KR20100014090A - A pharmaceutical composition for preventing or treating osteoporosis comprising benzamidine derivative or its salt, and bisphosphonate - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing benzamidine derivative and bisphosphonate is provided to suppress osteoclasts and prevent or treat osteoporosis. CONSTITUTION: A pharmaceutical composition for preventing or treating osteoporosis contains a novel benzamidine derivative of chemical formula 1 or its salt, and bisphosphonate of chemical formula 2. The benzamidine derivative and bisphosphonate are used simultaneously, separately, or in order. The bisphosphonate is etidronic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, ibandronic acid, or zoledronic acid.

Description

A pharmaceutical composition for preventing or treating osteoporosis comprising benzamidine derivative or its salt, and bisphosphonate, including: benzamidine derivatives or salts thereof, and bisphosphonates

The present invention relates to a pharmaceutical composition for the prevention or treatment of osteoporosis, including benzamidine derivatives or salts thereof, and bisphosphonates, and more particularly, to benzamidine and salts thereof, and bisphosphonates or salts thereof. It relates to a pharmaceutical composition for the prevention or treatment of osteoporosis, including benzamidine derivatives or salts thereof, and bisphosphonates, which have a better effect when administered in combination than when used.

Bone (bone) serves to preserve the amount and structure of bone required as a physical support of the body, a storage of calcium (Ca ²⁺ ), etc., and plays an important role in maintaining the blood concentration of calcium. Goals always perform decomposition and remodeling to accomplish this function. Thus, the bone maintains a dynamic state in which both bone absorption and bone formation are actively progressed to metabolism in equilibrium. When the equilibrium relationship between bone absorption and bone formation is broken, the bone absorption amount becomes larger than the bone formation amount, causing a decrease in bone density or bone mass, and osteoporosis in a state in which bone strength is not maintained may appear. It is a disease that is particularly common among middle-aged women.

Osteoporosis (osteoporosis) is caused by the breakdown of the balance between bone resorption and bone formation is due to the progression of excess bone absorption than bone formation. Osteoporosis is a symptom of diminished bone tissue, which causes thinning of the dense bone and widens the bone marrow cavity. The bones become weaker as the symptoms of osteoporosis progress, so they are more likely to fracture even with a small impact. Bone tissue is a dynamic tissue that is formed by osteoblasts and constantly destroyed and absorbed by osteoclasts.

In the past, the study was mainly focused on the minerals of bone, that is, metabolic abnormalities of calcium and phosphorus, but no significant progress was made in identifying the pathogenesis.

Such fracture induction not only increases the morbidity and mortality of osteoporosis patients, but also causes very serious problems of poor quality of life. Therefore, various osteoporosis treatments with various mechanisms have been developed for the purpose of increasing bone density and reducing the possibility of fracture.

Materials currently used for the treatment of osteoporosis include bisphosphonate preparations (alendronate, ethidronate, etc.), hormone preparations (raloxifene), vitamin D preparations, calcitonin preparations and calcium preparations, and recently, parathyroid hormone preparations that have osteogenic effects. Inforteo ^™ and the like are commercially available. Hormone preparations should be taken for life and long-term administration can cause side effects such as breast cancer, uterine cancer, gallstones and thrombosis. Vitamin D formulations are expensive and ineffective, calcitonin formulations are expensive and difficult to administer. Calcium preparations have fewer side effects, but are limited to preventive effects rather than treatment. The PTH formulation recently commercialized Forte O ^TM, but the advantage of a bone formation effect can be up for the weak points of existing drugs specific to bone resorption inhibitory be a administered in long-term daily injections, and also has the side effect of bone over-produce The problem is that their use is limited because they are very expensive.

Among the most prescribed drugs for treating osteoporosis, bisphosphonate-based drugs include alendronate and risedronate. These drugs have been demonstrated to increase bone density and prevent fractures due to strong bone resorption inhibitory effects, and have the advantages of oral use and cost-effective economical efficiency, and are widely used in the clinical trials as a treatment for diseases caused by calcium metabolism abnormalities.

However, because bisphosphonate preparations are poorly absorbed and cause esophagitis, they should be taken with plenty of water before breakfast. It has been reported to be very demanding and increases the risk of hypocalcemia. In recent research, problems such as suppression of bone turnover rate due to excessive bone repression, inhibition of bone formation by affecting bone formation rate, gastrointestinal disorder and necrosis necrosis have been raised. Recent reports have shown a fatal problem that increases the risk of fracture when used for long periods of time (Andrew S Neviaser et al., Journal of Othopaedic Trauma , 2008, 22 (5), 346-350 ).

As can be seen from the above, the therapeutic agent currently used in the clinic has a limitation in the balanced treatment of bone resorption and bone formation. Therefore, there is a need for the development of drugs and new therapies that can substantially reduce the risk of fracture by improving the balance of bone mass and improving bone quality for the fundamental treatment of osteoporosis.

Various studies have been conducted to overcome the above problems and to improve clinical therapeutic efficacy, and recently, there have been reports of the combined administration of parathyroid hormones and bone resorption inhibitors known to promote marketed bone formation. Details of these are as follows.

Examples of coadministration between alendronate and another bone resorption inhibitor include alendronate and estrogen (Lindsay et al. , J. Clin. Endocrinol. Metab . 84, 3073-3081 (1999)), alendronate and raloxifene (Johnell et al., J. Clin. Endocrinol. Metab . 87, 985-992 (2002)), alendronate and hormone replacement therapy (HRT) (Greenspan et al., JAMA , 289, 2525-2533 (2003)) and alendronate and calcitriol (WO 01/28564). The general view of these studies acknowledges that bone mineral density is increased over single administration, but the effect of lowering the risk of fracture has not been identified. In addition, the mechanisms are different, but due to the enhanced bone absorption inhibitory effect, fundamental problems such as rapid bone turnover rate and bone formation suppression still remain, these conditions require careful consideration and research.

Therefore, in combination with an osteogenic accelerator, an attempt has been made to reduce the effects of alendronate on bone formation and alleviate side effects. Representative examples are combination therapy with parathyroid hormone agents. Postmenopausal women (Black et al . , N. Eng. J. Med. 349, 1207-1215, (2003)) and elderly men (Finkelstein et al . , N. Eng. J. Med. 349, 1216-1226, (2003), the two drugs were co-administered at the same time, but no synergistic effect of bone mineral density was observed. Therefore, some researchers have raised the possibility that alendronate, a potent inhibitor of bone resorption, can simultaneously counterbalance the parathyroid hormone-stimulating effects. Subsequently, sequential co-administration between the two drugs is attempted, but more research is needed to determine the exact clinical findings.

From the previous studies, the inventors of the present invention found that a new benzamidine derivative or salt thereof, which is expected as an effective therapeutic agent for osteoporosis, in Korean Patent Registration No. 705875, Korean Patent Registration No. 875596 and Korean Patent Application No. 2008-0073710. And it was confirmed that it has an excellent effect as a therapeutic agent.

Accordingly, the present inventors have tried to save their advantages and reduce their disadvantages by co-administering the novel benzamidine component of Formula 1, which is effective as an agent for preventing or treating osteoporosis, with existing osteoporosis treatments that can be used as a single agent. As a result, by using a combination of benzamidine and its salt with bisphosphonates or salts of the formula (1), to provide a composition for preventing or treating osteoporosis having a superior inhibitory effect on the differentiation of osteoclasts than when each drug alone It was confirmed that the present invention was completed.

It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of osteoporosis comprising benzamidine derivatives or salts thereof, and bisphosphonates.

Another object of the present invention is a benzamidine derivative or salt thereof having a superior inhibitory effect on the differentiation of osteoclasts when co-administered with benzamidine and salts thereof, and bisphosphonates or salts thereof alone. And to provide a pharmaceutical composition for the prevention or treatment of osteoporosis comprising bisphosphonate.

Still another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of osteoporosis, including benzamidine derivatives or salts thereof, and bisphosphonates, which can enhance the effectiveness of the prevention and treatment of the lesions related to bone resorption including osteoporosis. It is to provide.

The above and other objects of the present invention can be achieved by the present invention described below.

In one embodiment, the present invention provides a pharmaceutical composition for the prevention or treatment of osteoporosis, comprising (a) and (b) below as active ingredients for use simultaneously, separately or sequentially:

(a) a novel benzamidine derivative represented by the following formula (1) or a salt thereof,

(b) bisphosphonates represented by the following formula (2),

In Chemical Formula 1,

로 치환된, C₁~C₆ 직쇄 또는 측쇄 알킬; C₃~C₆ 시클로알킬; 페닐; 벤질; C₁~C₆ 알킬로 치환 또는 비치환된 피리딘일; 구아니디노; NR₆R₇; CH₂NR₆R₇; C₁~C₆ 직쇄 또는 측쇄 알킬로 치환된 피리디닐 또는

그룹이고;

(A는 C₁~C₆ 알킬이고, m은 2 내지 6의 정수이다); 또는 C₁~C₆ 알킬로 치환 또는 비치환된

그룹이고; R ₁ is C ₁ -C ₆ alkyl unsubstituted or substituted with pyridine; Unsubstituted or substituted with hydroxy

C ₁ -C ₆ straight or branched alkyl, substituted with; C ₃ -C ₆ cycloalkyl; Phenyl; benzyl; Pyridinyl unsubstituted or substituted with C ₁ -C ₆ alkyl; Guanidino; NR ₆ R ₇ ; CH ₂ NR ₆ R ₇ ; Pyridinyl substituted with C ₁ to C ₆ straight or branched alkyl or

Group;

(A is C ₁ -C ₆ alkyl and m is an integer from 2 to 6); Or unsubstituted or substituted with C ₁ to C ₆ alkyl

Group;

로 치환된 C₁~C₆ 직쇄 또는 측쇄 알킬; 피롤리딘, 피페리딘 또는 이미다졸로 치환된 C₁~C₆ 직쇄 또는 측쇄 알킬이며; R ₂ is hydrogen; C ₁ -C ₆ straight or branched alkyl substituted or unsubstituted with NR ₈ R ₉ ; C ₃ -C ₆ cycloalkyl; Phenyl; benzyl; C ₁ -C ₆ straight or branched chain alkyl substituted with hydroxy, C ₁ -C ₆ alkoxy, halogen or C ₃ -C ₆ cycloalkyl; C ₁ -C ₆ alkenyl; Carbonyl substituted with NR ₈ R ₉ ;

C ₁ ~ C ₆ linear or branched alkyl substituted with; C ₁ -C ₆ straight or branched chain alkyl substituted with pyrrolidine, piperidine or imidazole;

R ₃ and R ₄ are each hydrogen; halogen; Hydroxy; C ₁ -C ₆ alkyl unsubstituted or substituted with halogen; C ₃ -C ₆ cycloalkylamino; C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkanoyloxy; C ₂ -C ₆ alkenyloxy; Phenyl-C ₁ -C ₆ alkoxy; Phenoxy; C ₂ ~ C ₆ alkenyl or phenyl alkanoyl oxy -C ₁ ~ C ₆ alkanoyloxy; Or C ₃ -C ₆ cycloalkyloxy substituted with one group selected from carboxy, esterified carboxy or amidated carboxy; Or an aminooxy group;

R ₅ is hydrogen or a hydroxy group;

중에서 선택된 하나의 기로 치환 또는 비치환된 C₁~C₆ 알킬; 페닐; 벤질; 피리딘일; C₁~C₆ 알킬, 히드록시, C₁~C₆ 알콕시, 페닐, 벤질, 피리딘 또는

중에서 선택된 하나의 기로 치환된 카보닐; 또는 C₁~C₆ 알칸술포닐이고; R ₆ and R ₇ are each hydrogen; Hydroxy, C ₁ -C ₆ alkoxy, pyridine or

C ₁ ~ C ₆ alkyl unsubstituted or substituted with one group selected from; Phenyl; benzyl; Pyridinyl; C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, phenyl, benzyl, pyridine or

Carbonyl substituted with one group selected from; Or C ₁ -C ₆ alkanesulfonyl;

중에서 선택된 하나의 기로 치환된 카보닐; 할로겐, C₁~C₆ 알콕시 또는 이미다졸 중에서 선택된 하나의 기가 치환된 C₁~C₆ 알킬로 치환된 카보닐; 또는 C₁~C₆ 알칸술포닐이며; R ₈ and R ₉ are each hydrogen; Hydroxy, C ₁ ~ C ₆ alkoxy, morpholine, imidazole or substituted with one NR ₆ R ₇ group selected from the group consisting of and unsubstituted C ₁ ~ C ₆ alkyl; C ₁ -C ₆ alkoxy; C ₃ -C ₆ cycloalkyl; Phenyl; benzyl; Pyridinyl; Morpholine; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl, benzyl, pyridine or

Carbonyl substituted with one group selected from; Carbonyl substituted with C ₁ -C ₆ alkyl substituted with one group selected from halogen, C ₁ -C ₆ alkoxy or imidazole; Or C ₁ -C ₆ alkanesulfonyl;

R ₁₀ and R ₁₁ are each hydrogen, C ₁ -C ₂ alkyl, C ₁ -C ₃ alkoxy or halide;

X ₁ and X ₃ are each O; S; NH; Or NC ₁ -C ₆ alkyl, NC ₃ -C ₆ cycloalkyl, N-benzyl or N-phenyl group;

X ₂ is C ₃ -C ₇ alkylene; C ₁ -C ₃ alkylene-C ₂ -C ₇ alkenylene-C ₁ -C ₃ alkylene; C ₁ -C ₃ alkylene-OC ₁ -C ₃ alkylene; C ₁ -C ₃ alkylene-SC ₁ -C ₃ alkylene; C ₁ -C ₃ alkylene-NH-C ₁ -C ₃ alkylene; C ₁ ~ C ₃ alkylene-phenylene -C ₁ -C ₃ alkylene; C ₁ -C ₃ alkylene-pyridylene group -C ₁ -C ₃ alkylene or C ₁ -C ₃ alkylene-naphthylene -C ₁ ~ C ₃ alkylene; C ₁ ~ C ₃ alkyl and hydroxyl chamber substituted C ₃ ~ C ₇ alkylene; C ₃ -C ₇ alkylene carbonyl; Or C ₃ -C ₇ alkylene interrupted by piperazine;

Y is O, S, NR ₆ or CH ₂ group;

n is an integer of 0, 1 or 2,

In Chemical Formula 2,

R ₁₂ is methyl, chloro, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 4-chlorophenylthio, 3-pyridylmethyl, (imidazo [1,2-a] pyridine -3-yl) methyl, 2- (N-methyl-Nn-pentyl) aminoethyl, cycloheptylamino, (1-imidazolyl) methyl or 1-pyrrolidinylethyl group,

R ₁₃ is hydrogen, chloro or a hydroxy group,

M is hydrogen or sodium,

z is any number, preferably an integer from 0 to 7.

또는

(A는 C₁~C₂ 알킬이고, m은 4 내지 5의 정수이다) 그룹이고;In Formula 1, in particular, R ₁ is methyl, ethyl, isopropyl, cyclohexyl, phenyl, aminomethyl, aminoethyl, amino, pyridinyl, NR ₆ R ₇ , CH ₂ NR ₆ R ₇ ,

or

(A is C ₁ -C ₂ alkyl and m is an integer from 4 to 5);

로 치환된 메틸 또는 에틸; 피롤리딘, 피페리딘 또는 이미다졸로 치환된 메틸 또는 에틸;

, 피페리딘 또는 트리아졸이며; R ₂ is hydrogen; methyl; ethyl; Isopropyl; Isobutyl; Methoxymethyl; Hydroxymethyl; Chloromethyl; Chloroethyl; Cyclopentyl; Cyclopentylmethyl; vinyl; Methyl or ethyl substituted with NR ₈ R ₉ ; Carbonyl substituted with NR ₈ R ₉ ;

Methyl or ethyl substituted with; Methyl or ethyl substituted with pyrrolidine, piperidine or imidazole;

, Piperidine or triazole;

R ₃ and R ₄ are each hydrogen, halogen, hydroxy or methoxy group;

R ₅ is hydrogen or a hydroxy group;

R ₆ and R ₇ are each hydrogen, methyl, ethyl, propyl, hydroxyethyl, methoxyethyl, 2-morpholinoethyl, benzyl, pyridin-3-yl, pyridin-4-yl, 2-morpholinoethyl , 4-pyridinylcarbonyl, 3-pyridinylcarbonyl, isobutylcarbonyl, ethanesulfonyl, hydroxyethyl or methoxyethyl group;

R ₈ and R ₉ are each hydrogen; methyl; ethyl; profile; Isopropyl; Butyl; Isobutyl; t-butyl; Cyclopropyl; Cyclohexyl; Ethyl substituted with one group selected from hydroxy, methoxy, 2-morpholino or NR ₆ R ₇ ; Propyl substituted with one group selected from 3-isopropoxy or 3-imidazole; Carbonyl substituted with one group selected from 3-pyridinyl, 4-pyridinyl or isopropyl;

R ₁₀ and R ₁₁ are each hydrogen or methyl;

X ₁ and X ₃ are each an oxygen, sulfur, amine or methylamine group;

X ₂ is propylene, butylene, pentylene, hexylene, ethylene-O-ethylene, ethylene-NH-ethylene, butylene carbonyl, 2-butenyl, methylene-1,2-phenylene-methylene, methylene-1 , 3-phenylene-methylene, methylene-1,4-phenylene-methylene or methylene-pyridinyl-methylene;

n is an integer of 0, 1 or 2.

In the compounds of formula 1 of the present invention, R ₃ and R ₄ are located in ortho or meta based on -X ₁ -or -X _3- , and -C (NH ₂ ) = NR ₅ is located in meta or para.

Preferred compounds among the benzamidine derivatives of formula 1 of the present invention are specifically as follows:

1) N-hydroxy-4- {5- [4- (2-isopropyl-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

2) 4- {5- [4- (2-isopropyl-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

3) N-hydroxy-4- {5- [4- (2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

4) N-hydroxy-4- {5- [4- (2-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

5) N-hydroxy-4- {5- [4- (2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

6) N-hydroxy-4- {5- [4- (2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

7) N-hydroxy-4- {5- [4- (2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

8) N-hydroxy-4- {5- [4- (2-cyclohexyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

9) N-hydroxy-4- {5- [4- (2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

10) N-hydroxy-4- {5- [4- (2,5-dimethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

11) N-hydroxy-4- {5- [4- (2-ethyl-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

12) N-hydroxy-4- {5- [4- (5-methyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

13) N-hydroxy-4- {5- [4- (5-methyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] phenoxy} -benzamidine,

14) N-hydroxy-4- {5- [4- (2-cyclohexyl-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

15) N-hydroxy-4- {5- [4- (5-methyl-2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

16) N-hydroxy-4- {5- [4- (2-t-butyl-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

17) N-hydroxy-4- {5- [4- (5-ethyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

18) N-hydroxy-4- {5- [4- (2,5-diethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

19) N-hydroxy-4- {5- [4- (5-ethyl-2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

20) N-hydroxy-4- {5- [4- (5-ethyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

21) N-hydroxy-4- {5- [4- (5-ethyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

22) N-hydroxy-4- {5- [4- (2-cyclohexyl-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

23) N-hydroxy-4- {5- [4- (5-ethyl-2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

24) N-hydroxy-4- {5- [4- (2-ethyl-5-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

25) N-hydroxy-4- {5- [4- (2,5-diisopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

26) N-hydroxy-4- {5- [4- (5-isopropyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

27) N-hydroxy-4- {5- [4- (5-isopropyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine ,

28) N-hydroxy-4- {5- [4- (5-isopropyl-2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

29) N-hydroxy-4- {5- [4- (2-methyl-5-propyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

30) N-hydroxy-4- {5- [4- (5-butyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

31) N-hydroxy-4- {5- [4- (5-butyl-2-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

32) N-hydroxy-4- {5- [4- (5-butyl-2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

33) N-hydroxy-4- {5- [4- (5-butyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

34) N-hydroxy-4- {5- [4- (5-butyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

35) N-hydroxy-4- {5- [4- (5-butyl-2-cyclohexyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

36) N-hydroxy-4- {5- [4- (5-butyl-2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

37) N-hydroxy-4- {5- [4- (5-butyl-2-t-butyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

38) N-hydroxy-4- {5- [4- (5-benzyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

39) N-hydroxy-4- {5- [4- (5-benzyl-2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

40) N-hydroxy-4- {5- [4- (5-benzyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

41) N-hydroxy-4- {5- [4- (5-benzyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

42) N-hydroxy-4- {5- [4- (5- (2-chloro-ethyl) -2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean,

43) N-hydroxy-4- {5- [4- (5-cyclopentyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

44) N-hydroxy-4- {5- [4- (5-isobutyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

45) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

46) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

47) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

48) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

49) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean,

50) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-cyclohexyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

51) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

52) 4- {5- [4- (2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

53) 4- {5- [4- (2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

54) 4- {5- [4- (2,5-dimethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

55) 4- {5- [4- (5-ethyl-2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

56) 4- {5- [4- (5-ethyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

57) N-hydroxy-4- {5- [4- (2-amino-1, 3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

58) N-hydroxy-4- {5- [4- (2-amino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

59) N-hydroxy-4- {5- [4- (2-guanidino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

60) N-hydroxy-4- {5- [4- (2-amino-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

61) N-hydroxy-4- {5- [4- (2-amino-5-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

62) N-hydroxy-4- {5- [4- (2-guanidino-5-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

63) N-hydroxy-4- {5- [4- (2-amino-5-butyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

64) N-hydroxy-4- {5- [4- (5-butyl-2-guanidino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

65) N-hydroxy-4- {5- [4- (2-amino-5-benzyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

66) N-hydroxy-4- {5- [4- (5-benzyl-2-guanidino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

67) N-hydroxy-4- {5- [4- (2-amino-5-cyclopentylmethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

68) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2- (1-propyl-piperidin-4-yl) -1,3-thiazol-4-yl) phenoxy Pentoxy} -benzamidine,

69) N-hydroxy-4- {5- [4- (2- (isobutyryl) amino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine

70) N-hydroxy-4- {5- [4- (5-isopropyl-2-morpholinomethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

71) N-hydroxy-4- {5- [4- (2-aminomethyl-5-benzyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

72) N-hydroxy-4- {5- [4- (5-methyl-2- (1-propyl-piperidin-4-yl) -1,3-thiazol-4-yl) phenoxy] Pentoxy} -benzamidine,

73) N-hydroxy-4- {5- [4- (5-isopropyl-2-aminomethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

74) N-hydroxy-4- {5- [4- (5-vinyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

75) N-hydroxy-4- {5- [4- (5-hydroxymethyl-2-methyl-1,3-thiazol-4-yl) phenoxy] phenoxy} -benzamidine,

76) N-hydroxy-4- {5- [4- (5-methoxymethyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

77) N-hydroxy-4- {5- [4- (5- (2-chloroethyl) -2-amino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine ,

78) N-hydroxy-4- {5- [4- (5-vinyl-2-amino-1, 3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

79) N-hydroxy-4- {5- [4- (5-vinyl-2- (pyridin-3-yl) -1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean,

80) N-hydroxy-4- {5- [4- (5- (2-chloroethyl) -2- (pyridin-3-yl) -1,3-thiazol-4-yl) phenoxy] Pentoxy} -benzamidine,

81) N-hydroxy-4- {5- [4- (2-amino-5-cyclopentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

82) N-hydroxy-4- {5- [4- (5-ethyl-2-aminomethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

83) N-hydroxy-4- {5- [4- (5-isopropyl-2- (piperidin-3-yl) -1,3-thiazol-4-yl) phenoxy] pentoxy} Benzamidine,

84) N-hydroxy-4- {5- [4- (2-ethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

85) N-hydroxy-4- {5- [4- (2-ethanesulfonylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

86) N-hydroxy-4- {5- [4- (5-methyl-2-methylamino-1, 3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

87) N-hydroxy-4- {5- [4- (2-ethylamino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

88) N-hydroxy-4- {5- [4- (5-methyl-2-propylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

89) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2- (3-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy } -Benzamidine,

90) N-hydroxy-4- {5- [4- (2-hydroxyacetylamino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

91) N-hydroxy-4- {5- [4- (5-methyl-2- (4-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy}- Benzamidine,

92) N-hydroxy-4- {5- [4- (5-methyl-2- (3-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy}- Benzamidine,

93) N-hydroxy-4- {5- [4- (2-ethanesulfonylamino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

94) N-hydroxy-4- {5- [4- (2- (2-methoxyethyl) amino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benz Amidine,

95) N-hydroxy-4- {5- [4- (2-ethanesulfonylamino-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

96) N-hydroxy-4- {5- [4- (5-ethyl-2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

97) N-hydroxy-4- {5- [4- (5-ethyl-2-ethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

98) N-hydroxy-4- {5- [4- (5-ethyl-2-propylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

99) N-hydroxy-4- {5- [4- (5-ethyl-2-methoxyacetylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

100) N-hydroxy-4- {5- [4- (5-ethyl-2- (4-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy}- Benzamidine,

101) N-hydroxy-4- {5- [4- (5-ethyl-2- (3-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy}- Benzamidine,

102) N-hydroxy-4- {5- [4- (5-ethyl-2- (2-methoxyethyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benz Amidine,

103) N-hydroxy-4- {5- [4- (5-isopropyl-2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

104) N-hydroxy-4- {5- [4- (2-ethylamino-5-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

105) N-hydroxy-4- {5- [4- (5-butyl-2-methylamino-1,3-thiazol-4-yl) phenoxy] phenoxy} -benzamidine,

106) N-hydroxy-4- {5- [4- (5-butyl-2-ethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

107) N-hydroxy-4- {5- [4- (5-benzyl-2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

108) N-hydroxy-4- {5- [4- (5-benzyl-2-ethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

109) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

110) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-ethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

111) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-propylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

112) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2- (4-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy } -Benzamidine,

113) N-hydroxy-4- {5- [4- (5-cyclopentyl-2-propylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

114) N-hydroxy-4- {5- [4- (5-isopropyl-2-[(pyridin-3-ylmethyl) amino] -1,3-thiazol-4-yl) phenoxy] phen Methoxy} -benzamidine,

115) N-hydroxy-4- {5- [4- (5- (2-chloroethyl) -2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean,

116) N-hydroxy-4- {5- [4- (2-methylamino-1, 3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

117) N-hydroxy-4- {5- [4- (5-ethyl-2- (pyridin-3-ylmethyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy}- Benzamidine,

118) N-hydroxy-4- {5- [4- (2- (ethanesulfonyl-methyl-amino) -1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

119) N-hydroxy-4- [5- (4- {2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy) pentoxy]- Benzamidine,

120) N-hydroxy-4- [5- (4- {2-[(2-hydroxyethyl) -methyl-amino] -5-methyl-1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

121) N-hydroxy-4- [5- (4- {2- [ethyl- (2-hydroxyethyl) -amino] -5-methyl-1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

122) N-hydroxy-4- [5- (4- {2- [bis- (2-methoxyethyl) -amino] -5-methyl-1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

123) N-hydroxy-4- [5- (4- {5-methyl-2- [methyl- (2-morpholinoethyl) -amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine,

124) N-hydroxy-4- [5- (4- {2- [ethyl-1- (2-morpholinoethyl) -amino] -5-methyl-1,3-thiazol-4-yl} Phenoxy) pentoxy] -benzamidine,

125) N-hydroxy-4- {5- (4- [2- (benzyl-methyl-amino) -5-methyl-1,3-thiazol-4-yl] phenoxy) pentoxy} -benzami Dean,

126) N-hydroxy-4- [5- {4- [5-methyl-2- (methyl-pyridin-3-yl-methyl-amino) -1,3-thiazol-4-yl] phenoxy} Pentoxy] -benzamidine,

127) N-hydroxy-4- [5- {4- [2- (benzyl-ethyl-amino) -5-methyl-1,3-thiazol-4-yl] phenoxy} pentoxy] -benzami Dean,

128) N-hydroxy-4- [5- (4- {2- [bis- (2-hydroxyethyl) -amino] -5-methyl-1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

129) N-hydroxy-4- [5- (4- {5-ethyl-2-[(2-hydroxyethyl) -methyl-amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

130) N-hydroxy-4- [5- (4- {5-ethyl-2- [ethyl- (2-hydroxyethyl) -amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

131) N-hydroxy-4- [5- (4- {5-ethyl-2- [methyl- (2-morpholinoethyl) -amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine,

132) N-hydroxy-4- [5- (4- {5-ethyl-2- [ethyl- (2-morpholinoethyl) -amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine,

133) N-hydroxy-4- [5- {4- [2- (benzyl-methyl-amino) -5-ethyl-1,3-thiazol-4-yl] phenoxy} pentoxy] -benzami Dean,

134) N-hydroxy-4- [5- (4- {5-ethyl-2- [methyl- (pyridin-3-ylmethyl) amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

135) N-hydroxy-4- (5- {4- [2- (benzyl-ethyl-amino) -5-ethyl-1,3-thiazol-4-yl] phenoxy} pentoxy) -benzami Dean,

136) N-hydroxy-4- {5- (4- [5-ethyl-2- (ethyl- [pyridin-3-ylmethyl] amino) -1,3-thiazol-4-yl] phenoxy) Pentoxy} -benzamidine,

137) N-hydroxy-4- [5- (4- {2- [bis- (pyridin-3-ylmethyl) amino] -5-ethyl-1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

138) N-hydroxy-4- {5- [4- (2-dipropylamino-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

139) N-hydroxy-4- [5- (4- {2- [bis- (2-hydroxyethyl) amino] -5-ethyl-1,3-thiazol-4-yl} phenoxy) phene Oxy] -benzamidine,

140) N-hydroxy-4- [5- (4- {2-[(2-hydroxyethyl) -methyl-amino] -5-isopropyl-1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine,

141) N-hydroxy-4- [5- (4- {5-isopropyl-2- [methyl- (pyridin-3-ylmethyl) amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine,

142) N-hydroxy-4- (5- {4- [2- (ethanesulfonyl-methyl-amino) -5-isopropyl-1,3-thiazol-4-yl] phenoxy} pentoxy) Benzamidine,

143) N-hydroxy-4- [5- (4- {5-butyl-2-[(2-hydroxyethyl) -methyl-amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

144) N-hydroxy-4- [5- (4- {5-butyl-2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

145) N-hydroxy-4- [5- (4- {5-butyl-2- [methyl- (pyridin-3-ylmethyl) amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine,

146) N-hydroxy-4- {5- [4- (5-butyl-2-dipropylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

147) N-hydroxy-4- [5- (4- {5-cyclopentylmethyl-2- [methyl- (pyridin-3-ylmethyl) amino] -1,3-thiazol-4-yl} phenoxy Pentoxy] -benzamidine,

148) N-hydroxy-4- [5- (4- {5-cyclopentylmethyl-2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy Pentoxy] -benzamidine,

149) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-dipropylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

150) N-hydroxy-4- {5- [4- (5-butyl-2-diethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

151) N-hydroxy-4- {5- [4- (5-butyl-2-ethylmethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

152) N-hydroxy-4- {5- [4- (5-butyl-2-dimethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

153) N-hydroxy-4- [5- (4- {5-cyclopentyl-2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine,

154) N-hydroxy-4- [5- (4- {5-isobutyl-2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine,

155) N-hydroxy-4- (5- {4- [5- (2-chloroethyl) -2-dimethylamino-1,3-thiazol-4- yl] phenoxy} pentoxy) -benzami Dean,

156) N-hydroxy-4- {5- [4- (5-cyclopentyl-2-diethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

157) N-hydroxy-4- {5- [4- (5-isopropyl-2-dipropylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

158) N-hydroxy-4- {5- [4- (5-ethyl-2-diethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

159) N-hydroxy-4- [5- (4- {5-isopropyl-2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine,

160) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-diethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

161) N-hydroxy-4- {5- [4- (5-isopropyl-2-dimethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

162) N-hydroxy-4- {5- [4- (5-isopropyl-2-diethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

163) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-dimethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

164) N-hydroxy-4- {5- [4- (5-methyl-2-piperidino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

165) N-hydroxy-4- {5- [4- (5-methyl-2-morpholino-1,3-thiazol-4-yl) phenoxy] phenoxy} -benzamidine,

166) N-hydroxy-4- {5- [4- (5-ethyl-2-piperidino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

167) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-piperidino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

168) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-morpholino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

169) N-hydroxy-4- {5- [4- (5-isopropyl-2-morpholin-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

170) N-hydroxy-4- {5- (4- [5-cyclopentylmethyl-2- (4-methylpiperazino) -1,3-thiazol-4-yl] phenoxy) pentoxy} Benzamidine,

