MXPA00008357A

MXPA00008357A - Cycloalkene derivatives, process for producing the same, and use

Info

Publication number: MXPA00008357A
Application number: MXPA/A/2000/008357A
Authority: MX
Inventors: Yuzo Ichimori; Masayuki Ii; Katsumi Itoh; Tomoyuki Kitazaki; Junji Yamada
Original assignee: Takeda Chemical Industries Ltd
Priority date: 1998-03-09
Filing date: 2000-08-25
Publication date: 2001-12-04

Abstract

Compounds represented byformula (1a) or salts thereof, which are preventives/remedies for heart diseases, autoimmune diseases, inflammatory diseases, septic shock, etc., wherein R represents an optionally substituted aliphatic hydrocarbon group, optionally substituted aromatic hydrocarbon group, optionally substituted heterocyclic group, group represented by OR1 (wherein R1 represents hydrogen or an optionally substituted aliphatic hydrocarbon group), or group represented by formula (A) (wherein R1b and R1c are the same or different and each represents hydrogen or an optionally substituted aliphatic hydrocarbon group);R0 represents hydrogen or an aliphatic hydrocarbon group, or R and R0 in combination represent a bond;Ar represents an optionally substituted aromatic hydrocarbon group;and (B) or (C) where n is an integer of 1 to 4.

Description

CYCLAL-CALCENE DERIVATIVES, ITS PRODUCTION AND ITS USE Technical Field The present invention concerns a novel cycloalkene derivative having an effect which inhibits the production of nitric oxide derived from nitric oxide tape and / or an inhibitory effect on the production of inflammatory cytokines such as TNF-a, IL-1 , IL-6 and the like, and which is useful as a prophylactic and therapeutic agent against diseases including cardiac diseases, autoimmune diseases, inflammatory diseases, central nervous system diseases, infectious diseases, sepsis, septic shock and the like, a method to produce the same and a use thereof.

Background It is known that nitric oxide has several activities in vivo in mammals, such as a vasodilator factor in the vascular system [Pharmacol. Rev. Vol. 43, p. 109-142 (1991)], a tumoricidal and bactericidal effect in the immune system [Curr. Opin. Immunol., REF 121408 Vol. 3, p. 65-70 (1991)], and a neurotransmitter in the nervous system [Neuron, Vol. 8, p. 3-11 (1992)]. NO is produced mainly from L-arginine by NO synthetase (NOS) and it is commonly known that there are three inducible isoforms, nominally NOS neuron, endothelial NOS and an inducible NOS (iNOS) [Cell, Vo. 70, p. 705-707 (1992)], and formator two are mentioned as much as constitutive NOS (cNOS) in view of their mode of existence, which is in contrast to late iNOS.

The cNOS is found in vascular endothelial cells and neurons and is dependent on calcium calmodulin and activated by several stimuli of receptors to produce a small amount of NO, by means of which it considers that it contributes to the regulatory effect described above. On the other hand, iNOS is induced in macrophages and a neutrophil by several cytokines and bacterial lipopolysaccharides (LPS) to produce a large amount of NO continuously, whose elaboration is believed to have not only the pharmacological effects described above but also cell-damage effects. and tissue- at the production site [Immunol. Today, Vol. 13, p. 157-160 (1992)]. Cells known to express iNOS different from those described above can, for example, be hepatocytes, Kupffer cells, equal cells, vascular smooth muscle cells, vascular endothelial cells, myoendocardium, myocardial cells, mesanglial cells, condorcytes, synovial cells, cells "ß-pancreatic, osteoclast and ssimilar [FASEB J., Vol.6, p.3051-3064 (1992), Arch. Surg., Vol. 128, pp. 396-401 (1993), J. Biol. Chem., Vol. 44, pp. 27580-2788 (1994), J. Cell. Biochem., Vol. 57, pp. 399-408. (1995)], and NO produced in these cells and tissues are known to be involved in various diseases and pathologies.

Accordingly, a substance that inhibits NO production by inducible iNOS cells is considered to be effective as a prophylactic and therapeutic agent against various diseases such as arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic failure, Alzheimer's disease, multiple sclerosis, septic shock, chronic rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerular nephritis, osteoporosis, pneumonia, hepatitis, psoriasis, graft rejection and pain.

From this point of view, several compounds that inhibit iNOS such as analogous L-arginine [Pharmacol. Rev. Vol. 43, p. 109-142 (1991)], aminoguanidine [Br.

J. Pharmacol., Vol. 110, p. 963-968 (1993)] and S-etilisotiourea [J. Biol .. Chem., Vol. 43, 26669- 26676 (1994)] were reported so far. However, any of these compounds is not satisfactory in terms of activity, and has a problematically undesirable inhibiting effect not only on iNOS but also on cNOS which is physiologically active.

On the other hand, cytokines such as TNF-α, IL-1 and IL-6 are secreted from several cells such as monocyte, macrophage, lymphocyte, neutrophil, fibroblasts and vascular endothelial cell, and are widely involved in inflammation-related biological defense and immune mechanisms. [The Cytokine Handbook, 2a. Ed., Academic Press Limited (1994), Advances Immunol. , Vol. 62, p. 257-304 (1996)], and therefore are mentioned as inflammatory cytokines. Since the target cells of these cytokines vary widely over the inflammatory system, vascular system, central nervous system, hematopoietic system and endocrine system, their biological activities are considered to be diverse, including biological activities representative of TNF-a and IL-1 which were reported to be (1) a pyrogenic activity, (2) an activation and promotion of chemotaxis of inflammatory cells such as macrophage and neutrophil, (3) an induction of inflammatory cytokines and acute phase proteins including IL-1- IL-6, IL-8, TNF-a and CSF and (4) an improvement in the production of several chemical mediators such as NO, 02-, PAF, prostaglandin, leukotriene and protease as well as those of IL-6 that are reported that they are (1) an acute phase protein induction, (2) an activity that increases. Thrombocytes, (3) a differentiation and activation of lymphocytes and NK cells and (4) an activity that increases osteoclasts. However, these cytokines, once produced excessively or produced in the wrong place or wrong time, exhibit undesirable biological effects, and it has been proven that they are involved in several - diseases such as cachexia due to protozoa, bacteria, fungi, viruses and cancers allergic diseases, chronic rheumatoid arthritis, abscesses, rejection of grafts, anemia, arteriosclerosis, autoimmune disease, diabetes, diseases of the central nervous system, inflammatory bowel diseases, cardiac arrest , hepatitis, hepatocirrosis, nephritis, osteoporosis, psoriasis, septic shock and the like. From this point of view, substances that have an inhibitory effect or antagonistic effects on the production of TNF-α, IL-1 and IL-6 and the like [Eur. J. Immunol., Vol. 18, p. 951-956 (1991), Immunol., Vol. 83, p. 262-267 (1994), Proc. Nati Acad. Sci., Vol. 93, p. 3967-3971 (1997), J. Immunol., Vol. 147, p. 1530-1536 (1991), Immunol. Today, Vol. 12, p. 404- 410 (1991)] was reported to be expected to serve as the therapeutic agents against the diseases listed above.

Description of the invention While various therapeutic agents for treating heart failure, autoimmune diseases, inflammatory diseases and septic shock have been known, any of them is not excellent in pharmaceutical properties such as efficacy and safety, and thus an objective of the invention is to provide a prophylactic and therapeutic agent. against cardiac failures, autoimmune diseases, inflammatory diseases and septic shock which is further improved with respect to the pharmaceutical properties mentioned above.

In view of this circumstance, we made an effort to obtain a prophylactic and therapeutic agent against the diseases listed above that have an inhibitory effect on the production of NO and / or the production of inflammatory cytosine by an iNOS-inducible cell, and finally managed to synthesize a new compound represented by the formula: wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR * (wherein R1 represents a hydrogen atom or a aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula: (wherein Rlb represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R 1: is, same with or different from Rlt :, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, ring A is a cycloalkene substituted by 1 to 4 selected from (i) an aliphatic hydrocarbon group optionally having substituents, (ii) an aromatic hydrocarbon group optionally having substituents, (iii) a group represented by the formula OR 1 (wherein R 1 represents the same meaning as mentioned above) and (iv) a halogen atom, R ° represents an atom of hydrogen or an aliphatic hydrocarbon group, or R and R ° represents a bond with each of the others, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: represents a group represented by the formula: and n is an integer from 1 to 4, or a salt thereof, and a new compound represented by the formula: wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR 1 (in D 1 represents a hydrogen atom or a group aliphatic hydrocarbon optionally having substituents) or a group represented by the formula: (wherein Rlt represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, Rlc is, equal to or different from Rlb, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents), R ° represents an atom of hydrogen or an aliphatic hydrocarbon group, or R and R ° represent a bond of each with the other, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: represents a group represented by the formula: or and n is an integer from 1 to 4, provided that when n is 1 or 2, and (i) R 1 is a hydrogen atom or an ethyl group, R ° is a methyl group and Ar is a phenyl group, or ( ii) R and R ° represents a bond with the other and Ar is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group or a 2, 6-dimethylphenyl group, a group represented by formula: is a group represented by the formula: or a salt thereof, which is characterized by a cycloalkene structure having a carboxylate group or a carbonyl group and a sulfonamide group (preferred examples among them include a novel compound represented by the formula: wherein R 2 represents a hydrogen atom or an aliphatic hydrocarbon group, R 1, Ar represents the same meaning as defined above, a group represented by the formula: represents a group represented by the formula: or , provided that when Ar is a phenyl group, R1 is an ethyl group and R2 is a methyl group, the group represented by the formula: is a group represented by the formula: etc.

In addition, the inventors have found that a compound represented by the formula: wherein Ra represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula ORla (where Rla represents a hydrogen atom or a hydrocarbon group) aliphatic having optionally substituents) or a group represented by the formula: wherein Rla represents the same meaning as defined above, Rlb, equal to or different from Rla, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R0a represents a hydrogen atom or an aliphatic hydrocarbon group, or Ra and R0a represent a bond of each with the other, Ar3 represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: represents a group represented by the formula: (CH2) T (CH T n represents an integer from 1 to 4, or a salt thereof containing (i) the new compound represented by the formula (laa) or a salt thereof, and (ii) the new compound represented by the formula (la) ( Preferred examples among them include a compound represented by the formula: wherein R_a represents a hydrogen atom or an aliphatic hydrocarbon group, Rla and Ara represents the same meaning as defined above, the group represented by the formula: represents a group represented by the formula: or which includes the new compound (Id) or a salt thereof, etc.) unexpectedly has an excellent NO and / or effect that inhibits the production of cytosine and has excellent pharmaceutical properties essential for a prophylactic and therapeutic agent against heart failure, autoimmune diseases , inflammatory diseases and septic shock.

Of course, in the diseases described above, the inflammatory cytokines such as TNF-a, IL-1 and IL-6 and NO are involved as being complicated with each of the others before being independent of each of the others with which further exacerbates the diseases, and thereby a compound having excellent effects, such as an inhibitory effect not only on NO production but also on the production of inflammatory cytosine by an inducible cell - iNOS, can be an agent prophylactic and therapeutic as any conventional agent, which results in a clinical utility.

That is, the present invention concerns: (1) A compound represented by the formula: wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR 1 (wherein R 1 represents a hydrogen atom or a group aliphatic hydrocarbon optionally having substituents) or a group represented by the formula: [wherein R 1b represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R 1c is, equal to or different from R 1, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents), R ° represents an hydrogen or an 'aliphatic hydrocarbon group, or R and R ° represents a bond with each other, ring A is a cycloalkene substituted by 1 to 4 selected from (i) an aliphatic hydrocarbon group optionally having substituents, (ii) an aromatic hydrocarbon group optionally having substituents, (iii) a group represented by the formula OR1 (wherein R1 represents the same meaning as mentioned above) and (iv) a halogen atom, Ar represents an aromatic hydrocarbon group having optionally substituents, a group represented by the formula: (CH,) "A represents a group represented by the formula; and n is an integer from 1 to 4, or a salt thereof, (2) A compound represented by the formula: wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR 1 (wherein R 1 represents a hydrogen atom or a group aliphatic hydrocarbon optionally having substituents) or a group represented by the formula: wherein R 1b represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R 2"is, equal to or different from R 1b, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R ° represents an atom of hydrogen or an aliphatic hydrocarbon group, or R and R ° represent a bond with each of the others, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: represents a group represented by the formula: and n is an integer from 1 to 4, provided that when n is 1 or 2 e (i) R1 is a hydrogen atom or an ethyl group, R ° is a methyl group and Ar is a phenyl group or (ii) R and R ° represents a bond with each of the others and Ar is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group or a 2-6-dimethylphenyl group, a group represented by the formula: is a group represented by the formula: or a salt of it, (3) A compound as defined in (2), wherein the compound represented by the formula (la) is a compound represented by the formula: wherein R2 represents a hydrogen atom or an aliphatic hydrocarbon group, R1, Ar, n and the group represented by the formula: represents the same meaning that was defined in (2), provided that when n is 1 or 2, Ar is a phenyl group, R1 is a hydrogen atom or an ethyl group and R "is a methyl group, the group represented by the formula: is a group represented by the formula: (4) A compound as defined in (2), wherein the compound represented by the formula (la) is a compound represented by the formula: where Ar and n represent the same meaning as defined in (2). (5) A compound defined in (1), wherein the compound represented by the formula (Iaa) is a compound represented by the formula: where each of the symbols represents the same meaning as defined in (1), (6) A compound as defined in (5), wherein ring A is a cycloalkene substituted by lower alkyl, phenyl or halogen. R1 is a lower alkyl group, Ar is a phenyl group optionally having substituents, and n is 2, (7) A compound as defined in (3), wherein R: is a lower alkyl group optionally having substituents, (8) A compound as defined in (3), wherein R1 is an ethyl group, (9) A compound as defined in (3), wherein R "is a hydrogen atom or a lower alkyl group. (10) A compound as defined in (3), wherein R "" is a hydrogen atom, (11) A compound as defined in (3), wherein Ar is a phenyl group optionally having substituents, (12) A compound as defined in (3), wherein Ar is a phenyl group substituted by halogen or / and lower alkyl, (13) A compound as defined in (3), wherein Ar is a group represented by the formula: wherein R'1 and R = are the same or different and represent a halogen atom or a lower alkyl group, and n is an integer from 0 to 2, (14) A compound as defined in (3), wherein the halogen atom is a fluorine atom or a chlorine atom, (15) A compound as defined in (3), wherein the group represented by the formula: is a group represented by the formula: where n is the same meaning as defined in (2), (16) A compound as defined in (3), where n is 1 to 3, (17) A compound as defined in (3), wherein R ~ is a lower alkyl group optionally having substituents, R2 is a hydrogen atom or a lower alsuyl group, Ar is a phenyl group optionally having substituents, is 1, 2 or 3, (18) A compound as defined in (3), wherein R1 is a lower alkyl group optionally having substituents, R2 is a hydrogen atom, Ar is a phenyl group substituted by a halogen atom, n is 2, (19) A compound as defined in (4), wherein ar is a phenyl group optionally having substituents, n is 2, (20) A compound as defined in (2), wherein the compound represented by the formula (la) is a compound represented by the formula: where R ~, R and Ar represent the same meaning as defined in! 3) a group represented by the formula: represents a group represented by the formula: or provided that when Ar is a phenyl group, R1 is a hydrogen atom or an ethyl group and R2 is a methyl group, the group represented by the formula: is a group represented by the formula: (21) A compound as defined in (2) which is 6- [N- (2, 4-dilfuorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate of d-ethyl or a salt thereof, (22) A compound as defined in (2) which is ethyl 6- [N- (2, 4-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate or a salt thereof, (23) A compound as defined in (2) which is 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate or a salt thereof, (24) A compound as defined in (2) which is 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-d-ethyl carboxylate or a salt thereof; (25) A method for producing a compound as defined in (3) which comprises reacting a re-purposed compound by the formula: wherein R1 and n represent the same meaning as defined in (3) and X1 represents a displaceable group, or a salt thereof with a compound represented by the formula: where each symbol represents the same meaning that was defined in (3), or a salt of it, (26) A method for producing a compound as defined in (4) which comprises subjecting a compound contained in the formula: where each of the symbols represents the same meaning as defined in (4), or a salt thereof to a reaction that closes the ring, (27) A method for producing a compound as defined in (20) which comprises reacting a compound represented by the formula: wherein R1 represents the same meaning as defined in (20) and X1 represents a displaceable group, or a salt thereof with a compound represented by the formula: where each of the symbols represents the same meaning as defined in (20), or a salt thereof, (28) A pharmaceutical composition containing a compound represented by the formula: wherein R represents an aliphatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: wherein R 'represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents or a group represented by the formula: (wherein R "represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R" is, equal to or different from Rlb, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents j, R ° represents an atom of hydrogen or an aliphatic hydrocarbon group, or R and R ° represent a bond with each other, ring A is a cycloalkene substituted by 1 to 4 selected from (i) an aliphatic hydrocarbon group optionally having substituents, (ii) ) an aromatic hydrocarbon group optionally having substituents, (iii) a group represented by the formula: OR1 (wherein R1 represents the same meaning as mentioned above) and (iv) a halogen atom, Ar represents an aromatic hydrocarbon group which optionally has substituents, a group represented by the formula.

(CH,) " represents a group represented by the formula: and n is an integer from 1 to 4, or a salt of it, (29) A pharmaceutical composition containing a compound represented by the formula: wherein Ra represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally has substituents, a group represented by the formula: ORla (where Rla represents a hydrogen atom or a group aliphatic hydrocarbon sue optionally has substituents) a group represented by the formula: (where Rla represents the same meaning as defined above, Rlb is, equal to or different from Rla, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, ROa represents a hydrogen atom or an aliphatic hydrocarbon group, or Ra and R0a represents a bond with each other, Ara represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: represents a group represented by the formula: (CHP. | \ A or n represents an integer from 1 to 4, or a salt thereof, (30) A pharmaceutical composition containing a compound represented by the formula: wherein Ra represents a hydrogen atom or an aliphatic hydrocarbon group, Rla, Ara, n and the group represented by the formula: represents the same meaning that was defined in (29), or a salt of it, (31) A pharmaceutical composition containing a redissolved co-oxide according to the formula: where R: R'5 and Ara represent the same meaning as defined in (30) and the group represented by the formula: is a group represented by the formula: or (32) The pharmaceutical composition as defined in any one of (28) to (31) which is an agent for inhibiting the production of nitric acid and / or cytokines, (33) The pharmaceutical composition as defined in (32) which is an agent for preventing or treating cardiac diseases, autoimmune diseases or septic shock, (34) Use of the compound represented by the formula (Iaa) or (Ie) to manufacture an agent to inhibit the production of nitric acid and / or cytosine, (35) A method for inhibiting the production of nitric oxide and / or cytosine in mammals which comprises administering to a subject in need an effective amount of the compound represented by the formula (Iaa) or (le), (36) Use of the compound represented by the formula (Iaa) or (Ie) to manufacture an agent to prevent or treat heart diseases, autoimmune diseases or septic shock, (37) A method for preventing or treating heart diseases, autoimmune diseases or septic shock in mammals which comprises administering to a subject in need an effective amount of the compound represented by the formula (Iaa) or (Ie), (38) A pro-drug of the compound as defined in (1) or (2), (39) A pharmaceutical composition containing the prodrug as defined in (38), and so on.

In the specification, R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR 1 (wherein R 1 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula: wherein R "~ represents a hydrogen atom or an aiiphatic hydrocarbon group optionally having substituents, R1" is, equal to, or different from Rlb, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, or R forms an linkage with RA, and among them the group represented by the formula: OR: (wherein R1 represents the same meaning as defined above) is preferred, Y, Ra represents an aliphatic hydrocarbon group sue optionally has substituents, an aromatic hydrocarbon group which optionally has substituents, a heterocyclic group optionally having substituents, a group represented by the formula: 0Rla (wherein Rla represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by Dor the formula: < R, b (where Rla represents the same meaning as defined above, Rlb is, equal to or different from Rla, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents), or forms a bond with R0a, and among them the group represented by the formula: 0Rla (where Rla represents the same meaning as defined above) is oreferido.

When R and R ° represents a bond with each of the others, the compound represented by the formula (Iaa (may be represented by the formula: where each of the symbols represents the same meaning, and can specifically be represented by the formula: where each of the symbols represents the same meaning, or the formula: (Ni) where each of the symbols represents the same meaning.

When R and R ° represent a bond with each of the others, the compound represented by the formula (la) can be represented by the formula: wherein each of the symbols represents the same meaning, and can specifically be represented by the formula: (le) where each of the symbols represents the same meaning, or the formula: where each of the symbols represents the same meaning.

When Rz and RCa represent a bond with each of the others, the compound represented by the formula (le) can be represented by the formula: where each of the symbols represents the same meaning, and can specifically be represented by the formula: where each of the symbols represents the same meaning, or the formula: where each of the symbols represents the same meaning.

When R is a group represented by the formula: OR1 (wherein R1 represents the same meaning as defined above), the compound represented by the formula (laa) may be represented by the formula: where each of the symbols represents the same meaning, and can specifically be represented by the formula: where each of the symbols represents the same meaning, or the formula: where each of the symbols represents the same meaning, or the formula: OR1 (where R * represents the same meaning as defined above), the compound represented by the formula (la) can be represented by the formula: where each of the symbols represents the same meaning, and can specifically be reoriented by the formula: where each of the symbols represents the same meaning, or the formula: where each of the symbols represents the same meaning.

When Ra is a group represented by the formula: 0Rla (where Rls represents the same meaning as defined above), the compound represented by the formula (le) can be represented by the formula. where each of the symbols represents the same meaning, and can specifically be represented by the formula: where each of the symbols represents the same meaning, or the formula: where each of the symbols represents the same meaning.

As the compound represented by the formula (Iaa), the compound represented by the formula (Ice) or the formula (Inn) is preferred, as the compound represented by the formula (la), the compound represented by the formula (le) or the formula (In) are preferred, and as the compound represented by the formula (le), the compound represented by the formula (Ik) or the formula (Ip) are preferred.

Similarly, the compound represented by the formula (Id) can be represented by the formula: where each of the symbols represents the same meaning, or the formula: wherein each of the symbols represents the same meaning, and the compound represented by the formula (Ig) may be represented by the formula: where each of the symbols represents the nismo meaning. where each of the symbols represents the same meaning.

As the compound represented by the formula (Id), the compound represented by the formula (Ir) is referenced, as the compound represented by the formula (Jg), the compound represented by the formula It) is preferred.

In the compound represented by the formula (la), when it is 1 or 2, e (i) R 1 is a hydrogen atom or an ethyl group, R ° is a methyl group and Ar is a f-nyl group, or (i) R and R ° represents a bond with each of the others and Ar is a phenyl group, a group 2-. a 4-bromophenyl group, a 4-rnetoxifeni Lo group or a 2, 6-dimethyl phenyl group. a group represent -... by the formula: (CH s a group represented by the formula: Further, when n is 1 to 4, e (i) R1 is a hydrogen atom or a lower alkyl group optionally having substituents, Rc is a lower alkyl group optionally having substituents, and Ar is a phenyl group optionally having substituents , or (ii) R and R represent a bond with each of the others and Ar is a phenyl group optionally having substituents, a group represented by the formula: it can be a group represented by the formula: in the compound represented by the formula (Ib), when n is 1 or 2, R 1 is a hydrogen atom or an ethyl group, R ° is a methyl group, and Ar is a phenyl group, a group represented by the formula: is a group represented by the formula: Further, when n is 1 to 4, and R 1 is a hydrogen atom or a lower alkyl group optionally having substituents, R ° is a lower alkyl group optionally having substituents, and Ar is a phenyl group optionally having substituents, a group represented by the formula: is a group represented by the formula: As in the "aliphatic hydrocarbon group" of the "aliphatic hydrocarbon group optionally having substituents" represented by R, R1, Rla, Rlc, and the "aliphatic hydrocarbon group represented by R °, R0a, R", R? A, for example , an alkenyl group, an alkynyl group, etc., are preferred.

As the alkyl group, for example, a linear or branched alkyl group having 1 to 20 carbons (for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a group isobutyl, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, a dodecyl group, etc.) are preferred, and particularly, for example, a lower alkyl group having 1 to 6 carbon atoms (for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an sec-butyl group, a tert-butyl group, etc.), etc., are preferred.

As the cycloalkyl group, for example, cycloalkyl group having 3 to 10 carbons (for example, a cyclopropyl group, a cyclobutyl group, a ciciopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc.), etc. Preferred, and particularly, for example, are a cycloalkyl group having 3 to 6 carbon atoms (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc.), etc. They are preferred.

As the cycloalkyl group, for example, a cycloalkylalkyl group having 4 to 12 carbon atoms (for example, a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptylmethyl group, etc.), etc. Preferred, and particularly, for example, are a cycloalkylalkyl group having 4 to 8 (particularly 4 to 7) carbons (for example, a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, etc.), etc. They are preferred.

As the alkenyl group, for example, a lower alkenyl group having 3 to 6 carbon atoms (for example, a propenyl group, a butenyl group, a pentenyl group, etc.), and particularly, for example, a lower alkenyl group which it has 3 or 4 carbons (for example a propenyl group, a butenyl group, etc.), etc., are preferred.

As the alkynyl group, for example, a lower alkynyl group has 3 to 6 carbons (for example, a propynyl group, a butynyl group, a pentynyl group, etc.), and particularly, for example, a lower alkenyl group having 3 or 4 carbons (for example, a propyl group, a butynyl group, etc.), etc., are preferred.

As the "substituents" of the above-mentioned "aliphatic hydrocarbon group optionally having substituents", for example, a heterocyclic group, an oxo group, a hydroxyl group, a C? -6 alkoxy group, a C3-b group (particularly, C3) -6 cycloalkyloxy, a heterocyclic oxy group, a Ci- 6 alkylthio group (the sulfur atom can be oxidized), a Cj-10 (particularly, C3-e) cycloalkylthio group (the sulfur atom can be oxidized), a group Ce-io arylthio (the sulfur atom can be oxidized), a group C-19 (particularly, C-12) arlakyloxy (the sulfur atom can be oxidized), a heterocyclic thio group, a heterocyclic sulfinyl group, a heterocyclic sulfonyl group, a nitro group, a halogen atom, a cyano group, a carboxyl group, a Ci-u group (particularly, C? -6) alkoxycarbonyl, a C3-6 cycloalkyloxycarbonyl group, a group C-aryloxycarbonyl, a C-19 (particularly C7-12) aralkyloxycarbonyl group, a heterocyclic oxycarbonyl group, a Cp-io arylcarbonyl group, a Cif group. alkanoyl, a C6-β alkanoyloxy group, a C3-5 alkenoyloxy group, a carbamoyl group having optionally substituents, a carbamoyloxy group optionally having substituents, a C? -6 aralkanoylamino group, a C6-? or aryl-carbonylamino group, a C: - group? (particularly, C? -6) alkoxycarboxamide, a C5-10 aryloxycarboxamide group, a C1-10 group (particularly, C? -6) alkoxycarbonyloxy, a C6-IQ aryloxycarbonyloxy group, a C group -7-10 (particularly C-12) aralkyloxycarbonyloxy, a C3-c (particularly C3-e) cycloalkyloxycarbonyloxy group, a ureido group optionally having substituents, a Cfc-10 aryl group optionally having substituents , etc., are used.

These substituents are substituted in substitutable positions in the aforementioned "aliphatic hydrocarbon group", and the substituents are not limited to one and can be the same or different and a small number (2 to 4).

As the "C? _d alkoxy group", for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a n-hexyloxy group, etc., are used, such as the "C3-10 cycloalkyloxy group. ", for example, a cyclopropyloxy group, a cyclohexyloxy group, etc., are used, as the" Cß-io aryloxy group ", for example, a phenoxy group, a naphthyloxy group, etc., are used, such as group C-- Aralkyloxy IQ, for example, a benzyloxy group, a 1-phenylethyloxy group, a 2-phenylethyloxy group, a benzydryloxy group, a 1-naphthyl ethyloxy group, etc., used as the "C? -6 alkylthio group (ei) sulfur atom can be oxidized), for example, a methylthio group, an ethylthio group, an n-propylthio group, an n-butythio group, a methylsulfinyl group, a methylsulfonyl group, etc., are used, as the "C3 group - or cycloalkylthio (the sulfur atom can be oxidized) ", for example, a cyclopropylthio group, a cyclohexythio group, a cyclopentylsulfinyl group, a cyclohexylsulfonyl group, etc. Used, such as the "C6-? or arylthio group (the sulfur atom can be oxidized, a naphthylthio group, a phenylsulfinyl group, a phenylsulfonyl group, etc., are used, such as the" C? _? 9 aralkylthio group (the sulfur atom can be oxidized), "for example, a benzylthio group, a phenylethylthio group, a benchidriitium group, a benzisulfinium group, a benzylsulfonyl group, etc., are used, such as the" halogen atom ", for example, an atom of fluorine, a chlorine atom, a bromine atom, an iodine atom, etc., are used, such as the "C? -? or alkoxycarbonyl group", for example a methoxycarbonyl group, an ethoxycarbonyl group, a group n - propoxycarbonyl, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, etc., are used, as the "C3_6 cycloalkyloxycarbonyl group", for example, a cyclopropyl oxycarbonyl group, a cyclopentyl oxycarbonyl group, an cyclohexyloxycarbonyl group, a norbonyloxycarbonyl group, etc., are used, such as the "Ce-1-aryioxycarbonyl group", for example, a phenoxycarbonyl group, a naphthyloxycarbonyl group, etc., are used, such as the "C-19 aralkyloxycarbonyl group", for example, a benzyloxycarbonyl group, a benchidryloxycarbonyl group, a 2-phenyloxycarbonyl group, etc., are used, as the "Cfc- or arylcarbonyl group", for example, a benzoyl group, a naphthoyl group, a phenylacetyl group, etc., are used, as the "Ci-e alkanoyl group", for example, a formyl group, an acetyl group, a propionyl group, a butyryl group, a valeryl group, a pivaloyl group, etc., are used, such as the "C3-5 alkenoyl group", for example, an acrinoyl group, a crotonoyl group, etc., are used, as the "group" C5-10 arylcarbonyloxy, a phenylacetoxy group, etc., are used, such as the group C2-6 aicanoyloxy ", for example, a acetoxy group, a propionyloxy group, a butyryloxy group, a valeryloxy group, a pivaloyloxy group, etc., are used, such as the "C3-5 alkenoyl group or ", for example, an acryloxy group, a crotonoyloxy group, etc., are used.

As the "carbamoyl group optionally having substituents", for example, a carbamoyl group or a cyclicaminocarbonyl group, which may be substituted by 1 or 2 substituents selected from C1"'alkyl (e.g., methyl, ethyl, etc.), C1" 4 alkoxy phenyl (e.g., methoxyphenyl, etc.), etc. and specifically for example a carbamoyl group, a N-methylcarbamoyl group, a N-ethylcarbamoyl group, a N, N-dimethylcarbamoyl group, a N, N-diethylcarbamoyl group, a N-f nylcarbamoyl group, an N-acetylcarbamoyl group, an N-benzylcarbamoyl group, a N- (p-methoxyphenyl) caarbamoyl group, a 1-pyrrolidinylcarbonyl group, a piperazinocarboyl group, a 1-piperazinylcarboyl group, a morpholinocarbamoyl group, etc., are used.

As the "thiocarbamoyl group optionally having substituents", for example, a thiocarbamoyl group which can be substituted by 1 or 2 substituents selected from C1"4 alkyl (e.g., methyl, ethyl, etc.), phenyl, etc., and specifically, for example, a thiocarbamoyl group, an N-methytiiocarbamoyl group, an N-phenylthiocarbamoyl group, etc., are used.

As the "carbamoyloxy group optionally having substituents", for example, a carbamoyloxy group which can be substituted by 1 or 2 substituents selected from C? -4 alkyl (eg, methyl, ethyl, etc.), phenyl, etc., and specifically for example a carbamoyloxy group, a N-methylcarbamoyloxy group, a N, N-dimethylcarbamoyloxy group, a N-ethylcarba oyloxy group, a N-phenylcarbamoyloxy group, etc., are used.

As the "Ci-alkanoylamino group," for example, an acetamide group, a propylamide group, a butyroamide group, a valeroamide group, a pivaroamide group, etc., are used, such as the "Ce-1 aryl-carbonylamide group". , for example, a benzamide group, a naphthoamide group, a phthalimide group, etc., are used, such as the "C? -? or alkoxycarboxamide group", for example, a methoxycarboxamide group (CH3OCONH-), an ethoxycarboxamide group , a tert-butoxycarboxamide group, etc., are used, such as the "CP-, q-aryloxycarboxamide group", for example, a phenoxycarboxamide group (CfcH50C0NH-) etc., are used, such as the "C-7-10 aralkyloxycarboxamide group", for example, a benzyloxycarboxamide group (C6H5CH2OCONH-), a benchloxycarboxamide group, etc., are used, as the "Ci group" -io alkoxycarbonyloxy ", for example, a methoxycarbonyloxy group, an ethoxycarbonyloxy group, an n-propoxycarbonyloxy group, an isopropoxycarbonyloxy group, an n-butoxycarbonyloxy group, a tert-butoxycarbonyloxy group, an n-pentyloxycarbonyloxy group, a n-group hexyloxycarbonyloxy, etc., are used, as the etc., are used, as the "Ce-y aryloxycarbonyloxy group", for example, a phenoxycarbonyloxy group, a naphthyloxycarbonyloxy group, etc., are used, as the "C7 group -19-aralkyloxycarbonyloxy, for example, a benzyloxycarbonyloxy group, a 1-phenylethyl oxycarbonyloxy group, a 2-phenylethyloxycarbonyloxy group, a bechloxycarbonyloxy group, etc., are used, and as the "Ci? Cycloalkyloxycarbonyloxy group", by example, a cyclopropyloxycarbonyloxy group, a cyclohexyloxycarbonyloxy group, etc., are used.

As the "ureido group optionally having substituents", for example, an ureido group optionally substituted by 1 to 3 substituents selected from a C? -alkyl group (e.g. - methyl group, an ethyl group, etc.), a phenyl group, etc., are used, and for example an ureido group, a 1-methylureido group, a 3-methylureido group, a 3-group, 3-di-ethylureido, a Group 1, 3- dimethylureide, a 3-phenylureide group, etc., are used.

When a heterocyclic group, a heterocyclic oxy group, a heterocyclic thio group, a heterocyclic sulfinyl group, a heterosulfonyl group or a heterocyclyloxycarbonyl group are used as the "substituents" of the "aliphatic hydrocarbon group optionally having substituents", the heterocyclic group represents a heterocyclic group. group formed by excluding a hydrogen atom which binds to the heterocycle, and io represents, for example, a 5- to 8-membered cyclic group (preferably cyclic 5- to 6-membered) containing up to a little , preferably 1 to 4 heteroatoms such as nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom, etc., or a condensed cyclic group thereof. As these heterocyclic groups, for example, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, an i, 2, 3-triazolyl group, a 1, 2, 3, 4-triazolyl group, a tetrazolyl group, a furyl group, a thienium group, a thiazolyl group, an isooxazolyl group, a 1, 2, 3-oxadiazolyl group, a 1, 2, 4-oxadiazoyl group, a 1, 2, 5-oxadiazolium group, a group 1, 3, 4-oxadiazolium, a thiazolyl group, an isothiazolyl group, a 1, 2, 3-thiadiazolyl group, a 1, 2, 4-thiadiazolyl group, a 1, 2, 5-thiadiazolyl group, a group 1, 3 4-thiadiazolyl, a pyridyl group, a pyridazinyl group, a pyrimisinyl group, a pyrazinyl group, an indolyl group, a pyranyl group, a thiopyranyl group, a dioxinyl group, a dioxolyl group, a quinolyl group, a pyrido group [2 , 3- d] pyrimidinyl, a group 1, 5, 1, 6-, 1, 7-, 1, 8-, 2, 6- or 2, 7- naphthyridyl, a thieno [2, 3-d] pyridyl group , a benzylpyranyl group, a tetrahydrofuri group, a tetrahydropyranyl group, a dioxoranyl group, a dioxanyl group, etc., are used.

These heterocyclic groups can be substituted at the possible positions by 1 to 3 substituents selected from C1-1 alkyl (eg, methyl, ethyl, etc.,), hydroxy, oxo, C? -4 alkoxy (eg, methoxy, ethoxy) , etc etc.

As the "Cfc-aryl group" the "C aryl group having optionally substituents", for example, a phenyl group, a naphthyl group, etc., are used. The C6-10 aryl group can be substituted in a substitutable position by a substituent selected from the ones listed as a "substituent" (except by an optionally substituted C6-aryl group) of the "aliphatic hydrocarbons optionally having substituents" described above. Such a substituent is substituted in a substitutable position in a C6- or aryl group, and the number of such substituents is not limited to one, the same or different, more than one (2 to 4) substituents may exist.

In the "aliphatic hydrocarbon group optionally having substituents", the substituent together with the aliphatic hydrocarbon group can form an optionally substituted fused ring group, and like these fused ring groups, an indanyl group, a group 1, 2, 3, 4 tetrahydronaphthyl, etc., are used.

This fused ring group can be substituted in a substitutable position by a substituent selected from the ones listed as a "substituent" of the "aliphatic hydrocarbon group optionally having substituents" described above. Such a substituent is substituted in a substitutable position in a fused ring group, and the number of such substituents is not limited to one, and, the same or different, more than one (2 to 4) substituents may exist.

As R, R1, Pla, Rlb, Rlc, for example, a lower alkyl group having from 1 to 6 carbon atoms (for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butoxycarbonylmethyl group, a hydroxyethyl group, and the like) optionally having substituents, and of them a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, etc., are preferably used. Particularly, a methyl group, an ethyl group, an n-propyl group and the like, etc., are preferred, and an ethyl group is particularly preferred.

As R2, R23, for example, a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms (for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a n-group) butyl, an isobutyl group, a t-butoxycarbonylmethyl group, a hydroxyethyl group and the like), etc., are preferably used, and a hydrogen atom, a methyl group, etc., are preferably used and particularly a hydrogen atom, etc., are preferably used.

As the "aromatic hydrocarbon group" of the "aromatic hydrocarbon group optionally having substituents" represented by Ar, Ara, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms (for example, a phenyl group, a naphthyl group, a biphenyl group, an anthryl group, an indolyl group, and the like), and the like, and particularly an aryl group having 6 to 10 carbon atoms and the like (e.g., phenyl and naphthyl groups) are preferred and Phenyl group and the like are particularly preferred.

As the "substituent" of the "aromatic hydrocarbon group optionally having substituents" represented by Ar, Ara, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine and the like), a lower alsuyl group C_4 ( for example, a methyl group, an ethyl group, a propyl group, a butyl group and the like), a group (Ci-? lower alkoxy (for example a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like), a lower (Ci-j) alkoxycarbonyl group (e.g., a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group and the like), a carboxyl group, a nitro group, a cyano group, a hydroxyl group, an acylamino group (for example, an alkanoylamino group having 1 to 4 carbon atoms), carbon such as an acetylamino group, a propionylamino group, a butyrylamino group and the like), a cycloalkylamino group having 3 to 6 carbon atoms (for example, a cyclopropyl group, a cyclopentyl group and the like), an aryl group has 6 to 10 carbon atoms (eg, a phenyl group, a naphthyl group, an indenyl group and the like), a (C? -4) lower alkyl-halogen group (eg, a trifluoromethyl group, a trifluoroethyl group and the like), a (C? -4) lower alkoxy-halogen group (e.g., a trifluoromethoc group, a 1, 1, 2, 2-tetrafluoroethoxy group, a 2, 2, 3, 3, 3- pentafluoropropoxy group and the like) and a lower (C? -4) alkylthio group (e.g., a methyl group, an etiitium group, a propionylthio group and the like), a lower (Ci-i) alkylsulfonyl group (for example, a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group and the like), a group (C? _4) lower alkanoyl (for example, a formyl group, an acetyl group, a propionyl group and the like), a 5-membered aromatic heterocyclic group (for example, a 1,2-triazolyl group, a 1, 2 group, 4- triazolyl, a tetrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolium group, an isooxyazoyl group, a thiazodiazolyl group, a thienyl group, a furyl group and the like), a carbamoyl group, a group (C? 4) lower alkylcarbamoyl (for example, a methylcarbamoyl group, a di-ethylcarbamoyl group, a propionylcarbamoyl group and the like), a lower carbonyl group- (C? -4) lower alkoxy (C? -4) alkylcarbamoyl ( for example, a butoxycarbonyl methylcarbamoyl group, an ethoxycarbonyl methyl group carbamoyl and similar ios), a 1,3-diacylguanidino- (C? -4) lower alkyl group and the like (eg, 1,3-diacetylguanidinomethyl, 1,3-bis-t-butoxycarbonyl guanidino ethyl and the like) are used, and a halogen atom (eg, fluorine, chlorine, bromine, iodine and the like atoms), a (C? _) lower alkyl group and the like (eg, a methyl group, an ethyl group, a propyl group, a butyl group and the like) are preferably used, and a fluorine atom, a chlorine atom and a methyl group. they are more preferably used.

These substituents are substituted at substitutable positions on the aromatic hydrocarbon group, and the number of substituents is preferably 1 to 5, more preferably 1 to 3, more preferably 1 to 2. When two or more such substituents are present, they may be present. be the same or different.

Typically, as Ar or Ar for example, a phenyl group, a halogen phenyl group, a lower (Ci-4) aiquilphenyl group, a lower (C 4 -4) alkoxyphenyl group, a lower (C 4 -4) alkoxycarbonylphenyl group, a carboxyphenyl group, a nitrophenyl group, a cyanophenyl group, a (C? -4) lower alkylphenyl- halogen group, a lower (C? -4) alkoxyphenyl- halogen group, a (C? _, :) lower alkanoylphenyl group, a 5-membered substituted phenyl-aromatic heterocycle, a (C 1-4) alkoxy-lower-carbonyl- (C 4) alkyl-lower alkylcarbamoylphenyl group, a 1,3-diacylguanidine- (C 1-4) lower alkylphenyl group, a halogen - and (C? _) lower alkoxy-substituted phenyl, a halogen- and a group (C1-4) substituted lower alkoxycarbonyl- substituted phenyl, a halogen- and substituted cyanophenyl, a halogen- and 5-membered aromatic heterocycle-substituted phenyl, a halogen- and lower (C? _4) alkoxycarbonyl- (C? -) lower alkyl- substituted carbamoyl phenyl and the like are used.

As Ar or Ara, a halogen phenyl group, a (C? _4) lower alkylphenyl group, a lower halogen- and (C? -4) akoxycarbonyl-substituted phenyl and the like are preferable used.

As Ar or Ar3, a group represented by the formula: where R 'and R ~ are the same or different and each represents a halogen atom or an alkyl group - lower, and n is an integer from 0 to 2, with one in which at least one of R4 and R5 is a halogen atom that is additionally preferred.

As the halogen atom represented by R 4 and R 5, a fluorine atom or a chlorine atom is preferred.

As the halogen phenyl group, for example, a 2, 3-difluorophenyl group, a 2,3-dichlorophenyl group, a 2, 4-difluorophenyl group, a 2-dichlorophenyl group, a 2, 5-difluorophenium group, a group 2, 5- dichlorophenyl, a 2,6-difluorophenyl group, a 2-6-dichlorophenyl group, a 3-difluorophenyl group, a 3-dichlorophenyl group, a 3-difluorophenyl group, a 3 group , 5-dichlorophenyl, a 2-fluorophenyl group, a 2-chlorophenyl group, a 3-fluorophenyl group, a 3-chlorophenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 2-fluoro-4-chlorophenyl group , a 2-chloro-4-fluorophenyl group, a 4-bromo-2-fluorophenyl group, a 2, 3, 4-trifluorophenyl group, a 2, 4, 5-trifluorophenyl group, a 2, 4,6-trifluorophenyl group and the similar ones are used.

As the group (C? _4) lower alkylphenyl, a 2-ethylphenyl group, a 2-6-diisopropylphenyl group and the like are preferably used, and as the lower (C1-4) alkoxyphenyl group, for example, a 4- group methoxyphenyl and the like are preferably used.

As the group (C? _4) lower alkoxycarbonylphenyl, a 2-ethoxycarbonylphenyl group, a 2-methoxycarbonylphenyl group, a 4-methoxycarbonylphenyl group and the like are preferably used, and as the (C? _4) lower alkylphenyl group- halogen, for example, a 2-trifluoromethylphenyl group and the like are preferably used, and as the group (C: -4) lower alkoxyphenyl- halogen, a 2-trifluoromethoxyphenyl group, a 4- (2, 2, 3, 3, 3-pentafluoropropoxy) phenyl and the like are preferably used.

As the (C? -4) lower alkanoyl phenyl group, for example, a 2-acetylphenyl group and the like are preferably used, and as the 5-membered aromatic heterocyclic group-substituted phenyl, for example, a 4- (2H-) group 1, 2, 3-triazol-2-yl) phenyl, a 4- (2H-tetrazol-2-yl) phenyl group, a 4- (1H-tetrazol-1-yl) phenyl group, a 4- (1H) group , 1, 2, 3-triazol-1-yl) phenyl and the like are preferably used, and as the group (C? -4 lower alkoxy- (C: -?) Lower alkylcarbamoylphenyl, for example, a group 4 - (N-ethoxycarbonylmethylcarbamoyl) phenyl and the like are preferably used, and like the group 1, 3- diacylguanidino- (C? -4) lower aliphenyl, for example, a 4- (1,3-bis- t-) group. butoxycarbonylguanidinomethyl) phenyl and the like are used.

As the phenyl group substituted by halogen and (C? -4) lower alkyl, for example a 2-fluoro-4-methylphenyl group, a 2-chloro-4-methylphenyl group, a 4- fluoro-2-methylphenyl group and the similar are preferably used, and as the phenyl group substituted by halogen and (C? _4) lower alkoxycarbonyl, for example, a 2-chloro-4-methoxycarbonylphenyl group, and the like are preferably used, and the phenyl group substituted by halogen and cyano, for example, a 2-chloro-4-cyanophenyl group and the like are preferably used, and as the phenyl group substituted by halogen and 5-membered aromatic heterocycle, for example, a 2- fluoro-4- (1H-) group 1, 2, 4-triazol-1-yl) phenyl, and the like are preferably used, and as the phenyl group substituted by halogen and (C 1-4) lower alkoxycarbonyl- (C 1-4) lower alkylcarbamoyl, for example , a 2-chloro-4- (N- t-butoxycarbonylmethylcarbamoyl) phenyl group, a 2-chloro-4- (N-ethoxy) group carbonylmethylcarbamoyl) phenyl and the simiiar are preferably used.

More specifically, as Ar or Ara, a phenyl group, a phenyl group substituted with 1 to 3 (particularly 1 to 2) halogen atoms (e.g., a 2, 3-diloforophenyl group, a 2,3-dichlorophenyl group, a group 2, 4-difluorophenyl, a group 2, 4-dichlorophenyl, a group 2, 5- dicfluorophenyl, a group 2, 5-dichlorophenyl, a group 2,6-difluorophenyl, a group 2, 6-dichlorophenyl, a group 3 , 4- difluorophenyl, a group 3, 4-dichlorophenyl, a group 3, 5-difluorophenyl, a group 3, 5-dichlorophenyl, a 4-bromo-2-fluorophenyl group, a 2-fluorophenyl group, a 2-chlorophenyl group , a 3-fluorophenyl group, a 3-chlorophenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 2-fluoro-4-chlorophenyl group, a 2-chloro-4-fluorophenyl group, a 2, 3 group , 4- trifluorophenyl, a 2, 4, 5-trifluorophenyl group and the like), a phenyl group substituted by halogen and (C? _4) lower alkyl (for example, a ~ 2-chloro-4-methylphenyl group, a group 4- fluoro - 2-methylphenyl, and the like), etc., are preferred. Of these, a phenyl group substituted with 1 to 3 (particularly 1 to 2) halogen atoms (for example, a 2,3-dichlorophenyl group, a 2, 4-difluorophenyl group, a 2-dichlorophenyl group, a group 2, 6-dichlorophenyl, a 2-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 2-chloro-4-fluorophenyl group, a 2, 4, 5-trifluorophenyl group and the like), a group phenyl substituted by haiogen and (Ci-) lower alkyl (for example, a 2-chloro-4-methyphenium group, a 4-fluoro-2-methylphenyl group and the like), etc., are preferred. Particularly, a 2, 4-difluorophenyl group, a 2-chlorophenyl group, a 2-chloro-4-fluorophenyl group, a 2-chloro-4-methylphenyl group and the like are preferred, and a 2,4-difluorophenium group, a 2-chloro-4-fluorophenyl group and the simiiar ones are preferred.

In this specification, ring A represents (i) an aliphatic hydrocarbon group optionally having substituents, (ii) an aromatic hydrocarbon group optionally having substituents, (iii) a group represented by the formula OR 1 (wherein R 1 is as defined above) and (iv) a cycloalkene substituted by 1 to 4 halogen atoms, and (i) an aliphatic hydrocarbon group optionally having substituents, (ii) an aromatic hydrocarbon group optionally having substituents and (iv) a cycloalkene substituted by 1 to 4 halogen atoms are preferred.

These substituents are substituted on substitutable carbon atoms in a ring A, and when the a ring is substituted by two or more such substituents, the substituents can be the same or different. A carbon atom can only be replaced by two substituents and different carbon atoms can be replaced by two or more substituents.

As the "aliphatic hydrocarbon group optionally having substituents" as a substituent on ring A, for example, the same of which as the "aliphatic hydrocarbon group optionally having substituents" represented by R, R1, Rla, R ", Rl described above can be used.

As the "aromatic hydrocarbon group optionally having substituents" as a substituent on the ring a, for example, the same of which as the "aromatic hydrocarbon group having optionally substituents" represented by Ar or Ara described above can be used.

As the "heterocyclic group optionally having substituents, the same of which as the" heterocyclic group "which is a" substituent "on the aliphatic hydrocarbon group optionally having substituents", represented by R, R1, Rla, Rlb, R1 =.

As the substituents for the A ring, 1 or 2 C1_5 alkyl groups (for example a C1_1 alkyl group such as a methyl group, a tert-butyl group, etc.), a phenylene group, a halogen atom ( for example, fluorine, chlorine, bromine, iodine, etc.), et., are preferably used.

The group represented by the formula: where n represents the same meaning as defined above, represents a group represented by the formula: wherein n represents the same meaning as defined above, and preferably a group represented by the formula: The group represented by the formula: where n represents the same meaning as defined above, represents a group represented by the formula: or wherein n represents the same meaning as defined above, and preferably a group represented by the formula: Y, the group represented by the formula: represents a group represented by the formula: and preferably a group represented by the formula: As the compound represented by the formula (la), the compound represented by the formula (Ibb) is preferred, and as the compound represented by the formula (la), the compound represented by the formula (Ib) is preferred.

As the compound represented by the formula (Ibb), the compound represented by the formula (Inn) is preferred, and as the compound represented by the formula (Ib), the compound represented by the formula (In) is preferred.

As the compound (Ibb), (Ib), a compound wherein R 1 is a lower alkyl group optionally having substituents, R 2 is a hydrogen atom or a lower alkyl group, Ar is a phenyl group optionally having substituents, n is 1, 2 or 3 is preferred, and a compound wherein R 1 is a lower alkyl group optionally having substituents, R 2 is a hydrogen atom, Ar is a phenyl group substituted by a halogen atom, n is 2 is more preferred .

As the compound represented by the formula (Ice), (le), a compound wherein Ar is a phenyl group optionally having substituents, n is 2 is preferred.

As the displaceable group represented by X1, for example, a halogen atom (eg, chlorine, bromine, iodine, etc.,), etc., are preferred and a chlorine atom is more preferred.

When the compounds represented by the formulas (Iaa), (Ibb), (Ice), (la), (Ib), (le), (Id), (le), (If) e (Ig) have stereoisomers, any of these stereoisomers and mixtures thereof are included in the invention.

When a compound represented by the formula (Iaa) is a compound represented by the formula (Ice) or (Inn), when a compound represented by the formula (le) or (In), when a compound represented by the formula (Ie) is a compound represented by the formula (Ik) or (Ip), when a compound represented by the formula (Id) is a compound represented by the formula (Ir), and when a compound represented by the formula (Ig) is a compound represented by the formula (It), then each compound can exist as an optical isomer with respect to the asymmetric carbon atom in a cycloalkene or cyclohexene ring, and any such optical isomers and mixtures thereof are included in the invention.

A compound represented by the formula (la) can preferably be 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-d-ethyl carboxylate, 6- [N- (2-chlorophenyl) sulfamoyl ] - ethyl 1- cyclohexene-1-carboxylate, 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate or 6- [N- (2-chloro- 4 - fiuorophenyl) sulfamoyl] - 1-cyclohexene-1-dicarboxylate of d-ethyl as well as a salt thereof.

In the aforementioned formulas, methods for producing a compound represented by the formula: wherein n is 1 or 2, and a compound represented by the formula: where n is 1 or 2, are reported in the Journal of the American Chemical Society, Vol. 101, pp 6981-6991 (1979).

And, a method to produce a compound represented by the formula: wherein Arb is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group or a 2-6-dimethylphenyl group, is reported in Tetrahedron, Vol. 52, pp 783-790 (1996) .

A method for producing an inventive compound (la), (Ib) or (le) or a salt thereof is discussed below.

While the following description of a production method may be applicable not only to an inventive compound (la), (Ib) or (le) but also to a salt thereof, the following description may sometimes employ a simple expression, for example , Compound (la), (Ib) or (le).

An inventive compound (Iaa), (Ibb) or (Ice) or a salt thereof may also be similarly produced.

