US 2004/0002480 A1 · Aminobutyric acid derivatives and pharmaceutical composition containing the same as active ingredient

Abstract

Aminobutylic acid derivatives of the formula (I): 1 wherein the symbols are as defined in specification; and non-toxic salts thereof. Because of inhibiting matrix metalloproteinase, the compounds of the formula (I) are useful for prevention and/or treatment of diseases, for example, rheumatoid diseases, arthrosteitis, osteoarthritis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, cornea ulcer, metastasis, invasion or growth of tumor cells, autoimmune disease, disease caused by vascular emigration or infiltration of leukocytes, arterialization, multiple sclerosis, arota aneurysm, endometriosis, restenosis after PTCA, unstable angina, acute myocardial infarction, transient ischemic attack.

Aminobutyric acid derivatives of the formula (I):

441
wherein R1 is —COOR10, —CONHOR10, —CONHNHR10, —(CH2)nSR50 or —Y—PO(OR51)2;
R10 is (i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) phenyl, (v) C1-8 alkyl substituted by phenyl or C1-8 alkoxy, or (vi) oxycarbonyl substituted by phenyl, benzyl or C1-8 alkyl;
n is 0-3;
R50 is (i) hydrogen, (ii) C1-8 alkyl, (iii) —COR52, in which R52 is C1-8 alkyl or phenyl, (iv) —SR53, in which R53 is hydrogen, C1-8 alkyl or phenyl;
R51 is hydrogen, C1-8 alkyl or phenyl;
Y is a single bond, —CH2— or —O—;
R2, R3, R4, R5, R6 and R7 each, independently, is
(1) hydrogen,
(2) C1-8 alkyl,
(3) C2-8 alkenyl,
(4) —OR11,
(5) —SR11,
(6) —NR12R13,
(7) Cyc1,
(8) C1-8 alkyl substituted by one or more groups selected from —OR11, —SR11, —NR12R13, —COR14, guanidino and Cyc1,
(9) C2-8 alkenyl substituted by one or more groups selected from —OR11, —SR11, —NR12R13, —COR14, guanidino and Cyc1,
(10) C2-8 alkynyl,
(11) C1-8 alkyl substituted by one or more groups selected from C3-8 alkenyloxy, with the proviso that a group having a double bond at 1-postion is excluded;
and C3-8 alkynyloxy, with the proviso that a group having a triple bond at 1-position is excluded;
or
R3 and R4, taken together is C1-8 alkylene, R5 and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene, R2 and R3, taken together is C2-8 alkylene, R4 and R5, taken together is C2-8 alkylene, or R6 and R7, taken together is C2-8 alkylene;
in which Cyc1 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atoms, (vii) cyano (viii) hydroxy, (ix) benzyloxy, (x) —NR101R102, in which R101 and R102 each, independently, is hydrogen or C1-8 alkyl, (xi) —COOR103, in which R103 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by —CONR104R105, in which R104 and R105 each, independently, is hydrogen, C1-8 alkyl or phenyl;
R11 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) Cyc1,
(iv) —COR18,
(v) C1-8 alkyl substituted by one or more groups selected from —OR15, —SR15, —NR16R17, —COR18, guanidino and Cyc1;
R15 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1 or C1-8 alkoxy;
R16 is hydrogen or C1-8 alkyl;
R17 is hydrogen, C1-8 alkyl or —COR19, in which R19 is C1-8 alkyl, Cyc1, C1-8 alkyl substituted by Cyc1;
R18 is hydroxy, C1-8 alkyl, C1-8 alkoxy or —NR20R21, in which R20 and R21, each independently, is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;
R12 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;
R13 is hydrogen, C1-8 alkyl, Cyc1, C1-8 alkyl substituted by Cyc1, or —COR22, in which R22 is C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1;
R14 is hydroxy, C1-8 alkyl, C1-8 alkoxy, Cyc1, C1-8 alkyl substituted by Cyc1, or —NR23R24, in which R23 and R24, each independently, is (i) hydrogen, (ii) C1-8 alkyl, (iii) Cyc1 or (iv) C1-8 alkyl substituted by Cyc1 or hydroxy;
(1) when R8 is
1) hydrogen,
2) C1-8 alkyl,
3) C1-8 alkoxycarbonyl,
4) C1-8 alkyl substituted by one or more groups selected from —OR26, —SR26, NR27R28 and —COR29, or
5) C1-8 alkoxycarbonyl substituted by Cyc2,
R9 is
442
(2) when R8 is
443
R9 is
1) C1-8 alkyl,
2) C1-8 alkoxy,
3) C1-8 alkoxy substituted by Cyc2,
4) C1-8 alkyl substituted by one or more groups selected from —OR26, —SR26, —NR27R28, —COR29 and Cyc2, or
5)
444
in which Cyc2 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atoms, (vii) cyano, (viii) hydroxy, (ix) benzyloxy, (x) —NR201R202, in which R201 and R202 each, independently, is hydrogen or C1-8 alkyl, (xi) —COOR203, in which R203 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by —CONR204R205, in which R204 and R205 each, independently, is hydrogen, C1-8 alkyl or phenyl;
R26 is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;
R27 is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;
R28 is hydrogen, C1-8 alkyl, Cyc2, C1-8 alkyl substituted by Cyc2, or —COR30, in which R30 is C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;
R29 is hydroxy, C1-8 alkyl, Cyc2, C1-8 alkyl substituted by Cyc2, or —NR31R32, in which R31 and R32, each independently, is hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2;
445
is carbocyclic ring or heterocyclic ring;
R25 is -E-G;
E is
1) a single bond,
2) —CONR33—,
3) —NR33CO—,
4) —CO—O—,
5) —O—CO—,
6) —NR33—CO—NR34—,
7) —CO—CH2—,
8) —CO—,
9) —O—CO—NR33—,
10) —NR33—CO—O—,
11) —O—CO—O—,
12) —CS—NR33—,
13) —NR33—CS—,
14) —CS—O—,
15) —O—CS—,
16) —NR33—CS—NR34—,
17) —CS—CH2—,
18) —CS—,
19) —O—CS—NR33—,
20) —NR33—CS—O—,
21) —O—CS—O—,
22) —CH2—CH2—,
23) —HC═CH—,
24) —C≡C—,
25) —SO2—NR33—,
26) —NR33—SO2—,
27) —SO2—CH2— or
28) —CH2—SO2—;
R33 and R34, each independently, is hydrogen, C1-8 alkyl, Cyc3 or C1-8 alkyl substituted by Cyc3;
Cyc3 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atoms, (vii) cyano, (viii) hydroxy, (ix) benzyloxy, (x) —NR301R302, in which R301 and R302 each, independently, is hydrogen or C1-8 alkyl, (xi) —COOR303, in which R303 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by —CONR304R305, in which R304 and R305 each, independently, is hydrogen, C1-8 alkyl or phenyl;
G is
1) hydrogen,
2) C1-8 alkyl,
3) Cyc4,
4) —OR35,
5) —SR35,
6) halogen atoms,
7) nitro,
8) cyano,
9) —NR36R37,
10) —COR38,
11) C1-8 alkyl substituted by one or more groups selected from Cyc4, —OR35, —SR35, halogen atoms, —NR36R37 and —COR38;
in which Cyc4 is carbocyclic ring or heterocyclic ring and these carbocyclic ring and heterocyclic ring may be substituted by one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) guanidino, (v) amidino, (vi) halogen atoms, (vii) cyano, (viii) hydroxy, (ix) benzyloxy, (x) —NR401R402, in which R401 and R402 each, independently, is hydrogen or C1-8 alkyl, (xi) —COOR403, in which R403 is hydrogen or C1-8 alkyl, (xii) trifluoromethyl, (xiii) trifluoromethyloxy, (xiv) phenyl, (xv) phenyl substituted by C1-8 alkyl or C1-8 alkoxy, (xvi) phenyloxy, (xvii) phenylsulfonyl, (xviii) C1-8 alkyl substituted by phenyl or cyano, (xix) heterocyclic ring, (xx) keto, (xxi) C1-8 alkoxy substituted by —CONR404R405, in which R404 and R405 each, independently, is hydrogen, C1-8 alkyl or phenyl;
R35 is hydrogen, C1-8 alkyl, C1-8 alkoxy, Cyc4 or C1-8 alkyl substituted by Cyc4;
R36 is hydrogen, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4;
R37 is hydrogen, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4, or —COR39, in which R39 is C1-8 alkyl, Cyc4 or C1-8 alkyl substituted by Cyc4;
R38 is hydroxy, C1-8 alkyl, Cyc4, C1-8 alkyl substituted by Cyc4, or —NR40R41, in which R40 and R41, each independently, is hydrogen, C1-8 alkyl, Cyc4 or C1-8 alkyl substituted by Cyc4;
or
-E-G taken together, is C1-4 alkylidene;
p is 1-5;
M is C1-8 alkylene;
J is a single bond, an oxygen atom, a sulfur atom or —NR42—, in which R42 is hydrogen or C1-8 alkyl;
{overscore (------)} is a single bond, or a double bond which prepared by two hydrogens are released, in the case of two of R2, R3, R4, R5, R6 and R7 which do not bond to a same carbon atom but bond to a neighboring carbon, are hydrogens;
with the proviso that
{overscore (------)} is not a double bond, when R3 and R4, taken together is C1-8 alkylene, R5 and R6, taken together is C1-8 alkylene, R3 and R6, taken together is C1-8 alkylene;
with the proviso that (1) at least one of R2, R3, R4, R5, R6 and R7 is C2-8 alkynyl, or C1-8 alkyl substituted by one or more groups selected from C3-8 alkenyloxy and C3-8 alkynyloxy,
(2) when
446
is benzene, and E is a single bond, then G is not hydrogen;
non-toxic acid thereof.

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Aminobutyric acid derivatives and pharmaceutical composition containing the same as active ingredient

Life of this patent

Aminobutyric acid derivatives and pharmaceutical composition containing the same as active ingredient

Life of this patent

Abstract

Claims10