Substituted aromatic-ring compounds, process for producing the same and use Number:7,417,059 from the United States Patent and Trademark Office (PTO) owispatent The present invention is directed to a class of cyclohexene derivatives bearing sulfamoyl and ester groups which have an inhibitory activity on nitric oxide (NO) production and cytokine production, and are useful as an agent for the prophylaxis and/or treatment of diseases such as, cardiac disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis, and septic shock.<H Substituted, producing, Substituted, aro, 7417059.html, Patent, pto, 7417059

Title: Substituted aromatic-ring compounds, process for producing the same and use

Abstract: The present invention is directed to a class of cyclohexene derivatives bearing sulfamoyl and ester groups which have an inhibitory activity on nitric oxide (NO) production and cytokine production, and are useful as an agent for the prophylaxis and/or treatment of diseases such as, cardiac disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis, and septic shock.

Patent Number: 7,417,059 Issued on 08/26/2008 to Tamura, et al.

Inventors: Tamura; Norikazu (Kobe, JP), Ichikawa; Takashi (Suita, JP), Ii; Masayuki (Minoo, JP)
Assignee: Takeda Pharmacetical Company Limited (Osaka, JP)

Appl. No.: 11/094,210

Filed: March 31, 2005

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
10048938		7078540
PCT/JP00/05197	Aug., 2000

Foreign Application Priority Data


Aug 06, 1999 [JP]			11-224248

Current U.S. Class: 514/350 ; 514/351; 514/354; 514/357; 514/432; 514/459; 514/460; 514/532; 514/538; 514/603; 546/184; 546/192; 549/28; 549/356; 549/416; 549/426; 549/427; 549/428; 560/12; 560/13; 560/9; 564/80; 568/28; 568/30; 568/31; 568/36

Current International Class: A61K 31/44 (20060101); A61K 31/18 (20060101); A61K 31/235 (20060101); A61K 31/34 (20060101); C07D 335/02 (20060101); C07D 315/00 (20060101); C07D 309/00 (20060101); C07D 211/08 (20060101); C07D 211/00 (20060101); C07C 321/00 (20060101); C07C 315/00 (20060101); C07C 303/00 (20060101); A61K 31/35 (20060101); A61K 31/38 (20060101)

Field of Search: 514/602,359,383,520,521,522,530,538,562,601,603,604,373 548/166,250,252,255,269.4,418 560/12,13 562/430 564/91,92 549/356,429

References Cited [Referenced By]

U.S. Patent Documents


5378703	January 1995	Dean et al.
6495604	December 2002	Ichimori et al.
7078540	July 2006	Tamura et al.
2003/0100580	May 2003	Dhanak et al.
2004/0002425	January 2004	Saitou et al.

Foreign Patent Documents


96/31492	Oct., 1996	WO
99/46242	Sep., 1999	WO

Other References

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Barbel Schulze, Sabine Kirrbach, Katrin Illgen and Peter Fuhrmann, "Synthesis of Stable Hydroperoxides of Sultams by Oxidation of Isothiazolium Salts" in Tetrahedron, Jan. 15, 1996, vol. 52, No. 3, pp. 783-790. cited by other .
Arend et al., "IL-1 Receptor Antagonist and IL-1.beta. Production in Human Monocytes are Regulated Differently", Journal of Immunology, vol. 147, No. 2, pp. 1530-1536, Sep. 1, 1991. cited by other .
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Neuner et al., "Pentoxifylline in vivo Down-Regulates the Release of IL-1.beta., IL-6, IL-8 and Tumor Necrosis Factor-.alpha. by Human Peripheral Blood Mononuclear Cells", Immunology, vol. 83, No. 2, pp. 262-267, Oct. 1994. cited by other .
Matsuda et al., "Establishiment of an Interleukin 6 (IL6)/B Cell Stimulatory Factor 2-Dependent Cell Line and Preparation of Anti-IL6 Monoclonal Antibodies", European Journal of Immunology, vol. 18, pp. 951-956, Jun. 1988. cited by other .
Cohen et al., "CNI-1493 Inhibits Monocyte/Macrophage Tumor Necrosis Factor by Suppression of Translation Efficiency", Proc. National Academy of Science USA, vol. 93, pp. 3967-3971, Apr. 1996. cited by other .
Forstermann et al., "Nitric Oxide Synthase Isozymes--Characterization, Purification, Molecular Cloning, and Functions", Hypertension, vol. 23, No. 6, Part 2, pp. 1121-1131, Jun. 1994. cited by other .
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Primary Examiner: Crane; L. E.
Attorney, Agent or Firm: Wenderoth, Lind & Ponack, L.L.P.

Parent Case Text

This is a divisional of Ser. No. 10/048,938, filed Feb. 6, 2002 now U.S. Pat. No. 7,078,540, which is a U.S. national stage of International Application No. PCT/JP00/05197 filed Aug. 3, 2000.

Claims

The invention claimed is:

1. A compound of the formula: ##STR00057## wherein R.sup.1 is a group of the formula: OR.sup.1a wherein R.sup.1a is a C.sub.1-6 alkyl group; X is a methylene group, --NH--, a sulfur atom or an oxygen atom; Y is a methylene group or --NH--, each of which optionally has C.sub.1-6 alkyl group(s); and ring A is a 6-membered ring optionally substituted further by 1 to 4 substituent(s) selected from a C.sub.1-6 alkyl group, a phenyl group and a halogen atom; Ar is a C.sub.6-14 aryl group optionally having substituent(s) selected from the group consisting of halogen atom, C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 alkoxy-carbonyl group, carboxyl group, nitro group, cyano group, hydroxy group, C.sub.1-4 alkanoylamino group, C.sub.3-6 cycloalkyl group, C.sub.6-10 aryl group, halogeno C.sub.1-4 alkyl group, halogeno C.sub.1-4 alkoxy group, C.sub.1-4 alkylthio group, C.sub.1-4 alkylsulfonyl group, C.sub.1-4 alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group, C.sub.1-4 alkyl-carbamoyl group, C.sub.1-4 alkoxy-carbonyl-C.sub.1-4 alkyl-carbamoyl group and 1,3-diacylguanidino-C.sub.1-4 alkyl group; or a salt thereof and; with the proviso that the group of the formula: ##STR00058## is a group of the formula: ##STR00059## and further provided that when X is a methylene group, Y is a methylene group optionally substituted with C.sub.1-6 alkyl group(s).

2. The compound of claim 1, wherein the ring A is a 6-membered ring optionally substituted by C.sub.1-6 alkyl, phenyl or halogen, R.sup.1 is OR.sup.1a where R.sup.1a is C.sub.1-6 alkyl group, and Ar is a phenyl group optionally having substituent(s) selected from the group consisting of halogen atom, C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 alkoxy-carbonyl group, carboxyl group, carboxyl group, nitro group, cyano group, hydroxy group, C.sub.1-4 alkanoylamino group, C.sub.3-6 cycloalkyl group, C.sub.6-10 aryl group, halogeno C.sub.1-4 alkyl group, halogeno C.sub.1-4 alkoxy group, C.sub.1-4 alkylthio group, C.sub.1-4 alkylsulfonyl group, C.sub.1-4 alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group, C.sub.1-4 alkyl-carbamoyl group, C.sub.1-4 alkoxy-carbonyl-C.sub.1-4 alkyl-carbamoyl group and 1,3-diacylguanidino-C.sub.1-4 alkyl group.

