

1.33 (3H, dd, J = 6.3.1.34 Hz), 2.34-2.47 (1H, a), 2.56-2.82 (1H, a), 3.01- 3.32 (3H, m), 3.33-3.39 (2H, m), 3.52-3.61 (1H, m), 4.02-4.22 (2H, m), 4, 57 (1H, t, J = 5.4Hz), 4.75-4.85 (2H, m), 4.87-5.07 (1H, m), 6.51 (1H, s), 6, 71-6.77 (1H, m), 6.87 (1H, d, J = 83Hz), 7.01-7.08 (2H, m), 7.19-7.25 (2H, m), 8.43 (1H, t, J = 5.4Hz).

image2

In the following, the structures of other compounds of the invention are shown in Tables 20 to 36. These are synthesized, or can be synthesized, using the production methods mentioned above or the methods 5 described in the Examples, or obvious methods for experts in the field or modified methods thereof. In this sense, the symbols in the tables represent the following meanings.

No.: compound number. R1A, -AA-BA, X, Y: substituent groups in the respective general formulas, iPr: isopropyl, tBu: tert-butyl, cBu: 10 cyclobutyl, nPen: normal pentyl, cPen: cyclopentyl, iAm: isoamyl, nHex: hexyl normal, pyrr: pyrrolidin-1-yl, pipe: piperidin-1-yl, pipe: piperazin-1-yl, mor: morpholin-4-yl, Ac: acetyl, Ms: methanesulfonyl, cyano: cyano.

image3

image 1

(Table 21) (Table 22)

image 1

image 1

(Table 23) (Table 24) (Table 25) (Table 26)

image 1

image 1

image 1

image 1

image 1

image 1

image 1

(Table 27)

image 1

image 1

(Table 28)

image 1

(Table 29)

image 1

image 1

(Table 30) (Table 31) (Table 32) (Table 33) (Table 34) (Table 35) (Table 36)

image 1

image 1

image 1

image 1

image 1

image 1

image 1

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image 1

Claims (8)

1. A 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by a formula (I) or a pharmaceutically acceptable salt thereof image 1 [the symbols in the formula mean the following, R1: a group represented by a formula image 1 in which, Z1: single bond, lower alkylene or-lower alkylene-C (= O) -, R11: lower alkyl which may be substituted with one or more groups selected from the group consisting of -OH, -O-lower alkyl, - CO2H, -CO2-lower alkyl and carbamoyl which may be substituted with one or two lower alkyls, or -H, R12: (1) when Z1 represents a single bond or lower alkylene, -H, -OH, -O-lower alkyl , -CO2H, -CO2 20 lower alkyl, carbamoyl which may be substituted with one or two lower alkyls, aryl which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), cycloalkyl which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), hetero aromatic ring that may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h) or ring non-aromatic hetero 25 which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), (2) when Z1 represents-lower alkylene-C (= O) -, a group represented by the formula (III) or a formula (IV), image 1 30 in which, Z2: single bond or lower alkylene, R15 : -H, -OH, -O-lower alkyl, -CO2H, -CO2-lower alkyl, carbamoyl which may be substituted with one or two lower alkyls, aryl which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), cycloalkyl which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), hetero aromatic ring which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h) or non-aromatic hetero ring which may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), R13, R14: together with the non-adjacent nitrogen atom, non-aromatic cyclic amino group that may be substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), R2: CF3 or halogen, R3: H or halogen, a: a simple link, b: a double bond, -X-: -CH = CH-, -Y-: -CH-, -A-: -O-S-, -NH-or -N (lower alkyl), B: lower alkyl, lower alkenyl or lower alkynyl, each of which is optionally substituted with one or more groups selected from the substituent groups shown in the following (a) to (g); or cycloalkyl or aryl, each of which is optionally substituted with one or more groups selected from the substituent groups shown in the following (a) to (h), where the substituents (a) to (h) are as indicated by continuation:

(to)

 halogen,

(b)

 -OH, -O-RZ, -O-aryl, -OCO-RZ, oxo (= O),

(C)

 -SH, -S-RZ, -S-aryl, -SO-RZ, -SO-aryl, -SO2-RZ, -SO2-aryl, sulfamoyl which may be substituted with 1 or 2RZ,

(d)

 amino which may be substituted with 1 or 2 RZ, -NHCO-RZ, -NHCO-aryl, -NHSO2-RZ, -NHSO2-aryl, nitro,

(and)

 -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl which may be substituted with 1 or 2 RZ, cyano,

(F)

 aryl or cycloalkyl which may be substituted respectively with one or more groups selected from the class consisting of -OH, -O-lower alkyl, amino which may be substituted with 1 or 2 lower alkyl, carbamoyl which may be substituted with 1 or 2 lower alkyl, aryl, hetero aromatic ring, halogen and RZ,

(g)

hetero aromatic ring or non-aromatic hetero ring that can be substituted respectively with one

or more groups selected from the class consisting of -OH, -O-lower alkyl, amino which may be substituted with 1 or 2 lower alkyl, carbamoyl which may be substituted with 1 or 2 lower alkyl, aryl, hetero aromatic ring, halogen and RZ, (h) lower alkyl or lower alkenyl which may be substituted respectively with one or more groups selected from the substituent groups shown in (a) to (g) mentioned above, and RZ: lower alkyl which may be substituted with one or more groups selected from the class consisting of -OH, -O-lower alkyl, amino which may be substituted with 1 or 2 lower alkyl, carbamoyl which may be substituted with 1 or 2 lower alkyl, aryl, hetero aromatic ring and halogen, and where the term "lower alkyl" refers to a straight or branched C1-6 carbon chain monvalent group, the term "lower alkylene" refers to a linear or branched C1-6 carbon chain divalent group, the term "lower alkenyl" refers to a linear or branched C2-6 carbon chain monvalent group, which has at least one double bond, the term "lower alkynyl" refers to a linear or branched C2-6 carbon chain monvalent group that It has at least one triple link, the term "cycloalkyl" refers to a monvalent C3-8 non-aromatic hydrocarbon ring group that can have a partially unsaturated bond, the term "aryl" refers to a monvalent aromatic hydrocarbon ring group, from monocyclic to tricyclic, C6-14, the term "hetero aromatic ring" refers to a monovalent aromatic ring group from monocyclic to tricyclic having a hetero atom or atoms, The term "non-aromatic hetero ring" refers to a 5 to 7-membered monvalent ring group that has a hetero atom or atoms, which can have a partially unsaturated bond and can be condensed with a aryl or hetero aromatic ring, and the term "non-aromatic cyclic amino group" refers to a monvalent group of non-aromatic cyclic amine of 3 to 10 members, which optionally have nitrogen, oxygen or sulfur, which may have a partially bond unsaturated].

2.

The compound described in claim 1, wherein -A-is -O-.

3.

The compound described in claim 2, wherein -B is lower alkyl which may be substituted with one or more groups selected from the substituent groups shown in the (a) to (g) mentioned in claim 1.

Four.

The compound described in claim 3, wherein R2 is trifluoromethyl, and R3 is -H or -F.

5.

The compound described in claim 1, which is (2Z) -N- (2-amino-2-oxoethyl) -2- {4,4,7-trifluoro-1- [4 - {[(2R) -2- fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro5H-1-benzazepin-5-ylidene} acetamide, (2Z) -N- (2-hydroxyethyl) -2- {4, 4,7-trifluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1benzazepin-5-ylidene} acetamide, (2Z) -N- (2-hydroxyethyl) -2- {4,4,7-trifluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1benzazepin-5-ylidene} acetamide, (2Z) -2- {4,4-difluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy } -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N - [(2S) -2,3-dihydroxypropyl] acetamide, 3 - [((2Z ) -2- {4,4,7-trifluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H -1-benzazepin-5ylidene} acetyl) amino] propanamide, (2Z) -N - [(2R) -2,3-dihydroxypropyl] -2- {4,4,7-trifluoro-1- [4 - {[( 2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylide no} acetamide, (2Z) -N- (2-amino-2-oxoethyl) -2- {4,4,7-trifluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2 - (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro5H-1-benzazepin-5-ylidene} acetamide, (2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- ( trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene} N- (2-hydroxyethyl) acetamide, (2Z) -2- {4,4 -difluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N- (2-hydroxyethyl) acetamide, (2Z) -2- {4,4-difluoro-1- [4 - {[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2, 3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N- (2-hydroxyethyl) acetamide, (2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoyl ] -4,4,7-Trifluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N- (2-hydroxyethyl) acetamide, (2Z) -N - [(2R) -2 , 3-dihydroxypropyl] -2- {4,4,7-trifluoro-1- [4-propoxy-2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1benzazepin-5-ylidene} acetamide, (2Z) -2- {4,4-difluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) be nzoil] -1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N - [(2S) -2,3-dihydroxypropyl] acetamide, (2Z) -2- {4,4-difluoro- 1- [4 - [(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} -N - [(2R) -2,3-dihydroxypropyl] acetamide, 3 - [((2Z) -2- {4,4,7-trifluoro-1- [4 - {[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl ) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5ylidene} acetyl) amino] propanamide, (2Z) -N - [(2R) -2,3-dihydroxypropyl] -2- {4 , 4,7-trifluoro-1- [4 - {[(2S) -2-fluoropropyloxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene} acetamide , 3 - [((2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoyl] -4,4,7-trifluoro-1,2,3,4-tetrahydro -5H-1-benzazepin-5ylidene} acetyl) amino] propanamide, (2Z) -2- {4,4-difluoro-1- [4-propoxy-2- (trifluoromethyl) benzoyl] -1,2,3,4 -tetrahydro-5H-1-benzazepin-5-yli-deno} -N - [(2R) -2,3dihydroxypropyl] acetamide, or (2Z) -2- {4,4-difluoro-1- [4-propoxy- 2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-5-yli-deno} -N - [(2S) -2,3dih idroxypropyl] acetamide,

or a pharmaceutically acceptable salt thereof.

6.

A pharmaceutical composition comprising the compound described in claim 1 as active ingredient.

7.

 The compound according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 6 for use in a method for treating urinary frequency, urinary incontinence, enuresis, central insipid diabetes, nocturia and nocturnal enuresis.

8.

 Use of the compound described in claim 1 for the preparation of a pharmaceutical composition for treating urinary frequency, urinary incontinence, enuresis, central diabetes insipidus, nocturia and nocturnal enuresis.