Sulphonamide compound and salt thereof


FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (II-A) or pharmaceutically acceptable salt thereof: [in which symbols denote the following: R10-R12: are identical or different and each denotes halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, R13: R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, ring B: benzene ring or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from O, S and N, R14: R0, halogen or -OR0, R0: are identical or different and each denotes H or lower alkyl, Y1: a single bond, lower alkylene, lower alkenylene or O-lower alkylene-, and Z1: -CO2R0 or -C0-NH-SO2-lower alkyl]. The invention also relates to a pharmaceutical composition based on the said compound, having antagonistic effect on the EP1 receptor.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in a medicinal agent for treating lower urinary tract symptoms.

6 cl, 56 tbl, 231 ex

 

The technical field

The present invention relates to an EP1 receptor antagonist, which can be used as a therapeutic agent for the treatment of symptoms of the lower urinary tract. In addition, the present invention relates to the connection sulfonamida, or its pharmaceutically acceptable salt that can be used as an antagonist of EP1 receptor.

The level of technology

Overactive bladder, which is one of the diseases that cause the symptom of a lower urinary tract refers to a clinical condition in which there are urgent urination, regardless of the presence or absence of urinary incontinence, which is usually accompanied by urgency to urinate and emergency night urination (non-patent document 1). For the treatment of this disease at present, mainly used anticholinergic agent, and the results of continuous treatment. However, it was reported that the anticholinergic agent is difficult to use in patients with hypertrophy of the prostate gland or elderly patients, since it is known that it causes side effects such as xerostomia, constipation and blurred vision, as well as the risk of urinary retention. In addition, some of what's patients using anticholinergics recovery does not occur. Due to the above facts high hopes for the drug with a new mechanism of action in respect of an overactive bladder.

Prostaglandin E2(PGE2) is a bioactive substance, the precursor arachidonic acid, and it is known that he is involved in the regulation of body functions through 4 subtype receptors associated with G-protein, i.e. EP1, EP2, EP3 and EP4.

It was known that intravesical instillation PGE2leads to severe urgent urination and reduce the volume of the urinary bladder in humans (non-patent document 2), and that this leads to a reduction in the urinary bladder of rats (non-patent document 3). Accordingly, it was assumed the possibility that PGE2affects the function of the lower urinary tract. Recently it was reported that the introduction of the EP1 receptor antagonist on the model rats with spinal cord injury improves urination (non-patent document 4), and an assumption was made that the pathology of the function of the bladder in mice with a urethral stricture is not observed in mice with a knockout in respect of EP1 receptor, and that intravesical instillation PGE2leads to hyperactivity pathological functions of urination (patent document 1). It was therefore made the assumption, the EP1 receptor antagonist can be used as a drug for the treatment of symptoms of the lower urinary tract.

In addition, the EP1 receptor antagonist has such a mechanism, which gives reason to expect that specific side effects caused by anticholinergic agent, will be eliminated, and also the expected effect on patients who were observed recovery in the treatment of anticholinergic agent. In addition, it is expected that this tool will improve some symptoms, additionally acting on sensory nerves. In addition, it was reported that this tool showed the effect of improvements in relation to the clinical condition, without reducing the effectiveness of urinating on the model rats with spinal cord injury (non-patent document 5), and thus, it is expected that it can be administered safely to patients with hypertrophy of the prostate gland or elderly patients.

In addition, it is widely known that PGE2is produced locally due to inflammation or tissue damage and enhances the reaction of inflammation and is involved in causing pain or fever. Recently it became known that the EP1 receptor antagonist is effective in animal models with pain of various types, such as inflammatory pain (not atentry document 6), postoperative pain (non-patent document 7) and neuropathic pain (non-patent document 8). There is also a report on the clinical effect of antagonist receptor EP1 in the case of visceral pain caused by hydrochloric acid (non-patent document 9). On this basis it is considered that the EP1 receptor antagonist also can be used as drugs to treat various types of pain.

In addition, it is known that the EP1 receptor antagonist has an inhibitory effect on aberrant foci crypts of the mucosa of the colon and large intestine and the formation of polyps in the intestine (patent document 2), thus, it is believed that it can be used as a drug in colon cancer, bladder cancer, prostate cancer, etc.

As connection sulfonamida, which has antagonistic activity against receptor EP1, for example, reported on the compounds mentioned in patent documents 3 and 4.

In patent document 3 discloses the compound represented by formula (A):

[Chem. 1]

(where A and B each independently represents C5-15carbon ring or a 5-7 membered heterocycle, Z3represents a simple bond or a C1-4alkylene, Z4means SO2or R 2denotes an amide bond, -O-C1-4alkylen or the like, R4represents (1) hydrogen, (2) C1-8alkyl, C2-8alkenyl or C2-8quinil, (3) C1-6alkyl, substituted by 1 or 2 substituents selected from the group consisting of COOZ8, CONZ9Z10, OZ8and C1-4alkoxy, (4) C3-7cycloalkyl or (5) C1-4alkyl, C2-4alkenyl or C2-4quinil, each of which is substituted by phenyl or C3-7cycloalkyl, and then Z8, Z9and Z10each independently represents hydrogen or C1-4alkyl. For other characters, you can refer to the publication).

However, there is no specific disclosure of the active ingredient represented by the formula (I), which is the active ingredient according to the present invention.

Further, in patent document 4 discloses the compound represented by formula (B).

[Chem. 2]

(where R5denotes isopropyl, isobutyl, 2-methyl-2-propenyl, cyclopropylmethyl, methyl, ethyl, propyl, 2-propenyl or 2-hydroxy-2-methylpropyl. For other characters, you can refer to the publication).

However, this compound has a basic structure that is different from the active ingredient, represented by the formula (I), which is the active ingredient according to the present invention, since R5 has no amide structure.

In addition, as the connection sulfonamida, for example, reported on the compounds mentioned in patent documents 5-8.

In patent document 5 revealed that the compound represented by formula (C), including a wide range of compounds possess inhibitory activity against the production of β-amyloid protein and can be used for treatment or prevention of Alzheimer's disease or other

[Chem. 3]

(symbols in the formula, see publication).

However, there is no description of the antagonistic activity of this compound on the receptor EP1, and there is no specific disclosure of the compound (II) according to the present invention.

In addition, in patent document 6 revealed that the compound represented by formula (D), including a wide range of compounds, has an antagonistic activity against farnesoid-X receptor (FXR) and can be used for the treatment of diseases associated with cholesterol abnormality, obesity, diabetes, or other

[Chem. 4]

(symbols in the formula, see publication).

However, there is no description of the antagonistic activity of this compound on the receptor EP1, and there is no specific disclosure of the compound (II) according to the present invention.

In addition, Pat is ntdom document 7 open, the compound represented by formula (E), has an antagonistic activity against receptor orexin and can be used to treat sleep disorders, disorders caused by stress, or the like

[Chem. 5]

(symbols in the formula, see publication).

However, there is no description of the antagonistic activity of this compound on the receptor EP1, and there is no specific disclosure of the compound (II) according to the present invention.

In addition, in patent document 8 revealed that the compound represented by the formula (F), has an inhibitory activity against diacylglycerides (DGAT) and can be used for treatment or prevention of obesity, hyperlipidemia, diabetes or other

[Chem. 6]

(symbols in the formula, see publication).

However, there is no description of the antagonistic activity of this compound on the receptor EP1, and there is no specific disclosure of the compound (II) according to the present invention.

In addition, were known 4-({[N-[(4-forfinal)sulfonyl]-N-(2-methoxyphenyl)glycyl]amino}methyl)methylbenzoate (registration number: 851172-09-3; for example, the name of the directory: Aurora Screening Library, Order No. kend-0100022) and N2-[(4-chlorophenyl)sulfonyl]-N2-(2,5-differenl)--[4-(1,2,3-thiadiazole-4-yl)benzyl]-D-alaninate (patent document 5, example 635), which has inhibitory activity against the production of β-amyloid protein.

However, there is no information regarding the antagonistic activity of these compounds against the EP1 receptor.

[Non-patent document 1] “Neurourology and Urodynamics”, (England), 2002, Vol. 21, p. 167-78

[Non-patent document 2] “Urological Research” (USA), 1990, Vol. 18, No. 5, p. 349-52

[Non-patent document 3] “The Journal of Urology”, (USA), June 1995, Vol. 153, No. 6, p. 2034-8

[Non-patent document 4] “Journal of The Japanese Urological Association, February 2001, Vol. 92, No. 2, p. 304

[Non-patent document 5] “The 89thAnnual Meeting of The Japanese Urological Association, Kobe, 2001, MP-305

[Non-patent document 6] “Anesthesiology”, (USA), November 2002, Vol. 97, No. 5, p. 1254-62

[Non-patent document 7] “Anesthesia and Analgesia”, (USA), December 2002, Vol. 95, No. 6, p. 1708-12

[Non-patent document 8] “Anesthesia and Analgesia”, (USA), October 2001, Vol. 93, No. 4, p. 1012-7

[Non-patent document 9] “Gastroenterology”, January 2003, Vol. 124, No. 1, p. 18-25

[Patent document 1] US2005/0020646

[Patent document 2] WO00/069465

[Patent document 3] WO98/027053

[Patent document 4] WO02/072564

[Patent document 5] WO 00/050391

[Patent document 6] WO 02/020463

[Patent document 7] WO 04/033418

[Patent document 8] the Publication of the patent application of Japan No. 2005-206492

DISCLOSURE of INVENTIONS

PROBLEMS SOLVED IN ACCORDANCE WITH the INVENTION

As described above, conventional medicine for the treatment of symptom n the life of the urinary tract does not meet the requirements in terms of efficiency, security and etc, and thus, there is a great need in a very effective and safe drug for the treatment of symptoms of the lower urinary tract.

A MEANS of addressing THESE PROBLEMS

As described above, it is expected that the EP1 receptor antagonist is a very safe drug for the treatment of symptoms of the lower urinary tract with a few side effects such as xerostomia and urinary retention. Therefore, the authors of the present invention conducted extensive studies of compounds with antagonistic activity against receptor EP1 in order to offer a connection that could be used to treat symptoms of the lower urinary tract, etc. In the result it was found that the compound represented by formula (I)as an active ingredient according to the present invention has a strong antagonistic activity against receptor EP1, and it was carried out, thereby the present invention.

Thus, the present invention relates to the next.

[1] the EP1 receptor Antagonist, comprising as active ingredient a compound sulfonamida represented by the formula (I)or its pharmaceutically acceptable salt.

[Chem. 7]

[where the symbols have the following meanings:

ring A: benzene ring, cycloalkane ring or heteroaromatic ring,

L1simple link or lowest alkylen,

L2: lower alkylene,

R1-R4: the same or different, each represents R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl, -S(O)n-lower alkyl, -CN, -NO2, nitrogen-containing heterocyclic group, cycloalkyl, -NH-CO-lower alkyl, -NH-CO-N(R00)2, -NH-CO-nitrogen-containing heterocyclic group, -CO2R0, -CON(R0)2, -CO-lower alkyl, -lower alkylene-OR0-the inferior alkylene-CO2R0, aryl which may be substituted, heteroaryl, which may be substituted, -O-aryl which may be substituted, -O-benzyl or-O-heteroaryl, which may be substituted, or

when R1and R2and R3and R4each are located on adjacent carbon atoms of the benzene ring or ring A, they may together with the ring atom to which they are attached, form a 5-7 membered cycloalkene ring, benzene ring or a heterocycle which may be substituted by a group selected from the following group G1,

group G1: lower alkyl, oxo, -OR0-the inferior alkylen-OR0and-CO-lower alkyl,

R0: the same or different, represent each H or lower alkyl,

R00:H or lower alkyl, which may be substituted by a group-OR0,

n: 0, 1 or 2,

RA: R0,

RB: R0-the inferior alkylen-aryl which may be substituted, lower alkylene-heteroaryl, which may be substituted, lower alkylene-O-aryl which may be substituted, or lower alkylene-O-heteroaryl, which may be substituted, or

RAand RBcan together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocycle. The same shall apply hereinafter].

[2] the EP1 receptor Antagonist, as described in [1], where RAdenotes N and RBindicates lowest alkylen-aryl which may be substituted, lower alkylene-heteroaryl, which may be substituted, lower alkylene-O-aryl which may be substituted, or lower alkylene-O-heteroaryl, which may be substituted.

[3] the Connection sulfonamida represented by the formula (II), or its pharmaceutically acceptable salt.

[Chem. 8]

[where the symbols have the following meanings:

ring A: benzene ring, cycloalkane ring or heteroaromatic ring,

L1simple link or lowest alkylen,

L2: lower alkylene,

R1-R4: the same or different, each represents R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl, -S(O) -lower alkyl, -CN, -NO2, nitrogen-containing heterocyclic group, cycloalkyl, -NH-CO-lower alkyl, -NH-CO-N(R00)2, -NH-CO-nitrogen-containing heterocyclic group, -CO2R0, -CON(R0)2, -CO-lower alkyl, -lower alkylene-OR0-the inferior alkylene-CO2R0, aryl which may be substituted, heteroaryl, which may be substituted, -O-aryl which may be substituted, -O-benzyl or-O-heteroaryl, which may be substituted, or

when R1and R2and R3and R4each are located on adjacent carbon atoms of the benzene ring or ring A, they may together with the ring atom to which they are attached, form a 5-7 membered cycloalkene ring, benzene ring or a heterocycle which may be substituted by a group selected from the following group G1,

group G1: lower alkyl, oxo, -OR0-the inferior alkylen-OR0and-CO-lower alkyl,

R0: the same or different, represent each H or lower alkyl,

R00: H or lower alkyl which may be substituted by a group-OR0,

n: 0, 1 or 2,

L3: lower alkylene,

X: simple bond or-O-,

ring B: benzene ring or heteroaromatic ring,

R5and R6: the same or different, each represents R0, halogen, halogen-lower alkyl,-OR 0, -O-halogen-lower alkyl, -CN or-NO2,

Y: a simple link, the lower alkylene, lower albaniles or-O-lower alkylene-,

Z: -CO2H or biological equivalent, -CONR7R8or nitrogen-containing heterocyclic group which may be substituted by a group selected from group G1,

R7and R8: the same or different, represent each H or lower alkyl which may be substituted by a group selected from the following group G2and

group G2: -OR0, -N(R0)2, -CO2R0and nitrogen-containing heterocyclic group,

provided that excluded 4-({[N-[(4-forfinal)sulfonyl]-N-(2-methoxyphenyl)glycyl]amino}methyl)methylbenzoate and N2-[(4-chlorophenyl)sulfonyl]-N2-(2,5-differenl)-N-[4-(1,2,3-thiadiazole-4-yl)benzyl]-D-alaninate. The same shall apply hereinafter].

[4] the Compound or its pharmaceutically acceptable salt, as described in [3], where L1indicates a simple relationship.

[5] the Compound or its pharmaceutically acceptable salt, as described in [4], where ring A is a benzene ring.

[6] the Compound or its pharmaceutically acceptable salt, as described in [5], where X denotes a simple link.

[7] the Compound or its pharmaceutically acceptable salt, as described in [6], where L2and L3both represent methylene.

[8] Obedinenie or its pharmaceutically acceptable salt, as described in [7], where Z denotes-CO2H or a biological equivalent.