3. The compound of claim 2, wherein R.sup.1a is an ethyl group.

4. The compound of claim 2, wherein Ar is a halogeno phenyl group, a C.sub.1-4 alkylphenyl group or a phenyl group substituted by halogen and C.sub.1-4 alkyl.

5. The compound of claim 2, wherein Ar is a group of the formula: ##STR00060## wherein R.sup.3 is a halogen atom or a C.sub.1-4 alkyl group and ring B is optionally further substituted by halogen atom.

6. The compound of claim 5, wherein Ar is a group of the formula: ##STR00061## wherein R.sup.3a and R.sup.3b are the same or different and each is a halogen atom.

7. The compound of claim 1, wherein R.sup.1 is a group of the formula: OR.sup.1a' wherein R.sup.1a' is a C.sub.1-6 alkyl group; the group of the formula: ##STR00062## is a group of the formula: ##STR00063## X is methylene or an oxygen atom, Y is methylene or --NH--, Ar is a phenyl group optionally having 1 or 2 substituent(s) selected from the group consisting of halogen atom and C.sub.1-6 alkoxy.

8. The compound of claim 1, wherein R.sup.1 is a group of the formula: OR.sup.1a' wherein R.sup.1a' is a C.sub.1-6 alkyl group, the group of the formula: ##STR00064## is a group of the formula: ##STR00065## X is methylene and Y is methylene, or X is an oxygen atom and Y is --NH--, and Ar is a phenyl group optionally having two halogen atoms.

9. A method of making a compound of the formula: ##STR00066## wherein the group of the formula: ##STR00067## is a group of the formula: ##STR00068## R.sup.1 is a group of the formula: OR.sup.1a wherein R.sup.1a is a C.sub.1-6 alkyl group; X.sup.1 is --NH--, a sulfur atom or an oxygen atom; ring A is a 6-membered ring optionally substituted further by 1 to 4 substituent(s) selected from a C.sub.1-6 alkyl group, a phenyl group and a halogen atom; R.sup.4 is a hydrogen atom or a C.sub.1-6 alkyl group; and Ar is a C.sub.6-14 aryl group optionally having substituent(s) selected from the group consisting of halogen atom, C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 alkoxy-carbonyl group, carboxyl group, nitro group, cyano group, hydroxy group, C.sub.1-4 alkanoylamino group, C.sub.3-6 cycloalkyl group, C.sub.6-10 aryl group, halogeno C.sub.1-4 alkyl group, halogeno C.sub.1-4 alkoxy group, C.sub.1-4 alkylthio group, C.sub.1-4 alkylsulfonyl group, C.sub.1-4 alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group, C.sub.1-4 alkyl-carbamoyl group, C.sub.1-4 alkoxy-carbonyl-C.sub.1-4 alkyl-carbamoyl group and 1,3-diacylguanidino-C.sub.1-4 alkyl group; or a salt thereof, which method comprises reacting a compound of the formula: ##STR00069## wherein Z.sup.1 is a leaving group and the other symbols are as defined above, or a salt thereof and a compound of the formula: ##STR00070## wherein each symbol is as defined above, or a salt thereof.

10. A method of making a compound of the formula: ##STR00071## wherein R.sup.1 is a group of the formula: OR.sup.1a wherein R.sup.1a is a C.sub.1-6 alkyl group; X is a methylene group, --NH--, a sulfur atom or an oxygen atom; ring A is a 6-membered ring optionally substituted further by 1 to 4 substituent(s) selected from a C.sub.1-6 alkyl group, a phenyl group and a halogen atom; Y.sup.1 is a methylene group optionally having C.sub.1-6 alkyl group(s); Ar is a C.sub.6-14 aryl group optionally having substituent(s) selected from the group consisting of halogen atom, C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 alkoxy-carbonyl group, carboxyl group, nitro group, cyano group, hydroxy group, C.sub.1-4 alkanoylamino group, C.sub.3-6 cycloalkyl group, C.sub.6-10 aryl group, halogeno C.sub.1-4 alkyl group, halogeno C.sub.1-4 alkoxy group, C.sub.1-4 alkylthio group, C.sub.1-4 alkylsulfonyl group, C.sub.1-4 alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group, C.sub.1-4 alkyl-carbamoyl group, C.sub.1-4 alkoxy-carbonyl-C.sub.1-4 alkyl-carbamoyl group and 1,3-diacylguanidino-C.sub.1-4 alkyl group; and the group of the formula: ##STR00072## is a group of the formula: ##STR00073## or a salt thereof, which method comprises reacting a compound of the formula: ##STR00074## wherein Z.sup.2 is a leaving group and the other symbols are as defined above, or a salt thereof, and a compound of the formula: HS--Y.sup.1--Ar (V1) wherein each symbol is as defined above, or a salt thereof, and oxidizing the obtained sulfide.

11. A pharmaceutical composition comprising a compound of the formula: ##STR00075## wherein R.sup.1 is a group of the formula: OR.sup.1a wherein R.sup.1a is a C.sub.1-6 alkyl group; X is a methylene group, --NH--, a sulfur atom or an oxygen atom; Y is a methylene group or --NH--, each of which optionally has C.sub.1-6 alkyl group(s); and ring A is a 6-membered ring optionally substituted further by 1 to 4 substituent(s) selected from a C.sub.1-6 alkyl group, a phenyl group and a halogen atom; Ar is a C.sub.6-14 aryl group optionally having substituent(s) selected from the group consisting of halogen atom, C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 alkoxy-carbonyl group, carboxyl group, nitro group, cyano group, hydroxy group, C.sub.1-4 alkanoylamino group, C.sub.3-6 cycloalkyl group, C.sub.6-10 aryl group, halogeno C.sub.1-4 alkyl group, halogeno C.sub.1-4 alkoxy group, C.sub.1-4 alkylthio group, C.sub.1-4 alkylsulfonyl group, C.sub.1-4 alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group, C.sub.1-4 alkyl-carbamoyl group, C.sub.1-4 alkoxy-carbonyl-C.sub.1-4 alkyl-carbamoyl group and 1,3-diacylguanidino-C.sub.1-4 alkyl group; a salt thereof, or a prodrug thereof in combination with a pharmaceutically acceptable carrier; and with the proviso that the group of the formula; ##STR00076## is a group of the formula: ##STR00077## and further provided that when X is a methylene group, Y is a methylene group optionally with C.sub.1-6 alkyl group(s).

12. A method for treating sepsis, septic shock, endotoxin shock, exotoxin shock, cytokine and/or nitric oxide-induced heart failure, shock, or cytokine and/or nitric oxide-induced hypotension, wherein said cytokine is selected from tumor necrosis factor (TNF), IL-1.beta., and a mixture thereof, which method comprises administering an effective amount of a compound of claim 1 or a prodrug thereof to a mammal in need thereof.

13. A method of making a pharmaceutical composition, which comprises mixing a compound of claim 1 or a prodrug thereof with a pharmacologically acceptable carrier, excipient or diluent.

14. A method for treating sepsis, septic shock, or endotoxin shock, which method comprises administering an effective amount of the compound of claim 1 or a prodrug thereof to a mammal in need thereof.

Description

TECHNICAL FIELD

The present invention relates to a novel cycloalkene derivative having a suppressive activity on the production of inducible nitric oxide synthase-derived nitric oxide (NO) production and/or a suppressive activity on the production of inflammatory cytokines such as TNF-.alpha., IL-1, IL-6 and the like, which is useful as an agent for the prophylaxis and treatment of diseases such as cardiac disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis, septic shock and the like, and a production method thereof and use thereof.

BACKGROUND ART

Nitric oxide (NO) has been reported to play various roles in the physiological activity in the body of mammal; for example, as a vasodilator in the vascular system [Pharmacol. Rev., vol. 43, 109-142 (1991)], as a factor showing tumor cell eradicating activity in the leukocyte system [Curr. Opin. Immunol., vol. 3, 65-70 (1991)], and as a neurotransmitter in the nervous system [Neuron, vol. 8, 3-11 (1992)]. Basically, NO is produced from L-arginine by NO synthase (NOS), and to date, the presence of three kinds of isoforms of genetically nerve NOS, vascular endothelial NOS and inducible NOS (iNOS) has been clarified [Cell, vol. 70, pp. 705-707 (1992)]. Based on the mode of presence, the former two are also referred to as constitutive NOS (cNOS) as contrasted with the latter as iNOS.

The cNOS is considered to be present in the vascular endothelial cell and neurocyte, be calcium calmodulin-dependant, produce a small amount of NO by activation of various receptor stimulations, and to be responsible for the aforementioned physiological control. In contrast, iNOS is known to be induced by various cytokines, bacterial lipopolysaccharides (LPS) and the like to produce a large amount of NO in a sustained manner in macrophage, neutrophile and the like, and to damage and hurt cells and tissues at a production site, while showing the above-mentioned physiological activity [Immunol. Today, vol. 13, 157-160 (1992)]. Known cells and tissues that express iNOS are the aforementioned cells, as well as hepatocyte, kupffer's cell, glia cell, vascular smooth muscle cell, vascular endothelial cell, inner membrane of cardiac muscle, cardiac muscle cell, mesangial cell, chondrocyte, synovial cell, pancreatic .beta. cell, osteoclast and the like [FASEB J., vol. 6, 3051-3064 (1992), Arch Surg., vol. 128, 396-401 (1993), J. Biol. Chem., vol. 44, 27580-27588 (1994), J. Cell. Biochem., vol. 57, 399-408 (1995)].

Heretofore, L-arginine analogs [Pharmacol. Rev., vol. 43, 109-142 (1991)], aminoguanidine [Br. J. Pharmacol., vol. 110, 963-968 (1993)], S-ethylisothiourea [J. Biol. Chem., vol. 43, 26669-26676 (1994)] and the like have been reported to inhibit iNOS.

It is also known that cytokines, such as TNF-.alpha., IL-1, IL-6 and the like, are secreted by various cells such as monocyte, macrophage, lymphocyte, neutrophile, fibroblast, vascular endothelial cell and the like and widely involved in biological defense and immune system based on inflammation [The Cytokine Handbook, 2nd ed Academic Press Limited (1994), Advances Immunol., vol. 62, 257-304 (1996)].

It has been clarified that TNF-.alpha. and IL-1 show activities such as (1) fever, (2) activation and promoted chemotaxis of inflammatory cells such as macrophage, neutrophile and the like, (3) induction of inflammatory cytokines such as IL-1, IL-6, IL-8, TNF, CSF and the like and acute protein, (4) promotion of production of various chemical mediators such as NO, O.sub.2.sup.-, PAF, prostaglandin, leukotriene, protease and the like; and that IL-6 shows activity such as (1) introduction of acute protein, (2) increasing blood platelet, (3) differentiation and activation of lymphocyte and NK cell, (4) growth of osteoclast, and the like. However, excess production of these cytokines and production thereof at inappropriate sites and time is inconvenient for organisms. For example, these cytokines have been found to be involved in various diseases such as cachexia, allergic disease, rheumatoid arthritis, abscess, graft rejection, anemia, arteriosclerosis, autoimmune disease, diabetes, central nervous system disease, inflammatory bowel disease, cardiac disease, hepatitis, cirrhosis, nephritis, osteoporosis, psoriasis, septic shock and the like, caused by protozoan, bacteria, fungi, virus, cancer and the like. It has been described that a substance that suppresses or antagonizes production of TNF-.alpha., IL-1, IL-6 and the like can be a therapeutic drug of these diseases [Eur. J. Immunol., vol. 18, 951-956 (1991), Immunol., vol. 83, 262-267 (1994), Proc. Natl. Acad. Sci., vol. 93, 3967-3971 (1997), J. Immunol., vol. 147, 1530-1536 (1991), Immunol. Today, vol. 12, 404-410 (1991)].

Because substances that suppress NO production by iNOS inducible cell, thereby to treat cardiac disease, autoimmune disease, inflammatory disease, septic shock and the like are considered to be effective as a prophylactic and therapeutic drug of various diseases, such as arteriosclerosis, myocarditis, cardiac myopathy, brain ischemic disorder, Alzheimer's disease, multiple sclerosis, septic shock, rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerular nephritis, osteoporosis, pneumonia, hepatitis, psoriasis, graft rejection, pain and the like, and because the cells targeted by cytokines are diversified over, for example, the inflammation system, the vascular system, the central nervous system, the hematopoietic system, the endocrine system and the like, the biological activities thereof are considered to be diversified, too. These compounds, however, are not entirely satisfactory from the aspect of activity, and are associated with problems that they inhibit not only iNOS but also cNOS responsible for physiological activity, and the like. Therefore, the invention provides an improved agent for the prophylaxis or treatment of diseases such as cardiac disease, autoimmune disease, inflammatory disease, septic shock and the like.