171) N-hydroxy-4- {5- [4- (5-vinyl-2-morpholin-4-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine ,

172) N-hydroxy-4- {5- [4- (5-cyclopentyl-2-morpholin-4-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean,

173) N-hydroxy-4- {5- [4- (5-isobutyl-2-morpholin-4-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean,

174) N-hydroxy-4- {5- (4- [5-ethyl-2- (4-methylpiperazino) -1,3-thiazol-4-yl] phenoxy) pentoxy} -benz Amidine,

175) N-hydroxy-4- {5- [4- (2-morpholin-4-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine,

176) N-hydroxy-4- {5- (4- [5-isopropyl-2- (4-methylpiperazino) -1,3-thiazol-4-yl] phenoxy) pentoxy}- Benzamidine,

177) N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentylamino} -benzamidine,

178) N-hydroxy-4- (2- {2- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -ethoxy} -ethoxy ) -Benzamidine,

179) N-hydroxy-4- {3-hydroxy-5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -3-methyl- Pentyloxy} -benzamidine,

180) N-hydroxy-4- (2- {2- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -1-methyl-ethylamino } -Ethoxy) -benzamidine,

181) N-hydroxy-4- [3- (4- {3- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -propyl}- Piperazin-1-yl) -propoxy] -benzamidine,

182) N-hydroxy-4-5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentanoyl-amino-benzamidine,

183) N-hydroxy-4-({5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyl} -methyl-amino)- Benzamidine,

184) N-hydroxy-4- {4- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -but-2-enyloxy} -benz Amidine,

185) N-hydroxy-4- {4- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine ,

186) N-hydroxy-4- (2- {2- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) phenoxy] -ethylamino} -ethoxy) Benzamidine,

187) N-hydroxy-2-fluoro-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyloxy}- Benzamidine,

188) 2, N-dihydroxy-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyloxy} -benzami Dean,

189) N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyloxy} -3-methoxy- Benzamidine,

190) N-hydroxy-2-cyclohexylamino-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyloxy} Benzamidine,

191) N-hydroxy-4- {5- [3-fluoro-4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyloxy}- Benzamidine,

192) N-hydroxy-2-fluoro-4- {5- [3-fluoro-4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -Pentyloxy} -benzamidine,

193) N-hydroxy-4- {3- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) phenoxy] propoxy} -benzamidine,

194) N-hydroxy-4- {4- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) phenoxy] butoxy} -benzamidine,

195) N-hydroxy-3- {5- [4- (5-isopropyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyl amino} -benzamidine,

196) N-hydroxy-4- {4- [4- (2-cyclohexyl-5-ethyl-thiazol-4-yl) -phenoxy] -butoxy} -benzamidine,

197) N-hydroxy-4- [5- (4- {5-ethyl-2-[(2-hydroxyethyl) -methyl-amino] -thiazol-4-yl} phenoxy) propoxy]- Benzamidine,

198) N-hydroxy-4- [5- (4- {5-ethyl-2-[(2-hydroxyethyl) -methyl-amino] -thiazol-4-yl} phenoxy) butoxy]- Benzamidine,

199) N-hydroxy-4- [5- (4- {5-ethyl-2- [methyl- (pyridin-3-ylmethyl) amino] -thiazol-4-yl} phenoxy) propoxy]- Benzamidine,

200) N-hydroxy-4- [5- (4- {5-ethyl-2- [methyl- (pyridin-3-ylmethyl) amino] -thiazol-4-yl} phenoxy) butoxy]- Benzamidine,

201) N-hydroxy-4- {4- [4- (5-cyclopentylmethyl-2-isopropyl-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine,

202) N-hydroxy-4- {4- [4- (5-butyl-2-isopropyl-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine,

203) N-hydroxy-4- {4- [4- (5-cyclopentylmethyl-2-amino-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine,

204) N-hydroxy-4- {4- [4- (5-cyclopentylmethyl-2-amino-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -2-fluoro-benzami Dean,

205) N-hydroxy-4- {4- [4- (2-methylamino-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine,

206) N-hydroxy-4- {6- [4- (5-isopropyl-2-methyl-thiazol-4-yl) -phenoxymethyl] -pyridin-2-ylmethoxy} -benzamidine,

207) N-hydroxy-2-fluoro-4- {5- [4- (5-isopropyl-2-methyl-thiazol-4-yl) -phenoxy] -butoxy} -benzamidine,

208) N-hydroxy-4- {2- [4- (5-isopropyl-2-methyl-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine,

209) N-hydroxy-4- {3- [4- (5-isopropyl-2-methyl-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine,

210) N-hydroxy-4- {4- [4- (5-cyclopentylmethyl-2-cyclohexyl-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine,

211) N-hydroxy-4- {6- [4- (5-isopropyl-2-methyl-thiazol-4-yl) phenoxy] -hexyloxy} -benzamidine,

212) N-hydroxy-4- {5- [2-ethyl-5-hydroxy-4- (2-methyl-thiazol-4-yl) phenoxy] -pentyloxy} -benzamidine,

213) N-hydroxy-4- {5- [2-ethyl-4- (2-methyl-thiazol-4-yl) -5-propoxy-phenoxy] -pentyloxy} -benzamidine

214) N-hydroxy-4- (5- {4- [5- (2-isobutylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean,

215) 4- (5- {4- [5- (2-isobutylaminoethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyl oxy) -benzamidine,

216) N-hydroxy-4- (5- {4- [2-methyl-5- (2-piperidin-1-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

217) N-hydroxy-4- [5- (4- {2-methyl-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine,

218) N-hydroxy-4- [5- (4- {5- [2- (3-imidazol-1-yl-propylamino) -ethyl] -2-methyl-thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine,

219) N-hydroxy-4- (5- {4- [5- (2-isopropylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean,

220) N-hydroxy-4- [5- (4- {5- [2- (3-isopropoxy-propylamino) -ethyl] -2-methyl-thiazol-4-yl} -phenoxy) -Pentyloxy] -benzamidine,

221) N-hydroxy-4- (5- {4- [5- (2-butylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine ,

222) N-hydroxy-4- (5- {4- [5- (2-imidazol-1-yl-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine,

223) N-hydroxy-4- (5- {4- [5- (2-cyclohexylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean,

224) N-hydroxy-4- (5- {4- [5- (2-diethylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean,

225) N-hydroxy-4- {5- [4- (5- {2- [bis- (2-hydroxy-ethyl) -amino] -ethyl} -2- methyl-thiazol-4-yl) -Phenoxy] -pentyloxy} -benzamidine,

226) N-hydroxy-4- (5- {4- [5- (2-diisopropylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benz Amidine,

227) N-hydroxy-4- [5- (4- {5- [2- (2,6-dimethyl-morpholin-4-yl) -ethyl] -2-methyl-thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine,

228) N-hydroxy-4- (5- {4- [2-methyl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

229) N-hydroxy-4- (5- {4- [2-amino-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine,

230) N-hydroxy-4- [5- (4- {5- [2- (2-dimethylamino-ethylamino) -ethyl] -2-methyl-thiazol-4-yl} -phenoxy)- Pentyloxy] -benzamidine,

231) N-hydroxy-4- (5- {4- [2-methyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine,

232) N-hydroxy-4- [5- (4- {2-methyl-5- [2- (4-methyl-piperazin-1-yl) -ethyl] -thiazol-4-yl} -phenoxy C) -pentyloxy] -benzamidine,

233) N-hydroxy-4- {5- [4- (5- {2- [bis- (2-methoxy-ethyl) -amino] -ethyl} -2-methyl-thiazol-4-yl) -Phenoxy] -pentyloxy} -benzamidine,

234) N-hydroxy-4- (5- {4- [5- (2-tert-butylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benz Amidine,

235) N-hydroxy-4- (5- {4- [5- (2-isobutylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean,

236) N-hydroxy-4- (5- {4- [5- (2-morpholin-4-yl-ethyl) -2-pyridin-3-yl-thiazol-4-yl] -phenoxy} -Pentyloxy) -benzamidine,

237) N-hydroxy-4- [5- (4- {5- [2- (4-methyl-piperazin-1-yl) -ethyl] -2-pyridin-3-yl-thiazole-4- Yl) -phenoxy) -pentyloxy] -benzamidine,

238) N-hydroxy-4- (5- {4- [2-pyridin-3-yl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy } -Pentyloxy) -benzamidine,

239) N-hydroxy-4- (5- {4- [5- (2-imidazol-1-yl-ethyl) -2-pyridin-3-yl-thiazol-4-yl] -phenoxy} -Pentyloxy) -benzamidine,

240) N-hydroxy-4- (5- {4- [2-isopropyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

241) N-hydroxy-4- [5- (4- {2-isopropyl-5- [2- (4-methyl-piperazin-1-yl) -ethyl] -thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine,

242) N-hydroxy-4- (5- {4- [5- (2-imidazol-1-yl-ethyl) -2-isopropyl-thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

243) N-hydroxy-4- [5- (4- {2-isopropyl-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine,

244) N-hydroxy-4- [5- (4- {5- [2- (3-imidazol-1-yl-propylamino) -ethyl] -2-isopropyl-thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine,

245) N-hydroxy-4- (5- {4- [2-isopropyl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyl Oxy) -benzamidine,

246) N-hydroxy-4- (5- {4- [2-cyclohexyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

247) N-hydroxy-4- [5- (4- {2-cyclohexyl-5- [2- (4-methyl-piperazin-1-yl) -ethyl] -thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine,

248) N-hydroxy-4- [5- (4- {2-cyclohexyl-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine,

249) N-hydroxy-4- (5- {4- [2-cyclohexyl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyl Oxy) -benzamidine,

250) N-hydroxy-4- (5- {4- [2-cyclohexyl-5- (2-dimethylamino-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean,

251) N-hydroxy-4- (5- {4- [2-cyclohexyl-5- (2-dipropylamino-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benz Amidine,

252) N-hydroxy-4- (5- {4- [2-cyclohexyl-5- (2-cyclopropylamino-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benz Amidine,

253) N-hydroxy-4- [5- (4- {2-amino-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine,

254) N-hydroxy-4- (5- {4- [5- (2-morpholin-4-yl-ethyl) -2-phenyl-thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine,

255) N-hydroxy-4- (5- {4- [2-ethyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine,

256) N-hydroxy-4- (5- {4- [2-ethyl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

257) N-hydroxy-4- (4- {4- [2-methyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -butoxy) Benzamidine,

258) 4- (5- {4- [2-cyclohexyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine ,

259) 4- (5- {4- [2-methyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine,

260) N-hydroxy-4- (5- {4- [2-methylamino-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

261) N-hydroxy-4- [5- (4- {2-methylamino-5- [2- (4-methyl-piperazin-1-yl) -ethyl] -thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine,

262) N-hydroxy-4- (5- {4- [2-methylamino-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyl Oxy) -benzamidine,

263) N-hydroxy-4- [5- (4- {2-methylamino-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine,

264) N-hydroxy-4- [5- (4- {5- [2- (3-imidazol-1-yl-propylamino) -ethyl] -2-methylamino-thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine,

265) 4- (5- {4- [2-Methylamino-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine ,

266) N-hydroxy-4- (5- {4- [2-dimethylamino-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

267) N-hydroxy-4- (5- {4- [2-dimethylamino-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyl Oxy) -benzamidine,

268) N-hydroxy-4- (5- {4- [2- (isobutyryl-methyl-amino) -5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -Phenoxy} -pentyloxy) -benzamidine,

269) N-hydroxy-4- (5- {4- [2- [benzyl- (2-morpholin-4-yl-ethyl) -amino] -5- (2-morpholin-4-yl-ethyl ) -Thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine,

270) N-hydroxy-4- (5- {4- [2-diethylamino-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyl Oxy) -benzamidine,

271) N-hydroxy-4- (5- {4- [2- [bis- (2-methoxy-ethyl) -amino] -5- (2-morpholin-4-yl-ethyl) -thiazole -4-yl] -phenoxy} -pentyloxy) -benzamidine,

272) N-hydroxy-4- (5- {4- [2-morpholin-4-yl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy } -Pentyloxy) -benzamidine,

273) N-hydroxy-4- (5- {4- [2-morpholin-4-yl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy Pentyloxy) -benzamidine,

274) N-hydroxy-4- [5- (4- {5- [2- (4-methyl-piperazin-1-yl) -ethyl] -2-morpholin-4-yl-thiazole-4 -Yl} -phenoxy) -pentyloxy] -benzamidine,

275) N-hydroxy-4- [5- (4- {2-morpholin-4-yl-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazole- 4-yl} -phenoxy) -pentyloxy] -benzamidine,

276) N-hydroxy-4- (5- {4- [5- (2-morpholin-4-yl-ethyl) -2-piperidin-1-yl-methyl-thiazol-4-yl] -Phenoxy} -pentyloxy) -benzamidine,

277) 4- (5- {4- [2-morpholin-4-yl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine,

278) N-hydroxy-4- (5- {4- [5- (2-isobutyrylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benz Amidine,

279) N-hydroxy-4- {5- [4- (5- {2- [isobutyl- (pyridine-3-carbonyl) -amino] -ethyl} -2-methyl-thiazol-4-yl ) -Phenoxy] -fetyloxy} -benzamidine,

280) N-hydroxy-4- {5- [4- (5- {2- [cyclopropyl- (pyridine-4-carbonyl) -amino] -ethyl} -2-isopropyl-thiazole-4- Yl) -phenoxy] -pentyloxy} -benzamidine,

281) N-hydroxy-4- {5- [4- (2-cyclohexyl-5- {2- [cyclopropyl- (pyridine-3-carbonyl) -amino] -ethyl} -thiazole-4- Yl) -phenoxy] -pentyloxy} -benzamidine,

282) N-hydroxy-4- {5- [4- (5-methylcarbamoyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

283) N-hydroxy-4- {5- [4- (5-isopropylcarbamoyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

284) N-hydroxy-4- {5- [4- (5- {3-imidazol-1-yl-propylcarbamoyl} -2-methyl-thiazol-4-yl) -phenoxy] -pentyl Oxy} -benzamidine,

285) N-hydroxy-4- {5- [4- (2-amino-5-methylcarbamoyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

286) N-hydroxy-4- {5- [4- (2-methyl-5-morpholin-4-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

287) N-hydroxy-4- (5- {4- [2-methyl-5- (4-methyl-piperazin-1-yl) -thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine,

288) N-hydroxy-4- {5- [4- (2-amino-5-morpholin-4-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

289) N-hydroxy-4- (5- {4- [5- (4-methyl-piperazin-1-yl) -2-morpholin-4-yl-thiazol-4-yl] -phenoxy } -Pentyloxy) -benzamidine,

290) N-hydroxy-4- {5- [4- (2,5-di-morpholin-4-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

291) N-hydroxy-4- {5- [4- (2-morpholin-4-yl-5-thiomorpholin-4-yl-thiazol-4-yl) -phenoxy] -pentyloxy} Benzamidine,

292) N-hydroxy-4- {5- [4- (2-morpholin-4-yl-5-pyrrolidin-1-yl-thiazol-4-yl) -phenoxy] -pentyloxy} Benzamidine,

293) N-hydroxy-4- {5- [4- (2-methyl-5-morpholin-4-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

294) N-hydroxy-4- (5- {4- [2-methyl-5- (4-methyl-piperazin-1-ylmethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

295) N-hydroxy-4- {5- [4- (2-methyl-5-thiomorpholin-4-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine ,

296) N-hydroxy-4- {5- [4- (2-methyl-5-piperidin-1-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine ,

297) N-hydroxy-4- {5- [4- (5-dimethylaminomethyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

298) N-hydroxy-4- {5- [4- (5-butylaminomethyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

299) N-hydroxy-4- (5- {4- [5- (isobutylamino-methyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine,

300) N-hydroxy-4- (5- {4- [5- (tert-butylamino-methyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine ,

301) N-hydroxy-4- {5- [4- (2-methyl-5-propylaminomethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

302) N-hydroxy-4- [5- (4- {2-methyl-5-[(2-morpholin-4-yl-ethylamino) -methyl] -thiazol-4-yl} -phenoxy ) -Pentyloxy] -benzamidine,