While a method for producing Compound (a) wherein R is represented by the formula OR 1 wherein R 1 is as defined above is described below, a compound wherein R is an optionally substituted aliphatic hydrocarbon group, an aromatic hydrocarbon group optionally substituted an optionally substituted heterocyclic group, a group represented by the formula: where each symbol is as defined above can also be produced similarly.

The compound (Ia) of the invention wherein R is represented by the formula OR 1 wherein R 1 is defined above and R ° is a hydrogen atom or an aliphatic hydrocarbon group, for example, Compound (Ib), typically Compounds (In. ) e (can), for example, be produced by reacting a compound represented by the formula: wherein each symbol is as defined above or a salt thereof with a compound represented by the formula: wherein each symbol is as defined above or a salt thereof, or by subjecting a pipeline obtained by a reaction of the Compound (lia) or a salt thereof with the compound (Illa) or a salt thereof to a known hydrolysis per se.

During the process of the reaction of Compound (lia) with Compound (Illa), a group of Compound (lia) represented by the formula: where n is as defined above can be isomerized in a group represented by the formula: wherein n is as defined above, which results in the production of a compound (Ib) wherein a group represented by the formula. where n is as defined above is a group represented by the formula: wherein n is as defined above, for example, a compound represented by the formula (In).

A reaction of the Component (Ia) or a salt thereof with the Compound (Illa) or a salt thereof may be effected in the absence or presence of a base in a solvent which does not adversely affect the reaction or not. use solvent. In this reaction, the amount of compound (Illa) or a salt used is preferably about 1 to about 5 times (molar ratio), -more preferably about 1 to about 2 times (molar ratio) of the compound (Ha) or a salt of this one The base that may be employed may, for example, be an inorganic base (eg, sodium hydride, potassium hydride, sodium hydroxide and the like), an inorganic base (eg, triethylamine, pyridine, diisopropylethylamine and the like). ), preferably an organic base such as triethylamine. The amount of a base, when used, is preferably about 0.5 to about 5 times (molar ratio), more preferably about 0.9 to about 2 times (molar ratio) that of the compound (Ha).

A solvent employed in the reaction of the compound (lia) with the Compound (Illa) which does not adversely affect the reaction may, for example, be a sulfoxide (for example, dimethyl sulfoxide and the like), an ether (for example, diethyl ether) , tetrahydrofuran, dioxane and the like), a nitrile (eg, acetonitrile and the like), an aromatic hydrocarbon (eg, benzene, toluene, xylene and the like), a halogenated hydrocarbon (eg, dichloromethane, chloroform, , 2-dichloroethane), an amide (for example, dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone and the like) and the like. Any of these solvents can be used alone or in combination of two or more in an appropriate ratio.

A reaction of Compound (Ha) with the Compound (Illa) is carried out at a temperature preferably of about -10 ° C to 100 ° C, more preferably about 0 ° C to 60 ° C. the range of reaction times from about 0.5 to about 50 hours, preferably about 0.5 hours to about 30 hours.

The compound (In) and the Compound (lo) which are the products of this reaction can each be produced as a single compound or in a mixture. When R2 in Compound (lo) is a hydrogen atom, a closed ring reaction may proceed under some reaction and / or isolation conditions, resulting in a compound represented in formula (II).

Compound (Ib) of the invention in which R2 is an "optionally substituted aliphatic hydrocarbon group" can, for example, be produced by reacting a compound represented by the formula: where each symbol is as defined above or a salt thereof with a compound represented by the formula: R2b-X2 (I I Ib) wherein X2 is a displaceable group (e.g., a halogen atom (e.g., chlorine atoms, bromine, iodine and the like) or a group represented by the formula -03SRJ wherein R3 is a lower alkyl group having 1 to 4 carbon atoms or an optionally substituted phenyl group, and Rb is an optionally substituted aliphatic hydrocarbon group and the like, or by subjecting a product obtained by the reaction of Compound (Ix) or a salt thereof with Compound (Illa) or a salt thereof to the hydrolysis known per se.

A reaction of Compound (Ix) or a salt thereof with Compound (IHb) can be effected in the absence or presence of a base in a solvent which does not adversely affect the reaction or do not use solvent.

In this reaction, the amount of the compound (IHb) used is preferably about 1 to about 5 times (molar ratio), more preferably about 1 to about 2 times (molar ratio) than of Compound (Ix). This base which can be used can, for example, be an inorganic base (for example, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide and the like), an inorganic base (for example, triethylamine, pyridine). , diisopropylethylamine and the like). The amount of a base, when used, is preferably about 0.5 to about 5 times (molar ratio), more preferably about 0.9 to 2 times (molar ratio) than of Compound (Ix).

A solvent employed in the reaction of Compound (Ix) with Compound (IHb) which does not adversely affect the reaction may, for example, be a sulfoxide (for example, dimethyl sulfoxide and the like), an ether (for example diethyl ether, tetrahydrofuran, dioxane and the like), a nitrile (eg, acetonitrile and the like), an aromatic hydrocarbon (eg, benzene, toluene, xylene and the like), a halogenated hydrocarbon (eg, dichloromethane, chloroform, 1, 2- dichloromethane and the like), an ether (e.g., ethyl acetate), an amide (e.g., dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-yl idazolidinone, 1-methyl-2-pyrrolidone and the similar ones) and the similar ones. Any of these solvents can be used alone or in combination of two or more in an appropriate ratio.

A reaction of the compound (Ix) with the Compound (IHb) is carried out at a temperature preferably of about -10 ° C to 100 ° C, more preferably about 0 ° C to 60 ° C. The ranges of reaction times from about 0.1 to about 50 hours, preferably about 0.5 hours to about 10 hours.

Compound (Ib) of the invention wherein R1 is an "optionally substituted aliphatic hydrocarbon group" can, for example, be produced by reaction of a compound represented by the formula: (ly) wherein M is a hydrogen atom or an alkali metal (for example, lithium, sodium, potassium and the like, and each of the other symbols is as defined above or a salt thereof with a compound represented by the formula: R'-Xz (lile) where each symbol is as defined above or a salt of it.

A reaction of Compound (Iy) with the Compound (lile) can be effected in the absence or presence of a base in a solvent that does not adversely affect the reaction or do not use solvent. In this reaction, the amount of the Compound (lile) used is preferably about 1 to about times (molar ratio), more preferably approximately 1 to approximately 5 times (molar ratio) than of Compound (Iy). The base that can be used can, for example, be an inorganic base (for example, sodium hydride, potassium hydride, sodium hydroxide and the like), an organic base (for example, triethylamine, pyridine, diisopropylethylamine and the like). ). The amount of a base, when used, is preferably about 0.5 to about 5 times (molar ratio), more preferably about 0.9 to about 2 times (molar ratio) that of Compound (Iy).

A solvent used in the reaction of the compound (Iy) with the compound (lile) which does not adversely affect the reaction may, for example, be a sulfoxide (for example, dimethyl sulfoxide and the like), an ether (eg, diethyl) ether, tetrahydrofuran, dioxane and the like), a nitrile (for example, acetonitrile and the like), an aromatic hydrocarbon (for example, benzene, toluene, xylene and the like), a halogenated hydrocarbon (e.g., dichloromethane, chloroform, 1,2-dichloroethane and the like), an ester (e.g., ethyl acetate), an amide (e.g., dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone) , 1-methyl-2-pyrrolidone and the like) and the like. Any of the solvents can be used alone or in combination of two or more in an appropriate ratio.

A reaction of Compound (Iy) with the compound (lile) is carried out at a temperature preferably of about -10 ° C to 150 ° C, more preferably about 0 ° C to 120 ° C. The reaction times range from about 0.5 to about 50 hours, preferably about 0.5 hours to about 30 hours.

Compound (Ib) of the invention wherein R1 is a (C? -) lower alkyl group can be produced by reaction of a compound represented by the formula: wherein R 1b is a hydrogen atom of a (Ci-e) lower alkyl group, and each of the others is as defined above or a salt thereof with a compound represented by the formula: J R -OH (I Id) wherein R is a group (C? _6 lower alkyl.

A reaction of the Compound (Iz) with the compound (IHd) can be carried out in the presence of an acid in a solvent which does not adversely affect the reaction or use solvent. In this reaction, the Compound (IHd) is used in excess of Compound (Iz), usually in an amount greater than about 10 to about 300 times (molar ratio). The acid that can be used can for example be an inorganic acid (for example, sulfuric acid, hydrochloric acid, phosphoric acid and the like) or an organic acid (for example, toluene sulfonic acid and the like), and the amount used is preferably about 0.001 to about 50 times (molar ratio), more preferably about 0.1 to about 5 times (molar ratio) that of Compound (Iz).

A solvent employed in the reaction of Compound (Iz) with Compound (IHd) which does not adversely affect the reaction may, for example, be a sulfoxide (e.g., dimethyl sulfoxide and the like), an ether (e.g., diethyl ether) , tetrahydrofuran, dioxane and the like), a nitrile (eg, acetonitrile and the like), an aromatic hydrocarbon (eg, benzene, toluene, xylene and the like), a halogenated hydrocarbon (eg, dichloromethane, chloroform, , 2- dichloromethane and the like), an amide (for example, dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone and the like) and the like. Any of these solvents can be used alone or in combination of two or more in an appropriate ratio.

A reaction of Compound (Iz) with Compound (IHd) is carried out at a temperature preferably of about 0 ° C to 150 ° C, more preferably about 10 ° C to 120 ° C.

The range of reaction times from about 1 to about 300 hours, preferably about up to 10 hours to about 200 hours.

Compound (Ia) of the invention wherein R and R "together form a bond and a group represented by the formula: where n is as defined above is a group represented by the formula: wherein n is as defined above, for example, the compound (le) can, for example, be produced by subjecting a compound represented by the formula: where each symbol is as defined above or a salt thereof to a closed ring reaction. Such a closed ring reaction can usually be effected by a method employed by dehydration of a carboxy group and an amino group to condense into an amido bond, such as one described in "Izumiya et al., Basics and Experiments of Peptide Synthesis, Maruzen ( 1985) ".

More typically, such a closed ring reaction can be effected by contacting the Compound (Hb) in contact with a condensing agent in a solvent that does not adversely affect the reaction in the presence or absence of a base and in the presence and absence of an additive A solvent employed in this reaction which does not adversely affect the reaction may, for example, be a sulfoxide (for example, dimethyl sulfoxide and the like), an ether (for example, diethyl ether, tetrahydrofuran, dioxane and the like), a nitrile (for example, acetonitrile and the like), an aromatic hydrocarbon (for example, benzene, toluene, xylene and the like), a halogenated hydrocarbon (for example, dichloromethane, chloroform, 1,2-dichloroethane and the like), an ester (for example, ethyl acetate and the like), an amide (for example, dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone and the like) and the like. Any of these solvents can be run alone or in combination of two or more in an appropriate ratio.

Such a base may, for example, be an organic base (for example, triethylamine, pyridine, diisopropylamine and the like) and the like. The amount of a base, when used, is preferably about 0.01 to about 100 times (molar ratio), more preferably about 0.1 to about 10 times (molar ratio) that of Compound (Hb).

The additive that can be used as described above can, for example, be an active esterifying agent (for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like). The amount of an additive, when used, is preferably about 0.01 to about 100 times (molar ratio) that of Compound (IIb).

A condensing agent may, for example, be N, N '-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, diphenylphosphoryl azide and carbonyldiimidazole., with N, N'-dicyclohexylcarbodiimide and diethyl cyanophosphate which is particularly preferred. The amount of condensing agent, when used, is preferably about 0.01 to about 100 times (molar ratio), more preferably about 0.1 to about 10 times (molar ratio) that of Compound (IIb). The reaction temperature is preferably about -10 ° C to 100 ° C, more preferably about 0 ° C to 50 ° C, the range of the reaction times from about 0.5 to about 50 hours, preferably about 0.5 hours to about 30 hours .

A Compound (Iaa), (Ibb), (Ice), (la), (Ib) or (le) Inventive thus obtained can be isolated and purified by a method known per se such as extraction, condensation, neutralization, filtration, crystallization, recrystallization, chromatography and the When a Compound (Iaa), (Ibb), (Ice), (the), (Ib) or (le) inventive thus obtained is a compound that is a mixture of the two compounds in each of which a group represented by the formula: where n is as defined above is a group represented by the formula: where n is as defined above and is a group represented by the formula: where n is as defined above, respectively, then the separation can be conducted by a known isomer separation method such as silica gel chromatography using ethyl acetate / water as an eluent, octadecyl chromatography column using methanol / water / acetic acid and the like.

Also when a product is a mixture of the two compounds in each of which a group represented by the formula: where n is as defined above is a group represented by the formula: where n is as defined above, and a group represented by the formula: CHP T where n is as defined above, respectively, then the separation can similarly be achieved.

A prodrug for a Compound (Iaa) or (the) inventive is a compound that is converted to Compound (Iaa) or (Ia) under a physiological condition as a result of a reaction with an enzyme or gastric acid, thus, a compound that it undergoes an enzymatic oxidation, reduction or hydrolyzation to form the compound (Iaa) or (la) and a compound hydrolyzed by gastric acid to form the compound (Iaa) or (la). A prodrug for Compound Iaa) or (la) may, for example, be a compound obtained by subjecting an amino group in Compound (Iaa) or (la) to an acylation, alkylation or phosphorylation (eg, a compound obtained by subjecting an amino group in Compound (Iaa) or (a) to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation and ter -butylation: a compound obtained by subjecting a hydroxy group in the compound (Iaa) or (la) to a cilation, alkylation, phosphorylation and boration (for example, a compound obtained by subjecting a hydroxy group in Compound (Iaa) or ( la) to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumalation, alanylation and dimethylaminomethylcarbonylation), a compound obtained by subjecting a carboxyl group in the compound (Iaa) or (la) to an esterification or amidation (for example, a compound obtained by subjecting a carboxyl group in the compound (Iaa) or (la) to an ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethyl aminomethyl esterification, pivaloyl oxymethyl esterification, ethoxycarbonyl oxyethyl esterification, fatlidyl esterification, ( 5- methyl-2-oxc-1,3-dioxolen-4-yl) methyl esterification, cyclohexyl oxycarbonyl ethylesterification and methylamidation) and the like. Any of these compounds can be produced from Compound (Iaa) or (Ia) by a method known per se.

A prodrug for the compound (Iaa) or (la) may also be one that is converted to Compound (Iaa) or (la) under physiological conditions, such as those described in "IYAKUHIN no KAIHATSU (Developement of Pharmaceuticals)", Vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

Alternatively, an Inventive Compound (Iaa), (Ibb), (Ice), (la), (Ib) or (le) or Compound (Ie) can, for example, be converted to salt with an inorganic base, organic base, inorganic acid, organic acid, basic amino acid or acid. A salt with an inorganic base may, for example, be an alkali metal salt such as sodium and potassium salts, a metal salt of alkaline earths such as calcium and magnesium salts, aluminum and ammonium salts, and a salt with an organic base, for example, a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine , dicyclohexylamine or N, N'-dibenzylethylenediamine. A sai with an organic acid can, for example, be a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, and a salt with an organic acid can, for example, be a salt with formic acid, acid acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. A salt with a basic amino acid can, for example, be a salt with arginine, lysine or ornithine, and a salt with acidic amino acid can, for example, be a salt with aspartic acid or glutamic acid.

In addition, a prodrug for the inventive Compound (Iaa) or (the) may also be converted to a similar salt.

An inventive compound (Iaa), (Ibb), (Ice), (the), (Ib) or (le) or the compound (le) can be a hydrate or an anhydride, and a prodrug for an inventive Compound (Iaa) or (la) can also be a hydrate or anhydride.

In addition, an Inventive Compound (Iaa), (Ibb), (Ice), (a), (Ib) or (le) or Compound (Ie) can be labeled with radioisotope (e.g., 3H, 14C, 5S, 125I and the like), and a prodrug for an inventive Compound (Iaa) or (la) may also be similarly labeled.

When an asymmetric carbon atom is present in a cycloalkene ring in an inventive Compound (Iaa), (Ibb), (la) or (Ib), Compound (Inn), (Ice), (In) or (Ic) can, for example, be present as any of at least two stereoisomers (optical isomers) such as those described above, which can be produced separately if necessary.

For example, a single isomer represented by the formula: where each symbol is as defined above, or by the formula: where each symbol is as defined above, or by the formula: where each symbol is as defined above, in which a group represented by the formula: where n is as defined above in an initial Compound (Ix), (Iy) or (Iz) is a group represented by the formula: wherein n is as defined above and * represents a single steric configuration of the designated carbon atom or a single isomer of a compound represented by the formula (Hb), for example, a compound represented by the formula: wherein each symbol is as defined above can be used to effect the reaction described above to obtain a single isomer of Inventive Compound (In) or (le).

When the Compound (Inn), (Ice), (In) or (le) is a mixture of two or more isomers, an ordinary method of separation, such as a method in which a salt with an optically active acid (e.g. camphor sulfonic acid and the like) or an optically active base (e.g., 1-methylbenzylamine and the like) is formed, various chromatographic methods (e.g., liquid chromatography or optically active column) and fractional recrystallization can be employed to solve in discrete isomers.

A compound represented by the formula (lia), (Illa), (Ix), (IHb), (Iy), (IIIc), (Iz), (Hb), (I'x), (I 'y), (I'z) or (H'b) ) can also be used as a salt, and such salt of each of these compounds can be any of the salts that do not adversely affect the reaction, such as a salt with an inorganic base, organic base, inorganic acid, basic amino acid or acid. A salt with an inorganic base may, for example, be an alkali metal salt such as sodium and potassium salts, an alkaline earth metal salt such as calcium and magnesium salts, aluminum and ammonium salts, and a salt with an organic base may, for example, be a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N'-dibenzylethylenediamine.

A salt with an inorganic acid can, for example, be a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, and a salt with an organic salt can, for example, be a salt with formic acid, acid acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. A salt with a basic amino acid may, for example, be a salt with arginine, lysine or ornithine, and a salt with an acidic amino acid may, for example, be a salt with aspartic acid or glutamic acid.

Compound (He) which is an initial compound (Ha) in the invention wherein R1 is ethyl and X1 is a chlorine atom can, for example, be produced by a method represented by the following scheme: (lie) (lid) (He) A method for producing an initial Compound (He) in this scheme is known per se, and may, for example, be in accordance with the description of Tetrahedron, Vol. 28, p. 5923 (1972) and Vol. 30, p. 3753 (1974) or analogous methods.

A method for producing a compound (Ha) wherein R 1 is ethyl, X 1 is a chlorine atom and wherein n is 1 represented by the formula: and where n is 2 represented by the formula: it is known per se, and may, for example, be in accordance with the description in Journal of the American Chemical Society, Vol. 101, p. 6981 (1979) or analogous methods.

A method for producing a compound (Ha) wherein R 1 is methyl, X 1 is a chlorine atom and n is 2 represented by the formula: it is known per se, and may, for example, be in accordance with the description in Biorganic and Medicinal Chemistry Letters, Vol. 5, p. 325 (1995) or analogous methods.

In order to produce other compounds encompassed in an initial Compound (Ha), a method described above or analogous methods (Hb) or (Iy) in the invention can, for example, be produced by a method represented by the following schemes: (l 'b) (Hb) where each symbol is as defined above, and: (Ib) Oy) where each symbol is as defined above.

A method for producing Compound (Iy) wherein M is a hydrogen atom, R 2 is a methyl group, Ar is a phenyl group, n is 2 and a group represented by the formula: is a group represented by the formula: which is a compound represented by the formula: is known per se, and may be in accordance with the description in Journal of the American Chemical Society, Vol. 101, p. 6981 (1979) or analogous methods.

An initial compound or an intermediate obtained as described above can be isolated and purified from a reaction mixture by a method known per se, such as extraction, concentration, neutralization, filtration, crystallization, recrystallization, column chromatography, thin layer chromatography. and the similar ones. It can also be used directly in the next stage without any isolation.

When a resulting initial or intermediate material is a mixture of the two compounds in each of which a group represented by the formula: where n is as defined above is a group represented by the formula: where n is as defined above and is a group represented by the formula: "(CH,), where n is as defined above, respectively, then the separation can be conducted by a known isomer separation method such as silica gel chromatography using ethyl acetate / water as eluent, octadecyl column chromatography using methanol / water / acetic acid as eluent, and the like.

Also when a product is a mixture of the two compounds in each of which a group represented by the formula: where n is as defined above is a group represented by the formula: where n is as defined above is a sruoo represented by the formula: where n is as defined above and is a group represented by the formula: where n is as defined above, respectively, then the separation can similarly be achieved.

Since an Inventive Compound (Iaa) or Compound (le) has a low toxicity, an effect that inhibits the production of nitric oxide and an inhibitory effect of the production of an inflammatory cytosine such as TNF-a, IL-1 and IL-6 , is useful as a therapeutic and / or prophylactic agent in a mammal (for example, cat, cow, dog, horse, goat, monkey, human and the like) against heart diseases, autoimmune diseases, inflammatory disease, nervous system disease central, infectious disease, sepsis, septic shock that includes icorremia, endotoxin shock, exotoxin shock, cardiac deficiency, shock, hypertension, rheumatoid arthritis, osteoarthritis, gastritis, ulcerative colitis, peptic ulcer, gastric ulcer-induced fatigue, Crohn's disease, autoimmune disease, tissue post-transplant failure and rejection, failure of post-ischemic reperfusion icas, acute coronary microvascular embolism, shock-induced vascular embolism (disseminated vascular coagulation (DIC) and the like), cerebral ischemic disorders, arterial sclerosis, pernicious anemia, Fanconi anemia, sickle cell disease, pancreatitis, nephrosis syndrome, nephritis, insulin-dependent diabetes with renal failure, insulin-dependent diabetes, hepatitis porphyria, alcoholism, Parkinson's disease, chronic leukemia, acute leukemia, tumor, myeloma, side effects of anticancer agents, respiratory and adult respiratory exhaustion syndrome, pulmonary emphysema, dementia, disease of Alzheimer's, multiple sclerosis, deficiency of vita E mine, old age, soi burns, muscular dystrophy, myocarditis, cardiomyopathy, myocardial infarction, sequelae of myocardial infarction, osteoporosis, pneumonia, hepatitis, psoriasis, pain, cataracts, infectious influenza, malaria, human immunodeficiency virus infection (HIV), radiation induced faults, burns, efficiency in in vitro fertilization, hypercalcemia, tonic spondylitis, osteopenia, Behcet bone disease, osteomalacia, fracture, acute bacterial meningitis, infection by Helicobacter pylori, invasive staphylococcal infection, tuberculosis, systemic mycosis , herpes simplex virus infection, herpes zoster-varicella virus infection, virus infection - human papilloma, acute viral encephalitis, encephalitis, asthma, atopic dermatitis, allergic rhinitis, reflux esophagitis, fever, hypercholesteremia, hyperglycemia, hyperlipidemia, diabetic complication, diabetic kidney disease, diabetic neuropathy, diabetic retinopathy, gout, gastric atony, hemorrhoids, systemic lupus erythematosus, spinal damage, insomnia, schizophrenia, epilepsy, cirrhosis, liver failure, unstable angina, valcular disease, dialysis-induced thrombocytopenia, cerebral ischemic stroke, acute cerebral thrombosis, cancer metastasis, cancer of the urinary bladder, breast cancer , uterine cervical cancer, colon cancer, gastric cancer, ovarian cancer, prostate cancer, parvicellular lung cancer, non-parvicular pulmonary cancer, malignant melanoma, Hodgkin's disease, non-Hodgkin's lymphoma and the like.

When the inventive Compound la) or the Compound (le) is administered to human, it is surely given as it is or in a mixture with a vehicle, excipient and diluent, pharmacologically acceptable, in the form of a dose such as oral formulations (eg, powder, granules, tablets, capsules and similar), a parenteral formulation (e.g., injectable formulation, dermal formulation (e.g., nasal formulation, percutaneous formulation and the like), suppositories (e.g., rectal suppository and vaginal suppository and the like) as well as other pharmaceutical compositions oral or parenteral.

Any of these formulations can be produced by any method known per se which is ordinarily employed to produce a pharmaceutical formulation. The amount of the Inventive Compound (Iaa) or the Compound (le) to be incorporated into a formulation may vary depending on the dosage forms, and is preferably about 10 to 95% by weight in an oral formulation described above and about 0.001 to about 95% by weight in a parenteral formulation described above.

For example, an injectable formulation can be produced by formulating the Inventive Compound (Iaa) or the Compound (le) together with a solubilizing agent (e.g., β-cyclodextrin and the like), a dispersant (e.g., Tween 80 (ATLASPO DER USA), HCO60 (NIKKO CHEMICALS), carboxymethylcellulose, sodium alginate and the like), a preservative (for example, methylparaben, propylparaben, benzyl alcohol, chlorobutanol and the like (, an isotonic agent (eg, sodium chloride, glycerin, sorbitol, glucose and the like) in aqueous injectable formulations in accordance with an ordinary method, or by suspending an emulsifying agent an active ingredient in a vegetable oil (for example, olive oil, sesame oil, peanut oil, oil of cottonseed, corn oil and the like) and propylene glycol to form an injectable oil-based formulation.An oral formulation can be produced by compressing the inv entivo (Iaa) or Compound (le) together with an excipient (e.g., lactose, sucrose, starch and the like} , a disintegrant (eg, starch, calcium carbonate and the like), a binder (eg, starch, gum arabic, carboxymethyl cellulose, polyvinyl, pyrrolidone, hydroxypropyl cellulose and the like) or a linker (eg, talc, stearate) of magnesium, polyethylene glycol 6000 and the like) as appropriate followed by a coating process known per se for the purpose of disguising the flavor, forming an enteric layer, or achieving sustained release.

Such coatings can, for example, be hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F 68, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate Eudragit / RHOME, Germany, a copolymer of methacrylic acid and acrylic acid), a dye (for example titanium oxide, red oxide and the like) as appropriate.

An inventive Compound (Iaa) or Compound (le) may also be employed as a dermal formulation in the form of a solid or semi-solid or a liquid. • For example, a solid dermal formulation can be an Inventive Compound (Iaa) or Compound (le) as such or in a mixture with an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose and the like), a slimming agent ( for example, natural gums, cellulose derivatives, acrylic acid polymers and the like) which are then converted into a powder composition. A semi-solid dermal formulation can be produced by a standard method in the form of an aqueous or oily gel or ointment. A liquid dermal formulation can be produced by a method employed to produce an injectable formulation or an analogous method in the form of an aqueous or oily suspension.

A solid, semi-solid or liquid formulation can also be substituted with a pH modifier (for example carbonated water, phosphoric acid, nitric acid, hydrochloric acid, sodium hydroxide and the like), an antiseptic (for example, p-oxybenzoates). , chlorobutanol, benzaiconium chloride and the like) and the like, as appropriate. Typically, a vaseiin or lanolin is used as a formulation base, per 1 g of which about 0.1 to 100 mg of an Inventive Compound (Iaa) or Compound (le) is contained to form an ointment.

An inventive Compound (Iaa) or Compound (le) can also be formulated as a suppository in oil base, aqueous solid, or semi-solid or liquid. An oil-based suppository can, for example, be a higher fatty glyceride (for example, cocoa butter, ITEPSOL (DYNAMIT NOBEL) and the like), a medium fatty acid (for example, MIGLYOL (DINAMITE NOBEL) and the like or a vegetable oil (for example, sesame oil, soybean oil, cottonseed oil and the like) and the like as appropriate.A watery base may, for example, be a polyethylene glycol or propylene glycol, and The base in aqueous gel may, for example, be a natural gum, a cellulose derivative, a vinyl polymer, an acrylic polymer and the like.

While the dose of an Inventive Compound (Iaa) or Compound (le) may vary depending on the age, body weight, and condition of the patient, the dosage form, mode and period of treatment may, for example, be generally from about 0.01 to about 1000 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, most preferably about 0.1 to about 50 mg / kg, and particularly about 1.5 to about 30 mg / kg per day in a patient who has a sepsis (adult weighing approximately 60 kg), said daily dose being administered orally or parenterally all at once or in portions during a day.

It is a matter of evolution that a lower daily dose may be sufficient or an excessive dose may be required since the dose may vary depending on several factors as discussed above.

BEST MODALITY TO CARRY OUT THE INVENTION The present invention is further described with reference to Reference Examples, Examples, Examples and Preparation Experiments, which are not intended to restrict the invention.

A 1H NMR spectrum was determined by a VARIAN GEMINI 200 spectrophotometer (200 MHz) using tetramethylsilane as an internal standard and represented as the full d values in ppm. The number at a level when a mixture of solvents was used is the ratio by volume of each mixture. One percent is one percent by weight unless otherwise specified. The proportion of the solvents in a chromatography on silica gel is the volume ratio of the solvents to be mixed.

A more polar diasterere means a diastereomer having a smaller Rf value when determined by a normal phase in thin layer chromatography under the same condition (for example using ethyl acetate / hexane as an eluent), a less polar diastereomer means a diastereomer having a larger Rf value in such a determination.

The meanings of the abbreviations as used in the examples are the following: S: single, d: doublet; t: triplet; q: quartet; DD: double doublet; tt: triple triplet; m: multipleto; br; large; J: coupling constant.

Examples: Reference Example 1 Sodium propoxybrate tetrahydrate (22.3 g) was mixed with acetic acid (120 ml) and heated to 50 to 55 ° C and then the solution of 2- mercapto-1-cyclohexene-1-ethyl carboxylate (9.0 g) is acetic acid (15 ml) was added dropwise during two hours. The mixture was stirred at 50 to 55 ° C for 3 hours and then at 80 to 85 ° C for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (200 ml) and stirred at room temperature for 3 hours and the resulting insolubles were removed from the filtrate. The insolubles were washed with acteonitrile (50 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resulting residue was dissolved in acetonitrile (150 ml) and stirred at room temperature for 2 hours. The resulting insolubles were removed from the filtrate, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (300 ml) and the powder that precipitated was isolated by filtration to obtain ethyl 2-sulfo-cyclohexene-1-carboxylate as a white poivo (18.8 g) containing inorganic substances. 2H NMR (DMSO-de) d: 1.17 (3H, t, J = 7Hz), 1.53 (4H, br), 2.08-2-09 (2H, m), 2.22-2.24 (2H, m), 3.99 (2H , q, J = 7Hz).

Reference Example 2 Peroxybutyl sodium tetrahydrate (74.3 g) was mixed with acetic acid (400 ml) and heated at 50 to 55 ° C and then a solution of ethyl 2- (2-mercapto-l-cyclohexene-1-carboxylate) (30.0 g) in acid Acetic acid (50 ml) was added dropwise during 2 hours. The mixture was stirred at 50 to 55 ° C for 3 hours and then at 80 to 85 ° C for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (660 ml) and stirred at room temperature for 1 hour and the resulting insolubles were removed from the filtrate. The insolubles were washed with acetonitrile (50 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resulting residue was dissolved in acetonitrile (500 ml) and stirred at room temperature for 2 hours. The resulting insolubles were removed from the filtrate, and the filtrate was concentrated under reduced pressure.

The residue was combined with diisopropyl ether (1000 ml) and the powder that precipitated was isolated by filtration to obtain ethyl 2-sulfo-1-cyclohexene-1-carboxylate as a white powder (55 g) containing inorganic substances. These were treated dropwise with thionyl chloride (150 ml) at 0 to 1 hour and then stirred at 80 to 85 ° C for 20 hours. The mixture was evaporated under reduced pressure to dryness and the residue was partitioned between ethyl acetate (300 ml) and a diluted brine (400 ml) and the aqueous layer was extracted with ethyl acetate (200 ml). The ethyl acetate layers were combined and washed with saturated brine (200 ml) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation to obtain a residue, and the residue was purified by flash chromatography on a silica gel column (eluent: ethyl acetate / hexane = 1/8 -> ethyl acetate / hexane = 1/5) to produce a solvent. -chlorosulfonyl-1-cyclohexene-1-ethyl carboxylate (21.5 g) as yellow crystals. 2 H-NMR (CDCl 3) d: 1.38 (3 H, t, J = 7.0 Hz), 1.70-1.89 (4 H, m), 2.52- 2.67 (4 H, m), 4.30 (2 H, q, J = 7.0 Hz). % calculated for Co.H? 3C104S: C, 42.77; H, 5.18 % found: C, 42.73, H, 5.15 Melting point: 31.5 to 32.5 ° C Reference Example 3 Sodium peroxyborate tetrahydrate (10.6 g) were mixed with acetic acid (57 ml) and heated at 50 to 55 ° C and then a solution of ethyl 2-mercapto-1-cyclopentene-1-carboxylate (3.9 g) , synthesized according to Tetrahedron, vol 30, p.3753 (1974)) in acetic acid (7 ml) were added for two hours.

The mixture was stirred at 50 to 55 ° C for 3 hours and then at 80 to 85 ° C for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (100 ml) and stirred at room temperature for 12 hours and the resulting insolubles were removed from the filtrate. The insolubles were washed with acetonitrile (10 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resulting residue was dissolved in acetonitrile (70 ml) and stirred at room temperature for 2 hours. The resulting insoluols were removed from the filtrate, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (20 ml) and the paste which precipitated was isolated by filtration to obtain ethyl 2-sulfo-1-cyclopentene-1-carboxylate as a white powder (7.8 g) containing inorganic substances.

This (1.0 g) was dissolved in thionyl chloride (3 ml) and then stirred at 80 to 90 ° C for 15 hours. The mixture was evaporated under reduced pressure to dryness and the residue was dissolved in ethyl acetate (50 ml). The resulting aqueous solution was washed successively with water (50 ml) and saturated brine (50 ml) and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation to obtain a residue, which was purified by flash chromatography on a silica gel column (eluent: ethyl acetate / hexane = 1/5) to yield ethyl 2-chlorosulfonyl-1-cyclopentene-1-carboxylate (153.7 mg) as a yellow oil. 2H-NMR (CDC13) d: 1.35 (3H, t, J = 7.0 Hz), 2.18 (2H, quintet, J = 8.0 Hz), 2.92- 3.08 (4H,), 4.33 (2H, q, J = 7.0 Hz ).

Reference Example 4 Peroxybotate sodium tetrahydrate (6.8 g) was mixed with acetic acid (37 ml) and heated at 50 to 55 ° C and then a solution of ethyl 2- (2-mercapto-1-cycloheptene-1-carboxylate) (3.0 g, synthesized in accordance with Tetrahedron, Vol. 30, p.33753 (1974)) in acetic acid (15 ml) was added dropwise over 1 hour.

The mixture was stirred at 50 to 55 ° C for 3 hours and then at 80 to 85 ° C for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (100 ml) and stirred at room temperature for 3 hours and the resulting insolubles were removed from the filtrate. The insolubles were washed with acetonitrile (10 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resulting residue was dissolved in acetonitrile (70 ml) and stirred at room temperature for 1 hour. The resulting insolubles were removed from the filtrate, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (100 ml) and the paste which precipitated was isolated by filtration to obtain ethyl 2-sulfo-1-cyclopentene-1-carboxylate as a white powder (3.4 g) containing inorganic substances.

This (1.5 g) was dissolved in thionyl chloride (4 ml) and then stirred at 80 to 90 ° C for 15 hours. The mixture was evaporated under reduced pressure to dryness and the residue was dissolved in ethyl acetate (30 ml). The obtained solution was washed with saturated brine (30 ml x 2) and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation to obtain the residue, which was purified by flash chromatography on silica gel column (eluent: ethyl acetate / hexane = i / 8) to produce 2-chlorosulfonyl-1-cyclopentene-1-carboxylate. ethyl (590 mg) as a brown oil.

: H- NMR (CDC13) d: 1.34 (3H, t, J = 7.4 Hz), 1.60 -2.00 (&H, m), 2.40- 2.90 (4H, m), 4.29 (2H, q, J = 7.4 Hz).

Reference Example 5: A solution of ethyl 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate obtained in Example 1 (Compound 1, 210 mg) in acetonitrile (29 ml) was added with IN aqueous sodium hydroxide solution (29 ml) and the mixture was stirred at 55 ° C for 12 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography CHP-20P (eluent: water-> methanol / water = 1/1). The effluent was concentrated under reduced pressure and the residue was dissolved in water (5 ml) and lyophilized to yield 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-sodium carboxylate (43 mg) as a white powder. lH- NMR d: 1.65-2.40 (6H, m), 4.55 (1H, d, J = 3.0 Hz), 6.86 (1H, t, J = 3.4 Hz), 7.19-7.33 (2H, m), 7.50 (1H , t, J = 9.0 Hz), % calculated for C13H12ClFNO.SNa. H2O: C, 41. 78; H, 3. 78; N, 3 75 % found: C, 41.52; H, 3.55; N, 3.84 SIMS: 356 (MH4") Reference Example 6 2,4-difluoronitrobenzene (8.0 g) were dissolved in N, N-dimethylformamide (110 ml) and the solution was mixed with 1H-1, 2, 4-triazole (3.47 g) and potassium carbonate (6.95 g) and ia The mixture was stirred under a nitrogen atmosphere at 70 ° C for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the ethyl acetate layers were combined and washed 5 times with water and then with saturated brine, and then dried over magnesium sulfate. The solvent was removed from the distillate under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / hexane = 1: 1.3). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ester to yield 1- (3-fluoro-4-nitrophenyl) -1H-1,2,4-triazole (5.29 g) as yellow powdered crystals.

XH-NMR (CDCl 3) d: 7.32- 7.42 (2H, ra), 8.13 (1H, dd, J = 9.8 Hz, 5.0 Hz), 8.15 (1H, s), 8.43 (1H, s). % calculated for C8H5FN4? 2: C, 46. 16; H, 2 42; N, 26 92 Found: C, 45.98; H, 22.43; N, 26 Fusion Point: 90 to 91 ° C.

Reference Example 7 (3-fluoro-4-nitrophenyl) -1H- 1, 2, 4-triazole (3.06 g) were dissolved in ethanol (100 ml) and mixed with 10% Pd / C (50% water, 612 mg) and then stirred under a nitrogen atmosphere at room temperature for 1 hour. After filtering to remove the catalyst, the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the resolving solution was washed successively with water and saturated brine, and dried over magnesium sulfate. The solution was removed from the distillate under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / hexane-1: 2). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to produce i- (4-amino-3-fluorophenyl) -1H-1,2,4-triazole (1.68 g) like yellow powdered crystals.

XH-NMR CDCl 3) d: 4.41 (2H, br), 6.78-6.85 (1H, m), 6.96-7.05 (2H, m), 8.16 (1H, s), 8.37 (1H, s), i calculated for C8H7F 4: C, 53. 93; H, 3. 96; N, l .40 % found: C, 54.07; H, 3.82; N, 31.55 Melting point: 103 to 103 ° C Reference Example 8 Methyl 4- amino-3-chlorobenzoate (5.65 g, synthesized according to Synthesis, 1985, 669) was dissolved in tetrahydrofuran (112 ml) and mixed with a solution of sodium bicarbonate (7.67 g) in water (84.8 ml) and benzionium chloroformate (39.1 ml) and the mixture was stirred under a nitrogen atmosphere at room temperature for 22.5 hours. The reaction mixture was extracted with ethyl acetate and the ethyl acetate layer was washed three times with water and then twice with saturated brine. The ethyl acetate layer was dried over magnesium sulfate and then the solvent was removed from the distillate under reduced pressure, and then the residue was purified by - column chromatography on silica gel (ethyl acetate / hexane = 1: 7). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield methyl 4-benzyloxycarbonylamino-3-chlorobenzoate (7.51 g) as white crystals. 1H-NMR (CDC13) d: 3.91 (3H, s), 5.25 (2H, s), 7. 38-7.44 (6H, m), 7.95 (1H, dd, J = 8.8 Hz, 2.0 Hz), 8.06 (1H, d, J = 2.0 Hz), 8.33 (1H, d, J = 8.8 Hz ). % calculated for C? 6Hi4ClN04: C, 60. 10; H, 4 41; N, 4 38 % found: C, 60.21; H, 4.42; N, 4.22 Melting point: 107.5 to 108.5 ° C Reference Example 9 T-potassium butoxide (24.7 g) was dissolved in dimethyl sulfoxide (221 ml) and mixed with methyl 4-benzyloxycarbonylamino-3-chlorobenzoate (4.52 g) and the mixture was stirred at room temperature for 25 minutes. The reaction mixture was poured into water (200 ml), which was then acidified with IN hydrochloric acid (225 ml) and then extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed from the distillate under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / hexane = 2: 5). A desired fraction was concentrated under reduced pressure to obtain 4-benzyloxycarbonylamino-3-chlorobenzoic acid (2.47 g) as a white powder.

XH-NMR (d6-DMSO) d: 3.34 (1H, br), 5.20 (2H, s), 7.34-7.47 (5H, m), 7.86 (1H, s), 7.93 (1H, s), 9.40 (1H , s). % calculated for C? 5H12ClN04: C, 58. 93; H, 3. 96; N, Four . 58 ° or found: C, 58.85; H, 3.93; N, 4.55 Melting point: 181.5 to 182.5 ° C Reference Example 10 4-Benzyloxycarbonylamino-3-chlorobenzoic acid (0.80 g) were dissolved in N, N-dimethylformamide (24.0 ml) and mixed at room temperature with t-butyl glycinate (0.44 g) and triethylamine (0.77 ml). Diethyl cyanophosphate (0.43 ml) was added under cooling with ice, and the mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined and washed three times with water and then twice with saturated brine, and then dried over magnesium sulfate. The solvent was removed from the distillate under reduced pressure, and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield N- (4-benzyloxycarbonylamino-3-chlorobenzoyl) t-butyl glycinate (0.93 g) as white crystals. . 1H-NMR (CDC13) d: 1.51 (9H, s), 4.12 (2H, d, J = 5.0 Hz), 5.24 (2H, s), 6.58 (1H, t, J = 5.0 Hz), 7.37 -7.45 ( 6H, m), 7.68 (1H, dd, J = 8.6 Hz), 7.89 (1H, d, J = 2.0 Hz), 8.32 (1H, d, J = 8.6 Hz). % calculated for C21H 3CIN2O5: C, 60. 22; N, 5 53; N, 6 69% found: C, 60.27; H, 5.50; N, 6.69 Melting point: 163 to 164 ° C Reference Example 11 N- (4-benzyloxycarbonylamino-3-chlorobenzoyl) t-butyl glycinate (0.80 g) were dissolved in tetrahydrofuran (30 ml) and then mixed with 10% Pd / C (50% water, 160 mg) and then mixed under an atmosphere of hydrogen at room temperature for 1.5 hours.

The catalyst was removed from the filtrate and the filtrate was diluted with ethyl acetate and washed three times with water and twice with saturated brine. The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed from the distillate under reduced pressure.

The residue was purified by column chromatography on silica gel (ethyl acetate / hexane = 1: 1). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of diisopropyl ether and hexane to yield N- (4-amino-3-chlorobenzoyl) t-butyl glycinate (0.49 g) as white crystals.

XH-NMR (CDC13) d: 1.50 (9H, s), 4.11 (2H, d, J = . 0 Hz), 4.38 (2H, s), 6.47 (1H,), 6.75 (1H, d, J = 8. 4 Hz), 7.54 (1H, dd, J = 8.4 Hz), 2.0 Hz), 7.77 (1H, d, J = 2.0 Hz). % calculated for C13H1 CIN2O3: C, 54. 84; H, 6 02; N, 9. 84 % found: C, 54.56; H, 5.85; N, 9.54 Melting point: 116 to 117 ° C Reference Example 12 A solution of ethyl 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate obtained in Example 3 (Compound 3, 2.5 g) in acetonitrile (288 ml) was mixed with a solution aqueous NaOH solution (288 ml) and the mixture was stirred at 55 ° C for 12 hours. The mixture was concentrated under reduced pressure and the residue was purified by CHP-20P column chromatography (eluent: water -> methanol / water = 1/1). The eluent was concentrated under reduced pressure and the residue was dissolved in water (10 ml) and lyophilized to yield 6- [N- (2, 4-difluorophenyl) sulfamoylS-1-cyclohexene-1-sodium carboxylate (0.50 g) as white crystals.

XH-NMR (d6-DMSO) d: 11.50- 1.65 (2H, m), 1.78-2.41 (4H, m), 4.13 (1H, d, J = 4Hz), 6.88-6.98 (2H, m), 7.09- 7.20 (1H, m), 7.42 (1H, dt, J = 9.0 Hz, 6.2 Hz). % calculated for C13H1.2F2NO4SNa. H2O: C, 43. 70; H, 3. 95; N, 3 92 % found: C, 44.17; H, 3.86; N, 3.57 SIMS: 340 (MH +) 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate sodium (0.48 g) were • dissolved in water (100 ml) and adjusted to pH 2 with IN HCL and then extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with water (100 ml x 2) and dried over anhydrous magnesium sulfate and then the solvent was removed from the distillate under reduced pressure. The residue was crystallized from diisopropyl ether to obtain 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid (0.44 g) as white pulverized crystals. 1E-NMR (d6-DMSO) d: 1.56-1.78 (2H, m), 2.00- 2.41 (4H, m), 4.31 (1H, d, J = 4.2 Hz), 7.08 (2H, br), 7.26-7.37 (1H, m), 7.44- 7.56 (1H,), 9.80 (1H, br), 12.38 (1H, br). % calculated for C 13 H 13 F 2 O 4 S: C, 49.21; H, 4.13; N, 4.41 % found: C, 49.47; H, 4.16; N, 4.62 SIMS: 317 (M +) Reference Example 13 2- ethyl oxo-5-phenylcyclohexane carboxylate (57.5 g) (synthesized in accordance with Chemical & Pharmaceutical Bulletin, Vol, 20, p. 277 (1972)) was subjected to a procedure described in Tetrahedron, Vol. 30, p. 3753 (1974) to produce 2-mercapto-5-f-nyl-1-cyclohexene-1-ethyl carboxylate (29.3 g) as pale yellow powdered crystals. 1H-NMR (CDC13) d: 1.27 (3H, t, J = 7.2 Hz), 1.76-2.05 (2H, m), 2.28- 2.91 (5H, m), 4.10 (1H, s), 4.21 (2H, q , J = 7.2 Hz), 7.19-7.38 (5H, m). calculated for C ^ Hi ^ S: C, 68.67; H, 6.92; % found: C, 68.86; H, 6.82 Reference example 14 Peroxybotate sodium tetrahydrate (35.2 g) were mixed with acetic acid (200 ml) and heated at 50 to 55 ° C and then a solution of 2-mercapto-phenyl-1-cyclohexene-1-ethyl carboxylate synthesized in the Reference Example 13 (20 g) in acetic acid (200 ml) was added dropwise over two hours. The mixture was stirred at 50 to 55 ° C for 3 hours and then at 80 to 85 ° C for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (500 ml) and stirred at room temperature for 1 hour and the resulting insolubles were removed from the filtrate. The insolubles were washed with acetonitrile (20 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resulting residue was dissolved in a mixture of acetonitrile (500 ml) and methanol (500 ml) and stirred at the temperature environment for 2 hours. The resulting insolubles were removed from the filtrate, and the filtrate was concentrated under reduced pressure.

The residue was combined with diisopropyl ether (500 ml) and the paste that precipitated was isolated by filtration to obtain ethyl 5-phenyl-2-sulfo-1-cyclohexene-1-carboxylate as a white powder (40.4 g) containing inorganic substances.

These (10 g) were treated dropwise with thionyl chloride (30 ml) at 0 ° C for 1 hour and then stirred at 85 to 90 ° C for 7 hours. The solution was evaporated under reduced pressure to dryness and the residue was dissolved in ethyl acetate (50 ml). The obtained solution was washed successively with water (50 ml) and saturated brine (50 ml) and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation to obtain a residue, which was purified by flash chromatography on silica gel column (eluent: ethyl acetate / hexane = 1/8) to yield 2-chlorosulfonyl-5-phenyl-1-cyclohexene. 1- ethyl carboxylate (4.8 g) as pale yellow crystals. 1H-NMR (CDC13) d: 1.35 (3H, t, J = 7.4 Hz), 1.85-2.02 (1H, m), 2.14-2.26"(1H, m), 2.56- 3.02 (5H, m), 4.31 ( 2H, q, J = 7.4 Hz), 7.19- 7.40 (5H, m).

Reference Example 15 - ethyl butyl-2-oxocyclohexene carboxylate (50.7 g) [synthesized according to Collect. Czech Chem. Common., 1976, 41, 2928] was subjected to a procedure described in Tetrahedron, Vol., 30, p. 3753 (1974) to produce ethyl t-butyl-2-mercapto-1-cyclohexene-1-carboxylate (39.6 g) as a yellow oil. 1E- NMR (CDCl 3) d: 0.90 (9H, s), 1.22-1.34 (1H, m), 1.32 (3H, t, J = 7.2 Hz), 1.75- 2.03 (3H, m), 2.40- 2.67 (3H , m), 3.91 (1H, s), 4.24 (2H, q, J = -7.2 Hz). % calculated for C13H22O S: C, 64. 42; H, 9. 15% found: C, 64.47; H, 9.29 Reference Example 16 Peroxybotate sodium tetrahydrate (38.2 g) was mixed with acetic acid (270 ml) and heated to 50 to 55 ° C and then a solution of ethyl 5-t-butyl-2-mercapto-cyclohexene-1-carboxylate ( 20.1 g) synthesized in Reference Example 15 in acetic acid (31 ml) was added dropwise over two hours. The mixture was stirred at 50 to 55 ° C for 3 hours and then at 80 to 85 ° C for 7.5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (445 ml) and stirred at room temperature for 3.5 hours and the resulting insolubles were removed from the filtrate. The insolubles were washed with acetonitrile (110 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resulting residue was dissolved in acetonitrile (320 ml) and stirred at room temperature for 15 hours. The resulting insolubles were removed from the filtrate, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (250 ml) and the paste that precipitated was isolated by filtration and concentrated under reduced pressure to obtain ethyl 5-t-butyl-2-sulfo-cyclohexene-1-carboxylate as a yellow oil. (17.6 g) containing inorganic substances.

This (16.4 g) was treated dropwise with thionyl chloride (49.2 ml) at 0 ° C for 0.5 hours and then stirred at 80 to 90 ° C for 7 hours. The solution was evaporated under reduced pressure to dryness and the residue was partitioned between ethyl acetate (200 ml) and dilute brine (240 ml) and the aqueous layer was extracted with ethyl acetate (100 ml). The combined layers of ethyl acetate were washed with saturated brine (120 ml) and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation to obtain a residue, which was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/10), and a desired fraction was concentrated under reduced pressure.

The residue was crystallized from hexane to yield ethyl 5-t-butyl-2-chlorosulfonyl-1-cyclohexene-1-carboxylate (7.4 g) as white crystals. 1 H-NMR (CDCl 3) d: 0.92 (9H, s), 1.22-1.46 (2H, m), 1.36 (3H, t, J = 7.2 Hz), 2.04- 2.35 (2H, m), 2.45- 2.65 (2H , m), 2.79- 2.92 (1H,), 4.31 (2H, q, J = 7.2 Hz). % calculated for C? 3H21C104S: C, 50.56; H, 6.85 % found: C, 50.47; H, 6.74 Reference Example 17 ,5-dimethyl-2-oxocyclohexene ethyl carboxylate (31.2 g) [synthesized in accordance with J. Org. Chem., 1953, 18, 661] was subjected to a procedure described in Tetrahedron, Vol. 30, p. 3753 (1974) to produce 5,5-dimethyl-2-mercapto-1-cyclohexene-1-ethyl carboxylate (29.9 g) as a yellow oil. 2H-NMR (CDCL3) d: 0.95 (6H, s), 1.31 (3H, t, J = 7.0 Hz), 1.43 (2H, t, J = 6.4 Hz), 2.14 (2H, t, J = 2.0 Hz), 2.45- 2.55 (2H, m), 3.88 (1H, s), 4.22 (2H, q, J = 7.0 Hz). % calculated for CnH? 802S: C, 61.64; H, 8.47 % found: C, 61.40; H, 8.68 Reference example 18 Sodium peroxyborate terahydrate (46.3 g) was mixed with acetic acid (270 ml) and heated at 50 to 55 ° C and then a solution of 5,5-dimethyl-2-mercapto-1-cyclohexene-1-ethyl carboxylate ( 20.2 g) synthesized in Reference Example 17 in acetic acid (30 ml) was added dropwise over 2 hours.

The mixture was stirred at 50 to 55 ° C for 3 hours and then at 80 to 85 ° C for 8 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (450 ml) and stirred at room temperature for 4 hours and the resulting insolubles were removed from the filtrate. The insolubles were washed with acetonitrile (120 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resulting residue was dissolved in acetonitrile (330 ml) and stirred at room temperature for 15 hours. The resulting insolubles were removed from the filtrate, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (300 ml) and the powder that precipitated was isolated by filtration to yield 5,5-dimethyl-2-sulfo-1-cyclohexene-1-carboxylate as an orange oil (26.5 g) which they contain inorganic substances (79 ml) and then stirred at 80 to 90 ° C for 7.5 hours. The solution was evaporated under reduced pressure to dryness and the residue was dissolved in ethyl acetate (150 ml). The solution thus obtained was combined with diluted brine (200 ml) and divided, and then the ethyl acetate layer was washed with saturated brine (100 ml) and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation to obtain a residue, which was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/8) to yield 2-chlorosulfonyl-5,5-dimethyl-1-cyclohexene- 1- ethyl carboxylate (12.4 g) as a brown oil. 1E- NMR (CDCl 3) d: 1.02 (6H, s), 1.34 (3H, t, J = 7.2 Hz), 1.61 (2H, t, J = 6.6 Hz), 2.31 (2H, t, J = 2.4 Hz) , 2.64-2.72 (2H, m), 4.30 (2H, q, J = 7.2 Hz). % calculated for C11H17CIO4S: C, 47. 06; H, 6. 10 % found: C, 47. 46; H, 6. 10 Example 1 Ethyl 2-sulfo-1-cyclohexene-1-carboxylate (7.11 g) obtained in Reference Example 1 was dissolved in thionyl chloride (21.0 ml) and heated under reflux for 14 hours and then the reaction mixture evaporated under pressure reduced to dryness. The residue was subjected three times to the procedure involving an addition of hexane (30 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate. This was combined with ethyl acetate (20 ml) and the resulting mixture was added to a mixture consisting of 4-chloro-2-fluoroaniline. (3.64 g), triethylamine (3.41 ml) and ethyl acetate (54 ml), and then stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (200 ml). The ethyl acetate layer was washed with diluted brine (100 ml x 3) and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation. The residue was combined with diisopropyl ether (8 ml) and the crystals which precipitated were isolated by filtration. The crystals thus obtained were washed with ethyl acetate (8 ml) to yield 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid ethyl ester (Compound 1; 1.60 g) as crystals similar to colorless needles. The mother liquor and washing were combined and subjected to chromatography on silica gel (eluent: ethyl acetate / hexane = 1/5 -> 1/4) and the effluent was concentrated under reduced pressure, and the residue was crystallized from acetate of ethyl- diisopropyl ether to yield the second crop of compound 1 (1.41 g). 1 H-NMR (DMSO-dd) d: 1.10 (3H, t, J = 7.2 Hz), 1.57-1.82 (2H,), 1.98- 2.44 (4H, m), 4.02 (2H, q, J = 7.2 Hz) , 4.32 (1H, d, J = 4.4 Hz), 7.12 (1H, t, J = 3.4 Hz), 7.23-7.31 (1H, m), 7.45- 7.54 (2H, m), 10.04 (1H, s). % calculated for C15 H ^ C1F04S: C, 49.79; H, 4.74; N, 3.87 % found: C, 49.93; H, 4.72; N, 4.09 Example 2 To a solution of ethyl 6- (N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 1; 250 mg) obtained in Example 1 was 1.60 g) in N, N - dimethylformamide (2.5 ml), methyl iodide (118 mg), potassium carbonate (191 mg) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (30 ml), washed with water (30 ml x 2) and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) to yield 6- [N- (4-chloro-2-fluorophenyl) -N-methylsulfamoyl] -1-cyclohexen- 1- ethyl carboxylate (Compound 2; 250 mg) as a colorless oil. 1H-NMR (DMSO-d6) d: 1.17 (3H, t, J = 7.2 Hz), 1.56-2.44 (6H, m), 7.16 (1H, t, J = 3.6 Hz), 7.33- 7.39 (1H, m ), 7.54- 7.62 (2H, m). % calculated for C? 5H? 9ClFN? 4S: C, 51. 13; H, 5. 10; N, 3 73 % found: C, 50. 91; H, 5 10; N, 3 Example 3 2- Ethyl 2-sulfo-cyclohexene-1-carboxylate (2.0 g) obtained in Reference Example 1 was dissolved in thionyl chloride (5.9 ml) and heated to reflux for 14 hours and then the mixture of The reaction was evaporated under reduced pressure to dryness. The residue was subjected three times to the procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate. This was combined with ethyl acetate (15 ml) and the resulting mixture was added to a mixture consisting of 2,4-difluoroaniline (1.29 g), triethylamine (2.0 ml) and ethyl acetate (10 ml) with ice-cooling. , and then stirred with cooling on ice for 30 minutes and then at room temperature for 20 hours.

The reaction mixture was diluted with ethyl acetate (100 ml) and washed with dilute brine (150 ml x 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was combined with diisopropyl ether (6 ml) and the crystals which precipitated were isolated by filtration to yield ethyl 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 3 0.61 g) as crystals similar to colorless needles. 1E-NMR (DMSO-d6) d: 1.07 (3H, t, J = 7.2 Hz), 1. 46- 1.82 (2H, m), 1.97- 2.50 (4H, m), 4.01 (2H, q, J = 7.2 Hz), 4.28 (1H, d, J = 4.8 Hz), 7.04- 7.15 (2H, m) , 7.29-7.54 (2H, m), 9.86 (1H, brs). % calculated for C15H17F2N04S: C, 52. 17; H, 4 96; N, Four . 06 % found: C, 52.27; H, 4.84; N, 3.98 Example 4 2- ethyl sulfo-1-cyclohexen-1-carboxylate (0.67 g) obtained in Reference Example 1 was dissolved in thionyl chloride / (2.0 ml) and heated to reflux for 8 hours and then the reaction mixture was evaporated under reduced pressure to dryness.

The procedure involving an addition of hexane (8 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate.

This was combined with ethyl acetate (5 ml) and the resulting mixture was added to a mixture consisting of 2,6-diisopropy aniline (0.89 g), triethylamine. (0.70 ml) and ethyl acetate (8 ml) with cooling on ice, and then stirred with cooling on ice for 30 minutes and then at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (40 ml) and dilute brine (40 ml) x 3) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off . The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/20 -> 1/9) to yield 6- [N- (2,6-diisopropylphonyl) sulfamoyl] -1-cyclohexen- 1-ethyl carboxylate (Compound 4; 0.12 g) as a colorless oil.

XH-NMR (DMSO-de) d: 0.99 (3H, t, J = 7.2), 1.15 (12H, d, J = 6.6 Hz), 1.58- 2.60 (6H, m), 3.39- 3.52 (2H, m) , 3.97 (2H, q, J = 7.2 Hz), 4.38 (1H, d, J = 5.4 Hz), 7.05 (1H, br), 7.15-7.31 (3H, m), 8.96 (1H, s).

Example 5 2- ethyl sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was dissolved in thionyl chloride (3.0 ml) and heated to reflux for 8 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate.

This was combined with ethyl acetate (10 ml) and the resulting mixture was added to a mixture consisting of 4-nitroaniline (0.69 g), triethylamine (0.70 ml) and ethyl acetate (8 ml) with cooling on ice, and then stirred with cooling on ice for 30 minutes and then at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with dilute brine (50 ml x 3) and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = W) and then crystallized from isopropyl ether to yield 6- [N- (4-nitrophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate ( Compound 5; 90 mg) as pale yellow powdered crystals.

XE-NMR (DMSO-de) d: 1.13 (3H, t, J = 7Hz), 1.60 - 1.85 (2H, m), 1.96- 2.46 (4H, m), 3.90- 4.16 (2H, m), 4.46 ( 1H, d, J = 5 Hz), 7.21 (1H, t, J = 3Hz), 7.38 (2H, d, J = 9 Hz), 8.22 (2H, d; J = 9 Hz), 10.92 (1H, s ). % calculated for C15H? 8N2? 6S: C, 50. 84; H, 5 12; N, 7 90 % found: C, 50.80; H, 4.99; H, 7.93 Example 6 2-sulfo-1-cyclohexene-1-ethyl carboxylate (0.67 g) obtained in Reference Example 1 was dissolved in thionyl chloride (2.0 ml) and heated to reflux for 8 hours and then the reaction mixture was vaporized under reduced pressure to dryness.

The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate.

This was combined with ethyl acetate (12 ml) and the resulting mixture was added to a mixture consisting of aniline (0.28 g), triethylamine (0.42 ml) and ethyl acetate (4 ml) with cooling on ice, and then stirred with cooling on ice for 30 minutes and then at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml) and 0.2 N HCl (50 ml) and water (50 ml x 2) and dried over anhydrous magnesium sulfate, and then the solvent it was removed by distillation. The residue was purified by chromatography on silica gel. (eluent: ethyl acetate / hexane = 1/4), and the first effluent was concentrated under reduced pressure and the residue was purified by chromatography on octadecyl column (ODS) (eluent: methanol / water = 7/3). The effluent was concentrated under reduced pressure to precipitate crystals which were collected by filtration to produce ethyl 2- (N- phenylsulfamoyl) -1-cyclohexene-1-carboxylate (Compound 7, 37 mg) as colorless powdered crystals. The second effluent was also concentrated under reduced pressure and the resulting residue was purified by chromatography on ODS column (eluent: methanol / water = 7/3).

The effluent was concentrated under reduced pressure and the residue was crystallized from methanol-water to yield ethyl 6- (N-phenylsulfamoyl) -1-cyclohexen-1-carboxylate (Compound 6; 56 mg) as colorless needle-like crystals.

Compound 6: XH.- NMR (DMSO- d6) d: 1.14 (3H, t, J = 7. 2 Hz), 1.55- 1.74 (2H, m), 1.98-2.42 (4H, m), 3.97-4.12 (2H, m), 4.32 (1H, d, J = 4.8 Hz), 7.02-7.35 (6H, m ), 10.03 (1H, brs). % calculated for C? 5H? 9N04S: C, 58.23; H, 6.19; N, 4. 53 % found: C, 58.28; H, 6.19; N, 4.55 Compound 7: XH-NMR (DMSO-d6) d: 1.23 (3H, t, J = 7 Hz), 1.54 (4H, br), 2.25 (4H, br), 4.14 (2H, q, J = 7 Hz), 7.02-7.32 (5H, m), 10.13 (1H, brs). % calculated for C? 5H19N04S: C, 58.23; H, 6.19; N, 4.53% found: C, 57.94; H, 6.10; N, 4.52 Example 7 2- ethyl sulfo-1-cyclohexen-1-carboxylate (2.0 g) obtained in reference example 1 was dissolved in thionyl chloride (5.0 ml) and heated under reflux for 14 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate.

This was combined with ethyl acetate (30 ml) and washed with diluted brine (30 ml x 2) and saturated brine (20 ml) and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting oil was stirred together with a solution of 4-chloro-2-fluoroaniline (0.55 g) in N, N-dimethylformamide (5 ml) at room temperature for 18 hours. The reaction mixture was combined with ice water (100 ml) and ethyl acetate (100 ml) and partitioned. The lime acetate layer was washed with water (80 ml x 2) and dried over anhydrous magnesium sulfate and then the solvent was removed by distillation. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and recrystallized from disiorpopyl ether to yield 2- [N- (4-chloro-2-fluorof nyl) sulfamoyl] -1-cyclohexene - 1-carboxylate (Compound 9; 44 mg) as colorless powdered crystals.

^ -NMR (DMSO-de) d: 1.06 (3H, t, J = 7.2 Hz), 1.62 (4H, br;, 2.25 (2H, br), 2.39 (2H, br), 3.95 (2H, q, J = 7.2 Hz), 7.23-7.37 (2H, m), 7.47-7.52 (1H, m), 10.11 (1H, s). % calculated for d5H17ClFN04S: C, 49. 79; H, 4 74; N, 3 87 % found: C, 49.84; H, 4.76; N, 3.92 Example 8 2-sulfo-1-cyclohexene-1-ethyl carboxylate (0.67 g) obtained in the Reference example 1 was dissolved in thionyl chloride (2.0 ml) and heated under reflux for 8 hours and then the reaction mixture was evaporated under reduced pressure to dryness.

This was combined with ethyl acetate (10 ml) and the resulting mixture was added to a mixture consisting of 4-methoxyaniline (0.37 g), triethylamine (0.42 ml) and ethyl acetate (4 ml) with cooling on ice, and then stirred with ice cooling for 30 minutes and then at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with dilute brine (80 ml), a 10% aqueous solution of phosphoric acid (50 ml) and dilute brine (50 ml x 2) and dried over sulphate. of anhydrous magnesium, and then the solvent was removed by distillation. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/2) and the effluent was concentrated to dryness and the residue was crystallized from ethyl acetate-diisopropyl ether to yield 2- (4-methoxyphenyl) - 4, 5, 6, 7 - tetrahydro- 1,2-benzisothiazole-3- (2H) -ketone 1, 1- dioxide (Compound 67, 40 mg) as crystals similar to colorless needles. The mother liquor was concentrated and purified by chromatography on ODS column (eluent: methanol / water = 7/3) and then the effluent was concentrated under reduced pressure to produce ethyl 2- (N-methoxyphenyl) sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 8; 15 mg ) as a colorless powder.

Compound 8: XH-NMR (DMSO-d6) [: 1.18 (3H, t, J = 7.0 Hz), 1.54, 1.56 (4H, br), 2.25 (4H, br), 3.72 (3H, s), 4.08 ( 2H, q, J = 7.0 Hz), 6.86 (2H, d, J = 8Hz), 7.07 (2H, d, J = 8Hz), 9.79 (1H, brs).

Compound 67: XH-NMR (CDC13) d: 1.70-1.88 (4H, m), 2.41- 2.60 (4H, m), 3.82 (3H, s), 7.11 (2H, d, J = 9.0 Hz), 7.31 ( 2H, d, J = 9.0 Hz). % calculated for C 14 H 15 NO 4 S: C, 57.32; H, 5.15; N, 4. 77 found: C, 57.41; H, 5.01; N, 4.7í Example 9 2- ethyl sulfo-1-cyclohexen-1-carboxylate (0.83 g) obtained in the Reference example 1 was dissolved in thionyl chloride (2.4 ml) and heated under reflux for 8 hours and then the reaction mixture was evaporated under reduced pressure to dryness.

The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate.

This was combined with ethyl acetate (10 ml) and the resulting mixture was added to a mixture consisting of 2-fluoroaniline (0.40 g), triethylamine (0.50 ml) and ethyl acetate (5 ml) with ice-cooling, and then stirred with ice cooling for 30 minutes and then at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with 0.5 N HCl (30 ml) and water (30 ml x 2), and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to yield 6- [N- (2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate of ethyl (Compound 10; 303 mg) as colorless needle-like crystals. 1H-NMR (DMSO- d6) d: 1.07 (3H, t, J = 7.2 Hz), 1.58-1.82 (2H, m), 2.05- 2.46 (4H, m), 4.01 (2H, q, J = 7.2 Hz ), 4.32 (1H, d, J = 4.6 Hz), 7.09-7.32 (4H, m), 7 ^ 44- 7.54 (1H, m), 9.91 (1H, brs). calculated for C? 5H? 8FN04S: C, 55. 03; H, 5 54; N, Four . 2 ' % found: C, 55.09; H, 5.44; N, 4.33 Example 10 2- ethyl sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in the Reference example 1 was dissolved in thionyl chloride (3.0 ml) and heated under reflux for 14 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate.

This was combined with lime acetate (12 ml) and the resulting mixture was added to a mixture consisting of 3-fluoroaniline (0.48 g), triethylamine (0.60 ml) and ethyl acetate (6 ml) with ice-cooling, and then stirred with ice cooling for 30 minutes and then at room temperature for 25 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml) and 0.5 N HCl (50 ml) and water (50 ml x 2) and dried over anhydrous magnesium sulfate, and then the solvent It was removed by distillation. The residue was purified by chromatography with silica gel (eluent: ethyl acetate / hexane = 1/3), and the first effluent was removed by distillation under reduced pressure and the residue was crystallized from diisopropyl ether to yield 6- [N- 3 - fluorophenyl] sulfamoyl) - 1-cyclohexen-1-carboxylic acid ethyl ester (Compound 11: 250 mg) as white powdered crystals.

XH-NMR (DMSO-de) d: 1.16 (3H, t, J = 7.0 Hz), 1.60-1.80 (2H,), 2.00- 2.33 (4H, m), 3.98- 4.15 (2H, m), 4. 37 (1H, d, J = 4.8 Hz), 6.87 (1H, dt, J = 8.4 Hz), 7. 00- 7.17 (3H, m), 7.34 (1H, dt, J = 8.4 Hz, 7.0 Hz), 10.33 (1H, brs). calculated for C? 5H? 8FN04S: C, 55.03 ,; H, 5.54; N, 4. 2' % found: C, 55.09; H, 5.44; N, 4.33 Example 11 2-sulfo-1-cyclohexene-1-ethyl carboxylate (0.72 g) obtained in reference example 1 was dissolved in thionyl chloride (2.1 ml) and heated under reflux for 5 hours and then the reaction mixture was evaporated under reduced pressure to dryness.

The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate. This was combined with lime acetate (10 ml) and the resulting mixture was added to a mixture consisting of 4-fluoroaniline (0.34 g), triethylamine (0.43 ml) and ethyl acetate (4 ml) with ice-cooling, and then stirred with cooling with ice for 30 minutes and then at room temperature for 40 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml) and 0.5 N HCl (30 ml) and water (30 ml x 2) and dried over anhydrous magnesium sulfate, and then the solvent It was removed by distillation. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane =), and the first effluent was removed by distillation under reduced pressure and the residue was crystallized from diisopropyl ether to produce 2- (4-fluorophenyl) - 4- 5, 6, 7-tetrahydro-1,2-benzisothiazole-3- (2H) -ketone 1, 1- dioxide (Compound 68: 33 mg) as white powdered crystals. The second effluent was also removed by distillation under reduced pressure and the resulting residue was crystallized from ethyl acetate-diisopropyl ether to obtain white polka crystals. This was purified by ODS column chromatography (eluent: methanol / water = 7/3), and the effluent was concentrated under reduced pressure to precipitate crystals which were then collected by filtration to yield 6- [N- (4- fluorophenyl) sulfamoyl) - ethyl 1-cyclohexen-1-carboxylate (Compound 12; 36 mg) as cristeles similar to colorless needles. The mother liquor obtained when the first effluent was crystallized from ethyl acetate-diisopropyl ether was concentrated under reduced pressure and then purified by ODS column chromatography. (eluent: methanol / water = 7/3) to yield 2- [N- (4-fluorophenyl) sulfamoyl) -1-cyclohexene-1-carboxylic acid ethyl ester (Compound 18, 25 mg) as colorless powder crystals.

Compound 12: 1E-NMR (DMSO-d6) d: 1.14 (3H, t, J = 7.2 Hz), 1.55- 1.77 (2H, m), 1.98- 2.44 (4H,), 3.97-4.13 (2H, m) , 4.28 (1H, d, J = 4.2 Hz), 7.10- 7.28 (5H, m), 10.03 (1H, brs). % calculated for C? 5H? 8N0S: C, 55.03; H, 5.54; N, 4.28 % found: C, 54.69; H, 5.43; N, 4.38 Compound 18: XH-NMR (DMSO-de) d: 1.20 (3H, t, J = 7.2 Hz), 1.54 (4H, br), 2.25 (4H, br), 4.11 (2H, q, J = 7.2 Hz) , 7.12 (2H, s), 7.16 (2H, s), 10.11 (1H, brs). % calculated for C? 5H18N04S: C, 55.03; H, 5.54; N, 4.28 % found: C, 55.07; H, 5.35; N, 4.33 Compound 68: 1H-NMR (DMSO-d6) d: 1.75-1.88 (4H, m), 2.42- 2.64 (4H, m), 7.40-7.49 (4H, m). % calculated for C? 3H? 2FN03S: C, 55.51; H, 4.30; N, 4.98. % found: C, 55.44; H, 4.24; N, 4.94 Example 12 2-sulfo-1-cyclohexene-1-ethyl carboxylate (1.0 g) obtained in Reference Example 1 was dissolved in thionyl chloride (3.0 ml) and heated under reflux for 12 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate.

This was combined with ethyl acetate (14 ml) and the resulting mixture was added to a mixture consisting of 2,6-difluoroaniline (0.56 g), triethylamine (0.60 ml) and ethyl acetate (6 ml) with ice cooling , and then stirred with cooling with ice for 0 minutes and then at room temperature for 64 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml). The ethyl acetate layer was washed with 0.5 N HCl (100 ml x 2) and a diluted brine (100 ml x 3) and dried under anhydrous magnesium sulfate, and then the solvent was removed by distillation. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/3) and then crystallized from disiopropyl ether to yield 6- [N- (2,6-difluorophenyl) sulfamoyl] -1-cyclohexen- 1 ethyl carboxylate (Compound 13; 135 mg) as colorless powder crystals.

XH-NMR (DMSO-de) d: 1.00 (3H, t, J = 7.0 Hz), 1.59-1.88 (2H, m), 2.08- 2.56 (4H, m), 3.97 (2H, dq, J = 7.0 Hz , 1.4 Hz), 4.39 (1H, d, J = 5.0 Hz), 7.07- 7.25 (3H, m), 7.34-7.50 (1H, m), 9.70 (1H, brs). % calculated for Ci5H? 7F2N04S: C, 52. 17; H, 4 96; H, 4 06 % found: C, 51. 76; H, 4 88; N, 4 04 Example 13 Ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Refectory Example 1 was dissolved in thionyl chloride (3.0 ml) and heated under reflux for 9 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate.

This was combined with ethyl acetate (14 ml) and the resulting mixture was added to a mixture consisting of 2,3-difluoroaniline (0.56 g), triethylamine (0.60 ml) and ethyl acetate (6 ml) with ice cooling , and then stirred with cooling with ice for 30 minutes and then at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml). The ethyl acetate layer was washed with 1N HCl (100 ml x 2) and dilute brine. (100 ml x 3) and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to yield 6- [N- (2,3-difluorophenyl) sulfamoyl] -1-cyclohexenyl- 1-ethyl carboxylate (Compound 14, 310 mg) as colorless powder crystals.

XH-NMR (DMSO-de) d: 1.10 (3H, t, J = 7.0 Hz), 1.58-1.83 (2H, m), 1.98- 2.43 (4H, m), 4.02 (2H, q, J = 7.0 Hz ), 4.38 (1H, d, J = 4.4 Hz), 7.13-7.36 (4H, m), 10.22 (1H, s). % calculated for C15H? 7F2N04S: C, 52. 17; H, 4 96; N, 4 06 % found: C, 52. 18; H, 4 88; N, 4 eleven EXAMPLE 14 Ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was dissolved in thionyl chloride (3.0 ml) and heated under reflux for 24 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate.

This was combined with ethyl acetate (14 ml) and the resulting mixture was added to a mixture consisting of 2,5-difluoroaniline (0.56 g), tritylamine (0.60 ml) and ethyl acetate (6 ml) with ice cooling , and then stirred with cooling with ice for 30 minutes and then at room temperature for 22 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml). The ethyl acetate layer was washed with IN HCl (100 ml x 2) and dilute brine (100 ml x 3) and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane / 1/4) and then crystallized from diisopropyl ether to yield 6- [N-2,5-difluorof nyl) ssulfamoyl] -1-cyclohexen- 1 ethyl carboxylate (Compound 15; 200 mg) as colorless powder crystals.

XH-NMR (DMSO-d6) d: 1.13 (3H, t, J = 7.0 Hz), 1.58-1.82 (2H, m), 2.05- 2.43 (4H, m), 4.04 (2H, q, J = 7.0 Hz), 4.38 (1H, d, J = 33.6 Hz), 6.95-7.07 (1H, m), 7.13- 7.18 (1H, m), 7.25- 7.39 (2H, m), 10.24 (1H, brs). % calculated for C15H17F2NO4S: C, 52. 17; H, 4 96; N, 4 06 % found: C, 52.23; H, 4.86; N, 4.11 Example 15 2- ethyl sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was dissolved in thionyl chloride (3.0 ml) and heated under reflux for 23 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate.

This was combined with ethyl acetate (14 ml) and the resulting mixture was added to a mixture consisting of 3,4-difluoroaniline (0.56 g), triethylamine (0.60 ml) and ethyl acetate (6 ml) with ice cooling , and then stirred with cooling with ice for 30 minutes and then at room temperature for 21 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml). The ethyl acetate layer was washed with IN HCl (100 ml x 2) and dilute brine. (100 ml x 3) and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation. The residue was purified by chromatography with silica gel (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to yield 6- [N- (3,4-difluorophenyl) sulfamoyl] -1-cyclohexen- 1 ethyl carboxylate (Compound 16; 170 mg) as colorless powder crystals.

^ -NMR (DMSO-de) d: 1.16 (3H, t, J = 7.0 Hz), 1.58-1.80 (2H, m), 1.98- 2.42 (4H, m), 3.99- 4.15 (2H, m), 4. 34 (1H, d, J = 3.6 Hz), 6.96- 7.04 (1H, m), 7.13- 7.29 (2H, m), 7.41 (1H, dt, J = 10.6 Hz, 9.0 Hz), 10.29 (1H, brs). % calculated for C15H? 7F2N? 4S: C, 52.17; H, 4.96; N, 4.06 % found: C, 52.29; H, 4.78; N, 4.04 Example 16 Ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference example 1 was dissolved in thionyl chloride (3.0 ml) and heated under reflux for 17 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate.

This was combined with ethyl acetate (14 ml) and the resulting mixture was added to a mixture consisting of 3,5-difluoroaniline (0.56 g), triethylamine (0.60 ml) and ethyl acetate (6 ml) with ice cooling , and then stirred with cooling with ice for 30 minutes and then at room temperature for 21 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml). The ethyl acetate layer was washed with IN HCl (100 ml x 2) and dilute brine (100 ml x 3) and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/3) and then crystallized from diisopropyl ether to yield 6- [3,5-difluorophenyl] sulfamoyl] -1-cyclohexene-1-carboxylate. ethyl (Compound 17; 250 mg) as colorless powder crystals.

XH-NMR (DMSO-de) d: 1.18 (3H, t, J = 7.0 Hz), 1.58-1.82 (2H, m), 11.96-2.44 (4H,), 3.99- 4.16 (2H, m), 4.42 ( 1H, d, J = 4.8 Hz), 6.83-6.95 (3H, m), 7.18 (1H, t, J = 4 Hz), 10.59 (1H, brs). % calculated for C? 5H? 7 2N0 S: C, 52. 17; H, 4 96; N, 4.06 % found: C, 52.22; H, 5.01; N, 4.1 Example 17 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 3, 200 mg) obtained in Example 3 was resolved by high pressure liquid chromatography (CHIRALPAL AD: eluent: hexane / ethanol = 9/1) in two optical isomers to produce 6- [N- (2, 4-difluorof nyl) sulfamoyl] -1- cyclohexen-1-ethyl carboxylate (Compound 19, 62 mg) and 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1- cyclohexen-1-carboxylate of d-ethyl (Compound , 51 mg) each as a white powder.

Compound 19 (40 mg) was crystallized from diisopropyl ether (2 ml) to obtain white powder crystals (26 mg) of Compound 19. 1H-NMR (ds-DMSO) d: 1.07 (3H, t, J = 7.2 Hz), 1.58-1.82 (2H, m), 1.98 2.44 (4H, m), 4.01 (2H, q, J = 7.2 Hz), 4.28 (1H, d, J = 4.5 Hz), 7.04- 7.15 (2H, m), 7.28-7.54 (2H, m), 9.85 (1H, s). % calculated for CI5HI-JF2N04S: C, 52.17; H, 4.96; N, 4.06 % found: C, 52.20; H, 4.85; N, 4.20 [a] 20D-105.7 ° (c = 0.5, in methanol) Compound 20 (35 mg) was crystallized from diisopropyl ether (2 ml) to obtain white powder crystals (18 mg) of compound 20.

XE-NMR (d6-DMSO) d: 1.07 (3H, t, J = 7.2 Hz), 1.58-1.82 (2H, m), 1.98- 2.44 (4H, m), 4.01 (2H, q, J = 7.2 Hz ), 4.28 (1H, d, J = 4.6 Hz), 7.05- 7.15 (2H, m), 7.28-7.55 (2H, m), 9.86 (1H, brs). % calculated for C? 5H1-7F2N04S: C, 52. 17; H, 4 96; N, 4 06 found: C, 52.10; H, 4.83; N, 4.21 [a] 20E + 105. 9 ° (c = 0.5 in methanol) EXAMPLE 18 Ethyl 2-sulfo-1-cyclohexen-1-carboxylate (2.0 g) obtained in reference example 1 was dissolved in thionyl chloride (6 ml) and heated under reflux for 15 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to yield ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate.

This was combined with ethyl acetate (20 ml) and the resulting mixture was added to a mixture consisting of ethyl anthranilate (1.42 g), triethylamine (1.20 ml) and ethyl acetate (12 ml) with ice cooling, and then stirred with cooling with ice for 30 minutes and then at room temperature for 70 hours. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (100 ml), 1 N HCl (100 ml x 2) and dilute brine (100 ml x 3) and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane 1/4) and then crystallized from diisopropyl ether to yield 6- [N- (2-ethoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (Compound 21; 0.44 g) as colorless crystals. lE-NMR (d6-DMSO) d: 1.12 (3H, t, J = 7.2), 1.35 (3H, t, J = 7.2 Hz), 1.62- 1.84 (2H, m), 1.92- 2.35 (4H, m), 3.85-4.10 (2H, m), 4.35 (2H, q, J = 7.2 Hz), 4.50 (1H, d, J = 4.2 Hz), 7.15- 7.23 (2H, m), 7.60-7.72 (2H, m), 8.01 (1H, d, J = 8.0 Hz), 10.42 (1H, s). % calculated for C18H23N06S: C, 56. 68; H, 6. 08; N, 3 67 % found: C, 56.56; H, 6.05; N, 3.68 Example 19 To a solution of 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 3, 300 mg) obtained in Example 3 in methanol (6 ml), concentrated sulfuric acid (0.4 ml) was added and the - mixture was stirred at reflux for 8 days. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with water (30 ml x 2) and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure.

The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane 0 1/5 -> ethyl acetate / hexane = 1/2) and then crystallized from diisopropyl ether to yield 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid ethyl ester (Compound 22, 95 mg) as colorless powder crystals.

? E-NMR (d6-DMSO): 1.58- 1.82 (2H, m), 1.98- 2.42 (4H, m), 3.56 (3H, s), 4.30 (1H, d, J = 4.5 Hz), 7.05-7.15 (2H, m), 7.28-7.55 (2H, m), 9.85 (1H, s). % calculated for C14H15N04S: C, 50. 75; H, 4 56; N, 4 2. 3 % found: C, 50. 79; H, 4 49; N, 4 07 Example 20 To a solution of ethyl 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 3, 300 mg) obtained in Example 3 in 1-propanol (6 ml), acid Concentrated sulfuric acid (0.3 ml) was added and the mixture was stirred at reflux for 50 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with water (30 ml x 2) and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was subjected to chromatography on silica gel (eluent: ethyl acetate / hexane = 1/5) and the desired fractions were concentrated under reduced pressure. The residue was purified by column chromatography on ocatdecylsilyl (ODS) (eluent: methanol / water = 4/1) and then crystallized from diisopropyl ether to yield 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1- cyclohexen - propyl carboxylate (Compound 23, 60 mg) as colorless crystals. 1H-NMR (d6-DMSO) d: 0.79 (3H, t, J = 7. Hz), 1.38-1.82 (4H, m), 2.02- 2.45 (4H, m), 3.91 (2H, t, J = 6.4 Hz), 4.27 (1H, d, J = 4.9 Hz), 7.05-7.12 (2H, m), 7.28-7.53 (2H, m), 9.86 (1H, s). % calculated for C16H19F2N04S: C, 53. 47; H, 5. 33; N, 3.90 % found: C, 53.01; H, 5.34; N, 3.63 Example 21 To a solution of ethyl 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate obtained in Example 1 (Compound 1, 250 mg) in methanol (5 ml), acid Concentrated sulfuric acid (0.2 ml) was added and the mixture was stirred at reflux for 8 hours daily. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with water (30 ml x 2) and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was chromatographed on silica gel (eluent: ethyl acetate / hexane = 1/4) and the desired fractions were concentrated under reduced pressure. The residue was purified by column chromatography over ODS (eluent: methanol / water = 4/1) and then crystallized from diisopropyl ether to yield 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexen Methyl-1-carboxylate (Compound 24, 58 mg) as crystals similar to colorless prisms.

? E-NMR (d6-DMSO) d: .158-1.82 (2H, m), 1.98-2.44 (4H,), 3.56 (3H, s), 4.34 (1H, br), 7.14 (1H, br), 7.25-7.50 (3H, m), 10.04 (1H, brs). % calculated for Ci4H15ClFN04S: C, 48. 35; H, 4 35; N, 4 03 % found: C, 48.27; H, 4 43; N, 4 08 Example 22 To a solution of ethyl 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate obtained in Example 3 (Compound 3, 200 mg) in 2-propanol (4 ml), acid Concentrated sulfuric acid (0.2 ml) was added and the mixture was stirred at reflux for 10 hours daily. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with dilute brine (30 ml x 2) and dried over anhydrous magnesium sulfate and the solvent was removed from 1 distillate under reduced pressure. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to yield 4- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexene- 1 - isopropyl carboxylate (Compound 25, 20 mg) as white powder crystals.

E-NMR (d6-DMSO) d: 1.04 (3H, d, J = 6.4 Hz), 1.09 (3H, d, J = 6.4 Hz), 1.58-1.82 (2H, m), 2.02- 2.45 (4H, m), 4.25 (1H, d, J = 4.8 Hz), 4.83 (1H, quintet, J = 6.4 Hz), 7.05- 7.15 (2H, m) 7.30- 7.54 (2H,), 9.86 (1H, s). % calculated for C? 6H19F2N04S: C, 53.47; H, 5.33; N, 3.90 % found: C, 53.67; H, 5.09; N, 3.77 Example 23 Ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was dissolved in thionyl chloride (3 ml) and heated at reflux for 9 hours and then the reaction mixture was evaporated under reduced pressure to dryness. The procedure involving an addition of hexane (10 ml) followed by evaporation under reduced pressure to dryness was repeated three times to produce ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate.

This was combined with ethyl acetate (12 ml) and the resulting mixture was added to a mixture consisting of ethyl anthranilate (6 ml) with ice cooling, and then stirred with ice cooling for 30 minutes and then at the temperature environment for 24 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml). The ethyl acetate layer was washed with 0.1 N HCl (50 ml x 2) and saturated brine (50 ml) and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation. The residue The residue was purified by flash chromatography (eluent: ethyl acetate / hexane = 1/5) and then crystallized from diisopropyl ether to yield 6- [N- (2-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 26; 190 mg) as pale yellow powder crystals.

XH-NMR (d6-DMSO) d: 1.21 (3H, t, J = 7.0 Hz), 1.68- 2.36 (6H, m), 33.90 (3H, s), 3.93- 4.07 (2H, m), 444.50 (1H ,, d, J = 4.4 Hz), 7.15- 7.23 (2H, m), 7.61-7.69 (2H, m), 8.0 (1H, d, J = 8.8 Hz), 10.39 (1H, s). % calculated for Ci7H23N06S: C, 55.57; H, 5.76; N, % found: C; 55.62; H, 5.76; N, 3.78 Example 24 By the procedure similar to that employed in Example 23, ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was derivatized to 2-chlorosulfonyl-1-cyclohexene-1-carboxylate. ethyl which was then reacted with 2-fluoro-4-methylaniline (0.54 g) to give ethyl 6- [N- (2-fluoro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 27: 223 mg) as colorless powder crystals.

XH-NMR (d6-DMSO) d: 1.08 (3H, t, J = 7.0 Hz), 1.62-1.80 (2H, m), 2.00- 2.43 (4H, m), 2.29 (3H, s), 4.01 (2H , q, J = 7.0 Hz), 4.27 (1H, d, J = 5.0 Hz), 6.97- 7.11 (3H, m), 7.33 (1H, t, J = 8.4 Hz), 9.71 (1H, s). % calculated for Ci6H20FNO4S: C, 56.29; H, 5.90; N, 4.10 % found: C, 56.26; H, 5.80; N, 4.03 Example 25 By the procedure similar to that employed in Example 23, ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was derivatized to 2-chlorosulfonyl-1-cyclohexene-1-carboxylate. ethyl which was then reacted with o-chloroaniline (0.55 g) to produce ethyl 6- [N-chlorophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 28, 0.28 g) as white crystals.

XH-NMR (d6-DMSO) d: 1.05 (3H, t, J = 7.0 Hz), 1.55-1.84 (2H, m), 1.99- 2.58 (4H, m), 4.00 (2H, q, J = 7.0 Hz9 , 4.30 (1H, d, J = 5.2 hz), 7.11 (1H, br), 7.19- 7.39 (2H, m), 7.48- 7.56 (2H, m), 9.66 (1H, s). % calculated for C15H? 6ClN? 4S: C, 52.40; H, 5.28; N, 4.07 % found: C, 52.39; H, 5.28; N, 4.19 Example 26 By the procedure similar to that employed in example 23, ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was derivatized to 2-chlorosulfonyl-1-cyclohexene-1-carboxylate of ethyl and reacted with 2-chloro-4-fluoroaniline (0.62 g) to yield ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 29; 0.35 g ) as white crystals.

? E-NMR (d6-DMSO) d: 1.05 (3H, t, J = 7.0 Hz), 1.52- 1.83 (2H, m), 1.98- 2.46 (4H, m), 4.00 (2H, q, J = 7.0 Hz), 4.29 (1H, d, J = 4.8 Hz), 7.10 (1H, br), 7.20-7.30 (1H, m), 7.49- 7.58 (2H, m), 9.80 (1H, s). % calculated for C? 5H: 7ClFN? 4S: C, 49.79; H, 4 74; N, 3 87 % found: C, 49. 74; H, 4 76; N, 3 98 Example 27 By the procedure similar to that used in Example 23, ethyl 2-sulfo-cyclohexene-1-carboxylate (1.0 g) obtained in reference example 1 was derivatized to 2-chlorosulfonyl-1-cyclohexen-1. ethyl carboxylate which was then reacted with p-chloroaniline (0.54 g) to yield 6- [N- (4-chlorophenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 30, 0.24 g) as white crystals .

? E-NMR (d5-DMS0) d: 1.15 (3H, t, J = 7.0 Hz), 1.51- 1.78 (2H, m), 1.95-2.20 (4H, m), 3.96-4.13 (2H, m), 4. 32 (1H, d, J = 4.0 Hz), 7.13 (1H, t, J = 4.0 Hz), 7.20- 7.24 (2H, m), 7.34- 7.39 (2H, m), 10.17 (1H, s). % calculated for C? 5 HlsClN04S: C, 52. 40; H, 5 28; N, Four . 07 % found: C, 52.33; H, 5.11; N, 3.87 Example 28 By the procedure similar to that used in Example 23, ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was derived to 2-chlorosulfonyl-1-cyclohexene-1-carboxylate from ethyl which was then reacted with 2,3,4-trifluoroaniline (0.63 g) to yield 6- [N- (2, 3, 4-trifluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (Compound 31; 0.36 g) as white crystals.

E-NMR (d6-DMSO) d: 1.11 (3H, t, J = 7.0 Hz), 1.54-1.86 (2H, m), 1.95-2.448 (4H, m), 4.03 (2H, q, J = 7.0 Hz), 4.34 (1H, d, J = 4.4 Hz), 7.13 (1H, br), 7.29-7.35 (2H, m), 10.15 (1H, s). % calculated for C, 449.58; H, 4.44; N, 3.85 % found: C, 449.51; H, 4.35; N, 3.76 Example 29 To a solution of 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate obtained in Example 3 (Compound 3, 200 mg) in isobutyl alcohol (4 ml), a concentrated sulfuric acid (0.2 ml) was added and the mixture was stirred at 80 to 85 C for 7 days. After cooling, the reaction mixture was diluted with ethyl acetate (80 ml) and washed with water (50 ml). The ethyl acetate layer was washed with 5% aqueous sodium bicarbonate solution (50 ml) and water (50 ml x 2), dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to dryness. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to yield 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexen- 1 isobutylcarboxylate (Compound 32, 35 mg) as white crystals.

XH-NMR (d6-DMSO) d: 0.80 (6H, d, J = 6.8 Hz), 1.58-1.84 (2h, m), 2.0- 2.47 (4H, m), 3.35- 3.45 (1H, m), 3.75 (2H, d, J = 6.8 Hz), 4.27 (1H, d, J = 4.8 Hz), 7.03- 7.13 (2H, m), 7.27-7.53 (2H, m), 9.85 (1H, s). % calculated for C? -H23F2N04S: C, 54. 68; H, 5 67; N, 3 75 % found: C, 54.64; H, 5.49; N, 3.78 Example 30 To a solution of ethyl 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate obtained in Example 3 (Compound 3, 180 mg) in 1-butanol (5 ml), a Concentrated sulfuric acid (0.12 ml) was added and the mixture was stirred at 80 to 85 ° C for 7 days. After cooling, the reaction mixture was diluted with ethyl acetate (60 ml) and washed with water (60 ml). The ethyl acetate layer was washed with water (60 ml x 5), dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to dryness. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4) and then crystallized from diisopropyl ether to yield 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexen- 1 -carboxylate (Compound 33, 52, mg) as white crystals.

XH-NMR (d6-DMSO) d: 0.83 (3H, t, J = 7 Hz), 1.18- 1.82 (6H, m), 2.00- 2.42 (4H, m), 3.95 (2H, br), 4.24 (1H , d, J = 4.4 Hz), 7.09 (2H, br), 7.30- 7.49 (2H,), 9.86 (1H, brs). % calculated for Ci7H21F2NO, S: C, 54. 68; H, 5.67; N, 3 75% found: C, 54.64; H, 5.48; N, 4.05 Example 31 By the procedure similar to that employed in Example 23, ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was derivatized to 2-chlorosulfonyl-1-cyclohexene-1-carboxylate. ethyl which was then reacted with 4-bromo-2-fluoroaniline (0.81 g) to yield 6- [N- (4-bromo-2-fluorophenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 34; 0.23 g) as white crystals.

XH-NMR (db-DMSO) d: 1.10 (3H, t, J = 7.0 Hz), 11. 54- 1.83 (2H,), 1.92- 2.46 (4H, m), 4.02 (2H, q, J = 7.0 Hz), 4.32 (1H, d, J = 4.4 Hz), 7.12 (1H, t, J = 4.2 Hz), 7.35-7.48 (2H, m), 7.56- 7.63 (1H, m), 10.04 (1H, s). % calculated for C? 5H? 7BrFN04S: C, 44. 35; H, 4.22; N, 3 Four. Five % found: C, 44. 40; H, 4.25; N, 3 .76 Example 32 By the procedure similar to that employed in Example 23, ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was derivatized to 2-chlorosulfonyl-1-cyclohexene-1-carboxylate. ethyl which was then reacted with 2,4-dichloroaniline (0.69 g) to yield 6- [N- (22, 4 -didlcorphenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 35, 0.24 g) as some white crystals.

^ - MR (d6- DMSO) d: 1.07 (3H, t, J = 7.0 H?), 1.54-1.82 (2H, m), 1.95- 2.45 (4H, m), 4.01 (2H, q, J = 7.0 Hz), 4.32 (1H, d, J = 4.8 Hz), 7.12 (1H, br), 7.40-7.67 (3H, m), 9.81 (1H, brs). % calculated for Cl5H, -C? 2N04S: C, 47.63; H, 4.53; N, 3.70 % found: C, 47.67; H, 4.59; N, 3.89 Example 33 2- acetaminophen (0.29 g) was dissolved in ethyl acetate (2.4 ml) and the resulting solution was mixed with triethylamine (0.46 ml) with ice cooling, and then a solution of 2-chlorosulfonyl-1-cyclohexen-1-carboxylate of ethyl (0.42 g) obtained in Reference Example 2 in ethyl acetate (4.8 ml) was added dropwise. The reaction mixture was stirred under a nitrogen atmosphere at 0 ° C for 30 minutes and then at room temperature for 20 hours.

The reaction mixture was diluted with ethyl acetate and washed successively with water (40 ml), hydrochloric acid (40 ml), water (40 ml x 2) and then saturated brine (40 ml). The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/4). A desired fraction was concentrated and the residue was crystallized from a mixture of lime acetate and hexane to yield ethyl 6- [N- (2-acetoxyphenyl) sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 36, 0.25 g) like white crystals.

XH-NMR (d6-DMSO) d: 1.12 (3H, t, J = 7.0 H?), 1.58-1.83 (2H, m), 1.90-2.40 (4H, m), 2.68 (3H, s), 3.88- 4.06 (2H, m), 4.48 (1H, d, J = 4.4 Hz), 7.17-7.26 (2H, m), 7.65-7.71 (2H, m), 8.09- 8.13 (1H, m), 11.31 (1H, s). % calculated for Ci H21N05S: C, 58.10; H, 6.02; N, 3. 99 % found: C, 58.12; K, 5.93; N, 4.10 Example 34 By the procedure similar to that employed in Example 23, ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in Reference Example 1 was derivatized to 2-chlorosulfonyl-1-cyclohexene-1-carboxylate. ethyl which was then reacted with m-chloroaniline (0.54 g) to yield 6- [N- (3-chlorophenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 37; 0.15 g) as white crystals. 1E-NMR (from DMSO) d: 1.16 (3H, t, J = 7.0 Hz), 1.54-1.81 (2H,), 1.94- 2.38 (4H, m), 4.00- 4.15 (2H, m), 4. 36 (1H, d, J = 4.4 Hz), 7.07 (1H, br), 7.11- 7.37 (4H, m), 10.29 (1H, s). % calculated for Ci5H16ClN04S: C, 52.40; H, 5.28; N, 4.07 % found: C, 52.44; H, 5.21; N, 4.32 Example 35 By the procedure similar to that used in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.42 g) obtained in Example 2 was reacted with 2,3-dichloroaniline (0.35 g) to produce 6- [N- (2, 3-dichlorophenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 38, 0.23 g) as white crystals.

XH-NMR (d6-DMSO) d: 1.08 (3H, t, J = 7.0 Hz), 1.55- 1.86 (2H, m), 1.97- 2.46 (4H, m), 4.01 (2H, q, J = 7.0 Hz ), 4.36 (1H, d, J = 4.8 Hz), 7.13 (1H, br), 7.32-7.56 (3H, m), 9.87 (1H, s). ? calculated for C15H17C12N04S: C, 47.63; H, 4.53; N, 3.70 % found: C, 47.43; H, 4.33; N, 4.02 Example 36 By the procedure similar to that used in example 23, ethyl 2-sulfo-1-cyclohexen-1-carboxylate (1.0 g) obtained in reference example 1 was derived from 2-cyosulfonyl-1-cyclohexene-1-carboxylate of ethyl which was then reacted with o-ethylaniline (0.52 g) to yield ethyl 6- [N- (2-ethylphenyl) sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 39; 0.20 g) as white crystals.

XH NMR (d6-DMSO) d: 1.06 (3H, t, J = 7.0 Hz), 1.16 (3H, t, J = 7.6 Hz), 1.52- 1.86 (2H, m), 1.99- 2.50 (4H, m), 2.72 (2H, q, J = 7.6 Hz), 4.01 (2H, q, J = 7.0 Hz), 4.39 (1H, d, J = 4.8 Hz), 7.10 (1H, br), 7.16-7.38 (4H, m), 9.18 (1H, s). % calculated for C? -? 23N04S: C, 60.51; H, 6.87; N, 4.15 % found: C, 60.15; H, 6.70; N, 4.10 EXAMPLE 37 By the procedure similar to that employed in Example 33, 2-ethylhexyl-1-cyclohexen-1-carboxylate of eethyl (0.42 g) obtained in Reference Example 2 was reacted with 4- (2H-1, 2, 3- triazole-2-yl) aniline (0.35 g) to produce 6- [N- [4- (2H-1,2,3-triazol-2-yl) phenyl) sulfamoyl] -1- cyclohexen-1-carboxylate of ethyl (Compound 40; 0.48 g) as white crystals.

^ -NMR (de-DMSO) d: 1.15 (3H, t, J = 7.0 Hz), 1.55-1.80 (2H, m), 2.02- 2.44 (4H, m), 4.00- 4.15 (2H, m), 4.38 (1H, d, J = 4.4 Hz), 7.15 (1H, br), 7.39 (2H, d, J = 9.2 Hz), 7.96 (2H, d, J = 9.2 Hz), 8.08 (2H, s), 10.29 (1H, s). % calculated for C? -? H2oN404S: C, 54. 24; H, 5 36; N, 14 88 found: C, 54.38; h, 5.10; N, 15.01 Example 38 By the procedure similar to that used in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.41 g) obtained in Reference Example 2 was reacted with 2,5-dichloroaniline (0.34 g) to produce 6- [N- (2, 5-dichlorof nyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 41, 0.21 g) as white crystals.

? E- NMR (de-DMSO) d: 1.10 (3H, t, J = 7.0 H?), 1.57-1.85 (2H, m), 1.96- 2.45 (4H, m), 4.04 (2H, q, J = 7.0 Hz), 4.36 (1H, d, J = 4.4 Hz), 7.15 (1H, br), 7.25-7.31 (1H,), 7.51- 7.59 (2H, m), 9.90 (1H, s). % calculated for C15H17C12N04S: C, 47. 63; H, 4 53; N, 3 70 % found: C, 47.75; H, 4.66; N, 3.80 Example 39 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.40 g) obtained in Reference example 2 was reacted with 2-trifluoromethoxyaniline (0.37 g) to produce 6- [N- (2- trifluoromethoxyphenyl) sulfamoyl] -1-cyclohexen-1-carboxylic acid ethyl ester (Compound 42; 316 mg) as colorless powder crystals.

XH-NMR (d6-DMSO) d: 1.10 (3H, t, J = 7.0 Hz), 1.54 -1.80 (2H,), 2.00- 2.51 (4H, m), 4.04 (2H, q, J = 7.0 Hz) , 4.38 (1H, d, J = 5.2 Hz), 7.13-7.40 (4H, m), 7.59-7.64 (1H, m), 10.02 (1H, s). % calculated for Ci6HlsF3N? 5S: C, 48.85; H, 4.61; N, 3.56 % found: C, 48.92; H, 4.62; N, 3.81 Example 40 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.40 g) obtained in reference example 2 was reacted with 2,4,5-trifluoroaniline (0.31 g) to produce ethyl 6- (N- (2, 4, 5-trifluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 43; 0.30 g) as white crystals.

XH-NMR (d6-DMSO) d: 1.13 (3H, t, J = 7.0 Hz), 1.55- 1.85 (2H, m), 1.96-2.48 (4H, m), 4.05 (2H, q, J = 7.0 Hz ), 4.35 (1H, d, J = 4.4 Hz), 7.14 (1H, br), 7.47-7.71 (2H, m), 10.17 (1H, s). % calculated for C? 5H16F3N04S: C, 449.58; H, 4.44; N, 3.85 % found: C, 49.83; H, 4.32; N, 4.01 Example 41 By the procedure similar to that used in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.41 g) obtained in Reference Example 2 was reacted with 4- (2H-tetrazol-2-yl) aniline (0.34 g) to produce ethyl 6- [N- [4- (2H-tetrazol-2-yl) phenyl) sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 44, 0.45 g) as white crystals.

? E-NMR (d6-DMSO) d: 1.15 (3H, t, J = 7.0 H?), 1.57- 1.85 (2H, m), 1.97- 2.45 (4H, m), 3.98-4.14 (2H,), 4.42 (1H, d, J = 4.4 Hz), 7.17 (1H, br), 7.46 (2H, d, J = 9.2 Hz), 8.04 (2H, d, J = 9.2 Hz), 9.20 (1H, s), . 5 (1H, s). % calculated for C? GH? 9Ns04S: C, 50.92; H, 5.07; N, 18.56 % found: C, 51.05; H, 5.24; N, 18.50 Example 42 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.42 g) obtained in Reference Example 2 was reacted with 2-chloro-4-methylaniline (0.31 g) to produce 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 45: 0.27 g) as white crystals.

XH-NMR (de-DMSO) d: 1.06 (3H, t, J = 7.0 H?), 1.51-1.83 (2H, m), 1. 99- 2.46 (4H, m), 2.29 (3H, s), 4.00 (2H, q, J = 7.0 Hz), 4. 29 (1H, d, J = 5.4 Hz), 7.08- (1H, br), 7.12-7.16 (1H,), 7.33- 7.41 (2H, m), 9.53 (1H, .s). % calculated for C? 6H2oClNO, S: C, 53.70; H, 5.63; N, 3.91 % found: C, 53.67; H, 5.61; N, 3.97 Example 43 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.41 g) obtained in Reference example 2 was reacted with 4-fluoro-2-methylaniline (0.26 g) to produce 6- [N- (4-fluoro-2-methylphenyl) sulfamoyl] -1-cyclohexen-1-carboxylate < (Compound 46; 0.36 g) as white crystals.

XH-NMR (de-DMSO) d: 1.06 (3H, t, J = 7.0 Hz), 1.56-.84 (2H, m), 2.00- 2.46 (4H, m), 2. 31 (3H, s), 4.01 (2H, q, J = 7. 0 Hz), 4.30 (1H, d, J = 5.0 Hz), 6.96- .13 (3H, m), 7.32-7.39 (1H, m), 9.24 (1H , S). % calculated for C? CH2? FN04? : C, 56 29; H, 5 90; N, 4 10 found: C, 56.33; H, 5.90; 3.93 Example 44 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.41 g) obtained in Reference example 2 was reacted with 2,6-dichloroaniline (0.34 g) to produce 6- [N- (2, 6-dichlorophenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 47; 0.05 g) as white crystals.

XH-NMR (d6-DMSO) d: 1.03 (3H, t, J = 7.0 Hz), 1.55-1.90 (2H, m), 2.03- 2.64 (4H, m), 3.94- 4.04 (2H.m), 4.65 (1H, d.J = 5.6 Hz), 7-.06 (1H, br), 7.32- 7.40 (1H, m), 7.54-7.58 (2H, m), 9.77 (1H, S). % calculated for C? 5H17C? 2N04S: C, 47. 63; H, 4 53; N, 3 70 % found: C, 47.76; H, 4.49; N, 3.54 Example 45 By the procedure similar to that used in the Example33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.40 g) obtained in Reference Example 2 was reacted with 4- (] H-tetrazol-1-yl) aniline (0.33 g) to produce 6. - [N- [4- (1H-tetrazol-1-yl) phenyl) -sulfonyl] -1-cyclohexen-1-carboxylic acid ethyl ester (Compound 48, 0.45 g) as white crystals. 1 H-NMR (d6-DMSO) d. 1.17 (3H, t, J = 7.0 HZ), 1.56-1.83 (2H, m), 1. 98- 2. 46 (4H,), 3. 99- 4.16 (2H, m), 4.41 (1H, d, J = 4. 2 Hz), 7.17 (1H, br), 7. 42 (2H, d, J = 9.0 Hz), 7.85 (2H, d, J = 9.0 Hz), 10.01 (1H, s), 10.45 (1H, s). % calculated for C? bH? 9N504S: C, 50.92; H, 5.07; N, 18.56 % found: C, 50.89; H, 5.12; N, 18.47 Example 46 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.39 g) obtained in Reference Example 2 was reacted with 4- (1H-1, 2, 3- triazol-1-yl) aniline (0.36 g) to produce 6- [N- [4- (1 H-1, 2, 3-triazol-1-yl) phenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 49: 0.41 g) as white crystals.

^ -H-NMR (d6-DMSO) d: 1.17 (3H, t, J = 7.0 H?), 1.57-1.82 (2H, m), 1. 98- 2.41 (4H, m), 4.02-4.12 (2H , m), 4.40 (1H, d, J = 4.6 Hz), 7.16 (1H, br), 7.40 (2H, d, J = 8.8 Hz), 7.84 (2H, d, J = 8.8 Hz), 7.93 (1H, s), 8.73 (1H, s), 10.34 (1H, s). % calculated for C17H2oN4? 4S: C, 54. 24; H, 5 36; N, 14 88 % found: C, 54.35; H, 5.37; N, 14.96 Example 47 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.37 g) obtained in Reference Example 2 was reacted with 2-trifluoromethylaniline (0.31 g) to produce 6- [N- (2-trifluoromethylphenyl) sulfamoyl] -1-cyclohexen-1-carboxylic acid ethyl ester (compound 50, 0.17 g) as a colorless oil.

XH-NMR (de-DMSO) d: 1.08 (3H, t, J = 7.0 HZ), 1.54-1.87 (2H, m), 1.99- 2.42 (4H, m), 4.03 (2H, q, J = 7.0 Hz ), 4.49 (1H, d, J = S.0Hz), 7.15 (1H-, br), 7.44- 7.52 (1H,), 7.64-7.70 (3H, m), 9.53 (1H, s).

MS (m /?); 3.78 (MH +) Example 48 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.41 g) obtained in the Referecnia 2 example was reacted with p-aminobenzoate (0.32 g) to produce 6- [N- (4-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 51; 0.46 g) as white crystals.

'H-NMR (de-DMSO) d: 1.14 (3H, t, J = 7. 0 Hz), 1.56- 1.85 (2H,), 1.99- 2.40 (4H, m)', 3.83 (3H, s), 3.96-4.13 (2H, m), 4.42 (1H, d, J = 2. 2 Hz), 7. 17 (1H, br) , 7. 31 (2H, d, J = 8.8 Hz), 7.90 (2H, d, J = 8.8 Hz), . 54 (1H, s). % calculated for C1H21 O6S: C, 55.57; H, 5.76; N, 3.81.

Example 49 To a solution of sodium 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (80 mg) obtained in Reference Example 12 in N, N-dimethylformamide (1 ml), Benzyl bromide (50 ng) was added with ice cooling, and the mixture was stirred at 0 ° C for 4 hours and then at room temperature for 17 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml). The ethyl acetate layer was washed with water (20 ml x 2) and dried over anhydrous magnesium sulfate and the solvent was removed from the distillate under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane 1/4) and crystallized from diisoprcpyl ether to yield 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate of benzyl (Compound 52, 14 mg) as white powder crystals.

XH-NMR (dd-DMSO) d.- 1.55- 1.83 (2H, m), 1.98- 2.44 (4H, m), 4.30 (1H, d, J = 4.2 Hz), 5. 00 (1H, d, J = 13 Hz), 5.11 (1H, d, J = 13 Hz), 6.93- 7.04 (1H, m), 1. -17 (1H, t, J = 4 Hz), 7.24-7.51 (7H, m), 9.88 (1H, S). % calculated for C2UH? sF2N04S: C, 58. 96; H, 4 70; N, 3 44 % found: C, 58. 67; H, 44 70; N, 3 49 Example 50 By the procedure similar to that used in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexen-1-carboxylane (0.4 g) obtained in Reference Example 2 was reacted with 4- [2, 3- bis (t- butoxycarbonyl) guanidinomethyl] aniline (0.71 g) to yield ethyl 6- [N- [4- [2-, 3- bis (t-butocarbonyl) guanidinomethyl] phenyl] sulfamoyl] -1-cyclohexen-1-carboxylate (Compound 53 : 492 mg) as a white powder XH-NMR (d6-DMS0) d: 1.15 (3H, t, J = 6.8 Hz), 1.40 (9H, S), 1.48 (9H, m), 1.50- 1.64 (2H, m), 2.13- 2.32 (4H, m), 3.97- 4.19 (2H, m), 4.32 (1H, d, J = 4.0 Hz), 4. 46 (2H, d, J = 5.4 H?), 7.11 (1H, t, J = 4.0 H?), 7.21 (2H, d, J = 9.2 Hz), 7.26 (2H, d, J = 9.2 Hz), 8.60 (1H, t, J = 5.4 Hz), 10.01 (1H, s), 11.52 (1H, S). % calculated for C27H4oN4OsS: C, 55. 84; H, 6 94; N, 9 65 % found: C, 55.52; H, 6.95; N, 9 42 Example 51 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.40 g) obtained in Reference example 2 was reacted with methyl 3-chloro-4-aminobenzoate methyl ester (0.39 g) to yield 6- [N- (2-chloro-4-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexen-1-ethyl carboxylate (Compound 54: 0.20 g) as white crystals.

XH-NMR (de-DMSO) d: 1.10 (3H, t, J = 7.0 HZ), 1.56-1.85 (2H, m), 1.99- 2.43 (4H, m), 3.86 (3H, s), 4.02 (2H, q, J = 7.0 Hz), 4. 44 (1H, d, J = 4.0 Hz), 7.18 (1H, br), 7.71 (1H, d, J = 8.4 H ?), 7.88 (1H, dd, J = 8.4 Hz, 1.8 Hz), 7.97 (1H, J, J = 1.8 Hz), 9.96 (1H, S). % calculated for C? 7H20ClN06S: C, 50.81; H, 5.02; N, 3.49 • •% found: C, 50.79; H, 4.98; N, 3.45 Example 52 By the procedure similar to that used in example 33, 2-chlorosulfonyl-1-cyclohexene-1-ethyl carboxylate (0.41 g) obtained in Reference example 2 was reacted with 4-amino-3-chlorobenzonitrile (0.32 g) to produce ethyl 6- (N- (2-chloro-4-cyanophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 55; 0.16 g) as white crystals.

XH-NMR (d6-DMSO) d: 1.12 (3H, .t, J = 7.0 Hz), 1.56- 1.84 (2H, m), 1.95- 2.42 (4H, m), 4.03 (2H, q, J = 7.0 Hz), 4.46 (1H, d, J = 4.8 Hz), 7.20 (1H, br), 7.70- 7.84 (2H, ra), 8.07 (1H, br), 10.09 (H, s). % calculated for C? 6H17ClN204S: C, 52. 10; H, 4 65; N, 7 60 % found: C, 52.15; H, 4.62; N, 7.46 Example 53 To a solution of sodium 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (100 mg) obtained in Reference Example 12 in N, N-dimethylformamide (2 ml), 2-bromoethanol (81 mg) was added with cooling on ice, and the mixture was stirred at room temperature for 72 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (30: 1). The ethyl acetate layer was washed with 5% aqueous sodium bicarbonate solution (30 ml) and saturated brine (30 ml) and dried over anhydrous magnesium sulfate and the solvent was removed from the solvent under reduced pressure. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/1) and crystallized from diisopropyl ether to yield 6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1 - 2-hydroxyethyl carboxylate (Compound 56, 35 mg) as white powder crystals.

XH-NMR (de-DMSO) d.- 1.58- 1.81 (2H, m), 2.00- 2.42 (4H, m), 3.51 (2H, br), 4.00 (2H, t, J = 5.0Hz), 4.34 (1H, d, J = 4.4 Hz), 4.77 (1H, br), 7.02-7.20 (2H, m), 7.26-7.37 (1H, m), 7.44- 7.56 (1H,), 9.82 (1H, br) . % calculated for C? 5 H 17 F 2 N 0 5 S: C, 49.86; H, 4.74; N, 3.88 % found: C, 49.65; H, 4.79; N, 3.94 Example 54 By the procedure similar to that used in Example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.40 g) obtained in Reference Example 2 was reacted with 2-chloro-4- (1H-1, 2,4-triazol-1-yl) aniline (0.37 g) to produce 6- [N- [2-fluoro-4- (1 H-1, 2, 4-triazol-1-yl) phenyl) sulfamoyl] - 1 - ethyl cyclohexene-1-carboxylate (Compound 57; 0.33 g) as white crystals.

XH-NMR (d6-DMSO) d. 1.08 (3H, t, J = 7.0 Hz), 1.50- 1.69 (2H, m), 1.86- 2.44 (4H, m), 4.00 (2H, q, J = 7.0 Hz), 4.32 (1H, d, J = 4.4 Hz), 7.10 (1H, br), 7.38- 7.47 (1H, m), 7.60 (1H, dd, J = 9.2 Hz, 3.0 Hz), 7.70 (1H, dd, J = 9.2 Hz, 5.4 Hz), 8.30 (1H, s), 8.99 (1H, s), 9. 64 (1H, s). % calculated for C? 7H19FN404S: C, 51.77; H, 4.86; N, 14.20 % found: C, 51.51; H, 5.01; B, 14.06 Example 55 A solution of ethyl 2-chlorosulfonyl-1-cyclopentene-1-carboxylate (0.14) obtained in reference example 3 in ethyl acetate (2 ml) was added to a mixture of 2,4-difluoroaniline (0.1 g), triethylamine (0.17 ml) and ethyl acetate (2 ml) with cooling on ice, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with 0.5 N HCl (30 ml x 2) and saturated brine (30 ml) and dried over anhydrous sodium sulfate and then the solvent was removed by distillation. The residue was subjected to flash chromatography on silica gel (eluent: ethyl acetate / hexane - 1/5) and the solvent in the first effluent was removed from the distillate to produce 2- [N- (2, 4- dicfluorophenyl) sulfamoyl] Ethyl-1-cyclopentene-1-carboxylate (Compound 66, 16.2 mg) as a brown oil. After distilling off the solvent in the second extracted effluent, the residue was crystallized from di-propyl ether to produce 5- [N- (2, 4-dilfuorophenyl) sulfamoyl] -1-cyclopentene-1-ethyl carboxylate (Compound 58 , 22. 8 mg) as colorless powder crystals.

Compound 58": 1H-NMR (d6-DMSO) d: 1.14 (3H, t, J = 7.0 Hz), 2.26- 2.74 (4H, m), 4.06 (2H, q, J = 7.0 Hz), 4.50 (1H, d, J = 8.0 Hz), 7.02- 7.13 (2H, m), 7.24-7.52 (2H, m), 9.79 (1H, S). % calculated for Ci4H, 5F2N04S: "C, 50.75; H, 4.56; N, 4. 2. 3 % found: C, 50.64; H, 4.51; N, 4.115 Compound 66 ': : H-NMR (CDCle) d: 1.34 (3H, t, J = 7.0 H?), 1.93 (2H, quintet, J = 7.6 Hz), 2.69- 2.88 (4H,), 4.32 (2H, q, J = 7.0 Hz), 6.79-6.93 (2H, m), 7.50- 7.62 (1H, m), 7.96 (1H, S).

Example 56 To a solution of 6- [N- (2, 4-difluoro-phenyl) sulfamoii] -1-cyclohexene-1-sodium carboxylate (112 mg) obtained in Reference Example 12 in N, N-dimethylformamide (2 ml), t-butyl bromoacetate (98 mg) was added with cooling on ice and the mixture was stirred at room temperature for 43 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (30 ml).

The ethyl acetate layer was washed with water (30 ml) and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure.

The residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/3) to yield [6- [N- (2, 4- dilfuorof nyl) sulfamoyl] -1- cyclohexen-1-yl] carbonyl-oxyacetate (Compound 59, 118 mg) as white powder crystals.

HH-NMR (de-DMSO) d- 1. 40 (9H, s), 1. 59- 1.85 (2H, m), 2.01- 2.46 (4H, m), 4.30 (1H, d, J = 5. O Hz), 4.50 (2H, s), 7.04-7. 14 (1H, m), 7.21-7.54 (3H, m), 9.84 (1H, s).

Example 57 To a solution of t-butyl [6- [N- (2, 4-dilfuorophenyl) sulfamoyl] -1-cyclohexen-1-yl] carbonyloxyacetate (Compound 59, 80 mg) obtained in Example 56 in ethyl acetate ( 4: 1), a solution of 4N hydrogen chloride in ethyl acetate (5 ml) was added with cooling on ice and the mixture was stirred at room temperature for 70 hours. The reaction mixture was evaporated under reduced pressure to dryness and the residue was purified by column chromatography on ODS. { eluent: methanol / water = 3/2) to yield [6- [N- (2, 4-dilfuorophenyl) sulfamoyl] -1-cyclohexen-1-yl] carbonyloxyacetic acid (Compound 60, 25 mg) as white powder crystals .

^ - R (de-DM? O) d. 1.60- 1.82 (2H, m), 1. 98- 2.42 (4H, m), 4.32 (1H, d, J = 4.4Hz), 4.52 (2H, s), 7.03-7. 13 (1H, m), 7.21- 7.54 (3H,), 10.02 (1H, .br), 13.0 (1H, br).

SIMS: 375 (M? Example 58 A solution of ethyl 2-chlorosulfonyl-1-cyclopentene-1-carboxylate (0.56 g) obtained in Reference Example 4 in ethyl acetate (3.5 ml) was added to a mixture of 2,4-difluoroaniline (0.35 g) , triethylamine (0.42 ml) and ethyl acetate 82 ml) with cooling on ice, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with 0.5 N HCl (30 ml x 2) and saturated brine 830 ml) and dried over anhydrous sodium sulfate and then the solvent was removed by distillation. The residue was subjected to flash column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/8) and column chromatography on ODS (eluent: acetonitrile / water = 6/4) and then crystallized from hexane to produce 7- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclopentene-1-ethyl carboxylate (Compound 61, 25.7 mg) as colorless powder crystals.

XH-NMR (de-DMSO) d. : 1. 1 2 (3H, t, J = 7. O Hz), 1. 60- 1.90 (3H, m), 2.02- 2.73 (5H, m), 4.03 (2H, q, J = 7. 0 Hz), 4.74 (1H, t, J = 4.0 Hz), 7.07 (1H, .t, J = 9.0 Hz), 7.26-7.35 (1H, m), 7.42- 7.54 (2H, m), 9.84 (1H , s). % calculated for C? 6H19F2N04S: C, 53.47; H, 5.33; N, 3.90 % found: C, 53.52; H, 5.09; N, 3.93 Example 59 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.30 g) obtained in Reference Example 2 was reacted with N- (4-amino-3-chlorobenzoyl) t-butyl glycinate (0.41 g) to yield 6- [N- [2-chloro-4- (N- t -butoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (Compound 62; 0.18 g ) as white crystals.

XH-NMR (de-DMSO) d: 1.10 (3H, t, J = 7.0 Hz), 1.42 (9H, s), 1. 55- 1.86 (2H, m), 1. 98- 2. 46 ( 4H, m), 3. 90 (2H, d, J = 5. 8Hz), 4.03 (2H, q, J = 7. O Hz), 4. 41 (1H, d, J = 4. 2 Hz), 7. 16 (1H, br), 7.65 (1H, d, J = 8.4 Hz), 7.83, (1H, dd, J = 8.4 Hz, 1.8 Hz) , 7.98 (1H, d, J = 1.8 Hz), 8.95 (1H, br), 9.89 (1H, s). % calculated for C22H2? C1N207S: C, 449.58; H, 4.44; N, 3.85 % found: C, 49.51; H, 4.35; N, 3.76 Example 60 6- [N- [2-chloro-4- (N- t -butoxycarbonylmethylcarbamoyl) phenylethyl] sulfamoyl] -1-cyclohexen-1-ethyl carboxylate 823 mg) was dissolved in ethyl acetate (0.5 ml) and then mixed with a 4N solution of hydrogen chloride in ethyl acetate (1.8 ml) and the mixture was stirred at room temperature for 51 hours. The reaction mixture was diluted with ethyl acetate and washed 2 times with saturated brine. The ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane = 11: 14) to yield 6- [N- [2-chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] - 1 ethyl cyclohexene-1-carboxylate (Compound 63: 18 mg) as a colorless oil.

XH-NMR (de-DMSO) d: 1.10 (3H, t, J = 7. OH Z), 1.21 (3H, t, J = 7.0 Hz), 1.57- 1.84 (2H, m), 1.91- 2.38 (4H, m), 3.98- 4.08 (4H, m), 4.12 (2H, q, J = 7.0 Hz), 4.41 (1H, d, J = 4.4 Hz), 7.16 (1H, br), 7.66 (1H, d, J = 8.5 Hz), 7.83 (1H, dd, J = 8.5 Hz, 1.8 Hz), 7.99 (1H, d, J = 1. 8 Hz), 9.04 (1H, br), 9.89 (1H, s).

Example 61 By the procedure similar to that used in example 55, 2-chlorosulfonyl-1-cyclopentene-1-ethyl carboxylate (0.39 g) obtained in reference example 3 was reacted with 2-chloro-4-fluoroaniline (0.31 g) to produce 5- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclopentene-1-carboxylic acid ethyl ester (Compound 64, 134 mg) as pale yellow crystals.

XH-NMR (d6-DMSO) d: 1.15 (3H, t, J = 7.0 H?), 2.22- 2.74 (4H, m), 4.07 (2H, q, J = 7.0 Hz), 4.50 (1H. J = 8.0 Hz), 7.10 (1H, S), 7.18- 7.28 (1H, m), 7.47- 7.56 (2H, m), 9.70 (1H, s). % calculated for C? 4H? 5ClFN04S: C, 48.35; H, 4.35; N, 4.03 % found: C, 48.42; H, 4.07; N, 4.04 Example 62 By the procedure similar to that used in example 33, 2-chlorosulfonyl-1-cyclohexene-1-ethyl carboxylate (0.41 g) obtained in Reference Example 2 was reacted with 4- (2, 2, 3, 3, 3, -pentafluoropropoxy) aniline (0.87 g) to produce 1, 1- 2- [4- (2, 2, 3, 3, 3-pentafluoropropoxy) phenyl] -4,5,6,7-tetrahydro-1 dioxide, 2- benzcisothiazole-3- (2H) -ketone (Compound 69; 0.09 g) as white crystals.

XH-NMR (de-DMSO) d-. 1.69-1.91 (4H,). 2.38- 2.54 (4H.m), 4.92 (2H, t, J = 7.4 Hz), 7.26 (2H, d, J = 7.2 Hz), 7.38 (2H, d, J = 7.2Hz). % calculated for C? 6H? 4F5N04S: C, 46.72; H, 3.43; N, 3.41 % found: C, 46.79; H, 3.38; N, 3.29 Example 63 By the procedure similar to that used in example 58, ethyl 2-chlorosulfonyl-1-cyclopentene-1-carboxylate (0.38 g) obtained in Reference example 4 was reacted with 2-chloro-4-fluoroaniline (0.27 g) to produce ethyl 7- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohepten-1-carboxylate (Compound 65, 19 mg) as pale-yellow powder crystals.

XH-NMR (de-DMSO) d-. 1. 23 (3H, t, J = 7. O Hz), 1. 19-1.38 (1H, m), 1.67-1.81 (3H, m), 2.02- 2.15 (1H, m), 2.15- 2.76 (3H, m), 4.05 (2H, q, J = 7. O Hz), 4. 80 (1H, t, J = 4. 6 Hz), 7. 17-7. 27 (1H, m), 7.44-7.59 (3H, m), 9.59 (1H, s). % calculated for C? 6H19ClFNO, S: C, 51.13; H, 5.10; N, 3.73% found: C, 51.16; H, 5.19, N, 3.89 Example 64 To a solution of N-methylmorpholine (41 mg) in N, N-dimethylformamide (1.5 ml), a solution of 6- [N- (2,4-dilfuorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid (64 mg) obtained in Reference Example 12 in N was added. N-dimethylformamide (1 ml) with cooling on ice. To this mixture, a solution of 1-hydroxybenzotriazole (41 mg) in N, N-dimethylformamide (0.5 ml) and dichlorohexylcarbodiimide (52 mg) were added and the mixture was stirred with cooling on ice for 1 hour and then at room temperature for 16 hours. The reaction mixture was combined with ethyl acetate (20 ml) and the insolubles were removed from the filtrate. The filtrate was washed successively with a 10% aqueous solution of phosphoric acid (20 ml), water (20 ml), water (20 ml) and then saturated brine (20 ml) and dried over anhydrous magnesium sulfate and the solvent was withdrawn from the distillate at reduced pressure. The residue was combined with ethyl acetate (83 ml) and the insolubles were removed from the filtrate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (eluent: ethyl acetate / hexane = 1/2) and crystallized from diisopropyl ether to give 1- (2-4) dioxide. difluorophenyl) - 5, 6, 7, 7a-tetrahydro-1, 2-benzoisothiazol-3 (2H) -ketone (Compound 70, 25 mg) as white powder crystals. 1H-NMR (de-DMSO) d: 1.59-1.82 (2H,), 1.98- 2.06 (1H, m), 2.37-2.46 (3H, m), 4.84-4.91 (1H, m), 7.17-7.37 (2H , m), 7.49- 7.65 (2H, m).

Example 65 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (11.8 g) obtained in Reference example 2 was reacted with 2-chloro-4-fluoroaniline (8.84 g). ) to produce 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid ethyl ester (Compound 29, 11.3 g) as white crystals.

This substance was physicochemically identical with the compound 29 obtained in Example 26.

Example 66 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (Compound 29, 2.01 g) obtained in Example 65 was resolved by high pressure liquid chromatography (CHIRALPAK AD; eluent: hexane / ethanol = 9/1) in two optical isomers to yield 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl-1-carboxylate (Compound 71, 979 mg ) and 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-d-ethyl carboxylate (Compound 72, 959 mg) as an oil, respectively.

Compound 71 (833 mg) was crystallized from a mixture of diisopropyl ether and hexane to obtain crystals similar to colorless prisms (681 mg) of Compound 71.

XH-NMR (de-DMSO) d- 1.05 (3H, t J = 7.0 Hz), 1.55-1.84 (2H, m), 1.96-2.43 (4H, m), 4.00 (2H, q, J = 7.0 Hz), 4.29 (1H, d, J = 5.0 H?), 7.10 (1H, br), 7.20-7.30 (IR, m), 7.50-7.58 (2H, m), 9.73 (1H, s). % calculated for C15H17C1FN04S: C, 49.79; H, 4.74; N, 3.87 % found: C, 49.55; H, 4.46; N, 4.08 [a] 20D -111.0 ° (c = 1.0, in methanol) Compound 72 (817 mg) was crystallized from a mixture of diisopropyl ether and hexane to obtain crystals similar to colorless prisms (634 mg) of Compound 72.

XH-NMR (de-DMSO) d: 1.05 (3H, t, J = 7.0 Hz), 1.56-1.83 (2H, m), 2.01- 2.43 (4H, m), 4.00 (2H, q, J = 7.0 Hz ), 4.30 (1H, d, J = 5.0H?), 7.10- (1H, br), 7.20-7.30 (1H,), 7.50-7.58 (2H, m), 9.74 (1H, s). % calculated for C, 5Hl7ClFN04S: C, 49.79; H, 4.74; N, 3.87 % found: C, 49.67; H, 4.72; N, 3.85 [a] 2 +111.0 ° (c = 1.0, in methanol) Example 67 By the procedure similar to that used in example 33, ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (0.43 g) obtained in Reference Example 2 was reacted with 2-bromo-4-fluoroaniline (0.42 g) to produce ethyl 6- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 73; 0.36 g) as white crystals.

XH-NMR (de-DMSO) d: 1.05 (3H, t, J = 7.0 H?), 1.55-1.86 (2H, m), 1.99- 2.45 (4H, m), 4.00 (2H, q, J = 7.0 Hz), 4.33 (1H, d, J = 5.2 Hz), 7.09 (1H, br), 7.24-7.34 (1H, m), 7.50- 7.68 (2H, m), 9.64, (1H, s). % calculated for C15Hi7BrFN04S: C, 44. 35; H, 4 22; N, 3 Four. Five % found: C, 44.27; H, 4 16; N, 3 73 Example 68 By the procedure similar to that employed in Example 33, ethyl 2-chlorosulfonyl-1-cyclobenzene-1-carboxylate (0.43 g) obtained in Reference Example 2 was reacted with 4-bromo-2-chloroaniline (0.45 g). ) to produce 6- [N- (4-bromo-2-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid ethyl ester (Compound 74; 0.23 g) as white crystals.

XH-NMR (de-DMSO) d: 1.08 (3H, t, J = 7.2 Hz), 1.45-1.83 (2H, m), 1.96-2.42 (4H, m), 4.01 (2H, q, J = 7.2 Hz ), 4.32 (1H, d, J = 5.2 Hz), 7.12 (1H, br), 7.45-7.57 (2H, m), 7.76-7.78 (1H, m), 9.80 (1H, s). % calculated for C15H? 7BrClN04S: C, 42. 62; H, 4 05; N, 3 31 - I found: C, 42.49; H, 3.99; N, 3.60 Example 69 2-Chlorosuifonyl-5-phenyl-1-cyclohexene-1-ethyl carboxylate (0.5 g) obtained in Reference Example 14 was added to a mixture of 2,4-difluoroaniline (0.26 g), triethylamine (0.42 ml) and ethyl acetate (3 ml) with cooling on ice, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate 830 ml) and washed with water 830 ml). The ethyl acetate layer was washed with 0.5 N HCl (30 ml) and saturated brine (30 ml) and dried over anhydrous sodium sulfate and then the solvent was removed by distillation. The residue was subjected to flash column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/10) and flash column chromatography on ODS (eluent: methanol / water / acetic acid = 7/3 / 0.02) to produce a more polar diastereomer (Compound 75, 56 mg, colorless powder crystals) and a less polar diastereomer (Compound 76, 84 mg, colorless powder crystals) of 6- [N- (2, 4-difluorophenyl) sulfamoyl] - 3 - ethyl phenyl-1-cyclohexene-1-carboxylate.

Most polar diastereomer (Compound 75): 1 H-NMR (db-DMSO) d: 1.08 (3H, t, J = 7.2 Hz), 1.90-2.57 (4H, m), 3.54-3.70 (1H, m), 4.04 (2H, q, J = 7.2 Hz ), 4.36 (1H, brs), 6.96- 7.59 (9H, m), 9.98 (1H, S). % calculated for C2? H2? F2N04S: C, 59. 85; H, 5. 02; N, 3 32% found: C, 59.86; H, 5.03; N, 3.21 Less polar dioastereomer (Compound 76).

XH-NMR (CDCl3) d: 1. 09 (3H, t, J = 7.4 Hz), 1.55-1.61 (1H, m), 1.81-1.99 (1H, m), 2.28-2.34 (1H, m), 2. 49-2.59 (1H, m), 3.72- 3.84 (1H, m), 4. 05 (2H, q, J = 7 4Hz), 4. 43 (1H, d, J = 5.O Hz), 7. 03-7. 57 (9H, m), 9.94 (1H., S). % calculated for C2? H2? F2N04S: C, 59.85; H, 5.02; N, 3.32 % found: C, 59.96; H, 5.17; N, 3.17 Example 70 By the procedure similar to that employed in Example 69, ethyl 2-chlorosulfonyl-5-phenyl-1-cyclohexene-1-carboxylate obtained in Reference Example 14 was reacted with 2-chloro-4-fluoroaniline (0.29 g) to produce a more polar diastereomer (Compound 77, 89 mg, colorless powder crystals) and a less polar diastereomer (Compound 78, 51 mg, colorless powder crystals) of 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-phenyl-1-cyclohexene-1-ethyl carboxylate.

Most polar diastereomer (Compound 77): XH-NMR (de-DMSO) d-. 1.06 (3H, t, J = 7.0 H?), 1.88-2.26 (3H, m), 2.49- 2.63 (1H, m), 3.58-3.67 (1H, m), 4. 04 (2H, q, J = 7.0Hz) # 4.0 (1H, d, J = 3.6 Hz), 6.97 (1H, d, J = 2.6 Hz), 7.22- 7.41 (6H, m), 7.51- 7.63 (2H ,), 9.85 (1H, s). % calculated for C2: H2? ClFNO, S: C, 57. 60; H, 4 83; N, 3 twenty % found: C, 57.60; H, 4.87; N, 3.06 Less polar diasteromer (Compound 78): ^ -NMR (CDCl3) d: 1. 08 (3H, t, J = 7.2 Hz), 1.54- 1.63 (1H, m), 1.81- 1.98 (1H, m), 2.30- 2.65 (2H, m), 3.77 - 3.79 (1H, m), 4.05 (2H, q, J = 7.2 Hz), 4.44 (1H, d, J = 4.8 Hz), 7.05- 7.61 (9H, m), 9.83 (1H, s). % calculated for C2, H21C1FN04S: C, 57. 69; H, 4 83; N, 3.20 % found: C, 57-57; H, 4.86; N, 3.07 Example 71 2,4-difluoroaniline (0.39 g) was dissolved in ethyl acetate (5 ml) and the resulting solution was mixed with triethylamine (0.65 ml) with cooling on ice, and then treated dropwise with a solution of 5%. ethyl t-butyl-2-chlorosulfonyl-1-cyclohexen-1-carboxylate (0.72 g) obtained in reference example 16 in ethyl acetate (9 ml). The reaction phase was stirred under nitrogen flow at 0 ° C for 30 minutes then at room temperature for 46 hours. The reaction mixture was diluted with ethyl acetate, and washed successively with water (80 ml), 0.5 N HCl (80 ml), water (80 ml x 2) and saturated brine (80 ml). The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed by distillation. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/7 -> 1/6) and the desired fractions were concentrated under reduced pressure. The residue was subjected to chromatography on ODS at medium pressure (eluent: methanol / water = 6/4) and then to high pressure liquid chromatography (YMC-Pack, ODS, eluent: acetonitrile / water- 55/45 -> 60 / 40) to isolate a more polar compound and a less polar compound separately.

Each desired fraction was concentrated under reduced pressure and the residue was extracted with ethyl acetate and then washed with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate from a mixture of ethyl acetate and hexane to yield a more polar diastereomer (Compound 79, 0.08 g) and a less polar diastereomer (Compound 80; 0.03) of 6- [N - (2,4-difluorophenyl) sulfamoyl] -3-t-butyl-1-cyclohexen-1-ethyl carboxylate each as white crystals.

Most polar diastereomer (Compound 79: XH-NMR (de-DMSO) d: 0.91 (9H, s), 1.10 (3H, t, J = 7. 2 Hz), 1.35-1.51 (1H, m), 1.90-2.30 (4H, m), 4.04 (2H, q, J = 7.2Hz), 4.40 (1H, d, J = 4.6 Hz), 7.02- 7.14 ( 1H, m), 7.13 (1H, br), 7.41-7.53 (2H, m), 9.85 (1H, s). % calculated for C? 9H25F2N0 S: C, 56.84; H, 6.28; N, 3.49 % found: C, 56.77; H, 6.04; N, 3.64 Less polar diastereomer (Compound 80): -NMR (de-DMSO) d: 0.93 (9H, s), 1.07 (3H, t, J = 7.0 Hz), 1.58- 2.43 (5H, m), 4.02 (2H, q, J = 7.0 Hz), 4.24 (1H, d, J = 4.8 H?), 7.03-7.12 (1H, m), 7.11 (1H, br), 7.27-7.55 (2H, m), 9.86 (1H, s). % calculated for Ci7H22F2NO, S: C, 56.84; H, 6.28; N, 3.49 % found: C, 56.75; H, 6.15; N, 3.66 Example 72 By the procedure similar to that used in Example 71, ethyl t-butyl-2-chlorosulfonyl-1-cyclohexen-1-carboxylate, obtained in Reference Example 16 with 2-chloro-4-, was reacted. fluoroaniline (0.45 g) to produce a more polar diastereomer (Compound 81; 0.04 g) and a less polar diastereomer (Compound 82; 0.02 g) of 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3 t-butyl-1-cyclohexene-1-ethyl carboxylate each as white crystals.

Most polar diastereomer (Compound 81): XH-NMR (de-DMSO) d: 0.91 (9H; s), 1.08 (3H.t, J = 7.0 Hz), 1.38- 1.53 (1H, m), 1.92- 2.31 (4H, m), 4.04 (2H, q, J = 7.0 Hz), 4.41 (1H, d, J = 6.6 Hz), 7.14 (1H, br), 7.19-7.27 (1H, m), 7.48-7.57 (2H, m), 9.73 ( 1H, s). % calculated for C? 9H25ClFN04S: C, 54. 60; H, 6. 03; N, 3 35 % found: C, 54.35; H, 5.89; N, 3.51 Less polar diastereomer (Compound 82): XH-NMR (de-DMSO) d: 0.92 (9H, s), 1. 05 (3H, t, J = 7.0 Hz), 1.59- 2.55 (5H, m), 4.00 (2H, q, J = 7.0 Hz), 4.26 (1H, d, J = 4.6 Hz), 7.10 (1H, br), 7.20-7.30 (1H, m), 7.49- 7.58 (2H, m), 9.73 (1H, s). % calculated for C19H25C1FN04S: C, 54. 60; H, 6 03; N, 3 35% found: C, 54. 42; H, 5.99; N, 3 38 Example 73 2,4-difluoroaniline (1.51 g) was dissolved in ethyl acetate (33 ml) and the resulting solution was mixed with triethylamine (2.51 ml) with cooling on ice, and then treated dropwise with a solution of 2-chlorosulfonyl. Ethyl 5,5-dimethyl-1-cyclohexene-1-carboxylate (2.53 g) obtained in Reference example 18 in ethyl acetate 817 ml). The reaction mixture was stirred under nitrogen flow at 0 ° C for 30 minutes then at room temperature for 64.5 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water (120 ml), 0.5 N HCl (120 ml), water (120 ml x 2) and saturated brine (120 ml). The ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane = 1/9 -> 1/7).

A desired fraction was concentrated under reduced pressure, and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield 6- [N- (2,4-difluorophenyl) sulfonyl] -3,3-dimethyl. - 1-cyclohexene-1-carboxylate (Compound 83; 0.83 g) as white crystals.

XH-NMR (de-DMSO) d- 0.99 (3H, s), 1.08 (3H, t, J = 7.0 H?), 1.08 (3H, s), 1.39-1.45 (1H, m), 1.88-2.12 ( 2H, m), 2.30- 2.37 (1H, m), 4. 01 (2H, q, J = 7. OH?), 4. 23 (1H, d.J = 4. 4H?), 6. 79 (1H, s), 7.04-7.08 (1H, m), 7.12- 7.36 (1H, m), 7.42- 7.54 (1H, m), 9.88 (1H, S). % calculated for C? 7H2? F2N04S: C, 54. 68; H, 5 67; N, 3 . 75 % found: C, 54.59; H, 5.72; N, 3.72 Example 74 By the procedure similar to that used in the Example 73, 2-chlorosulfonyl-5,5-dimethyl-1-cyclohexen-1-ethyl carboxylate (0.62 g) obtained in Reference Example 18 was reacted with 2-chloro-4-fluoroaniline (0.42 g) to produce 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethyl-1-cyclohexen-1-ethyl carboxylate (Compound 84; 0.13 g) as white crystals.

^ -NMR (de-DMSO) d: 0.99 (3H, s), 1.05 (3H, t, J = 7.0 Hz), 1.08 (3H, s), 1.40- 1.45 (1H, m), 1.90- 2.11 (2H , m), 2.36- 2.43 (1H, m), 4.00 (2H, q, J = 7.0 Hz), 4.24 (1H, d, J = 4.4 Hz), 6.79 (1H, s), 7.20-7.30 (1H, m), 7.50-7.57 (2H, m), 9.77 (1H, S). % calculated for C? -H21C1FN04S: C, 52. 37; H, 5. 43; N, 3 59% found: C, 52. 30; H, 5..28; N, 3 62 Example 75 To a solution of 6- [N- (2,4-difluorophenyl sulfamoyl] -1-cyclohexene-1-carboxylate (100 mg) obtained in Example 3 in chlorobenzene (2 ml), N-bromosuccinimide (56.7 mg) was added. and 2, 2'-azobisisobutyronitrile (0.5 mg) and the mixture was stirred at 90 ° C for 7 hours.The reaction mixture was combined with ice water (20 ml), extracted with ethyl acetate (20 ml), washed with saturated brine (20 ml) and dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting residue was purified by flash chromatography on silica gel (eluent: ethyl acetate = 1/20 - > ethyl acetate / hexane = 1/10) and crystallized from hexane to give 3-bromo-6- [N- (2, 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate (Compound 85, 27 mg) as colorless powder crystals.

^ -NMR (de-DMSO) d: 1.04 (3H, t, J = 7.0 HZ), 2.03-2.20 (2H, m), 2.42- 2.77 (2H,), 4.05 (2H, q, J = 7.0 Hz) , 4.42 (1H, d, J = 5.4 Hz), 5.32 (1H, t, J = 4.0Hz), 7.07 (1H, d, J = 4.8 Hz), 7.06- 7.16 (1H, m), 7.31- 7.55 ( 2H,), 10.07 (1H, s). % calculated for C15H16BrF2N04S: C, 42. 46; H, 3. 80; N, 3 30 % found: C, 42. 4 Table 1 Table 2 Table 3 Table 4 Table 5 Experiment 1 Inhibitory effect of the production of DO NOT The macrophage cell line RA 264.7 was used as an inducible iNOS cell and a test compound was examined for its% inhibition of NO production. The test compound was dissolved at 10 mM in N, N-dimethylformamide and diluted with RPMI-1640 medium to the concentration of 0.1 mM. The concentration was further adjusted using the medium so that a final concentration range from 10 μM to 10 nM would be obtained by a series of 10-fold dilutions.

On the day before the experiment, the cell was adjusted to 5 x 10 5 / ml in RPMI-1640 medium supplemented with 10% inactivated calf fetal serum and inoculated into a 96-well microplate at 1 x 10 5 cells / 0.2 ml by pocilio. After incubation at 37 ° C under an atmosphere of 5% C02 / 95% air overnight, the test compound adjusted as described above was added and then LPS and interferon-gamma were added at the final concentrations of 5 ng / ml and 1 U / ml, respectively. After further incubation overnight, the supernatant culture was examined for the concentration of nitrite ions (stable NO metabolite) which was used as an index of NO production.

The concentration of nitrite ions was determined by the addition of 25 μl of 20 μg / ml 2, 3-diaminonaphthalene (DAN) to 50 μl of the culture supernatant, followed by incubation at room temperature for 10 minutes, followed by addition of 25 μl of 0.5 N NaOH, followed by fluorescence determination at 450 nm (excitation wavelength: 365 nm). The results obtained are shown in Table 6. An IC50 represents the concentration of the test compound that inhibits 50% of NO production.

Table 6 6 0 7 .. 9 6 1 2. 8 6 2 3. 8 6 3 8. 4 6 4 0. 2 5 6 5 0. 3 2 6 6 8. 1 6 7 6. 0 6 8 5. 1 6 9 6. 8 70 0. 35 In Table 6, compounds 1 and 9 were examined 7 and 9 times, respectively, and the minimum and the maximum of IC50 were indicated.

Any of the test compounds exhibited a potent inhibitory effect on NO production by the RA 264.7 cell, which reveals that an oxazole derivative of the invention had an excellent inhibitory effect on NO production.

Experiment 2 Inhibitory effect of cytokine production Using the mouse macrophage line RAW264.7, a test compound was examined for its% inhibition of a cytokine production. The test compound was dissolved at 10 mM in N, N-dimethylformamide and diluted with RPMI-1640 medium to the concentration of 0.1 mM.

The concentration was further adjusted using the medium so that a final concentration range from 10 μM to -10 nM was obtained by a series of 10-fold dilutions and the test compound was added to a culture medium. On the day before the experiment, the cell was adjusted to 5 x 10 5 / ml in RPMI-1640 medium supplemented with 10% inactivated calf fetal serum and inoculated in a 96-well microplate at 1 x 10 5 cells / 0.2 ml by pocilio.

After incubation at 37 ° C under an atmosphere of 5% C02 / 95% air overnight, the test compound adjusted as described above was added and then LPS and interferon-gamma were added to the final concentrations of 5 ng / ml and 1 U / ml, respectively.

After further incubation overnight, the supernatant culture was examined for the concentrations of TNF-α and IL-6. IL-la was determined using 1.0 μg / ml of LPS in the absence of interferon gamma in other similar conditions. Each of the cytokines was determined using a test kit manufactured by Amersham. The results obtained are shown in Table 7. An IC50 represents the concentration of the test compound that inhibits 50% of the cytokine production.

Table 7 in Table 7, TNF-α and IL-6 were examined twice and each indicated IC 50.

Experiment 3 Effect on the increase of the level of nitric oxide in blood When NO is produced in vivo as a result of the defense mechanism against infection or immune abnormality, it is easily metabolized to nitrous acid or nitric acid, resulting in an increase in the concentration of nitric oxide in blood (Nox). Accordingly, an experimental animal was used to examine the effect of the test compounds on the increase in blood of the NOx level.

BALB / c female mice (6 weeks old) were purchased and acclimated for 1 week and assigned to the groups in each of which 6 to 8 animals were included. In a treated group, 30 mg / kg of a compound suspended in a 0.5% aqueous solution of methyl cellulose administered orally. In a control group, the vehicle was administered similarly. After 1 hour, LPS (10 mg / kg) was intraperitoneally administered to each of the animals in the treated and control groups, and blood was taken 6 hours after the administration of LPS and examined for serum concentration of Nitrite ions + nitrate ions. The nitrate ion was converted to the nitrite ion using nitrate reductase, and the measured values, which were obtained by the fluorescent method using DAN described above, were represented as the total concentration of nitrite ions.

A% inhibition in a treated group when compared to the control group is set forth in the Table Table 8 Experiment 4 Effect on the blood increase of the cytokine level As a result of a defense mechanism against an infection or an immune abnormality, several cytokines were produced in vivo. Accordingly, an experimental animal model was used to examine the effect of a test compound on the increase of the cytokine level in blood.

Female BALB / c mice (6 weeks old) were purchased and acclimated for 1 week and assigned to groups in each of which 6 to 8 animals were included. In the treatment group, 30 mg / kg of a test compound suspended in 0.5% aqueous solution of methylcellulose was orally administered. In a control group, the vehicle was similarly administered. After 1 hour, LPS (10 mg / kg) was administered peritoneally to each animal in the treatment and control groups, and blood was taken 1 hour after the administration of LPS and examined for serum concentration of TNF- to.

The concentrations of IL-la, IL-lβ and IL-6 were determined using blood serum taken 6 hours after the administration of LPS. A% inhibition of in the treatment group when compared to the control group is set forth in Table 9. Each of the cytokines was determined using the assay kit manufactured by Amersham.

Table 9 as is evident from tables 6 to 9, compound (le) had an excellent inhibitory effect on NO production, inhibitory effect on cytokine production, inhibitory effect on the increase in blood concentration of nitric oxide and the effect inhibitor on the increase of cytokine concentration.

The number of compounds in Tables 6 to 9 corresponds to the number of compounds in Tables 1 to 5.

Industrial Application An inventive compound (Iaa) and Compound (le) have an effect that inhibits the production of nitric oxide (NO) and an effect that inhibits the production of cytosine, and are useful as a prophylactic and therapeutic agent against diseases including cardiac diseases, autoimmune diseases , inflammatory diseases, diseases of the central nervous system, infectious diseases, sepsis, septic shock and the like.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, it is claimed as property in the following:

Claims

1. A compound that is characterized because it is represented by the formula: wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR 1 (wherein R 1 represents or an aliphatic hydrocarbon group having optionally substituents) or a group represented by the formula: Ib .R% " (wherein Rlb represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, Rlc is, equal to or different from Rlb, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R ° represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ° represent a bond with each of the others, ring A is a cycloalkene substituted by 1 to 4 selected from (i) an aliphatic hydrocarbon group optionally having substituents, (ii) a aromatic hydrocarbon group optionally having substituents, (iii) a group represented by the formula: OR1 (wherein R1 represents the same meaning as mentioned above) and (iv) a halogen atom, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: represents a group represented by the formula: or and n is an integer from 1 to 4, or a salt thereof.

2. A compound that is characterized because it is represented by the formula: wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR 1 (wherein R 1 represents a hydrogen atom or a group aliphatic hydrocarbon optionally having substituents) or a group represented by the formula. ? ' (wherein Rlb represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, Rlc is, equal to or different from Rlb, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents), R ° represents an atom of hydrogen or an aliphatic hydrocarbon group, or R and R ° represent a bond with each of the others, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: represents a group represented by the formula: O and n is an integer from 1 to 4, provided that when n is 1 or 2 and (i) R1 is a hydrogen atom or an ethyl group, R ° is a methyl group and Ar is a phenyl group or (ii) R and R ° represent a bond with each of the others and Ar is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group or a 2-6-dimethylphenyl group, a group represented by the formula: is a group represented by the formula: or a salt of these.

3. A compound as claimed in claim 2, characterized in that the compound represented by the formula (la) is a compound represented by the formula: wherein R 2 represents a hydrogen atom or an aliphatic hydrocarbon group, R 1, Ar, n and the group represented by the formula: represents the same meaning as defined in claim 2, provided that when n is 1 or 2, Ar is a phenyl group, R1 is a hydrogen atom or an ethyl group and R2 is a methyl group, the group represented by the formula: is a group represented by the formula:

4. A compound as claimed in claim 2, characterized in that the compound represented by the formula (la) is a compound represented by the formula; wherein Ar and n represent the same meaning as defined in claim 2.

5. A compound as claimed in claim 1, which is characterized in that the compound represented by the formula (Iaa) is a compound represented by the formula: wherein each of the symbols represents the same meaning as defined in claim 1.

6. A compound as claimed in claim 5, characterized in that the ring A is a cycloalkene substituted by a lower alkyl, phenyl or halogen, R1 is a lower alkyl group, Ar is a phenyl group optionally having substituents, and n is 2 .

7. A compound as recited in claim 3, which is characterized in that R1 is a lower alkyl group optionally having substituents.

8. A compound as claimed in claim 3, which is characterized in that R1 is an ethyl group.

9. A compound as claimed in claim 3, which is characterized in that R 2 is a hydrogen atom or a lower alkyl group.

10. A compound as claimed in claim 3, characterized in that R2 is a hydrogen atom.

11. A compound as claimed in claim 3, which is characterized in that Ar is a phenyl group optionally having substituents.

12. A compound as claimed in claim 3, which is characterized in that Ar is a phenyl group substituted by halogen or / and lower alkyl.

13. A compound as claimed in claim 4, which is characterized in that Ar is a group represented by the formula: wherein R and R are the same or different and represent a halogen atom or a lower alkyl group, and n is an integer from 0 to 2.

14. A compound as claimed in claim 3, characterized in that the halogen atom is a fluoro or chloro atom.

15. A compound as claimed in claim 3, which is characterized in that the group represented by the formula: is a group represented by the formula: wherein n is the same meaning as defined in claim 2.

16. A compound as claimed in claim 3, which is characterized in that n is 1 to 3.

17. A compound as claimed in claim 3, which is characterized in that R1 is a lower alkyl group optionally having substituents, R2 is a hydrogen atom or a lower alkyl group, Ar is a phenyl group optionally having substituents, is 1, 2 or 3.

18. A compound as claimed in claim 3, which is characterized in that R1 is a lower alkyl group optionally having substituents, R2 is a hydrogen atom, Ar is a phenyl group substituted by a halogen atom, n is 2.

19. A compound as claimed in claim 4, which is characterized in that Ar is a phenyl group optionally having substituents, n is 2.

20. A compound as claimed in claim 2, characterized in that the compound represented by the formula (la) is a compound represented by the formula: wherein R1, R2 and Ar represent the same meaning as defined in claim 3, a group represented by the formula: represents a group represented by the formula: or provided that when Ar is a phenyl group, R1 is a hydrogen atom or an ethyl group and R2 is a methyl group, the group represented by the formula: is a group represented by the formula:

21. A compound as claimed in claim 2 which is characterized in that it is 6- [N- (2,4-dilfuorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate of d-ethyl or a salt thereof.

22. A compound as claimed in claim 2 which is characterized in that it is ethyl 6- [N- (2, 4-chlorophenyl) sulfamoyl] -1-cyclohexen-1-carboxylate or a salt thereof.

23. A compound as claimed in claim 2, which is characterized in that it is 6-] N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-ethyl carboxylate or a salt thereof.

24. A compound as claimed in claim 2 which is characterized in that it is 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1- c-chlorhexen-1-d-ethyl carboxylate or a salt thereof.

25. A method for producing a compound as claimed in claim 3 which is characterized in that it comprises reacting a * compound represented by the formula: wherein R and n represent the same meaning as defined: or in claim 3 and X1 represents a non-pillable group, or a salt thereof with a compound represented by the formula: wherein each of the symbols represents the same meaning as that claimed in claim 3, or a salt thereof.

26. A method for producing a compound as claimed in claim 4 which is characterized in that it comprises subjecting a compound represented by the formula: wherein each of the symbols represents the same meaning as claimed in claim 4, or a salt thereof to a ring closure reaction.

27. A method for producing a compound as claimed in claim 20 which is characterized in that it comprises reacting a compound represented by the formula: wherein R1 represents the same meaning as defined in claim 20 and X1 represents a displaceable group, or a salt thereof with a compound represented by the formula: H * A1 (Illa) Ar wherein each of the symbols represents the same meaning as that claimed in claim 20, or a salt thereof.

28. A pharmaceutical composition which is characterized in that it contains a compound represented by the formula: wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR 1 (wherein R 1 represents a hydrogen atom or a group aliphatic hydrocarbon optionally having substituents) or a group represented by the formula: R, b (wherein R 1b represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R 1c is, equal to or different from R 1b, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents), P, ° represents a hydrogen atom or an aliphatic hydrocarbon group, or R and RO represent a bond with each of the others, ring A is a cycloalkene substituted by 1 to 4 selected from (i) an aliphatic hydrocarbon group optionally having substituents, (iii) a group represented by the formula: OR1 (wherein R1 represents the same meaning as mentioned above) and (iv) a halogen atom, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula : represents a group represented by the formula: o and n is an integer from 1 to 4, or a salt thereof.

29. A pharmaceutical composition which is characterized in that it contains a compound represented by the formula: wherein Ra represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: 0Rla (wherein Rla represents a hydrogen atom or a group aliphatic hydrocarbon optionally having substituents) or a group represented by the formula: ? " (where Rla represents the same meaning as defined above, Rlb is, equal to or different from Rla, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R0a represents a hydrogen atom or an aliphatic hydrocarbon group, or Ra and R0a represents a bond with each of the others, Ara represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula represents a group represented by the formula: o n represents an integer from 1 to 4, or a salt thereof.

30. A pharmaceutical composition that is characterized in that it contains a compound represented by the formula: wherein R > 2a represents a hydrogen atom or an aliphatic hydrocarbon group, Rla, Ara, n and the group represented by the formula: it represents the same meaning as defined in claim 29, or a salt thereof.

31. A pharmaceutical composition which is characterized in that it contains a compound represented by the formula. wherein R, R and Ara represent the same meaning as defined in claim 30 and the group represented by the formula: is a group represented by the formula: or

32. The pharmaceutical composition claimed in any one of claims 28 to 31 which is characterized in that it is an agent for inhibiting the production of nitric oxide or cytokine.

33. The pharmaceutical composition claimed in claim 32 which is characterized in that it is an agent for preventing or treating heart diseases, autoimmune diseases or septic shock.

34. Use of the compound represented by the formula (Iaa) or (reads) to make an agent to inhibit the production of nitric oxide and / or cytokine.

35. A method for inhibiting the production of nitric oxide and / or cytokines in mammals that is characterized in that it comprises administering to a subject in need an effective amount of the compound represented by the formula (Iaa) or (le).

36. Use of the compound represented by the formula (Iaa) or (le) to make an agent to prevent or treat heart diseases, autoimmune diseases or septic shock.

37. A method for preventing or treating cardiac diseases, autoimmune diseases or septic shock in mammals which is characterized in that it comprises administering to a subject in need an effective amount of the compound represented by the formula (Iaa) or (le).

38. A pro-drug of the compound claimed in claims 1 6 2.

39. A pharmaceutical composition that is characterized in that it contains the prodrug as claimed in claim 38. SUMMARY OF THE INVENTION The present invention provides a compound represented by the formula: wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR 1 (wherein R 1 represents a hydrogen atom or a group aliphatic hydrocarbon optionally having substituents) or a group represented by the formula: A < R. "wherein Rlb represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, Rlc is, equal to or different from Rl, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R ° represents an atom of hydrogen or an aliphatic hydrocarbon group, or R and R ° represent a bond with each of the others, Ar represents an aromatic hydrocarbon group optionally having substituents, and n is an integer from 1 to 4, or a salt thereof, which is an agent for preventing or treating diseases such as cardiac diseases, autoimmune diseases, septic shock, etc.