DISCLOSURE OF THE INVENTION

In view of the current situation, the present inventors have conducted researches and study of an agent for the prophylaxis or treatment of the aforementioned diseases, which suppresses NO production from iNOS inducible cells and/or production of inflammatory cytokines, and synthesized, for the first time, a compound of the formula:

##STR00001## wherein R.sup.1 is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heterocyclic group, a group of the formula: OR.sup.1a wherein R.sup.1a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or a group of the formula:

##STR00002## wherein R.sup.1b and R.sup.2c are the same or different and each is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group; X is a methylene group, a nitrogen atom, a sulfur atom or an oxygen atom; Y is an optionally substituted methylene group or an optionally substituted nitrogen atom; and ring A is a 5 to 8-membered ring optionally substituted further by 1 to 4 substituent(s) selected from the following (1) to (4): (1) an optionally substituted aliphatic hydrocarbon group, (2) an optionally substituted aromatic hydrocarbon group, (3) a group of the formula: OR.sup.2 wherein R.sup.2 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group and (4) a halogen atom; Ar is an optionally substituted aromatic hydrocarbon group; a group of the formula:

##STR00003## is a group of the formula:

##STR00004## or the formula:

##STR00005## m is an integer of 0 to 2; and n is an integer of 1 to 3 where the sum of m and n is not more than 4, provided that when X is a methylene group, Y is an optionally substituted methylene group, and a salt thereof, which are characterized by a chemical structure where at least one of a carboxylic acid ester group or carbonyl group, and a sulfonamide group or sulfonyl group is substituted at a constituent carbon of

##STR00006## and the both are substituted at two adjacent cycloalkene-constituting carbons, and found that the obtained compound unexpectedly has, based on its chemical structure, a superior inhibitory activity on NO and/or cytokine production and the like, has a superior action of inhibiting not only NO production from iNOS inducible cell but also production of inflammatory cytokines, can be a prophylactic and therapeutic agent more effective than conventional drugs, and that the compound has superior properties of a clinically useful pharmaceutical agent against the diseases such as cardiac disease, autoimmune disease, inflammatory disease, septic shock and the like, where inflammatory cytokines, such as TNF-.alpha., IL-1, IL-6 and the like, and NO are considered to not act independently from each other but cause progression of the diseases because of their complicated relationship.

Accordingly, the present invention relates to: [1] a compound of the formula:

##STR00007## wherein R.sup.1 is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heterocyclic group, a group of the formula: OR.sup.1a wherein R.sup.1a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or a group of the formula:

##STR00008## wherein R.sup.1b and R.sup.1c are the same or different and each is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group; X is a methylene group, a nitrogen atom, a sulfur atom or an oxygen atom; Y is an optionally substituted methylene group or an optionally substituted nitrogen atom; and ring A is a 5 to 8-membered ring optionally substituted further by 1 to 4 substituent(s) selected from the following (1) to (4): (1) an optionally substituted aliphatic hydrocarbon group, (2) an optionally substituted aromatic hydrocarbon group, (3) a group of the formula: OR.sup.2 wherein R.sup.2 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group and (4) a halogen atom; Ar is an optionally substituted aromatic hydrocarbon group; a group of the formula:

##STR00009## is a group of the formula:

##STR00010## or the formula:

##STR00011## m is an integer of 0 to 2; and n is an integer of 1 to 3 where the sum of m and n is not more than 4 provided that when X is a methylene group, Y is an optionally substituted methylene group, or a salt thereof, [2] the compound of [1] wherein R.sup.1 is (i) an aliphatic hydrocarbon group selected from C.sub.1-20 alkyl group, C.sub.3-10 cycloalkyl group, C.sub.4-12 cycloalkylalkyl group, C.sub.3-6 alkenyl group and C.sub.3-6 alkynyl group, wherein these aliphatic hydrocarbon groups optionally have 1 to 4 substituent(s) selected from the group consisting of heterocyclic group, oxo group, hydroxy group, C.sub.1-6 alkoxy group, C.sub.3-10 cycloalkyloxy group, C.sub.6-10 aryloxy group, C.sub.7-19 aralkyloxy group, heterocyclyloxy group, C.sub.1-6 alkylthio group (the sulfur atom being optionally oxidized), C.sub.3-10 cycloalkylthio group (the sulfur atom being optionally oxidized), C.sub.6-10 arylthio group (the sulfur atom being optionally oxidized), C.sub.7-19 aralkylthio group (the sulfur atom being optionally oxidized), heterocyclylthio group, heterocyclylsulfinyl group, heterocyclylsulfonyl group, nitro group, halogen atom, cyano group, carboxyl group, C.sub.1-10 alkoxy-carbonyl group, C.sub.3-6 cycloalkyloxycarbonyl group, C.sub.6-10 aryloxy-carbonyl group, C.sub.7-19 aralkyloxy-carbonyl group, heterocyclic oxycarbonyl group, C.sub.6-10 arylcarbonyl group, C.sub.1-6 alkanoyl group, C.sub.3-5 alkenoyl group, C.sub.6-10 aryl-carbonyloxy group, C.sub.2-6 alkanoyloxy group, C.sub.3-5 alkenoyloxy group, carbamoyl group optionally substituted by 1 or 2 substituent(s) selected from C.sub.1-4 alkyl, phenyl, C.sub.1-7 acyl and C.sub.1-4 alkoxy-phenyl), thiocarbamoyl group (optionally substituted by 1 or 2 substituent(s) selected from C.sub.1-4 alkyl and phenyl), carbamoyloxy group (optionally substituted by 1 or 2 substituent(s) selected from C.sub.1-4 alkyl and phenyl), C.sub.1-6 alkanoylamino group, C.sub.6-10 aryl-carbonylamino group, C.sub.6-10 alkoxy-carboxamido group, C.sub.6-10 aryloxy-carboxamido group, C.sub.7-19 aralkyloxy-carboxamido group, C.sub.1-10 alkoxy-carbonyloxy group, C.sub.6-10 aryloxy-carbonyloxy group, C.sub.7-19 aralkyloxy-carbonyloxy group, C.sub.3-10 cycloalkyloxy-carbonyloxy group and ureido group (optionally having 1 to 3 substituent(s) selected from C.sub.1-4 alkyl group and phenyl group) (hereinafter substituent group A) and a group consisting of C.sub.6-10 aryl group optionally having 1 to 4 substituent(s) selected from substituent group A (hereinafter substituent group B), the aforementioned heterocyclic group is a 5 to 8-membered heterocyclic group having, besides carbon atoms, 1 to 4 hetero atom(s) selected from a nitrogen atom (optionally oxidized), an oxygen atom and a sulfur atom, or a fused ring thereof, which optionally has 1 to 3 substituent(s) selected from C.sub.1-4 alkyl, hydroxy, oxo and C.sub.1-4 alkoxy, and the above-mentioned substituents may form, together with an aliphatic hydrocarbon group, a fused ring optionally having 1 to 4 substituent(s) selected from substituent group B, (ii) C.sub.6-14 aryl group optionally having 1 to 5 substituent(s) selected from a group consisting of halogen atom, C.sub.1-4 alkyl group, C.sub.1-4 alkoxy group, C.sub.1-4 alkoxy-carbonyl group, carboxyl group, nitro group, cyano group, hydroxy group, C.sub.1-4 alkanoylamino group, C.sub.3-6 cycloalkyl group, C.sub.6-10 aryl group, halogeno C.sub.1-4 alkyl group, halogeno C.sub.1-4 alkoxy group, C.sub.1-4 alkylthio group, C.sub.1-4 alkylsulfonyl group, C.sub.1-4 alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group, C.sub.1-4 alkyl-carbamoyl group, C.sub.1-4 alkoxy-carbonyl-C.sub.1-4 alkyl-carbamoyl group and 1,3-diacylguanidino-C.sub.1-4 alkyl group (hereinafter substituent group C), (iii) a 5 to 8-membered heterocyclic ring having, besides carbon atoms, 1 to 4 hetero atom(s) selected from a nitrogen atom (optionally oxidized), an oxygen atom and a sulfur atom, or a fused ring thereof, which heterocyclic group may have 1 to 3 substituent(s) selected from C.sub.1-4 alkyl, hydroxy, oxo and C.sub.1-4 alkoxy, (iv) a group of the formula: OR.sup.1a wherein R.sup.1a is a hydrogen atom or an aliphatic hydrocarbon group selected from C.sub.1-20 alkyl group, C.sub.3-10 cycloalkyl group, C.sub.4-12 cycloalkylalkyl group, C.sub.3-6 alkenyl group and C.sub.3-6 alkynyl group optionally having substituent(s) selected from substituent group B, or (v) a group of the formula:

##STR00012## wherein R.sup.1b and R.sup.1c are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group selected from C.sub.1-20 alkyl group, C.sub.3-10 cycloalkyl group, C.sub.4-12 cycloalkylalkyl group, C.sub.3-6 alkenyl group and C.sub.3-6 alkynyl group optionally having substituent(s) selected from substituent group B; X is a methylene group, a nitrogen atom, a sulfur atom or an oxygen atom; Y is (i) a methylene group optionally having substituent(s) selected from C.sub.1-6 alkyl group, hydroxy substituted-C.sub.1-6 alkyl group and C.sub.1-4 alkoxy-carbonyl-C.sub.1-4 alkyl group or (ii) a nitrogen atom optionally having substituent(s) selected from C.sub.1-6 alkyl group, hydroxy substituted-C.sub.1-6 alkyl group and C.sub.1-4 alkoxy-carbonyl-C.sub.1-4 alkyl group; ring A is a 5 to 8-membered ring optionally substituted further by 1 to 4 substituent(s) selected from the following (1) to (4): (1) an aliphatic hydrocarbon group selected from C.sub.1-20 alkyl group, C.sub.3-10 cycloalkyl group, C.sub.4-12 cycloalkylalkyl group, C.sub.3-6 alkenyl group and C.sub.3-6 alkynyl group optionally having substituent(s) selected from substituent group B, (2) C.sub.6-14 aryl group optionally having substituent(s) selected from substituent group C, (3) a group of the formula: OR.sup.2 wherein R.sup.2 is a hydrogen atom, or an aliphatic hydrocarbon group selected from C.sub.1-20 alkyl group, C.sub.3-10 cycloalkyl group, C.sub.4-12 cycloalkylalkyl group, C.sub.3-6 alkenyl group and C.sub.3-6 alkynyl group, optionally having substituent(s) selected from substituent group B and (4) a halogen atom; Ar is a C.sub.6-14 aryl group optionally having substituent(s) selected from substituent group C; the group of the formula:

##STR00013## is a group of the formula:

##STR00014## or the formula:

##STR00015## m is an integer of 0 to 2; and n is an integer of 1 to 3 where the sum of m and n is not more than 4, [3] the compound of [1], wherein the ring A is a 5 to 8-membered ring optionally substituted by lower alkyl, phenyl or halogen, R.sup.1 is OR.sup.1a where R.sup.1a is optionally substituted lower alkyl group, and Ar is an optionally substituted phenyl group, [4] the compound of [3], wherein R.sup.1a is an ethyl group, [5] the compound of [3], wherein Ar is a halogenophenyl group, a lower alkylphenyl group or a phenyl group substituted by halogen and lower alkyl, [6] the compound of [3], wherein Ar is a group of the formula:

##STR00016## wherein R.sup.3 is a halogen atom or a lower alkyl group and ring B may be further substituted by halogen atom, [7] the compound of [1], wherein the group of the formula:

##STR00017## is a group of the formula:

##STR00018## [8] the compound of [6], wherein Ar is a group of the formula:

##STR00019## wherein R.sup.3a and R.sup.3b are the same or different and each is a halogen atom, [9] the compound of [1], wherein R.sup.1 is a group represented by OR.sup.1a (R.sup.1a is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s)), m is 1, and n is 1, [10] the compound of [1], wherein R.sup.1 is a group of the formula: OR.sup.1a' (R.sup.1a' is a C.sub.1-6 alkyl group), a group of the formula:

##STR00020## is a group of the formula:

##STR00021## X is methylene or an oxygen atom, Y is methylene or --NH--, Ar is a phenyl group optionally having 1 or 2 substituent(s) selected from the group consisting of halogen atom and C.sub.1-6 alkoxy, [11] the compound of [1], wherein R.sup.1 is a group of the formula: OR.sup.1a' (R.sup.1a' is a C.sub.1-6 alkyl group), a group of the formula:

##STR00022## is a group of the formula:

##STR00023## X is methylene and Y is methylene, or X is an oxygen atom and Y is --NH--, and Ar is a phenyl group optionally having two halogen atoms (e.g., 2-chloro-4-fluorophenyl group and the like), [12] ethyl 6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate, ethyl (+)-6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate or ethyl 3-[(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carbo- xylate, [13] a prodrug of the compound of [1], [14] a production method of a compound of the formula:

##STR00024## wherein a group of the formula:

##STR00025## is a group of the formula:

##STR00026## or the formula:

##STR00027## R.sup.1 is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heterocyclic group, a group of the formula: OR.sup.1a wherein R.sup.1a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or a group of the formula:

##STR00028## wherein R.sup.1b and R.sup.1c are the same or different and each is a hydrogen atom, or an optionally substituted aliphatic hydrocarbon group; X.sup.1 is a nitrogen atom, a sulfur atom or an oxygen atom; ring A is a 5 to 8-membered ring optionally substituted further by 1 to 4 substituent(s) selected from the following (1) to (4): (1) an optionally substituted aliphatic hydrocarbon group, (2) an optionally substituted aromatic hydrocarbon group, (3) a group of the formula: OR.sup.2 wherein R.sup.2 is hydrogen atom or an optionally substituted aliphatic hydrocarbon group and (4) a halogen atom; R.sup.4 is a hydrogen atom or an optionally substituted lower alkyl group; Ar is an optionally substituted aromatic hydrocarbon group; m is an integer of 0 to 2; and n is an integer of 1 to 3 where the sum of m and n is not more than 4, or a salt thereof, which method comprises reacting a compound of the formula:

##STR00029## wherein Z.sup.1 is a leaving group and other symbols are as defined above, or a salt thereof, and a compound of the formula:

##STR00030## wherein each symbol is as defined above, or a salt thereof, [15] a production method of a compound of the formula:

##STR00031## wherein R.sup.1 is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heterocyclic group, a group of the formula: OR.sup.1a wherein R.sup.1a is a hydrogen atom or optionally substituted aliphatic hydrocarbon group, or a group of the formula:

##STR00032## wherein R.sup.1b and R.sup.1c are the same or different and each is a hydrogen atom, or an optionally substituted aliphatic hydrocarbon group; X is a methylene group, a nitrogen atom, a sulfur atom or an oxygen atom; ring A is a 5 to 8-membered ring optionally substituted further by 1 to 4 substituent(s) selected from the following (1) to (4): (1) an optionally substituted aliphatic hydrocarbon group, (2) an optionally substituted aromatic hydrocarbon group, (3) a group of the formula: OR.sup.2 wherein R.sup.2 is hydrogen atom or an optionally substituted aliphatic hydrocarbon group and (4) a halogen atom; Y.sup.1 is an optionally substituted methylene group; Ar is an optionally substituted aromatic hydrocarbon group; a group of the formula:

##STR00033## is a group of the formula:

##STR00034## or the formula:

##STR00035## m is an integer of 0 to 2; and n is an integer of 1 to 3 where the sum of m and n is not more than 4, or a salt thereof, which method comprises reacting a compound of the formula:

##STR00036## wherein Z.sup.2 is a leaving group, and other symbols are as defined above, or a salt thereof, and a compound of the formula: HS--Y.sup.1--Ar (V1) wherein each symbol is as defined above, or a salt thereof, and oxidizing the obtained sulfide, [16] a pharmaceutical composition containing a compound of the formula:

##STR00037## wherein R.sup.1 is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heterocyclic group, a group of the formula: OR.sup.1a wherein R.sup.1a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or a group of the formula:

##STR00038## wherein R.sup.1b and R.sup.1c are the same or different and each is a hydrogen atom or an aliphatic hydrocarbon group optionally having substituent(s); X is a methylene group, a nitrogen atom, a sulfur atom or an oxygen atom; Y is an optionally substituted methylene group or an optionally substituted nitrogen atom; and ring A is a 5 to 8-membered ring optionally substituted further by 1 to 4 substituent(s) selected from the following (1) to (4): (1) an optionally substituted aliphatic hydrocarbon group, (2) an optionally substituted aromatic hydrocarbon group, (3) a group of the formula: OR.sup.2 wherein R.sup.2 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group and (4) a halogen atom; Ar is an optionally substituted aromatic hydrocarbon group; a group of the formula:

##STR00039## is a group of the formula:

##STR00040## or the formula:

##STR00041## m is an integer of 0 to 2; and n is an integer of 1 to 3 where the sum of m and n is not more than 4, provided that when X is a methylene group, Y is an optionally substituted methylene group, a salt thereof, or a prodrug thereof, [17] the pharmaceutical composition of [16], which is an agent for suppressing nitric oxide (NO) and/or cytokine production, [18] the pharmaceutical composition of [16], which is an agent for the prophylaxis or treatment of a cardiac disease, an autoimmune disease or septic shock, [19] a method for suppressing nitric oxide (NO) and/or cytokine production, which method comprising administering an effective amount of the compound of [1] or a prodrug thereof to a mammal, [20] a method for the treatment of a cardiac disease, an autoimmune disease or septic shock, which method comprising administering an effective amount of the compound of [1] or a prodrug thereof to a mammal, [21] use of the compound of [1] or a prodrug thereof for the production of an agent for suppressing nitric oxide (NO) and/or cytokine production, and [22] use of the compound of [1] or a prodrug thereof for the production of an agent for the prophylaxis or treatment of a cardiac disease, an autoimmune disease or septic shock.

BEST MODE FOR EMBODYING THE INVENTION

In the present specification, R.sup.1 is an aliphatic hydrocarbon group optionally having substituent(s), an aromatic hydrocarbon group optionally having substituent(s), an heterocyclic group optionally having substituent(s), a group of the formula: OR.sup.1a, or a group of the formula (a). Particularly, a group of the formula: OR.sup.1a is preferable.

As the "aliphatic hydrocarbon group" of the "aliphatic hydrocarbon group optionally having substituent(s)" represented by R.sup.1, for example, alkyl group, cycloalkyl group, cycloalkylalkyl group, alkenyl group, alkynyl group and the like are preferable.

As the alkyl group, for example, straight chain or branched alkyl group having 1 to 20 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group and the like) and the like are preferable. For example, lower alkyl group having 1 to 6 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like) and the like are particularly preferable.

As the cycloalkyl group, for example, cycloalkyl group having 3 to 10 carbon atoms (e.g., cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like) and the like are preferable. For example, cycloalkyl group having 3 to 6 carbon atoms (e.g., cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like) and the like are particularly preferable.

As the cycloalkylalkyl group, for example, cycloalkylalkyl group having 4 to 12 carbon atoms (e.g., cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group and the like) and the like are preferable. For example, cycloalkylalkyl group having 4 to 8 (particularly 4 to 7) carbon atoms (e.g., cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group and the like), and the like are particularly preferable.

As the alkenyl group, for example, lower alkenyl group having 3 to 6 carbon atoms (e.g., propenyl group, butenyl group, pentenyl group and the like) and the like are preferable. For example, lower alkenyl group having 3 or 4 carbon atoms (e.g., propenyl group, butenyl group and the like) and the like are particularly preferable.

As the alkynyl group, for example, lower alkynyl group having 3 to 6 carbon atoms (e.g., propynyl group, butynyl group, pentynyl group and the like) and the like are preferable. For example, lower alkynyl group having 3 or 4 carbon atoms (e.g., propynyl group, butynyl group and the like) and the like are particularly preferable.

As the aforementioned "substituent" of the "aliphatic hydrocarbon group optionally having substituent(s)", for example, heterocyclic group, oxo group, hydroxy group, C.sub.1-6 alkoxy group, C.sub.3-10 (particularly C.sub.3-6) cycloalkyloxy group, C.sub.6-10 aryloxy group, C.sub.7-19 (particularly C.sub.7-12) aralkyloxy group, heterocyclyloxy group, C.sub.1-6 alkylthio group (the sulfur atom being optionally oxidized), C.sub.3-10 (particularly C.sub.3-6) cycloalkylthio group (the sulfur atom being optionally oxidized), C.sub.6-10 arylthio group (the sulfur atom being optionally oxidized), C.sub.7-19 (particularly C.sub.7-12) aralkylthio group (the sulfur atom being optionally oxidized), heterocyclic thio group, heterocyclic sulfinyl group, heterocyclic sulfonyl group, nitro group, halogen atom, cyano group, carboxyl group, C.sub.1-10 (particularly C.sub.1-6) alkoxy-carbonyl group, C.sub.3-6 cycloalkyloxy-carbonyl group, C.sub.6-10 aryloxy-carbonyl group, C.sub.7-19, (particularly C.sub.7-12) aralkyloxy-carbonyl group, heterocyclic oxycarbonyl group, C.sub.6-10 aryl-carbonyl group, C.sub.1-6 alkanoyl group, C.sub.3-5 alkenoyl group, C.sub.6-10 aryl-carbonyloxy group, C.sub.2-6alkanoyloxy group, C.sub.3-5 alkenoyloxy group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted carbamoyloxy group, C.sub.1-6 alkanoylamino group, C.sub.6-10 aryl-carbonylamino group, C.sub.1-10 (particularly C.sub.1-6) alkoxy-carboxamido group, C.sub.6-10 aryloxy-carboxamido group, C.sub.7-19 (particularly C.sub.7-12)aralkyloxy-carboxamido group, C.sub.1-10 (particularly C.sub.1-6) alkoxy-carbonyloxy group, C.sub.6-10 aryloxy-carbonyloxy group, C.sub.7-19 (particularly C.sub.7-12) aralkyloxy-carbonyloxy group, C.sub.3-10 (particularly C.sub.3-6) cycloalkyloxy-carbonyloxy group, optionally substituted ureido group, optionally substituted C.sub.6-10 aryl group and the like are used.

These substituents are substituted at substitutable positions of the aforementioned "aliphatic hydrocarbon group". The substituent is not limited to one but may be in plurality (2 to 4), which may be the same or different.

As the "C.sub.1-6 alkoxy group", for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group and the like are preferable; as the "C.sub.3-10 cycloalkyloxy group", for example, cyclopropyloxy group, cyclohexyloxy group and the like are preferable; as the "C.sub.6-10 aryloxy group", for example, phenoxy group, naphthyloxy group and the like are preferable; as the "C.sub.7-19 aralkyloxy group", for example, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, benzhydryloxy group, 1-naphthylmethyloxy group and the like are preferable; as the "C.sub.1-6 alkylthio group (the sulfur atom being optionally oxidized)", for example, methylthio group, ethylthio group, n-propylthio group, n-butylthio group, methylsulfinyl group, methylsulfonyl group and the like are preferable; as the "C.sub.3-10 cycloalkylthio group (the sulfur atom being optionally oxidized)", for example, cyclopropylthio group, cyclohexylthio group, cyclopentylsulfinyl group, cyclohexylsulfonyl group and the like are preferable; as the "C.sub.6-10 arylthio group (the sulfur atom being optionally oxidized)", for example, phenylthio group, naphthylthio group, phenylsulfinyl group, phenylsulfonyl group and the like are preferable; as the "C.sub.7-19 aralkylthio group (the sulfur atom being optionally oxidized)", for example, benzylthio group, phenylethylthio group, benzhydrylthio group, benzylsulfinyl group, benzylsulfonyl group and the like are preferable; as the "halogen atom", for example, fluorine atom, chlorine atom, bromine atom, iodine atom and the like are preferable; as the "C.sub.3-10 alkoxy-carbonyl group", for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group and the like are preferable; as the "C.sub.3-6 cycloalkyloxycarbonyl group", for example, cyclopropyloxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, norbornyloxycarbonyl group and the like are preferable; as the "C.sub.6-10 aryloxy-carbonyl group", for example, phenoxycarbonyl group, naphthyloxycarbonyl group and the like are preferable; as the "C.sub.7-19 aralkyloxy-carbonyl group", for example, benzyloxycarbonyl group, benzhydryloxycarbonyl group, 2-phenethyloxycarbonyl group and the like are preferable; as the "C.sub.6-10 aryl-carbonyl group", for example, benzoyl group, naphthoyl group, phenylacetyl group and the like are preferable; as the "C.sub.1-6 alkanoyl group", for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, pivaloyl group and the like are preferable; and as the "C.sub.3-5 alkenoyl group", for example, acryloyl group, crotonoyl group and the like are preferable; as the "C.sub.6-10 aryl-carbonyloxy group", for example, benzoyloxy group, naphthoyloxy group, phenylacetoxy group and the like are preferable; as the "C.sub.2-6alkanoyloxy group", for example, acetoxy group, propionyloxy group, butyryloxy group, valeryloxy group, pivaloyloxy group and the like are preferable; as the "C.sub.3-5 alkenoyloxy group", for example, acryloyloxy group, crotonoyloxy group and the like are preferable.

As the "optionally substituted carbamoyl group", for example, carbamoyl group, cyclic aminocarbonyl group and the like optionally substituted by 1 or 2 substituent(s) selected from C.sub.1-4 alkyl (e.g., methyl, ethyl and the like), phenyl, C.sub.1-7 acyl (e.g., acetyl, propionyl, benzoyl and the like), C.sub.1-4 alkoxy-phenyl (e.g., methoxyphenyl and the like) and the like are used, which is specifically, for example, carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N,N-dimethylcarbamoyl group, N,N-diethylcarbamoyl group, N-phenylcarbamoyl group, N-acetylcarbamoyl group, N-benzoylcarbamoyl group, N-(p-methoxyphenyl)carbamoyl group, 1-pyrrolidinylcarbonyl group, piperidinocarbonyl group, 1-piperazinylcarbonyl group, morpholinocarbonyl group and the like. As the "optionally substituted thiocarbamoyl group", for example, thiocarbamoyl group optionally substituted by 1 or 2 substituent(s) selected from C.sub.1-4 alkyl (e.g., methyl, ethyl and the like), phenyl and the like is used, which is specifically, for example, thiocarbamoyl group, N-methylthiocarbamoyl group, N-phenylthiocarbamoyl group and the like. As the "optionally substituted carbamoyloxy group", for example, carbamoyloxy group optionally substituted by 1 or 2 substituent(s) selected from C.sub.1-4 alkyl (e.g., methyl, ethyl and the like), phenyl and the like are used, which is specifically, for example, carbamoyloxy group, N-methylcarbamoyloxy group, N,N-dimethylcarbamoyloxy group, N-ethylcarbamoyloxy group, N-phenylcarbamoyloxy group and the like.

As the "C.sub.1-6 alkanoylamino group", for example, acetamido group, propionamido group, butyramido group, valeramido group, pivalamido group and the like are used; as the "C.sub.6-10 aryl-carbonylamino group", for example, benzamido group, naphtamido group, phthalimido group and the like are used; as the "C.sub.1-10 alkoxy-carboxamide group", for example, methoxycarboxamido group (CH.sub.3OCONH--), ethoxycarboxamido group, tert-butoxycarboxamido group and the like are used; as the "C.sub.6-10 aryloxy-carboxamido group", for example, phenoxycarboxamido group (C.sub.6H.sub.5OCONH--) and the like are used; as the "C.sub.7-10 aralkyloxy-carboxamido group", for example, benzyloxycarboxamido group (C.sub.6H.sub.5CH.sub.2OCONH--), benzhydryloxycarboxamido group and the like are used; as the "C.sub.1-10 alkoxy-carbonyloxy group", for example, methoxycarbonyloxy group, ethoxycarbonyloxy group, n-propoxycarbonyloxy group, isopropoxycarbonyloxy group, n-butoxycarbonyloxy group, tert-butoxycarbonyloxy group, n-pentyloxycarbonyloxy group, n-hexyloxycarbonyloxy group and the like are used; as the "C.sub.6-10 aryloxy-carbonyloxy group", for example, phenoxycarbonyloxy group, naphthyloxycarbonyloxy group and the like are used; as the "C.sub.7-19 aralkyloxy-carbonyloxy group", for example, benzyloxycarbonyloxy group, 1-phenylethyloxycarbonyloxy group, 2-phenylethyloxycarbonyloxy group, benzhydryloxycarbonyloxy group and the like are used; and as the "C.sub.3-10 cycloalkyloxy-carbonyloxy group", for example, cyclopropyloxycarbonyloxy group, cyclohexyloxycarbonyloxy group and the like are used.