[9] the Connection sulfonamida represented by formula (II-A), or its pharmaceutically acceptable salt.

[Chem. 9]

[where the symbols have the following meanings:

R10-R12: the same or different, represent, each, halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or-CN,

R13: R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or-CN,

ring B: benzene ring or heteroaromatic ring,

R14: R0, halogen or-OR0,

R0: the same or different, represent each H or lower alkyl,

Y1: a simple link, the lower alkylene, lower albaniles or-O-lower alkylene-, and

Z1: -CO2H or a biological equivalent. The same shall apply hereinafter].

[10] the Compound or its pharmaceutically acceptable salt, as described in [3], which is selected from the group consisting of the following compounds:

4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,

3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,

3-[({N-(3-chloro-2-were)-N-[(4-chlorophenyl)sulfonyl]glycyl}amino)methyl]benzoic acid,

3-[({N-(3-chlor-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]venexiana acid,

4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]-N-(methylsulphonyl)benzamid,

3-[({N-(3-chloro-2-were)-N-[(4-cyanophenyl)sulfonyl]glycyl}amino)methyl]benzoic acid,

3-{[(N-(3-chloro-2-were)-N-{[4-(trifluoromethyl)phenyl]sulfonyl}glycyl)amino]methyl}benzoic acid,

4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]-2-methoxy-N-(methylsulphonyl)benzamid,

3-[({N-(2,3-dichlorophenyl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,

3-[({N-(3-chloro-2-methoxyphenyl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,

3-[({N-(3-bromo-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,

3-[({N-(3-chloro-2-were)-N-[(4-ethylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid,

3-[({N-(3-chloro-2-ethylphenyl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,

3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]cinnamic acid,

3-{3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]phenyl}propionic acid,

5-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]thiophene-3-carboxylic acid,

3-[({N-(3-chloro-2-ethylphenyl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]cinnamic acid,

3-{[(N-(3-chloro-2-were)-N-{[4-(trifluoromethyl)phenyl]sulfonyl}glycyl)amino]METI the}cinnamic acid,

3-[({N-(3-chloro-2-were)-N-[(4-chlorophenyl)sulfonyl]glycyl}amino)methyl]cinnamic acid,

3-(3-{[(N-(3-chloro-2-were)-N-{[4-(trifluoromethyl)phenyl]sulfonyl}glycyl)amino]methyl}phenyl)propionic acid,

3-[({N-(3-chloro-2-were)-N-[(2-fluoro-4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,

2-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]-1,3-oxazole-4-carboxylic acid,

4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]thiophene-2-carboxylic acid,

(2S)-2-{3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]phenoxy}propionic acid and

(2R)-2-{3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]phenoxy}propionic acid.

[11] a Pharmaceutical composition containing as active ingredient the compound or its pharmaceutically acceptable salt, as described in [3].

[12] a Pharmaceutical composition as described in [11], which is an antagonist of EP1 receptor.

[13] the Pharmaceutical composition as described in [11], which is a therapeutic tool for the treatment of symptoms of the lower urinary tract.

[14] the Pharmaceutical composition as described in [13], and disease, leading to the symptom of a lower urinary tract is overactive bladder, benign prostatic hyperplasia PR is Stateline gland, contracture of the neck of the bladder, cystitis, or prostatitis.

[15] Use of the compound or its pharmaceutically acceptable salts, as described in [3], to obtain funds for the treatment of symptoms of the lower urinary tract.

[16] the Use as described in [15], and disease, leading to the symptom of a lower urinary tract is overactive bladder, benign prostatic hyperplasia, bladder neck contracture, cystitis, or prostatitis.

[17] a Method of treating symptoms of the lower urinary tract, including the introduction to the patient a therapeutically effective amount of the compound or its pharmaceutically acceptable salts, as described in [3].

[18] the Method as described in [17], and disease, leading to the symptom of a lower urinary tract is overactive bladder, benign prostatic hyperplasia, bladder neck contracture, cystitis, or prostatitis.

The present invention also relates to the next.

[19] the EP1 receptor Antagonist, comprising as an active ingredient derived sulfonamida represented by formula (I-A), or its pharmaceutically acceptable salt.

[Chem. 10]

[where the symbols have the following meanings:

ring A: benzene nucleus, cycloalkane ring or heteroaromatic ring,

L1simple link or lowest alkylen,

L2: lower alkylene,

R1-R4: the same or different, represent, each, H, halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl, -CN, -NO2, -CO2R0, -CO-lower alkyl, -lower alkylene-OR0-the inferior alkylene-CO2R0, aryl which may be substituted, heteroaryl, which may be substituted, -O-aryl which may be substituted, -O-benzyl or-O-heteroaryl, which may be substituted, or

when R1and R2and R3and R4each are located on adjacent carbon atoms of the benzene ring or ring A, they may together with the ring carbon atom to which they are attached, form a 5-7 membered cycloalkene ring or a heterocycle which may be substituted by a group selected from the following group G1,

group G1lower alkyl and oxo,

R0: H or lower alkyl,

RA: H or lower alkyl,

RB: H, lower alkyl, -lower alkylene-aryl which may be substituted, lower alkylene-heteroaryl, which may be substituted, lower alkylene-O-aryl which may be substituted, or lower alkylene-O-heteroaryl, which may be substituted, or

RAand RBcan together with the nitrogen atom to which they are attached, form a nitrogen-containing g is tetracycl. The same shall apply hereinafter].

[20] Derived sulfonamida represented by formula (II-B), or its pharmaceutically acceptable salt.

[Chem. 11]

[where the symbols have the following meanings:

ring A: benzene ring, cycloalkane ring or heteroaromatic ring,

L1simple link or lowest alkylen,

R1-R4: the same or different, represent, each, H, halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl, -CN, -NO2, -CO2R0, -CO-lower alkyl, -lower alkylene-OR0-the inferior alkylene-CO2R0, aryl which may be substituted, heteroaryl, which may be substituted, -O-aryl which may be substituted, -O-benzyl or-O-heteroaryl, which may be substituted, or

when R1and R2and R3and R4each are located on adjacent carbon atoms of the benzene ring or ring A, they may together with the ring carbon atom to which they are attached, form a 5-7 membered cycloalkene ring or a heterocycle which may be substituted by a group selected from the following group G1,

group G1lower alkyl and oxo,

R0: H or lower alkyl,

L3: lower alkylene,

X: simple bond or-O-,

B: benzene ring or heteroatom the political ring,

R5and R6: the same or different, represent, each, H, halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl, -CN or-NO2,

Y: a simple link, the lower alkylene, lower albaniles or-O-lower alkylene-,

Z: -CO2R0, -CONR7R8, -CONH-SO2-R9or nitrogen-containing heterocyclic group which may be substituted by a group selected from group G1,

R7and R8: the same or different, represent each H or lower alkyl which may be substituted by a group selected from the following group G2,

group G2: -OR0, -N(R0)2and nitrogen-containing heterocyclic group, and

R9: lower alkyl which may be substituted by a group selected from the group-OR0and the group-O-CO-lower alkyl,

provided that excluded 4-({[N-[(4-forfinal)sulfonyl]-N-(2-methoxyphenyl)glycyl]amino}methyl)methylbenzoate and N2-[(4-chlorophenyl)sulfonyl]-N2-(2,5-differenl)-N-[4-(1,2,3-thiadiazole-4-yl)benzyl]-D-alaninate. The same shall apply hereinafter].

The EFFECT of the INVENTION

The compound represented by formula (I), which is the active ingredient according to the present invention, or its pharmaceutically acceptable salt, has a strong antagonistic activity against receptor EP1 and the respectively, can be used as a drug for the treatment of diseases associated with the EP1 receptor, in particular, symptoms of the lower urinary tract.

The BEST WAY of carrying out the INVENTION

Below the present invention will be described in more detail.

Since the compounds represented by formula (II), formula (II-A), formula (I-A) and formula (II-B)included in the compound represented by formula (I), which is the active ingredient according to the present invention, these compounds may together be referred to as "compound according to the present invention".

In the description, the term "lower" means a linear or branched hydrocarbon chain having 1-6 carbon atoms (hereinafter in this document simply called C1-6), unless specifically stated otherwise.

"Lower alkyl" means C1-6alkyl. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Preferably the alkyl has 1-3 carbon atoms and, more preferably, is a methyl, ethyl or isopropyl.

"Lower alkylene" means a divalent group in which one hydrogen atom at any position of the C1-6the alkyl removed. Specific examples include methylene, ethylene, METROTILE, dimethylmethylene and trimethylene. Before actualname are methylene, ethylene or trimethylene, and more preferred are a methylene or ethylene.

"Lower albaniles" means C2-6lowest alkylen having a double bond in any position. Specific examples include vinile, propylen, 1-butylen and 2-butylen. It is preferable to vinile.

"Cycloalkane ring" means a saturated ring C3-10hydrocarbon, or it can form a United bridging the communication ring. Specific examples include cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, adamantane and norbornane. Preferred are a cyclopentane or cyclohexane. "Cycloalkyl" means a ring group consisting of cycloalkanones rings.

"5-7-Membered cycloalkene ring" means C5-7hydrocarbon ring having one double bond. Specific examples include cyclopentene, cyclohexene and cycloheptene. Preferred are cyclopenten or cyclohexane, and more preferred is cyclopenten.

"Halogen" means F, Cl, Br and I. Preferred are F, Cl or Br.

"Halogen-lower alkyl" means "lower alkyl"defined above in which one or more hydrogen atoms substituted by one or more identical or different atoms "halogen", as defined above. Specific examples include formati is, deformity, trifluoromethyl, 2,2,2-triptorelin and pentaverate. Preferred is trifluoromethyl.

"Aryl" means C6-14mono-, bi - and tricyclic aromatic hydrocarbon ring group, and examples include the ring group which is condensed with C5-7cycloalkanones ring group. However, if C5-7cycloalkene the condensed ring, the link is on the aromatic ring. Specific examples include phenyl, naphthyl, indanyl, tetrahydronaphthyl and fluorenyl. Preferred is phenyl.

"Heterocycle" is 4-12-membered, mono - or bicyclic saturated or unsaturated ring containing 1-4 heteroatoms selected from O, S and N. examples of the unsaturated ring include aromatic heterocycle. In addition, the o-ring atom, S or N, can be oxidized with the formation of oxide or dioxide. Specific examples of monocyclic rings include azetidin, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, ASEAN, diazepan, oxetane, tetrahydrofuran, tetrahydropyran, 1,3-dioxole, 2,3-dihydro-1,4-dioxin, pyrazolidine, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazol, isoxazol, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrazin, pyrimidine, pyridazine, triazine and 2,3-dihydro-1,3-oxazol, and examples of bicyclic rings include 1,3-b is sodickson, 2,3-dihydro-1,4-benzodioxin, indole, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, indazole, benzotriazole, quinoline, isoquinoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cinoxacin, hinzelin and phthalazine. It is preferable monocyclic heterocycle. "Heterocyclic group" means a ring group consisting of the above heterocycle.

"Aromatic heterocycle" means, among the above "heterocyclic compounds", a ring selected from (i) monocyclic, 5 - or 6-membered aromatic heterocycle containing 1-4 heteroatoms selected from O, S and N, (ii) a bicyclic heterocycle, in which the aromatic heterocycle in the above (i) condensed matter (provided that the two aromatic heterocycle, which condenses, may be the same or different from each other), and (iii) a bicyclic heterocycle, in which the aromatic heterocycle in the above i) and benzene ring or a 5-7 membered cycloalkane condensed. Specific examples include (i) pyridine, pyrazin, pyrimidine, pyridazine, triazine, pyrrole, furan, thiophene, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazol, oxadiazole, thiazole, isothiazol and thiadiazole, (ii) nafcillin, imidazopyridine, pyrrolopyrimidine, thienopyridine and thienopyrrole and iii) benzimidazole, benzofuran, insatiate, benzothiadiazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline, isoquinoline, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, hinzelin, cinoxacin, phthalazine, indole, isoindole, tetrahydroimidazo, chroman and indazole. Preferred are the above (i) or iii), and more preferred is (i) monocyclic, 5-or 6-membered aromatic heterocycle. "Heteroaryl" means a ring group consisting of the above aromatic heterocycle.

"Nitrogen-containing heterocycle" means a heterocycle containing at least one N atom as a constituent of the ring element in the "heterocycle". Specific examples include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, ASEAN, diazepan, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyridine, pyrazin, pyrimidine, pyridazine, triazine, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazol, oxadiazole, thiazole, isothiazol, thiadiazole, benzimidazole, benzothiadiazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline, isoquinoline, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, hinzelin, cinoxacin, phthalazine, indole, isoindole, tetrahydroimidazo and indazole. "Nitrogen-containing heterocyclic group" means a ring group consisting of the above nitrogen-containing Goethe is of ozila.

"CO2H or biological equivalent" is a carboxylic acid, or an atom or a group having electrically or spatial equivalent configuration and having in common with her biological property. They include the so-called bioisostere carboxylic acid, which is typically used by a specialist, a protected carboxyl group, and a prodrug carboxylic acids, including, for example, carboxylic acid, ether carboxylic acids, hydroxamic acid (-CO-NH-OH), allcinema (-CO-NH-CN), arylsulfonate (-CO-NH-SO2-R or-SO2-NH-CO-R) or tetrazole, 5-oxo-1,2,4-oxadiazole, 3-hydroxyethoxy, 5-oxo-1,2,4-thiadiazole, 3-hydroxy-1,2,5-thiadiazole and 3-hydroxy-γ-pyrone. Preferred are carboxylic acid, arylsulfonic, tetrazole or 5-oxo-1,2,4-oxadiazol, and more preferred are carboxylic acid or arylsulfonate.

In addition, examples of R in arylsulfonamides (-CO-NH-SO2-R or-SO2-NH-CO-R) include lower alkyl which may be substituted by the Deputy selected from the group consisting of-OH, -O-lower alkyl and-O-CO-lower alkyl.

The expression "may be substituted" means "not substituted" or "substituted by the same or different 1 to 5 substituents, preferably 1-2 substituents".

In addition, in the case when there are many groups, as in the case of R0in-N(R0 )2or similar, these groups (in this case, R0) may be the same or different from each other.

Examples of the substituent for R1-R4that is acceptable for the "aryl" and "heteroaryl" in the "aryl which may be substituted", "heteroaryl, which may be substituted", "-O-aryl which may be substituted" and "-AU-heteroaryl, which may be substituted"include a group selected from the following group G3.

Group G3: halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl, -NO2and-CN.

Examples of the substituent for RBthat is acceptable for the "aryl" and "heteroaryl in the lowest alkylen-aryl which may be substituted", the group "lowest alkylen-heteroaryl, which may be substituted", the group "lowest alkylene-O-aryl which may be substituted" and the group "lowest alkylen-O-heteroaryl, which may be substituted"include a group selected from group G3, -O-benzyl, -N(R0)2, -N(R0)-CO-lower alkyl, -N(R0)-SO2-lower alkyl, -S(O)n-lower alkyl, -SO2-N(R0)2, phenyl which may be substituted by a group selected from group G3that group is the lowest alkylen-OR0or-Y-Z.

Preferred embodiments of the active ingredient (I) according to present the invention are as follows.

(1-a) L1preferably refers to a simple link.

(2-a) L2preferably represents methylene.

(3-a) Ring A is preferably a benzene ring.

(4-a) R1and R2preferably are the same or different and each represents halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl, -CN or-NO2more preferably halogen, lower alkyl or-OR0and even more preferably Cl, Br, methyl, ethyl or methoxy. In addition, the position of substituted on the benzene ring, R1and R2preferably the position of the 2 or 3 position, is attached to L1substituted with the same or different groups, as described above.

(5-a) R3and R4preferably are the same or different and each denotes R0, halogen, -CN, halogen-lower alkyl, -CO-lower alkyl or-lower alkylene-OR0more preferably R0, halogen, -CN or halogen-lower alkyl, and even more preferably H, methyl, ethyl, Br, Cl, F, -CN, or trifluoromethyl.

Even more preferably, one of R3and R4denotes H or F, and the other denotes the group described above, different from H and F.

(6-a) RApreferably denotes N.

(7-a) RBpreferably indicates the lowest alkylen-the reel, which may be substituted, or lower alkylene-heteroaryl, which may be substituted, and more preferably methylene-aryl which may be substituted, or-methylene-heteroaryl, which may be substituted. Here aryl preferably represents phenyl, and heteroaryl preferably represents thienyl, furyl, pyridyl or pyrimidinyl. In addition, aryl which may be substituted, and heteroaryl, which may be substituted, preferably represent aryl and heteroaryl, each of which is not substituted, or aryl and heteroaryl, each of which is substituted by a group selected from the group consisting of halogen, -OR0, -O-halogen-lower alkyl, -CN, group-lower alkylene-OR0, -N(R0)-CO-lower alkyl and-Y-Z, and more preferably aryl and heteroaryl, each of which is not substituted, or aryl and heteroaryl, each of which is substituted by a group selected from the group consisting of-OR0and-Y-Z.

Particularly preferred variant of the active ingredient (I) according to the present invention is a compound obtained by combination of each preferred group described above in (1-a)-a(7-a). Another preferred variant is a compound represented by the formula (II).

Preferred embodiments of the ratio of compound (II) according to the present izopet the tion are as follows.

(1-b) L1preferably refers to a simple link.

(2-b) L2preferably represents methylene.

(3-b) Ring A preferably denotes a benzene ring.

(4-b) R1and R2preferably are the same or different and each represents halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or-CN, more preferably halogen, lower alkyl or-OR0and even more preferably Cl, Br, methyl, ethyl or methoxy. In addition, the position of substituted on the benzene ring, R1and R2preferably the position of the 2 or 3 position, is attached to L1substituted with the same or different groups, as described above.

(5-b) R3and R4preferably are the same or different and each denotes R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or-CN, more preferably, R0, halogen, halogen-lower alkyl or-CN, and more preferably H, methyl, ethyl, Br, Cl, F, -CN, or trifluoromethyl.

Even more preferably, one of R3and R4denotes H or F, and the other denotes the group described above, different from H and F.

(6-b) L3preferably represents methylene or ethylene, and more preferably methylene.

(7-b) X preferably denotes Rostow connection.

(8-b) Ring B preferably denotes a benzene ring, thiophene ring, furan ring, oxazoline ring, pyridine ring or a pyrimidine ring, and more preferably benzene ring, thiophene ring or oxazoline ring.

(9-b) R5and R6preferably are the same or different and each denotes R0, halogen or-OR0more preferably H or halogen, and more preferably both R5and R6denote H, or one of R5and R6denotes H and the other represents F.

(10-b) Y preferably denotes (i) a simple bond, ethylene, vinile, propylen, -O -, methylene or-O-METROTILE, when Z represents-CO2H or biological equivalent, or-CONR7R8; or (ii) a simple relationship in the case where Z denotes a nitrogen-containing heterocyclic group which may be substituted by the Deputy selected from the group G1.

(11-b) Z preferably denotes-CO2H or biological equivalent, more preferably-CO2H, arylsulfonate, tetrazole or 5-oxo-1,2,4-oxadiazol, and even more preferably CO2H or-CONH-SO2Me.

Particularly preferred variant of the active ingredient (II) according to the present invention is a compound obtained by combination of each paragraph is edocfile group, described above in (1-b)-(11-b).

In addition, preferred embodiments of the ratio of compound (II-B) according to the present invention are as follows.

(1) L1preferably refers to a simple link.

(2) L2preferably represents methylene.

(3) the Ring A preferably denotes a benzene ring.

(4) R1and R2preferably are the same or different and each represents halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl, -CN or-NO2and more preferably halogen, lower alkyl or-OR0. In addition, the position of substituted on the benzene ring, R1and R2preferably ortho - or meta-position relative to the position that is attached to the L1substituted with the same or different groups, as described above.

(5) R3and R4preferably are the same or different and each represents H, lower alkyl, halogen, -CN, halogen-lower alkyl, -CO-lower alkyl or-lower alkylene-OR0and more preferably methyl, ethyl, Br, Cl, -CN, trifluoromethyl, acetyl, or hydroxymethyl. Even more preferably, one of R3and R4denotes H and the other represents the group described above, different from N.

(6) L3preferably represents methylene or ethylene, and more preferably methylene.

(7) X preferably denotes a simple link.

(8) the Ring B preferably denotes a benzene ring, thiophene ring or a pyridine ring, and more preferably benzene ring.

(9) R5and R6preferably are the same or different and each represents H or-O-lower alkyl, and more preferably both R5and R6denote H, or one of R5and R6denotes H and the other represents-O-lower alkyl.

(10) Y preferably denotes (i) a simple bond, ethylene, vinile or-O-methylene when Z represents-CO2R0, -CONR7R8or-CONH-SO2-R9; or (ii) a simple relationship in the case where Z denotes a nitrogen-containing heterocyclic group which may be substituted by the Deputy selected from the group G1.

(11) Z preferably denotes CO2H, -CONH-(CH2)2OH, -CONH-(CH2)2NMe2, -CONH-SO2Me, or-CONH-SO2-(CH2)3OH.

Particularly preferred variant of the active ingredient (II) according to the present invention is a compound obtained by combination of each preferred group of the above in(1)-(11).

The connection according to the present invention may sometimes exist in the form of a geometric isomer or tautomer, depending on vidanapathirana. The present invention includes an isolated form, and a mixture of these isomers.

The connection according to the present invention may have asymmetric carbon atom and, therefore, exist in the form of optical isomers such as (R)-form and (S)-form. The connection according to the present invention includes both mixtures and selected forms of these optical isomers.

In addition, the connection according to the present invention includes pharmaceutically acceptable prodrugs". "Pharmaceutically acceptable prodrug" is a compound having a group which is converted in NH2HE CO2H, etc. according to the present invention by solvolysis or under physiological conditions. Examples of the group capable of forming a prodrug include groups described in “Progress in Medicine, Life Science Medical, vol. 5, 2157-2161 (1985), and “Iyakuhin no Kaihatsu (Development of Drugs) (Hirokawa Shoten, vol. 7), Bunshi Sekkei (Molecular Design)", 163-198 (1990).

The connection according to the present invention can form a salt with an acid or a base, depending on the kind of substituents. These salts are pharmaceutically acceptable salts, and specific examples include additive salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid and phosphoric who Isleta; with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, aspartic acid and glutamic acid; inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; and organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, and ammonium salts.

In addition, the present invention also includes various hydrates, solvate and polymorphic substances of the compound or its salt according to the present invention.

Ways to get

The connection according to the present invention and its pharmaceutically acceptable salt can be obtained by applying various known synthesis methods, using the characteristics based on their basic skeletal structures or substituents. Further, depending on the type of functional groups, sometimes effectively from the point of view of obtaining methods to protect a functional group suitable protective group, or to replace it with a group that can be easily converted into the functional group, in the process stages from the original substances to temporarily what's connections. Examples of such functional groups include amino group, hydroxyl group and carboxyl group, and examples of such protective groups are described in the publication “Protective Groups in Organic Synthesis", edited by T.W. Greene and P.G.M. Wuts, (USA), 3rdedition, John Wiley & Sons, 1999, which can be optionally selected and used depending on the reaction conditions. In this way, the desired compound can be obtained by introducing a protective group for the reaction, and then, if desirable, the removal of the protective group or its conversion into the desired group.

In addition, the prodrug compounds according to the present invention can be obtained by introducing a specific group during the stages from the original materials to intermediates, in the same way as for the above-mentioned protective groups, or through the implementation of response to the received connection according to the present invention. The reaction can be carried out using a method known to the expert, such as a conventional esterification, amidation and dehydration.

Below are examples of methods for producing compounds according to the present invention. Hereinafter, methods of production according to the present invention is not limited to the examples shown below.

The method of obtaining 1

[Chem. 12]

This stage is predstavljaet a method of producing compound (I) according to the present invention by reacting the compound (IV) with compound (III) or its reactive derivative. Examples of the reactive derivative include gelegenheid acid (the acid chloride acid, bromohydrin acid and the like), acid anhydride (mixed acid anhydrides obtained by reaction with atilglukuronida, benzylcarbamoyl, phenylcarbamates, p-toluensulfonate acid, isovalerianic acid, and the like, or a symmetric acid anhydrides), active esters (ester, which can be obtained using phenol, which can be replaced by removing the electron group (for example, the nitro-group, a fluorine atom and the like), 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HONSu), and the like), esters of lower alkyl and acid azide. These reactive derivatives can be obtained in the usual way. The reaction can be carried out using equimolar amounts of compounds of carboxylic acid (III) or its reactive derivative and the compound (IV), or one of them in excess, in the range of from cooling to heating in a reaction-inert solvent such as aromatic hydrocarbons, halogenated hydrocarbons, ethers, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-organic (NMP), ethyl acetate and acetonitrile. Depending on the form of a reactive derivative, sometimes for smooth reaction preferably is to perform the reaction in the presence of a base (preferably, of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine and the like). Pyridine can also serve as a solvent.

When using the free carboxylic acid, it is desirable to use a condensing agent (N,N'-dicyclohexylcarbodiimide (DCC), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC), 1,1'-carbonyldiimidazole (CDI), N,N'-disuccinimidyl, the reagent Thief (produced by Aldrich, USA), tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (TBTU), hexaflurophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU), azide diphenylphosphinic acid (DPPA), the acid chloride phosphoric acid, trichloride phosphorus, triphenylphosphine/N-bromosuccinimide and the like) and, if desired, additives (for example, HONSu and HOBt).

The method of obtaining 2

[Chem. 13]

(where Lv2denotes a leaving group. The same shall apply hereinafter).

This stage is a method of obtaining the compound (I) according to the present invention by alkylation of compound (VI) to compound (V) with the use of leaving groups. This group presented Lv2may be any leaving group that is usually used in the reaction of nucleophilic substitution, and, for example, it is preferable to use a halogen, such as chlorine and bromine; sulfonyloxy, such as meth is sulfonyloxy, p-toluensulfonate, tripterocalyx; sulfonyl, such as lower alkylsulfonyl and arylsulfonyl; etc. as alkylation reaction at this stage you can use the alkylation is typically used by a specialist. For example, it may be carried out in the range from room temperature to heating under reflux without solvent or in a reaction-inert solvent such as the aforementioned aromatic hydrocarbons, such as benzene, toluene and xylene, esters such as ethyl acetate, ethers, such as simple diethyl ether, tetrahydrofuran (THF) and dioxane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, DMF, DMA, NMP, dimethylsulfoxide (DMSO) and acetonitrile, or in a solvent such as alcohols, etc. In depending on the compounds, for smooth reaction is sometimes preferred to conduct the reaction in the presence of an organic base (suitable for use are triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine and the like), or the base metal salt (suitable for use are potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-piperonyl potassium and the like).

The method of obtaining 3

[Chem. 14]

(where Lv1denotes a leaving group. The same shall apply hereinafter).

This stage is a method of obtaining the compound (I) according to the present invention by sulfonylurea compound (VII) with compound (VIII). As the leaving group Lv1suitable for use is a halogen, such as chlorine and bromine. The reaction can be performed, for example, using conditions sulfonylamine described in the above publication, “Protective Groups in Organic Synthesis”. In particular, the reaction can be carried out without solvent or in a solvent such as THF, methylene chloride and acetonitrile, if necessary, in the presence of a base such as triethylamine and pyridine, in the range of from cooling to heating under reflux.

The method of obtaining 4

[Chem. 15]

(where ALK denotes a lower alkyl. The same shall apply hereinafter).

This stage is a method of producing compound (II-b) according to the present invention, in which Z is a carboxyl group, by hydrolysis of compound (II-a) according to the present invention, in which Z is a complex ester. The hydrolysis reaction at this stage may be performed, for example, in accordance with the reaction of removing the protective group, described the in the above publication, “Protective Groups in Organic Synthesis”.

In addition, some compounds represented by formulas (I) and (II)can be obtained from the compounds according to the present invention obtained by the above methods and their variations, or any combination of known methods, which can usually be used by a specialist, such as alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis and the removal of the protective group.

Starting compound used in the preparation of the compounds according to the present invention can be obtained, for example, using methods described below, known methods or their variations.

Synthesis of starting compound 1

[Chem. 16]

The first stage

This stage is a method of obtaining compound (VI) by sulfonylurea compounds (IX) with compound (VIII). Sulfonylamine at this stage can be carried out in the same manner as sulfonylamine in the way of getting 3.

The second stage

This stage is a method of obtaining compound (XI) by alkylation of the compound (VI) with compound (X)containing a leaving group. Alkylation at this stage can be carried out in the same manner as alkylation in the way of getting 2.

The third stage

This stage represents the procedure of obtaining compound (III) from compound (XI) by hydrolysis. The hydrolysis reaction at this stage can be carried out in the same manner as the hydrolysis reaction in the method of obtaining 4.

Synthesis of starting compound 2

[Chem. 17]

(where Lv3denotes a leaving group. The same shall apply hereinafter).

This stage is a method of obtaining the compound (V) by acylation of the compound (IV) with compound (XII)containing a leaving group. As the leaving group Lv3suitable for use is a halogen, such as chlorine and bromine. For example, the reaction can be performed using the conditions of acylation, as described in the above publication, “Protective Groups in Organic Synthesis”. In particular, it can be performed without solvent or in a solvent such as THF, methylene chloride and acetonitrile, if necessary, in the presence of a base such as triethylamine and pyridine, in the range of from cooling to heating under reflux.

Synthesis of starting compound 3

[Chem. 18]

This stage is a method of obtaining compound (VII) by alkylation of the compound (IX) with compound (V)containing a leaving group. Alkylation at this stage can be carried out in the same manner as alkylation in the way of getting 2.

the reaction Products, received by each of the methods of preparation, can be isolated and purified in the form of the free compounds or their salts or solvate such as a hydrate. Salts can be obtained after performing a conventional salt-forming processing.

Isolation and purification can be performed using conventional chemical operations such as extraction, concentration, removal by distillation, crystallization, filtration, recrystallization and various chromatography methods.

Various isomers can be isolated in the usual way using the differences in physicochemical properties among the isomers. For example, optical isomers can be separated by conventional methods, optical separation, for example by fractional crystallization, chromatography, etc. in Addition, the optical isomers can be obtained from the appropriate starting compounds that are optically active.

The effects of the compounds according to the present invention were confirmed by the following tests.

1. Measurement of antagonistic activity to the receptor using cells expressing the receptor EP1.

The HEK293 cells (American type culture Collection), which stably expressed receptors EP1 rats were distributed in 96-well tablet coated with poly-D-lysine (product name: Biocat, PDL96W black/clear, Nippon Becton Dickinson), in the amount of 2×104cells/well the day before the experiment and incubated over night at 37°C in atmosphere of 5% carbon dioxide (CO2) in a medium containing 10% fetal bovine serum (FBS) (product name: DMEM, Invitrogen Corporation). The culture medium was replaced with loading buffer (wash solution containing 4 μm fluorescent indicator (product name: Fluo3-AM, Tong Ren Tang Technologies Co. Ltd.):balanced salt solution Hank (HBSS), 20 mm 2-[4-(2-hydroxyethyl)-1-piperazinil]econsultancy acid (HEPES), sodium hydroxide (NaOH), 2.5 mm Probenecid, 0.1% of bovine serum albumin (BSA)) and left at room temperature for 3 hours, the cells were washed using a device for washing the tablet, which was introduced leaching solution (product name: ELx405, BIO-TEK instrument Corporation). Added the connection, which was pre-dissolved and diluted in the washing solution, and placed into the system for measuring the concentration of calcium (CA) in the cage (product name: FLIPR, Molecular Devices Corporation). After 5 minutes was added PGE2at a final concentration of 100 nm and measured the change in the concentration of CA in the cell. The difference between the maximum value and minimum value of the concentration of CA in the cells was determined and kept as measurement data. Assuming a 0% response after adding 100 nm PGE2and when is ima for 100% response after adding buffer, the concentration causing 50% inhibition was determined as the value of the IC50.

The results are shown in the following table 1. In this table, the Rev. means of preparative example as described below, Etc. indicates the example number, as described below.

Table 1
ConnectionIC50(nm)
Prep16
Prep12
PR1,6
PR2,4
PR1,4
PR1,0
PR2,5
PR1,5
PR0,72
PR1,0

(2) Test the receptor binding using cells expressing the receptor EP1.

The signal peptide (MKTIIALSYIFCLVFA: sequence 1) and the sequence FLAG (DYKDDDDK: sequence 2) embedded in the N-end d is aptara EP1 rats with subsequent sublimemovies in the expression vector (product name: pCEP4, Invitrogen Corporation). Cell HEK293EBNA (American type culture Collection) were transfusional expression vector EP1 rats, using a transfection reagent (product name: Fugene-6, Roche Diagnostics K.K.), and then were cultured for 2 days in medium containing 10% FBS (product name: DMEM, Invitrogen Corporation)at 37°C in an atmosphere of 5% CO2. After cultivation, cells were collected, treated cell lysate (20 mm buffer Tris(hydroxymethyl)aminomethan (Tris) pH 7.5, 5 mm ethylenediaminetetraacetic acid (EDTA)) and ultracentrifugal (23000 rpm, 25 minutes×2) for coarse gain drug membrane.

The reaction solution containing the resulting preparation of the membrane (15 µg) and3H-PGE2(150 µl composition: 10 mm 2-(N-morpholino)econsultancy acid (MES)/potassium hydroxide (KOH) pH6,0, 1 mm EDTA, 10 mm of magnesium chloride (MgCl2), 0,02% 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate (CHAPS)), incubated at room temperature for 1 hour. The reaction was stopped by ice buffer and the medium was filtered by suction under reduced pressure to capture the associated 3H-PGE2on a glass fiber filter (product name: UNIFILTER-96, GF/B, PerkinElmer Japan Co., Ltd.), for measurement of radioactivity binding using a scintillation counter for microplate (product name: TopCount, Packard) using Microscinti (name of the product is: Microscinti 20, PerkElmer Japan Co., Ltd.).

The dissociation constant (Kd) and maximum binding (Bmax) were determined using Scatchard graph (Annals of the New York Academy of Science, US, volume 51, page 660, 1949). Nonspecific binding was defined as binding in the presence of excess (2.5 μm) PGE2without tags.Study of the inhibitory activity of a compound against the binding3H-PGE2carried out by adding 2.5 nm3H-PGE2and the connection.

The inhibition constant Ki (nm) for each compound was obtained using the following formula:

Ki=IC50/(1+([C]/Kd))

where [C] denotes the concentration of3H-PGE2used in the reaction system.

The results are shown in table 2.

Table 2
ConnectionKi (nm)
Prep0,68
PR0,57
PR1,00
PR0,74
PR0,48
PR0,33
PR

(3) Effects on rats induced with acetic acid, the frequent urge to urinate.

The action of the compounds against pollakiuria was evaluated using the pathological model. It was reported that the use of acetic acid on the urinary bladder of the rat damage the mucous membrane of the bladder, thereby activating afferent conduction of nociceptive stimulus (The Journal of Neuroscience, US, 12 (12): p.4878-89). Because urination induced by treatment with acetic acid inside the bladder, it is possible to evaluate therapeutic effects of compounds against these symptoms.

For the experiment used male Wistar rats (Charles River Laboratories) weighing from 200 to 450, the bladder was removed to the outside via midline laparotomy under anesthesia by pentobarbital (50 mg/kg intraperitoneally) and residual urine in the bladder was removed with a syringe equipped with a needle gauge 27G. Then the bladder was introduced from 0.5 to 0.7 ml of 1% solution of acetic acid and the wound was closed. After 2 days conducted a further experiment. Rats were placed in metabolic cages for acclimatization for 1 hour and then were administered the test drug. Immediately after this change in the output of urine is consistently measured within 6 hours. Total urine output was divided by the total number of cases of urination, to calculate the effective capacity of the bladder. It was noted that the effective capacity of the bladder group, bladder which was treated with acetic acid, was reduced compared with the untreated group, and thus, if you experience symptoms of frequent urination. On the other hand, the connection according to the invention resulted in a significant improvement in the symptom of frequent urination.

On the basis of test results (1)-(3) it was confirmed that the compound according to the present invention has a strong antagonistic activity against receptor EP1, and that it leads to a significant improvement in the symptom of frequent urination.

Thus, the connection according to the present invention is effective as a drug for treatment-related receptor EP1 diseases, especially for symptoms of the lower urinary tract.

Examples of diseases that cause the symptom of a lower urinary tract" in the present invention include overactive bladder, national Department of standardization (benign prostatic hyperplasia, bladder neck contracture, cystitis, prostatitis, etc.

"The symptom of a lower urinary tract" in the present invention includes symptoms associated with h is the accumulation of urine, such as frequent daytime urination, frequent night urination, urgent urination, and incontinence of urine; symptoms associated with emptying, such as weak urination, interrupted urine flow and delayed urination; symptoms after urination, such as the feeling of residual urine; and the pain in his groin/lower abdomen, such as pain in the bladder, urethral pain, perineal pain, scrotal pain and pelvic pain. In addition, the symptoms associated with the accumulation of urine, symptoms associated with emptying and symptoms after urination include symptoms associated with the accumulation of urine, symptoms associated with emptying and symptoms after urination associated with benign prostatic hyperplasia. In addition, the symptoms associated with the accumulation of urine include symptoms associated with the accumulation of urine associated with overactive bladder, cystitis and prostatitis.

Pharmaceutical composition comprising at least one or more kinds of the compound or its salt according to the present invention as an active ingredient, obtained using pharmaceutical carriers, excipients and other additives and the like, usually used in this field according to conventional methods.

therapeutic introduction of m which can be made in any form for oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc. and for parenteral administration in the form of injectable solutions for intravenous and intramuscular injections, suppositories, transdermal preparations, transnasal preparations, inhalers, etc. Dose respectively determined depending on the individual case, taking into account the symptoms, age and sex of the patient, etc. but it usually ranges from about 0.001 mg/kg to about 100 mg/kg per day per adult in the case of oral administration, and is administered in one dose or divided into 2-4 servings. In addition, in the case of intravenous administration it is usually introduced within the range of from 0.0001 mg/kg to 10 mg/kg per day for an adult, once a day, or two or more times a day. In the case of transnasal introducing her to enter usually within the range of from 0.0001 mg/kg to 10 mg/kg per day for an adult, once a day, or two or more times a day. In addition, in the case of asthma, the drug is administered usually in the range of from 0.0001 mg/kg to 1 mg/kg for an adult, once a day or several times a day.

Relatively solid composition according to the present invention for oral administration using tablets, powders, granules, etc. In such solid compositions one or more active substances are mixed with at least one inactive ek is sapientum, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and alumosilicate magnesium. In the usual way, the composition may contain inactive additives such as lubricants, such as magnesium stearate, a disintegrator such as carboximetilkrahmal sodium, and means imparting solubility. Depending on the case of tablets or pills may, if necessary, covered with sugar or remedy for gastric or small bowel coating.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert solvents such as purified water or ethanol. In addition to the inert solvent, the composition may contain auxiliary tools, such as tools, giving the solubility, moisturizers and suspendresume agents, sweeteners, corrective tools, flavorings and preservatives.

Injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. As the aqueous solvent, for example, included distilled water for injection and physiological saline. Examples of non-aqueous solvent include propylene glycol, polyeth lepicol, vegetable oil, such as olive oil, alcohols such as ethanol, and Polysorbate 80 (Pharmacopoeia). Such a composition may further comprise means for giving toychest, antiseptics, moisturizers, emulsifiers, dispersing agents, stabilizers and means imparting solubility. They are sterilized, for example, by filtration through inhibiting bacteria filter, adulteration of germicidal or irradiation. In addition, they can also be used in the form of sterile solid compositions which are dissolved or suspended in sterile water or a sterile solvent for injection before use.

Medicinal product for external use may include ointments, plasters, creams, gels, bandages, sprays, lotions, eye drops, eye ointments, etc. Medicinal product contains commonly used ointment bases, lotion, aqueous or non-aqueous solutions, suspensions, emulsions and the like, Examples of ointment bases or foundations lotion include polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylenated gidrirovannoe castor oil, glycerylmonostearate, stearyl alcohol, cetyl alcohol, lauromacrogol and sorbitan sesquioleate.

Relative to the means for insertion through the mucous membrane, such as inhalers and transnat the global funds they are used in solid, liquid or semi-solid form, and they can be obtained in accordance with the well-known manner. For example, if necessary, these can be optionally added excipients, such as lactose and starch, as well as pH regulators, antiseptics, surfactants, lubricants, stabilizers, thickeners, etc. For their introduction you can use the appropriate device for inhalation or insufflation. For example, the connection can be entered individually or as a mixed composition in powder form or in the form of solutions or suspensions, by combining with pharmaceutically acceptable carriers using well known devices or systems, such as inhalers with a measured dose. Dry powder inhalers or the like can be single or multiple injections, and you can use dry powder or containing powder capsules. Alternatively, they can be in the form, such as aerosol spray high-pressure, etc. in which the use of a suitable propellant, such as a suitable gas, such as chlorphenesin, hydrofluroalkane and carbon dioxide.

Preparative examples and examples

Following methods to obtain the compounds according to the present invention will be described in more detail with reference to the preparative examples and examples, the s compounds according to the present invention, but the present invention is not limited to these preparative examples and examples. In addition, the methods of obtaining the starting compounds for the compounds according to the present invention will be described in reference examples.

In this regard, the symbols in the reference examples, preparative examples and examples have the following meanings (the same shall apply hereinafter).

Rf: reference example, Pre: preparative example number, Ex: example number, Str: structural formula, Syn: method get (the numbers indicate that the compound was obtained by using the original connection, similar to case of the compounds of example, having number as an example. If added before the number R, the numbers indicate that the compound was obtained by using the original connection, similar to case of the compounds of reference example having a number as a reference example, a number such and such, and if added before the number P, the numbers indicate that the compound was obtained by using the original connection such occasion compounds from preparative example with the room as preparative example number so-and-so. If there are a lot of ways to obtain, for example, using *as in P1*1, this means that the connection is received, performing the reaction in the specified order, the beginning is cited from the left or top and using appropriate source connection) Dat: physicochemical data (EI: EI-MS([M]+); EP: ESI-MS (positive) (in the absence of description, [M+H]+); EN: ESI-MS (negative) ([M-H]-); API: API-MS (positive) (in the absence of description, [M+H]+); FP: FAB-MS (positive) (in the absence of description, [M+H]+); FN: FAB-MS (negative) (in the absence of description, [M-H]-); AMR: δ (ppm) peaks in the1H-NMR using DMSO-d6; Me: methyl, Et: ethyl, nPr: n-propyl, iPr: isopropyl, Bn: benzyl, Ac: acetyl, Ms: methanesulfonyl.

Reference example 1

18.7 g of 3-chloro-2-methylaniline was dissolved in 120 ml of pyridine was added in portions during 30 minutes 22.9 grams p-toluensulfonate, followed by stirring at room temperature over night. The reaction liquid was concentrated under reduced pressure and the obtained residue was added water, followed by extraction with ethyl acetate. The organic layer washed with 1 M hydrochloric acid, saturated salt solution, saturated aqueous sodium hydrogen carbonate and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining of 34.6 g of N-(3-chloro-2-were)-4-methylbenzenesulfonamide.

Reference example 2

of 34.5 g of N-(3-chloro-2-were)-4-methylbenzenesulfonamide was dissolved in 232 ml of DMF and added to 21.4 g Ativ is Amaretto and 19.3 g of potassium carbonate, followed by stirring at 100°C for 1 hour. The reaction liquid was cooled to room temperature and then was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate=80:20), receiving of 34.6 g of N-(3-chloro-2-were)-N-[(4-were)sulfonyl]ethylglycine.

Reference example 3

35,8 g of N-(3-chloro-2-were)-N-[(4-were)sulfonyl]ethylglycine was dissolved in 157 ml of ethanol and 157 ml of 1,4-dioxane was added 157 ml of 1 M aqueous sodium hydroxide solution, followed by stirring at 60°C over night. The reaction liquid was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in water, acidified by adding 1 M hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining of 29.3 g of N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycine.

Reference example 4

7,42 g of 4-methoxybenzylamine was dissolved in 70 ml of methylene chloride and at -10°C was added the solution (10 ml) of 23.2 g of bromoacetamide in methylene chloride. To the reaction liquid was added dropwise a solution (10 ml) and 8.0 ml of triethylamine in methylene chloride at 0°C, followed by stirring at room temperature for 30 minutes. To the reaction liquid under ice cooling was added water, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 90:10 to 0:100)to give the product, which was recrystallized from ethyl acetate, getting 6.11 g of 2-bromo-N-(4-methoxybenzyl)ndimethylacetamide.

Reference example 5

3,93 g of 3-chloro-2-methylaniline was dissolved in 10 ml of DMF and was added to 2.00 g of potassium carbonate, followed by the addition in portions over 1 hour 3.55 g of 2-bromo-N-(4-methoxybenzyl)ndimethylacetamide. The mixture was stirred at room temperature over night and was added to ice water, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 70:30 to 30:70), receiving 2,89 g N2-(3-chloro-2-methylp the Nile)-N-(4-methoxybenzyl)glycinamide.

Reference example 6

to 1.00 g of 3-chloro-2-methylaniline was dissolved in 10 ml hexamethylphosphoramide and added successively of 1.80 g of sodium bicarbonate and 1.19 g of methyl-3-bromopropionate, followed by stirring at room temperature for 4 hours. To the reaction liquid was added water, followed by extraction simple diisopropyl ether. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 95:5 to 85:25), getting to 0.92 g of N-(3-chloro-2-were)methyl-β-alanine.

Reference example 7

0,92 g of N-(3-chloro-2-were)methyl-β-alanine was dissolved in 5 ml of pyridine and cooled with ice was added 1.19 g of p-toluensulfonate, followed by stirring at room temperature over night. To the reaction liquid was added water, followed by extraction simple diisopropyl ether. The organic layer washed with 1 M hydrochloric acid, saturated salt solution and saturated aqueous sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silicagel is e (hexane:ethyl acetate = 90:10 to 70:30), getting to 0.92 g of N-(3-chloro-2-were)-N-[(4-were)sulfonyl]-methyl-β-alanine.

Reference example 8

652 mg of 4-{[(3-chloro-2-were)amino]sulfonyl}benzoic acid was dissolved in 10.0 ml THF in an argon atmosphere was added to 6.00 ml of 1 M borane-THF, followed by stirring at room temperature for 4 hours. To the reaction liquid was added to 1.00 ml of a mixed solution of water-acetic acid (1:1) was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, getting 467 mg of N-(3-chloro-2-were)-4-(hydroxymethyl)benzosulfimide.

Reference example 9

830 mg of 4-cyano-2-methylcarbamate was dissolved in 20,0 ml of ethanol and 20.0 ml of aqueous ammonia was added 160 mg of Raney Nickel, followed by stirring at room temperature for 4 hours in hydrogen atmosphere. The reaction liquid was filtered through celite, the filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform:methanol=10:1)to give 410 mg of 4-(aminomethyl)pyridine-2-carboxamide.

Reference example 10

20,0 g (3 cianfrocca)ethyl acetate races is varali in 100 ml of ethanol and added to 5.58 ml of acetic acid and of 4.00 g of 10% Pd-C (Kawaken, type of AD, the water content 54%), followed by stirring at room temperature overnight in a hydrogen atmosphere. The reaction liquid was filtered through celite, the filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform:methanol=10:1). The obtained product was dissolved in ethyl acetate and was added 10.0 ml of 4 M solution of hydrogen chloride/ethyl acetate, followed by stirring at room temperature for 1 hour. The precipitated crystal was collected by filtration, washed with ethyl acetate and dried under reduced pressure, obtaining of 6.49 g of the hydrochloride [3-(aminomethyl)phenoxy]ethyl acetate.

Reference example 11

To a mixture of 41 mg of copper iodide, 1,82 g tribalista, 38 mg of N,N'-dimethylethylenediamine, and 1.00 g of 1-(4-iodophenyl)of methylamine and 510 mg of 2-piperidone added 4,29 ml of toluene, followed by stirring at 80°C overnight in an argon atmosphere. The reaction liquid was filtered through celite, the filtrate was then concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform:methanol=10:1)to give 552 mg of 1-[4-(aminomethyl)phenyl]piperidine-2-it.

Reference example 12

to 5.00 g of 4-fluoro-3-methylbenzoic acid was dissolved in 100 ml of ethanol and added at 2.59 ml of concentrated sulfuric acid, with the settlement of edusim by heating under reflux over night. The reaction liquid was cooled to room temperature, then concentrated under reduced pressure and the obtained residue was podlachian (pH=8) by addition of an aqueous saturated solution of sodium bicarbonate under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, getting 5,86 g of 4-fluoro-3-ethylmethylamino.

Reference example 13

3.00 g of 4-fluoro-3-ethylmethylamino was dissolved in a 50.0 ml of carbon tetrachloride was added and 4.40 g of N-bromosuccinimide and 1.35 g of 2,2'-azobisisobutyronitrile, followed by heating under reflux for 4 hours. The reaction liquid was cooled to room temperature, then concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate=7:3)to give 1.73 g of 3-(methyl bromide)-4-foretelleth.

Reference example 14

1.56 g of di-tert-butylmethacrylate was dissolved in 20,0 ml of DMF was added under ice cooling 804 mg of tert-butoxide potassium, followed by stirring at room temperature for 1 hour. To the reaction liquid was added dropwise a solution (10.0 ml) 1.70 g of 3-(methyl bromide)-4-foretelleth in DMF, followed by peremeci what W at room temperature over night. The reaction liquid was poured into water, followed by extraction with ethyl acetate, the organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining at 2.59 g of 3-{[bis(tert-butoxycarbonyl)amino]methyl}-4-fermenting acid.

Reference example 15

2,59 g of 3-{[bis(tert-butoxycarbonyl)amino]methyl}-4-fermenting acid was dissolved in 10.0 ml of ethyl acetate was added 10.0 ml of 4 M solution of hydrogen chloride/ethyl acetate, followed by stirring at room temperature for 4 hours. The reaction liquid was concentrated under reduced pressure and the obtained residue was led by addition of ethyl acetate and hexane, obtaining 2,59 g of the hydrochloride of 3-(aminomethyl)-4-foretelleth.

Reference example 16

374 mg of 60% sodium hydride suspended in 20,0 ml dimethoxyethane and at -5°C was added dropwise at 1.91 g diethylphosphonoacetate, followed by stirring at room temperature for 10 minutes. To the reaction liquid was added dropwise a solution of (3-formylmethyl)tert-BUTYLCARBAMATE in dimethoxyethane (5,00 ml), followed by stirring at 60°C for 4 hours. The reaction liquid was cooled to room temperature, followed by addition of water and extraction with ethyl acetate. The organic layer is amywali saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining 3-{[(tert-butoxycarbonyl)amino]methyl}ethylcinnamate. It was dissolved in 5,00 ml of ethyl acetate was added 8,50 ml of 4 M solution of hydrogen chloride/ethyl acetate, followed by stirring at room temperature for 6 hours. The precipitate was collected by filtration, washed with ethyl acetate and then dried under reduced pressure, getting 1,71 g of the hydrochloride of 3-(aminomethyl)ethylcinnamate.

Reference example 17

779 mg of 3-(aminomethyl)ethylcinnamate was dissolved in 5,00 ml of ethanol and was added 80 mg of 10% Pd-C (Kawaken, type AD), followed by stirring at room temperature for 3 hours in hydrogen atmosphere. The reaction liquid was filtered through celite and the filtrate was concentrated under reduced pressure, getting 773 mg of 3-[3-(aminomethyl)phenyl]ethylpropylamine.

Reference example 18

670 mg 5-formyl-1-methyl-1H-pyrrol-2-methylcarbamate was dissolved in 10.0 ml THF and at -20°C was added 303 mg sodium borohydride, followed by stirring at -20°C for 30 minutes and then at 0°C for another 1 hour. To the reaction liquid was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution and then dried over betwo the major sodium sulfate. The solvent is evaporated under reduced pressure, getting 592 mg of 5-(hydroxymethyl)-1-methyl-1H-pyrrol-2-methylcarbamate.

Reference example 19

590 mg of 5-(hydroxymethyl)-1-methyl-1H-pyrrol-2-methylcarbamate, 770 mg phthalimide and 1.83 g of triphenylphosphine was dissolved in 10.0 ml THF was added under ice cooling to 2.75 ml of diethylazodicarboxylate, followed by stirring at room temperature over night. The reaction liquid was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 3:1 to 1:1)to give 650 mg of 5-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]-1-methyl-1H-pyrrol-2-methylcarbamate.

Reference example 20

650 mg of 5-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]-1-methyl-1H-pyrrol-2-methylcarbamate was dissolved in 20,0 ml of methanol and was added 109 mg of hydrazine monohydrate, followed by stirring at room temperature over night. The reaction liquid was concentrated under reduced pressure, the obtained residue was added chloroform was filtered and the insoluble substance. Then the filtrate was concentrated under reduced pressure, getting 294 mg of 5-(aminomethyl)-1-methyl-1H-pyrrol-2-methylcarbamate.

Reference example 21

a 4.86 g of 5-(hydroxymethyl)thiophene-3-methylcarbazole was dissolved in a 50.0 ml dichloromethane and EXT is ulali under ice cooling 4,12 ml of thionyl chloride, followed by stirring at room temperature for 15 hours. The reaction liquid was concentrated under reduced pressure, to the obtained residue were added ethyl acetate and then washed with a saturated aqueous solution of sodium bicarbonate and a saturated solution of salt. The residue was dried over anhydrous magnesium sulfate and then the solvent evaporated, receiving of 4.90 g of 5-(chloromethyl)thiophene-3-methylcarbazole.

Reference example 22

3.57 g of 3-cyanophora was dissolved in 60,0 ml of acetonitrile and added 5,81 ml of 2-bromo-2-methylethylamine and 14.6 g of cesium carbonate, followed by heating under reflux over night. The reaction liquid was cooled to room temperature, followed by addition of water and extraction with ethyl acetate. The organic layer was washed with a saturated solution of salt. It was dried over anhydrous magnesium sulfate, the solvent evaporated and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=9:1)to give 6.75 g of 2-(3-cianfrocca)-2-methylethylamine.

Reference example 96

2.50 g of 3-hydroxybenzaldehyde, 2.77 g of methyl L-(-)-lactate and 6,44 g of triphenylphosphine was dissolved in 25,0 ml of THF was added under ice cooling of 22.2 ml of a 2.2 M solution of diethylazodicarboxylate/toluene, followed by stirring at room temperature over night. To implement the operating liquid was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 7:3 to 1:1), obtaining a rate of 1.67 g of (2R)-2-(3-formylphenoxy)methylpropionate. The obtained (2R)-2-(3-formylphenoxy)methylpropionate was dissolved in 33.3 ml of methanol was added under ice cooling 394 mg of sodium borohydride, followed by stirring for 30 minutes. To the reaction liquid were added ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, getting 1.68 g of (2R)-2-[3-(hydroxymethyl)phenoxy]methylpropionate.

Reference example 97

300 mg of (2R)-2-[3-(hydroxymethyl)phenoxy]methylpropionate, 465 mg of di-tert-butylmethacrylate and 543 mg of triphenylphosphine was dissolved in of 3.00 ml of toluene was added under ice cooling 445 mg of diisopropylcarbodiimide, followed by stirring at room temperature over night. The reaction liquid was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = the t 95:5 to 0:100), getting 584 mg (2R)-2-(3-{[bis(tert-butoxycarbonyl)amino]methyl}phenoxy)methylpropionate.

Compounds according to the reference examples 1-104, shown below in tables 3-10, was obtained in the same manner as in the methods according to the reference examples 1-22, 96 and 97, using in each case the corresponding parent compound. Furthermore, patterns, methods of synthesis and physicochemical data of the compounds according to the reference examples are shown in tables 3-10.

Preparative example 1

707 mg of N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycine was dissolved in 8,00 ml DMF and added 302 mg of 4-methoxybenzylamine, 324 mg of HOBt and 460 mg of WSC, followed by stirring at room temperature over night. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate=4:1), receiving 881 mg of N2-(3-chloro-2-were)-N-(4-methoxybenzyl)-N2-[(4-were)sulfonyl]glycinamide.

Preparative example 2

449 mg of N-(3-chloro-2-were)-4-forbindelsesfaneblad was dissolved in of 3.00 ml of DMF and was added 387 mg of 2-bromo-N-(4-methoxybenzyl)ndimethylacetamide and 207 mg of potassium carbonate, with the following stirring at room temperature over night. To the reaction liquid was added an aqueous solution of sodium bicarbonate, followed by extraction with chloroform, the organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate)to give the product, which was led from a mixture of hexane/ethyl acetate, getting 466 mg of N2-(3-chloro-2-were)-N-(4-methoxybenzyl)-N2-[(4-forfinal)sulfonyl]glycinamide.

Preparative example 3

200 mg of N2-(3-chloro-2-were)-N-(4-methoxybenzyl)glycinamide was dissolved in 2.0 ml of pyridine and the solution was added (2.0 ml) of 200 mg 4-hydroxybenzenesulfonate in dichloroethane, followed by stirring at 80°C during the night. The reaction liquid was concentrated under reduced pressure, to the residue was added water, followed by extraction with ethyl acetate, the organic layer washed with 1 M hydrochloric acid and water and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 70:30 to 30:70), was further purified column chromatography on silica gel (chloroform:methanol = 100:0 to 97:3) and obtained estato who had led from simple diisopropyl ether, getting 68 mg of N2-(3-chloro-2-were)-N2-[(4-hydroxyphenyl)sulfonyl]-N-(4-methoxybenzyl)glycinamide.

Preparative example 4

668 mg of N-[4-(benzyloxy)benzyl]-N2-(3-chloro-2-were)-N2-[(4-were)sulfonyl]glycinamide was dissolved in 5,00 ml of methanol and was added 2.00 ml of THF and 70 mg of 10% Pd-C (Kawaken, AD type, water content 54%), followed by stirring at room temperature for 6.5 hours in a hydrogen atmosphere. The reaction liquid was filtered through celite, the filtrate was evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 50:50 to 30:70)to give the product, which was recrystallized from a mixture of ethanol/water, getting 373 mg of N2-(3-chloro-2-were)-N-(4-hydroxybenzyl)-N2-[(4-were)sulfonyl]glycinamide.

Preparative example 5

300 mg of 4-[((3-chloro-2-were){2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoic acid was dissolved in 5,00 ml of THF and was added 340 mg of ethylchloride and 326 mg of triethylamine, followed by stirring at room temperature for 1 hour. To the reaction liquid for 30 minutes was added dropwise an aqueous solution (0,80 ml) 360 mg sodium borohydride, followed by stirring at room temperature for 2 hours. The reaction liquid was acidified d is the addition of 8.0 ml of 1 M hydrochloric acid, then was extracted with a mixed solvent of chloroform/methanol (5/1) and the organic layer was dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform:methanol = 100:0 to 90:10)to give the product, which was led from simple diisopropyl ether, receiving 118 mg of N2-(3-chloro-2-were)-N2-{[4-(hydroxymethyl)phenyl]sulfonyl}-N-(4-methoxybenzyl)glycinamide.

Preparative example 6

330 mg of N2-(3-chloro-2-were)-N2-[(4-were)sulfonyl]-N-(pyridine-4-ylmethyl)glycinamide was dissolved in 5.0 ml of methylene chloride was added 166 mg of m-chloroperbenzoic acid, followed by stirring at room temperature for 4 hours. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution and then was extracted with chloroform. The organic layer was concentrated under reduced pressure, the obtained residue was purified column chromatography on silica gel (chloroform:methanol=99:1) and the obtained residue was led from a mixture of hexane/ethyl acetate, getting 179 mg of N2-(3-chloro-2-were)-N2-[(4-were)sulfonyl]-N-[(1-oxidability-4-yl)methyl]glycinamide.

Preparative example 25

220 mg of 4-{[(3-chloro-2-were)amino]sulfonyl}motive is souta was dissolved in 1,10 ml of DMF and was added 168 mg of 2-bromo-N-(4-methoxybenzyl)ndimethylacetamide and 100 mg of potassium carbonate, followed by stirring at room temperature for 7 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate, the organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 7:3 to 4:6)to give 270 mg of 4-[((3-chloro-2-were)-{2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]methylbenzoate. Obtained 4-[((3-chloro-2-were)-{2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]methylbenzoate was dissolved in 2.00 ml of methanol and 1.50 ml of THF and was added to 1.05 ml of 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 2 days. The reaction liquid was acidified by adding 1 M hydrochloric acid, then was extracted with a mixed solvent of chloroform/methanol (5/1) and the organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified by chromatography on silica gel (chloroform:methanol = 100:0 to 90:10)to give 204 mg of 4-[((3-chloro-2-were){2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoic acid.

Preparative example 33

100 mg of N2-(3-chloro-2-were-N-[3-(hydroxymethyl)benzyl]-N 2-[(4-were)sulfonyl]glycinamide received 240 mg of 3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid in the same manner as in preparative example 5.

Example 1

308 mg of 4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]methylbenzoate was dissolved in 5,00 ml of methanol and 2.00 ml of THF and added to 2.40 ml of 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature over night. Then to the reaction liquid was added to 3.00 ml of THF, followed by stirring at 60°C for 4 hours. The reaction liquid was cooled with ice, acidified by adding 2,60 ml of 1 M hydrochloric acid, then was extracted with a mixed solvent of chloroform/methanol (5/1) and the organic layer was dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform:methanol = 100:0 to 90:10), receiving 601 mg 4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid.

Example 2

185 mg of 4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid, 25 mg of ammonium chloride and 62 mg of HOBt was dissolved in 2.00 ml of DMF and was added 78 mg of WSC, followed by stirring at room temperature during the night. To the reaction liquid was added water, followed by extraction with ethyl acetate, the organic layer was washed with water, aqueous sodium hydrogen carbonate solution and water and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 20:80 to 0:100)to give the product, which was recrystallized from a mixture of ethanol/water (95:5)to give 89 mg of amide 4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid.

Example 3

300 mg of N2-(3-chloro-2-were)-N-(4-hydroxybenzyl)-N2-[(4-were)sulfonyl]glycinamide was dissolved in 2.00 ml of DMF and was added 110 mg of potassium carbonate and 133 mg of ethylbromoacetate, followed by stirring at room temperature over night. To the reaction liquid was added water, followed by extraction with ethyl acetate, the organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate = 60:40 to 30:70)to give 370 mg of 4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]Ethylenediamine.

Example 4

182 mg of 3-[({N-(3-chloro-2-methylphe who yl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid was dissolved in 0,50 ml of DMF and was added 75 mg of 1,1'-carbonyldiimidazole, followed by stirring at room temperature for 1 hour. To the reaction liquid was added 40 mg of methanesulfonamide and 66 mg of DBU, followed by stirring at 50°C for 8 hours. The reaction liquid was acidified by the addition of 2.50 ml of 1 M hydrochloric acid, then was extracted with a mixed solvent of chloroform/methanol (5/1) and the organic layer was dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform:methanol = 100:0 to 95:5)to give 207 mg of 3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]-N-(methylsulphonyl)benzamide.

Example 230

404 mg of N2-(3-chloro-2-were)-N-(3-cyanobenzyl)-N2-[(4-were)sulfonyl]glycinamide was dissolved in 8,08 ml of ethanol and was added 120 mg of hydroxylamine hydrochloride and 0,241 ml of triethylamine, followed by heating under reflux for 6 hours. The reaction liquid was cooled to room temperature, then was extracted with ethyl acetate, the organic layer was washed with water and saturated salt solution and then concentrated under reduced pressure. The obtained residue was dissolved in 5,00 ml of DMF was added under ice cooling and 88 mg of pyridine and 167 mg of 2-ethylhexylcarbonate, with subsequent paramashiva is receiving at 5°C for 1 hour. The reaction liquid was diluted with water, then was extracted with ethyl acetate, the organic layer was washed with water and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was dissolved in 8,54 ml of xylene, followed by heating under reflux for 13 hours. The reaction liquid was concentrated under reduced pressure, the obtained residue was added chloroform and hexane and the precipitate was collected by filtration. The resulting product was recrystallized from a mixture of ethanol/simple diisopropyl ether, receiving 298 mg of N2-(3-chloro-2-were)-N2-[(4-were)sulfonyl]-N-[3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]glycinamide.

Example 231

300 mg of N2-(3-chloro-2-were)-N-(3-cyanobenzyl)-N2-[(4-were)sulfonyl]glycinamide was dissolved in 5,00 ml of DMF and was added 125 mg of sodium azide and 103 mg of ammonium chloride, followed by stirring at 100°C for 6 hours. The reaction liquid was concentrated under reduced pressure and the obtained residue was added water, followed by extraction with chloroform. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting mod is to purified preparative thin-layer chromatography (chloroform:methanol=80:20). The resulting product was recrystallized from a mixture of ethanol/simple diisopropyl ether, getting to 82.6 mg (N2-(3-chloro-2-were)-N2-[(4-were)sulfonyl]-N-[3-(2H-tetrazol-5-yl)benzyl]glycinamide.

Compounds of preparative examples 1-122 shown in tables 11-22, and the compounds of examples 1-231 shown in table 23-45, was obtained in the same manner as in preparative methods of examples 1-6, 25 and 33 and examples 1-4, 230 and 231, using in each case the corresponding parent compound. In addition, methods of preparation and physicochemical data of the compounds according to preparative examples are shown in tables 46-48, and methods of preparation and physicochemical data of the compounds according to the examples shown in tables 49-56.

AMR: 2,28 (3H, s)to 2.41 (3H, s), 3,7 (2H, s), of 3.73 (3H, s)to 4.01 (2H, d, J=5,GC), to 4.46 (2H, s), 6,85 (2H, d, J=8,Hz), 7,03 (2H, d, J=8,Hz), 7,12-7,14 (1H, m), 7,2 (1H, d, J=6,8gts), was 7.36-7,37 (3H, m), 7,73 (2H, d, J=8,2 Hz), 8,08 (1H, t, J=5,8gts)
Table 48
PreDat
1AMR: 2,31 (3H, s), 2,42 (3H, s), 3,71 (3H, s), 4,05-4,32 (4H, m), 6,72 (1H, d, J=8,1 Hz), is 6.78 (2H, d, J=8,2 Hz), 6,91 (2H, d,J=8,1 Hz), 7,13 (1H, t, J=8,1 Hz), 7,38-of 7.48 (3H, m), 7,54 (2H, d, J=7,Hz), with 8.33 (1H, USS)
2 AMR: 2,31 (3H, s), 3,71 (3H, s), 4,1 (2H, d, J=4,0 Hz), 4,17 (1H, d, J=16hz), 4,27 (1H, d, J=16hz), 6,76-6,8 (3H, m), 6,93 (2H, d, J=8,0Hz), to 7.15 (1H, t, J=8,0 Hz), 7,43-of 7.48 (3H, m), 7,72-7,76 (2H,, m), 8,35 (1H, t, J=6,0 Hz)
3AMR: 2,32 (3H, s), 3,70 (3H, s), was 4.02 (1H, d, J=15,4 Hz), 4,07-to 4.14 (2H, m), 4,25 (1H, d, J=15 and 3 Hz), 6,72 (1H, d, J=7,GC), is 6.78 (2H, d, J=8,Hz), 6,89-6,92 (4H, m), 7,13 (1H, t, J=8,0 Hz), 7,43 (1H, d, J=8,0 Hz), 7,47 (2H, d, J=8,Hz), 8,31 (1H, t, J=5,8gts), of 10.58 (1H, s)
4AMR: 2,28 (3H, s), 2,42 (3H, s), as 4.02-Android 4.04 (2H, m), 4,08 (1H, d, J=15,5 Hz), 4.26 deaths (1H, d, J=15,4 Hz), is 6.61 (2H, d, J=8,5Hz), 6,72 (1H, d, J=7,1Hz), is 6.78 (2H, d, J=8,Hz), 7,13 (1H, t, J=8,0Hz), 7,40-7,42 (3H, m), 7,54 (2H, d, J=8,3 Hz), compared to 8.26 (1H, t, J=5,8gts), a 9.25 (1H, s)
5AMR: 2,31 (3H, s), 3,71 (3H, s), 4,08-4,12 (3H, m), 4,28 (1H, d, J=15,4 Hz), to 4.62 (2H, d, J=5,GC), vs. 5.47 (1H, t, J=5,GC), 6,72 (1H, d, J=7,8gts), is 6.78 (2H, d, J=8,Hz), 6,91 (2H, d, J=8,5Hz), 7,13 (1H, t, J=8,0Hz), was 7.45 (1H, d, J=7,Hz), 7,53 (2H, d, J=8,4 Hz), a 7.62 (2H, d, J=8,3 Hz), a 8.34 (1H,t, J=5.8 Hz)
6AMR: to 2.29 (3H, s), 2,42 (3H, s), 4,1-4,16 (3H, m), 4,32 (1H, d, J=8,0 Hz), 6,74 (1H, d, J=4,0 Hz), 6,98 (2H, d, J=3,5 Hz), to 7.15 (1H, t, J=4,0 Hz), 7,41-7,46 (3H, m), 7,54 (2H, d, J=4,1 Hz), 8,06 (2H, d, J=3,5 Hz), 8,54 (1H, t, J=3 Hz)
15AMR: to 2.29 (3H, s), 2,42 (3H, s), 4,19 (1H, d, J=15,GC), 4,25-4,27 (2H, m), 4,37 (1H, d, J=15,GC), 6,76 (1H, d, J=7,Hz), of 6.96 (1H, d, J=5,2Hz), to 7.15 (1H, t, J=8,1 Hz), 7,42 (2H, d, J=8,1 Hz), 7,46 (1H, d, J=8,3 Hz), 7,56 (2H, d, J=8,3 Hz), 8,61-8,66 (2H, m), 9,04 (1H, d, J=1,4 Hz)
19

Table 53
Etc.Data
1AMR: 2,31 (3H, s), 2,42 (3H, s), of 4.12 (1H, d, J=15,4 Hz), 4,18-4,19 (2H, m)to 4.33 (1H, d, J=15,4 Hz), was 6.73 (1H, d, J=7,8gts), 7,06 (2H, d, J=8,2Hz), to 7.15 (1H, t, J=8,0 Hz), 7,42 (2H, d, J=8,2Hz), was 7.45 (1H, d, J=8,2 Hz), 7,55 (2H, d, J=8,3 Hz), 7,79 (2H, d, J=8,2 Hz), and 8.50 (1H, t, J=6,0 Hz), 12,74(1H, USS)
2AMR: 2,31 (3H, s), 2,42 (3H, s), 4,12-to 4.15 (4H, m), of 6.75 (1H, d, J=7,Hz), 7,05 (2H, d, J=8,2 Hz), 7,14 (1H, t, J=8,0 Hz), and 7.3 (1H, USS), 7,41 (2H, d, J=8,2 Hz), 7,46 (1H, d, J=7,8gts), 7,55 (2H,, d, J=8,3 Hz), 7,73 (2H, d, J=8,2 Hz), and 7.9 (1H, USS), of 8.47 (1H, t, J=5,GC)
4AMR: 2,30 (3H, s), 2,42 (3H, s)to 3.36 (3H, s), 4,13 (1H, d, J=15,GC), to 4.23 (2H, d, J=5,GC), 4,30 (1H, d, J=15,GC), 6,74 (1H, d, J=8,0 Hz), 7,12 (1H, t, J=8,0 Hz), 7,2 (1H, d, J=7,Hz)that was 7.36 (1H, d, J=7,Hz), 7,39-7,44 (3H, m), 7,54 (2H, d, J=8,3 Hz), 7,72 (1H, s), to 7.77 (1H, d, J=7,8gts), and 8.5 (1H, t, J=5,GC), 12,11 (1H, USS)
5AMR: 2,32 (3H, s)to 2.41 (3H, s), a 4.03-Android 4.04 (4H, m), 4.26 deaths (1H, d, J=15,4 Hz), 4,37 (1H, d, J=3,8gts), of 6.65 (2H, d, J=8,Hz), 6,72 (1H, d, J=7,8gts), 6,83 (2H, d, J=8,5Hz), 7,12 (1H, t, J=8,0 Hz), 7,40-7,42 (3H, m), 7,54 (2H, d, J=8,3 Hz), at 8.36 (1H, t, J=5,GC)
7AMR: 2,30 (3H, s)to 2.41 (3H, s), 4,13 (1H, d, J=15,GC), to 4.23 (2H, d, J=5,GC), the 4.29 (1H, d, J=15,GC), 6,74 (1H, d, J=7,2 Hz), 7,11 (1H, t, J=8,0 Hz), 7,20 (1H, d, J=7,8gts), 7,35 (1H, t, J=7,Hz), 7,39-7,40 (3H, m), 7,54 (2H, d, J=8,4 Hz), of 7.75(1H, s), 7,78 (1H, d, J=7,8gts), 8,49 (1H, t, J=5,GC), 12,93 (1H, USS)
9AMR: 2,30 (1H, s), 4,23-or 4.31 (4H, m), PC 6.82 (2H, d, J=7,8gts), 7,14 (1H, t, J=8,0 Hz), 7,22 (1H, d, J=7,GC), was 7.36 (1H, t, J=7,Hz), 7,44 (1 H, d, J=7,8gts), to 7.67 (4H, USS), of 7.75 (1H, s), 7,79 (1H, d, J=7,8gts), 8,51 (1H,t, J=5,GC), 12,94 (1H, USS)
16AMR: 2,31 (3H, s), 2,42 (3H, s), 4,11-to 4.15 (3H, m), the 4.29 (1H, d, J=15,GC), br4.61 (2H, s), 6,55 (1H, d, J=7,Hz), of 6.68 (1H, s), 6,72 to 6.75 (2H, m), 7,11-to 7.15 (2H, m), 7,4-7,44 (3H, m), 7,55 (2H, d, J=8,2 Hz), and 8.4 (1H, t, J=5,GC), 12,97 (1H, USS)

Table 54
Etc.Data
20AMR: 2,30 (3H, s), 2,42 (3H, s), 3,37 (3H, s), 4,14 (1H, d, J=15,GC), 4,25 (2H, t, J=5,GC), 4,32 (1H, d, J=15,GC), to 6.75 (1H, d, J=7,2 Hz), 7,11 (2H, d, J=8,3 Hz), 7,16 (1H, d, J=8,1 Hz), 7,42 (2H, d, J=8,3 Hz), 7,46 (1H, d, J=7,2 Hz), 7,55 (2H, d, J=8,3 Hz), 7,81 (2H, d, J=8,3 Hz), charged 8.52 (1H, t, J=6,0 Hz), 12,07 (1H, USS)
21AMR: to 2.29 (3H, s), 4,24 (2H, d, J=5,GC), 4,30 (H, d, J=6,8gts), 6,83 (1H, d, J=8,0 Hz), 7,14 (1H, t, J=8,0 Hz), 7,19-7,29 (1H, m), 7,37 (1H, t, J=8,0 Hz), 7,46 (1H, d, J=8,0 Hz), 7,70-of 7.90 (4H, m), 8,03-of 8.15 (2H, m), 8,46-8,58 (1H, m), 12,94 (1H, USS)
22AMR: to 2.29 (3H, s)to 4.23 (2H, d, J=5,GC), 4,30 (2H, d, J=4,0 Hz), at 6.84 (1H, d, J=8,0Hz), to 7.15 (1H, t, J=8,0 Hz), 7,22 (1H, d, J=7,GC), was 7.36 (1H, t, J=8,0 Hz), 7,46 (1H, d, J=8,0 Hz), 7,71-of 7.82 (2H, m), 7,88 (2H, d, J=8,4 Hz), 7,98 (2H, d, J=8,4 Hz), of 8.47-8,58 (1H, m)
24AMR: 2,30 (3H, s), 2,42 (3H, s), 3,83 (3H, s), 4.09 to of 4.35 (4H, m), of 6.73 (1H, d, J=8,0 Hz), and 7.1 (2H, d, J=8,0Hz), to 7.15 (1H, t, J=8,2 Hz), 7,41-7,46 (3H, m), 7,55 (2H, d, J=8,0 Hz), 7,81 (2H, d, J=8,0 Hz), 8,53 (1H, t, J=5,GC)
26AMR: 2,31 (3H, s), 2,42 (3H, s), 4,11-to 4.33 (4H, m), 6,53 (1H, t, J=2,0Hz), to 6.75 (1H, d, J=7,8gts), 7,11 (2H, d, J=8,5Hz), 7,16 (1H, d, J=8,0 Hz), 7,41-7,46 (3H, m), 7,56 (2H, d, J=8,2 Hz), 7.68 per-7,72 (3H, m), 8,44-8,46 (2H, m)
28AMR: 2,30 (3H, s), 2,42 (3H, s)to 3.33 (3H, s)to 4.15 (1H, d, J=15,8gts), 4,25 (2H, d, J=5,8gts), 4,32 (1H, d, J=15,GS), only 6.64 (1H, d, J=8,0 Hz), 6,76 (1H, d, J=8,0Hz), to 6.95 (1H, s), 7,14 (1H, t, J=8,0 Hz), 7,41-7,47 (4H, m), 7,55 (2H, d, J=8,2 Hz), charged 8.52 (1H, t, J=6,0 Hz), of 11.29 (1H, USS)
37AMR: 2,40 (3H, s), 4,14 (1H, USS), 4,25 (2H, d, J=6,0 Hz), 4,50 (1H, USS), 7,22-the 7.43 (6H, m), 7,54-to 7.68 (3H, m), 7,73-7,83 (2H, m), 8,48-8,58 (1H, m), 12,95 (1H, USS)
38AMR: 2,39 (3H, s), 3,71 (3H, s)to 4.23 (2H, d, J=6,0 Hz), 4,32 (2H, s), 7,05 (1H, t, J=8.0 Hz), 7,11 (1H, DD, J=8,0 Hz, 2,0 Hz), 7,26 (1H, d, J=7,Hz), 7,32-7,41 (3H, m), 7,46 (1H, is d, J=8,0 Hz, 2,0 Hz), 7,66 (2H, d, J=8,4 Hz), of 7.75 (1H, USS), 7,79 (1H, d, J=8,0 Hz), 8,45-8,58 (1H, m), 12,93 (1H, USS)

Table 55
Etc.Data
39AMR: of 2.33 (3H, s)to 2.41 (3H, s), 4,07 is 4.35 (4H, m), 6,77 (1H, d, J=7,Hz),? 7.04 baby mortality (1H, t, J=8,0 Hz), 7,19 (1H, d, J=8,0 Hz), 7,35 (1H, t, J=8,0 Hz), 7,40 (2H, d, J=8,0 Hz), 7,53 (2H, d, J=8,0Hz), 7,58 (1H, d, J=8,0 Hz), 7,74 (1H, USS), 7,78 (1H, d, J=8,0Hz), to 8.41-8,56 (1H, m), 12,93 (1H, USS)
40AMR: to 1.16 (3H, t, J=8,0Hz), is 2.41 (3H, s), 2,82 (2H, d, J=8,0 Hz), 4,14-the 4.29 (4H, m), 6,76 (1H, DD, J=8,0 Hz, 0,8gts), 7,11 (1H, t, J=8,0 Hz), 7,21 (1H, d, J=8,0 Hz), 7,33-7,44 (4H, m), 7,56 (2H, d, J=8,0 Hz), 7,72-of 7.82 (2H, m), 8,46-8,55 (1H, m), 12,93 (1H, USS)
42AMR: to 1.21 (3H, t, J=7,Hz), of 2.28 (3H, s), 2,71 (2H, q, J=7,Hz), 4,07 is 4.35 (4H, m), of 6.75 (1H, d, J=8,0 Hz), 7,11 (1H, t, J=8,0 Hz), 7,19 (1H, d, J=8,0 Hz), 7,35 (1H, t, J=8,0 Hz), 7,39-7,47 (3H, m), 7,56 (2H, d, J=8,0 Hz), 7,74 (1H, USS), 7,78 (1H, d, J=8,0 Hz), 8,44-8,55 (1H, m), 12,93 (1H, USS)
49AMR: 2,30 (3H, s)to 2.41 (3H, s), 4,11 (1H, d, J=15,Hz), 4.26 deaths (1H, d, J=15,GC), 4,32 (2H, d, J=5,8gts), to 6.75 (1H, d, J=7,1Hz), 7,10 (1H, t, J=7,Hz), 7,17 (1H, d, J=1.0 Hz), 7,38-7,42 (3H, m), 7,54 (2H, d, J=8,3 Hz), with 8.05 (1H, d, J=1,4 Hz), to 8.57 (1H, t, J=5,8gts), 12,50-12,70 (1H, ush.)
50AMR: 2,30 (3H, s), 2,42 (3H, s), 4,07-4,37 (4H, m), 6,47 (1H, d, J=16,0Hz), to 6.75 (1H, d, J=8,0G is), 7,01 (1H, d, J=8,0 Hz), 7,13 (1H, t, J=8,0 Hz), 7,27 (1H, t, J=8,0 Hz), 7,34-to 7.59 (8H, m), 8,39-8,49 (1H, m), 12,42 (1H, USS)
51AMR: 2,31 (3H, s)to 2.41 (3H, s), 2,47 (2H, t, J=8,0Hz), is 2.74 (2H, t, J=8,0 Hz), 4,05-4,34 (4H, m), 6,74 (1H, d, J=8,0 Hz), 6,78 (1H, d, J=8,0 Hz), 6,92 (1H, s), 7,05 (1H, d, J=8,0 Hz), 7,13 (2H,, t, J=8,0Hz), was 7.36-7,47 (3H, m), 7,55 (2H, d, J=8,0 Hz), 8,33-8,43 (1H, m), 12,12 (1H,s)
74AMR: to 1.16 (3H, t, J=7,GC), is 2.41 (3H, s)2,84 (2H, q, J=7,Hz), 4,11-or 4.31 (4H, m), 6,47 (1H, d, J=16,0 Hz), 6,76 (1H, d, J=8,0 Hz), 7,02 (1H, d, J=8,0 Hz), 7,12 (1H, t, J=8,0 Hz), 7,28 (1H, t, J=8,0Hz), was 7.36-7,46 (4H, m), 7,51 (1H, d, J=16,0 Hz), 7,52 (1H, d, J=8,0 Hz), EUR 7.57 (2H, d, J=8,0 Hz), scored 8.38-charged 8.52 (1H, m), 12,40 (1H, USS)

Table 56
Etc.Data
78AMR: 2,30 (3H, s), is 4.21 (2H, d, J=5,GC), or 4.31 (2H, s), 6,46 (1H, d, J=16,0Hz), at 6.84 (1H, d, J=8,0 Hz),? 7.04 baby mortality (1H, d, J=8,0 Hz), 7,17 (1H, t, J=8,0 Hz), 7,29 (1H, t, J=8,0 Hz), 7,38 (1H, s), 7,43-EUR 7.57 (3H, m), 7,89 (2H, d, J=8,4 Hz), to 7.99 (2H, d, J=8,4 Hz), 8,44-and 8.50 (1H, m)
79AMR: 2,31 (3H, s), 4,17 is 4.35 (4H, m), 6,46 (1H, d, J=16,0 Hz), PC 6.82 (1H, d, J=8,0 Hz), 7,03 (1H, d, J=8,0 Hz), 7,16 (1H, t, J=8,0 Hz), 7,28 (1H, t, J=8,0 Hz), 7,38 (1H, s), 7,43-7,56 (3H, m), 7.68 per (4H, s), to 8.41-8,51 (1H, m)
82AMR: 2,32 (3H, s), 2,47 (2H, t, J=8,0Hz), is 2.74 (2H, t, J=8,0 Hz), 4,15 (2H, d, J=5,GC), 4,24 is 4.36 (2H, m), 6,77-6,87 (2H, m), 6,93 (1, C)7,06 (1H, d, J=8,0 Hz), 7,11-7,21 (2H, m), 7,47 (2H, d, J=8,0Hz), of 7.90 (2H, d, J=8,0Hz), to 7.99 (2H, d, J=8,0 Hz), at 8.36-to 8.45 (1H, m), 12,12 (1H, s)
85AMR: to 2.25 (3H, s), is 2.40 (3H, s), 4,17-of 4.44 (4H, m), 7,05 (1H, d, J=8,0 Hz), 7,11-to 7.18 (2H, m), 7.23 percent (1H, d, J=8,0 Hz), 7,31 (1H, d, J=12,0Hz), was 7.36 (1H, t, J=8,0 Hz), 7,42 (1H, d, J=8,0 Hz), 7,49 (1H, t, J=8,0 Hz), 7,74 (1H, USS), of 7.75 (1H, s), 7,79 (1H, d, J=8.0 Hz), 8,46-8,55 (1H, m), 12,93 (1H, USS)
114AMR: to 2.29 (3H, s)to 2.41 (3H, s), 4,16-4,34 (4H, m), 6,77 (1H, d, J=7,Hz), 7,12 (1H, t, J=8,0 Hz), 7,39-7,42 (3H, m), 7,53 (2H, d, J=8,4 Hz), 8,63 (1H, s), 8,67 (1H, t,J=6,0 Hz)
116AMR: to 2.29 (3H, s), a 2.45 (3H, s), 4.09 to be 4.29 (4H, m), 6,77 (1H, d, J=8,0 Hz), 7,12 (1H, t, J=7,Hz), 7,31 (1H, s), 7,34-7,49 (3H, m)to 7.50 (1H, s), 7,56 (2H, d, J=7,Hz), 8,42 (1H, t, J=6,0 Hz)
119AMR: the 1.44 (3H, d, J=6,8gts), 2,31 (3H, s), 2,42 (3H, s), 4,10-4,30 (4H, m), 4,65-of 4.67 (1H, m), 6,51 (1H, d, J=7,Hz), 6,61 is 6.67 (2H, m), 6,74 (1H, d, J=8,0 Hz), 7,08-to 7.15 (2H, m), 7,39-7,44 (3H, m), at 7.55 (2H, d, J=8,0 Hz), scored 8.38 (1H, t, J=5,2Hz)
120AMR: a 1.45 (3H, d, J=6,8gts), 2,31 (3H, s), 2,42 (3H, s), 4,11-4,30 (4H, m), 4,66-and 4.68 (1H, m), of 6.52 (1H, d, J=7,2 Hz), 6,61 of 6.68 (2H, m), of 6.75 (1H, d, J=8,0 Hz), 7,08-to 7.15 (2H, m), 7,39-7,44 (3H, m), at 7.55 (1H, d, J=8,0 Hz), scored 8.38 (1H, t, J=5,GC)

INDUSTRIAL APPLICABILITY

Connection sulfonamida according to the present invention or its pharmaceutically acceptable salt has a strong antagonistic activity against Retz is ptor EP1 and thus, can be used as a drug for the treatment of diseases associated with the EP1 receptor, in particular, for the treatment of symptoms of the lower urinary tract.

The sequence listing free text

Number <223> in the following sequence listing describes the "artificial sequence". In particular, the amino acid sequence of SEQ ID NO:1 in the sequence listing is an artificially synthesized sequence of the signal peptide. In addition, the amino acid sequence of SEQ ID NO:2 in the sequence listing is an artificially synthesized sequence FLAG.

1. Connection sulfonamida represented by formula (II-A), or its pharmaceutically acceptable salt:
[Chem. 21]

[in which the symbols have the following meanings:
R10-R12: the same or different represent each a halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or-CN,
R13: R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or-CN,
ring: benzene ring or a 5-6-membered heteroaromatic ring containing 1-2 heteroatoms selected from O, S and N,
R14: R0, halogen or-OR0,
R0: about the be otherness or different, represent each H or lower alkyl,
Y1: a simple link, the lower alkylene, lower albaniles or-O-lower alkylene-, and
Z1: -CO2R0or-CO-NH-SO2-lower alkyl].

2. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound is selected from the following groups:
4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,
3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,
3-[({N-(3-chloro-2-were)-N-[(4-chlorophenyl)sulfonyl]glycyl}amino)methyl]benzoic acid,
3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]venexiana acid,
4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]-N-(methylsulphonyl)benzamid,
3-[({N-(3-chloro-2-were)-N-[(4-cyanophenyl)sulfonyl]glycyl}amino)methyl]benzoic acid,
3-{[(N-(3-chloro-2-were)-N-{[4-(trifluoromethyl)phenyl]sulfonyl}glycyl)amino]methyl}benzoic acid,
4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]-2-methoxy-N-(methylsulphonyl)benzamid,
3-[({N-(2,3-dichlorophenyl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,
3-[({N-(3-chloro-2-methoxyphenyl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,
3-[({N-(3-bromo-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic Ki the lot,
3-[({N-(3-chloro-2-were)-N-[(4-ethylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid,
3-[({N-(3-chloro-2-ethylphenyl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,
3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]cinnamic acid,
3-{3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]phenyl}propionic acid,
5-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]thiophene-3-carboxylic acid,
3-[({N-(3-chloro-2-ethylphenyl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]cinnamic acid,
3-{[(N-(3-chloro-2-were)-N-{[4-(trifluoromethyl)phenyl]sulfonyl}glycyl)amino]methyl}cinnamic acid,
3-[({N-(3-chloro-2-were)-N-[(4-chlorophenyl)sulfonyl]glycyl}amino)methyl]cinnamic acid,
3-(3-{[(N-(3-chloro-2-were)-N-{[4-(trifluoromethyl)phenyl]sulfonyl}glycyl)amino]methyl}phenyl)propionic acid,
3-[({N-(3-chloro-2-were)-N-[(2-fluoro-4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,
2-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]-1,3-oxazole-4-carboxylic acid,
4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]thiophene-2-carboxylic acid,
(2S)-2-{3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]phenoxy}propionic acid and
(2R)-2-{3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}AMI is about)methyl]phenoxy}propionic acid.

3. The compound or its pharmaceutically acceptable salt according to claim 2 where the compound is selected from the following groups:
3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,
3-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]venexiana acid,
4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]-N-(methylsulphonyl)benzamid,
3-[({N-(3-chloro-2-ethylphenyl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]benzoic acid,
3-[({N-(3-chloro-2-ethylphenyl)-N-[(4-were)sulfonyl]glycyl}amino)methyl]cinnamic acid,
4-[({N-(3-chloro-2-were)-N-[(4-were)sulfonyl]glycyl}amino)methyl]thiophene-2-carboxylic acid and
(2R)-2-{3-[({N-(3-chloro-2-were)-N-(4-were)sulfonyl]glycyl}amino)methyl]phenoxy}propionic acid.

4. Pharmaceutical composition having antagonistic activity against receptor ER containing as active ingredient the compound or its pharmaceutically acceptable salt according to claim 1.

5. The pharmaceutical composition according to claim 4, which is a therapeutic tool for the treatment of frequent urination.

6. The pharmaceutical composition according to claim 5, where the cause of these frequent urination is overactive bladder, benign prostatic hyperplasia, contra the round neck of the bladder cystitis or prostatitis.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of cyclohexan-1,4-diamine of the general formula (I): possessing binding property with ORLI receptors and showing homology to opioid μ-, κ- and δ-receptors. Compounds can be used for preparing drugs possessing analgesic effect. In the formula (I) R1 and R2 mean independently of one another (C1-C8)-alkyl, or residues R1 and R2 form in common a ring and mean -CH2-CH2NR6CH2CH2 or -(CH2)3-6 wherein R means (C1-C8)-alkyl; R3 means phenyl, naphthyl or 5-membered sulfur-containing heteroaryl wherein each of them is unsubstituted or monosubstituted with halogen atom, or unsubstituted phenyl added through saturated unsubstituted (C1-C4)-alkyl group; R4 means hydrogen atom (H), saturated (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen (O) or sulfur (S) atom; R means H or (C1-C8)-alkyl either unsubstituted phenyl or phenyl substituted with halogen atom; R5 means (C3-C8)-cycloalkyl, adamantyl, aryl or 5-membered heteroaryl comprising 1-3 heteroatoms chosen from nitrogen, oxygen or sulfur and condensed with one or two benzene rings and wherein each of them is unsubstituted or monosubstituted with a substitute chosen from halogen atom, lower alkyl, lower alkoxy, hydroxy or benzyloxy; or -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12 wherein Y means O or H2; R11 means H, saturated, linear or branched (C1-C7)-alkyl, saturated or unsaturated, linear or branched, mono- or multisubstituted either unsubstituted -C(O)O-(C1-C6)-alkyl; R12 means phenyl or 5-membered heteroaryl comprising 1-3 heteroatoms chosen from nitrogen, oxygen or sulfur condensed with one or two benzene rings each of them is unsubstituted or mono- or multisubstituted and wherein in values R11 and R12 substituted of alkyl, phenyl or heteroaryl are chosen from halogen atom, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or benzyloxy; or R4 and R5 form in common 5-membered nitrogen-containing heterocycle that represents unsaturated, monosubstituted lower alkoxycarbonyl-lower alkyl, halogen atom, or it is unsubstituted and condensed with benzene ring under condition that if R means substituted or unsubstituted phenyl and at least one R1 or R2 means (C1-C8)-alkyl then R4 can't mean alkyl, and R3 and R5 can't form in common heterocycle, or if R3 means unsubstituted phenyl and R1 and R2 mean in common -(CH2)5 then R4 means H or (C1-C8)-alkyl; Y means O, and R5 doesn't mean (C1-C6)-alkyl. Also, invention relates to a method for synthesis of compounds of the formula (I) and a drug.

EFFECT: valuable medicinal properties of compounds.

40 cl, 1 tbl, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-aminocyclohexanol of the general formula (I) being optionally as their physiologically acceptable salts and first of all physiologically compatible acids. In compound of the general formula (I) R1 and R2 mean independently of one another hydrogen atom (H) or (C1-C8)-alkyl that can be saturated or unsaturated but both R1 and R2 can't mean simultaneously H, or residues R1 and R form a ring in common and mean (CH2)3-6; R2 means unsubstituted phenyl or phenyl substituted with halogen atom that is added through saturated or unsaturated, branched or linear (C1-C4)-alkyl group; R4 means heteroaryl chosen from 5-membered heteroaryl wherein heteroatoms are chosen from nitrogen, oxygen or sulfur atoms and each of these atoms is condensed with benzene ring and means unsubstituted or monosubstituted (C1-C8)-alkyl; -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7 wherein R6 represents H; R7 represents phenyl that can be unsubstituted or mono- either multi-substituted with halogen atoms. Also, invention relates to a method for synthesis of compounds of the formula (I) and a medicinal agent based on thereof. Synthesized compounds can be sued for preparing a medicinal agent designated for treatment of pain being first of all acute, visceral, neuropathic or chronic pain, and to a medicinal agent designated for treatment of diseases mediated by function of ORL1-receptor, for example, such as fear state, epilepsy, cardiovascular diseases.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and drug.

10 cl, 1 tbl, 21 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein A means benzene ring optionally substituted with one or more the following groups: -OR2 wherein R2 mean linear or branched (C1-C5)-alkyl; X means -CH=, -CH2-, -N= or -NH-radical; Y means radical -CH2, oxygen or sulfur atom or group -NR7 wherein R7 means hydrogen atom or linear or branched (C1-C5)-alkyl; R1 means hydrogen atom, linear or branched (C1-C5)-alkyl, and to pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition showing anti-diabetic activity. The pharmaceutical composition comprises compound of the general formula (I) as an active component and an inert excipient. Invention provides bicyclic derivatives of guanidine eliciting anti-diabetic activity.

EFFECT: valuable medicinal properties of compounds and composition.

8 cl, 2 tbl, 4 ex

The invention relates to derivatives of 2-phenyl-benzo(b) furan and thiophene, which may be suitable for the treatment of dependent estrogenos diseases, such as prostatic hyperplasia, breast cancer, endometrial cancer, populating infertility and melanoma

The invention relates to the field of organic synthesis and relates to new organic compounds, method of their obtaining for several options and pharmaceutical compositions containing these compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to acyloxyalkylcarbamate prodrugs (±)4-amino-3-(4-chlorophenyl)butanoic acid, to based pharmaceutical compositions and to their application, for treating spasticity or a spasticity symptom, gastroesophageal reflux disease (GERD), drug addiction, alcohol addiction or alcohol abuse, or cough, or vomiting. Acyloxyalkylcarbamate prodrugs represent a compound of formula (V) or its pharmaceutically acceptable salt where R1 is selected from C1-C6alkyl substituted by C1-C6alkyl, C3-C6cycloalkyl, phenyl, phenyl C1-C6alkyl substituted by phenyl C1-C6alkyl, phenylC2-C6alkenyl, C5-C6heteroaryl containing 1 nitrogen, oxygen or sulphur atom as a heteroatom; R2 and R3 are independently selected from hydrogen, C1-C6alkyl and C3-C6cycloalkyl; R4 is selected from: hydrogen, phenyl, phenyl C1-C6alkyl and C1-C6alkyl and where "substituted" means a group wherein one or two hydrogen atoms are substitute by a substitute which represent C1-C6alkoxy. Also, the invention refers to an intermediate compound of formula (VII) and its pharmaceutically acceptable salt where X represents: fluorine, chlorine, bromine or iodine; R2 and R3 are independently selected from hydrogen and C1-C6alkyl; R4 is selected from: hydrogen, C1-C6alkyl, phenyl and phenyl C1-C6alkyl.

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23 cl, 3 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention describes N-cycloalkylbenzylamide derivatives of formula

, where A denotes a saturated 5-member heterocyclic group, Z1 denotes a substituted C3-C7-cycloalkyl; Z2 and Z3, which can be identical or different from each other, denote a hydrogen atom; C1-C8-alkyl; cyano; C1-C8-alkoxycarbonyl; a method of producing said compounds, use thereof as fungicidal active substances, particularly in form of fungicidal compositions, and method of controlling phytopathogenic fungi, mainly in plants, using said compounds or compositions.

EFFECT: higher activity, low amount of active substance while maintaining efficiency at least equivalent to that of existing compounds.

11 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: described is 2-alkyl-cycloalk(en)yl-carboxamides of formula

, in which X, s, R1 , L, R2 and A assume values given in the formula of invention, a method of producing said compounds, an agent and use of said compounds against unwanted microorganisms.

EFFECT: higher activity compared to existing compounds, low toxicity and high toleration by plants.

6 cl, 8 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to hot or sweet flavourants in form of a synthetic amide compound or edible salt thereof in amount ranging from approximately 0.001 parts per million to approximately 100 parts per million. The amide compound has formula

where A is a phenyl or a 5- or 6-member heteroaryl ring selected from a group comprising pyridine, pyrazine, pyrazole, thiazole, furan, thiophene, benzofuran and benzothiophene; m equals 1, 2 or 3, each R1 is independently selected from hydroxyl, fluorine, chlorine, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy and isopropoxy, or alternatively two R1 are bonded to form a saturated C1-C3 alkylenedioxy ring on the phenyl; and R2 is a C3-C10 branched alkyl. The amide compound also has formula

in which substitutes A, B, R50, R60, R70, R80, n and m assume values given in the formula of invention. The amide compound is also a specific chemical compound.

EFFECT: obtaining hot and sweet taste modifiers and boosters for food and medicinal products.

39 cl, 7 tbl, 180 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or salts thereof, (1), where R1 denotes a hydrogen atom or a C1-6alkyl group; R2 denotes a hydrogen atom, R3 denotes a hydrogen atom or a C1-6alkyl group when R4 and R5 denote hydrogen atoms, R6 denotes a hydrogen atom or a cyano group, or in >C(R6) C(R5)(R4) - denotes a double bond, R4 and R6 are absent, and R5 denotes a hydrogen atom; or R4 denotes a hydrogen atom and R5 denotes a hydroxy group or a halogen atom, R6 denotes a hydrogen atom or a cyano group, R7 denotes one or two substitutes selected from a group comprising a hydrogen atom, a halogen atom, a nitro group and C1-6alkoxy group, A denotes a 5-member or a 6-member non-aromatic heterocyclic ring which contains one sulphur atom (the sulphur atom can form an oxide), W denotes an oxo group, two hydrogen atoms, two fluorine atoms or a combination of a hydrogen atom and a hydroxy group, and X denotes an oxygen atom or a sulphur atom.

EFFECT: medicinal agent based on these compounds have inhibitory action on production of prostaglandin E2 and can be used in medicine to treat urological diseases.

5 cl, 7 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing dimethyl ether of 2,5-thiophene dicarboxylic acid by reacting thiophene with carbon tetrachloride in the presence of methanol and a tris(2,4-pentanedionato)iron catalyst Fe(acac)3 which is activated by a nitrogen-containing ligand - quinoline or pyridine, at temperature 150°C for 6 hours in molar ratio 0.04:0.4:4:45:30. Dimethyl ether of 2,5-thiophene dicarboxylic acid is used in production of electroconductive polymers, electrodes, sensors, capacitors, displays, optical brighteners, gel electrolytes and ion-exchange membranes.

EFFECT: high output of product.

1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing dimethyl ether of 2,5-thiophene dicarboxylic acid, , which involves reaction of 2-thiophene carboxylic acid with methanol and CCl4 in the presence of a catalyst tris(2,4-pentanedionato)iron Fe(acac)3, activated with a nitrogen-containing ligand - pyridine with molar ratio [Fe(acac)3] : [C5H5N] : [2-thiophene carboxylic acid] : [methanol] : [CCl4]=0.01:0.05-0.1:1:45-135:30, at temperature of 140-160°C for 3-6 hours.

EFFECT: high output of dimethyl ether of 2,5-thiophene dicarboxylic acid which is the base material for production of electroconductive polymers, electrodes, sensors, capacitors, displays, gel electrolytes, ion-exchange membranes and optical bleaching agents.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel biologically active compounds of formula , where substitutes R, R1, R2 and R3 are defined in the formula of invention, and can be obtained using a method which involves reaction of corresponding chloroacetamides with a prepared solution of elementary sulphur with morpholine or piperidine, passing the obtained solution of monothiooxamides through a layer of sorbent and then reaction of monothiooxamides with hydrazine-hydrate, reaction of the obtained compound with aldehydes in dimethyl formamide at room temperature and precipitation with methanol which gives good output of the end product.

EFFECT: obtained compounds are highly effective against pathogenic bacteria, are characterised by selectivity and can be used to inhibit type III secretion in pathogenic bacteria.

3 cl, 8 dwg, 1 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted derivatives of oxamic acid thiohydrazides of general formula: , where R and R1 denote H, unsubstituted or substituted Het, phenyl, Alk, wherein substitutes can be Alk, Hal, CF3, COOR3, SR3, or R+R1=C2H4OC2H4; R2 denotes H, Alk, OR3, Hal, where R3=Alk; Het denotes a 5- or 6-member ring which contains one or two heteroatoms selected from N and S. The invention also relates to a method for synthesis of said compounds.

EFFECT: obtaining novel compounds which exhibit antibacterial activity and can be used as antibacterial agents for inhibiting pathogenic bacteria, including Chlamydia.

4 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new biologically active substances and specifically to 4-(methylphenyl)-4-oxo-2-[3-ethoxycarbonyl-4,5-R2,R1-thiophen-2-ylamino]but-2-enoic acid of general formula: R1,R2=CH3 R1+R2=(CH2)3.

EFFECT: obtaining new compounds having anti-inflammatory and analgesic activity, as well as low toxicity, which can be used as medicinal agents.

1 cl, 1 tbl, 4 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to fluorine and trifluoralkyl-containing heterocyclic sulfonamides of general formula I , where T - CHO, COR8 and C(OH)R1R2; R1 and R2 -hydrogen, C1-6alkyl; R3 -hydrogen; R4 - (CF3)nalkyl, (CF3)nalkylphenyl, and (F)ncycloalkyl; N equals 1-2; R5 - hydrogen, halogen, dien, condensed with Y, when Y stands for C, and dien, condensed with Y, when Y stands for C and substituted with halogen; W, Y and Z - C, CR6 and N, on condition that at least one of W or Y, or Z must be C; R6 -hydrogen halogen or C1-6alkyl; X - S and NR7; R7 - C1-6alkyl; and R8 - C1-6alkyl. Also described are method of obtaining compounds I, pharmaceutical composition and application of compounds, intermediate compounds, used in synthesis.

EFFECT: obtaining compounds which can be used to inhibit beta-amyloid formation and for treatment of Alzheimer's disease.

48 cl, 5 tbl, 42 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of formulas (Ip3) or (Ip4) wherein R1P3 means unsubstituted or substituted phenyl or thienyl wherein substitutes represent halogen atom, (C1-C6)-alkyl, (C1-C4)-halogenalkyl, nitro group, (C1-C4)-alkoxy group; R16P3 and R17P3 in common with carbon atom to which they are bound mean a bridge-bound saturated (C5-C12)-ring system that is substituted with (C4-C12)-alkyl, (C1-C6)-alkoxycarbonylamino group, for example, tert.-butoxycarbonylamino group; R18P3 means hydrogen atom; R1P4 means unsubstituted or substituted phenyl or thienyl wherein substitutes represent halogen atom, (C1-C6)-alkyl, (C1-C4)-halogenalkyl, nitro group, (C1-C4)-alkoxy group; R16P4 and R17P4 in common with carbon atom to which they are bound mean a substituted bridge-bound saturated (C5-C12)-cycloalkyl ring system, substituted piperidine or substituted bridge-bound piperidine wherein substitutes mean (C1-C6)-alkoxyoxycarbonyl, (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with (C4-C12)-alkyl, (C1-C4)-halogenalkyl, nitro group, aminocarbonyl; R18P4 means hydrogen atom or hydroxyl but hydrogen atom preferably; mP4 means 1. Compounds of formulas (Ip3) and (Ip4) inhibit activity of steroid sulfatase that allows their using as components of pharmaceutical composition.

EFFECT: valuable biochemical and medicinal properties of compounds and pharmaceutical composition.

7 cl, 13 tbl, 386 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

20 cl, 4 tbl, 70 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

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