303) N-hydroxy-4- [5- (4- {5-[(3-imidazol-1-yl-propylamino) -methyl] -2-methyl-thiazol-4-yl} -phenoxy ) -Pentyloxy] -benzamidine,

304) N-hydroxy-4- {5- [4- (2-methyl-5-pyrrolidin-1-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine ,

305) N-hydroxy-4- {5- [4- (5-imidazol-1-ylmethyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

306) N-hydroxy-4- (5- {4- [5- (benzylamino-methyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine,

307) N-hydroxy-4- {5- [4- (5-cyclopropylaminomethyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

308) N-hydroxy-4- {5- [4- (2-methylamino-5-morpholin-4-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

309) N-hydroxy-4- (5- {4- [2- (methyl-pyridin-4-ylmethyl-amino) -5-morpholin-4-ylmethyl-thiazol-4-yl] -phenoxy Pentyloxy) -benzamidine,

310) N-hydroxy-4- [5- (4- {2-[(2-hydroxy-ethyl) -methyl-amino] -5-morpholin-4-ylmethyl-thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine,

311) N-hydroxy-4- (5- {4- [2- (ethyl-methyl-amino) -5-morpholin-4-ylmethyl-thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

312) N-hydroxy-4- (5- {4- [2- (benzyl-methyl-amino) -5-morpholin-4-ylmethyl-thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

313) N-hydroxy-4- [5- (4- {2- [methyl- (2-morpholin-4-yl-ethyl) -amino] -5-morpholin-4-ylmethyl-thiazole- 4-yl} -phenoxy) -pentyloxy] -benzamidine,

314) N-hydroxy-4- [5- (4- {2- [methyl- (2-morpholin-4-yl-ethyl) -amino] -5-thiomorpholin-4-ylmethyl-thiazole -4-yl} -phenoxy) -pentyloxy] -benzamidine,

315) N-hydroxy-4- [5- (4- {5-{[bis- (2-methoxy-ethyl) -amino] -methyl} -2- [methyl-(2-morpholine-4- Yl-ethyl) -amino] -thiazol-4-yl} -phenoxy) -pentyloxy] -benzamidine,

316) N-hydroxy-4- (5- {4- [2- [methyl- (2-morpholin-4-yl-ethyl) -amino] -5- (4-methyl-piperazin-1-yl Methyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine,

317) N-hydroxy-4- [5- (4- {5- (isopropylamino-methyl) -2- [methyl- (2-morpholin-4-yl-ethyl) -amino] -thiazole- 4-yl} -phenoxy) -pentyloxy] -benzamidine,

318) N-hydroxy-4- [5- (4- {5-[(2-methoxy-ethylamino) -methyl] -2- [methyl- (2-morpholin-4-yl-ethyl)- Amino] -thiazol-4-yl} -phenoxy) -pentyloxy] -benzamidine,

319) N-hydroxy-4- [5- (4- {2-[(2-methoxy-ethyl) -methyl-amino] -5-morpholin-4-ylmethyl-thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine,

320) N-hydroxy-4- (5- {4- [2- (methyl-propyl-amino) -5-morpholin-4-ylmethyl-thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine,

321) N-hydroxy-4- (5- {4- [2- (methyl-pyridin-3-ylmethyl-amino) -5-morpholin-4-ylmethyl-thiazol-4-yl] -phenoxy Pentyloxy) -benzamidine,

322) N-hydroxy-4- {5- [4- (2-methyl-5-methylamino-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

323) N-hydroxy-4- [5- (4- {2-methyl-5-[(pyridine-4-carbonyl) -amino] -thiazol-4-yl} -phenoxy) -pentyloxy] Benzamidine,

324) N-hydroxy-4- [5- (4- {2-methyl-5-[(pyridine-3-carbonyl) -amino] -thiazol-4-yl} -phenoxy) -pentyloxy] Benzamidine,

325) N-hydroxy-4- [5- (4- {2-phenyl-5-[(pyridin-3-carbonyl) -amino] -thiazol-4-yl} -phenoxy) -pentyloxy] Benzamidine,

326) N-hydroxy-4- {5- [4- (5-dimethylamino-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

327) N-hydroxy-4- {5- [4- (5-dimethylamino-2-phenyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

328) N-hydroxy-4- {5- [4- (2-cyclohexyl-5-dimethylamino-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

329) N-hydroxy-4- {5- [4- (2-methyl-5- [1,2,4] triazol-1-yl-thiazol-4-yl) -phenoxy] -pentyloxy } -Benzamidine,

330) N-hydroxy-4- {5- [4- (5-amino-2-phenyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

331) N-hydroxy-4- {5- [4- (5-amino-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

332) N-hydroxy-4- {5- [4- (5-amino-2-pyridin-3-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

333) N-hydroxy-4- {5- [4- (5-amino-2-ethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

334) N-hydroxy-4- {5- [4- (5-amino-2-cyclohexyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine,

335) N-hydroxy-4- {5- [4- (2-methylamino-5-morpholin-4-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine ,

336) N-hydroxy-4- {5- [4- (2-morpholin-4-yl-5-morpholin-4-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} Benzamidine, and

337) N-hydroxy-4- {5- [4- (5-morpholin-4-yl-2-piperidin-1-yl-thiazol-4-yl) -phenoxy] -pentyloxy} Benzamidine.

More preferred compounds among the benzamidine derivatives of Formula 1 of the present invention are specifically as follows:

1) 2-fluoro-N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentyloxy} benzamidine,

2) N-hydroxy-4- {5- [4- (2-dipropylamino-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentyloxy} benzamidine,

3) N-hydroxy-4- {5- [4- (2- {methyl [morpholinoethyl] amino} -1,3-thiazol-4-yl) phenoxy] pentyloxy} benzamidine, and

4) N-hydroxy-4- {5- [4- (5-isopropyl-2- (morpholin-4-yl) -1,3-thiazol-4-yl) phenoxy] pentyloxy} benz Amidine.

Preferred compounds of the bisphosphonates of formula 2 of the present invention are specifically as follows:

1) etidronic acid,

2) chlodronic acid,

3) pamideonic acid,

4) tiludronic acid,

5) risedronic acid,

6) minodronic acid,

7) ibandronic acid,

8) zoledronic acid,

9) Alendronic acid.

Benzamidine derivatives of formula (1) of the present invention can be used in the form of pharmaceutically acceptable salts, and acid salts formed by pharmaceutically acceptable free acid are useful as salts. The inorganic acid and organic acid may be used as the free acid, and hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, and trifluoric acid may be used as the organic acid. Roacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine ethanesulfonic acid, camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, gallic acid Luteuronic acid, emboic acid, glutamic acid, aspartic acid and the like can be used. Preferably, hydrochloric acid or phosphoric acid may be used as the inorganic acid, and methanesulfonic acid may be used as the organic acid.

In the present invention, the terms used in the substituents of the compounds of the formulas (1) and (2) are defined as follows:

The term "halogen" refers to a halogen atom and includes radicals such as chlorine, fluorine, bromine, iodine and the like.

The term "alkyl" means a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like. Include.

The term "alkoxy" means an alkyl radical is a linear or branched group having 1 to 6 carbon atoms that is associated with oxygen and, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec- butoxy, tert - Butoxy and the like.

The term "cycloalkyl" refers to a non-aromatic hydrocarbon ring having 3 to 6 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "alkenyl" refers to a straight or branched chain unsaturated hydrocarbon of 2 to 6 carbon atoms, having one or more double bonds.

The term "alkanoyloxy" means an oxy-comprising radical wherein the terminal carbon atom of the alkyl group is replaced with a carbonyl radical.

The term "alkenoyloxy" means an oxy-comprising radical wherein the terminal carbon atom of the alkenyl group is substituted with a carbonyl radical.

The term "alkenyloxy" refers to an oxy-containing alkenyl group.

The term "alkylene" means a straight or branched chain saturated hydrocarbon radical of 1 to 7 carbon atoms having a point of attachment for two or more covalent bonds, and includes, for example, methylene, ethylene, methylethylene, isopropylidene and the like.

The term "alkenylene" refers to a straight or branched chain unsaturated hydrocarbon radical of 2 to 7 carbon atoms having a point of attachment for at least two covalent bonds and at least one double bond, for example 1,1-vinylidene (CH ₂ = C), 1,2-vinylidene (-CH = CH-), 1,4-butadienyl (-CH = CH-CH = CH-) and the like.

The term "carbonyl" means a carbon radical in which two of the four covalent bonds are shared with an oxygen atom.

Benzamidine of Formula 1 or a salt thereof used in the present invention is a drug that can be used as a therapeutic or preventive agent for osteoporosis having an excellent bone resorption inhibitory effect and a bone formation promoting effect.

Benzamidine derivatives of Chemical Formula 1 may be prepared by the known methods described in Korean Patent Registration No. 705875, Korean Patent Registration No. 875596 and Korean Patent Application No. 2008-0073710.

In the present invention, the term "osteoporosis" refers to a state in which there is no abnormality in the remaining bones, and the amount of minerals and substrates that form the bones is excessively reduced, so that a lot of small holes are formed in the bones, such as sponges, so that they are soft and easily broken. Also known as osteoporosis or osteoporosis.

In the present invention, the term "fracture" is a state in which bone continuity is completely or incompletely lost, and anatomically (eg, epiphyseal, metaphyseal, metaphyseal, intraarticular, or proximal, liver, distal, etc.), the degree of fracture ( Complete, incomplete, etc.), the direction of the fracture (horizontal, filamentary, spiral, longitudinal, etc.), the presence or absence of open windows (open, closed), the number of fractures (simple or linear, crushed, segmented, etc.), the stability of the fracture (stability, Instability), and refers to the physical damage of various bones classified by the presence or absence of dislocation.

The dose of benzamidine derivatives or salts thereof according to Formula 1 may vary depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, severity of disease, type of combination therapy, frequency of treatment, and the like. Although the range thereof cannot be determined uniformly, in general, when used as a therapeutic or prophylactic agent, it may be administered in an amount effective to treat osteoporosis through each route of administration, and the dosage form, dosage, etc. thereof may be used for the purpose of administration, Those skilled in the art can easily determine the route of administration, the condition and weight of the administration target, and the like. Specifically, the daily dose of the benzamidine derivative or salt thereof is approximately 1 to 1,000 mg, preferably 5 to 400 mg.

The dosage of the bisphosphonate of Formula 2 varies depending on the weight, age, sex, health condition, diet, administration time, administration method, excretion rate, severity of disease, type of combination therapy, frequency of treatment, etc. Although it cannot be determined uniformly, in general, when used as a therapeutic or prophylactic agent, it may be administered in an amount effective to treat osteoporosis through each route of administration, and the dosage form, dosage route, and administration thereof may be administered. It can be easily determined by those skilled in the art in consideration of the condition and weight of the subject. Specifically, the daily dose of bisphosphonate is approximately 1 to 1000 mg, preferably 1 to 400 mg.

In the present invention, the benzamidine of Formula 1 or a salt thereof and the bisphosphonate of Formula 2 may be used in any ratio.

In the present invention, the benzamidine of Formula 1 or a salt thereof and the bisphosphonate of Formula 2 may be administered at the same time by mixing, but each may be administered simultaneously or serially or separately over time. It is possible. When it is not administered simultaneously, two effective ingredients may be alternately administered, for example, and it is also possible to continue administering one, and to administer another.

In the present invention, the benzamidine of Formula 1 or a salt thereof and the bisphosphonate of Formula 2 may be any type of drug. For example, the mixture containing two active ingredients may be comprised, and may be comprised as a single agent, respectively. Here, the mixture means a mixture of two active ingredients of the benzamidine of Formula 1 or a salt thereof and bisphosphonate of Formula 2 in one formulation, and a single agent contains one active component in one formulation each. Say what you did. In the present invention, the therapeutic agent and the prophylactic agent in the case where the two active ingredients are monosaccharides each mean a medicament used in combination with a single available agent. Therefore, the drug containing two active ingredients may be different dosage forms, respectively. When the two active ingredients are monosaccharides, they may be in the form of a kit having two components at once.

In addition, the prophylactic or therapeutic agent for osteoporosis of the present invention may be administered daily or intermittently, and the number of administrations per day can be administered once or divided into two or three times. The frequency of administration in the case where the two active ingredients are single drugs may be the same or different times.

The benzamidine of formula (1) or a salt thereof and bisphosphonate of formula (2) of the present invention may be formulated by known methods alone or with suitable excipients such as those described below. Specific examples of such formulations include oral, injectable or external preparations such as soft capsules, hard capsules, tablets and syrups.

Pharmaceutically acceptable carriers as such excipients include any of the standard pharmaceutical carriers used in known formulations such as sterile solutions, tablets, coated tablets and capsules. Typically such carriers are polyvinylpyrrolidone, dextrin, starch, milk, sugar, certain types of clays, gelatin, stearic acid, talc, vegetable oils (e.g. cooking oil, cottonseed oil, coconut oil, almond oil, peanut oil), Excipients such as oily esters such as neutral fatty acid glycerides, mineral oils, petrolatum, animal fats and fats, cellulose derivatives (e.g. crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose), or other known excipients It includes. Such carriers may also include antioxidants, wetting agents, viscosity stabilizers, flavoring agents, color additives and other ingredients. Compositions containing such carriers can be formulated by known methods.

The pharmaceutical composition for preventing or treating osteoporosis of the present invention includes bensamidine of Formula 1 or a salt thereof and two types having different mechanisms of action such as bisphosphonates of Formula 2 as active ingredients. Compared to the case used as a provides a significant improvement in bone density and bone strength.

The pharmaceutical composition for preventing or treating osteoporosis of the present invention may be used alone or in combination with methods using surgery, hormone therapy, drug treatment and biological response modifiers for the prevention and treatment of osteoporosis.

The present invention has a very good inhibitory effect on the differentiation of osteoclasts with bone resorption function, benzamidine derivatives or salts thereof, which can increase the efficiency of the prevention and treatment of the lesions related to bone resorption including osteoporosis, And it has the effect of the invention to provide a pharmaceutical composition for the prevention or treatment of osteoporosis comprising bisphosphonate.

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the Examples.

Preparation Example 1  Preparation of Benzamidine Derivatives of Chemical Formula 1

2-Fluoro-N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentyloxy} benzamidine (Compound 1 ), N-hydroxy-4- {5- [4- (2-dipropylamino-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentyloxy} benzamidine (Compound 2) , N-hydroxy-4- {5- [4- (2- {methyl [morpholinoethyl] amino} -1,3-thiazol-4-yl) phenoxy] pentyloxy} benzamidine (Compound 3 ) And N-hydroxy-4- {5- [4- (5-isopropyl-2- (morpholin-4-yl) -1,3-thiazol-4-yl) phenoxy] pentyloxy} benz Amidine (Compound 4) was prepared according to the production method disclosed in Korean Patent Registration No. 705875, Korean Patent Registration No. 875596 and Korean Patent Application No. 2008-0073710. The foregoing patent documents are all included in the present invention by reference.

Example 1 Effect of Etidronic Acid (2 μM) and Compounds 1 to 4 alone or in combination on osteoclast differentiation

To induce osteoclast differentiation from mouse bone marrow-derived cells, a commonly used co-culture system was used, and the drug was measured by measuring the extent to which the osteoclast differentiation was inhibited by treatment with a single agent or a combination. The effect of was evaluated. Co-culture was performed using mouse-derived bone marrow cells and osteoblasts.

1. Preparation of bone marrow cells and osteoblasts

Co-culture was performed using mouse-derived bone marrow cells and osteoblasts.

Bone marrow cells were harvested by the normal method using a syringe by extracting the femur and tibia from 6-8 week old male ddY mice. After erythrocytes were removed from the bone marrow, the bone marrow cells recovered by centrifugation were placed in α-MEM medium to which 10% fetal bovine serum was added, and nucleated cells were counted and used immediately for co-culture.

In the case of osteoblasts, skulls were extracted from 1-2 days old ICR mice and osteoblasts were isolated by continuous reaction with 0.2% collagenase enzyme solution. Osteoblasts recovered by centrifugation of the cell-suspended supernatant were grown in α-MEM medium to which 10% fetal bovine serum was added for a certain period of time, and then diluted to a desired cell number.

2. Osteoclast differentiation experiment by coexistence culture

The bone marrow cells and osteoblasts prepared above were diluted in α-MEM medium to which 10% fetal bovine serum was added so as to have a number of 1 × 10 ⁵ cells and 3,000 cells per 96 wells, respectively. The culture medium used to induce osteoclast differentiation was a differentiation medium to which differentiation factors 1α, 25-dihydroxyvitamin D ₃ (10 ^-8 M, hereinafter vitamin D ₃ ) and dexamethasone (10 ^-8 M) were added. . The cells were replaced every 2-3 days with fresh medium containing differentiation factors.

After 7 days from the start of culture, it was confirmed that the osteoclasts with the multinucleus were formed, the medium was removed, and the cells were fixed with 10% phosphate buffered formalin solution. The degree of formation of mature osteoclasts was determined using the characteristics of osteoclasts with a positive response to tartaric acid-resistant phosphatase (TRAP) stain. The TRAP staining buffer solution was prepared by dissolving the substrate naphthol AS-MS phosphate and pigment (Fast Red Violet LB salt) in N, N-dimethylformamide, and storing it in cold storage after adding 0.1 N NaHCO ₃ buffer containing 50 mM tartaric acid. It was used as a liquid. Under the light microscope, 6-7 or more multinucleated cells among TRAP-positive cells were recognized as mature osteoclasts.

3. Effect of test substance on osteoclast differentiation

The effects of osteoid differentiation upon treatment of etidronic acid, Compound 1, Compound 2, Compound 3 and Compound 4 alone or in combination treatment of etidronic acid with Compound 1, Compound 2, Compound 3 or Compound 4 It was evaluated through osteoclast differentiation experiment. All experiments were performed in α-MEM differentiation medium supplemented with 10% fetal bovine serum, vitamin D3 and dexamethasone.

Compound 1, Compound 2, Compound 3, and Compound 4 were dissolved at a concentration of 0.1 mM using DMSO, and then diluted 1,000-fold with differentiation medium to a final 0.1 μM. Ethidronic acid was dissolved at a concentration of 2 mM using purified water, and then diluted 1,000-fold in the medium to obtain a final concentration of 2 µM. At this time, the control group was maintained in a state containing 0.1% DMSO.

As described above, co-cultures were started by adding diluted sample material and cells to 96-well, respectively, in desired settings, and exchanged with fresh differentiation medium containing sample material on days 3 and 5 of the culture. On the seventh day of the experiment, osteoclast differentiation was performed to measure mature osteoclasts with multinuclei through TRAP staining. Only osteoclasts with six or more nuclei were observed under the microscope and counted. Experimental results were set to 100% osteoclasts of the control group using only solvent, and the number of osteoclasts observed in each experimental group was expressed as a relative percentage (%) compared to the control. Experiments were performed with populations of four wells (n = 4) per experimental group, and the results are expressed as mean ± standard deviation. In addition, the embodiment was carried out at least three repeated experiments, the mutual significance test for each experimental group was applied through the Student t-test. The experimental results are shown in Table 1 below.

Effect of Etidronic Acid and Compound 1, Compound 2, Compound 3, and Compound 4 in Combination or Combined Treatment on Osteoclast Differentiation % Percentage of osteoclast numbers (vs. solvent control) con (-) Etidronic acid Compound 1 Compound 2 Compound 3 Compound 4 end. Solvent control 100 ± 8.1 I. Compound alone treatment group (0.1 μM) 67 ± 7.4 ^* 71 ± 6.5 ^* 66 ± 8.3 ^* 78 ± 8.6 ^* All. Ethidronic acid monotreated group (2μM) 86 ± 6.9 ^* la. Compound + etidronic acid combination treatment group 41 ± 7.5 ^{*, #, @} 40 ± 8.4 ^{*, #, @} 38 ± 8.2 ^{*, #, @} 49 ± 9.7 ^{*, #, @} [stock. Control (con (-)): 0.1% DMSO solvent b. Compound 1, Compound 2, Compound 3, and Compound 4 (0.1 μM) alone treatment group. C. Treatment group of etidronic acid (2 μM) d. Combination treatment group of Compound 1, Compound 2, Compound 3, or Compound 4 (0.1 µM) with Etidronic Acid (2 µM) * p <0.0001 vs. Solvent control, # p <0.0001 vs. Group treated with each compound, @ p <0.0001 vs. Ethedronic acid treatment group

As shown in Table 1, the number of osteoclasts formed in each of the experimental groups treated with Compound 1, Compound 2, Compound 3, and Compound 4 alone after 100% of the number of TRAP-positive osteoclasts formed in the solvent control group was 100%. Is expressed as a percentage. Inhibition of osteoclast differentiation of these single substances added to the co-cultured cells at the same concentration of 0.1 μM alone was 67%, 71%, 66% and 78%, respectively.

In addition, in the experimental group treated with 2 μM concentration of etidronic acid alone, the osteoclast formation value of about 86% was measured as compared to the solvent control group. These reductions were shown to be significant in inhibiting osteoclast differentiation.

When the individually treated etidronic acid and Compound 1, Compound 2, Compound 3, or Compound 4 were simultaneously treated together, the simultaneous treatment of Compound 1 and Etidronic Acid was 41% of osteoclasts compared to the solvent control group. Formed a bay. This value is significantly lower than the sum of Compound 1 and the result of etidronic acid treatment alone, suggesting a strong parallel treatment effect. Significant parallel effect through simultaneous treatment with etidronic acid was also confirmed in the experimental group with Compound 2 (40%), Compound 3 (38%) and Compound 4 (49%). The above results demonstrate that the simultaneous treatment of two single substances, that is, co-treatment, can induce much higher efficacy than expected from the sum of individual effects of single substances.

Example 2 Effect of Chlodronic Acid (1 μM) and Compounds 1 to 4 alone or in combination on osteoclast differentiation

Except for using 1 μM of clodronic acid instead of 2 μM of etidronic acid, the effect of the monoclonal treatment or the combination of Clodronic Acid and Compounds 1 to 4 on osteoclast differentiation was investigated in the same manner as in Example 1.

Chlodronic acid was dissolved in a concentration of 1 mM using purified water, diluted 1,000-fold in the medium, and used to have a final concentration of 1 μM.

The results are shown in Table 2 below.

Effect of Chlodronic Acid and Compound 1, Compound 2, Compound 3, or Compound 4 on the Osteoclast Differentiation % Percentage of osteoclast numbers (vs. solvent control) con (-) Chlodronic acid Compound 1 Compound 2 Compound 3 Compound 4 end. Solvent control 100 ± 8.1 I. Compound alone treatment group (0.1 μM) 67 ± 7.4 ^* 71 ± 6.5 ^* 66 ± 8.3 ^* 78 ± 8.6 ^* All. Chlodronic acid monotreated group (1μM) 88 ± 9.7 ^* la. Compound + Clononic acid combination group 60 ± 15.2 ^{*, @} 54 ± 11.9 ^{*, #, @} 47 ± 13.0 ^{*, #, @} 59 ± 14.0 ^{*, #, @} [stock. Control (con (-)): 0.1% DMSO solvent b. Compound 1, Compound 2, Compound 3, and Compound 4 (0.1 μM) alone treatment group. Group treated with Chlodronic acid (1 μM) d. Combination treatment group of Compound 1, Compound 2, Compound 3, or Compound 4 (0.1 µM) with Chlodronic Acid (1 µM) * p <0.001 vs. Solvent control, # p <0.0001 vs. Group treated with each compound, @ p <0.0001 vs. Chlodronic acid single treatment group

As mentioned in the results of Example 1, the osteoclast formation values of Compound 1, Compound 2, Compound 3 and Compound 4 treated alone were significantly lower than that of the solvent control. The experimental group of 1 μM of Chlodronic Acid treated with co-cultured cells alone showed a significant reduction effect with relative osteoclast formation of 88% (Table 2). Each of these single materials was co-treated with the same experimental method. The results were statistically significant with the experimental groups that were treated separately in the simultaneous treatment of Compound 2 (54%), Compound 3 (47%) and Compound 4 (59%), except for the combination of Compound 1 and Clodronic Acid. However, significant synergistic effects were observed in osteoclast differentiation by combination treatment.

Example 3 Effect of Pamideronic Acid (0.1 μM) and Compounds 1 to 4 alone or in combination on osteoclast differentiation

Except for using pamideronic acid 0.1μM instead of 2μM etidronic acid was examined the effect of the treatment of osteomyeloid differentiation of the single or combined treatment of pamidronic acid and compounds 1 to 4 in the same manner as in Example 1.

Pamidronic acid was dissolved in purified water at a concentration of 0.1 mM, diluted 1,000-fold in the medium, and used at a final concentration of 0.1 μM.

The results are shown in Table 3 below.

Effect of Pamidronic Acid and Compound 1, Compound 2, Compound 3, or Compound 4 in Combination or Combined Treatment on Osteoclast Differentiation % Percentage of osteoclast numbers (vs. solvent control) con (-) Pamideronic acid Compound 1 Compound 2 Compound 3 Compound 4 end. Solvent control 100 ± 8.1 I. Compound alone treatment group (0.1 μM) 67 ± 7.4 ^* 71 ± 6.5 ^* 66 ± 8.3 ^* 78 ± 8.6 ^* All. Pamidronic acid single treatment group (0.1μM) 82 ± 6.7 ^* la. Compound + Pamidronic Acid Combination Treatment Group 47 ± 10.5 ^{*, #, @} 42 ± 6.2 ^{*, #, @} 37 ± 5.0 ^{*, #, @} 50 ± 8.7 ^{*, #, @} [stock. Control (con (-)): 0.1% DMSO solvent b. Compound 1, Compound 2, Compound 3, and Compound 4 (0.1 μM) alone treatment group. C. Treatment group of pamidronic acid (0.1 μM) d. Combination treatment group of Compound 1, Compound 2, Compound 3, or Compound 4 (0.1 µM) with Pamidronic Acid (0.1 µM) * p <0.0001 vs. Solvent control, # p <0.001 vs. Group treated with each compound, @ p <0.0001 vs. Pamidronic acid single treatment group

As can be seen in Table 3, the osteoclasts in the Pamilonic acid (0.1 μM) alone test group showed a significant decrease of 82% compared to the control group. As mentioned above, simultaneous treatment of Compound 1, Compound 2, Compound 3, or Compound 4 with pamidronic acid, which showed a significant inhibitory effect on osteoclast differentiation by single treatment, was attempted. The results of the combination treatment of pamidonic acid with Compound 1 were 47%, 42% with Compound 2, 37% with Compound 3, and 50% with Compound 4, respectively. In particular, the parallel treatment effect of pamidronic acid with Compound 2, Compound 3 and Compound 4 improved the osteoclast inhibitory effect by about 10% or more than the sum of the effects alone.

Example 4 Effects of Alendronic Acid (0.2 μM) and Compounds 1 to 4 alone or in combination on osteoclast differentiation

Except for using 0.2 μM of alendronic acid instead of 2 μM of etidronic acid, the effect of the treatment of allelenic acid and the compounds 1 to 4 alone or in combination on osteoclast differentiation was examined in the same manner as in Example 1.

Alendronic acid was dissolved in a concentration of 0.2 mM using purified water, and then diluted 1,000-fold in the medium so as to have a final concentration of 0.2 μM.

The results are shown in Table 4 below.

Effect of Alendronic Acid and Compound 1, Compound 2, Compound 3, or Compound 4 alone or in combination on osteoclast differentiation % Percentage of osteoclast numbers (vs. solvent control) con (-) Alendronic acid Compound 1 Compound 2 Compound 3 Compound 4 end. Solvent control 100 ± 8.1 I. Compound alone treatment group (0.1 μM) 67 ± 7.4 ^* 71 ± 6.5 ^* 66 ± 8.3 ^* 78 ± 8.6 ^* All. Alendronic acid treatment group (0.2 μM) 80 ± 5.7 ^* la. Compound + Alendronic acid combination group 32 ± 8.1 ^{*, #, @} 32 ± 8.9 ^{*, #, @} 29 ± 5.3 ^{*, #, @} 44 ± 7.4 ^{*, #, @} [stock. Control (con (-)): 0.1% DMSO solvent b. Compound 1, Compound 2, Compound 3, and Compound 4 (0.1 μM) alone treatment group. C. Treatment Group of Alendronic Acid (0.2 μM) d. Combination treatment group of Compound 1, Compound 2, Compound 3, or Compound 4 (0.1 µM) with Alendronic Acid (0.2 µM) * p <0.0001 vs. Solvent control, # p <0.0001 vs. Group treated with each compound, @ p <0.0001 vs. Alendronic acid treatment group

Table 4 shows the results of the parallel treatment of Compound 1, Compound 2, Compound 3, and Compound 4 with 0.2 μM of alendronic acid and 80% of osteoclasts compared to the solvent control group, and a significant osteoclast reduction effect. It was. When Compound 1 and Alendronic acid at the same concentration were simultaneously used in combination with 67% of the relative osteoclast formation value, the number of osteoclasts was remarkably decreased, showing a very low value of 32%. In addition, the experimental group in combination with Compound 2 (32%), Compound 3 (29%) and Compound 4 (44%) also confirmed that the number of osteoclasts was strongly reduced. These results were recognized to be more potent than the expected combination of the effects of each single substance.

Example 5 Effect of Lysedronic Acid (0.1 μM) and Compounds 1 to 4 alone or in combination on osteoclast differentiation

The effect of risedronic acid and compound 1 to 4 alone or in combination on osteoclast differentiation was investigated in the same manner as in Example 1 except that 0.1 μM of risedronic acid was used instead of 2 μM of etidronic acid.

Lysedronic acid was dissolved in purified water at a concentration of 0.1 mM, diluted 1,000-fold in the medium, and used at a final concentration of 0.1 μM.

The results are shown in Table 5 below.

Effects of Lysedronic Acid and Compound 1, Compound 2, Compound 3, or Compound 4 on or in combination with osteoclast differentiation % Percentage of osteoclast numbers (vs. solvent control) con (-) Risedronic acid Compound 1 Compound 2 Compound 3 Compound 4 end. Solvent control 100 ± 8.1 I. Compound alone treatment group (0.1 μM) 67 ± 7.4 ^* 71 ± 6.5 ^* 66 ± 8.3 ^* 78 ± 8.6 ^* All. Risedronic acid single treatment group (0.1μM) 82 ± 5.2 ^* la. Compound + risedronic acid combination treatment group 40 ± 6.6 ^{*, #, @} 35 ± 8.2 ^{*, #, @} 38 ± 6.8 ^{*, #, @} 42 ± 7.6 ^{*, #, @} [stock. Control (con (-)): 0.1% DMSO solvent b. Compound 1, Compound 2, Compound 3, and Compound 4 (0.1 μM) alone treatment group. C. Treatment group of risedronic acid (0.1 μM) d. Combination treatment group of Compound 1, Compound 2, Compound 3 or Compound 4 (0.1 µM) with risedronic acid (0.1 µM) * p <0.0001 vs. Solvent control, # p <0.0001 vs. Group treated with each compound, @ p <0.0001 vs. Risedronic acid treatment group

The synergistic effect of osteoclast differentiation, i.e., the combined effect of risedronic acid and the four single substances, was also confirmed through experiments (Table 5). The addition of 0.1 μM risedronic acid alone showed a relative osteoclast level of about 82% and showed a significant decrease in comparison with the solvent control. Treatment of each of these cells with co-cultured cells at the same time resulted in low osteoclast formation rates of risedronic acid with Compound 1, Compound 2, Compound 3 or Compound 4, respectively 40%, 35%, 38 and 42%. . These combined treatment results can be seen to be a powerful effect showing a significant difference not only the solvent control group but also the results of the single treatment experimental group of each single material.

Example 6 Effect of Ibandronic Acid (0.1 μM) and Compounds 1 to 4 alone or in combination on osteoclast differentiation

Except for using 0.1 μM of ibandronic acid instead of 2 μM of etidronic acid, the effect of ibandronic acid and the compound 1 to 4 alone or in combination treatment on osteoclast differentiation was investigated in the same manner as in Example 1.

Ibandronic acid was dissolved at a concentration of 0.1 mM using purified water, and then diluted 1,000-fold in the medium to be used at a final concentration of 0.1 μM.

The results are shown in Table 6 below.

Effects of Ibandronic Acid and Compound 1, Compound 2, Compound 3, or Compound 4 alone or in combination on osteoclast differentiation % Percentage of osteoclast numbers (vs. solvent control) con (-) Ibandronic acid Compound 1 Compound 2 Compound 3 Compound 4 end. Solvent control 100 ± 8.1 I. Compound alone treatment group (0.1 μM) 67 ± 7.4 ^* 71 ± 6.5 ^* 66 ± 8.3 ^* 78 ± 8.6 ^* All. Ibandronic acid treatment group (0.1 μM) 77 ± 8.2 ^* la. Compound + ibandronic acid combination treatment group 42 ± 8.1 ^{*, #, @} 45 ± 7.6 ^{*, #, @} 36 ± 9.8 ^{*, #, @} 54 ± 8.7 ^{*, #, @} [stock. Control (con (-)): 0.1% DMSO solvent b. Compound 1, Compound 2, Compound 3, and Compound 4 (0.1 μM) alone treatment group. Single treatment group of ibandronic acid (0.1 μM) d. Combination treatment group of Compound 1, Compound 2, Compound 3, or Compound 4 (0.1 µM) with ibandronic acid (0.1 µM) * p <0.0001 vs. Solvent control, # p <0.0001 vs. Group treated with each compound, @ p <0.0001 vs. Ibandronic acid treatment group

Treatment with ibandronic acid (0.1 μM) alone resulted in a significant decrease in the formation of TRAP-positive osteoclasts by 77% compared to the solvent control. The combination group of ibandronic acid and Compound 1 showed an osteoclast formation rate of 42%, and a significant reduction effect was observed compared to the individual treatment groups. The results of the combination group of ibandronic acid and the remaining substances also showed a significant low osteoclast count as shown in Table 6.

Example 7 Effect of Zoledronic Acid (0.01 μM) and Compounds 1 to 4 alone or in combination on osteoclast differentiation

Except for using 0.01 μM of zoledronic acid instead of 2 μM of etidronic acid, the effect of zoledronic acid and treatment alone or in combination with Compounds 1 to 4 on osteoclast differentiation was investigated in the same manner as in Example 1.

Zoledronic acid was dissolved in a concentration of 0.01 mM using purified water, and then diluted 1,000-fold in the medium to be used at a final concentration of 0.01 μM.

The results are shown in Table 7 below.

Effect of Zoledronic Acid, Compound 1, Compound 2, Compound 3, or Compound 4 or Combined Treatment on Osteoclast Differentiation % Percentage of osteoclast numbers (vs. solvent control) con (-) Zoledronic acid Compound 1 Compound 2 Compound 3 Compound 4 end. Solvent control 100 ± 8.1 I. Compound alone treatment group (0.1 μM) 67 ± 7.4 ^* 71 ± 6.5 ^* 66 ± 8.3 ^* 78 ± 8.6 ^* All. Zoledronic acid treatment group (0.01μM) 84 ± 4.1 ^* la. Compound + zoledronic acid combination treatment group 43 ± 4.5 ^{*, #, @} 48 ± 8.9 ^{*, #, @} 42 ± 8.1 ^{*, #, @} 59 ± 8.2 ^{*, #, @} [stock. Control (con (-)): 0.1% DMSO solvent b. Compound 1, Compound 2, Compound 3, and Compound 4 (0.1 μM) alone treatment group. Single treatment group of zoledronic acid (0.01 μM) d. Combination treatment group of Compound 1, Compound 2, Compound 3 or Compound 4 (0.1 μM) with zoledronic acid (0.01 μM) * p <0.0001 vs. Solvent control, # p <0.0001 vs. Group treated with each compound, @ p <0.0001 vs. Zoledronic acid treatment group

Each of the four single substances having a significant reduction in osteoclast number was subjected to co-treatment with 0.01 μM of zoledronic acid. The effect of zoledronic acid alone on osteoclast formation was significantly reduced to 84% compared to solvent control. Simultaneous treatment of zoledronic acid with Compound 1 resulted in 43% of osteoclast formation, and this result was lower than the sum of the results predicted by the single treatment of the two substances. Suggested. In the experimental group of the remaining substances it was confirmed the synergistic effect by the combination treatment (Table 7).

Pharmaceutical composition for the prevention or treatment of osteoporosis comprising benzamidine derivatives or salts thereof, and bisphosphonates according to the present invention has an excellent inhibitory effect on the differentiation of osteoclasts, osteoporosis including osteoporosis in parallel administration of the two substances It can be usefully used as a prophylactic or therapeutic pharmaceutical composition that can increase the efficiency of the preventive and therapeutic effects of the lesions related to absorption.

Claims (7)

A pharmaceutical composition for the prevention or treatment of osteoporosis comprising the following (a) and (b) as an active ingredient for use simultaneously, separately or sequentially: (a) a novel benzamidine derivative represented by the following formula (1) or a salt thereof, (b) bisphosphonates represented by the following formula (2), [Formula 1]

In Chemical Formula 1, R ₁ is C ₁ -C ₆ alkyl unsubstituted or substituted with pyridine; Unsubstituted or substituted with hydroxy

C ₁ -C ₆ straight or branched alkyl, substituted with; C ₃ -C ₆ cycloalkyl; Phenyl; benzyl; Pyridinyl unsubstituted or substituted with C ₁ -C ₆ alkyl; Guanidino; NR ₆ R ₇ ; CH ₂ NR ₆ R ₇ ; Pyridinyl substituted with C ₁ to C ₆ straight or branched alkyl or

Group;

(A is C ₁ -C ₆ alkyl and m is an integer from 2 to 6); Or unsubstituted or substituted with C ₁ to C ₆ alkyl

Group; R ₂ is hydrogen; C ₁ -C ₆ straight or branched alkyl substituted or unsubstituted with NR ₈ R ₉ ; C ₃ -C ₆ cycloalkyl; Phenyl; benzyl; C ₁ -C ₆ straight or branched chain alkyl substituted with hydroxy, C ₁ -C ₆ alkoxy, halogen or C ₃ -C ₆ cycloalkyl; C ₁ -C ₆ alkenyl; Carbonyl substituted with NR ₈ R ₉ ;

C ₁ ~ C ₆ linear or branched alkyl substituted with; C ₁ -C ₆ straight or branched chain alkyl substituted with pyrrolidine, piperidine or imidazole; R ₃ and R ₄ are each hydrogen; halogen; Hydroxy; C ₁ -C ₆ alkyl unsubstituted or substituted with halogen; C ₃ -C ₆ cycloalkylamino; C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkanoyloxy; C ₂ -C ₆ alkenyloxy; Phenyl-C ₁ -C ₆ alkoxy; Phenoxy; C ₂ ~ C ₆ alkenyl or phenyl alkanoyl oxy -C ₁ ~ C ₆ alkanoyloxy; Or C ₃ -C ₆ cycloalkyloxy substituted with one group selected from carboxy, esterified carboxy or amidated carboxy; Or an aminooxy group; R ₅ is hydrogen or a hydroxy group; R ₆ and R ₇ are each hydrogen; Hydroxy, C ₁ -C ₆ alkoxy, pyridine or

C ₁ ~ C ₆ alkyl unsubstituted or substituted with one group selected from; Phenyl; benzyl; Pyridinyl; C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, phenyl, benzyl, pyridine or

Carbonyl substituted with one group selected from; Or C ₁ -C ₆ alkanesulfonyl; R ₈ and R ₉ are each hydrogen; Hydroxy, C ₁ ~ C ₆ alkoxy, morpholine, imidazole or substituted with one NR ₆ R ₇ group selected from the group consisting of and unsubstituted C ₁ ~ C ₆ alkyl; C ₁ -C ₆ alkoxy; C ₃ -C ₆ cycloalkyl; Phenyl; benzyl; Pyridinyl; Morpholine; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl, benzyl, pyridine or

Carbonyl substituted with one group selected from; Carbonyl substituted with C ₁ -C ₆ alkyl substituted with one group selected from halogen, C ₁ -C ₆ alkoxy or imidazole; Or C ₁ -C ₆ alkanesulfonyl; R ₁₀ and R ₁₁ are each hydrogen, C ₁ -C ₂ alkyl, C ₁ -C ₃ alkoxy or halide; X ₁ and X ₃ are each O; S; NH; Or NC ₁ -C ₆ alkyl, NC ₃ -C ₆ cycloalkyl, N-benzyl or N-phenyl group; X ₂ is C ₃ -C ₇ alkylene; C ₁ -C ₃ alkylene-C ₂ -C ₇ alkenylene-C ₁ -C ₃ alkylene; C ₁ -C ₃ alkylene-OC ₁ -C ₃ alkylene; C ₁ -C ₃ alkylene-SC ₁ -C ₃ alkylene; C ₁ -C ₃ alkylene-NH-C ₁ -C ₃ alkylene; C ₁ ~ C ₃ alkylene-phenylene -C ₁ -C ₃ alkylene; C ₁ -C ₃ alkylene-pyridylene group -C ₁ -C ₃ alkylene or C ₁ -C ₃ alkylene-naphthylene -C ₁ ~ C ₃ alkylene; C ₁ ~ C ₃ alkyl and hydroxyl chamber substituted C ₃ ~ C ₇ alkylene; C ₃ -C ₇ alkylene carbonyl; Or C ₃ -C ₇ alkylene interrupted by piperazine; Y is O, S, NR ₆ or CH ₂ group; n is an integer of 0, 1 or 2, [Formula 2]

In Chemical Formula 2, R ₁₂ is methyl, chloro, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 4-chlorophenylthio, 3-pyridylmethyl, (imidazo [1,2-a] pyridine -3-yl) methyl, 2- (N-methyl-Nn-pentyl) aminoethyl, cycloheptylamino, (1-imidazolyl) methyl or 1-pyrrolidinylethyl group, R ₁₃ is hydrogen, chloro or a hydroxy group, M is hydrogen or sodium, z is an integer of 0-7. According to claim 1, wherein the compound of Formula 1 1) N-hydroxy-4- {5- [4- (2-isopropyl-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 2) 4- {5- [4- (2-isopropyl-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 3) N-hydroxy-4- {5- [4- (2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 4) N-hydroxy-4- {5- [4- (2-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 5) N-hydroxy-4- {5- [4- (2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 6) N-hydroxy-4- {5- [4- (2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 7) N-hydroxy-4- {5- [4- (2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 8) N-hydroxy-4- {5- [4- (2-cyclohexyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 9) N-hydroxy-4- {5- [4- (2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 10) N-hydroxy-4- {5- [4- (2,5-dimethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benz amidine, 11) N-hydroxy-4- {5- [4- (2-ethyl-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 12) N-hydroxy-4- {5- [4- (5-methyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 13) N-hydroxy-4- {5- [4- (5-methyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 14) N-hydroxy-4- {5- [4- (2-cyclohexyl-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 15) N-hydroxy-4- {5- [4- (5-methyl-2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 16) N-hydroxy-4- {5- [4- (2-t-butyl-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 17) N-hydroxy-4- {5- [4- (5-ethyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 18) N-hydroxy-4- {5- [4- (2,5-diethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 19) N-hydroxy-4- {5- [4- (5-ethyl-2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 20) N-hydroxy-4- {5- [4- (5-ethyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 21) N-hydroxy-4- {5- [4- (5-ethyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 22) N-hydroxy-4- {5- [4- (2-cyclohexyl-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 23) N-hydroxy-4- {5- [4- (5-ethyl-2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 24) N-hydroxy-4- {5- [4- (2-ethyl-5-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 25) N-hydroxy-4- {5- [4- (2,5-diisopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 26) N-hydroxy-4- {5- [4- (5-isopropyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 27) N-hydroxy-4- {5- [4- (5-isopropyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine , 28) N-hydroxy-4- {5- [4- (5-isopropyl-2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 29) N-hydroxy-4- {5- [4- (2-methyl-5-propyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 30) N-hydroxy-4- {5- [4- (5-butyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 31) N-hydroxy-4- {5- [4- (5-butyl-2-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 32) N-hydroxy-4- {5- [4- (5-butyl-2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 33) N-hydroxy-4- {5- [4- (5-butyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 34) N-hydroxy-4- {5- [4- (5-butyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 35) N-hydroxy-4- {5- [4- (5-butyl-2-cyclohexyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 36) N-hydroxy-4- {5- [4- (5-butyl-2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 37) N-hydroxy-4- {5- [4- (5-butyl-2-t-butyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 38) N-hydroxy-4- {5- [4- (5-benzyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 39) N-hydroxy-4- {5- [4- (5-benzyl-2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 40) N-hydroxy-4- {5- [4- (5-benzyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 41) N-hydroxy-4- {5- [4- (5-benzyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 42) N-hydroxy-4- {5- [4- (5- (2-chloro-ethyl) -2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean, 43) N-hydroxy-4- {5- [4- (5-cyclopentyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 44) N-hydroxy-4- {5- [4- (5-isobutyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 45) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 46) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 47) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 48) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 49) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-pyridin-3-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean, 50) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-cyclohexyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 51) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-pentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 52) 4- {5- [4- (2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 53) 4- {5- [4- (2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 54) 4- {5- [4- (2,5-dimethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 55) 4- {5- [4- (5-ethyl-2-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 56) 4- {5- [4- (5-ethyl-2-phenyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 57) N-hydroxy-4- {5- [4- (2-amino-1, 3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 58) N-hydroxy-4- {5- [4- (2-amino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 59) N-hydroxy-4- {5- [4- (2-guanidino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 60) N-hydroxy-4- {5- [4- (2-amino-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 61) N-hydroxy-4- {5- [4- (2-amino-5-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 62) N-hydroxy-4- {5- [4- (2-guanidino-5-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 63) N-hydroxy-4- {5- [4- (2-amino-5-butyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 64) N-hydroxy-4- {5- [4- (5-butyl-2-guanidino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 65) N-hydroxy-4- {5- [4- (2-amino-5-benzyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 66) N-hydroxy-4- {5- [4- (5-benzyl-2-guanidino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 67) N-hydroxy-4- {5- [4- (2-amino-5-cyclopentylmethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 68) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2- (1-propyl-piperidin-4-yl) -1,3-thiazol-4-yl) phenoxy Pentoxy} -benzamidine, 69) N-hydroxy-4- {5- [4- (2- (isobutyryl) amino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine 70) N-hydroxy-4- {5- [4- (5-isopropyl-2-morpholinomethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 71) N-hydroxy-4- {5- [4- (2-aminomethyl-5-benzyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 72) N-hydroxy-4- {5- [4- (5-methyl-2- (1-propyl-piperidin-4-yl) -1,3-thiazol-4-yl) phenoxy] Pentoxy} -benzamidine, 73) N-hydroxy-4- {5- [4- (5-isopropyl-2-aminomethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 74) N-hydroxy-4- {5- [4- (5-vinyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 75) N-hydroxy-4- {5- [4- (5-hydroxymethyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 76) N-hydroxy-4- {5- [4- (5-methoxymethyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 77) N-hydroxy-4- {5- [4- (5- (2-chloroethyl) -2-amino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine , 78) N-hydroxy-4- {5- [4- (5-vinyl-2-amino-1, 3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 79) N-hydroxy-4- {5- [4- (5-vinyl-2- (pyridin-3-yl) -1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean, 80) N-hydroxy-4- {5- [4- (5- (2-chloroethyl) -2- (pyridin-3-yl) -1,3-thiazol-4-yl) phenoxy] Pentoxy} -benzamidine, 81) N-hydroxy-4- {5- [4- (2-amino-5-cyclopentyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 82) N-hydroxy-4- {5- [4- (5-ethyl-2-aminomethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 83) N-hydroxy-4- {5- [4- (5-isopropyl-2- (piperidin-3-yl) -1,3-thiazol-4-yl) phenoxy] pentoxy} Benzamidine, 84) N-hydroxy-4- {5- [4- (2-ethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 85) N-hydroxy-4- {5- [4- (2-ethanesulfonylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 86) N-hydroxy-4- {5- [4- (5-methyl-2-methylamino-1, 3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 87) N-hydroxy-4- {5- [4- (2-ethylamino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 88) N-hydroxy-4- {5- [4- (5-methyl-2-propylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 89) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2- (3-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy } -Benzamidine, 90) N-hydroxy-4- {5- [4- (2-hydroxyacetylamino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 91) N-hydroxy-4- {5- [4- (5-methyl-2- (4-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy}- Benzamidine, 92) N-hydroxy-4- {5- [4- (5-methyl-2- (3-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy}- Benzamidine, 93) N-hydroxy-4- {5- [4- (2-ethanesulfonylamino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 94) N-hydroxy-4- {5- [4- (2- (2-methoxyethyl) amino-5-methyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benz Amidine, 95) N-hydroxy-4- {5- [4- (2-ethanesulfonylamino-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 96) N-hydroxy-4- {5- [4- (5-ethyl-2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 97) N-hydroxy-4- {5- [4- (5-ethyl-2-ethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 98) N-hydroxy-4- {5- [4- (5-ethyl-2-propylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 99) N-hydroxy-4- {5- [4- (5-ethyl-2-methoxyacetylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 100) N-hydroxy-4- {5- [4- (5-ethyl-2- (4-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy}- Benzamidine, 101) N-hydroxy-4- {5- [4- (5-ethyl-2- (3-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy}- Benzamidine, 102) N-hydroxy-4- {5- [4- (5-ethyl-2- (2-methoxyethyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benz Amidine, 103) N-hydroxy-4- {5- [4- (5-isopropyl-2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 104) N-hydroxy-4- {5- [4- (2-ethylamino-5-isopropyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 105) N-hydroxy-4- {5- [4- (5-butyl-2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 106) N-hydroxy-4- {5- [4- (5-butyl-2-ethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 107) N-hydroxy-4- {5- [4- (5-benzyl-2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 108) N-hydroxy-4- {5- [4- (5-benzyl-2-ethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 109) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 110) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-ethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 111) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-propylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 112) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2- (4-pyridylcarbonyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy } -Benzamidine, 113) N-hydroxy-4- {5- [4- (5-cyclopentyl-2-propylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 114) N-hydroxy-4- {5- [4- (5-isopropyl-2-[(pyridin-3-ylmethyl) amino] -1,3-thiazol-4-yl) phenoxy] phen Methoxy} -benzamidine, 115) N-hydroxy-4- {5- [4- (5- (2-chloroethyl) -2-methylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean, 116) N-hydroxy-4- {5- [4- (2-methylamino-1, 3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 117) N-hydroxy-4- {5- [4- (5-ethyl-2- (pyridin-3-ylmethyl) amino-1,3-thiazol-4-yl) phenoxy] pentoxy}- Benzamidine, 118) N-hydroxy-4- {5- [4- (2- (ethanesulfonyl-methyl-amino) -1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 119) N-hydroxy-4- [5- (4- {2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy) pentoxy]- Benzamidine, 120) N-hydroxy-4- [5- (4- {2-[(2-hydroxyethyl) -methyl-amino] -5-methyl-1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 121) N-hydroxy-4- [5- (4- {2- [ethyl- (2-hydroxyethyl) -amino] -5-methyl-1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 122) N-hydroxy-4- [5- (4- {2- [bis- (2-methoxyethyl) -amino] -5-methyl-1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 123) N-hydroxy-4- [5- (4- {5-methyl-2- [methyl- (2-morpholinoethyl) -amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine, 124) N-hydroxy-4- [5- (4- {2- [ethyl-1- (2-morpholinoethyl) -amino] -5-methyl-1,3-thiazol-4-yl} Phenoxy) pentoxy] -benzamidine, 125) N-hydroxy-4- {5- (4- [2- (benzyl-methyl-amino) -5-methyl-1,3-thiazol-4-yl] phenoxy) pentoxy} -benzami Dean, 126) N-hydroxy-4- [5- {4- [5-methyl-2- (methyl-pyridin-3-yl-methyl-amino) -1,3-thiazol-4-yl] phenoxy} Pentoxy] -benzamidine, 127) N-hydroxy-4- [5- {4- [2- (benzyl-ethyl-amino) -5-methyl-1,3-thiazol-4-yl] phenoxy} pentoxy] -benzami Dean, 128) N-hydroxy-4- [5- (4- {2- [bis- (2-hydroxyethyl) -amino] -5-methyl-1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 129) N-hydroxy-4- [5- (4- {5-ethyl-2-[(2-hydroxyethyl) -methyl-amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 130) N-hydroxy-4- [5- (4- {5-ethyl-2- [ethyl- (2-hydroxyethyl) -amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 131) N-hydroxy-4- [5- (4- {5-ethyl-2- [methyl- (2-morpholinoethyl) -amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine, 132) N-hydroxy-4- [5- (4- {5-ethyl-2- [ethyl- (2-morpholinoethyl) -amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine, 133) N-hydroxy-4- [5- {4- [2- (benzyl-methyl-amino) -5-ethyl-1,3-thiazol-4-yl] phenoxy} pentoxy] -benzami Dean, 134) N-hydroxy-4- [5- (4- {5-ethyl-2- [methyl- (pyridin-3-ylmethyl) amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 135) N-hydroxy-4- (5- {4- [2- (benzyl-ethyl-amino) -5-ethyl-1,3-thiazol-4-yl] phenoxy} pentoxy) -benzami Dean, 136) N-hydroxy-4- {5- (4- [5-ethyl-2- (ethyl- [pyridin-3-ylmethyl] amino) -1,3-thiazol-4-yl] phenoxy) Pentoxy} -benzamidine, 137) N-hydroxy-4- [5- (4- {2- [bis- (pyridin-3-ylmethyl) amino] -5-ethyl-1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 138) N-hydroxy-4- {5- [4- (2-dipropylamino-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 139) N-hydroxy-4- [5- (4- {2- [bis- (2-hydroxyethyl) amino] -5-ethyl-1,3-thiazol-4-yl} phenoxy) phene Oxy] -benzamidine, 140) N-hydroxy-4- [5- (4- {2-[(2-hydroxyethyl) -methyl-amino] -5-isopropyl-1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine, 141) N-hydroxy-4- [5- (4- {5-isopropyl-2- [methyl- (pyridin-3-ylmethyl) amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine, 142) N-hydroxy-4- (5- {4- [2- (ethanesulfonyl-methyl-amino) -5-isopropyl-1,3-thiazol-4-yl] phenoxy} pentoxy) Benzamidine, 143) N-hydroxy-4- [5- (4- {5-butyl-2-[(2-hydroxyethyl) -methyl-amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 144) N-hydroxy-4- [5- (4- {5-butyl-2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 145) N-hydroxy-4- [5- (4- {5-butyl-2- [methyl- (pyridin-3-ylmethyl) amino] -1,3-thiazol-4-yl} phenoxy) Pentoxy] -benzamidine, 146) N-hydroxy-4- {5- [4- (5-butyl-2-dipropylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 147) N-hydroxy-4- [5- (4- {5-cyclopentylmethyl-2- [methyl- (pyridin-3-ylmethyl) amino] -1,3-thiazol-4-yl} phenoxy Pentoxy] -benzamidine, 148) N-hydroxy-4- [5- (4- {5-cyclopentylmethyl-2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy Pentoxy] -benzamidine, 149) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-dipropylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 150) N-hydroxy-4- {5- [4- (5-butyl-2-diethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 151) N-hydroxy-4- {5- [4- (5-butyl-2-ethylmethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 152) N-hydroxy-4- {5- [4- (5-butyl-2-dimethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 153) N-hydroxy-4- [5- (4- {5-cyclopentyl-2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine, 154) N-hydroxy-4- [5- (4- {5-isobutyl-2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine, 155) N-hydroxy-4- (5- {4- [5- (2-chloroethyl) -2-dimethylamino-1,3-thiazol-4-yl] phenoxy} pentoxy) -benzami Dean, 156) N-hydroxy-4- {5- [4- (5-cyclopentyl-2-diethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 157) N-hydroxy-4- {5- [4- (5-isopropyl-2-dipropylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 158) N-hydroxy-4- {5- [4- (5-ethyl-2-diethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 159) N-hydroxy-4- [5- (4- {5-isopropyl-2- [methyl- (2-morpholinoethyl) amino] -1,3-thiazol-4-yl} phenoxy ) Pentoxy] -benzamidine, 160) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-diethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 161) N-hydroxy-4- {5- [4- (5-isopropyl-2-dimethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 162) N-hydroxy-4- {5- [4- (5-isopropyl-2-diethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 163) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-dimethylamino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 164) N-hydroxy-4- {5- [4- (5-methyl-2-piperidino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 165) N-hydroxy-4- {5- [4- (5-methyl-2-morpholino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 166) N-hydroxy-4- {5- [4- (5-ethyl-2-piperidino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 167) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-piperidino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 168) N-hydroxy-4- {5- [4- (5-cyclopentylmethyl-2-morpholino-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 169) N-hydroxy-4- {5- [4- (5-isopropyl-2-morpholin-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 170) N-hydroxy-4- {5- (4- [5-cyclopentylmethyl-2- (4-methylpiperazino) -1,3-thiazol-4-yl] phenoxy) pentoxy} Benzamidine, 171) N-hydroxy-4- {5- [4- (5-vinyl-2-morpholin-4-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine , 172) N-hydroxy-4- {5- [4- (5-cyclopentyl-2-morpholin-4-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean, 173) N-hydroxy-4- {5- [4- (5-isobutyl-2-morpholin-4-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzami Dean, 174) N-hydroxy-4- {5- (4- [5-ethyl-2- (4-methylpiperazino) -1,3-thiazol-4-yl] phenoxy) pentoxy} -benz Amidine, 175) N-hydroxy-4- {5- [4- (2-morpholin-4-yl-1,3-thiazol-4-yl) phenoxy] pentoxy} -benzamidine, 176) N-hydroxy-4- {5- (4- [5-isopropyl-2- (4-methylpiperazino) -1,3-thiazol-4-yl] phenoxy) pentoxy}- Benzamidine, 177) N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentylamino} -benzamidine, 178) N-hydroxy-4- (2- {2- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -ethoxy} -ethoxy ) -Benzamidine, 179) N-hydroxy-4- {3-hydroxy-5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -3-methyl- Pentyloxy} -benzamidine, 180) N-hydroxy-4- (2- {2- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -1-methyl-ethylamino } -Ethoxy) -benzamidine, 181) N-hydroxy-4- [3- (4- {3- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -propyl}- Piperazin-1-yl) -propoxy] -benzamidine, 182) N-hydroxy-4-5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentanoyl-amino-benzamidine, 183) N-hydroxy-4-({5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyl} -methyl-amino)- Benzamidine, 184) N-hydroxy-4- {4- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -but-2-enyloxy} -benz Amidine, 185) N-hydroxy-4- {4- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine, 186) N-hydroxy-4- (2- {2- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) phenoxy] -ethylamino} -ethoxy) Benzamidine, 187) N-hydroxy-2-fluoro-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyloxy}- Benzamidine, 188) 2, N-dihydroxy-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyloxy} -benzami Dean, 189) N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyloxy} -3-methoxy- Benzamidine, 190) N-hydroxy-2-cyclohexylamino-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyloxy} Benzamidine, 191) N-hydroxy-4- {5- [3-fluoro-4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -pentyloxy}- Benzamidine, 192) N-hydroxy-2-fluoro-4- {5- [3-fluoro-4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) -phenoxy] -Pentyloxy} -benzamidine, 193) N-hydroxy-4- {3- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) phenoxy] propoxy} -benzamidine, 194) N-hydroxy-4- {4- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) phenoxy] butoxy} -benzamidine, 195) N-hydroxy-3- {5- [4- (5-isopropyl-2-methyl-thiazol-4-yl) -phenoxy] -pentylamino} -benzamidine, 196) N-hydroxy-4- {4- [4- (2-cyclohexyl-5-ethyl-thiazol-4-yl) -phenoxy] -butoxy} -benzamidine, 197) N-hydroxy-4- [5- (4- {5-ethyl-2-[(2-hydroxyethyl) -methyl-amino] -thiazol-4-yl} phenoxy) propoxy]- Benzamidine, 198) N-hydroxy-4- [5- (4- {5-ethyl-2-[(2-hydroxyethyl) -methyl-amino] -thiazol-4-yl} phenoxy) butoxy]- Benzamidine, 199) N-hydroxy-4- [5- (4- {5-ethyl-2- [methyl- (pyridin-3-ylmethyl) amino] -thiazol-4-yl} phenoxy) propoxy]- Benzamidine, 200) N-hydroxy-4- [5- (4- {5-ethyl-2- [methyl- (pyridin-3-ylmethyl) amino] -thiazol-4-yl} phenoxy) butoxy]- Benzamidine, 201) N-hydroxy-4- {4- [4- (5-cyclopentylmethyl-2-isopropyl-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine, 202) N-hydroxy-4- {4- [4- (5-butyl-2-isopropyl-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine, 203) N-hydroxy-4- {4- [4- (5-cyclopentylmethyl-2-amino-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine, 204) N-hydroxy-4- {4- [4- (5-cyclopentylmethyl-2-amino-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -2-fluoro-benzami Dean, 205) N-hydroxy-4- {4- [4- (2-methylamino-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine, 206) N-hydroxy-4- {6- [4- (5-isopropyl-2-methyl-thiazol-4-yl) -phenoxymethyl] -pyridin-2-ylmethoxy} -benzamidine, 207) N-hydroxy-2-fluoro-4- {5- [4- (5-isopropyl-2-methyl-thiazol-4-yl) -phenoxy] -butoxy} -benzamidine, 208) N-hydroxy-4- {2- [4- (5-isopropyl-2-methyl-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine, 209) N-hydroxy-4- {3- [4- (5-isopropyl-2-methyl-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine, 210) N-hydroxy-4- {4- [4- (5-cyclopentylmethyl-2-cyclohexyl-thiazol-4-yl) -phenoxymethyl] -benzyloxy} -benzamidine, 211) N-hydroxy-4- {6- [4- (5-isopropyl-2-methyl-thiazol-4-yl) phenoxy] -hexyloxy} -benzamidine, 212) N-hydroxy-4- {5- [2-ethyl-5-hydroxy-4- (2-methyl-thiazol-4-yl) phenoxy] -pentyloxy} -benzamidine, 213) N-hydroxy-4- {5- [2-ethyl-4- (2-methyl-thiazol-4-yl) -5-propoxy-phenoxy] -pentyloxy} -benzamidine 214) N-hydroxy-4- (5- {4- [5- (2-isobutylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean, 215) 4- (5- {4- [5- (2-isobutylaminoethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine, 216) N-hydroxy-4- (5- {4- [2-methyl-5- (2-piperidin-1-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 217) N-hydroxy-4- [5- (4- {2-methyl-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine, 218) N-hydroxy-4- [5- (4- {5- [2- (3-imidazol-1-yl-propylamino) -ethyl] -2-methyl-thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine, 219) N-hydroxy-4- (5- {4- [5- (2-isopropylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean, 220) N-hydroxy-4- [5- (4- {5- [2- (3-isopropoxy-propylamino) -ethyl] -2-methyl-thiazol-4-yl} -phenoxy) -Pentyloxy] -benzamidine, 221) N-hydroxy-4- (5- {4- [5- (2-butylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine , 222) N-hydroxy-4- (5- {4- [5- (2-imidazol-1-yl-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine, 223) N-hydroxy-4- (5- {4- [5- (2-cyclohexylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean, 224) N-hydroxy-4- (5- {4- [5- (2-diethylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean, 225) N-hydroxy-4- {5- [4- (5- {2- [bis- (2-hydroxy-ethyl) -amino] -ethyl} -2-methyl-thiazol-4-yl) -Phenoxy] -pentyloxy} -benzamidine, 226) N-hydroxy-4- (5- {4- [5- (2-diisopropylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benz Amidine, 227) N-hydroxy-4- [5- (4- {5- [2- (2,6-dimethyl-morpholin-4-yl) -ethyl] -2-methyl-thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine, 228) N-hydroxy-4- (5- {4- [2-methyl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 229) N-hydroxy-4- (5- {4- [2-amino-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine, 230) N-hydroxy-4- [5- (4- {5- [2- (2-dimethylamino-ethylamino) -ethyl] -2-methyl-thiazol-4-yl} -phenoxy)- Pentyloxy] -benzamidine, 231) N-hydroxy-4- (5- {4- [2-methyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine, 232) N-hydroxy-4- [5- (4- {2-methyl-5- [2- (4-methyl-piperazin-1-yl) -ethyl] -thiazol-4-yl} -phenoxy C) -pentyloxy] -benzamidine, 233) N-hydroxy-4- {5- [4- (5- {2- [bis- (2-methoxy-ethyl) -amino] -ethyl} -2-methyl-thiazol-4-yl) -Phenoxy] -pentyloxy} -benzamidine, 234) N-hydroxy-4- (5- {4- [5- (2-tert-butylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benz Amidine, 235) N-hydroxy-4- (5- {4- [5- (2-isobutylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean, 236) N-hydroxy-4- (5- {4- [5- (2-morpholin-4-yl-ethyl) -2-pyridin-3-yl-thiazol-4-yl] -phenoxy} -Pentyloxy) -benzamidine, 237) N-hydroxy-4- [5- (4- {5- [2- (4-methyl-piperazin-1-yl) -ethyl] -2-pyridin-3-yl-thiazole-4- Yl) -phenoxy) -pentyloxy] -benzamidine, 238) N-hydroxy-4- (5- {4- [2-pyridin-3-yl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy } -Pentyloxy) -benzamidine, 239) N-hydroxy-4- (5- {4- [5- (2-imidazol-1-yl-ethyl) -2-pyridin-3-yl-thiazol-4-yl] -phenoxy} -Pentyloxy) -benzamidine, 240) N-hydroxy-4- (5- {4- [2-isopropyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 241) N-hydroxy-4- [5- (4- {2-isopropyl-5- [2- (4-methyl-piperazin-1-yl) -ethyl] -thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine, 242) N-hydroxy-4- (5- {4- [5- (2-imidazol-1-yl-ethyl) -2-isopropyl-thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 243) N-hydroxy-4- [5- (4- {2-isopropyl-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine, 244) N-hydroxy-4- [5- (4- {5- [2- (3-imidazol-1-yl-propylamino) -ethyl] -2-isopropyl-thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine, 245) N-hydroxy-4- (5- {4- [2-isopropyl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyl Oxy) -benzamidine, 246) N-hydroxy-4- (5- {4- [2-cyclohexyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 247) N-hydroxy-4- [5- (4- {2-cyclohexyl-5- [2- (4-methyl-piperazin-1-yl) -ethyl] -thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine, 248) N-hydroxy-4- [5- (4- {2-cyclohexyl-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine, 249) N-hydroxy-4- (5- {4- [2-cyclohexyl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyl Oxy) -benzamidine, 250) N-hydroxy-4- (5- {4- [2-cyclohexyl-5- (2-dimethylamino-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benzami Dean, 251) N-hydroxy-4- (5- {4- [2-cyclohexyl-5- (2-dipropylamino-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benz Amidine, 252) N-hydroxy-4- (5- {4- [2-cyclohexyl-5- (2-cyclopropylamino-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benz Amidine, 253) N-hydroxy-4- [5- (4- {2-amino-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine, 254) N-hydroxy-4- (5- {4- [5- (2-morpholin-4-yl-ethyl) -2-phenyl-thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine, 255) N-hydroxy-4- (5- {4- [2-ethyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine, 256) N-hydroxy-4- (5- {4- [2-ethyl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 257) N-hydroxy-4- (4- {4- [2-methyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -butoxy) Benzamidine, 258) 4- (5- {4- [2-cyclohexyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine , 259) 4- (5- {4- [2-methyl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine, 260) N-hydroxy-4- (5- {4- [2-methylamino-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 261) N-hydroxy-4- [5- (4- {2-methylamino-5- [2- (4-methyl-piperazin-1-yl) -ethyl] -thiazol-4-yl}- Phenoxy) -pentyloxy] -benzamidine, 262) N-hydroxy-4- (5- {4- [2-methylamino-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyl Oxy) -benzamidine, 263) N-hydroxy-4- [5- (4- {2-methylamino-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine, 264) N-hydroxy-4- [5- (4- {5- [2- (3-imidazol-1-yl-propylamino) -ethyl] -2-methylamino-thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine, 265) 4- (5- {4- [2-Methylamino-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine , 266) N-hydroxy-4- (5- {4- [2-dimethylamino-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 267) N-hydroxy-4- (5- {4- [2-dimethylamino-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyl Oxy) -benzamidine, 268) N-hydroxy-4- (5- {4- [2- (isobutyryl-methyl-amino) -5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -Phenoxy} -pentyloxy) -benzamidine, 269) N-hydroxy-4- (5- {4- [2- [benzyl- (2-morpholin-4-yl-ethyl) -amino] -5- (2-morpholin-4-yl-ethyl ) -Thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine, 270) N-hydroxy-4- (5- {4- [2-diethylamino-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyl Oxy) -benzamidine, 271) N-hydroxy-4- (5- {4- [2- [bis- (2-methoxy-ethyl) -amino] -5- (2-morpholin-4-yl-ethyl) -thiazole -4-yl] -phenoxy} -pentyloxy) -benzamidine, 272) N-hydroxy-4- (5- {4- [2-morpholin-4-yl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy } -Pentyloxy) -benzamidine, 273) N-hydroxy-4- (5- {4- [2-morpholin-4-yl-5- (2-thiomorpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy Pentyloxy) -benzamidine, 274) N-hydroxy-4- [5- (4- {5- [2- (4-methyl-piperazin-1-yl) -ethyl] -2-morpholin-4-yl-thiazole-4 -Yl} -phenoxy) -pentyloxy] -benzamidine, 275) N-hydroxy-4- [5- (4- {2-morpholin-4-yl-5- [2- (2-morpholin-4-yl-ethylamino) -ethyl] -thiazole- 4-yl} -phenoxy) -pentyloxy] -benzamidine, 276) N-hydroxy-4- (5- {4- [5- (2-morpholin-4-yl-ethyl) -2-piperidin-1-yl-methyl-thiazol-4-yl] -Phenoxy} -pentyloxy) -benzamidine, 277) 4- (5- {4- [2-morpholin-4-yl-5- (2-morpholin-4-yl-ethyl) -thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine, 278) N-hydroxy-4- (5- {4- [5- (2-isobutyrylamino-ethyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benz Amidine, 279) N-hydroxy-4- {5- [4- (5- {2- [isobutyl- (pyridine-3-carbonyl) -amino] -ethyl} -2-methyl-thiazol-4-yl ) -Phenoxy] -fetyloxy} -benzamidine, 280) N-hydroxy-4- {5- [4- (5- {2- [cyclopropyl- (pyridine-4-carbonyl) -amino] -ethyl} -2-isopropyl-thiazole-4- Yl) -phenoxy] -pentyloxy} -benzamidine, 281) N-hydroxy-4- {5- [4- (2-cyclohexyl-5- {2- [cyclopropyl- (pyridine-3-carbonyl) -amino] -ethyl} -thiazole-4- Yl) -phenoxy] -pentyloxy} -benzamidine, 282) N-hydroxy-4- {5- [4- (5-methylcarbamoyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 283) N-hydroxy-4- {5- [4- (5-isopropylcarbamoyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 284) N-hydroxy-4- {5- [4- (5- {3-imidazol-1-yl-propylcarbamoyl} -2-methyl-thiazol-4-yl) -phenoxy] -pentyl Oxy} -benzamidine, 285) N-hydroxy-4- {5- [4- (2-amino-5-methylcarbamoyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 286) N-hydroxy-4- {5- [4- (2-methyl-5-morpholin-4-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 287) N-hydroxy-4- (5- {4- [2-methyl-5- (4-methyl-piperazin-1-yl) -thiazol-4-yl] -phenoxy} -pentyloxy) Benzamidine, 288) N-hydroxy-4- {5- [4- (2-amino-5-morpholin-4-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 289) N-hydroxy-4- (5- {4- [5- (4-methyl-piperazin-1-yl) -2-morpholin-4-yl-thiazol-4-yl] -phenoxy } -Pentyloxy) -benzamidine, 290) N-hydroxy-4- {5- [4- (2,5-di-morpholin-4-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 291) N-hydroxy-4- {5- [4- (2-morpholin-4-yl-5-thiomorpholin-4-yl-thiazol-4-yl) -phenoxy] -pentyloxy} Benzamidine, 292) N-hydroxy-4- {5- [4- (2-morpholin-4-yl-5-pyrrolidin-1-yl-thiazol-4-yl) -phenoxy] -pentyloxy} Benzamidine, 293) N-hydroxy-4- {5- [4- (2-methyl-5-morpholin-4-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 294) N-hydroxy-4- (5- {4- [2-methyl-5- (4-methyl-piperazin-1-ylmethyl) -thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 295) N-hydroxy-4- {5- [4- (2-methyl-5-thiomorpholin-4-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine , 296) N-hydroxy-4- {5- [4- (2-methyl-5-piperidin-1-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine , 297) N-hydroxy-4- {5- [4- (5-dimethylaminomethyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 298) N-hydroxy-4- {5- [4- (5-butylaminomethyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 299) N-hydroxy-4- (5- {4- [5- (isobutylamino-methyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine, 300) N-hydroxy-4- (5- {4- [5- (tert-butylamino-methyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine , 301) N-hydroxy-4- {5- [4- (2-methyl-5-propylaminomethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 302) N-hydroxy-4- [5- (4- {2-methyl-5-[(2-morpholin-4-yl-ethylamino) -methyl] -thiazol-4-yl} -phenoxy ) -Pentyloxy] -benzamidine, 303) N-hydroxy-4- [5- (4- {5-[(3-imidazol-1-yl-propylamino) -methyl] -2-methyl-thiazol-4-yl} -phenoxy ) -Pentyloxy] -benzamidine, 304) N-hydroxy-4- {5- [4- (2-methyl-5-pyrrolidin-1-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine , 305) N-hydroxy-4- {5- [4- (5-imidazol-1-ylmethyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 306) N-hydroxy-4- (5- {4- [5- (benzylamino-methyl) -2-methyl-thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine, 307) N-hydroxy-4- {5- [4- (5-cyclopropylaminomethyl-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 308) N-hydroxy-4- {5- [4- (2-methylamino-5-morpholin-4-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 309) N-hydroxy-4- (5- {4- [2- (methyl-pyridin-4-ylmethyl-amino) -5-morpholin-4-ylmethyl-thiazol-4-yl] -phenoxy Pentyloxy) -benzamidine, 310) N-hydroxy-4- [5- (4- {2-[(2-hydroxy-ethyl) -methyl-amino] -5-morpholin-4-ylmethyl-thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine, 311) N-hydroxy-4- (5- {4- [2- (ethyl-methyl-amino) -5-morpholin-4-ylmethyl-thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 312) N-hydroxy-4- (5- {4- [2- (benzyl-methyl-amino) -5-morpholin-4-ylmethyl-thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 313) N-hydroxy-4- [5- (4- {2- [methyl- (2-morpholin-4-yl-ethyl) -amino] -5-morpholin-4-ylmethyl-thiazole- 4-yl} -phenoxy) -pentyloxy] -benzamidine, 314) N-hydroxy-4- [5- (4- {2- [methyl- (2-morpholin-4-yl-ethyl) -amino] -5-thiomorpholin-4-ylmethyl-thiazole -4-yl} -phenoxy) -pentyloxy] -benzamidine, 315) N-hydroxy-4- [5- (4- {5-{[bis- (2-methoxy-ethyl) -amino] -methyl} -2- [methyl- (2-morpholine-4- Yl-ethyl) -amino] -thiazol-4-yl} -phenoxy) -pentyloxy] -benzamidine, 316) N-hydroxy-4- (5- {4- [2- [methyl- (2-morpholin-4-yl-ethyl) -amino] -5- (4-methyl-piperazin-1-yl Methyl) -thiazol-4-yl] -phenoxy} -pentyloxy) -benzamidine, 317) N-hydroxy-4- [5- (4- {5- (isopropylamino-methyl) -2- [methyl- (2-morpholin-4-yl-ethyl) -amino] -thiazole- 4-yl} -phenoxy) -pentyloxy] -benzamidine, 318) N-hydroxy-4- [5- (4- {5-[(2-methoxy-ethylamino) -methyl] -2- [methyl- (2-morpholin-4-yl-ethyl)- Amino] -thiazol-4-yl} -phenoxy) -pentyloxy] -benzamidine, 319) N-hydroxy-4- [5- (4- {2-[(2-methoxy-ethyl) -methyl-amino] -5-morpholin-4-ylmethyl-thiazol-4-yl} -Phenoxy) -pentyloxy] -benzamidine, 320) N-hydroxy-4- (5- {4- [2- (methyl-propyl-amino) -5-morpholin-4-ylmethyl-thiazol-4-yl] -phenoxy} -pentyloxy ) -Benzamidine, 321) N-hydroxy-4- (5- {4- [2- (methyl-pyridin-3-ylmethyl-amino) -5-morpholin-4-ylmethyl-thiazol-4-yl] -phenoxy Pentyloxy) -benzamidine, 322) N-hydroxy-4- {5- [4- (2-methyl-5-methylamino-thiazol-4-yl) -phenoxy] -pentyl oxy} -benzamidine, 323) N-hydroxy-4- [5- (4- {2-methyl-5-[(pyridine-4-carbonyl) -amino] -thiazol-4-yl} -phenoxy) -pentyloxy] Benzamidine, 324) N-hydroxy-4- [5- (4- {2-methyl-5-[(pyridine-3-carbonyl) -amino] -thiazol-4-yl} -phenoxy) -pentyloxy] Benzamidine, 325) N-hydroxy-4- [5- (4- {2-phenyl-5-[(pyridine-3-carbonyl) -amino] -thiazol-4-yl} -phenoxy) -pentyloxy] Benzamidine, 326) N-hydroxy-4- {5- [4- (5-dimethylamino-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 327) N-hydroxy-4- {5- [4- (5-dimethylamino-2-phenyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 328) N-hydroxy-4- {5- [4- (2-cyclohexyl-5-dimethylamino-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 329) N-hydroxy-4- {5- [4- (2-methyl-5- [1,2,4] triazol-1-yl-thiazol-4-yl) -phenoxy] -pentyloxy } -Benzamidine, 330) N-hydroxy-4- {5- [4- (5-amino-2-phenyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 331) N-hydroxy-4- {5- [4- (5-amino-2-methyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 332) N-hydroxy-4- {5- [4- (5-amino-2-pyridin-3-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 333) N-hydroxy-4- {5- [4- (5-amino-2-ethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 334) N-hydroxy-4- {5- [4- (5-amino-2-cyclohexyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine, 335) N-hydroxy-4- {5- [4- (2-methylamino-5-morpholin-4-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} -benzamidine , 336) N-hydroxy-4- {5- [4- (2-morpholin-4-yl-5-morpholin-4-ylmethyl-thiazol-4-yl) -phenoxy] -pentyloxy} Benzamidine, and 337) N-hydroxy-4- {5- [4- (5-morpholin-4-yl-2-piperidin-1-yl-thiazol-4-yl) -phenoxy] -pentyloxy} -A pharmaceutical composition for the prevention or treatment of osteoporosis, characterized in that it is selected from the group consisting of benzamidine. According to claim 1, wherein the compound of Formula 1 1) 2-fluoro-N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1,3-thiazol-4-yl) phenoxy] pentyloxy} benzamidine, 2) N-hydroxy-4- {5- [4- (2-dipropylamino-5-ethyl-1,3-thiazol-4-yl) phenoxy] pentyloxy} benzamidine, 3) N-hydroxy-4- {5- [4- (2- {methyl [morpholinoethyl] amino} -1,3-thiazol-4-yl) phenoxy] pentyloxy} benzamidine, and 4) N-hydroxy-4- {5- [4- (5-isopropyl-2- (morpholin-4-yl) -1,3-thiazol-4-yl) phenoxy] pentyloxy} benz A pharmaceutical composition for the prevention or treatment of osteoporosis, characterized in that selected from the group consisting of amidine. According to claim 1, wherein the bisphosphonate of formula (2) is a group consisting of etidronic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, minoidronic acid, ibandronic acid, zoledronic acid and alandonic acid Pharmaceutical composition for the prevention or treatment of osteoporosis, characterized in that it is selected from. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition for preventing or treating osteoporosis is in the form of a mixture comprising (a) a novel benzamidine derivative or a salt thereof represented by Formula 1, and (b) a bisphosphonate represented by Formula 2. Pharmaceutical composition for the prevention or treatment of osteoporosis, characterized in that formulated as. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition for preventing or treating osteoporosis comprises (a) a novel benzamidine derivative represented by Formula 1 or a salt thereof, and (b) a bisphosphonate represented by Formula 2, respectively. A pharmaceutical composition for the prevention or treatment of osteoporosis, characterized in that it is formulated in the form of a single agent. According to claim 1, wherein the pharmaceutical composition for preventing or treating osteoporosis is independent comprising (a) a novel benzamidine derivative or a salt thereof represented by Formula 1, and (b) a bisphosphonate represented by Formula (2), respectively A pharmaceutical composition for the prevention or treatment of osteoporosis, characterized in that one single drug consists of two kits.