As the "optionally substituted ureido group", for example, ureido group optionally substituted by 1 to 3 (particularly 1 or 2) substituent(s) selected from C.sub.1-4 alkyl (e.g., methyl, ethyl and the like), phenyl and the like is used. Examples thereof include ureido group, 1-methylureido group, 3-methylureido group, 3,3-dimethylureido group, 1,3-dimethylureido group, 3-phenylureido group and the like.

When heterocyclic group, heterocyclic oxy group, heterocyclic thio group, heterocyclic sulfinyl group, heterocyclic sulfonyl group or heterocyclic oxycarbonyl group is used as the "substituent" of the "aliphatic hydrocarbon group optionally having substituent(s)", the heterocyclic group means a group obtained by removing one of hydrogen atoms linked to the heterocyclic ring. Examples thereof include 5 to 8-membered ring (particularly 5 to 6-membered ring) containing 1 to several, preferably 1 to 4, hetero atom(s) such as nitrogen atom (optionally oxidized), oxygen atom, sulfur atom and the like, or a fused ring thereof. Examples of heterocyclic group include pyrrolyl group, pyrazolyl group, imidazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, thiazolyl group, isothiazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, pyranyl group, thiopyranyl group, dioxynyl group, dioxolyl group, quinolyl group, pyrido[2,3-d]pyrimidyl group, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, thieno[2,3-d]pyridyl group, benzopyranyl group, tetrahydrofuryl group, tetrahydropyranyl group, dioxolanyl group, dioxanyl group and the like.

These heterocyclic groups may be substituted by 1 to 3 substituent(s) selected from C.sub.1-4 alkyl (e.g., methyl, ethyl and the like), hydroxy, oxo, C.sub.1-4 alkoxy (e.g., methoxy, ethoxy and the like) and the like at substitutable position(s).

As the "C.sub.6-10 aryl group" of the "optionally substituted C.sub.6-10 aryl group", for example, phenyl group, naphthyl group and the like are used. The C.sub.6-10 aryl group may be substituted by substituent(s) selected from the "substituents" of the aforementioned "aliphatic hydrocarbon group optionally having substituent(s)" (except optionally substituted C.sub.6-10 aryl group) at substitutable position (s). Such substituents are substituted at substitutable position(s) of the C.sub.6-10 aryl group. The substituent is not limited to one but may be in plurality (2 to 4), which may be the same or different.

With regard to the "aliphatic hydrocarbon group optionally having substituent(s)", the substituent may form, together with aliphatic hydrocarbon group, an optionally substituted fused ring. As such fused ring, indanyl group, 1,2,3,4-tetrahydronaphthyl group and the like are used. This fused ring may be substituted by substituent(s) selected from the "substituents" of the aforementioned "aliphatic hydrocarbon group optionally having substituent(s)" and optionally substituted at substitutable position(s). These substituents are substituted at substitutable positions of the fused ring, wherein the substituent is not limited to one but may be in plurality (2 to 4), which may be the same or different.

As the "aromatic hydrocarbon group" of the "aromatic hydrocarbon group optionally having substituent(s)" represented by R.sup.1, aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., phenyl group, naphthyl group, biphenyl group, anthryl group, indenyl group and the like) and the like are preferable. Among others, for example, aryl group having 6 to 10 carbon atoms (e.g., phenyl group, naphthyl group and the like) and the like are preferable. Of these, phenyl group and the like are particularly preferable.

As the "substituent" of the "aromatic hydrocarbon group optionally having substituent(s)" represented by R.sup.1, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), lower (C.sub.1-4)alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group and the like), lower (C.sub.1-4)alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, butoxy group and the like), lower (C.sub.1-4)alkoxy-carbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group and the like), carboxyl group, nitro group, cyano group, hydroxy group, acylamino group (e.g., alkanoylamino group having 1 to 4 carbon atom(s) such as acetylamino group, propionylamino group, butyrylamino group and the like, and the like), cycloalkyl group having 3 to 6 carbon atoms (e.g., cyclopropyl group, cyclopentyl group and the like), aryl group having 6 to 10 carbon atoms (e.g., phenyl group, naphthyl group, indenyl group and the like), halogeno lower (C.sub.1-4)alkyl group (e.g., trifluoromethyl group, trifluoroethyl group and the like), halogeno lower (C.sub.1-4)alkoxy group (e.g., trifluoromethoxy group, 1,1,2,2-tetrafluoroethoxy group, 2,2,3,3,3-pentafluoropropoxy group and the like), lower (C.sub.1-4)alkylthio group (e.g., methylthio group, ethylthio group, propionylthio group and the like), lower (C.sub.1-4)alkylsulfonyl group (e.g., methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group and the like), lower (C.sub.1-4)alkanoyl group (e.g., formyl group, acetyl group, propionyl group and the like), 5-membered aromatic heterocyclic group (e.g., 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, thienyl group, furyl group and the like), carbamoyl group, lower (C.sub.1-4)alkyl-carbamoyl group (e.g., methylcarbamoyl group, dimethylcarbamoyl group, propionylcarbamoyl group and the like), lower (C.sub.1-4)alkoxy-carbonyl-lower (C.sub.1-4)alkyl-carbamoyl group (e.g., butoxycarbonylmethylcarbamoyl group, ethoxycarbonylmethylcarbamoyl group and the like), 1,3-diacylguanidino-lower (C.sub.1-4)alkyl group (e.g., 1,3-diacetylguanidinomethyl group, 1,3-bis-tert-butoxycarbonylguanidinomethyl group and the like) and the like are used, with preference given to halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom and the like), lower (C.sub.1-4)alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group and the like) and the like, and more preference given to fluorine atom, chlorine atom and methyl group.

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

The "heterocyclic group" of the "heterocyclic group optionally having substituent(s)" represented by R.sup.1 is, for example, a 5 to 8-membered ring (particularly 5 to 6-membered ring) containing 1 to several, preferably 1 to 4, hetero atom(s) from nitrogen atom (optionally oxidized), oxygen atom, sulfur atom and the like, or a fused ring thereof. These heterocyclic groups are, for example, pyrrolyl group, pyrazolyl group, imidazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl g