4-aminobutanoic acid derivatives and drugs containing these...

Details 4-aminobutanoic acid derivatives and drugs containing these... 4-aminobutanoic acid derivatives and drugs containing these...

2001-10-05

2003-05-27

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C564S155000, C562S465000, C558S415000, C558S169000, C558S170000, C560S170000, C560S173000, C514S140000, C514S506000, C514S616000

Reexamination Certificate

active

06569899

ABSTRACT:

TECHNICAL FIELD
This invention relates to aminobutyric acid derivatives, processes for the preparation thereof and pharmaceutical agents comprising aminobutyric acid derivatives as active ingredient.
More particularly, this invention relates to:
[1] aminobutyric acid derivatives of the formula (I):
wherein all the symbols are as hereinafter defined, and non-toxic salts thereof, processes for the preparation thereof and pharmaceutical agents comprising aminobutyric acid derivatives as active ingredient, and
[2] a compound which is selected from
(1)5-ethoxymethoxy-4(S)-[N-(4-iodophenylcarbonyl)amino]pentanoic acid,
(2)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-methoxymethylpentanoic acid,
(3)2(R)-ethoxymethyl-5-ethoxymethoxy-4 (S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(4) 5-ethoxymethoxy-2 (S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(5)5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(6)2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(7)5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(8)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyhenylcarbonyl)amino]pentanoic acid,
(9)5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanoic acid,
(10)5-ethoxymethoxy-4(S)-[N-(4-cyanophenylcarbonyl)amino]-2(R)-ethoxymethylpentanoic acid,
(11)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(12)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanoic acid,
(13)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanoic acid,
(14)5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanoic acid,
(15)5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanoic acid,
(16)5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(17)5-methoxyethoxymethoxy-2(S)-methyl-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanoic acid,
(18)trans-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexanoic acid,
(19)trans-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexanoic acid,
(20)trans-2-[(4-nitrophenylcarbonyl)amino]cyclohexylacetic acid,
(21)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,
(22)N-hydroxy-2(R)-ethoxymethyl-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(23)N-hydroxy-5-ethoxymethoxy-2(S)-(3-thienylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(24)N-hydroxy-5-ethoxymethoxy-2(S)-(3-furylmethyl)-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(25)N-hydroxy-2(S)-benzyl-5-pivaroyloxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(26)N-hydroxy-5-acetyloxy-2(S)-benzyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(27)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-phenoxyphenylcarbonyl)amino]pentanamide,
(28)N-hydroxy-5-ethoxymethoxy-2(R)-methoxymethyl-4(S)-[N-(4-(2-furyl)phenylcarbonyl)amino]pentanamide,
(29)N-hydroxy-5-ethoxymethoxy-2(R)-ethoxymethyl-4(S)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,
(30)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(31)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,
(32)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-bromophenylcarbonyl)amino]pentanamide,
(33)N-hydroxy-5-ethoxymethoxy-2(S)-methoxymethyl-4(R)-[N-(4-cyanophenylcarbonyl)amino]pentanamide,
(34)N-hydroxy-5-ethoxymethoxy-2(S)-benzyl-4(S)-[N-(4-chlorocyclohexylcarbonyl)amino]pentanamide,
(35)N-hydroxy-5-ethoxymethoxy-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(36)N-hydroxy-2(S)-methyl-5-methoxyethoxymethoxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(37)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-nitrophenylcarbonyl)amino]pentanamide,
(38)N-hydroxy-5-hydroxy-2(R)-methoxymethyl-4(S)-[N-(4-chlorophenylcarbonyl)amino]pentanamide,
(39)N-hydroxy-2(S)-(2-benzothiophen-3-yl)methyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(40)N-hydroxy-2(S)-allyl-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(41)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-bromophenylcarbonyl)amino]pentanamide,
(42)N-hydroxy-2(S)-(3-phenylpropyl)-5-hydroxy-4(S)-[N-methyl-N-(4-nitrophenylcarbonyl)amino]pentanamide,
(43)N-hydroxy-2(S)-methyl-5-hydroxy-4(S)-[N-methyl-N-[(5-nitro-2-thienyl)carbonyl]amino]pentanamide,
(44)N-hydroxy-2(S)-benzyl-5-hydroxy-4(S)-[N-methyl-N-[(5-bromo-2-thienyl)carbonyl]amino]pentanamide,
(45)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-nitrophenylcarbonyl)aminomethyl]cyclohexane,
(46)trans-1-(N-hydroxyaminocarbonyl)-2-[(4-(3-methoxy-1-propynyl)phenylcarbonyl)aminomethyl]cyclohexane,
(47)trans-1-(N-hydroxyaminocarbonylmethyl)-2-[(4-nitrophenylcarbonyl)amino]cyclohexane,
and methyl ester, t-butyl ester, benzyl ester, allyl ester, and non-toxic salts thereof, and pharmaceutical agents comprising the compound and non-toxic salts thereof as active ingredient.
BACKGROUND ART
The matrix metalloproteinases (MMPs) are neutral metalloproteinases and zinc (Zn
2+
) is essential in the active site for their activation. They degrade collagen, laminin, proteoglycans, fibronectin, elastin, gelatin etc. under physiological conditions and therefore, are effective on growth and tissue remodeling of articulation tissue, bone tissue and connective tissue. At least 10 classes of MMPs, which differ in primary structure, are identified. Concretely, there are Interstitial Collagenase (MMP-1), Neutrophil Collagenase (MMP-8), Gelatinase A (MMP-2), Gelatinase B (MMP-9), Stromelysin-1 (MMP-3), Stromelysin-2 (MMP-10), Matrilysin (MMP-7), metalloelastase (MMP-12) etc.
As common characteristics of these enzymes, MMPs
(1) have Zn
2+
in the active site and the activity depends on calcium ion (Ca
2+
)
(2) are secreted as an inactive proenzyme and activated outside of cells,
(3) have high homology on amino acid sequence,
(4) have an ability to degrade on various extracellular matrix components in vivo,
(5) are regulated by tissue inhibitors of metalloproteinases (TIMP) which are specific to MMPs.
MMP inhibitors are useful for prevention and/or treatment of various diseases induced by overexpression and excess activation of MMP. Such diseases are, 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 (Crohn's disease, Sjogren's syndrome), disease caused by vascular emigration or infiltration of leukocytes, arterialization, multiple sclerosis, aorta aneurysm, endometriosis, restenosis after PTCA, unstable angina, acute myocardial infarction, transient ischemic attack.
Some compounds possessing inhibitory activity against MMP are known. A sequence in the vicinity of cleavage site of collagen (Gly-Ile-Ala-Gly or Gly-Leu-Ala-Gly) has high affinity for collagenase. Much research and development on substrate analogous MMP inhibitors, which are chemically modified so as to have zinc affinity groups on a cleaving site of the substrate, has energetically been carried out [Inhibitors of matrix metalloproteinases (MMP's), Nigel R A Beeley, Phillip R J Ansell, Andrew J P Docherty et. al., Curr. Opin. Ther. Patents., A, 7-16 (1994), Current Drugs Ltd ISSN 0962-2594]. However,

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