Pyrrolopyridazine derivatives Number:7,153,854 from the United States Patent and Trademark Office (PTO) owispatent The invention relates to compound of the formula (I) or its salt, in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in the description, their use of as medicament, the process for their preparation and use for the treatment of PDE-IV or TNF-.alpha. mediated diseases ##STR00001##<H Pyrrolopyridazine, derivatives, Pyrrolopyridazi, 7153854.html, Patent, pto, 7153854

Title: Pyrrolopyridazine derivatives

Abstract: The invention relates to compound of the formula (I) or its salt, in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in the description, their use of as medicament, the process for their preparation and use for the treatment of PDE-IV or TNF-.alpha. mediated diseases ##STR00001##

Patent Number: 7,153,854 Issued on 12/26/2006 to Abe, et al.

Inventors: Abe; Yoshito (Osaka, JP), Inoue; Makoto (Osaka, JP), Mizutani; Tsuyoshi (Osaka, JP), Sawada; Kozo (Osaka, JP), Ohne; Kazuhiko (Osaka, JP), Okumura; Mitsuaki (Osaka, JP), Sawada; Yuki (Osaka, JP), Imamura; Kenichiro (Osaka, JP)
Assignee: Astellas Pharma Inc. (Tokyo, JP)

Appl. No.: 10/747,079

Filed: December 30, 2003

Foreign Application Priority Data


Jan 09, 2003 [AU]			2003900189
Jul 14, 2003 [AU]			2003903628

Current U.S. Class: 514/234.5 ; 514/248; 544/116; 544/235

Current International Class: C07D 487/04 (20060101); A61K 31/5025 (20060101)

Field of Search: 544/116,235 514/248,234.5

References Cited [Referenced By]

U.S. Patent Documents


6472389	October 2002	Ohtani et al.
2005/0075342	April 2005	Abe et al.

Foreign Patent Documents


2 792 938	Nov., 2000	FR
WO 91/18903	Dec., 1991	WO
WO 9118903	Dec., 1991	WO
WO 03/082208	Oct., 2003	WO

Other References

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STN search printout (p. 66-70). cited by examiner .
Mark Giembycz, Current Opinion in Pharmacology, 2005, 5:238-244. cited by examiner .
W. Flitsch, et al., Tetrahedron Letters, vol. 12, XP-002273465, pp. 1479-1484, "Synthesen Und Reaktionen Von 5-AZA-Indolizinen Und 5-AZA-Cycl(3.2.2)Azin-Derivaten", 1968. cited by other .
Takashi Ichiyama, et al., "Cerebrospinal Fluid and Serum Levels of Cytokines and Soluble Tumor Necrosis Factor Receptor in Influenza Virus-associated Encephalopathy", Scand J Infect Dis, Taylor & Francis healthciences, vol. 35, 2003, pp. 59-61. cited by other .
Jun-ichi Kawada, et al., "Systemic Cytokine Responses in Patients with Influenza-Associated Encephalopathy", Major Article, Sep. 1, 2003, pp. 690-698. cited by other .
Duan Zhong-Ping, et al., "Clinical characteristics and mechanism of liver injury in patients with severe acute respiratory syndrome", Chin J. Hepatol, vol. 11, No. 8, Aug. 2003, pp. 493-496 (with English Abstract). cited by other .
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Primary Examiner: Habte; Kahsay
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier & Neustadt, P.C.

Claims

What is claimed is:

1. A compound of the formula I or a pharmaceutically acceptable salt thereof, or a prodrug thereof: ##STR00020## wherein R.sup.1 is a phenyl, a pyrrolyl, an isooxazolyl, a furanyl, a thienyl, a lower alkyl optionally substituted by a lower alkoxy, a piperazinyl or a morpholinyl, wherein a lower alkoxy is optionally substituted by a cyclo(lower)alkyl or a pyridinyl, R.sup.2 is --(CH2)n-R.sup.7, wherein n is an integer which may range from 2 to 5, and R.sup.7 is a carboxy or an esterified carboxy, and R.sup.7 is (1) a hydrogen, (2) a substituted aryl or an unsubstituted aryl, (3) a substituted heterocyclic group or an unsubstituted heterocyclic group, (4) a carboxy, a protected carboxy or CONR.sup.10R.sup.11, (5) an acyl or a halocarbonyl, (6) a cyano, (7) an amino, a protected amino, a or mono- or di(lower)alkylamino, (8) a hydroxy, an aryloxy, an acyloxy or a lower alkyl optionally substituted by a hydroxy or an acyloxy, (9) a lower alkylthio, a lower alkylsulfinyl or a lower alkylsulfonyl, or (10) --O--R.sup.12, R.sup.3 is (1) a phenyl optionally substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a halogen, a cyano, or a carbamoyl; or (2) a pyridinyl substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a carbamoyl or a halogen, R.sup.4 is a hydrogen, a halogen, a cyano, a carbamoyl, an acyl, a thiocyanate, a lower alkylthio, a lower alkenyl, a hydroxyl(lower)alkyl, a trihalo(lower)alkyl, or a lower alkyl, R.sup.10 and R.sup.11 each independently represents a hydrogen, a lower alkylsulfonyl, a heterocyclic group, or a lower alkyl optionally substituted by a hydroxy, an alkoxy, a sulfo, a carboxy, a protected carboxy or --R.sup.17 or alternatively R.sup.10 and R.sup.11, together with a nitrogen atom to which they are attached, represent a N-containing heterocyclic group, and R.sup.12 and R.sup.17 are each independently a group derived from a protected sugar or an unprotected sugar by removal of the hydroxy group therefrom.

2. The compound of claim 1, wherein R.sup.4 is a lower alkyl.

3. The compound of claim 1, which is (1) 3-[7-Ethyl-2-methyl-3-(4-pyridinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonit- rile, (2) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, (3) 4-[7-Ethyl-2-methyl-3-(methylsulfonyl)-pyrrolo[1,2-b]pyridazin-4-yl]b- enzonitrile, (4) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide, (5) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentano- ate, (6) 2-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-- yl]methyl}-1,3-propanediol, (7) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propa- noic acid, (8) 5-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoi- c acid, (9) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]- pentanoic acid, (10) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, (11) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]pentanoic acid, (12) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]propanoic acid, (13) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]p- yridazin-3-yl]pentanoic acid, (14) Ethyl(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridaz- in-3-yl]-2-propenoate, (15) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-- yl}hexanoic acid, (16) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]propanoic acid, (17) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]butanoic acid, (18) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[- 1,2-b]pyridazin-3-yl]pentanoic acid, (19) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo- [1,2-b]pyridazin-3-yl}pentanoic acid, (20) 4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo- [1,2-b]pyridazin-3-yl}butanoic acid, (21) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]- pyridazin-3-yl]butanoic acid, (22) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]butanoic acid, (23) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, (24) 5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]- pyridazin-3-yl}pentanoic acid, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, which is (1) ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentano- ate, (2) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-- yl]propanoic acid, (3) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]- pentanoic acid, (4) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, (5) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]pentanoic acid, (6) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]propanoic acid, (7) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]p- yridazin-3-yl]pentanoic acid, (8) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-- yl}hexanoic acid, (9) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]propanoic acid, (10) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]butanoic acid, (11) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[- 1,2-b]pyridazin-3-yl]pentanoic acid, (12) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo- [1,2-b]pyridazin-3-yl}pentanoic acid, (13) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]butanoic acid, (14) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, or a pharmaceutically acceptable salt thereof.

5. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, or a prodrug thereof: ##STR00021## wherein R.sup.1 is (1) a carboxy or a protected carboxy, (2) --CONR.sup.5R.sup.6, (3) a hydroxy or a lower alkoxy, (4) an amino, a cyclo(lower)alkylamino or a mono- or di(lower)alkylamino optionally substituted by a lower alkoxy, (5) a trihalo(lower)alkyl, (6) a trihalo(lower)alkylsulfonyloxy or an arylsulfonylamino, (7) a substituted lower alkyl or an unsubstituted lower alkyl, (8) a substituted aryl or an unsubstituted aryl, or (9) a substituted heterocyclic group or an unsubstituted heterocyclic group, R.sup.2 is R.sup.7 or -(A.sup.1)p-X-A.sup.2-R.sup.7, wherein p is an integer of 0 or 1 A.sup.1 is a (C.sub.1 C.sub.2)alkylene or --CH.dbd.CH--; A.sup.2 is --(CH.sub.2)n- or --(CH.dbd.CH)m- wherein n is an integer which may range from 1 to 6, and m is an integer which may range from 1 to 3; X is a single bond, --O--, --NR.sup.8--, --C(.dbd.O)--, --C(.dbd.NR.sup.9)-- or a hydroxy(C.sub.1 C.sub.2)alkylene wherein R.sup.8 is a hydrogen or a lower alkyl, and R.sup.9 is a substituted N-containing heterocyclic group, an unsubstituted N-containing heterocyclic group, and R.sup.7 is (1) a hydrogen, (2) a substituted aryl or an unsubstituted aryl, (3) a substituted heterocyclic group or an unsubstituted heterocyclic group, (4) a carboxy, a protected carboxy or CONR.sup.10R.sup.11, (5) an acyl or a halocarbonyl, (6) a cyano, (7) an amino, a protected amino, a or mono- or di(lower)alkylamino, (8) a hydroxy, an aryloxy, an acyloxy or a lower alkyl optionally substituted by a hydroxy or an acyloxy, (9) a lower alkylthio, a lower alkylsulfinyl or a lower alkylsulfonyl, or (10) --O--R.sup.12, or R.sup.1 and R.sup.2 are combined together to form a lower alkylene or a lower alkenylene group which is optionally interrupted by an amino or a sulfonyl, and optionally fused with a benzene ring, and optionally substituted by the group consisting of a lower alkyl, a hydroxy, an oxo, and a lower alkoxy, R.sup.3 is a substituted aryl, an unsubstituted aryl, a substituted heterocyclic group, or an unsubstituted heterocyclic group, R.sup.4 is a hydrogen, a halogen, a cyano, a carbamoyl, an acyl, a thiocyanate, a lower alkylthio, a lower alkenyl, a hydroxyl(lower)alkyl, a trihalo(lower)alkyl, or a lower alkyl, R.sup.5, R.sup.6, R.sup.10 and R.sup.11 each independently represents a hydrogen, a lower alkylsulfonyl, a heterocyclic group, or a lower alkyl optionally substituted by a hydroxy, an alkoxy, a sulfo, a carboxy, a protected carboxy or --R.sup.17 or alternatively R.sup.5 and R.sup.6, or R.sup.10 and R.sup.11, together with a nitrogen atom to which they are attached, represent a N-containing heterocyclic group, and R.sup.12 and R.sup.17 are each independently a group derived from a protected sugar or an unprotected sugar by removal of the hydroxy group therefrom, the process comprising: (1) reacting a compound (II) of formula ##STR00022## wherein R.sup.3 and R.sup.4 are as defined for formula (I) or a salt thereof with a compound (III) of formula ##STR00023## wherein R.sup.1 and R.sup.2 are as defined for formula (I) or a salt thereof to obtain a compound (I) of formula ##STR00024## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined for formula (I) or a salt thereof, or (2) reacting a compound (V) of formula ##STR00025## wherein R.sup.4 is as defined for formula (I) or a salt thereof with a compound (VI) of formula ##STR00026## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined for formula (I) or a salt thereof to obtain a compound (I) of formula ##STR00027## or a salt thereof.

6. A pharmaceutical composition comprising: a compound of claim 1 in admixture with a pharmaceutically acceptable carrier.

7. The compound of claim 1, wherein R.sup.7 is (1) a hydrogen, (2) a substituted aryl or an unsubstituted aryl, (3) a cyano, (4) an amino, a protected amino, a or mono- or di(lower)alkylamino, or (5) a lower alkylthio, a lower alkylsulfinyl or a lower alkylsulfonyl.

8. The compound of claim 3, which is 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]propanoic acid or a pharmaceutically acceptable salt thereof.

9. A composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier.

10. The compound of claim 4, which is 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]propanoic acid.

11. A composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier.

12. The process of claim 5, where in the compound of formula (I) R.sup.1 is (1) a carboxy or a protected carboxy, (2) --CONR.sup.5R.sup.6 wherein R.sup.5 and R.sup.6 each independently represents a lower alkyl, or alternatively R.sup.5 and R.sup.6, together with a nitrogen atom to which they are attached represents a saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s), (3) a hydroxy or a lower alkoxy, (4) an amino, a cyclo (lower) alkylamino, or a mono- or di(lower)alkylamino optionally substituted by a lower alkoxy, (5) a trihalo(lower)alkyl, (6) a trihalo(lower)alkylsulfonyloxy or an arylsulfonylamino, (7) a lower alkyl optionally substituted by (i) a halogen; (ii) a carboxy; (iii) a protected carboxy; (iv) a cyano; (v) a carbamoyl; (vi) --OCONR.sup.15R.sup.16 wherein R.sup.15 and R.sup.16 each independently represents a hydrogen, an aryl or a lower alkyl optionally substituted by an aryl, or R.sup.15 and R.sup.16, together with the nitrogen atom to which they are attached, represents a saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing an oxygen atom; (vii) a lower alkylthio; (viii) a lower alkylsulfonyl; (ix) a lower alkylsulfonyloxy; (x) a lower alkylsulfonylamino; (xi) a mono- or di(lower)alkylamino optionally substituted by a hydroxy, a lower alkoxy, an aryloxy, or a substituted or an unsubstituted aryl; (xii) an amino; (xiii) an acylamino; (xiv) a protected amino; (xv) a hydroxy; (xvi) an acyloxy; (xvii) a cyclo(lower)alkyloxy; (xviii) an aryloxy; (xix) an aryl; (xx) a saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 3 nitrogen atom(s) and also optionally containing an oxygen atom or a sulfur atom which is optionally substituted by a lower alkyl, a hydroxy(lower)alkyl, an aryl or an oxo; or (xxi) a lower alkoxy optionally substituted by a carboxy, a protected carboxy, a hydroxy, a protected hydroxy, a lower alkoxy, a cyclo(lower)alkyl, a substituted aryl, an unsubstituted aryl, a saturated or an unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) optionally substituted by a lower alkyl, or --CONR.sup.13R.sup.14 wherein R.sup.13 and R.sup.14 each independently represents a hydrogen or a lower alkyl optionally substituted by an aryl, or R.sup.13 and R.sup.14, together with a nitrogen atom to which they are attached, represents a saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing an oxygen atom, (8) an aryl optionally substituted by the substituent(s) selected from the group consisting of a halogen, or (9) a saturated or an unsaturated 5- or 6-membered heteromonocyclic group optionally substituted by a lower alkyl or a halogen, R.sup.2 is R.sup.7 or -(A.sup.1)p-X-A.sup.2-R.sup.7 wherein p is 0 or 1; A.sup.1 is a (C.sub.1 C.sub.2)alkylene or --CH.dbd.CH--; A.sub.2 is --(CH.sub.2)n- or --(CH.dbd.CH)m- wherein n is an integer which may range from 1 to 6, and m is an integer which may range from 1 to 3; X is a single bond, --O--, --NR.sup.8--, --C(.dbd.O)--, --C(.dbd.NR.sup.9)-- or a hydroxy(C.sub.1 C.sub.2)alkylene; wherein R.sup.8 is a hydrogen or a lower alkyl, and R.sup.9 is a substituted pyrrolyl, or an unsubstituted pyrrolyl R.sup.7 is (1) a hydrogen, (2) an aryl optionally substituted by a lower alkoxy, (3) an unsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s), (4) a carboxy, an esterified carboxy or --CONR.sup.10R.sup.11 wherein R.sup.10 and R.sup.11 each independently represents a hydrogen, a lower alkylsulfonyl, an unsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s) or a lower alkyl optionally substituted by a hydroxy, an alkoxy, a carboxy, a protected carboxy, a sulfo or --R.sup.17, or alternatively R.sup.10 and R.sup.11, together with a nitrogen atom to which they are attached, represents a saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing an oxygen atom including a morpholinyl, (5) an acyl or a halocarbonyl, (6) a cyano, (7) an amino, a protected amino or a mono- or di(lower)alkylamino, (8) a hydroxy, an aryloxy, an acyloxy or a lower alkoxy optionally substituted by a hydroxy or an acyloxy, (9) a lower alkylthio, a lower alkylsulfinyl or a lower alkylsulfonyl, or (10) --O--R.sup.12, or ##STR00028## is represents by the following formula: ##STR00029## R.sup.3 is (1) an aryl optionally substituted by at least one substituent(s) selected from the group consisting of (i) a halogen, (ii) a carboxy, (iii) a protected carboxy, (iv) a cyano, (v) --CONR.sup.15R.sup.16 wherein R.sup.15 and R.sup.16 each independently represents a hydrogen, a lower alkyl optionally substituted by a hydroxy, (vi) a lower alkyl, (vii) a cyclo(lower)alkyl, (viii) a hydroxy(lower)alkyl, (ix) a lower alkoxy, (x) a trihalo(lower)alkyl, (xi) an unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 2 nitrogen atom(s), (xii) a lower alkylsulfonyl, (xiii) a nitro, (xiv) a sulfamoyl, and (xv) a protected sulfamoyl; or (2) a heterocyclic group selected from the group consisting of a pyridinyl, a pyrazinyl, an oxazolyl, an isooxazolyl, a furanyl, a thienyl, a quinolinyl, a benzofuranyl and a benzothienyl, wherein said heterocyclic group is optionally substituted by at least one substituent(s) selected from the group consisting of (i) a lower alkyl, (ii) a cyclo(lower)alkyl, (iii) a lower alkoxy, (iv) an acyl, (v) an amino, (vi) a mono- or di(lower)alkylamino, (vii) a protected amino, (viii) a cyano, (ix) a carboxy, (x) a protected carboxy, (xi) --CONR.sup.15R.sup.16 wherein R.sup.15 and R.sup.16 each independently represents a hydrogen, a lower alkyl optionally substituted by a hydroxy, (xii) a lower alkenyl optionally substituted by a lower alkoxy, (xiii) a halogen, (xiv) a lower alkylthio and (xv) a hydroxyl; R.sup.4 is a hydrogen, a halogen, a cyano, a carbamoyl, an acyl, a thiocyanate, a lower alkylthio, a lower alkenyl, a hydroxyl(lower)alkyl, a trihalo(lower)alkyl, or a lower alkyl, R.sup.12 and R.sup.17 are each independently a group derived from a protected sugar, or an unprotected sugar by removal of a hydroxy group therefrom.

13. The process of claim 12, where in the compound of formula (I) R.sup.4 is a lower alkyl.

14. The process of claim 13, where in the compound of formula (I) R.sup.1 is (1) a mono- or di(lower)alkylamino, (2) a phenyl, (3) a saturated or unsaturated 5 to 6 membered heteromonocyclic group selected from the group consisting of a pyrrolidinyl, a pyrrolyl, an oxazolyl, an isooxazolyl, a thiazolyl, a furanyl, a thienyl, and a pyridinyl, or (4) a lower alkyl optionally substituted by (i) a lower alkoxy or (ii) a saturated 5- or 6-membered heteromonocyclic group selected from the group consisting of a piperazinyl and a morpholinyl, wherein the lower alkoxy is optionally substituted by a cyclo(lower)alkyl or a pyridinyl.

15. The process of claim 14, where in the compound of formula (I) R.sup.2 is R.sup.7 or -A.sup.2-R.sup.7, wherein A.sup.2 is --(CH2)n- or --(CH.dbd.CH)m- wherein n is an integer which may range from 2 to 6, and m is an integer of 1 or 2, and R.sup.7 is a hydrogen, a lower alkyl sulfonyl, a carboxy, an esterified carboxy or a pyridinyl, R.sup.3 is (1) a phenyl optionally substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a halogen, a cyano, or a carbamoyl; or (2) a quinolinyl; or a pyridinyl substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a carbamoyl or a halogen.

16. The process of claim 15 where in the compound of formula (I) R.sup.1 is a phenyl, a pyrrolyl, an isooxazolyl, a furanyl, a thienyl, a lower alkyl optionally substituted by a lower alkoxy, a piperazinyl or a morpholinyl, wherein a lower alkoxy is optionally substituted by a cyclo(lower)alkyl or a pyridinyl, R.sup.2 is --(CH2)n-R.sup.7, wherein n is an integer which may range from 2 to 5, and R.sup.7 is a carboxy or an esterified carboxy, and R.sup.3 is (1) a phenyl optionally substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a halogen, a cyano, or a carbamoyl; or (2) a pyridinyl substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a carbamoyl or a halogen.

17. The process of claim 15, wherein the compound of formula (I) is (1) 3-[7-Ethyl-2-methyl-3-(4-pyridinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonit- rile, (2) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, (3) 4-[7-Ethyl-2-methyl-3-(methylsulfonyl)-pyrrolo[1,2-b]pyridazin-4-yl]b- enzonitrile, (4) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide, (5) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentano- ate, (6) 2-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-- yl]methyl}-1,3-propanediol, (7) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propa- noic acid, (8) 5-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoi- c acid, (9) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]- pentanoic acid, (10) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, (11) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]pentanoic acid, (12) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]propanoic acid, (13) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]p- yridazin-3-yl]pentanoic acid, (14) Ethyl(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridaz- in-3-yl]-2-propenoate, (15) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-- yl}hexanoic acid, (16) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]propanoic acid, (17) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]butanoic acid, (18) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[- 1,2-b]pyridazin-3-yl]pentanoic acid, (19) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo- [1,2-b]pyridazin-3-yl}pentanoic acid, (20) 4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo- [1,2-b]pyridazin-3-yl}butanoic acid, (21) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]- pyridazin-3-yl]butanoic acid, (22) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]butanoic acid, (23) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, (24) 5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]- pyridazin-3-yl}pentanoic acid, or a pharmaceutically acceptable salt thereof.

18. The process of claim 16, wherein the compound of formula (I) is (1) ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]p- entanoate, (2) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propa- noic acid, (3) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]- pentanoic acid, (4) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, (5) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]pentanoic acid, (6) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]propanoic acid, (7) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]p- yridazin-3-yl]pentanoic acid, (8) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-- yl}hexanoic acid, (9) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]propanoic acid, (10) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]butanoic acid, (11) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[- 1,2-b]pyridazin-3-yl]pentanoic acid, (12) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo- [1,2-b]pyridazin-3-yl}pentanoic acid, (13) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]butanoic acid, (14) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, or a pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD

This invention relates to new pyrrolopyridazine derivatives and pharmaceutically acceptable salts thereof which inhibit enzymatic activity of phosphodiesterase IV (PDE IV) and production of tumor necrosis factor-.alpha. (TNF-.alpha.).

BACKGROUND ART

Cyclic adenosine monophosphate (adenosine 3',5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as an intracellular second messenger, which is intermediated by a first messenger (hormone, neurotransmitter or autacoid) and the cellar responses. The first messenger stimulates the enzyme responsible for synthesis of cAMP, and then the cAMP intervenes in many functions such as metabolic, contractile or secretory. The effect of cAMP end when it is degraded by cyclic nucleotide phosphodiesterases, in particular phosphosiesterase-4 (PDE4 or PDE-IV), which is specific for cAMP. PDE-IV have been identified in many tissues including the central nervous systems, the heart, vascular smooth muscle, airway smooth muscle, myeloid lines, lymphoid, and the like. Evaluation of cAMP level by using the PDE-IV inhibitor would produce beneficial effect on inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.

A major concern with the use of PDE-IV inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C. Burnouf et al., (Ann. Rep. In Med. Chem., 33:91 109(1998)). Burnouf describe the wide variation of the severity of the undesirable side effects exhibited by various compounds.

Some condensed heterocyclic derivatives having the inhibitory activity of PDE-IV have been known, for example in WO03/016279, WO03/018579, WO03/000679 and the like. However, there remains a need for novel compounds that inhibit PDE-IV with minimal side effects. Although some pyrrolopyridazine derivatives having the inhibitory activity of hydroxymethylglutaryl (HMG) CoA reductase have been known, for example, in WO91/18903, pyrrolopyridazine derivatives having the inhibitory activity of PDE-IV have not been known.

DISCLOSURE OF INVENTION

This invention relates to new pyrrolopyridazine derivatives.

The compounds of this invention inhibit cAMP phosphodiesterase enzymes, in particular phosphodiesterase-4 enzyme, and also inhibit the production of tumor necrosis factor-.alpha. (TNF-.alpha.), a serum glycoprotein.

Accordingly, one object of this invention is to provide the new and useful pyrrolopyridazine derivatives and pharmaceutically acceptable salts thereof which possess a strong phosphodiesterase-4 (PDE IV)-inhibitory activity and a strong inhibitory activity on the production of tumor necrosis factor (TNF).

Another object of this invention is to provide processes for preparation of the pyrrolopyridazine derivatives and salts thereof.

A further object of this invention is to provide a pharmaceutical composition comprising said pyrrolopyridazine derivatives or a pharmaceutically acceptable salt thereof.

Still further object of this invention is to provide a use of said pyrrolopyridazine derivatives or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of PDE-IV and TNF mediated diseases such as chronic inflammatory diseases, specific autoimmune diseases, sepsis-induced organ injury, and the like in human being and animals.

The object pyrrolopyridazine derivatives of the present invention are novel and can be represented by the following general formula (I):

##STR00002## in which R.sup.1 is (1) carboxy or protected carboxy, (2) --CONR.sup.5R.sup.6, (3) hydroxy or lower alkoxy, (4) amino, cyclo(lower)alkylamino or mono- or di(lower)alkylamino optionally substituted by lower alkoxy, (5) trihalo(lower)alkyl, (6) trihalo(lower)alkylsulfonyloxy or arylsulfonylamino, (7) substituted or unsubstituted lower alkyl, (8) substituted or unsubstituted aryl, or (9) substituted or unsubstituted heterocyclic group, R.sup.2 is R or -(A.sup.1)p-X-A.sup.2-R.sup.7, wherein p is integer of 0 or 1; A.sup.1 is (C.sub.1 C.sub.2)alkylene or --CH.dbd.CH--; A.sup.2 is --(CH.sub.2)n- or --(CH.dbd.CH)m- [wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3]; X is single bond, --O--, --NR.sup.8--, --C(.dbd.O)--, --C(.dbd.NR.sup.9)-- or hydroxy(C.sub.1 C.sub.2)alkylene [wherein R.sup.8 is hydrogen or lower alkyl, and R.sup.9 is substituted or unsubstituted N-containing heterocyclic group]; and R.sup.7 is (1) hydrogen, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heterocyclic group, (4) carboxy, protected carboxy or CONR.sup.10R.sup.11, (5) acyl or halocarbonyl, (6) cyano, (7) amino, protected amino, or mono- or di(lower)alkylamino, (8) hydroxy, aryloxy, acyloxy or lower alkoxy optionally substituted by hydroxy or acyloxy, (9) lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl, or (10) --O--R.sup.12, or R.sup.1 and R.sup.2 are combined together to form lower alkylene or lower alkenylen group, which is optionally interrupted by amino or sulfonyl and optionally fuse with benzene ring, and also is optionally substituted by the group consisting of lower alkyl, hydroxy, oxo and lower alkoxy, R.sup.3 is substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group, R.sup.4 is hydrogen, halogen, cyano, carbamoyl, acyl, thiocyanate, lower alkylthio, lower alkenyl, hydroxyl(lower)alkyl, trihalo(lower)alkyl or lower alkyl, R.sup.5, R.sup.6, R.sup.10 and R.sup.11 each independently represents hydrogen, lower alkylsulfonyl, heterocyclic group or lower alkyl optionally substituted by hydroxy, alkoxy, sulfo, carboxy, protected carboxy or --R.sup.17, or alternatively R.sup.5 and R.sup.6 or R.sup.10 and R.sup.11, together with the nitrogen atom to which they are attached, represent N-containing heterocyclic group, and R.sup.12 and R.sup.17 are each independently a group derived from protected or unprotected sugar by removal of the hydroxy group therefrom, or a pharmaceutically acceptable salt thereof, or prodrug thereof.

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).

The "prodrug" means the derivatives of the object compound (I) having a chemically or metabolically degradable group, which became pharmaceutically active after chemo- or biotransformation.

Preferred embodiments of the object compound (I) are as follows.

##STR00003## in which R.sup.1 is (1) carboxy or esterified carboxy (more preferably, ethoxycarbonyl), (2) --CONR.sup.5R.sup.6 [wherein R.sup.5 and R.sup.6 each independently represents lower alkyl, or alternatively R.sup.5 and R.sup.6, together with nitrogen atom to which they are attached represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s).] (more preferably, dimethylcarbamoyl or 1-pyrrolidinylcarbonyl), (3) hydroxy or lower alkoxy, (4) amino, cyclo(lower)alkylamino, or mono- or di(lower)alkylamino optionally substituted by lower alkoxy, (5) trihalo(lower)alkyl, (6) trihalo(lower)alkylsulfonyloxy or arylsulfonylamino, (7) lower alkyl optionally substituted by (i) halogen; (ii) carboxy; (iii) protected carboxy; (iv) cyano; (v) carbamoyl; (vi) --OCONR.sup.15R.sup.16 [wherein R.sup.15 and R.sup.16 each independently represents hydrogen, aryl or lower alkyl optionally substituted by aryl, or R.sup.15 and R.sup.16, together with the nitrogen atom to which they are attached, represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom.] (more preferably, dimethylcarbamoyloxy, methyl-phenylcarbamoyloxy, morpholinylcarbonyloxy or pyrrolidinylcarnbonyloxy); (vii) lower alkylthio; (viii) lower alkylsulfonyl; (ix) lower alkylsulfonyloxy; (x) lower alkylsulfonylamino; (xi) mono- or di(lower)alkylamino optionally substituted by hydroxy, lower alkoxy, aryloxy, or substituted or unsubstituted aryl; (xii) amino; (xiii) acylamino (more preferably, lower alkanoylamino such as acetylamino, aroylamino such as benzoylamino, or heterocycliccarbonylamino such as pyrazinylcarbonylamino); (xiv) protected amino such as phthalimide, benzylamino or lower alkoxycarbonylamino; (xv) hydorxy; (xvi) acyloxy (more preferably, lower alkanoyloxy such as acetyloxy); (xvii) cyclo(lower)alkyloxy; (xviii) aryloxy; (xix) substituted or unsubstituted aryl (more preferably, phenyl); (xx) saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 3 nitrogen atom(s) and also optionally containing oxygen atom or sulfur atom (more preferably, piperazinyl, morpholinyl, oxazolidinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or triazolyl) optionally substituted by lower alkyl, hydroxy(lower)alkyl, aryl or oxo; or (xxi) lower alkoxy optionally substituted by carboxy, protected carboxy, hydroxy, protected hydroxy, lower alkoxy, cyclo(lower)alkyl, substituted or unsubstituted aryl (more preferably, phenyl optionally substituted by cyano, carboxy, protected carboxy or carbamoyl), saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, pyridinyl, pyrazinyl or piperazinyl) optionally substituted by lower alkyl, or --CONR.sup.13R.sup.14 [wherein R.sup.13 and R.sup.14 each independently represents hydrogen or lower alkyl optionally substituted by aryl, or R.sup.13 and R.sup.14, together with the nitrogen atom to which they are attached, represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom.] (more preferably, carbamoyl, methylcarbamoyl, benzylcarbamoyl or morpholinylcarbonyl), (8) aryl (more preferably, phenyl) optionally substituted by the substituent(s) selected from the group consisting of halogen, or (9) saturated or unsaturated 5- or 6-membered heteromonocyclic group (more preferably, pyrrolidinyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, furanyl, thienyl, pyridinyl) optionally substituted by lower alkyl or halogen, R.sup.2 is R.sup.7 or -(A.sup.1)p-X-A.sup.2-R.sup.7 wherein p is 0 or 1, A.sup.1 is (C.sub.1 C.sub.2)alkylene or --CH.dbd.CH--; A.sup.2 is --(CH.sub.2)n- or --(CH.dbd.CH)m- [wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3]; X is single bond, --O--, --NR.sup.8--, --C(.dbd.O)--, --C(.dbd.NR.sup.9)-- or hydroxy(C.sub.1 C.sub.2)alkylene; [wherein R.sup.8 is hydrogen or lower alkyl, and R.sup.9 is substituted or unsubstituted pyrrolyl such as 2-ethyl-5-(4-fluorobenzoyl)pyrrolyl] R.sup.7 is (1) hydrogen, (2) aryl (more preferably, phenyl) optionally substituted by lower alkoxy, (3) unsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s), (more preferably, pyridinyl), (4) carboxy, esterified carboxy (more preferably, lower alkoxycarbonyl) or --CONR.sup.10R.sup.11 [wherein R.sup.10 and R.sup.11 each independently represents hydrogen, lower alkylsulfonyl, unsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s) such as pyridinyl or lower alkyl optionally substituted by hydroxy, alkoxy, carboxy, protected carboxy, sulfo or --R.sup.17, or alternatively R.sup.10 and R.sup.11, together with the nitrogen atom to which they are attached, represents saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom such as morpholinyl], (5) acyl (e.g. lower alkanoyl such as formyl or acetyl, and heterocycliccarbonyl such as pyridinylcarbonyl) or halocarbonyl, (6) cyano, (7) amino, protected amino such as lower alkoxycarbonylamino, or mono- or di(lower)alkylamino, (8) hydroxy, aryloxy, acyloxy or lower alkoxy optionally substituted by hydroxy or acyloxy (e.g. lower alkanoyloxy), (9) lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl, or (10) --O--R.sup.12, or R.sup.1 and R.sup.2 are combined together to form lower alkylene or lower alkenylen group which is optionally interrupted by amino or sulfonyl and also is optionally substituted by the group consisting of lower alkyl, hydroxy, oxo and lower alkoxy, which is represented by the following formula:

##STR00004## that may include the following ones;

##STR00005## R.sup.3 is (1) aryl (more preferably, phenyl or naphthyl) optionally substituted by at least one substituent(s) selected from the group consisting of (i) halogen, (ii) carboxy, (iii) protected carboxy, (iv) cyano, (v) --CONR.sup.15R.sup.16 [wherein R.sup.15 and R.sup.16 each independently represents hydrogen, lower alkyl optionally substituted by hydroxy], (vi) lower alkyl, (vii) cyclo(lower)alkyl, (viii) hydroxy(lower)alkyl, (ix) lower alkoxy, (x) trihalo(lower)alkyl, (xi) unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 2 nitrogen atom(s) such as oxazolyl, (xii) lower alkylsulfonyl, (xiii) nitro, (xiv) sulfamoyl, and (xv) protected sulfamoyl; or (2) heterocyclic group selected from the group consisting of pyridinyl, pyrazinyl, oxazolyl, isooxazolyl, furanyl, thienyl, quinolyl, benzofuranyl and benzothienyl, wherein said heterocyclic group is optionally substituted by at least one substituent(s) selected from the group consisting of (i) lower alkyl, (ii) cyclo(lower)alkyl, (iii) lower alkoxy, (iv) acyl such as lower alkanoyl, (v) amino, (vi) mono- or di(lower)alkylamino, (vii) protected amino such as lower alkoxycarbonylamino, (viii) cyano, (ix) carboxy, (x) protected carboxy such as ethoxycarbonyl or methoxycarbonyl, (xi) --CONR.sup.15R.sup.16 [wherein R.sup.15 and R.sup.16 each independently represents hydrogen, lower alkyl optionally substituted by hydroxy], (xii) lower alkenyl optionally substituted by lower alkoxy, (xiii) halogen, (xiv) lower alkylthio and (xv) hydroxy; R.sup.4 is hydrogen, halogen, cyano, carbamoyl, lower alkanoyl, thiocyanate, lower alkylthio, lower alkenyl, hydroxyl(lower)alkyl, trihalo(lower)alkyl or lower alkyl, and R.sup.12 and R.sup.17 are each independently a group derived from protected or unprotected sugar such as galactose by removal of the hydroxy group therefrom, or a pharmaceutically acceptable salt thereof.

More preferred compounds of formula (I) are those in which: R.sup.1 is (1) mono- or di(lower)alkylamino, (2) aryl such as phenyl, (3) satulated or unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 hetero atom(s) selected from nitrogen, oxygen or sulfur atom(s) (more preferably, pyrrolidinyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, furanyl, thienyl, pyridinyl, etc), or (4) lower alkyl optionally substituted by lower alkoxy or saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom (more preferably, piperazinyl or morpholinyl), wherein lower alkoxy is optionally substituted by cyclo(lower)alkyl or unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, pyridinyl), R.sup.2 is R.sup.7 or -A.sup.2-R.sup.7, wherein A.sup.2 is --(CH.sub.2)n- or --(CH.dbd.CH)m- [wherein n is integer which may range 2 to 6 and m is integer of 1 or 2, and R.sup.7 is hydrogen, lower alkylsulfonyl, carboxy, protected carboxy or unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, pyridinyl), R.sup.3 is (1) aryl optionally substituted by lower alkyl, cyclo(lower)alkyl, halogen, cyano or carbamoyl; or (2) unsaturated condensed heterocyclic group containing 1 to 2 nitrogen atom(s) (more preferably, quinolinyl); or unsaturated 5 to 6 membered heteromonocyclic group containing at least one nitrogen atom(s) (more preferably, 3-pyridinyl and 4-pyridinyl) substituted by lower alkyl, cyclo(lower)alkyl or halogen, and R.sup.4 is lower alkyl.

Most preferred compounds of formula (I) are those in which: R.sup.1 is phenyl, satulated or unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 hetero atom(s) selected from nitrogen, oxygen or sulfur atom(s) (more preferably, pyrrolyl, isooxazolyl, furanyl, thienyl, etc.) or lower alkyl optionally substituted by lower alkoxy or saturated or saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing oxygen atom (more preferably, piperazinyl or morpholinyl), wherein lower alkoxy is optionally substituted by cyclo(lower)alkyl or unsaturated 5 to 6 membered heteromonocyclic group containing at least one nitrogen atom(s) (more preferably, pyridinyl), R.sup.2 is --(CH.sub.2)n-R.sup.7, wherein n is integer which may range 2 to 5, and R.sup.7 is carboxy or protected carboxy, R.sup.3 is (1) phenyl optionally substituted by lower alkyl, cyclo(lower)alkyl, lower alkoxy, halogen, cyano or carbamoyl; or (2) unsaturated 5 to 6 membered heteromonocyclic group containing at least one nitrogen atom(s) (more preferably, 3-pyridinyl and 4-pyridinyl) substituted by lower alkyl, cyclo(lower)alkyl, lower alkoxy, carbamoyl or halogen, and R.sup.4 is lower alkyl.

Preferred concrete compound of formula (I) is: (1) 3-[7-Ethyl-2-methyl-3-(4-pyridinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonit- rile, (2) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, (3) 4-[7-Ethyl-2-methyl-3-(methylsulfonyl)-pyrrolo[1,2-b]pyridazin-4-yl]b- enzonitrile, (4) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide, (5) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentano- ate, (6) 2-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-- yl]methyl}-1,3-propanediol, (7) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propa- noic acid, (8) 5-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoi- c acid, (9) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]- pentanoic acid, (10) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, (11) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]pentanoic acid, (12) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]propanoic acid, (13) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]p- yridazin-3-yl]pentanoic acid, (14) Ethyl(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridaz- in-3-yl]-2-propenoate, (15) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-- yl}hexanoic acid (16) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]propanoic acid, (17) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]butanoic acid, (18) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[- 1,2-b]pyridazin-3-yl]pentanoic acid, (19) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo- [1,2-b]pyridazin-3-yl}pentanoic acid. (20) 4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo- [1,2-b]pyridazin-3-yl}butanoic acid, (21) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]- pyridazin-3-yl]butanoic acid, (22) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]butanoic acid, (23) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, or (24) 5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]- pyridazin-3-yl}pentanoic acid, or a pharmaceutically acceptable salt thereof.

More preferred concrete compound of formula (I) is: (1) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentano- ate, (2) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-- yl]propanoic acid, (3) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]- pentanoic acid, (4) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, (5) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]pentanoic acid, (6) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyrida- zin-3-yl]propanoic acid, (7) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]p- yridazin-3-yl]pentanoic acid, (8) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-- yl}hexanoic acid (9) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]propanoic acid, (10) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridaz- in-3-yl]butanoic acid, (11) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[- 1,2-b]pyridazin-3-yl]pentanoic acid, and (12) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo- [1,2-b]pyridazin-3-yl}pentanoic acid, (13) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]butanoic acid, or (14) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyrida- zin-3-yl]pentanoic acid, or a pharmaceutically acceptable salt thereof.

The object compound (I) of the present invention can be prepared by the following processes.

##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each as defined above, R.sup.1.sub.a is the same as above R.sup.1 having protected carboxy moiety, R.sup.1.sub.b is the same as above R.sup.1 having carboxy moiety, R.sup.1.sub.c is --CONR.sup.5R.sup.6, R.sup.1.sub.d is carbamoyl(lower)alkyl, R.sup.1.sub.e is amino, mono- or di(lower)alkylamino-, lower alkoxy(lower)alkylamino, nitrogen-containing heterocyclic group, amino(lower)alkyl, mono- or di(lower)alkylamino(lower)alkyl, lower alkoxy(lower)alkylamino(lower)alkyl, nitrogen-containing heterocyclic(lower)alkyl, R.sup.1.sub.f is lower alkylthio(lower)alkyl, R.sup.1.sub.g is lower alkylsulfonyl(lower)alkyl, R.sup.1.sub.h is trifluoromethanesulfonyloxy or trifluoromethanesulfonyloxy(lower)alkyl, R.sup.1.sub.i is lower alkoxy or lower alkoxy(lower)alkyl, R.sup.1.sub.j is hydroxy or hydroxy(lower)alkyl, R.sup.2.sub.a is lower alkoxycarbonyl, R.sup.2.sub.b is the same as above R.sup.2 having protected carboxy moiety, R.sup.2.sub.c is the same as above R.sup.2 having carboxy moiety, R.sup.2.sub.d is the same as above R.sup.2 having carbamoyl moiety, R.sup.2.sub.e is the same as above R.sup.2 having protected hydroxy moiety, R.sup.2.sub.f is the same as above R.sup.2 having hydroxy moiety, R.sup.2.sub.g is the same as above R.sup.2 having hydroxymethyl moiety, R.sup.2.sub.h is --OR.sup.12, R.sup.2.sub.i is lower alkoxycarbonyl or lower alkylsulfonyl, R.sup.2.sub.j is substituted or unsubstituted lower alkenyl as mentioned in the above R.sup.2, wherein said lower alkenyl is lower 1-alken-1-yl, R.sup.2.sub.k is the same as above R.sup.2 having hydroxy(lower)alkyl moiety, R.sup.2.sub.l is the same as above R.sup.2 having oxo(lower)alkyl moiety, R.sup.2.sub.m is the same as above R.sup.2 having protected amino moiety, R.sup.2.sub.n is the same as above R.sup.2 having amino moiety, R.sup.2.sub.o is the same as above R.sup.2 having protected hydroxy moiety, R.sup.2.sub.p is the same as above R.sup.2 having hydroxy(lower)alkylamino(lower)alkyl moiety, R.sup.2.sub.q is the same as above R.sup.2 having lower alkoxycarbonyl(lower)alkyl moiety, R.sup.2.sub.r is the same as above R.sup.2 having lower alkoxycarbonylmethylcarbonyl moiety, R.sup.3.sub.a is the same as above R.sup.3 having cyano moiety, R.sup.3.sub.b is the same as above R.sup.3 having carbamoyl moiety, R.sup.3.sub.c is the same as above R.sup.3 having carboxy moiety, R.sup.3.sub.d is the same as above R.sup.3 having protected sulfamoyl moiety, R.sup.3.sub.e is the same as above R.sup.3 having sulfamoyl moiety, R.sup.3.sub.f is the same as above R.sup.3 having --CONR.sup.10R.sup.11 moiety, R.sup.3.sub.g is the same as above R.sup.3 having haloheterocyclic moiety, R.sup.3.sub.h is the same as above R.sup.3 having alkoxyheterocyclic, thioalkoxyheterocyclic or hydroxy moiety, R.sup.3.sub.i is the same as above R.sup.3 having 1-(lower)alkoxy(lower)alken-1-ylheterocyclic moiety, R.sup.3.sub.j is the same as above R.sup.3 having lower alkanoylheterocyclic moiety, R.sup.3.sub.k is the same as above R.sup.3 having aminomethylheterocyclic moiety, R.sup.3.sub.l is the same as above R.sup.3 having mono- or di(lower)alkylaminoheterocyclic moiety, R.sup.3.sub.m is the same as above R.sup.3 having (lower)alken-1-ylheterocyclic group or 1-(lower)alkoxy-1-(lower)alken-1-yl-heterocyclic moiety, R.sup.4.sub.a is halogen, R.sup.4.sub.b is formyl, R.sup.4.sub.c is lower 1-alken-1-yl, R.sup.4.sub.d is lower alkyl, R.sup.12 is lower alkyl or a group derived from protected or unprotected sugar by removal of the hydroxy group therefrom, X is a leaving group, and a group of the formula:

##STR00016## is lower alkylene interrupted by imino moiety and substituted by oxo groups.

The starting compound (II) of the present invention can be prepared according to a conventional manner or in a similar manner as described in the following Preparations and/or Examples.

Another point to be noted is that the pyrrolopyridazine moiety of the compound (I) can also exist in the tautomeric form, and such tautomeric equilibrium can be represented, for example, by the following formula.

##STR00017## wherein R.sup.1 R.sup.2, R.sup.3 and R.sup.4 are each as defined above.

Both of the above tautomeric isomers are included within the scope of the present invention, and in the present specification and claims, however, the object compound (I) is represented for convenience' sake by one expression of the possible tautomeric forms of pyrrolopyridazine ring.

In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.

The term "lower" is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.

Suitable "lower alkyl" and "lower alkyl moiety" may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, and in which more preferable example may be C.sub.1 C.sub.4 alkyl.

Suitable "lower alkenyl" may include vinyl(ethenyl), 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, 1-methylvinyl, 1-ethylvinyl, 1-(or 2-)methyl-1-(or 2-)propenyl, 1-(or 2-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferable example may be C.sub.2 C.sub.4 alkenyl.

Suitable "lower alkynyl" may include ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, and the like.

Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, propylene, and the like, in which more preferable example may be C.sub.1 C.sub.4 alkylene and the most preferable one may be methylene.

Example of hydroxy(C.sub.1 C.sub.2)alkylene is hydroxymethylene, (hydroxymethyl)methylene or 1-(or 2-)hydroxyethylene.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.

Suitable "halogen" and "halogen moiety" may include fluorine, bromine, chlorine and iodine.

Suitable "trihalo(lower)alkyl" may include trichloromethyl, trifluoromethyl, trichloroethyl, tribromoethyl, and the like.

Suitable "mono- or di(lower)alkylamino" may include amino group substituted by one or two lower alkyl such as methylamino, ethylamino, dimethylamino, and the like.

Example of "mono- or di(lower)alkylamino substituted by lower alkoxy" may be methoxymetylamino, methoxyethylamino, methoxyethyl(methyl)amino, methoxyethyl(ethyl)amino, di(methoxyethyl)amino, ethoxymethylamino, ethoxyethylamino, and the like.

Suitable "lower alkylthio" may include conventional ones such as methylthio, ethylthio, propylthio, butylthio, and the like.

Suitable "lower alkylsulfinyl" may include conventional ones such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like.

Suitable "lower alkylsulfonyl" may include conventional ones such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, bytylsulfonyl, and the like.

Suitable "trihalo(lower)alkylsulfonyloxy" may include sulfonyloxy group substituted by trihalo(lower)alkyl such as trifluoromethylsulfonyloxy, trifluoroethylsulfonyloxy, trichloromethylsulfonyloxy, and the like.

Suitable "protected carboxy" and "protected carboxy moiety" may include esterified carboxy and the like.

And suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); lower alkylthio(lower)alkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropoxythiomethyl ester, etc.); mono(or di or tri)halo(lower)alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, 1-(or 2-)-[methoxycarbonyloxy]ethyl ester, 1-(or 2-)-[ethoxycarbonyloxy]ethyl ester, 1-(or 2-)-[propoxycarbonyloxy]ethyl ester, 1-(or 2-)-[isopropoxycarbonyloxy]ethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or 2-)-isopropoxycarbonyloxyethyl ester, etc.); phthalidylidene(lower)alkyl ester; (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; mono(or di or tri)aryl(lower)alkyl ester, for example, mono(or di or tri)phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may have one or more suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri(lower)alkylsilyl ester (e.g. trimethylsilyl ester, triethylsilyl ester, etc.); tri(lower)alkylsilyl(lower)alkyl ester (e.g. 2-trimethylsilylethyl ester, etc.); and the like, in which more preferable example may be lower alkyl ester, i.e., lower alkoxycarbonyl (e.g. ethoxycarbonyl, etc.).

The term "protected amino" means an amino group bonded to the amino-protecting group. Example of such amino-protectnig group include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.); lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.); optionally substituted aryl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.); phthalimide; and the like. Further example of amino-protecting group are well-known in organic synthesis and are described by T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," Second Edition, John Wiley and Sons, New York, N.Y., which is herein incorporated by reference.

The term "protected sulfamoyl" means sulfamoyl group having the amino-protecting group mentioned above on the nitrogen atom. A preferred amino-protecting group is aryl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.); and the like.

Suitable "acyl" and "acyl moiety" may include aliphatic acyl group, and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.

Suitable example of said acyl may be illustrated as follows: Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); in which preferable "lower alkanoyl" may include straight or branched one such as formyl, acetyl, propionyl, butyryl, and the like. lower or higher alkenoyl (e.g., acryloyl, 2-(or 3-)-butenoyl, 2-(or 3- or 4-)pentenoyl, 2-(or 3- or 4- or 5-)-hexenoyl, etc.); lower alkadienoyl (e.g., heptadienoyl, hexadienoyl, etc.); cyclo(lower)alkylcarbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); lower alkylglyoxyloyl (e.g., methylglyoxyloyl, ethylglyoxyloyl, propylglyoxyloyl, etc.); lower alkoxyglyoxyloyl (e.g., methoxyglyoxyloyl, ethoxyglyoxyloyl, propoxyglyoxyloyl, etc.); or the like; Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenyl