PL183619B1 - Aniline derivatives exhibiting inhibitive effect in respect to nitrogen oxide synthesis - Google Patents

Abstract

1. Aniline derivatives of the general formula (1), or a possible stereoisomer or an optically active form of the compound, or a pharmaceutically acceptable salt thereof PL 183619 B1 (1) wherein R1 is SR $ or NR7R8; R5 is an optionally fluoro substituted straight chain or branched alkyl group having 1-6 carbon atoms, or a straight chain or branched alkenyl group having 2-6 carbon atoms; R7 is a hydrogen atom, a straight or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having <^ 3-8 carbon atoms, a straight-chain or branched alkynyl group of 3-6 carbon atoms, a straight-chain or branched alkoxy group of 1-6 atoms carbon, or nitro group, Rg is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; R2 is a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group, the alkyl part of which is a straight or branched alkyl group having 1-6 carbon atoms, or a carboxyl group, or can combine with R3 to form 3- to An 8-membered carbocyclic ring; R3 is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms, or may combine with R2 to form 3- to 8-membered carbocyclic ring; ............................................ .................................................. .......................................... 15. A drug for cerebrovascular diseases, containing an active ingredient and optionally additional ingredients, characterized as the active ingredient contains a compound represented by general formula (1) or a possible stereoisomer, or an optically active form of the compound, or a pharmaceutically acceptable form thereof salt, (1) wherein R1 is SRe or NR7R8, R6 is an optionally fluorinated straight chain or branched alkyl group having 1-6 carbon atoms, or a straight chain or branched alkenyl group having 2-6 carbon atoms; R7 is a hydrogen atom, a straight chain or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms, a straight or branched alkynyl group having 3-6 carbon atoms, a straight or branched alkoxy group having 1-6 atoms carbon or nitro group; Rg is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; ....

Description

The invention relates to N-substituted aniline derivatives, more particularly compounds represented by general formula (1) having an inhibitory effect on nitric oxide synthase (NOS) in order to reduce the production of nitric oxide (NO) and thus effective against pathologies in cerebrovascular diseases, in particular, occlusive cerebrovascular diseases in which NO or NO metabolites are involved, as well as traumatic brain injuries, attacks, headaches and other pain, tolerance and dependence on morphine, Alzheimer's disease, Parkinson's disease, Septic shock, chronic rheumatoid arthritis, inflammation bone, viral or non-viral infections and diabetes; The invention also relates to possible stereoisomers and optically active forms of the compounds, their pharmaceutically acceptable salts, as well as preventive and therapeutic agents containing them as an effective ingredient.

Occlusion or low perfusion pressure in the cerebral or carotid artery by some mechanism causes ischemic necrosis in the brain tissue, a condition known as "cerebral infarction". Cerebral infarction is classified roughly as cerebral embolism and cerebral thrombosis depending on the mechanism.

Cerebral embolism is characterized by the formation of clots in the cerebral artery due to the separation of intracardiac blood clots or, less commonly, blood clots in the walls of the arteries, and cerebral thrombosis is mainly based on sclerotic defects in the cerebral arteries, complicated by increased blood viscosity or decreased perfusion pressure causing occlusion of the arteries, which may develop into ischemic necrosis of brain tissue ("NOKEKKAN SHOGAI", compilation edited by Hisao MANABE and Terno OMAE, published by Life Science, pp. 54-55,1992).

Whether the cause is cerebral embolism or thrombosis, edema formation is seen in ischemic brain tissue in parallel or prior to the development of an infarction. Vascular cerebral edema occurs within hours of onset of cerebral ischemia and lasts for approximately one week after onset. Thereafter, the swelling of the brain gradually subsides and, depending on the area of the infarction, the swelling lasts as the area of the infarction for one to three months. As the brain is covered with a rigid skull, swelling of the brain causes an increase in brain volume. If the swelling of the brain exceeds a certain limit, a sudden increase in tissue pressure and pressure occurs

183,619 intracranial failure, often causing a fatal hernia and finally increasing brain damage defining the area of further infarction ("CT, MRI JIDAI NO NOSOTCHUGAKU, PART I in two volumes", Kenji INAMURA and Akio TERASHI, published by Nihon Rinshosh, pp. 231-239 , 1993). In addition, when a region of the brain infects, the functions of the damaged area, such as perception, sensing and memory, are lost.

Thus, treatment of cerebral edema and infarction, which is particularly important for the patient's quality of life and disease prognosis, is a clinically very important goal. Regarding cerebral edema, recent treatments include hyperventilation, cerebrospinal fluid drainage, and the use of hypertonic solutions, steroids, and more; however, in almost all cases these methods are only transient and there is little hope of ultimate therapeutic efficacy ("NOSOTCHU CHIRYO MANUAŁ", Masakuni KAMEYAMA Ed., published by Igaku Shoin, pp. 34-36,1991). Thus, it is desirable to develop drugs which operate by an entirely different mechanism than conventional etiological observation and which will prove effective in treating ischemic cerebrovascular diseases.

The currently dominant theory based on DNA genetic analysis holds that NOS exists in at least three isoforms, i.e., calcium dependent N-cNOS (type 1) which is constitutively present in neurons, calcium dependent E-cNOS (type 3) which is present constitutively in vascular endothelial cells and apparently calcium-independent iNOS (type 2) which is induced and synthesized by stimulation of cytokines and / or lipopolysaccharides (LPS) in macrophages and many other cells (Nathan et al., FASEB J. 16.3051-3064 , 1992; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).

The mechanism proposed as most likely to explain the brain tissue damage associated with cerebral ischemia is a pathway that includes the sequence of increasing extracellular glutamic acid levels, hyperactivating glutamic acid receptors at post-synapses, elevating intracellular calcium levels, and activating dependent decalcifying enzymes (Siesjó, J. Cereb. BloodFlowMetab. 1,155 -185, 1981; Siesjó, J.Neurosurg. 60, 883-908, 1984; Choi, TrendsNeurosci. 11, 465-469, 1988; Siesjo and Bengstsson, J. Cereb. BloodFlowMetab. 9, 127-140, 1989). As already mentioned, N-cNOS is calcium dependent, and thus inhibition of the aberrant activation of this type of NOS isoform will contribute to the neuroprotective effects of NOS inhibitors (Dawson et al., Annals Neurol. 32, 297-311, 1992).

In fact, the level of N-cNOS mRNA and the number of N-cNOS containing neurons begins to increase immediately after cerebral ischemia and their temporal changes coincide with the development of infarction in rats (Zhang et al., Brain Res. 654, 85-95, 1994). Furthermore, in a mouse model of focal cerebral ischemia, the percent inhibition of N-cNOS activity and the percent reduction in infarct volume correlate with each other at least in the range of L-NA doses that reduce infarct volume (Carreau et al., Eur. J. Pharmacol. 256, 241-). 249, 1994). Moreover, it has been published that in N-cNOS deficient mice, the infarct volume observed after focal cerebral ischemia is significantly lower than in control mice (Huang et al., Science 265, 1883-1885, 1994).

There has also been a report that suggests the involvement of iNOS in the mechanism of the occurrence and development of ischemic brain injuries. Briefly, after 12 hours of focal cerebral ischemia in rats, the level of iNOS mRNA began to increase in the cerebral cortex of the affected hemisphere and, after 2 days, reached its maximum accompanying iNOS activity, possibly derived from multinucleated leukocytes (Ladecola et al., J. Cereb. BloodFlowMetab. 15.52-59, 1995; Ladecola et al., J. Cereb. BloodFlowMetab. 15.378-384, 1995). It was reported that when N ^G -nitro-L-arginine methyl ester (L-NAME), one of the NOS inhibitors, was administered after 3 hours of ischemia with the temporal changes described above, the infarct volume decreased significantly (Zhang et al. Cereb. Blood Flow Metab. 15, 595-601, 1995).

Furthermore, the degree of iNOS or its enzymatic activity has been reported to increase in astrocytes or cerebral microvasculature following cerebral ischemia in rats (Endohiin., Neurosci. Lett. 154, 125-128, 1993; Endoh et al., BrainRes. 651.92-100, 1994; Na

183,619 Gafuji et al. In Brain Edem IX (Ito et al. Ed.), 60, pp. 285-288, 1994, Springer-Verlag; Toshiaki NAGAFUJIiToruMATSUI, Jikkenlgaku, 13, 127-135, 1995; Nagafujiiin., Mol. Chem.Neuropathol. 26, 107-157,1995).

These reports suggest that N-cNOS or iNOS may be strongly involved in the mechanism of occurrence and development of tissue damage following cerebral ischemia.

As for NO, it is at least one of the secretions of endothelial relaxing factor (EDRF) and is therefore believed to be involved in the regulation of vascular tone and blood flow (Moncada et al., Pharmacol. Rev. 43,109-142, 1991). In fact, it was reported that when rats were administered high doses of L-NNA, cerebral blood circulation decreased in a dose-dependent manner with increasing blood pressure (Toru MATSUI et al., Jikken Igaku, 11,55-60,1993). The brain has a mechanism to fix the cerebral blood circulation at a constant level regardless of changes in blood pressure within the given range (usually called "blood mechanism within the given range (usually called" autoregulation mechanism ") (" NOSOTCHU JIKKEN HANDBOOK "compilation edited by Keiji SANO, published by IPC , 247-249, 1990) A report by Matsui et al. Suggests a failure of this “autoregulation mechanism.” Thus, if E-cNOS is particularly inhibited above a certain limit in an episode of cerebral ischemia, cerebral blood circulation will drop and blood pressure will increase, worsening the dynamics of microcirculation, possibly leading to the expansion of ischemic damage.

The present inventors have previously discovered that N ^G -nitro-L-arginine (L-NNA), known as a NOS inhibitor, has a mitigating effect on cerebral edema and infarction in a rat model of focal cerebral ischemia (Nagafuji et al., Neurosci. Lett. 147,159). -162,1992; Japanese Patent Specification No. 192080/1994), as well as on neuronal death in the Gerbill forebrain ischemia model (Nagafuji et al., Eur. J. Pharmacol. Env. Tox. 248, 325-328, 1993). On the other hand, relatively high doses of NOS inhibitors have been shown to be completely ineffective against ischemic brain injuries or at times worsened them (Ladecola et al., J. Cereb. Blood Flow Metab. 14, 175-192, 1994; Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku, 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995). It should be noted that, in fact, all publications dealing with changes in NO or its metabolites in the brain following permanent or temporary cerebral ischemia report consistent results showing an increase in levels of these substances (Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku, 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).

One of the explanations for the existence of contradictory reports on the effectiveness of NOS inhibitors in brain ischemia models may be the low selectivity of the NOS inhibitors used for N-cNOS or iNOS. Indeed, none of the existing NOS inhibitors, including L-NNA and L-NAME, have a highly selective inhibitory effect on specific NOS isoforms (Nagafuji et al., Neuroreport 6,1541-1545,1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995). Thus, it can be concluded that the desired drugs for ischemic cerebrovascular diseases should have a selective inhibitory effect on N-cNOS or iNOS (Nowicki et al., Eur. J. Pharmacol. 204,339-340,1991; Dawson et al., Proc. Natl, Acad. Sci. USA 88, 6368-6371, 1991; Ladecola et al., J. Cereb. Blood Flow Metab. 15.52-59.1995; Ladecola et al., J. Cereb. Blood Flow Metab. 15.378 -384,1995; Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).

It has also been proposed that N-cNOS inhibitors can be used as drugs for traumatic brain injuries (Oury et al., J. Biol. Chem. 268, 15394-15398, 1993; MacKenzieiin., Neuroreport 6, 1789-1794, 1995), (Rigaud-Monnet et al., J. Cereb. Blood Flow Meta. 14, 581-590; 1994), headache and other aches and pains (Moore et al., Br. J. Pharmacol. 102, 98-202, 1992; Olesen. , Trends Pharmacol. 15, 149-153, 1994), tolerance and dependence on morphine (Kolesnikov et al., Eur. J. Pharmacol. 221, 399-400, 1992; Cappendijk et al., Neurosci. Lett. 162, 97 -100, 1993), Alzheimer's disease (Hu and EI-FaKahany, Neuroreport 4,760-762,1993; Meda et al., Nature 374, 647-650, 1995) and Parkinson's disease (Youdim et al., Advances Neurol. 60, 259-266, 1993; Schulz et al., J. Neurochem. 64, 936-939, 1995).

183 619

When stimulated by certain types of cytokines and / or LPS, iNOS is induced in immunocytes such as macrophages and glial cells and other cells, and the large amount of NO produced will dilate the blood vessels causing a dangerous drop in blood pressure. Thus, it is hypothesized that an iNOS inhibitor may be effective against septic shocks (Kilboum and Griffith, J.Natl. CancerInst. 84,827-831,1992; Cobb et al., Crit. CareMed. 21, 1261-1263, 1993; Lorente and et al., Crit. Care Med. 21, 1287-1295, 1993).

Moreover, it has been proposed that iNOS inhibitors are useful as drugs for chronic rheumatoid arthritis and osteitis (Farrell et al., Ann. Rheum. Dis. 51, 1219-1222, 1992; Hauselmann et al., FEBS Lett. 352, 361- 364, 1994; Islante et al., Br. J. Pharmacol. 110, 701-706, 1993), viral or non-viral infections (Zembvitz and Vane, Proc. Nat. Acad. Sci. USA 89, 2051-2055, 1992; Koprowski et al., Proc. Natl. Acad. Sci. USA 90, 3024-3027, 1993) and diabetes (Kolb et al., Life Sci. PL213-PL217, 1991).

NOS inhibitors reported to have selectivity for N-cNOS are N ^G -cyclopropyl-L-arginine (LCPA) (Lamberte et al., Eur. J. Pharmacol. 216, 131-134, 1992), L-NNA (Furfme et al., Biochem. 32, 8512-8517, 1993), S-methyl-L-thiocitrulline (L-MIN) (Narayanan and Griffith, J. Med. Chem. 37, 885-887, 1994; Furfine et al., J. Biol. Chem. 37, 885-887, 1994; Furfine et al., J. Biol. Chem. 269, 26677-26683, 1994; WO95 / 09619; Narayanan et al., J. Biol. Chem. 270, 11103-11110, 1995; Nagafujiiin ., Neuroreport6,1541-1545,1995) iS-ethyl-L-thiocitrulline (L-EIN) (Furfine et al., J. Biol. Chem. 269, 26677-26683, 1994; WO95 / 09619; Narayanan et al. , J. Biol. Chem. 270, 11103-11110,1995).

In addition, inhibitors reported to be selective for iNOS include N ^G -iminoethyl L-omithin (L-NIO) (Mc Cali et al., Br. J. Pharmacol. 102, 238-238, 1991) and aminoguanidine (AG) (Griffith and et al., Br. J. Pharmacol. 110, 963-968, 1993; Hasan et al. Eur. J. Pharmacol. 249, 101-106, 1993).

The present invention relates to novel compounds having a selective inhibitory effect on calcium-dependent NOS present constitutively in the brain, particularly neurons (N-cNOS), or apparently calcium-independent and inducible NOS (iNOS), and useful as drugs in cerebrovascular diseases, Alzheimer's, analgesia, morphine tolerance or dependence, sepsis, chronic rheumatoid arthritis, osteitis, viral or non-viral infections, diabetes and Parkinson's disease.

As a result of intensive studies carried out in order to achieve the set goal, the present inventors have found that the N-substituted aniline derivatives represented by the general formula (1), object of the invention, or possible stereoisomers or optically active forms of the compounds, as well as pharmaceutically acceptable salts thereof, inhibitory effect or selectivity for N-cNOS or iNOS much better than the existing NOS inhibitors, therefore show significant efficacy as drugs in cerebrovascular diseases (especially as drugs in occlusive cerebrovascular diseases):

where

Rj is SR ₆ or NR ₇ R ₈ ;

1 ^ is an optionally fluoro substituted straight chain or branched alkyl group having 1-6 carbon atoms or a straight chain or branched alkene group having 2-6 carbon atoms;

R ₇ is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, cyclic alkyl group having 3-8 carbon atoms, straight or branched chain

183 619 branched alkynyl group having 3-6 carbon atoms, straight chain or branched alkoxy group having 1-6 carbon atoms, or nitro group

R _g is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms;

R ₂ represents a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group the alkyl portion of which is a straight or branched alkyl group having 1-6 carbon atoms, or a carboxyl group, or can combine with R ₃ to give 3- to 8- a membered carbocyclic ring;

R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R ₂ to form a 3- to 8-membered carbocyclic ring;

R ₄ is a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, an amidino group which may be substituted on the nitrogen atom a cyclic alkyl group having 3-8 carbon atoms or a nitro group

R ₅ represents a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, an alkoxycbonylamino group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, or an amino group

Y _t , Y ₂ , Y ₃ and Y ₄ , the same or different, represent a hydrogen atom, a halogen atom, a straight or branched chain alkyl hydroxyl group having 1-6 carbon atoms, which may be substituted by 1-3 halogens, the group NY ₅ Y ₆ where Y ₅ and Y ₆ , same or different, represent a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or a linked or branched alkyl group having 1-6 carbon atoms for Y _5, and Y ₆ form a piperidine or pyrrolidine ring;

n and m are an integer of 0 or 1;

except:

a) a hydrochloride of the compound of formula I, where Rj = -NH ₂ , R ₂ = -COOH, R ₃ = methyl, R ₄ and R ₅ = Η, n = 1, m = 0, Y _r Y ₄ - H;

b) a compound of formula 1, where R 1 = -SCH ₃ , R ₂ = COOH ₃ , R ₃ = methyl, R ₄ = acetyl, R ₅ = H, n = 1, m = 0, Y _r Y ₄ = H;

c) the R stereoisomer of the compound of formula 1, where R 1 = -NH ₂ , R ₂ = -COOH, R ₃ = -H, R ₄ = acetyl, R ₅ = Η, n = 0 and m = 0, Y _Γ Υ ₄ = H;

d) the hydrochloride of the R-isomer of the compound of formula I, wherein Rj = NH ₂ , R ₂ = -COOH, R ₃ , R ₄ , R ₅ = Η, n and n = 0; Y _r Y ₄ - H;

e) hydrochlorides of the R and S isomers of the compound of formula 1, wherein Rj = -NH ₂ , R ₂ = -COOCH ₃ , R ₃ , R ₄ , R ₅ = Η, n and _m = 0, Y _r Y ₄ = H;

f) a compound of Formula 1 wherein R! = = NHNO ₂ , R ₂ = -COOH, R ₃ , R ₄ , R ₅ = Η, η = 1, m = 0, YrY ₄ = H;

g) a compound of formula I, where R 1 = -NHNO ₂ , R ₂ = -COOH, R ₃ = H, R ₄ = t-butoxycarbonyl, R ₅ = Η, n = 1, m = 0, Y _r Y ₄ = H.

The intermediates useful in the synthesis of compounds represented by the general formula (1) are compounds of the general formula (21):

183 619 where

R ₂ represents a hydrogen atom ,, a linear or branched alkyl group having 1-6 carbon atoms, or may combine with R ₃ to form a 3- to 8-membered ring;

R ₃ is a straight or branched alkyl group having 1-6 carbon atoms, or may combine with R ₂ to form a 3- to 8-membered ring;

Y], Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms that may be substituted with 1-3 halogen atoms, the group NY ₅ Y ₆ , where Y ₅ and Y ₆ , which may be the same or different, represent a hydrogen atom, a straight chain alkyl group of 1-6 carbon atoms, an acyl group of 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine or pyrrolidine ring .

Japanese Patent No. 13391/1975; Clin. Sci. Moth. Med. 53,355-364,1977; J. Chem. Eng. Data, 22, 3, 224-245, 1977; Clin. Sci. Moth. Med. 54, 673-677,1978; J. Biochem. 94, 123-128, 1983 and the international publication WO94 / 21621 define compounds related to the compounds of the invention represented by general formula (1).

Moreover, some of the compounds represented by the general formula (1) are presented generically in the Japanese Nos patents. 97933/1977, 99227/1977 and 158249/1987. However, these patents do not fully address the NOS inhibitory activity of the compounds corresponding to the compounds of the invention or other aspects thereof such as their use as medicaments in cerebrovascular diseases, traumatic brain injuries, seizures, Alzheimer's disease, Parkinson's disease, headache and other pain. , tolerance or dependence on morphine, septic shock, chronic rheumatoid arthritis, osteitis, viral or non-viral infections and diabetes.

It should also be noted that international publication WO95 / 00505 not published before the priority date of this application (December 12, 1994) but published later, and J. Chem. Soc. Perkin Trans. 1, 2025-2030, 1977 show some compounds represented by the general formula (1), and the international publication also discloses some compounds in a generic order. Prior art compounds of formula I are excluded.

Moreover, the international publication WO95 / 09619, not published before the priority date of this application (December 12, 1994), but published later, describes a part of the compounds of the invention of general formula (1) in a generic order.

As will be shown by the tests described below, the compounds described in the examples according to the invention show an excellent NOS inhibitory effect as well as an extremely high selectivity for N-cNOS and iNOS compared to the compounds described in the international publications WO95 / 00505 and WO / 09619.

Figure 1 is a graph showing the effectiveness of the compound of Example 96 in reducing brain edema arising after 48 hours of occlusion in a rat's left middle cerebral artery; and

Figure 2 is a graph showing the effectiveness of the compound of Example 96 in ameliorating a cerebral infarction arising after 3 hours of left middle cerebral artery occlusion and a subsequent 24 hours of reperfusion in rat.

The best way to carry out the invention

In the present invention, a straight or branched alkyl group having 1-6 carbon atoms may be represented, for example, by methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl or hexyl or the like;

the cyclic alkyl group having 3-6 carbon atoms may be represented, for example, by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or the like;

a straight or branched alkenyl group having 2-6 carbon atoms may be represented, for example, by vinyl, allyl, butenyl or pentenyl, or the like;

a cyclic alkyl group having 3-6 carbon atoms can be represented, for example, by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or the like;

a straight or branched alkynyl group having 3-6 carbon atoms may be represented, for example, by propynyl, butynyl or pentenyl, or the like;

A straight or branched alkoxy group having 1-6 carbon atoms may represent, for example, methoxy, ethoxy, i-propoxy or n-propoxy or the like;

an alkoxycarbonyl group whose alkyl portion is a straight chain or branched alkyl group having 1-6 carbon atoms may be represented, for example, by methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl or t-butoxycarbonyl, or the like;

an acyl group having 1-8 carbon atoms may be, for example, acetyl, propionyl, butyryl, isobutyryl or benzoyl or the like;

a straight-chain or branched alkylthio group having 1-6 carbon atoms may be represented, for example, by a methylthio, ethylthiol or propylthio group, or the like;

a substituent on an optionally substituted straight chain or branched alkyl group having 1-6 carbon atoms may represent, for example, a halogen atom, a hydrocarbyl group such as a phenyl group or the like;

an optionally substituted straight or branched alkyl group having 1-6 carbon atoms may be represented by, for example, methyl, ethyl, 2-fluoroethyl or n-propyl or the like;

NY ₅ Y ₆ may be represented, for example, by an amino, methylamino, ethylamino, dimethylamino, ethylmethylamino, piperidine, acetamide, N-methylacetamide, t-butoxycarbonylamino or N-methyl-t-butoxycarbonylamino group or the like;

R] is preferably an alkylthio group in which the alkyl portion is a substituted straight or branched alkyl group having 1-6 carbon atoms, or an amino group substituted with a straight or branched alkyl group having 1-6 carbon atoms or a nitroamino group, with methylthio being particularly preferred. ethylthiol, ethylamine or nitroamine;

R ₂ is preferably a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms, particularly preferred is hydrogen, methyl or ethyl;

R ₃ is preferably hydrogen or a straight or branched alkyl group having 1-6 carbon atoms, with hydrogen or methyl being particularly preferred;

the substituent when R ₂ and R ₃ combine to form a 3- to 8-membered ring may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R ₄ is preferably hydrogen;

R ₅ is preferably a hydrogen atom;

m and n are preferably 0 if the substituents other than Y _b Y _2, Y ₃ and Y ₄ in the general formula (1) alone-substituted on the benzene nucleus and if the substituents other than Y _b Y _2, Y ₃ and Y ₄ in the general formula (1 ) are p-substituted on the benzene ring, preferably m is 1 and n is 0 or m is 0 and n is 1,

Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, are preferably a hydrogen atom, a halogen atom, a hydroxyl group, a straight or branched chain alkyl group having 1-6 carbon atoms which may optionally be substituted with 1-3 atoms halogen, methylamino, ethylamino, dimethylamino or ethylmethylamino, and more preferably hydrogen, halogen, straight or branched chain alkyl having 1-6 carbon atoms which may optionally be substituted with 1-3 halogen atoms, methylamino, ethylamino dimethylamino and ethylmethylamino .

Compounds of the invention represented by general formula (1) can typically be synthesized according to the following schemes:

183 619

(10)

Among the compounds of formula (1), one represented by formula (6) with Rj being SR ₆ can be synthesized from a compound of formula (3) via a compound of formula (4).

183 619

A compound of formula (6), where

R ₂ represents hydrogen, straight-chain or branched alkyl group having 1 to 6 carbon atoms, or an alkoxycarbonyl group wherein the alkyl part a linear or branched alkyl group having 1 to 6 carbon atoms, or may combine with R ₃ to form a 3- to 8 a member carbocyclic ring;

R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms or may combine with R ₂ to form a 3- to 8-membered carbocyclic ring;

R ₄ represents an alkoxycarbonyl group whose alkyl portion is a straight chain or branched alkyl group having 1-6 carbon atoms or an acyl group having 1-8 carbon atoms;

R ₅ represents a hydrogen atom, a straight or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, or an alkoxycarbonylamino group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms;

R ₆ is an optionally substituted straight or branched alkyl group having 1-6 carbon atoms or a straight or branched alkenyl group having _2-6 carbon atoms;

Yp Y ₂ , _Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms which may be substituted with 1-3 halogens, the group NY ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a ring piperidine or pyrrolidine;

m is the integer 0 or 1 and n is the integer 0 or 1;

can be synthesized as follows if only R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y _b Y ₂ , Y ₃ , Y ₄ , min in the following formulas (3), (4), (5) and ( 6) are the same as defined above and X is bromine or iodine.

The compound represented by formula (3) is reacted with thiophosgene in the presence of an inorganic base such as calcium carbonate or potassium carbonate, or an organic base such as triethylamine or Ν, Ν-dimethylaminopyridine, preferably in the presence of calcium carbonate or Ν, Ν-dimethylaminopyridine, in a solvent reaction inert such as chloroform, methylene chloride, water or dimethylformamide, preferably in methylene chloride or a mixture of methylene chloride and water, at a temperature between 0 ° C and the boiling point of the reaction mixture, preferably at room temperature, and the reaction product is then treated with a concentrated solution ammonia to obtain the compound represented by the formula (4).

The compound of formula (4) is then reacted with the compound of formula (5) in a reaction-inert solvent such as acetonitrile, acetone, 1,4-dioxane, methanol or ethanol at a temperature between room temperature and the boiling point of the reaction mixture, preferably acetonitrile with heating the reaction mixture at reflux to obtain a compound of formula (6).

Alternatively, a compound of formula (6) where

R ₂ is hydrogen, prostołańcuchowąlub rozgałęzionągrupę alkyl group having 1-6 carbon atoms or may combine with R ₃ to form a 3- to 8-membered carbocyclic ring; R ₄ and R ₅ , which may be the same or different, represent a straight or branched alkyl group having 1-6 carbon atoms;

R ₃ , Y], Y ₂ , Y ₃ , Y ₄ , X, m and n are the same as defined above;

can be synthesized as follows if only R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y _b Y ₂ , Y ₃ , Y ₄ , X, min in the following formulas (3), (4), (5) and (6) are the same as defined above.

The compound represented by the formula (3) is reacted with benzoyl chloride and ammonium thiocyanate in a reaction-inert solvent such as acetone at a temperature between

At room temperature and at the reflux temperature of the reaction mixture, preferably at room temperature, and then, the reaction mixture is heated at reflux together with a 10% aqueous sodium hydroxide solution to provide the compound of formula (4).

Subsequently, a compound of formula (4) is reacted with an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid to form a quaternary ammonium salt, which is subsequently reacted with a compound of formula (5) in a reaction inert solvent such as acetonitrile, acetone, 1,4-dioxane, methanol or ethanol, at a temperature between room temperature and the reflux temperature of the reaction mixture, preferably in acetonitrile with heating the reaction mixture at reflux to provide the compound of formula (6).

Among the compounds of formula (1), the compound represented by formula (8) with R _t being NR ₇ R ₈ , where

R ₂ represents hydrogen, straight-chain or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group wherein the alkyl moiety is a straight or branched group having 1-6 carbon atoms, or may combine with R ₃ to form a 3- to 8-membered a carbocyclic ring;

R ₄ is a straight chain or branched alkyl group having 1-6 carbon atoms, a straight or branched alkoxycarbonyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, if only when R ₅ is hydrogen, R ₄ is not a group alkyl;

R ₅ represents a hydrogen atom, a straight chain or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched chain group having 1-6 carbon atoms, or an alkoxycarbonylamino group whose alkyl portion is a straight or branched carbon group having 1-6 carbon atoms;

R ₇ is a straight chain, branched or cyclic alkyl group having 1-6 carbon atoms, or a straight chain or branched alkynyl group having 3-8 carbon atoms;

R ₈ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; and

R ₃ , Y], Y ₂ , Y ₃ , Y ₄ , m and n are the same as defined above;

can be synthesized using the compounds of formulas (6), (4) and (3) as starting materials, if R _2, R _3, R _4, R _5, R _7, R _8, Y ₁₅ Y _2, Y _3, Y ₄ , X, m and n in the following formulas (3), (4), (5), (6), (7), (34), (35), (36) and (37) are the same as defined above, with R _{6 an} optionally substituted straight or branched alkyl group having 1-6 carbon atoms.

A compound of formula (8) can be obtained by reacting a compound of formula (6) with an amine of formula (35) in a heating-inert solvent, preferably dimethylformamide at 80 ° C.

Alternatively, a compound of formula (8) can be obtained by converting a compound of formula (4) into a compound of formula (34) according to the method of C. A. Maryanoff et al. (J. Org. Chem. 51, 1882-1884, 1986) and then reacting compound (34) with an amine of formula (35).

In addition, a compound of formula (8) can be obtained by heating a compound of formula (3) at reflux together with a compound of formula (7) in a solvent such as pyridine.

Alternatively, a compound of formula (8) can be obtained by reacting a compound of formula (3) with a compound of formula (36) according to the method of M.A. Possa et al. (Tetrahedron Lett. 33, 5933-5936, 1992) to prepare the compound of formula (37) and then removing the t-butoxycarbonyl protecting group under the conditions shown below.

Among the compounds of formula (1), the compound represented by the formula (9) with R being NHNO ₂ and the compound represented by the formula (10) with R being NH ₂ can be synthesized from a compound of formula (3) as a substrate, if R _2, R ₃ , R ₄ , R ₅ , Y _b Y ₂ , Y ₃ , Y ₄ , m and _n in formulas (3), (9) and (10) are the same as defined above.

A compound of formula (9) can be obtained by reacting a compound of formula (3) with N-methyl-N'-nitro-N-nitrosoguanidine or N-nitro-S-methylisothiourea in a reaction-inert solvent such as acetonitrile, ethanol, methanol or water, preferably in acetonitrile, at a temperature between room temperature and the boiling point of the mixture

Preferably at room temperature, optionally in the presence of triethylamine or acetic acid.

The compound represented by the formula (10) can be obtained by reducing the compound represented by the formula (9). The reduction can be performed in a reaction-inert solvent such as methanol in the presence of formic acid and palladium black at room temperature.

Among the compounds of formula (1), a compound in which R ₄ is a hydrogen atom can be synthesized as follows.

Among the compounds represented by the formulas (6), (8), (9) or (10), compounds in which R ₄ is an alkoxycarbonyl protecting group, the alkyl portion of which is a straight chain or branched group having 1-6 carbon atoms, are deprotected by treatment with a deprotecting agent with to form compounds in which R ₄ is hydrogen. Deprotection may be carried out under such conditions as are usually used in connection with the particular type of protecting group to be removed. For example, if R ₄ is a t-butoxycarbonyl group, deprotection is preferably carried out in a reaction inert solvent such as methylene chloride, ethyl acetate, methanol, ethanol, 1,4-dioxane or water, or in the absence of solvents at a temperature between 0 ° C and at room temperature in the presence of a deprotecting agent such as trifluoroacetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, and more preferably trifluoroacetic acid at room temperature under anhydrous conditions. It should be noted, however, that those compounds wherein _R2, Yj, Y _2, Y ₃ and Y ₄ represent a t-butoxycarbonyl group are converted to such compounds that each of the substituents mentioned above is a carboxyl group whereas those compounds wherein R ₅ is t-butoxycarbonylamino is converted by deprotection into compounds such that R ₅ is amino.

ΝΗ.ΗΧ

Among the compounds of formula (1), compounds represented by formulas (12) and (13) can be synthesized with a compound of formula (11) as substrate if only R ₇ , R ₈ , X and n in the following formulas (7), (12) and (13) are the same as defined above.

A compound represented by the formula (12) can be prepared by heating a compound of formula (11) which is a compound of formula (9) wherein R _2, R _3, R _4, R _5, Y, _b Y _2, Y ₃ and Y ₄ are hydrogen im is 0, at reflux with a compound of formula (7) in a solvent such as pyridine.

Furthermore, the compound represented by the formula (13) can be obtained by reacting the compound represented by the formula (11) with N-methyl-N'-nitro-N-nitrosoguanidine in a solvent such as pyridine at a temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature.

The compound of formula (3), from which compounds of formula (1) are to be prepared, can typically be prepared according to the following schemes:

183 619

A compound of formula (3), where

R ₂ represents hydrogen, straight-chain or branched alkyl group having 1-6 carbon atoms, or an alkoxycarbonyl group wherein the alkyl moiety is a straight or branched alkyl yl group having 1-6 carbon atoms or may combine with R ₃ to form a 3- to 8 a member carbocyclic ring;

R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R ₂ to form a 3- to 8-membered carbocyclic ring;

R ₄ is a straight or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, or an acyl group having 1-8 carbon atoms;

R ₅ represents a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, or an alkoxycarbonylamino group whose alkyl portion is a straight or branched alkyl group having 1 -6 carbon atoms;

Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms which may optionally be substituted with 1-3 halogen atoms, the NY ₅ Y group ₆ where Y ₅ and Y ₆ , which may be the same or different, are atoms, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a ring piperidine or pyrrolidine;

m is an integer of 0 or 1; n is an integer of 0 or 1 may be synthesized from a compound of formula (2) used as a substrate, if R _2, R _3, R _4, R _5, Y, _b Y _2, Y _3, Y _4, m and wponiższych formulas ( 2) and (3) are the same as defined above.

The compound of formula (2) is catalytically reduced in a reaction-inert solvent such as ethanol, methanol, ethyl acetate, acetic acid or 1,4-dioxane, preferably in ethanol

183 619 or methanol, under a hydrogen atmosphere at a temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature, with palladium on carbon, Raney nickel or platinum oxide as a catalyst; alternatively, the compound of formula (2) is reduced with nickel (II) chloride and sodium borohydride, etc .; in each case, the nitro group in the compound of formula (2) is reduced to form the compound of formula (3).

Those compounds of formula (3) in which R ₄ is an alkoxycarbonyl group whose alkyl portion is a straight or branched group having 1-6 carbon atoms can also be obtained by converting the amino group represented by NHR ₅ in those compounds of formula (3), wherein R ₄ is hydrogen, w carbamate. When R ₄ is a methoxycarbonyl group, the above reaction for producing a carbamate that contains an alkoxycarbonyl group whose alkyl portion is a straight or branched group having 1-6 carbon atoms can be carried out with methyl chlorocarbonate in a reaction inert solvent such as methylene chloride in the presence of an organic base such as like triethylamine or Ν, Ν-dimethylaminopyridine at a temperature between 0 ° C and room temperature. If R ₄ is a t-butoxycarbonyl group, the reaction can be carried out with di-t-butyl bicarbonate in a reaction-inert solvent such as methylene chloride, dimethylformamide or a mixture of 1,4-dioxane and water in the presence of an organic base such as triethylamine or Ν, Ν- dimethylaminopyridine, or an inorganic base such as sodium hydroxide, or sodium bicarbonate at a temperature between 0 ° C and room temperature.

Among the compounds of the formula (3), the compound represented by the formula (44) where

Re is a straight or branched alkyl group having 1-6 carbon atoms or a straight or branched alkoxy group having 1-6 carbon atoms;

Yj, Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, which may optionally be substituted with 1-3 halogens, or NY ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, represent a straight chain alkyl group having 1-6 carbon atoms or, alternatively, Y ₅ and Y ₆ may be linked together to form a piperidine or pyrrolidine ring, may be synthesized with compounds of formulas (38) and (39) as substrates, if only R ₉ in the following formulas (38), (39), (40), (41), (42), (43) and (44) is such same as defined above, and R _n is an amino group protected by a t-butoxycarbonyl group with a phthaloyl group, a trifluoroacetyl group or the like, and if Y _b Y ₂ , Y ₃ and Y ₄ , in the following formulas (38), (41), (42 ), (43) and (44) are the same as defined above.

By replacing the primary hydroxyl group in the compound of formula (38), a bromine atom, can be prepared a compound of formula (40) (wherein Y _b Y _2, Y ₃ and Y ₄ are the same as defined above). Bromination can be carried out in a reaction inert solvent such as methylene chloride in the presence of carbon tetrabromide and triphenylphosphine at a temperature between 0 ° C and room temperature.

Further, a compound of formula (40) (where Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, are hydrogen, halogen, or NY ₅ Y ₆ where Y ₅ and Y ₆ which may be the same or different, represent a hydrogen atom or a straight chain alkyl group having 1-6 carbon atoms or, Y ₅ and Y ₆ may be linked together to form a piperidine or pyrrolidine ring) can also be obtained by subjecting a compound of formula (39) (wherein Y, Y ₂ , Y ₃ and Y ₄ are the same as defined above) by reaction with N-bromosuccinimide in a reaction-inert solvent such as carbon tetrachloride or benzene in the presence of α, α'-azobis (isobutyronitrile) at reflux with heating.

Then, a compound of formula (40) (where Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, are hydrogen, halogen, straight or branched chain alkyl having 1-6 carbon atoms, which may optionally be substituted with 1-3 halogen atoms, or NY ₅ Y ₆ , where Y ₅ and Y ₆ , which may be the same or different, represent a straight chain alkyl group having 1-6 carbon atoms or, alternatively, Y ₅ and Y ₆ may be linked together forming a pipa ring

183,619 of ridines or pyrrolidines) are reacted with sodium cyanide or potassium cyanide to provide the compound of formula (41). The amino protecting group of the resulting compound of formula (41) is removed to give the compound of formula (42) which is then reacted with a hydrogenating reducing agent, preferably lithium aluminum hydride, in the presence of sulfuric acid in a reaction inert solvent such as ether or tetrahydrofuran, preferably in ether at a temperature between room temperature and the reflux temperature of the reaction mixture, preferably at reflux with heating, whereupon cyan flu is reduced to give the compound of formula (43). The aliphatic amino group in a compound of formula (43) is subsequently acylated or converted to a carbamate with a compound of formula (28) or (29) to provide a compound of formula (44). If R ₉ is a methyl group, acylation of the amino group can be carried out by reacting a compound of formula (43) with an acetylating agent such as acetyl chloride or acetic anhydride in a reaction-inert solvent such as methylene chloride in the presence of an organic base such as triethylamine or Ν, Ν- dimethylaminopyridine at a temperature between 0 ° C and room temperature.

Compounds of formula (2), from which compounds of formula (3) are to be prepared, can typically be prepared according to the following schemes outlined in Figure 3.

Among the compounds of formula (2), the compound represented by formula (17) (wherein R ₄ and R ₅ , which may be the same or different, represent a straight or branched chain alkyl group having 1-6 carbon atoms; n is an integer of 1 or 2;

Y _b Y ₂ , Y ₃ and Y ₄ are the same as defined above) can be synthesized from a compound of formula (27) via compounds of formulas (14) and (15) if only R ₄ , R ₅ , Y], Y ₂ , Y ₃ , Y _{4 and} n in the following formulas (27), (14), (15), (16) and (17) are the same as defined above and X is chlorine or bromine.

The carboxyl group in the compound of formula (27) is reduced with a reducing / hydrogenation agent, preferably diborane, by heating to reflux in a reaction inert solvent such as tetrahydrofuran to provide the compound of formula (14).

The primary hydroxyl group in the compound of formula (14) is then replaced with a halogen atom under the usual reaction conditions to provide a compound of formula (15). When X is chlorine, the halogenation reaction can be carried out with thionyl chloride in a reaction-inert solvent such as benzene in the presence of a suitable base such as pyridine at a temperature between 0 ° C and room temperature.

The resulting compound of formula (15) is then reacted with an amine of formula (16) in a reaction-inert solvent such as dimethylformamide in the presence of an organic base such as triethylamine or Ν, Ν-dimethylaminopyridine or an inorganic base such as sodium bicarbonate or potassium carbonate at a temperature between 0 ° C and room temperature to obtain a compound of formula (17).

Among the compounds of formula (2), the compound represented by formula (17) (wherein R ₄ and R ₅ are alkoxycarbonyl groups, the alkyl portion of which is a straight or branched group having 1-6 carbon atoms;

n is 1; and

Y _b Y ₂ , Y ₃ and Y ₄ are the same as defined above) can be synthesized as follows if only R ₄ , R ₅ , X, Y ,, Y ₂ , Y ₃ , Y _{4 and} n in the following formulas (15 ), (16) and (17) are the same as defined above.

A compound of formula (15) is reacted with a compound of formula (16) in a reaction-inert solvent such as dimethylformamide in the presence of sodium hydride at a temperature between 0 ° C and room temperature to yield a compound of formula (17).

Among the compounds represented by formula (2), the compound represented by formula (30) (where R ₅ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms;

Y], Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms which may be substituted by 1-3 halogens, the group NY ₅ Y ₆ where Y ₅ and Y ₆ can be the same

183 619 or different, represent a hydrogen atom, a straight chain alkyl group of 1-6 carbon atoms, an acyl group of 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine or pyrrolidine ring;

R _{9 and} n are the same as defined above) can be synthesized from compounds of formulas (15) and (19) via a compound of formula (18) if only X, Y _b Y ₂ , Y ₃ , Y ₄ and n in the following formulas (15) ), (18), (19), (20), (28), (29) and (30) are the same as defined above.

By reacting a compound of formula (15) with ammonia in a reaction inert solvent such as hydrated dimethylsulfoxide at a temperature between 0 ° C and room temperature, a compound of formula (18) (where R ₅ is hydrogen) can be obtained.

In addition, by subjecting a compound of formula (19) to reductive amination with an amine of formula (20) (where R ₅ is a straight or branched chain alkyl group having 1-6 carbon atoms), a compound of formula (18) (where R ₅ is the same as as defined above).

The reductive amination can be carried out with a suitable reducing agent such as sodium cyanoborohydride in a reaction inert solvent such as ethanol or methanol at a temperature between 0 ° C and room temperature.

Then, the amino group in the compound of formula (18) (where R ₅ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms) is acylated or converted to a carbamate in the same manner as described above to give a compound of formula (30) (where R ₅ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms).

Among the compounds of formula (2), the compound represented by formula (32) (where Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, are hydrogen, a straight chain alkyl group having 1-6 carbon atoms which may be substituted 1 -3 halogen atoms, NY ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are hydrogen, straight chain alkyl having 1-6 carbon atoms, acyl group having 1-8 carbon atoms, or Y ₅ and Y _{6 can} be linked together to form a piperidine or pyrrolidine ring:

Rp and n are the same as defined above) can be synthesized from compounds of formulas (14) and (15) via a compound of formula (31) if only Rg, X, Y _b Y ₂ , Y ₃ , Y _{4 and} n in the following formulas ( 14), (15), (28), (29), (31) and (32) are the same as defined above.

The compound of formula (31) can be obtained either by subjecting the compound of formula (14) and phthalimide to a Mitsunobu reaction, or by reacting the compound of formula (15) with potassium phthalimide in a reaction inert solvent such as dimethylformamide at room temperature.

The phthalimide protecting group in the compound of formula (31) is then removed in the presence of hydrazine and the conversion to carbamate or acylation is performed in the same manner as described above to give the compound of formula (32).

Among the compounds of formula (2), the compound represented by the formula (22) (wherein R ₂ and R _3, which mogąbyć the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms, or R ₂ and R ₃ can be joined together to form a 3- to 8-membered carbocyclic ring;

R ₁₀ is a straight or branched alkyl group having 1-6 carbon atoms;

Y], Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms which may be substituted with 1-3 halogens, the group NY ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine ring or pyrrolidines;

can be obtained by subjecting a compound of formula (21)

183 619 (wherein R _2, R _3, Y _{b Y2,} Y3 and Y4 are the same as defined above), Curtius rearrangement, and the addition reaction of various alcohols of the formula (33) (wherein R ₁₀ is as defined above) .

The reaction Curtius rearrangement and addition reactions of various alcohols can be carried out by reacting a compound of formula (21) (wherein R _2, R _3, Y], Y _2, Y ₃ and Y ₄ are as defined above) with a reagent such as diphenylphosphorylazide at room temperature to form the acid azide from the carboxylic acid and then reacting the acid azide with an alcohol such as methanol, ethanol, or t-butanol at reflux with heating. Alternatively, the reaction can be carried out by reacting a compound of formula (21) with a reagent such as diphenylphosphorylazide at reflux with heating to form an acid azide from a carboxylic acid in an alcohol such as methanol, ethanol, or t-butanol in the presence of an organic base such as triethylamine or N, N-dimethylamino-pyridine.

Among the compounds represented by formula (2), the compound represented by formula (24) (where Re is a straight or branched alkoxy group having 1-6 carbon atoms; and

R ₁₀ is as defined above) can be obtained by converting the amino group into the compound of formula (23) into the carbamate as described above and then performing the esterification in the usual manner. The esterification may typically be carried out using an appropriate condensing agent and the various alcohols in a reaction-inert solvent in the presence of an organic base at a temperature of 0 ° C - 50 ° C. In the case of the preparation of t-butyl ester, the reaction can be carried out with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and t-butanol in methylene chloride in the presence of an organic base such as triethylamine or N, N-dimethylaminopyridine at 0 ° C C - 50 ° C, preferably at room temperature. Alternatively, for the preparation of the methyl ester, the reaction can be carried out with trimethylsilyl diazomethane in a reaction-inert solvent such as methanol or an ether, which is used alone or in admixture at a temperature between 0 ° C and room temperature.

Among the compounds of formula (2), a compound represented by formula (26) (where R and R ₁₀ are as defined above) can be obtained from a compound of formula (25) by first converting it to a 3- or 4-nitro-DL-phenylglycine according to with the method of H. Tsunematsu et al. (Journal of biochemistry 88,1773-1783,1980) and then converting the amino group to carbamate as described above and performing esterification.

If the compounds according to the invention represented by the general formula (1) contain asymmetric carbon atoms in the structure, pure forms of their stereoisomers and optically active forms can be obtained by known techniques, such as chromatography on an optical isomer separating column and fractional crystallization.

The compounds of the invention represented by general formula (1) can be converted into any pharmaceutically acceptable salts including, e.g., salts with inorganic acids such as hydrochloric, sulfuric, nitric, hydrobromic and hydrogen iodine, salts with organic acids such as formic, acetic, oxalic acid. and tartaric, alkali metal salts such as sodium and potassium, and alkaline earth metals such as calcium and magnesium.

The compounds of the invention or their salts can be formulated with suitable excipients, adjuvants, lubricants, antiseptics, disintegrating agents, buffering agents, binders, stabilizing, wetting, emulsifying, coloring, flavoring, perfuming, etc. into tablets, granules, fine granules, powders, capsules, syrups, elixirs, suspensions, emulsions, injectables, etc. for oral or parenteral administration. When the cerebrovascular disease to be treated is in the hyperacute phase (immediately after a stroke), in the acute phase (from a stroke to 2 or 3 days later) or in the subacute phase (2 or 3 days to 2 weeks after a stroke), administration will most likely be by intramuscular or intravenous injection. . In addition, oral administration can be carried out in the chronic phase (third week after stroke and beyond) if the patient is comfortable swallowing.

183 619

The compounds of the invention or their salts may be administered at doses that vary with the patient's physical make-up, age, physical condition, severity of the disease, sometimes the onset of the disease, and other factors; typical daily doses may range from 0.1 to 100 mg / person. It should be noted that even when the same dose is administered, the plasma concentration may sometimes fluctuate significantly between patients; therefore, the optimal drug dose should be accurately determined for the patient on the basis of observed plasma concentrations.

When the compounds of the invention or their salts are formulated as preparations for internal use, lactose, sucrose, sorbitol, mannitol, starches such as potato or corn starch, starch derivatives and common additives such as cellulose or gelatin derivatives, with the aid of lubricants such as magnesium stearate, carbon waxes and polyethylene glycol optionally added simultaneously; the resulting mixtures can be formulated in the usual way into granules, tablets, capsules or other forms suitable for internal use.

When the compounds of the invention or their salts are formulated as aqueous preparations, effective amounts of the main ingredients may be dissolved in distilled water for injection, if necessary with antioxidants, stabilizers, solubilizers, buffers, preservatives, etc., and filtered after the solutions have been formed. them, filled into ampoules, sealed and sterilized with a suitable agent such as high pressure steam or dry heating to provide an injection fluid.

When the compounds according to the invention or their salts are formulated as lyophilized preparations, aqueous solutions containing the main ingredients dissolved in distilled water for injection can be freeze-dried in the usual manner, optionally after adding lyophilization-promoting excipients such as sugars (e.g. lactose, maltose and sucrose). ), sugar alcohols (e.g. mannitol and inositol), glycine and the like.

The preparation of the compounds of the invention is described in more detail below with reference to the following examples, but it should be understood that the invention is by no means limited to these examples.

In addition, to demonstrate the utility of the invention, the selective inhibitory effect of the compounds of formula (1) on the three NOS isoforms and their alleviating effect on occlusive cerebrovascular disease in a rat model of stroke were investigated and the results are presented below in the tests.

Examples

Tables 1-26 show the chemical structures of the compounds prepared in the corresponding examples.

Abbreviations cited in the tables have the following meanings:

Bz - benzoyl

Bn - benzyl

Bu - t-butyl

Boc - t-butoxy

183 619

Table 1

Example

Example

Example

Example

Example

Example

Example

BocHN

Me

Example no ₂

BocHN

Me

NH

Example

Example

BocHN

Me

Example

Η N 2

Me

Example

Example

Me

Example

BocHN

Et

Example no ₂

BocHN

NH

Et

Example

BocHN

Et

Example

BocHN

Et

Example

Example

BocHN

Et

Example

Et

Example

BocHN

N0 ₂

BocHN

NH 2

BocHN

N NH

H ²

Example

Example

Example 24

BocHN

H.HI

N SMe

H.

H £ N

H-2HC1

N SMe

H.

BocHN

H.HI

N SEt

H.

Example 25

Example 26

Example 27

183 619

Table 2

Example 29

Example 30

BocHN

Example 31 Example 32 Example 33

Example 34 Example 35 Example 36

Example 37 Example 38 Example 39

Example 40 Example 41 Example 42

Example 43 Example 44 Example 45

Example 46 Example 47 Example 48

Example 49 Example 50 Example 51

Example 52 Example 53 Example 54

183 619

Example 55

Table 3

Example 58

Example 56

JT

BocHN ^^^ N ^ SMe H

Example 57

[Λΐ ^NH-1 H 2HC1

BocHN

H.

Example 61

NHNOj

Example 59 Example 60

ΒοοΗΝ ^ χν ^ / "~ ac -ra_,

H.

Example 62 Example 63

Example 64

H.

Example 67

Example 65

^Η 2 ^Ν > ΆΆι NH. HI I * 1 U.

MeO ₂ CH

Example 68

Example 66

Example 71 Example 72

Example 70

BocHN ^ / γ. NH-HI t-BuO ₂ CH

Example 74

Example 81

183 619

Table 4

Example 85 Example 86

Example 84

Example 87

Example 88 Example 89

Example 90

BocHN

H.

Example 91

H.2HC1

H.

Example 94

Example 97

Example 92 Example 93

S-n-Bu

Example 95 Example 96

Example 98

Example 99

Example 101 Example 102

Example 103

Example 104

183 619

Table 5

Example 105

Example 106

Example 107

Example 111

Example 109

Example 110

Example 113

NH

Example 123

Example 118

Example 124

Example 119

XIF ^HI

H Example 126

Example 127

183 619

Table 6

Cl

Example 132

Example 138a Example 138b Example 139

Example 140 Example 141 Example 142

146

Example

Example 147a Example 147b

Example

148

Example 149

Example 150

183 619

Table 7

Example 154 Example 155 Example 156a

Example 156b

Example 157

Example 158

Example 163 Example 163b

Example 162

Example 164 Example 165 Example 166

Example 167 Example 168 Example 169

Example 170

Example 171

Example 172

183 619

Table 8

Example 173

Example 174 Example 175

BocHN

Example 176

Example 178a

Example 180

Example 178b

Example 182 Example 183

Example 181

Example 188

Example 189

Example 190

BocHN

Example 191

Example 193 Example 194

Example 195

183 619

Example 196

Table 9

ABOUT

Example 197

Example 199

Me

Example 200

Example 201 Example 202 Example 203

ABOUT

Example 204

Example 205

Example 206

H.

Example 209

Example 210

Example 211

Example 214

Example 215

H.

Example 216

Example 217

Example 218

183 619

Table 10

Example 225 Example 226

Example 227

BocHN

Example 230

Example 229

Example 228

Example

231

Me Me

Example 232

Me Me

Me Me

Example Ic

Example la

Me

Example 8a

Example Ib

Example 8b

Et

Example 15a ₂ n

NHBoc

Et

Example 15b

183 619

Table 11

Example 251

Example 253

Example 252

BocHN

Example 257

Example 258

Example 259

183 619

Table 12

Η N 2

H.HC1

N NHNO ₂

H.

260

Example 261

Br

no ₂

262

Example

Example

with

265

Example

Example 264

Example 263

Me ₇ N

Boc ₂ N

grade

Me, N

N NHEt H

H ₂ N

H.3HC1

Me, N

Example 266

NHEt H

Example 267

Boc ₂ N

N NH ₂

H.

Example 268

Me ₂ N

Boc ₂ N

Me, N

Example

SEt H

269 h ₂ n

H.3HC1

SEt H

Example 270

MeO

BocHN

H.

Example 271

NHNO ₂

F ' ^HCl

Η

Example 272

NH.2HC1

H.

Example 274

example 275

NH.2HC1

H ₂ fx / ® < _N A _NHMe

Example 276 Example 277

Example 278

MeO

Me

Η N 2

H.2HC1

Boc ₂ N

Example

N NHNO ₂

H 280

NH.2HC1

Η ^ χ / ^ C ^ N ^ NHNOj

H.

Example 281

NH-n-Pr H

Example 279

Example 283 Ife

Et-N

Example 282 How many Et — N

Η N 2

H.3HC1

NHEt H Example 285

Boc ₂ N

Example

N 2

H 286

183 619

Table 13

Η

Example 287 ^Et ~ ^N > © 1 NH.3HCl

H.

Example 288

Example 290

Η N

H.2HC1

NHOMe H

Example 289

OMe

OMe

Example 293

Example 291

Example 292

OMe

Example 295

Example 296

Example 294

H.

Example 299

Example 297

Example 300

Example 298

H.

Example 302

Η N 2

2HC1

Example 301

Me, H.

Example 303

Η N 2

H.2HC1

H ^H Me

Example 304

Example 305

Example 306 Example 307

Example 311

Example 312

Example 313

183 619

Table 14

Boc ₂ N

Example

NH

314

Boc ₂ N

Example 315

ABOUT

NH ₂

BocHN

SEt H

Example 316

Η N 2

.2HC1

SEt

H.

Example

° 2

ABOUT

Example 318

EtO

319

Example

EtO no ₂

EtO

317

BocHN

Example

NOj 320

BocHN

NH

321

EtO

BocHN

H.HI

Example

N SEt

H 323

Example

EtO

. 2HC1

N SEt

H.

Example 324

EtO

HN 2

H.2HC1

EtO

BocHN

S.

N ^ NH ₂

H 322

BocHN

EtO example

Boc

N NHEt

H.

Example 325

N NHEt

H.

326

BocHN

EtO

Η N 2

.HC1

NHNO ₂

Example of O

NH

NHNO ₂ H

Example 327

ABOUT

NHCOCF ₃

H.

Example 328

ABOUT

331

ABOUT

Example

NHCOCFj

ABOUT

Example

ABOUT

Example 329

ABOUT

Example 332

NHCOCFj

330

334

Example

333

BnO

BocHN

N NH ₂

H.

BocHN

Example

BnO

BnO

Example 335

BnO

BocHN

Boc

N NHEt H

N SEt

H.

Example 336

BnO

Η N 2

H.2HCI

N NHEt H

Η N 2

H.2HC1

N SEt

H.

BocHN

Example 337

BnO

N NHNO ₂ H

Example 340

Example 338

Example 339

183 619

Table 15

BnO

H.HC1

NHNO, H

Example 341

Me Example

342

Example

Example 344

343

with

347

Example

346

Example

345

Example

BocHN

349

Example

348

Example

350

Example

BocHN

351 no ₂

BocHN

NH

Example

Example 353 f · " ¹

Example 354

Example 352

Example 355

Example 356 Example 357

BocNH (CH _z )

Example 358

Example 359 Example 360 Example 361

Example 362 Example 363 Example 364

Example 365 Example 366 Example 367

183 619

Table 16

Example 368 Example 369 Example 370

Example 371 Example 372 Example 373

Example 374 Example 375 Example 376

Example 377 Example 378 Example 379

Me

I ί | Ί NH.2HC1 s: ec H

H.

Example 382

Example 380

Example 381

Example 385

Example 383

Example 384

JAC

H.

example 386

Example 389

Example 387

Example 308

K ^H * ^2HCl MeHN4AA _N ANH _Et

H.

Example 392

Example 390

Example 391

Example 393

Example 394

183 619

Table 17

Example 397

Example 398

Example 396

Example 400 ^Μβ ° ΥΎ NH.2HCl ^Me AA> \ As _E t

Η

Example 401

Example 402

Example 404

T ^HI

H.

Me

Example 407

Example 405

Me

Example 408

Example 403

Example 413

Example 416

Example 417

Example 415

OMe

OMe

Example 419

Example 418

OMe

Example 420

OMe

Example 421

183 619

Table 18

Example 422 Example 423 Example 424

Example 425 Example 426 Example 427

Example 431 Example 432 Example 433

Example 434 Example 435

Example 437

3HC1

HEt H.

Example 440

NH.3HC1

H.

Example 438

Example 439

Example 441

Example 442

Η N 2

H.2HC1

NHEt H

Example 445

Example 446 Example 447

Example 448

183 619

Table 19

Example 449

Example 450 Example 451

NH.3HC1 h ^^^ n- ^ sec H Example 452

Example 453 Example 454

Example 455

Example 456

Example 457

Example 458

NH.3HC1

Example 459

Example 461

Example 460

Example 464

Example 467

Example 462

Example 463

NH.2HC1

H.

Example 466

H.

Example 470

H.

Example 468

Example 472

Example 473

Example 474

Example 475

183 619

T a b e 1 a 20

Example 477 Example 478

Example 481

Example 482 Example 483 Example 484

0 O

Example 485 Example 486 Example 487

Example 488 Example 489 Example 490

Example 491 Example 492 Example 493

Example 494 Example 495 Example 496

Example 497 Example 498 Example 499

Example 500

Example 502

183 619

Table 21

Example 503 Example 504 Example 505

Example 509 Example 510 Example 511

MeO

HNO

BocHN

Example 518

Me

Example 521

Example 519

Example 520

Example 524

Example 522

Example 526

Example 525

Example 527

Example 528

Example 529

183 619

Table 22

Example 530 Example 531 Example 532

Example 533 Example 534 Example 535

Example 536

Example 539

Example 540

Example 541

Example 546 Example 547

Example 552 Example 553

Example 551

Example 554

Example 555

Example 556

183 619

Table 23

BocHN

SEt

H.

Example 557

Η N

H-2HC1

SEt

N

H 558

Boc ₂ N

Η N

.2HC1

Example

Example of BnO

MeOOC

Me Me

NHEt H 560

Example of BnO

MeOOC

Me

NBoc N ^ NHEt H

559

no ₂

Me

Example 561

no ₂

BnO

HOOC

Me Me

Example 563

BnO

Η N 2

Me

no ₂

Example 562 BnO

BocHN

Me

Example 565

BnO

HN

Me

N0 ₂

Example 564

BnO

BocHN

Me

nh ₂

BnO

BocHN

Me Me

Example

BnO

BocHN

Me

566

Me

Boc

NHEt H

Example 569

BnO

BocHN

Me Me

Example

N ^ SEt

H.

572

H00C

Me

NO ₂

Me OBn

Example 575

BocHN

Me Me OBn

Example 578

nh ₂

HNO ₂

Me ¹¹

Example 567

NHNOj

BnO

Η N

Me

Me

Example

NHEt H

570

Example 568 BnO BocHN

Me Me ¹¹

Example 571

NH ₂

BnO h _of n Me

Me

U ^ SEt H

MeOOC

Me

NO ₂

Me OBn

Example 574

Example 573

HN

Me

N0 ₂ MeoBn

Example 576

Boc

^B0CBN HO,

Me Me OBn

BocHN

Me

NHEt

Example 579

SEt

Η N z

Me

577

Example

NHEt

Me OBn ^H

Example 580

SEt

Η N 2

Me

Example 583

BocHN

Me

Example 582

BocHN

Me

Example 581

183 619

Table 24

Example 593

Example 591 Example 592

Example 596

Example 597 Example 598

Example 600 Example 601

Example 602

Example 603 Example 604

183 619

Table 25

Example 611 Example 612

Η ye Bn-N

. 3HC1

SEt

H.

Example 614 ye Bn-N

Boc _from N

Boc

NHEt

Example 613

N

H.

Example

N0 ₂

Me Me

Example 617

615

BocHN

Me

Me ° z

Example

BocHN

Me Me

Example 620

NH _Z

618

BocHN

SEt

Me Me

Example 621

Example 616

BocHN

Boc

NHEt

Me Me ¹

Example 623

BzHN

N SEt H

NH.2HC1 ^e 2 Ν'γ '^' γ '^ -' ^ ΝΗΕ t Me Me ^H

Example 624

ΒζΗΝ ^ γΡ ^ NBoc ^^ N ^ NHEt

H.

Example 622

Example 628

626

Example

629

Example

BzHN

grade

NHEt

H.

Example 632

Example 627

Example 631

Example 633

Example 634

Example 635

Example 636

Example 637

183 619

Table 26

Example 638

NH.2HC1 ^e N ^{Boc H} z ^N 'sX ^> ^z > J ^' SEt

Example 639

Example 640

MeO

2HC1

HEc

H ₂ N

Me ⁿ

Example 641 ¥ ^e AcN

Boc ₂ N

H.

Example 644 nh ₂

Example 645

Example 643

NH.2HC1

Ή

Example 646

BoCjN

Example 647

HO

NMe ₂

Example 650

N0 ₂

N NHEt H

Example 651 Example 652

BocHN

Boc

NHEt

NMe ₂

Example 653

HO

HN

H.2HC1

Example 656

N NHEt H

Example 657

BzHN

Η N z

N SEt H

Example 660

Example 661

Example 659

BzN

HN 2

HEt H.

Example 662

Example 663

Example 664

Among the compounds prepared in the examples, compounds represented by the general formula (1) are shown in Tables 27-48.

183 619

T a b e 1 a 27

183 619

Table 28

^Y Y 2 t Al RWI NH? _2/4 and IL ₃ R,% ¹ Η _Y4 γ ^acid acid HCl 1 HCl HBr HCl 1 1 HCOOH HC1 _ CH3COOH ΗΝΟ3, HCl IH 1 HCl HI HCl ^{k The} number indicates the position of the substitution on the benzene ring. R, ** Z = ~ Wn <HCH,) rn- <r ₃ r ₅ m X X X X X X X X X X Me Me Me Me X X X t-BuOCO ί X t-Bu0C0 X t-Bu0C0 X t-BuOCO X Me Me t-BuOCO 1 X t-BuOCO X ε about ABOUT about ABOUT about ABOUT about ABOUT about 0 0 0 0 loam t — 1 CO a: X X X X X X X X X X X X X X X OJ (X X X X X X X X X X X X X X X X c about about about about about about about about about 0 0 0 0 0 0 position Z ** What What What What What What What What What What What What What H-9 and H-9 H-9 1 H-9। H-9 H-9 6-Η 6-H H-9 6-H H-9 H-9 H-9 H-9 6-H | * WHAT > < 5-H 5-H 5-H ^5-H ί 5-H 5-H ⁵ - ^H 1 5-H ^5-H 5-H 5-H. 5-H 5-H 5-H 5-H 04 > < 4-H 4-H 4-H 4-H 4-H 4-H 4-H 4-H 4-H 4-H X 1 4-H 1 4-H 3-H 3-H Yl * \ 2-H 2-H 2-H ! 2-H AND 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H | 2-H 2-H 2-H cT SEt sch ₂ ch ₂ f sch ₂ ch ₂ f OJ X U II X u OJ X u what sch ₂ ch = ch ₂ nhno ₂ nhno ₂ OJ X Z nh ₂ nhno ₂ SMe SEt | SMe SMe Example no 28 29 thirty 31 32 33 WHAT LT) CO 36 39 41 46 51 52

183 619

acid 1 1 IH 1 HCl 1 HCl HI HCl 1 1 HI HCl 1 IH ιΓ) cc in X X X X X X X X X X X X X r ₄ t-BuOCO X t-BuOCO X t-BuOCO, and X t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO t-BuOCO g rd rd rd rd rd r-w 0 0 0 0 0 0 0 0 what cc X X X X X X X X X X X X X X * 3 * ί (Μ Μ Ο Ια AND Ρ. acid OJ CC X X X X X X COOMe COOMe COOMe COOMe COO-t-Bu X 0 0 u COO-t-Bu COOMe nzen <Ν | ρΓ α about about about about about about rd rd rd rd rd rd rd 0 1 be Μ ο > Γ r- | - . > Η position- I with** What What What What ’ΪΤ thinned > <K ^ = d τΓ > < H-9 H-9 H-9 6-H 6-H H-9 6-H H-9 H-9 H-9 H-9 H-9 6-H H-9 in the pier χ__ 2Κ ρΓ *What 5-H 5-H 5-H 5-H 1 5-H 5-H 5-H 5-H 1 H-9 i 5-H ί 5-H 5-H 5-H 5-H awnings OJ 3-H 3-H * 1 4-H 4-H। 4-H 3-H 3-H 3-H H- £ 1 H-E 3-H 3-H 3-H j podsti Yl * 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H item; • _E and* nhno ₂ nhno ₂ SMe SMe nhno ₂ NHNO3 SMe SMe nhno ₂ nhno ₂ SMe SMe nhno ₂ SMe means and ί ^ φ-ώ ’a and (0 | At- example no 53 10 59 EYE 5 OJ col KO WHAT KO 69 70 75 KO oe * Lychee II +

183 619

Table 30

183 619

acid 1 HNO ₃ , HCl hno ₃ , hci 1 HCl HI HCl HI HCl 1 1 HI HCl HI HCl ^S H Me Me Me X X X Me Me Me Me Me Me Me X X & Me Me Me t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO X e ABOUT ABOUT ABOUT about about ABOUT ABOUT ABOUT ABOUT ABOUT about ABOUT about ABOUT about X From he CC X X X X X X X X X X X X X X X nzen. 2 - (CH ₂ ) ^ ³ . acid CM X X X X X X Me Me Me Me Me Me X X X X from-o-from cn ¹ c 0 rH r-H rH rH t — 1 ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT about about about about at Λ jo θ H 7 \> r position Z ** Ό Sr What 00 What WHAT What 00 What 00 What WHAT 0) about \ ** of ⁰⁴ Y ₄ * H-9 6-H 6-H 6-H H-9 H-9 H-9 6-H H-9 H-9 H-9 H-9 H-9 H-9 H-9 in the pier ot * oo > < Η-ς 5-H H-9 5-H 5-H 5-H 5-H H-9 5-H 5-H 5-H 5-H 5-H 5-H ^5-H awnings * CM> < 3-H 3-H 3-H X 1 co 3-H 4-H 4-H 4-H 4-H 4-H 4-H 4-H 4-H 4-OMe 4-OMe j, base; ^Y l * 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H ^{2 H.} 2-H 2-H 2-H 2-H 2-H position Λ ^R 5 nhno ₂ SMe AND SEt SEt SEt SMe SMe SEt SEt nhno ₂ nhno ₂ SMe SMe SEt SEt ia means - (cą) ,, 5- (0¾) Example no 66 101 102 103 104 109 110 111 112 113 114 115 116 121 122 * Lychee ** Z =

183 619

Table 32

183 619

Table 33

183 619 tS υ £ β

Η

Ε c

m Φ

ΖΙ

acid HCl 1 1 1 HCl 1 HCl 1 HCl 1 HCl HI HCl 1 HI HCl m α X X X X X X X X X X X X X X X r ₄ X t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO X Ε about ABOUT about r-w r-w i-4 ABOUT about ABOUT about ABOUT about ABOUT ABOUT C0 α X X X Me Me Me Me Me Me Me Me X X X X r ₂ Me Et Et Me Me Me Me Me Me Me Me X X X X C. ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT rd rd rH rd about about about about position Z ** en What What What What What What * > < H-9 H-9 H-9 H-9 H-9 H-9 6-H 6-H | 6-H 6-H H-9 6-OMe 6-OMe | 6-C1 about 1 to 1 Υ ₃ * 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H Vj> 4-H 4-H 4-H 3-H 3-H 3-H 4-H 3-H 3-H 3-H 3-H X 1 4-H 4-H 4-H Yl * 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 1 2-H and SEt SEt SEt SEt SEt nhno ₂ Cl O z X z SEt , SEt nhno ₂ nhno ₂ SEt SEt 1 SEt SEt Example no 175 176 177 184 185 186 187 192 193 194 195 201 202 1 208 209

Ο β Φ Ν C Φ

in ο

£

Φ

Φ

Ν U β Ν Ο

Φ β Φ υ '«ι Μ φ φ · υ

Φ §

Ν ϋ υ ώύ-ίΓ φ =

183 619

Table 35 • ε a: in QC 3

ABOUT

acid l HCl vol And HC1। l HCl 1 HCl vol HCl HI HCl HCl HCl HI in a: X X X X X X X X X X X X X X X and t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO X t-BuOCO X X X X ε ABOUT about ABOUT about r-w r-w rH rH t-w rH ABOUT ABOUT about about about CO a: X X X X X X X X X X X X 1 in CM X O 1 1 CM X u 1 1 co CM X U 1 cm Ρί COOMe COOMe COOMe COOMe COOMe COOMe X O O O C00H COOMe COOMe X X c ABOUT ABOUT tH r-w ABOUT ABOUT about ABOUT ABOUT ABOUT about about about about about position Z ** What What WHAT WHAT «· CM CM What What What H-9 6-H 6-H H-9 H-9 6-H H-9 H-9 6-H H-9 6-H H-9 H-9 ' H-9 6-H what> 5-H i 1 5-H j 5-H 5-H 5-H ¹ 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H ί ______ 5-H 5-H * cm 4-H 4-H 1 4-H X 1 3-H 3-H 3-H 3-H 3-H 3-H 4-H 4-H 4-H 1________ 4-H X 1 I 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H 3-H 3-H 2-H 2-H 2-H χ ¹ SMe SMe SMe SMe nhno ₂ ¹ cJ O z X z nhno ₂ O z X z SEt SEt SEt SEt NHEt NHEt NHEt Example no 211 212, 1 216 217 220 221 222 223 225 226 231 232 234 236 238

o c OJ N c OJ

□ <ύ w

Oh o>

u <0 c

<u <0

U to M OJ c OJ

N

U u (0 c N o

183 619

Table 36 p

what cb

acid 1 HCl 1 HC1 and ___________ 1 HCl HCl 1 HCl HCl 1 HCl 1 HCl HCl UO X t-BuOCO X t-BuOCO X X X X X X X t-BuOCO X X X X Λ t-BuOCO X t-BuOCO X t-BuOCO X X t-BuOCO X X t-BuOCO X t-BuOCO X X ε ABOUT 0 0 0 0 0 0 0 0 0 0 0 0 0 0 cn a: X X X X X X X X X X X X X X X CM X X X X X X X X X X X X X X X X c about 0 0 0 rH t-4 rH rH 0 0 0 0 0 0 0 position Z ** What What What What ’Τ about· WHAT What What WHAT What What ♦ : * H-9 H-9 6-H H-9 6-H H-9 H-9 H-9 H-9 H-9 H-9 6-H H-9 6-H H-9 what> 5-CF ₃ 5-CF3 5-CF3 5-CF3 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H 5-H * CM 4-H 4-H 4-H 4-H 3-F 3-F 3-F 3-F Ui 1 co CM Φ X X 1 CM X X 1 CM d X X 1 4-OMe 4-OMe 4-OMe Yl * 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H ^2-H 2-H 2-H 2-H 2-H 2-H 2-H βΓ SEt SEt nhno ₂ nhno ₂ SEt SEt NHEt nhno ₂ nhno ₂ i NHEt SEt and SEt nhno ₂ nhno ₂ NHEt Example no 244 245 246 247 255 256 258 259 260 267 269 270 271 272 274

N

ABOUT

it is Fr.

o>

at

H c CU u is 14 (U

O β (D N U (U c

Φ H id for what; =

S g ο γ rO '

183 619

Table 37

(to) -ó (to)

183 619 (CH ₂ ) -C- (CH ₂ ) _m

Η

183 619

Table 39

183 619

Table 40 p

Φ 3

acid HCl 1 HCl 1 HCl HCl HCl HCl IH HCl HCl HI HC1 ........ HCl HCl = H. X t-BuOCO X Me Me X Me Me Et Et X Me Me 1 Me Me Λ X t-BuOCO X Me Me Me Bn Bn t-BuOCO X Me t-BuOCO X Me Me s about ABOUT about ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT about ABOUT ABOUT about ABOUT ABOUT What Di X X X X X X X X X X X X X X X Father cc X X X X X X X X X X X X X X X c about about about about about about about about about about about about about about about item- | I with** What What What What WHAT What WHAT What What yy WHAT What WHAT What What 4c H-9 6-H H-9 H-9 H-9 H-9 H-9 H-9 H-9 H-9 H-9 H-9 6-H 1 H-9 H-9 what> < 5-H 5-H 5-H 5-H 5-H \ 5-H 5-H 5-H 5-H 5-H 5-H 5-H : 5-H and 5-H 5-H 4c OJ > < 4-H 4-H 4-H 4-H 4-H 4-H 4-H 4-H 4-H 4-H 4-OMe 4-OMe 4-OMe ^ I__________________________________________________________________________________________________________________________________________________________________________________________________________ 4-OMe 4-OMe * 1 * 2-H 2-H 2-H 2-H 2-H 2-H 2-H 2-H ² - ^H. 2-H 2-H 2-H 2-H 2-H 2-H and? NHEt NH-n-Pr NH-n-Pr SEt NHEt NHEt SEt NHEt SEt SEt And NHEt 1 SEt SEt | NHEt SEt Example no 369 • 370 371 372 374 376 380 382 387 388 392 394 395 1 399 401

φ o

φ u

ci φ

c: φ c φ H 3 Φ u οεφ.ο?

φ j =

S £

About V

O c: φ N C Φ

183 619

Table 41

(te) (to)

183 619

Table 42

183 619

Table 43

(ch,) ,, - 0 (0¾)

183 619 (CH ₂ ) -e- (CH ₂ )

Λ Η e

σι <ΰ 3

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183 619

Table 45

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183 619

Table 46

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183 619

Table 47

183 619

Table 48

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183 619

Example 1

Synthesis of N- (1-methyl-1- (3-nitrophenyl) ethyl) carbamic acid t-butyl ester

Example la

A solution of 3-nitrophenylacetic acid t-butyl ester (1.56 g) in dimethylformamide (30 ml) was added dropwise to a mixture of sodium hydride (content - 60%; 631 mg) and dimethylformamide (45 ml) at 0 ° C. After the reaction mixture was stirred for 10 minutes, methyl iodide (2 eq, 0.9 ml) was added dropwise at 0 ° C, stirred for 30 min and stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 97: 3) to give 367 mg of 2-methyl-2- (3-nitrophenyl) propionic acid t-butyl ester (28% yield).

Ή-NMR (CDCl ₃ ) δ: 1.39 (9H, s), 1.59 (6H, s), 7.46-7.69 (2H, m), 8.08-8.25 (2H, m)

Example Ib

A mixture of the dimethyl compound (1.1 g) obtained in the above reaction and trifluoroacetic acid (25 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 4: 6) to obtain 0.87 g of 2-methyl-2- (3-nitrophenyl) propionic acid from quantitative yield.

Ή-NMR (CDCl 3) δ: 1.67 (6H, s), 7.52-7.76 (2H, m), 8.12-8.29 (2H, m)

Example Ic

A mixture of 2-methyl-2- (3-nitrophenyl) propionic acid (866 mg) prepared in Example 1b, diphenylphosphorylazide (0.89 ml), triethylamine (0.58 ml) and t-butanol (15 ml) was heated to reflux. for 16 hours and concentrated under reduced pressure. The residue was dissolved in benzene and washed sequentially with 5% aqueous citric acid, water, saturated aqueous sodium chloride, and saturated aqueous sodium bicarbonate; the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 85: 15) to give 649 mg of the title compound (yield 56%).

Ή-NMR (CDCl 3) δ: 1.38 (9H, s), 1.65 (6H, s), 5.08 (1H, brs), 7-46-7.75 (2H, m), 8, 07-8.28 (2H, m)

MS (m / z) 280 (M ⁺ )

Example 2

Synthesis of N- (1-methyl-1- (3-aminophenyl) ethylcarbamic acid t-butyl ester

A mixture of the compound (649 mg) obtained in Example 1.10% palladium on carbon (300 mg) and ethanol (100 ml) was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 7: 3) to give 439 mg of the title compound (76% yield).

Ή-NMR (CDCl 3) δ: 1.37 (9H, s), 1.60 (6H, s), 3.62 (2H, brs), 4.87 (1H, brs), 6.53-6, 81 (3H, m), 7.07-7.13 (1H, m)

MS (m / z) 250 (M ⁺ )

Example 3

Synthesis of N- (1-methyl-1- (3-thioureidophenyl) ethyl) carbamic acid t-butyl ester Thiophosgene (0.12 ml) and a solution of the compound (284 mg) obtained in Example 2 in methylene chloride (10 ml) was added dropwise to a suspension of calcium carbonate (319 mg) in water (5 ml) in

Room temperature and stirred at room temperature for 5 hours; then, 28% aqueous ammonia solution (5 ml) was added to the reaction mixture and stirred at room temperature for 16 hours. After neutralizing with 2N HCl, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 6: 4) to give 351 mg of the title compound (89% yield).

Ή-NMR (CDCl ₃ ) δ: 1.36 (9H, s), 1.60 (6H, s), 5.04 (1H, brs), 6.21 (2H, brs), 7.05-7 , 42 (4H, m), 8.07 (1H, br s) MS (m / z) 309 (M ⁺ ) Example 4

Synthesis of N- (1-methyl-1- (3- (S-methylisothioureido) phenyl) ethyl) carbamic acid t-butyl ester iodide

Methyl iodide (0.1 ml) was added to a mixture of the compound (164 mg) obtained in Example 3 and acetonitrile (15 ml), and the reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 95: 5) to give 130 mg of the title compound (yield 54%).

Ή-NMR (CDCl 3) δ: 1.37 (9H, s), 1.60 (6H, s), 2.47 (3H, s), 4.93 (1H, br s), 6.77-7, 29 (4H, m) Example 5

Synthesis of N- (1-methyl-1 - (3 - (S-methylisothioureido) phenyl) ethyl) amine dichlorohydride

A mixture of the compound (130 mg) obtained in Example 4 and trifluoroacetic acid (15 ml) was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in ethanol (5 mL) and a solution of hydrogen chloride in 1,4-dioxane (4N, 0.29 mL) was added at room temperature, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, washed with ethyl acetate, and freeze dried to give 100 mg of the title compound (84% yield).

Ή-NMR (D ₂ O) δ: 1.77 (6H, s), 2.70 (3H, s), 7.40-7.68 (4H, m)

MS (m / z) 223 (M ⁺ )

Example 6

Synthesis of N- (1-methyl-1- (3- (N'-nitroguanidino) phenyl) ethyl) carbamic acid t-butyl ester

A mixture of the compound (145 mg) obtained in Example 2, acetonitrile (10 ml), N-methyl-N'-nitro-N-nitrosoguanidine (85 mg), triethylamine (0.08 ml) and acetic acid (0.03 ml) stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 1: 1) to give 106 mg of the title compound (54% yield).

Ή-NMR (CDCl 3) δ: 1.36 (9H, s), 1.62 (6H, s), 5.06 (1H, brs), 7.16-7.47 (4H, m), 9, 73 (1H, brs)

FAB-MS (m / z) 338 (M ⁺ + 1)

Example 7

Synthesis of N- (1-methyl-1 - (3- (N'-nitroguanidino) phenyl) ethyl) amine hydrochloride

Using the compound obtained in Example 6 as the starting material, 66 mg of the title compound were obtained according to the procedure in Example 5 (77% yield).

Ή-NMR (D ₂ O) δ: 1.76 (6H, s), 7.37-7.62 (4H, m)

FAB-MS (m / z) 238 (M ⁺ + 1)

183 619

Example 8

Synthesis of N- (1- (3-nitrophenyl) ethyl) carbamic acid t-butyl ester

Example 8a

Using 3-nitrophenylacetic acid t-butyl ester as a substrate and methyl iodide (1 eq) as a reagent, 2- (3-nitrophenyl) propionic acid was obtained according to the procedure in Examples 1 a and 1 b.

Ή-NMR (CDCl ₃ ) δ: 1.59 (3H, d, J = 7.3 Hz), 3.88 (1H, q, J = 7.3 Hz), 7.49-7.68 (2H , m), 8.13-8.21 (2H, m)

Example 8b

Using 2- (3-nitrophenyl) propionic acid as starting material, 183 mg of the title compound were obtained according to the procedure in Example Ic (67% yield).

'1-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.48 (3H, d, J = 6.6 Hz), 4.68-5.06 (2H, m), 7, 47-7.66 (2H, m), 8.10-8.17 (2H, m)

MS (m / z) 266 (M ⁺ )

Example 9

Synthesis of N- (1- (3-aminophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 8 as a starting material, 496 mg of the title compound were obtained according to the procedure in Example 2 (78% yield).

1-NMR (CDCl ₃ ) δ: 1.40-1.42 (12H, m), 3.66 (2H, brs), 4.58-4.86 (2H, m), 6.55-6 . 70 (3H, m), 7.08-7.14 (1H, m)

Example 10

Synthesis of N- (1- (3-thioureidophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 9 as starting material, the procedure of Example 3 gave 246 mg of the title compound (89% yield).

'Η-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.43 (3H (3H, d, J = 6.9 Hz), 4.67-4.79 (1H, m), 4.80-4.98 (1H, m), 6.14 (2H, brs), 7.09-7.43 (4H, m), 7.97 (1H, brs)

Example 11

Synthesis of N- (1- (3- (S-methylisothioureido) phenyl) ethyl) carbamic acid t-butyl ester iodide

Using the compound obtained in Example 10 as the starting material, the procedure of Example 4 gave 318 mg of the title compound (87% yield).

1-NMR (CDCl 3) δ: 1.42-1.45 (12H, m), 2.60 (3H, s), 4.68-4.91 (2H, m), 7.03-7, 37 (4H, m)

Example 12

Synthesis of N- (1- (3 - (S-methylisothioureidophenyl) ethyl) amine dichlorohydride

Using the compound obtained in Example 11 as the starting material, the procedure of Example 5 gave 192 mg of the title compound in quantitative yield.

'Η-NMR (D ₂ O) δ: 1.67 (3H, d, J = 6.9 Hz), 2.70 (3H, s), 4.61 (1H, q, J = 6.9 Hz ), 7.42-7.67 (4H, m)

MS (m / z) 209 (M ⁺ )

Example 13

Synthesis of N- (1- (3- (N'-nitroguanidino) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 9 as a starting material, the procedure of Example 6 gave 13 mg of the title compound (40% yield).

-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.46 (3H, d, J = 6.9 Hz), 4.72-4.80 (1H, m), 4, 89 (1H, d, J = 6.3Hz), 7.17-7.49 (4H, m), 9.25 (1H, brs)

FAB-MS (m / z) 324 (M ⁺ + 1)

183 619

Example 14

Synthesis of N- (1- (3- (N'-nitroguanidino) phenyl) ethyl) amine hydrochloride

Using the compound obtained in Example 13 as a starting material, the procedure of Example 7 gave 92 mg of the title compound (84% yield).

Ή-NMR (D ₂ O) δ: 1.66 (3H, d, J = 6.9 Hz), 4.58 (1H, q, J = 6.9 Hz), 7.38-7.61 ( 4H, m)

FAB-MS (m / z) 224 (M ⁺ + 1)

Example 15

Synthesis of N- (1- (3-nitrophenyl) propyl) carbamic acid t-butyl ester

Example 15a

Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using ethyl iodide (1 eq.) As a reagent, the procedure in Examples 1 a and 1 b gave 2- (3-nitrophenyl) butyric acid.

Ή-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.3 Hz), 1.79-1.95 (1H, m), 2.10-2.26 (1H, m) , 3.60 (1H, t, J = 7.6 Hz), 7.49-7.78 (2H, m), 8.13-8.28 (2H, m)

Example 15b

Using 2- (3-nitrophenyl) butyric acid as starting material, 1.0 g of the title compound was obtained according to the procedure in Example 1c (96% yield).

Ή-NMR (CDCl 3) δ: 0.93 (3H, t, J = 7.3 Hz), 1.42 (9H, s), 1.73-1.84 (2H, m), 4.51- 4.71 (1H, m), 4.78-4.98 (1H, m), 7.47-7.67 (2H, m), 8.10-8.13 (2H, m)

Example 16

Synthesis of N- (1- (3-aminophenyl) propyl) carbamic acid t-butyl ester

Using the compound obtained in Example 15 as starting material, the procedure in Example 2 gave 701 mg of the title compound (79% yield).

Ή-NMR (CDCl 3) δ: 0.87 (3H, t, J = 7.3 Hz), 1.42 (9H, s), 1.68-1.85 (2H, m), 3.64 ( 2H, brs), 4.30-4.50 (1H, m), 4.62-4.86 (1H, m), 6.55-6.66 (3H, m), 7.07-7. 13 (1H, m)

Example 17

Synthesis of N- (1- (3-thioureidophenyl) propyl) carbamic acid t-butyl ester

Using the compound obtained in Example 16 as the starting material, the procedure of Example 3 gave 371 mg of the title compound (97% yield).

Ή-NMR (CDCl 3) δ: 0.92 (3H, t, J = 7.3 Hz), 1.40 (9H, s), 1.69-1.80 (2H, m), 4.40- 4.60 (1H, m), 4.80-5.00 (1H, m), 6.15 (2H, br s), 7.09-7.42 (4H, m), 7.97 (1H, brs)

Example 18

Synthesis of N- (1- (3- (S-methylisothioureidophenyl) propyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 17 as a starting material, the procedure of Example 4 gave 443 mg of the title compound (82% yield).

Ή-NMR (CDCl 3) δ: 0.90 (3H, t, J = 7.3 Hz), 1.41 (9H, s), 1.70-1.80 (2H, m), 2.59 ( 3H, s), 4.39-4.61 (1H, m), 4.85 (1H, d, J = 7.6 Hz), 7.01-7.36 (4H, m)

Example 19

Synthesis of N- (1- (3- (S-methylisothioureidophenyl) propyl) amine dihydrochloride

Using the compound obtained in Example 18 as starting material, the procedure of Example 5 gave 267 mg of the title compound (93% yield).

Ή-NMR (D ₂ O) δ: 0.89 (3H, t, J = 7.3 Hz), 1.91-2.16 (2H, m), 2.70 (3H, s), 4, 30-4.36 (1H, m), 7.43-7.70 (4H, m)

MS (m / z) 223 (M ⁺ )

183 619

Example 20

Synthesis of N- (1- (3- (N'-nitroguanidino) phenyl) propyl) carbamic acid t-butyl ester

Using the compound obtained in Example 16 as the starting material, the procedure of Example 6 gave 406 mg of the title compound (87% yield).

1 H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.3 Hz), 1.40 (9H, s), 1.72-1.83 (2H, m), 4, 43-4.58 (1H, m), 4.84-5.01 (1H, m), 7.19-7.48 (4H, m), 9.56 (1H, brs)

FAB-MS (m / z) 338 (M ⁺ + 1)

Example 21

Synthesis of N- (1 - (3- (N'-nitroguanidino) phenyl) propyl) amine hydrochloride

Using the compound obtained in Example 20 as starting material, the procedure of Example 5 gave 270 mg of the title compound (83% yield).

1 H-NMR (D ₂ O) δ: 0.89 (3H, t, J - 7.3 Hz), 1.93-2.12 (2H, m), 4.30 (1H, t, J = 8.6 Hz), 7.39-7.61 (4H, m)

FAB-MS (m / z) 238 (M ⁺ + 1)

Example 22

Synthesis of N- (3-nitrophenylmethyl) carbamic acid t-butyl ester

Triethylamine (2.8 ml) and di-t-butyl bicarbonate (2.3 g) were added to a solution of 3-nitrobenzylamine hydrochloride (1.5 g) in dimethylformamide (30 ml) and stirred at room temperature for 16 hours. Water and 2N HCl were added to the reaction mixture to adjust the pH to 3; then extracted with ethyl acetate, the organic layer was successively washed with a saturated aqueous sodium chloride solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 6: 4) to give 1.9 g of the title compound (yield 94%).

1 H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 4.42 (2H, d, J = 6.3 Hz), 4.92-5.10 (1H, m), 7, 48-7.65 (2H, m), 8.11-8.15 (2H, m) Example 23

Synthesis of N- (3-aminophenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 22 as the starting material, 1.1 g of the title compound were obtained in quantitative yield according to the procedure in Example 2.

1 H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.66 (2H, brs), 4.21 (2H, d, J = 5.9 Hz), 4.73-4, 87 (1H, m), 6.56-6.67 (3H, m), 7.07-7.13 (lH, m)

Example 24

Synthesis of N- (3-thioureidophenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 23 as a starting material, the procedure of Example 3 gave 382 mg of the title compound (81% yield).

1 H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 4.32 (2H, d, J = 5.9 Hz), 4.97-5.11 (1H, m), 6, 22 (2H, brs), 7.12-7.27 (3H, m), 7.36-7.42 (1H, m), 8.19 (1H, brs)

FAB-MS (m / z) 282 (M ⁺ + 1)

Example 25

Synthesis of N- (3- (S-methylisothioureido) phenylmethyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 24 as a starting material, the procedure of Example 4 gave 489 mg of the title compound (85% yield).

Ή-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.46 (3H, s), 4.28 (2H, d, J - 5.6 Hz), 4.75-4.89 (1H, m), 6.81-6.97 (3H, m), 7.24-7.29 (1H, m)

FAB-MS (m / z) 296 (M ⁺ + 1)

183 619

Example 26

Synthesis of N- (3- (S-methylisothioureidophenylmethyl) amine dihydrochloride

Using the compound obtained in Example 25 as a starting material, the procedure of Example 5 gave 150 mg of the title compound (94% yield).

Ή-NMR (D ₂ O) δ: 2.70 (3H, s), 4.25 (2H, s), 7.31-7.66 (4H, m)

FAB-MS (m / z) 196 (M ⁺ + 1)

Example 27

Synthesis of N- (3- (S-ethylisothioureidophenylmethyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 24 as the starting material and also using ethyl iodide as a reagent, the procedure in Example 4 gave 178 mg of the title compound (68% yield).

Ή-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.3 Hz), 1.46 (9H, s), 3.06 (2H, q, J = 7.3 Hz), 4.29 (2H, d, J = 5.9Hz), 4.78-4.92 (1H, m), 6.87-7.31 (4H, m)

Example 28

Synthesis of N- (3- (S-ethylisothioureidophenylmethyl) amine dihydrochloride

Using the compound obtained in Example 27 as a starting material, 105 mg of the title compound were obtained according to the procedure in Example 5 (92% yield).

Ή-NMR (D ₂ O) δ: 1.43 (3H, t, J = 7.3 Hz), 3.25 (2H, q, J = 7.3 Hz), 4.25 (2H, s) , 7.43-7.66 (4H, m)

MS (m / z) 209 (M ⁺ )

Example 29

Synthesis of N- (3- (S- (2-fluoroethyl) isothioureidophenylmethyl) carbamic acid t-butyl ester

1-Bromo-2-fluoroethane (0.26 ml) was added to a mixture of the compound (500 mg) obtained in Example 24 and acetonitrile (20 ml), and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was distilled under reduced pressure and the resulting residue was dissolved in ethyl acetate and washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and the organic layer was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate - 6: 4) to give 50 mg of the title compound (yield 9%).

Ή-NMR (CDCl 3) δ: 1.46 (9H, s), 3.36 (2H, distorted dt, J = 22.1.5.9 Hz), 4.27 (2H, d, J = 5, 6 Hz), 4.66 (2H, distorted dt, J - 47.2.5.9 Hz), 4.80-4.94 (1H, m), 6.77-6.97 (3H, m) , 7.24-7.29 (1H, m) Example 30

Synthesis of N- (3- (S- (2-fluoroethyl) isothioureidophenylmethyl) amine dihydrochloride

Using the compound obtained in Example 29 as a starting material, the procedure in Example 5 gave 36 mg of the title compound (79% yield).

Ή-NMR (D ₂ O) δ: 3.61 (2H, distorted dt, J = 25.4.5.3 Hz), 4.24 (2H, s), 4.82 (2H, distorted dt, J = 46.5, 5.3Hz), 7.41-7.71 (4H, m)

Example 31

Synthesis of N- (3- (S- (2-propenyl) isothioureido) phenylmethyl) carbamic acid t-butyl ester hydrobromide

Using the compound obtained in Example 24 as the starting material and also using allyl bromide as a reagent, the procedure in Example 4 gave 118 mg of the title compound (34% yield).

Ή-NMR (CDCl3)

183 619

5: 1.46 (9Η, s), 3.85 (2Η, d, J - 6.6Hz), 4.30 (2H, d, J = 5.9Hz), 4.93-5.05 (IH, m), 5.28 (IH, d, J = 9.9 Hz), 5.44 (IH, d, J = 16.8 Hz), 5.83-5.98 (IH, m) , 7.03-7.36 (4H, m)

MS (m / z) 321 (M ⁺ ).

Example 32

Synthesis of N- (3- (S- (2-propenyl) isothioureido) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 31 as starting material, the procedure in Example 5 gave 73 mg of the title compound (85% yield).

'H-NMR (D ₂ O)

5: 3.91 (2H, d, J = 6.6Hz), 4.24 (2H, s), 5.36 (IH, d, J = 10.2Hz), 5.44 (IH, d , J - 16.8 Hz), 5.93-6.08 (IH, m), 7.42-7.66 (4H, m)

MS (m / z) 221 (M ⁺ )

Example 33

Synthesis of N- (3 - (N'-nitroguanidino) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 23 as a starting material, the procedure of Example 6 gave 201 mg of the title compound (70% yield).

Ή-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 4.33 (2H, d, J = 6.3 Hz), 4.86-5.00 (IH, m), 6.55 (IH, brs), 7.17-7.47 (4H, m), 9.03 (IH, brs)

FAB-MS (m / z) 310 (M ⁺ + 1)

Example 34

Synthesis of N- (3- (N'-nitroguanidino) phenylmethyl) amine

A mixture of the compound (230 mg) obtained in Example 33, methylene chloride (3 ml) and trifluoroacetic acid (1.15 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a 25% aqueous ammonia solution was added to the obtained residue, and the reaction mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent, methanol) to give 117 mg of the title compound (yield 75%).

Ή-NMR (CDCl ₃ ) δ: 4.14 (2H, s), 7.30-7.34 (2H, m), 7.45 (IH, d, J = 7.9 Hz), 7.56 (Ih, s)

Example 35

Synthesis of N- (3-guanidino) phenylmethyl) carbamic acid t-butyl ester formate

A solution of the compound (190 mg) obtained in Example 33 in 4.4% formic acid-methanol (10 ml) was added dropwise to a suspension of palladium black (200 mg) in 4.4% formic acid-methanol (10 ml) at room temperature and stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 8: 2) to give 71 mg of the title compound (yield 37%).

Ή-NMR (CDCl ₃ ) δ: 1.39 (9H, s), 4.22 (2H, d, J = 5.9 Hz), 5.59-5.76 (IH, m), 7.05 -7.36 (4H, m), 9.72 (1H, brs)

FAB-MS (m / z) 265 (M ⁺ + 1)

Example 36

Synthesis of N- (3-guanidino) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 35 as a starting material, the procedure of Example 5 gave 57 mg of the title compound in quantitative yield.

-NMR (D ₂ O) δ: 4.22 (2H, s), 7.35-7.60 (4H, m)

FAB-MS (m / z) 165 (M ⁺ + 1)

183 619

Example 37

Synthesis of N- (3- (S-nitrophenylmethyl) dimethylamine

A solution of m-nitro-x-bromotoluene (3.2 g) in dimethylformamide (50 ml) was added dropwise to a solution of dimethylamine hydrochloride (1.45 g) and triethylamine (4.36 ml) in dimethylformamide (50 ml). The reaction mixture was stirred at room temperature for 1 hour and then its temperature was raised to 50 ° C and stirred for 3 hours. The reaction mixture was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 2: 1) to give 2.56 g of the title compound (96% yield).

'Η-NMR (CDC1 ₃₎

6: 2.26 (6H, s), 3.15 (2H, s), 7.49 (1H, dd, J = 7.9.7.6Hz), 7.67 (1H, d, J = 7.6 Hz), 8.12 (1H, d, J = 7.9Hz), 8.19 (1H, s)

Example 38

Synthesis of N- (3-aminophenylmethyl) dimethylamine

Using the compound obtained in Example 37 as a starting material, the procedure in Example 2 gave 1.6 g of the title compound (99% yield).

'Η-NMR (CDCl ₃ ) δ: 2.24 (6H, s), 3.37 (2H, s), 3.45 (2H, brs), 6.58 (1H, d, J = 6.6Hz ), 6.66-6.69 (2H, m), 7.10 (1H, dd, J = 7.6, 6.6Hz)

Example 39

Synthesis of N- (3- (N'-nitroguanidino) phenylmethyl) dimethylamine acetate

Using the compound obtained in Example 38 as the starting material, the procedure of Example 6 gave 0.11 g of the title compound (42% yield).

'H-NMR (DMSO-d ₆ )' δ: 2.13 (3H, s), 2.16 (6H, s), 3.37 (2H, s), 7.08 (1H, d, J = 7.3Hz), 7.22-7.30 (3H, m), 8.26-8.80 (1H, m)

MS (m / z) 191 (M + -46)

Example 40

Synthesis of N- (3-thioureidophenylmethyl) dimethylamine

Benzoyl chloride (0.18 ml) was added to a solution of ammonium thiocyanite (0.12 g) in acetone (7 ml) and heated to reflux for 5 minutes. A solution of the compound (0.21 g) obtained in Example 38 in acetone (6 ml) was then added. The reaction mixture was stirred at room temperature for 20 minutes and then water was added to form a yellow precipitate which was filtered off. A 10% aqueous sodium hydroxide solution (20 mL) was added to the recovered product and heated to reflux for 5 minutes. The reaction mixture was acidified with 35% HCl, then basified weakly with 28% aqueous ammonia, and concentrated to 20 mL under reduced pressure. The resulting precipitate was filtered off and the filtrate was extracted with chloroform; the organic layer was dried with anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent, chloroform: methanol = 5: 1) to give 0.1 g of the title compound (yield 35%).

Ή-NMR (DMSO-d ₆ ) δ: 2.22 (6H, s), 3.49 (2H, s), 6.72 (2H, brs), 7.15-7.36 (4H, m) , 9.12 (1H, brs)

MS (m / z) 209 (M ⁺ )

Example 41

Synthesis of N- (3- (S-methylisothioureidophenylmethyl) dimethylamine mononitrate monohydrochloride

To a mixture of the compound (42.7 mg) obtained in Example 40 and tetrahydrofuran (2 ml), 60% nitric acid (0.1 ml) was added, and the resulting mixture was concentrated under reduced pressure.

183,619 to give the nitrate which was subjected to the same reaction as in Example 4; the residue was dissolved in ethanol (1 ml) and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added at room temperature; then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, washed with ethyl acetate and freeze dried to give 46.9 mg of the title compound (71% yield).

Ή-NMR (DMSO-d ₆ ) δ: 2.34 (6H, s), 2.42 (3H, s), 3.54 (2H, s), 4.45 (3H, br), 6.86 (1H, d, J = 7.9 Hz), 6.92 (1H, s), 6.99 (1H, d, J = 7.6 Hz), 7.25 (1H, dd, J = 7, 9, 7.6Hz), 7.69 (1H, s)

MS (m / z) 223 (M ⁺ )

Example 42

Synthesis of N- (3-nitrophenylmethyl) methylamine

To a mixture of sodium cyanoborohydride (2.52 g), triethylamine (18.7 ml), methylamine hydrochloride (5.42 g) and methanol (660 ml), m-nitrobenzaldehyde (10.10 g) was added dropwise over 20 minutes at room temperature, and the resulting mixture was stirred at room temperature for 20 hours. The pH of the reaction mixture was adjusted to 2 with 10% HCl, and methanol was distilled off under reduced pressure. The residue was washed with chloroform and a 10% aqueous potassium hydroxide solution was added to the aqueous layer to adjust the pH to 12, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 95: 5) to give 3.0 g of the title compound (yield 27%).

Ή-NMR (CDCl ₃ ) δ: 1.52 (1H, brs), 2.47 (3H, s), 3.87 (2H, s), 7.50 (1H, dd, J = 7.8, 7.8 Hz), 7.68 (1H, d, J = 7.8 Hz), 8.20 (1H, d, J - 7.8 Hz), 8.44 (1H, s)

Example 43

Synthesis of N- (3-nitrophenylmethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 42 as the starting material, the procedure of Example 22 gave 4.1 g of the title compound (85% yield).

Ή-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.87 (3H, s), 4.51 (2H, s), 7.49-7.56 (2H, m), 8 , 11-8.15 (2H, m) Example 44

Synthesis of N- (3-aminophenylmethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 43 as the starting material, the procedure in Example 2 gave 2.96 g of the title compound (81% yield).

Ή-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.80 (3H, s), 3.40 (2H, br), 4.33 (2H, s), 6.44-6 . 64 (3H, m), 7.10 (1H, dd, J = 7.8, 7.8Hz)

FAB-MS (m / z) 236 (M ⁺ )

Example 45

Synthesis of N- (3-thioureidophenylmethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 44 as the starting material, the procedure of Example 3 gave 2.21 g of the title compound (86% yield).

Ή-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.84 (3H, s), 4.42 (2H, s), 6.36 (2H, brs), 7.10-7 , 18 (3H, m), 7.39 (1H, dd, J = 7.8, 7.8Hz), 8.56 (1H, s)

FAB-MS (m / z) 296 (M ⁺ + 1)

Example 46

Synthesis of N- (3- (S-ethylisothioureidophenylmethyl) methylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 45 as the starting material, the procedure of Example 27 gave 0.27 g of the title compound (69% yield).

183 619

Ή-NMR (CDCl ₃ ) δ: 1.35 (3H, t, J = 7.3 Hz), 1.48 (9H, s), 2.81 (3H, s), 3.01 (2H, q , J = 7.3Hz), 4.38 (2H, s), 4.55 (1H, brs), 6.78-6.82 (2H, m), 6.89 (1H, d, J = 7.6 Hz), 7.25 (1H, dd, J = 7.6, 7.6H)

FAB-MS (m / z) 324 (M ⁺ + 1)

Example 47

Synthesis of N- (3 - (S-ethylisothioureidophenylmethyl) methylamine dihydrochloride

Using the compound obtained in Example 46 as a starting material, the procedure of Example 5 gave 85.5 mg of the title compound (87% yield).

Ή-NMR (D ₂ O) δ: 1.43 (3H, t, J = 7.3 Hz), 2.78 (3H, s), 3.27 (2H, q, J = 7.3 Hz) , 4.37 (2H, s), 7.47-7.51 (2H, m), 7.56 (1H, d, J = 7.6Hz), 7.66 (1H, dd, J = 7 , 6, 7.3Hz)

Example 48

Synthesis of N- (4-nitrophenylmethyl) carbamic acid t-butyl ester

Using N- (4-nitrophenylethyl) amine hydrochloride as a starting material, the procedure of Example 22 gave the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 2.72-3.02 (2H, m), 3.19-3.50 (2H, m), 7.23 (2H, d, J = 9.0 Hz), 8.05 (2H, d, J = 9.0 Hz)

FAB-MS (m / z) 267 (M ⁺ + 1)

Example 49

Synthesis of N- (4-aminophenylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 48 as a starting material, the title compound was obtained according to the procedure in Example 2 (yield 78%).

Ή-NMR (CDCl 3) δ: 1.43 (9H, s), 2.62-2.69 (2H, m), 3.22-3.36 (2H, m), 3.57 (2H, brs ), 4.56-4.72 (1H, m), 6.61 (2H, d, J = 8.3 Hz), 6.95 (2H, d, J = 8.3 Hz)

MS (m / z) 236 (M ⁺ )

Example 50

Synthesis of N- (4-thioureidophenylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 49 as starting material, the procedure of Example 3 gave the title compound (71% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.39 (9H, s), 2.57-2.71 (2H, m), 3.10-3.21 (2H, m), 6.70- 6.84 (1H, m), 7.13 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz), 9.59 (1H, s)

MS (m / z) 295 (M ⁺ )

Example 51

Synthesis of N- (4- (S-methylisothioureidophenylethyl) carbamic acid t-butyl ester hydroiodide

By using the compound obtained in Example 50 as a starting material, the procedure of Example 4 gave the title compound in quantitative yield.

Ή-NMR (CDCl 3) δ: 1.42 (9H, s), 2.71 (3H, s), 2.99 (2H, t, J = 6.9 Hz), 3.26-3.38 ( 2H, m), 4.80-4.92 (1H, m), 6.75-7.08 (2H, m), 7.18-7.27 (4H, m)

MS (m / z) 309 (M ⁺ )

Example 52

Synthesis of N- (4- (S-methylisothioureidophenylethyl) amine dihydrochloride

Using the compound obtained in Example 51 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 2.71 (3H, s), 3.08 (2H, t, J - 7.3 Hz), 3.30-3.36 (2H, m), 7, 35-7.52 (4H, m)

FAB-MS (m / z) 210 (M ⁺ + 1)

183 619

Example 53

Synthesis of N- (4- (N'-nitroguanidino) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 49 as a starting material, the title compound was obtained according to the procedure in Example 6 (yield 35%).

'Η-NMR (DMSO-d ₆ ) δ: 1.38 (9H, s), 2.66-2.72 (2H, m), 3.10-3.18 (2H, m), 6.82 (1H, brs), 7.20 (4H, s), 8.13 (1H, brs), 9.52 (1H, s)

FAB-MS (m / z) 324 (M ⁺ + 1)

Example 54

Synthesis of N- (4- (N'-nitroguanidino) phenylethyl) amine

Using the compound obtained in Example 53 as a starting material, the reaction was conducted as in Example 5 and the product was purified by basic silica gel column chromatography (eluent, methylene chloride: methanol = 95: 5) and recrystallized from a mixture of ethanol and diethyl ether to give the title compound ( 57% yield).

Ή-NMR (DMSO-d ₆ ) δ: 2.60-2.65 (2H, m), 2.77 (2H, t, J = 6.9 Hz), 5.75 (2H, br), 7 . 20 (4H, s), 8.27-8.30 (2H, m)

FAB-MS (m / z) 224 (M ⁺ + 1)

Example 55

Synthesis of 3- (2-bromoethyl) nitrobenzene

Carbon tetrabromide (2.48 g) and triphenylphosphine (2.35 g) were added to a mixture of 3-nitrophenethyl alcohol (1.0 g) and methylene chloride (20 ml) under ice-cooling and stirred for 30 minutes under ice-cooling. The reaction mixture was distilled under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 4: 1) to give 1.58 g of the title compound in quantitative yield.

'Η-NMR (CDCl ₃ ) δ: 3.29 (2H, t, J = 6.9 Hz), 3.65 (2H, t, J = 6.9 Hz), 7.48-7.61 ( 2H, m), 8.08-8.10 (2H, m)

MS (m / z) 230 (M ⁺ )

Example 56

Synthesis of N- (3-nitrophenylethyl) carbamic acid t-butyl ester

To a mixture of the compound (1.58 g) obtained in Example 55 and dimethylsulfoxide (30 ml) was added 28% aqueous ammonia (15 ml), and the resulting mixture was stirred at room temperature for 2.5 hours. The unreacted 28% aqueous ammonia solution was distilled off under reduced pressure, and di-t-butyl dicarbonate (6.5 g) and triethylamine (1.3 ml) were added to the obtained residue. The reaction was carried out at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate and washed sequentially with 2N HCl and water; the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 4: 1) to obtain 1.22 g of the title compound (77% yield).

'Η-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.91-2.97 (2H, m), 3.41-3.46 (2H, m), 4.98-5 , 13 (1H, m), 7.45-7.58 (2H, m), 8.05-8.08 (2H, m)

MS (m / z) 266 (M ⁺ )

Example 57

Synthesis of N- (3-aminophenylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 56 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 69%).

'1-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.70 (2H, t, J = 6.9 Hz), 3.34-3.48 (2H, m), 4, 48-4.60 (1H, m), 6.53-6.60 (3H, m), 7.80 (1H, t, J = 7.6Hz)

MS (m / z) 236 (M ⁺ )

183 619

Example 58

Synthesis of N- (3-thioureidophenylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 57 as starting material, the procedure of Example 3 gave the title compound (82% yield).

1 H-NMR (CDCl ₃ ) δ: 1.29 (9H, s), 2.76-2.81 (2H, m), 3.35-3.49 (2H, m), 4.53-4 , 68 (1H, m), 6.46 (2H, br s), 7.02-7.35 (4H, m), 8.09 (1H, br s)

MS (m / z) 295 (M ⁺ )

Example 59

Synthesis of N- (3- (S-methylisothioureidophenylethyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 58 as starting material, the title compound was obtained according to the procedure in Example 4 (yield 94%).

1 H-NMR (CDCl ₃ ) δ: 1.39 (9H, s), 2.76 (3H, s), 2.81 (2H, t, J = 6.9Hz), 3.35-3.38 (2H, m), 4.75-4.87 (1H, m), 7.15-7.19 (3H, m), 7.30-7.38 (1H, m), 7.72 (2H , br)

MS (m / z) 309 (M ⁺ )

Example 60

Synthesis of N- (3- (S-methylisothioureidophenylethyl) amine dichlorohydride

Using the compound obtained in Example 59 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

1 H-NMR (D ₂ O) δ: 2.72 (3H, s), 3.05-3.11 (2H, m), 3.34 (2H, t, J = 7.3 Hz), 7 . 31-7.59 (4H, m)

MS (m / z) 209 (M ⁺ )

Example 61

Synthesis of N- (3- (N'-nitroguanidino) phenylethyl) carbamic acid t-butyl ester

By using the compound obtained in Example 57 as a starting material, the procedure of Example 6 gave the title compound (59% yield).

1 H-NMR (CDCl ₃ ) δ: 1.29 (9H, s), 2.79 (2H, t, J = 6.3 Hz), 3.38-3.43 (2H, m), 4, 91-5.03 (1H, m), 7.11-7.36 (4H, m), 9.76 (1H, brs)

FAB-MS (m / z) 324 (M ⁺ + 1)

Example 62

Synthesis of N- (3- (N'-nitroguanidino) phenylethyl) amine hydrochloride

Using the compound obtained in Example 61 as a starting material, the procedure of Example 5 gave the title compound (yield 44%).

'H-NMR (D ₂ O)

6: 3.04 (2H, t, J = 7.3Hz), 3.31 (2H, t, J = 7.3Hz), 7.26-7.55 (4H, m)

Example 63

Synthesis of 2-t-butoxycarbonylamino-3 - (4-nitrophenyl) propionic acid

A 2N aqueous sodium hydroxide solution (12.3 ml) and di-t-butyl bicarbonate (6.36 g) were added to a mixture of 4-nitrophenylalanine (5.35 g), 1,4-dioxane (80 ml) and water (40 ml) with ice-cooling and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate and washed sequentially with 2N HCl and water; the organic layer was dried with anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and n-hexane to afford the title compound in quantitative yield.

1 H-NMR (CDCl ₃ ) δ: 1.36 (9H, s), 3.06-3.25 (2H, m), 4.01-4.78 (1H, m), 7.45 (2H , d, J = 9.0 Hz), 8.08 (2H, d, J = 9.0 Hz)

MS (m / z) 310 (M ⁺ )

183 619

Example 64

Synthesis of 2-t-butoxycarbonylamino-3- (4-nitrophenyl) propionic acid methyl ester

To a mixture of the compound (1.15 g) obtained in Example 63, diethyl ether (6 ml) and methanol (14 ml), a solution of trimethylsilyl diazomethane in n-hexane (2.0 M, 7.4 ml) was added, and the resulting mixture was stirred with room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give the title compound in a quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.08-3.31 (2H, m), 3.75 (3H, s), 4.38-4.78 (1H, m), 4.95-5.42 (1H, m), 7.28 (2H, d, J = 9.0 Hz), 8.09 (2H, d, J = 9.0 Hz)

MS (m / z) 324 (M ⁺ )

Example 65

Synthesis of 2-t-butoxycarbonylamino-3- (4-aminophenyl) propionic acid methyl ester

Using the compound obtained in Example 64 as a starting material, the title compound was obtained according to the procedure in Example 2 (yield 87%).

Ή-NMR (CDCl 3) δ: 1.41 (9H, s), 2.95 (2H, d, J = 5.8 Hz), 3.61 (2H, brs), 3.68 (3H, s) , 4.40-4.58 (1H, m), 5.04-5.08 (1H, m), 6.58 (2H, d, J = 8.3Hz), 6.88 (2H, d , J = 8.3 Hz)

MS (m / z) 294 (M ⁺ )

Example 66

Synthesis of 2-t-butoxycarbonylamino-3- (4-thioureidophenyl) propionic acid methyl ester

Using the compound obtained in Example 65 as starting material, the title compound was obtained according to the procedure in Example 3 (yield 73%).

Ή-NMR (CDCl3)

6: 1.41 (9H, s), 2.97-3.19 (2H, m), 3.74 (3H, s), 4.56-4.60 (1H, m), 5.11 ( 1H, d, J = 7.9Hz), 6.28 (2H, brs), 7.18 (2H, d, J = 5.9Hz), 7.21 (2H, d, J = 5.9 Hz), 8.36 (1H, s)

FAB-MS (m / z) 354 (M ⁺ + 1)

Example 67

Synthesis of 2-t-butoxycarbonylamino-3- (4- (S-methylisothioureidophenyl) propionic acid methyl ester hydroiodide

Using the compound obtained in Example 66 as a starting material, the title compound was obtained according to the procedure in Example 4 (yield 80%).

Ή-NMR (CDCl 3) δ: 1.42 (9H, s), 2.64 (3H, s), 2.99-3.17 (2H, m), 3.72 (3H, s), 4, 48-4.53 (1H, m), 5.04 (1H, d, J = 7.9Hz), 6.25-6.53 (2H, m), 7.13 (2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz)

FAB-MS (m / z) 368 (M ⁺ + 1)

Example 68

Synthesis of 2-amino-3- (4- (S-methylisothioureidophenyl) propionic acid methyl ester dihydrochloride

Using the compound obtained in Example 67 as the starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 2.70 (3H, s), 3.28-3.47 (2H, m), 3.85 (3H, s), 4.45-4.52 (1H , m), 7.39 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz)

FAB-MS (m / z) 268 (M ⁺ + 1)

Example 69

Synthesis of 2-t-butoxycarbonylamino-3- (4- (N'-nitroguanidino) phenyl) propionic acid methyl ester

Using the compound obtained in Example 65 as a starting material, the procedure of Example 6 gave the title compound (74% yield).

183 619

Ή-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 3.00-3.20 (2H, m), 3.73 (3H, s), 4.50-4.36 (1H, m), 5.20 (1H, d, J = 7.6 Hz), 7.20-7.28 (4H, m)

FAB-MS (m / z) 382 (M ⁺ + 1)

Example 70

Synthesis of 2-amino-3- (4- (N'-nitroguanidino) phenyl) propionic acid methyl ester

Using the compound obtained in Example 69 as a starting material, the title compound was obtained according to the procedure of Example 54 (yield 65%).

Ή-NMR (CDCl ₃ ) δ: 2.80-2.91 (1H, m), 3.07-3.17 (1H, m), 3.74 (3H, s), 3.70-3, 82 (1H, m), 7.24-7.34 (4H, m)

FAB-MS (m / z) 282 (M ⁺ + 1)

Example 71

Synthesis of 2-t-butoxycarbonylamino-3- (4-nitrophenyl) propionic acid t-butyl ester

To a mixture of the compound (6.9 g) obtained in Example 63 and methylene chloride (70 ml) was added t-butanol (20 ml), N, N-dimethylaminopyridine (2.63 g) and 1-ethyl-3- (3) hydrochloride -dimethylaminopropyl) carbodiimide (4.9 g) and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and washed sequentially with 2N HCl and a saturated aqueous sodium chloride solution; the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 3: 1) to obtain 7.64 g of the title compound (97% yield).

Ή-NMR (CDCl ₃ ) δ: 1.417 (9H, s), 1.419 (9H, s), 3.08-3.30 (2H, m), 4.45-4.53 (1H, m), 5 . 02-5.11 (1H, m), 7.36 (2H, d, J = 8.6 Hz), 8.16 (2H, d, J = 8.6 Hz)

FAB-MS (m / z) 367 (M ⁺ + 1)

Example 72

Synthesis of 2-t-butoxycarbonylamino-3- (4-amino) phenylpropionic acid t-butyl ester

Using the compound obtained in Example 71 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 84%).

Ή-NMR (DMSO-d ₆ ) δ: 1.36 (18H, s), 2.51-2.80 (2H, m), 3.88-3.94 (1H, m), 4.58- 4.80 (2H, m), 6.48 (2H, d, J = 7.9Hz), 6.86 (2H, d, J = 7.9Hz)

FAB-MS (m / z) 337 (M ⁺ + 1)

Example 73

Synthesis of 2-t-butoxycarbonylamino-3- (4-thioureidophenyl) propionic acid t-butyl ester

Using the compound obtained in Example 72 as a starting material, the procedure of Example 3 gave the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.42 (9H, s), 2.96-3.14 (2H, m), 4.22-4.46 (lH, m), 5.16 (1H, d, J = 7.3Hz), 6.40 (2H, brs), 7.18 (2H, d, J = 8.3Hz), 7.24 (2H, d, J = 8.3Hz), 8.70 (1H, brs)

FAB-MS (m / z) 396 (M ⁺ + 1)

Example 74

Synthesis of 2-t-butoxycarbonylamino-3- (4- (S-methylisothioureidophenyl) propionic acid t-butyl ester hydroiodide

Using the compound obtained in Example 73 as a starting material, the procedure of Example 4 gave the title compound (99% yield).

Ή-NMR (CDC1 ₃₎

183 619 δ: 1.42 (18Η, s), 2.76 (3Η, s), 2.99-3.16 (2H, m), 4.42-4.45 (1H, m), 5, 07 (1H, d, J = 7.9Hz), 7.26 (4H, s), 8.55 (2H, br)

FAB-MS (m / z) 410 (M ⁺ + 1)

Example 75

Synthesis of 2-amino-3- (4- (S-methylisothioureido) phenyl) propionic acid dihydrochloride

Using the compound obtained in Example 74 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 91%).

Ή-NMR (D ₂ O) δ: 2.69 (3H, s), 3.23-3.36 (2H, m), 4.21-4.26 (1H, m), 7.37 (2H , d, J = 8.6 Hz), 7.46 (2H, d, J = 8.6 Hz)

MS (m / z) 253 (M ⁺ )

Example 76

Synthesis of 2-t-butoxycarbonylamino-3- (4- (N'-nitroguanidino) phenyl) propionic acid t-butyl ester

Using the compound obtained in Example 72 as starting material, the procedure of Example 6 gave the title compound (67% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.36 (9H, s), 1.39 (9H, s), 2.80-2.98 (2H, m), 4.02-4.07 ( 1H, m), 7.10 (1H, d, J = 7.9Hz), 7.19-7.26 (4H, m), 8.14 (1H, br s), 9.49 (1H, s )

FAB-MS (m / z) 424 (M ⁺ + 1)

Example 77

Synthesis of 2-amino-3- (4- (N'-nitroguanidino) phenyl) propionic acid hydrochloride

Using the compound obtained in Example 76 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

'Η-NMR (DMSO-d ₆ + D ₂ O)

6: 3.05-3.22 (2H, m), 4.12-4.17 (1H, m), 7.25-7.33 (4H, m) FAB-MS (m / z) 268 ( M ⁺ + l) Example 78

Synthesis of 2-t-butoxycarbonylamino-2- (4-aminophenyl) acetic acid methyl ester

To a mixture of 4-nitrophenylacetic acid (2.0 g), benzene (40 ml) and N-bromosuccinimide (3.3 g), 2,2'-azobis (2-methylpropionitrile) (0.16 g) was added and heated to at boiling point for 22 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with 2N HO and water; the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate: acetic acid = 57:25: 1) to give 2-bromo-2- (4-nitrophenyl) acetic acid. The resulting bromo compound was mixed with 28% aqueous ampniac solution (5 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure; 1N aqueous sodium hydroxide solution (20 ml), 1,4-dioxane (10 ml) and di-t-butyl dicarbonate (7.2 g) were added to the obtained residue, and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in a mixture of methanol (20 mL) and diethyl ether (10 mL); a solution of trimethylsilyl diazomethane (2.0 M) in n-hexane was added until foaming ceased in the reaction mixture; the reaction mixture was then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate + 3: 1) to give 2-t-butoxycarbonylamino-2- (4-nitrophenyl) -acetic acid methyl ester. The resulting methyl ester was processed as in Example 2 to give 0.77 g of the title compound (25% yield).

'Η-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 3.68 (3H, s), 3.75 (2H, brs), 5.16 (1H, d, J = 6.9 Hz) , 5.45-5.56 (1H, m), 6.60 (2H, d, J = 8.6 Hz), 7.10 (2H, d, J = 8.6 Hz) MS (m / z ) 280 (M ⁺ )

183 619

Example 79

Synthesis of 2-t-butoxycarbonylamino-2- (4-thioureidophenyl) acetic acid methyl ester

Using the compound obtained in Example 78 as a starting material, the procedure of Example 3 gave the title compound (43% yield).

Ή-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 3.73 (3H, s), 5.25-5.38 (1H, m), 5.73- (5.90 (1H m), 6.41 (2H, brs), 7.23 (2H, d,> 8.3Hz), 7.42 (2H, d, J = 8.3Hz), 8.70 (1H, brs)

MS (m / z) 339 (M ⁺ )

Example 80

Synthesis of 2-t-butoxycarbonylamino-2- (4- (S-methylisothioureidophenyl) acetic acid metal ester iodide

Using the compound obtained in Example 79 as starting material, the title compound was obtained according to the procedure in Example 4 (52% yield).

Ή-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.70 (3H, s), 3.73 (3H, s), 5.30-5.34 (1H, m), 5 , 73-5.77 (1H, m), 7.27 (2H, d,> 8.3Hz), 7.38-7.60 (4H, m) MS (m / z) 353 (M ⁺ )

Example 81

Synthesis of 2-amino-2- (4- (S-methylisothioureidophenyl) acetic acid methyl ester dihydrochloride

Using the compound obtained in Example 80 as a starting material, the procedure of Example 5 gave the title compound (88% yield).

Ή-NMR (D ₂ O) δ: 2.71 (3H, s), 3.85 (3H, s), 5.40 (1H, s), 7.52 (2H, d,> 8.6 Hz ), 7.64 (2H, d, J = 8.6 Hz)

MS (m / z) 253 (M ⁺ )

Example 82

Synthesis of N- (4-aminophenylmethyl) carbamic acid t-butyl ester

Sodium hydroxide (1.77 g) was added to a mixture of N- (4-aminophenylmethyl) amine (3.0 g) and water (30 ml) under ice-cooling and stirred for 5 minutes under ice-cooling; then di-t-butyl dicarbonate (4.88 g) was added to the reaction mixture under ice-cooling and stirred for 10 hours at room temperature. The precipitate formed during the reaction was filtered off to give 5.83 g of the title compound (92% yield).

Ή-NMR (CDCl 3) δ: 1.45 (9H, s), 3.64 (2H, brs), 4.18 (2H, d, J = 5.5 Hz), 6.64 (2H, d, > 8.5Hz), 7.07 (2H, d,> 8.5Hz)

Example 83

Synthesis of N- (4- (N'-cyclopropylguanidino) phenylmethyl) carbamic acid t-butyl ester

The compound (0.946 g) obtained in Example 82 was added to a mixture of N-cyclopropyl-S-methylisothiourea hydroiodide (1.0 g) and pyridine (10 ml) and heated to reflux for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 2: 1) to give 0.131 g of the title compound (12% yield).

Ή-NMR (CD3OD) δ: 0.61-0.65 (2H, m), 0.76-0.86 (2H, m), 1.44 (9H, s), 2.72- (2, 86 (1H, m), 4.18-4.24 (2H, m), 7.23-7.34 (4H, m)

Example 84

Synthesis of N- (4- (N'-cyclopropylguanidino) phenylmethyl) amine

Using the compound obtained in Example 83 as starting material, the title compound was obtained according to the procedure in Example 34 (yield 53%).

Ή-NMR (CD3OD)

183 619 δ: 0.58-0.65 (2Η, m), 0.73-0.86 (2Η, m), 2.72-2.88 (1H, m), 3.76 (2H, s ), 7.30 (2H, d,> 8.6 Hz), 7.35 (2H, d,> 8.6 Hz)

Example 85

Synthesis of N- (4- (N'-nitroguanidino) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 82 as a starting material, the title compound was obtained according to the procedure in Example 6 (yield 56%).

Ή-NMR (CD ₃ OD) δ: 1.44 (9H, s), 4.22 (2H, s), 7.27 (2H, d,> 8.5 Hz), 7.34 (2H, d ,> 8.5 Hz)

Example 86

Synthesis of N- (4- (N'-nitroguanidino) phenylmethyl) amine

Using the compound obtained in Example 85 as starting material, the title compound was obtained according to the procedure of Example 34 (yield 75%).

Ή-NMR (CD ₃ OD) δ: 4.12 (2H, s), 7.41 (2H, d,> 8.6 Hz), 7.49 (2H, d,> 8.6 Hz)

Example 87

Synthesis of N- (3- (N'-cyclopropylguanidino) phenylmethyl) carbamic acid t-butyl ester

By using the compound obtained in Example 23 as a starting material, the procedure of Example 83 gave the title compound (yield 8.8%).

Ή-NMR (CDCl ₃ ) δ: 0.62-0.76 (2H, m), 0.80-0.95 (2H, m), 1.46 (9H, s), 2.73 (2, 92 (1H, m), 4.30 (2H, d,> 5.5Hz). 4.93-5.07 (1H, m), 6.52 (1H, brs), 7.12-7. 39 (4H, m), 7.98 (1H, brs)

Example 88

Synthesis of N- (3- (N'-cyclopropylguanidino) phenylmethyl) amine

Using the compound obtained in Example 87 as a starting material, the procedure of Example 34 gave the title compound (51% yield).

Ή-NMR (CD3OD) δ: 0.61-0.69 (2H, m), 0.80-0.87 (2H, m). 2.72-2.90 (1H, m), 3.77 (2H, s), 7.13-7.35 (4H, m)

Example 89

Synthesis of N- (3- (N'-cyclopropylguanidinomethyl) phenyl-N'-nitroguanidine

Using the compound obtained in Example 34 as starting material, the title compound was obtained according to the procedure of Example 83 (yield 22%).

Ή-NMR (CD3OD) δ: 0.57-0.62 (2H, m), 0.78-0.84 (2H, m), 2.52-2.68 (1H, m), 4.86 (2H, s), 7.18-7.40 (4H, m)

Example 90

Synthesis of N- (3- (N'-nitroguanidinomethyl) phenyl) -N'-nitroguanidine using the compound obtained in example 34 as a starting material and also using N-methyl-N'-nitro-N-nitrosoguanidine as a reagent, the reaction was carried out as in example 83 to afford the title compound (25% yield).

Ή-NMR (CD3OD) δ: 4.50 (2H, s), 7.20-7.22 (1H, m), 7.32-7.43 (3H, m)

Example 91

Synthesis of N- (3- (S-n-propylisothioureido) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 24 as a starting material and also using n-propyl iodide as a reagent, the reaction was conducted as in Example 29 to give 227 mg of the title compound (99% yield).

Ή-NMR (CDCl3) δ: 1.04 (3H, t,> 7.3Hz), 1.46 (9H, s), 1.68-1.81 (2H, m), 3.10 (2H , t,> 7.3 Hz), 4.31 (2H, d,> 5.6 Hz), 4.84-4.98 (1H, m), 6.98-7.35 (4H, m)

FAB-MS (m / z) 324 (M ⁺ + 1)

183 619

Example 92

Synthesis of N- (3- (S-n-propylisothioureido) phenylmethyl) amine hydrochloride

Using the compound obtained in Example 91 as starting material, the procedure of Example 5 gave 173 mg of the title compound ('yield 83%).

'H-NMR (D ₂ O)

Ó: 1.05 (3H, t,> 7.3Hz), 1.73-1.87 (2H, m), 3.22 (2H, t, J = 7.3Hz), 4.25 ( 2H, s), 7.43-7.66 (4H, m)

FAB-MS (M / S) 224 (M ⁺ + 1)

Example 93

Synthesis of N- (3- (S-n-butylisothioureido) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 24 as a starting material and also using n-butyl iodide as a reagnet, the reaction was conducted as in Example 29 to give 220 mg of the title compound (92% yield).

1 H-NMR (CDCl ₃ ) δ: 0.94 (3H, t,> 7.3Hz), 1.39-1.53 (2H, m), 1.46 (9H, s), 1.64 -1.75 (2H, m), 3.14 (2H, t,> 7.3Hz), 4.31 (2H, d,> 5.6Hz), 4.82-4.98 (1H, m), 7.02-7.36 (4H, m)

FAB-MS (m / z) 338 (M ⁺ + 1)

Example 94

Synthesis of N- (3- (S-n-butylisothioureido) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 93 as a starting material, the procedure of Example 5 gave 194 mg of the title compound (96% yield). 1 H-NMR (D ₂ O) δ: 0.93 (3H, t,> 7.3 Hz). 1: 40-1.53 (2H, m), 1.70-1.80 (2H, m), 3.23 (2H, t,> 7.3Hz), 4.24 (2H, s), 7.43-7.65 (4H, m)

FAB-MS (m / z) 238 (M ⁺ + 1)

Example 95

Synthesis of N- (1-methyl-1- (3- (S-ethylisothioureido) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 3 as a starting material and also using ethyl iodide as a reagent, the reaction was conducted as in Example 29 to give 110 mg of the title compound (97% yield).

1 H-NMR (CDCl 3) δ: 1.37 9H, s), 1.37 (3H, t,> 7.3Hz), 1.60 (6H, s), 3.04 (2H, q,> 7.3Hz), 4.92 (1H, brs), 6.77-7.28 (4H, m)

MS (m / z) 337 (M ⁺ )

Example 96

Synthesis of N- (1-methyl-1- (3- (S-ethylisothioureido) -phenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 95 as a starting material, the procedure of Example 5 gave 72 mg of the title compound (71% yield).

1 H-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.3 Hz), 1.77 (6H, s), 3.24 (2H, q,> 7.3 Hz), 7.37-7.68 (4H, m)

MS (m / z) 237 (M ⁺ )

Example 97

Synthesis of N- (4-nitrophenylethyl) dimethylamine

Using p-nitrophenethyl bromide as a starting material and also using sodium bicarbonate as base, the procedure of Example 37 gave 2.3 g of the title compound (54% yield).

1 H-NMR (CDCl 3) δ: 2.30 (6H, s), 2.56 (2H, t,> 7.3 Hz), 2.89 (2H, t,> 7.3 Hz), 7, 37 (2H, d,> 8.9Hz), 8.14 (2H, d,> 8.9Hz),

MS (m / z) 194 (M ⁺ )

183 619

Example 98

Synthesis of N- (4-aminophenylethyl) dimethylamine dihydrochloride

Using the compound obtained in Example 97 as the starting material and adding a solution of hydrogen chloride (4N) in 1,4-dioxane according to the procedure of Example 2, 2.37 g of the title compound were obtained (85% yield).

Ή-NMR (CDCl ₃ ) δ: 2.27 (6H, s), 2.55 (2H, t, J = 6.9 Hz), 2.80 (2H, t,> 6.9 Hz), 7 . 23 (2H, d,> 8.3 Hz), 7.31 (2H, d,> 8.3 Hz),

MS (m / z) 164 (M ⁺ )

Example 99

Synthesis of N- (4- (N'-nitroguanidino) phenylethyl) dimethylamine

Using the compound obtained in Example 98 as the starting material and dissolving it in a solvent system composed of acetonitrile and methanol, the procedure of Example 6 gave 45 mg of the title compound (30% yield).

Ή-NMR (CDCl ₃ ) δ: 2.28 (6H, s), 2.43-2.49 (2H, m), 2.64-2.69 (2H, m), 6.61 (2H, d,> 8.2Hz), 6.98 (2H, d,> 8.2Hz)

MS (m / z) 219 (M ⁺ -32)

Example 100

Synthesis of N- (4-thioureido) phenylethyl) dimethylamine

Using the compound obtained in Example 98 as the starting material, the procedure in Example 3 gave 1.46 g of the title compound (99% yield).

Ή-NMR (CDCl3)

S: 2.29 (6H, s), 2.54 (2H, t,> 6.9Hz), 2.80 (2H, t,> 6.9Hz), 6.04 (2H, brs), 7.15 (2H, d,> 8.6 Hz), 7.28 (2H, d,> 8.6 Hz), 7.85 (1H, brs)

MS (m / z) 223 (M ⁺ )

Example 101

Synthesis of N- (4- (S-methylisothioureido) phenylethyl) dimethylamine mononitrate monohydrochloride

Using the compound obtained in Example 100 as the starting material, the procedure of Example 41 gave 0.18 g of the title compound (99% yield).

Ή-NMR (DMSO-d ₆ ) δ: 2.68 (3H, s), 2.86 (6H, s), 2.99-3.05 (2H, m), 3.17-3.44 ( 2H, m), 7.31 (2H, d,> 8.3Hz), 7.43 (2H, d,> 8.3Hz), 9.27 (1H, brs), 9.69 (1H, brs), 11.22 (1H, brs)

MS (m / z) 237 (M ⁺ )

Example 102

Synthesis of N- (4- (S-ethylthioureido) phenylethyl) dimethylamine mononitrate monohydrochloride

Using the compound obtained in Example 100 as the starting material and also using ethyl iodide as a reagent, the procedure of Example 41 gave 107 mg of the title compound (48% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.22 (3H, t,> 7.3 Hz), 2.27 (6H, s), 2.50-2.60 (2H, m), 2, 64-2.85 (2H, m), 2.89 (2H, q,> 7.3Hz), 6.74 (2H, d,> 7.9Hz), 7.07 (2H, d,> 7.9 Hz)

MS (m / z) 251 (M ⁺ )

Example 103

Synthesis of N- (4- (S-ethylisothioureido) phenylethyl) carbamic acid t-butyl ester

By using the compound obtained in Example 50 as the starting material and also using ethyl iodide as reagent, the procedure of Example 29 provided the title compound (85% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.22 (3H, t,> 7.3 Hz), 1.38 (9H, s), 2.58-2.65 (2H, m), 2, 90 (2H, q,> 7.3Hz), 3.06-3.15 (2H, m), 6.21-6.58 (1H, brs), 6.68-6.84 (2H, m ), 7.05 (2H, d,> 8.3Hz)

MS (m / z) 323 (M ⁺ )

183 619

Example 104

Synthesis of N- (4- (S-ethylisothioureido) phenylethyl) amine dihydrochloride

Using the compound obtained in Example 103 as a starting material, the procedure of Example 5 gave the title compound (93% yield).

1 H-NMR (D ₂ O) δ: 1.41 (3H, t, J-7.3 Hz), 3.02-3.10 (2H, m) 3.18-3.34 (4H, m ), 7.36 (2H, d, J = 8.3 Hz), 7.47 (2H, d, J = 8.3 Hz)

FAB-MS (m / z) 224 (M ⁺ + 1)

Example 105

Synthesis of N- (1- (3-nitrophenyl) ethyl) methylamine

By using 3'-nitroacetophenone as the starting material, the procedure of Example 42 gave 4.14 g of the title compound (80% yield).

'H-NMR (CDCl ₃ ) δ: 1.38 (3H, d, J = 6.8 Hz), 2.32 (3H, s), 3.79 (1H, q, J = 6.8 Hz) , 7.51 (1H, dd, J = 7.8.7.8Hz), 7.69-7.74 (1H, m), 8.03-8.14 (1H, m), 8.17 -8.26 (1H, m)

Example 106

Synthesis of N- (1- (3-nitrophenyl) ethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 105 as a starting material, the procedure of Example 22 gave the title compound in quantitative yield.

1 H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.55 (3H, d, J = 5.8 Hz), 2.64 (3H, s), 5.34 (5, 71 (1H, m), 7.43-7.69 (2H, m), 8.07-8.20 (2H, m)

Example 107

Synthesis of N- (1- (3-aminophenyl) ethyl) methyl carbamic acid t-butyl ester

Using the compound obtained in Example 106 as a starting material, the title compound was obtained according to the procedure in Example 2 (yield 86%).

H-NMR (CDC1 ₃₎

6: 1.44 (3H, d, J = 6.9Hz), 1.49 (9H, s), 2.58 (3H, s), 3.53 (3.75 (2H, m), 5, 37-5.59 (1H, m),

6.55-6.87 (3H, m), 7.11 (1H, dd, J = 8.2.7.6Hz)

Example 108

Synthesis of N- (1- (3-thioureido) phenyl) ethyl) methyl carbamic acid t-butyl ester

Using the compound obtained in Example 107 as a starting material, the procedure of Example 3 gave the title compound in quantitative yield.

1 H-NMR (CDCl ₃ ) δ: 1.39-1.55 (12H, m), 2.61 (3H, s), 5.30-5.50 (1H, m), 6.32 (2H , brs), 7.11-7.22 (3H, m), 7.38 (1H, dd, J = 8.2, 7.9Hz), 8.72 (1H, brs)

MS (m / z) 309 (M ⁺ )

Example 109

Synthesis of N- (1- (3- (S-methylisothioureido) phenyl) ethyl) methylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 108 as a starting material, the title compound was obtained according to the procedure in Example 4 (yield 87%).

1 H-NMR (CDCl ₃ ) δ: 1.44-1.53 (12H, m), 2.61 (3H, s), 2.77 (3H, s), 5.26-5.57 (1H , m), 7.14-7.57 (4H, m), 8.51 (2H, br)

Example 110

Synthesis of N- (1- (3- (S-methylisothioureido) phenyl) ethyl) methylamine dihydrochloride

By using the compound obtained in Example 109 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

'H-NMR (D ₂ O)

6: 1.71 (3H, d, J = 6.8Hz), 2.63 (3H, s), 2.72 (3H, s), 4.45 (1H, q, J = 6.8Hz ), 7.34-7.84 (4H, m)

MS (m / z) 223 (M ⁺ )

100

183 619

Example 111

Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) ethyl) methylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 108 as starting material, the procedure of Example 27 provided the title compound (83% yield).

Ή-NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.3 Hz), 1.43-1.61 (12H, m), 2.62 (3H, s), 3.35 (2H, q,> 7.3Hz), 5.29-5.56 (1H, m), 7.16-7.28 (2H, m), 7.28-7.34 (1H, m) , 7.35-7.43 (1H, m), 8.17 (2H, br)

Example 112

Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) ethyl) methylamine dihydrochloride

Using the compound obtained in Example 111 as a starting material, the procedure of Example 5 gave the title compound (98% yield).

Ή-NMR (D ₂ O) δ: 1.43 (3H, t,> 7.3 Hz), 1.70 (3H, d,> 6.8 Hz), 2.63 (3H, s), 3 , 25 (2H, q,> 7.3Hz), 4.44 (1H, q,> 6.8Hz), 7.40-7.74 (4H, m)

MS (m / z) 237 (M ⁺ )

Example 113

Synthesis of N- (1- (3- (N'-nitroguanidino) phenyl) ethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 107 as a starting material, the procedure of Example 6 gave the title compound (yield 61%).

Ή-NMR (CDCl ₃ ) δ: 1.43-1.48 (12H, m), 2.56 (3H, s), 3.52-3.82 (1H, m), 6.52-6, 68 (3H, m), 7.10 (1H, dd,> 8.2, 7.6 Hz)

Example 114

Synthesis of N- (1- (3- (N'-nitroguanidino) phenyl) ethyl) methylamine

Using the compound obtained in Example 113 as a starting material, the title compound was obtained according to the procedure in Example 55 (yield 29%).

Ή-NMR (CDCl ₃ ) δ: 1.33 (3H, d,> 6.8 Hz), 2.31 (3H, s), 3.54 (1H, q,> 6.8 Hz), 6, 49-6.73 (3H, m), 7.11 (1H, dd, J = 7.8.7.3Hz)

MS (m / z) 237 (M ⁺ )

Example 115

Synthesis of N- (3- (S-methylisothioureido) phenylmethyl) methylcarbamic acid t-butyl ester iodide

Using the compound obtained in Example 45 as starting material, the title compound was obtained according to the procedure in Example 4 (yield 56%).

Ή-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.44 (3H, s), 2.81 (3H, s), 4.38 (2H, s), 6.79- 6.83 (2H, m), 6.90 (1H, d,> 7.6 Hz), 7.25 (1H, dd,> 8.6, 7.6 Hz)

Example 116

Synthesis of N- (3- (S-methylisothioureido) phenylmethyl) methylamine dihydrochloride

Using the compound obtained in Example 115 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 56%).

Ή-NMR (D ₂ O) δ: 2.70 (3H, s), 2.75 (3H, s), 4.28 (2H, s), 7.40-7.71 (4H, m)

Example 117

Synthesis of N- (2-methoxy-5-nitrophenylmethyl) phthalimide

Potassium phthalimide (836 mg) was added to a solution of 2-methoxy-5-nitrobenzyl bromide (1.01 g) in dimethylformamide (41 ml) and stirred at room temperature for 10 minutes. Water and 2N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then, the organic layer was washed sequentially with a saturated aqueous bicarbonate solution

183 619

101 of sodium and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was washed successively with ethyl acetate and hexane to obtain 1.2 g of the title compound (yield 94%).

Ή-NMR (DMSO-d ₆ ) δ: 3.97 (3H, s), 4.80 (2H, s), 7.26 (IH.d, J = 9.3 Hz), 7.82-7 , 93 (4H, m), 7.99 (IH, d,> 2.9 Hz), 8.40 (IH, dd,> 9.3, 2.9 Hz)

Example 118

Synthesis of N- (2-methoxy-5-nitrophenylmethyl) carbamic acid t-butyl ester

To a mixture of the compound (357 mg) obtained in Example 117 and methanol (10 ml), hydrazine monohydrate (0.06 ml) was added and stirred at room temperature for 3 hours. The reaction mixture was acidified by the addition of 2N HCl and washed with ethyl acetate. The aqueous layer was made basic by the addition of a 2N aqueous sodium hydroxide solution and extracted with ethyl acetate; then, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in dimethylformamide (10 ml), di-t-butyl dicarbonate (274 mg) and triethylamine (0.17 ml) were added, and stirred at room temperature for 3 hours. Water and 2N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then the organic layer, washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 1: 1) to give 62 mg of the title compound (yield 20%).

Ή-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.96 (3H, s), 4.23-4.40 (2H, m), 4.80-5.09 (IH, m), 6.92 (IH, d,> 9.3 Hz), 8.16-8.20 (2H, m)

Example 119

Synthesis of N- (5-amino-2-methoxyphenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 118 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 95%)

Ή-NMR (CDCl3) δ: 1.44 (9H, s), 3.34 (2H, br), 3.76 (3H, s), 4.22 (2H, d,> 5.9 Hz), 4.80-5.19 (IH, m), 6.57 (IH, dd,> 8.6, 3.0 Hz), 6.64-6.82 (2H, m)

Example 120

Synthesis of N- (2-methoxy-5-thioureido) phenylmethyl) carbamic acid t-butyl ester To a mixture of the compound (52 mg) obtained in Example 119 and N, N-dimethylaminopyridine (53 mg) in methylene chloride (5 ml) was added dropwise thiophosgene (0.02 ml) and stirred at room temperature for 15 minutes. A 28% aqueous ammonia solution (5 ml) was added to the reaction mixture and stirred at room temperature for 1.5 hours. After neutralizing with 2N HCl, the reaction mixture was extracted with methylene chloride, and the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate) to give 58 mg of the title compound (91% yield).

Ή-NMR (CDCl3) δ: 1.44 (9H, s), 3.86 (3H, s), 4.27 (2H, d,> 6.3 Hz), 4.90-5.05 (IH , m), 5.95 (2H, brs), 6.88 (IH, d,> 8.6Hz), 7.09-7.16 (2H, m), 7.66 (IH, brs)

Example 121

Synthesis of N- (5- (S-ethylisothioureido) -2-methoxy) phenylmethyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 129 as starting material, the procedure of Example 27 gave the title compound (yield 90%).

Ή-NMR (CDC1 ₃₎

102

183 619 δ: 1.38 (3Η, t, J = 7.3 Hz), 1.45 (9H, s), 3.30 (2H, q,> 7.3 Hz), 3.86 (3H, s), 4.18-4.31 (2H, m), 5.00-5.15 (1H, m), 6.89 (1H, d, J = 9.3Hz), 7.14-7 .26 (2H, m)

MS (m / z) 339 (M ⁺ )

Example 122

Synthesis of N- (5- (S-ethylisothioureido) -2-methoxyphenyl) methyl) amine dihydrochloride

Using the compound obtained in Example 121 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O)

Ó: 1.41 (3H, t,> 7.3Hz), 3.23 (2H, q, J = 7.3Hz), 3.95 (3H, s), 4.22 (2H, s) , 7.22 (1H, d,> 8.9Hz), 7.35 (1H, d,> 2.6Hz), 7.44 (1H, dd,> 8.9, 2.6Hz)

MS (m / z) 178 (M ⁺ - 61)

Example 123

Synthesis of N- (3-nitrophenylmethyl) acetamide

Acetic anhydride (0.08 ml) was added dropwise to a solution of 3-nitrobenzylamine hydrochloride (139 mg) and triethylamine (0.22 ml) in methylene chloride (10 ml) and stirred at room temperature for 2 hours. 2N HCl was added to the reaction mixture and extraction with methylene chloride was performed; then the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 102 mg of the title compound (71% yield).

Ή-NMR (CDCl ₃ ) δ: 2.03 (3H, s), 4.51 (2H, d,> 5.8 Hz), 6.43-6.86 (1H, m), 7.48 ( 1H, dd,> 7.8, 6.8Hz), 7.63 (1H, d,> 7.8Hz), 8.07-8.11 (1H, m)

Example 124

Synthesis of N- (3-aminophenylmethyl) acetamide

Using the compound obtained in Example 123 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 69%).

1 H-NMR (CDCl ₃ ) δ: 1.97 (3H, s), 3.70 (2H, brs), 4.28 (2H, d,> 5.9 Hz), 6.00-6.28 (1H, m), 6.48-6.68 (3H, m), 7.00-7.14 (1H, m)

Example 125

Synthesis of N- (3-thioureido) phenylmethyl) acetamide

Using the compound obtained in Example 124 as a starting material, the procedure of Example 120 afforded the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.98 (3H, s), 4.33 (2H, d,> 5.8 Hz), 6.94 (2H, brs), 7.00-7.14 ( 1H, m), 7.20-7.37 (3H, m), 7.71-7.91 (1H, m), 9.49 (1H, brs)

Example 126

Synthesis of N- (3- (S-ethylisothioureido) phenylmethyl) acetamide hydroiodide

Using the compound obtained in Example 124 as a starting material, the procedure of Example 27 provided the title compound (67% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.33 (3H, t,> 7.3 Hz), 1.89 (3H, s), 3.31 (2H, q,> 7.3 Hz), 4.30 (2H, d,> 5.9Hz), 7.19-7.22 (2H, m), 7.29 (1H, d,> 7.6Hz), 7.46 (1H, dd ,> 7.6.7.6Hz), 8.30-8.50 (1H, m), 9.33 (2H, br)

MS (m / z) 251 (M ⁺ )

Example 127

Synthesis of N- (2-methyl-3-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

A solution of 2-methyl-3-nitrobenzyl chloride (1.07 g) in dimethylformamide (30 ml) was added dropwise to a solution of di-t-butyl iminodicarboxylate (1.38 g) and sodium hydride (content,

183 619

103

60%; 0.30 g) in dimethylformamide (30 ml) at 0 ° C. After 1 hour of stirring at room temperature, the temperature of the mixture was raised to 80 ° C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 10: 1) to give 1.49 g of the title compound (yield 96%).

Ή-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.48 (9H, s), 2.43 (3H, s), 4.37-4.41 (2H, m), 7 , 30 (1H, dd,> 8.1, 8.0 Hz), 7.51 (1H, d,> 8.0 Hz) 7.69 (1H, d,> 8.1 Hz)

Example 128

Synthesis of N- (3-amino-2-methylphenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 127 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 74%).

Ή-NMR (CDCl 3) δ: 1.46 (9H, s), 2.11 (3H, s), 3.62 (2H, brs), 4.29 (2H, d,> 5.3 Hz), 4.55-4.78 (1H, m), 6.63-6.71 (2H, m), 6.99 (1H, dd,> 7.8.7.6Hz)

MS (m / z) 236 (M ⁺ )

Example 129

Synthesis of N- (2-methyl-3-thioureido) phenylmethyl) carbamic acid t-butyl ester Using the compound obtained in Example 128 as a starting material, the title compound was obtained according to the procedure of Example 120 (88% yield).

Ή-NMR (CDCl 3) δ: 1.46 (9H, s), 2.27 (3H, s), 4.34 (2H, d, J = 5.6 Hz), 4.71-4.94 ( 1H, m), 5.83 (2H, br), 7.15-7.30 (5H, m), 7.71 (1H, brs)

Example 130

Synthesis of N- (3- (S-ethylisothioureido) -2-methylphenylmethyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 129 as starting material, the procedure of Example 27 gave the title compound (89% yield).

Ή-NMR (CDCl3) δ: 1.40 (3H, t,> 7.8Hz), 1.47 ((9H, s), 2.32 (3H, s), 3.27 (2H, q, > 7.8Hz), 4.36 (2H, d,> 5.7Hz), 4.66-4.86 (1H, m), 7.19-7.37 (3H, m)

Example 131

Synthesis of N- (3- (S-ethylisothioureido) -2-methylphenyl) methyl) amine dihydrochloride

Using the compound obtained in Example 130 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 66%).

Ή-NMR (D ₂ O) δ: 1.43 (3H, t,> 7.6 Hz), 2.29 (3H, s), 3.25 (2H, q,> 7.6 Hz), 4 , 31 (2H, s), 7.37-7.54 (3H, m) MS (m / z) 223 (M ⁺ )

Example 132

Synthesis of (2-chloro-3-nitrophenyl) methanol

Borane-tetrahydrofuran complex (1.0 M, 20 ml) was added dropwise to a solution of 2-chloro-3-nitrobenzoic acid (5.0 g) in anhydrous tetrahydrofuran (30 ml) under nitrogen atmosphere and the mixture was heated to reflux for 16 hours. . Water was added to the reaction mixture, which was extracted with ethyl acetate: the organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 5: 2) to give 3.5 g of the title compound (yield 84%).

Ή-NMR (CDCl3)

104

183 619 δ: 2.04 (1Η, t,> 5.9 Hz), 4.88 (2H, d, J = 5.9 Hz), 7.45 (1H, dd,> 7.9, 7, 9 Hz), 7.72-7.82 (2H, m)

Example 133

Synthesis of N- (2-chloro-3-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

A mixture of the compound (1.01 g) obtained in Example 132 and thionyl chloride (50 ml) was heated under reflux for 48 hours. The reaction mixture was concentrated under reduced pressure; the resulting residue was dissolved in dimethylformamide (25 ml) and added dropwise to a solution of sodium hydride (content, 60%; 0.24 g) and di-t-butyl iminodicarboxylate (1.29 g) in dimethylformamide (25 ml) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour and stirred at 80 ° C for 2 hours. Water and 2N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 5: 1) to obtain 1.70 g of the title compound (82% yield).

Ή-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.48 (9H, s), 4.97 (2H, s), 7.32-7.42 (2H, m), 7 , 66-7.72 (1H, m) Example 134

Synthesis of N- (3-amino-2-chlorophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 133 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 67%).

Ή-NMR (CDCl3) δ: 1.44 (9H, s), 1.48 (9H, s), 4.10 (2H, brs), 4.86 (2H, s), 6.53-6, 66 (2H, m), 7.06 (1H, dd,> 8.3, 7.8Hz)

MS (m / z) 356 (M ⁺ )

Example 135

Synthesis of N- (2-chloro-3-thioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 134 as starting material, the title compound was obtained according to the procedure of Example 120 (yield 82%).

Ή-NMR (CDCl 3) δ: 1.46 (9H, s), 1.47 (9H, s), 4.90 (2H, s) 6.35 (2H, brs), 7.11-7.13 (1H, m), 7.31-7.43 (2H, m), 8.05 (1H, br s)

Example 136

Synthesis of N- (2-chloro-3- (S-ethylisothioureido) phenyl) methyl) iminodicarboxylic acid di-t-butyl ester hydroiodide

Using the compound obtained in Example 135 as a starting material, the procedure of Example 27 gave the title compound (38% yield).

Ή-NMR (CDCl3) δ: 1.40 (3H, t,> 7.3 Hz), 1.45 (18H, s), 3.34 (2H, q,> 7.3 Hz), 4.92 (2H, s), 7.22-7.356 (3H, m) Example 137

Synthesis of N- (2-chloro-3- (S-ethylisothioureido) phenyl) methyl) amine dihydrochloride

Using the compound obtained in Example 136 as a starting material, the procedure of Example 5 gave the title compound (97% yield).

Ή-NMR (D ₂ O) δ: 1.44 (3H, t,> 7.3 Hz), 3.26 (2H, q,> 7.3 Hz), 4.42 (2H, s), 7 . 53-7.70 (3H, m)

MS (m / z) 243 (M ⁺ )

Example 138

Synthesis of N- (1- (3-nitrophenyl) cyclohexyl) carbamic acid t-butyl ester

183 619

105

Example 138a

Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,5-dibromopentane (1 eq) as a reagent, the procedure of Examples 1 a and Ib gave 1- (3-nitrophenyl) cyclohexanarboxylic acid.

H-NMR (CDC1 ₃₎

6: 1.19-1.86 (8H, m), 2.49-2.54 (2H, m), 7.49-7.81 (2H, m), 8.10-8.33 (2H , m)

Example 138b

Using 1- (3-nitrophenyl) cyclohexane carboxylic acid as starting material, 110 mg of the title compound was obtained according to the procedure in Example 1c (yield 28%).

1 H-NMR (CDCl ₃ ) δ: 1.39 (9H, s), 1.52-1.82 (8H, m), 2.21-2.25 (2H, m), 4.94 (1H , brs), 7.46-7.77 (2H, m), 8.06-8.29 (2H, m)

Example 139

Synthesis of N- (1- (3-aminophenyl) cyclohexyl) carbamic acid t-butyl ester

Using the compound obtained in Example 138 as starting material, the procedure in Example 2 gave 877 mg of the title compound (65% yield).

1 H-NMR (CDCl ₃ ) δ: 1.38 (9H, s), 1.48-1.78 (8H, m), 2.08-2.30 (2H, m), 3.59 (2H , brs), 4.75 (1H, brs), 6.52-6.82 (3H, m), 7.06-7.12 (1H, m)

Example 140

Synthesis of N- (1 - (3-thioureido) phenyl) cyclohexyl) carbamic acid t-butyl ester

Using the compound obtained in Example 139 as starting material, the procedure of Example 120 gave 224 mg of the title compound (93% yield).

1 H-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.50-1.81 (8H, m), 2.06-2.17 (2H, m), 4.93 (1H , brs), 6.21 (2H, brs), 7.03-7.42 (4H, m), 8.03 (1H, brs)

Example 141

Synthesis of N- (1- (3- (S-methylisothioureido) phenyl) cyclohexyl) carbamic acid t-butyl ester

Using the compound obtained in Example 140 as a starting material and also using methyl iodide as a reagent, the reaction was conducted as in Example 29 to give 85 mg of the title compound (70% yield).

1 H-NMR (CDCl ₃ ) δ: 1.36 (9H, s), 1.49-1.83 (8H, m), 2.15-2.20 (2H, m), 2.46 (3H , s), 4.55 (1H, brs), 4.81 (1H, brs), 6.75-7.26 (4H, m)

Example 142

Synthesis of N- (1- (3- (S-methylisothioureido) phenyl) cyclohexyl) amine dihydrochloride

Using the compound obtained in Example 141 as starting material, 74 mg of the title compound were obtained according to the procedure in Example 5 (94% yield).

1 H-NMR (D ₂ O) δ: 1.43-2.02 (8H, m), 2.48-2.52 (2H, m), 2.69 (3H, s), 7.44- 7.78 (4H, m)

FAB-MS (m / z) 264 (M ⁺ + 1)

Example 143

Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) cyclohexyl) carbamic acid t-butyl ester

Using the compound obtained in Example 140 as starting material, the procedure of Example 95 gave 108 mg of the title compound (93% yield).

1 H-NMR (CDCl ₃ ) δ: 1.34-1.39 (3H, m), 1.37 (9H, s), 1.49-1.82 (8H, m), 2.15-2 . 20 (2H, m), 2.92-3.20 (2H, m), 4.52 (1H, brs), 4.80 (1H, brs), 6.75-7.28 (4H, m )

106

183 619

Example 144

Synthesis of N- (1- (3-S-ethylisothioureido) phenyl) -cyclohexyl) amine dihydrochloride

Using the compound obtained in Example 143 as starting material, 79 mg of the title compound were obtained according to the procedure in Example 5 (87% yield).

'Η-NMR (D ₂ O)

Ó: 1.32-2.08 (8H, m), 1.41 (3H, t, J = 7.3Hz), 2.47-2.52 (2H, m), 3.23 (2H, q, J = 7.3Hz), 7.43-7.74 (4H, m)

FAB-MS (m / z) 278 (M ⁺ + 1)

Example 145

Synthesis of N- (1- (3-S-n-propylisothioureido) phenyl) cyclohexyl) carbamic acid t-butyl ester

Using the compound obtained in Example 140 as a starting material, 78 mg of the title compound were obtained according to the procedure of Example 91 (69% yield).

Ή-NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.3 Hz), 1.36 (9H, s), 1.49-1.82 (10H, m), 2.15 -2.20 (2H, m), 2.90-3.14 (2H, m), 4.52 (1H, brs), 4.80 (1H, brs), 6.73-7.28 (4H , m)

Example 146

Synthesis of N- (1- (3- (S-n-propylisothioureido) phenyl) cyclohexyl) amine dihydrochloride

Using the compound obtained in Example 145 as a starting material, the procedure of Example 5 gave 64 mg of the title compound (98% yield).

Ή-NMR (D ₂ O) δ: 1.04 (3H, t, J = 7.3 Hz), 1.39-2.05 (10H, m), 2.47-2.52 (2H, m ), 3.20 (2H, t, J = 7.3Hz), 7.43-7.74 (4H, m)

FAB-MS (m / z) 292 (M ⁺ + 1)

Example 147

Synthesis of N- (1- (3-nitrophenyl) cyclopentyl) carbamic acid t-butyl ester

Example 147a

Using 3-nitrophenylacetic acid t-butyl ester as a substrate and also using 1,4-dibromobutane (1 eq.) As a reagnet, the procedure of Examples 1a and 1b gave 1- (3-nitrophenyl) cyclopentanecarboxylic acid.

Ή-NMR (CDCl 3) δ: 1.78-2.05 (6H, m), 2.68-2.74 (2H, m), 7.46-7.74 (2H, m), 8.10 -8.25 (2H, m)

Example 147b

Using 1- (3-nitrophenyl) cyclopentanecarboxylic acid as the starting material, the procedure in Example 1c gave 211 mg of the title compound (54% yield).

^! H-NMR (CDCl 3) δ: 1.37 (9H, s), 1.86-2.23 (8H, m), 4.97 (1H, brs), 7.45-7.78 (2H, m ), 8.06-8.27 (2H, m)

Example 148

Synthesis of N- (1- (3-aminophenyl) cyclopentyl) carbamic acid t-butyl ester

Using the compound obtained in Example 147 as the starting material, the procedure in Example 2 gave 1.81 g of the title compound (96% yield)

Ή-NMR (CDCl 3) δ: 1.35 (9H, s), 1.72-2.18 (8H, m), 3.60 (2H, brs), 4.83 (1H, brs), 6, 51-7.11 (4H, m)

Example 149

Synthesis of N- (1- (3-thioureido) phenyl) cyclopentyl) carbamic acid t-butyl ester

Using the compound obtained in Example 148 as a starting material, the procedure of Example 120 gave 296 mg of the title compound in quantitative yield.

Ή-NMR (CDCl 3) δ: 1.33 (9H, s), 1.84-2.21 (8H, m), 4.91 (1H, brs), 6.24 (2H, brs), 6, 87-7.40 (4H, m), 7.90 (1H, brs)

183 619

107

Example 150

Synthesis of N- (1- (3- (S-methylisothioureido) phenyl) cyclopentyl) carbamic acid t-butyl ester

Using the compound obtained in Example 149 as a starting material and also using methyl iodide as a reagent, the reaction was conducted as in Example 29 to give 82 mg of the title compound (94% yield).

Ή-NMR (CDCl ₃ ) δ: 1.34 (9H, s), 1.80-2.18 (8H, m), 2.47 (3H, s), 4.57 (1H, brs), 4 . 84 (1H, br s), 6.78-7.27 (4H, m)

Example 151

Synthesis of N- (1 - (3 - (S-methylisothioureido) phenyl) cyclopentyl) amine dihydrochloride

Using the compound obtained in Example 150 as a starting material, the procedure of Example 5 gave 72 mg of the title compound (95% yield).

Ή-NMR (D ₂ O) δ: 1.87-1.97 (4H, m), 2.30-2.35 (4H, m), 2.70 (3H, s), 7.39-7 .67 (4H, m)

FAB-MS (m / z) 250 (M ⁺ + 1)

Example 152

Synthesis of N- (1 - (3- (S-ethylisothioureido) phenyl) cyclopentyl) carbamic acid t-butyl ester

Using the compound obtained in Example 149 as a starting material, the procedure of Example 95 gave 97 mg of the title compound (97% yield).

Ή-NMR (CDCl ₃ ) δ: 1.26-1.39 (12H, m), 1.80-2.30 (8H, m), 2.95-3.20 (2H, m), 4, 55 (1H, brs), 4.86 (1H, brs), 6.77-7.24 (4H, m)

Example 153

Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) cyclopentyl) amine dihydrochloride

Using the compound obtained in Example 152 as starting material, 79 mg of the title compound were obtained according to the procedure in Example 5 (88% yield).

Ή-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.3 Hz), 1.88-1.98 (4H, m), 2.30-2.35 (4H, m) , 3.24 (2H, q,> 7.3Hz), 7.39-7.68 (4H, m)

FAB-MS (m / z) 264 (M ⁺ + 1)

Example 154

Synthesis of N- (1- (3- (S-n-propylisothioureido) phenyl) cyclopentyl) carbamic acid t-butyl ester

Using the compound obtained in Example 149 as a starting material, the procedure of Example 91 gave 94 mg of the title compound (98% yield).

Ή-NMR (CDCl ₃ ) δ: 1.03 (3H, t,> 7.3 Hz), 1.34 (9H, s), 1.70-2.17 (10H, m), 2.95- 3.15 (2H, m), 4.54 (1H, br s), 4.85 (1H, br s), 6.76-7.25 (4H, m)

Example 155

Synthesis of N- (1- (3 - (S-n-propylisothioureido) phenyl) cyclopentyl) amine dihydrochloride

Using the compound obtained in Example 154 as the starting material, the procedure of Example 5 gave 83 mg of the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.04 (3H, t,> 7.3 Hz), 1.73-1.97 (6H, m), 2.29-2.35 (4H, m) , 3.20 (2H, t,> 7.3Hz), 7.40-7.64 (4H, m)

FAB-MS (m / z) 278 (M ⁺ + 1)

Example 156

Synthesis of N- (1- (3-nitrophenyl) cyclobutyl) carbamic acid t-butyl ester

108

183 619

Example 156a

Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,3-dibromopropane (1 eq) as a reagent, the procedure of Examples 1a and 1b gave 1- (3-nitrophenyl) cyclobutanecarboxylic acid.

Ή-NMR (CDCl ₃ ) δ: 1.86-2.27 (2H, m), 2.50-2.62 (2H, m), 2.88-2.97 (2H, m), 7, 48-7.64 (2H, m), 8.10-8.17 (2H, m)

Example 156b

Using 1- (3-nitrophenyl) cyclobutanecarboxylic acid as starting material, the procedure in Example 1c gave 2.0 g of the title compound (89% yield).

1-NMR (CDCl ₃ ) δ: 1.36 (9H, s), 1.85-2.26 (2H, m), 2.46-2.62 (4H, m), 5.28 (1H , brs), 7.51-8.28 (4H, m)

Example 157

Synthesis of N- (1- (3-aminophenyl) cyclobutyl) carbamic acid t-butyl ester

Using the compound obtained in Example 156 as a starting material, the procedure of Example 2 gave 1.2 g of the title compound (62% yield).

Ή-NMR (CDCl ₃ ) δ: 1.36 (9H, s), 1.72-2.12 (2H, m), 2.48-2.53 (4H, m), 3.64 (2H, brs), 4.99 (1H, brs), 6.54-7.15 (4H, m)

Example 158

Synthesis of N- (1- (3-thioureido) phenyl) cyclobutyl) carbamic acid t-butyl ester

Using the compound obtained in Example 157 as the starting material, the procedure of Example 120 gave 302 mg of the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.34 (9H, s), 1.80-2.24 (2H, m), 2.37-2.59 (4H, m), 5.24 (1H, brs), 6.34 (2H, brs), 7.04-7.45 (4H, m), 8.24 (1H, s)

Example 159

Synthesis of N- (1- (3- (S-methylisothioureido) phenyl) cyclobutyl) carbamic acid t-butyl ester

Using the compound obtained in Example 158 as a starting material and also using methyl iodide as a reagent, the reaction was conducted as in Example 29 to give 150 mg of the title compound (96% yield).

Ή-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.76-2.20 (2H, m), 2.46-2.72 (7H, m), 4.56 (1H, brs), 5.07 (1H, brs), 6.78-7.25 (4H, m)

Example 160

Synthesis of N- (l - (3- (S-methylisothioureido) phenyl) cyclobutyl) amine dihydrochloride

Using the compound obtained in Example 159 as a starting material, 110 mg of the title compound were obtained according to the procedure in Example 5 (86% yield).

Ή-NMR (D ₂ O) δ: 1.88-2.29 (2H, m), 2.60-2.84 (7H, m), 7.42-7.69 (4H, m)

Example 161

Synthesis of N- (1 - (3 - (S-ethylisothioureido) phenyl) cyclobutyl) carbamic acid t-butyl ester

Using the compound obtained in Example 158 as starting material, the procedure of Example 95 gave 150 mg of the title compound (91% yield).

Ή-NMR (CDCl ₃ ) δ: 1.26-1.43 (12H, m), 1.79-2.16 (2H, m), 2.48-2.54 (4H, m), 2, 90-3.14 (2H, m), 4.54 (1H, brs), 5.07 (1H, brs), 6.78-7.24 (4H, m)

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109

Example 162

Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) cyclobutyl) amine dihydrochloride

Using the compound obtained in Example 161 as starting material, the procedure of Example 5 gave 100 mg of the title compound (83% yield).

Ή-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.3 Hz), 1.94-2.23 (2H, m), 2.60-2.84 (4H, m) , 3.24 (2H, q, J = 7.3Hz), 7.42-7.69 (4H, m)

Example 163

Synthesis of N- (1- (3-nitrophenyl) cyclopropyl) carbamic acid t-butyl ester

Example 163a

Using the 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,2-dibromoethane (1 eq) as a reagent, the procedure in Examples 1 a and 1 b gave 1- (3-nitrophenyl) cyclopropanecarboxylic acid.

Ή-NMR (CDCl ₃ ) δ: 1.34 (2H, dd,> 7.3,4.3 Hz), 3.56 (2H, dd,> 7.3,4.3 Hz), 7.46 -7.71 (2H, m), 8.13-8.21 (2H, m)

Example 163b

Using 1- (3-nitrophenyl) cyclopropanecarboxylic acid as starting material, the procedure in Example 1c gave 162 mg of the title compound (78% yield).

Ή-NMR (CDCl3) δ: 1.31-1.45 (13H, m), 5.34 (1H, brs), 7.43-7.48 (2H, m), 8.03-8.08 (2H, m)

Example 164

Synthesis of N- (1- (3-aminophenyl) cyclopropyl) carbamic acid t-butyl ester

Using the compound obtained in Example 163 as the starting material, the procedure of Example 2 gave 18.7 mg of the title compound (2% yield).

Ή-NMR (CDCl 3) δ: 1.18-1.28 (4H, m), 1.43 (9H, s), 3.61 (2H, brs), 5.24 (1H, brs), 6, 49-6.61 (2H, m), 7.03-7.09 (2H, m)

Example 165

Synthesis of N- (1 - (3-thioureido) phenyl) cyclopropyl) carbamic acid t-butyl ester

Using the compound obtained in Example 164 as starting material, the procedure of Example 120 gave 20 mg of the title compound (87% yield).

Ή-NMR (CDCl 3) δ: 1.24-1.35 (4H, m), 1.43 (9H, s), 5.31 (1H, brs), 6.21 (2H, brs), 7, 03-7.37 (4H, m), 8.10 (1H, brs)

Example 166

Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) cyclopropyl) carbamic acid t-butyl ester

Using the compound obtained in Example 165 as starting material, the procedure of Example 95 gave 20 mg of the title compound (92% yield).

Ή-NMR (CDCl3) δ: 1.21-1.25 (4H, m), 1.35 (3H, t,> 7.3Hz), 1.43 (9H, s), 2.95-3 . 10 (2H, m), 5.29 (1H, br s), 6.73-6.88 (2H, m), 7.18-7.27 (2H, m)

Example 167

Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) cyclopropyl) amine dihydrochloride

Using the compound obtained in Example 166 as a starting material, the procedure of Example 5 gave 21 mg of the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.31-1.49 (7H, m) 3.23 (2H, q,> 7.3 Hz), 7.39-7.44 (2H, m), 7.59-7.61 (2H, m)

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Example 168

Synthesis of N- (1- (3- (N'-nitroguanidino) phenyl) cyclohexyl) carbamic acid t-butyl ester

Using the compound obtained in Example 139 as a starting material, the procedure of Example 6 gave 63 mg of the title compound (32% yield).

Ή-NMR (CDC1 ₃₎

Ó: 1.35 (9H, s), 1.51-1.86 (8H, m), 2.14-2.19 (2H, m), 4.95 (1H, brs), 7.15- 7.47 (4H, m), 9.66 (1H, br s)

Example 169

Synthesis of N- (1- (3- (N-nitroguanidino) phenyl) cyclohexyl) amine hydrochloride

Using the compound obtained in Example 168 as a starting material, the procedure in Example 5 gave 51 mg of the title compound (97% yield).

Ή-NMR (D ₂ O) δ: 1.43-2.07 (8H, m), 2.48-2.53 (2H, m), 7.37-7.62 (4H, m)

Example 170

Synthesis of N- (1- (3- (N'-nitroguanidino) phenyl) cyclopentyl) carbamic acid t-butyl ester

Using the compound obtained in Example 148 as the starting material, the procedure of Example 6 gave 121 mg of the title compound (61% yield).

Ή-NMR (CDCl 3) δ: 1.34 (9H, s), 1.87-2.24 (8H, m), 4.94 (1H, brs), 7.14-7.45 (4H, m ), 9.67 (1H, brs)

Example 171

Synthesis of N- (1- (3- (N'-nitroguanidino) phenyl) cyclopentyl) amine hydrochloride

Using the compound obtained in Example 170 as starting material, 78 mg of the title compound were obtained according to the procedure in Example 5 (98% yield).

Ή-NMR (p ₂ O) δ: 1.90-1.97 (4H, m), 2.29-2.32 (4H, m), 7.37-7.61 (4H, m)

Example 172

Synthesis of N- (1- (3- (N-nitroguanidino) phenyl) cyclobutyl) carbamic acid t-butyl ester

Using the compound obtained in Example 157 as a starting material, 106 mg of the title compound were obtained according to the procedure in Example 6 (53% yield).

Ή-NMR (CDCl3) δ: 1.35 (9H, s), 1.87-2.28 (2H, m), 2.38-2.63 (4H, m), 5.26 (1H, brs ), 7.15-7.48 (4H, m), 9.69 (1H, brs)

Example 173

Synthesis of N- (1- (3- (N'-nitroguanidino) phenyl) cyclobutyl) amine hydrochloride

Using the compound obtained in Example 172 as a starting material, the procedure in Example 5 gave 72 mg of the title compound (98% yield).

Ή-NMR (D ₂ O) δ: 1.90-2.28 (2H, m), 2.59-2.84 (4H, m), 7.38-7.63 (4H, m)

Example 174

Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 10 as the starting material, the procedure of Example 95 gave 71 mg of the title compound (74% yield).

Ή-NMR (CDCl 3) δ: 1.34-1.44 (15H, m), 2.90-3.12 (2H, m), 4.42-4.54 (1H, m), 4.76 (1H, brs), 6.82-7.29 (4H, m)

Example 175

Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 174 as starting material, the procedure of Example 5 gave 53 mg of the title compound (97% yield).

183 619

111 'H-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.6 Hz), 1.67 (3H, d, J = 6.9 Hz), 3.25 (2H, q ,> 7.6 Hz), 4.60 (1H, q,> 6.9 Hz), 7.42-7.67 (4H, m)

Example 176

Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) propyl) carbamic acid t-butyl ester

Using the compound obtained in Example 17 as a starting material, the procedure of Example 95 gave 820 mg of the title compound (91% yield).

1 H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J-7.3 Hz), 1.30-1.50 (12H, m), 1.72-1.78 (2H, m ), 3.00-3.17 (2H, m), 4.40-4.58 (2H, m), 4.78 (1H, br s), 6.80-6.94 (2H, m), 7.22-7.28 (2H, m)

Example 177. Synthesis of N- (1- (3- (S-ethylisothioureido) phenyl) propyl) amine dihydrochloride

Using the compound obtained in Example 176 as substart, the procedure of Example 5 gave 653 mg of the title compound (82% yield).

1 H-NMR (D ₂ O) δ: 0.89 (3H, t,> 7.3 Hz), 1.42 (3H, t,> 7.3 Hz), 1.94-2.13 (2H , m), 3.24 (2H, q,> 7.3Hz), 4.33 (1H, t,> 7.3Hz), 7.44-7.68 (4H, m)

Example 178

Synthesis of 2-methyl-2- (4-nitrophenyl) propanol

Example 178a

By using 4-nitrophenylacetic acid diphenylmethyl ester as a starting material and also using methyl iodide (2 eq) as a reagent, the procedure in Examples 1a and 1b gave 2-methyl-2- (4-nitrophenyl) propionic acid.

'H-NMR (CDCl3) δ: 1.65 (6H, s), 7.57 (2H, d,> 8.9 Hz), 8.20 (2H, d,> 8.9 Hz)

Example 178b

Using 2-methyl-2- (4-nitrophenyl) propionic acid as the starting material, the procedure of Example 132 gave 172 mg of the title compound (88% yield).

1 H-NMR (CDCl 3) δ: 1.38 (6H, s), 3.69 (2H, s), 7.56 (2H, d,> 8.9 Hz), 8.18 (2H, d, > 8.9 Hz)

Example 179

Synthesis of N- (2-methyl-2- (4-nitrophenyl) propyl) phthalimide

A solution of the compound (152 mg) obtained in Example 178 in anhydrous tetrahydrofuran (10 ml) was added dropwise to a mixture of triphenylphosphine (484 mg), diethyl azodicarboxylate (0.29 ml) and anhydrous tetrahydrofuran (20 ml) at 0 ° C under nitrogen atmosphere . Then, a solution of phthalimide (272 mg) in anhydrous tetrahydrofuran (10 ml) was added dropwise to the reaction mixture at 0 ° C, stirred for 10 minutes and stirred for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 8: 2) to give 439 mg of the title compound (88% yield).

1 H-NMR (CDCl 3) δ: 1.46 (6H, s), 3.84 (2H, s), 7.72 (2H, d,> 8.9 Hz), 7.75-7.83 ( 4H, m), 8.17 (2H, d,> 8.9Hz) Example 180

Synthesis of N- (2-methyl-2- (4-nitrophenyl) propyl) amine

Hydrazine monohydrate (0.05 ml) was added to a mixture of the compound (152 mg) obtained in Example 179, methanol (10 ml) and chloroform (10 ml) and heated to reflux for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; then 2N HCl was added, the mixture was washed with ethyl acetate. The aqueous layer was then basified with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, osu 112

The 183,619 was treated with anhydrous sodium sulfate and concentrated under reduced pressure to give 71 mg of the title compound (78% yield).

Ή-NMR (CDCl ₃ ) δ: 1.36 (6H, s), 2.87 (2H, s), 7.52 (2H, d,> 8.9 Hz), 8.18 (2H, d, > 8.9 Hz)

Example 181

Synthesis of N- (2-methyl-2- (4-nitrophenyl) propyl) carbamic acid t-butyl ester

Using the compound obtained in Example 180 as starting material, the procedure of Example 22 gave 77 mg of the title compound (86% yield).

Ή-NMR (CDCl ₃ ) δ: 1.37 (6H, s), 1.38 (9H, s), 3.36 (2H, d,> 6.3 Hz), 4.30-4.40 ( 1H, m), 7.53 (2H, d,> 8.9

Hz), 8.18 (2H, d,> 8.9Hz)

Example 182

Synthesis of N- (2- (4-aminophenyl) -2-methyl) propyl) carbamic acid t-butyl ester

Using the compound obtained in Example 181 as a starting material, the procedure of Example 2 gave 796 mg of the title compound (65% yield).

Ή-NMR (CDCl ₃ ) δ: 1.26 (6H, s), 1.40 (9H, s), 3.26 (2H, d,> 5.9 Hz), 3.60 (2H, brs) , 4.20-4.38 (1H, m), 6.66 (2H, d,> 8.6Hz), 7.12 (2H, d,> 8.6Hz)

Example 183

Synthesis of N- (2-methyl-2- (4-thioureido) phenyl) propyl) carbamic acid t-butyl ester

Using the compound obtained in Example 182 as the starting material, the procedure of Example 120 gave 240 mg of the title compound (98% yield).

Ή-NMR (CDCl 3) δ: 1.32 (6H, s), 1.38 (9H, s), 3.30 (2H, d,> 6.3 Hz), 4.38-4.50 (1H , m), 6.20 (2H, brs), 7.20 (2H, d,> 8.3Hz), 7.42 (2H, d,> 8.3Hz), 8.19 (1H, brs )

Example 184

Synthesis of N- (2- (4- (S-ethylisothioureido) phenyl) -2-methylpropyl) carbamic acid t-butyl ester

Using the compound obtained in Example 183 as the starting material, the procedure of Example 95 gave 120 mg of the title compound (91% yield).

Ή-NMR (CDCl 3) δ: 1.30 (6H, s), 1.34-1.40 (12H, m), 3.00-3.18 (2H, m), 3.29 (2H, d > 6.3Hz), 4.20 (1H, brs), 4.40-4.60 (1H, m), 6.80-6.95 (2H, m), 7.28 (2H, d ,> 7.6 Hz)

Example 185

Synthesis of N- (2- (4- (S-ethylisothioureido) phenyl) -2-methylpropyl) amine dihydrochloride

Using the compound obtained in Example 184 as the starting material, the procedure of Example 5 gave 110 mg of the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.39-1.46 (9H, m), 3.19-3.29 (4H, m), 7.40 (2H, d,> 8.6 Hz) , 7.63 (2H, d,> 8.6Hz)

Example 186

Synthesis of N- (2-methyl-2- (4- (N'-nitroguanidino) phenyl) propyl) carbamic acid t-butyl ester

Using the compound obtained in Example 182 as the starting material, 163 mg of the title compound were obtained according to the procedure in Example 6 (82% yield).

Ή-NMR (CDCl3) δ: 1.34 (6H, s), 1.39 (9H, s), 3.32 (2H, d,> 6.3 Hz), 4.18-4.28 (1H , m), 7.29 (2H, d,> 8.3

Hz), 7.48 (2H, d,> 8.3 Hz), 9.85 (1H, brs)

Example 187

Synthesis of N- (2-methyl-2- (4- (N ^/ -nitroguanidino) phenyl) propyl) amine hydrochloride

Using the compound obtained in Example 186 as the starting material according to the procedure of Example 5, 90 mg of the title compound was obtained (92% yield).

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113 H-NMR (D ₂ 0) δ: 1.45 (6H, s), 3.27 (2H, s), 7.38 (2H, d,> 8.6 Hz), 7.58 (2H , d,> 8.6 Hz)

Example 188

Synthesis of N- (1,1-dimethyl-2- (4-nitrophenyl) ethyl) amine

A solution of phentermine (1.0 g) in chloroform (20 ml) was added dropwise to sulfuric acid (3.57 ml) at 0 ° C; then fuming nitric acid (density = 1.52; 2.8 ml) was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 hours, basified with water and 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate solution, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 9: 1) to give 367 mg of the title compound (yield 28%).

1 H-NMR (CDCl ₃ ) δ: 1.15 (6H, s), 2.78 (2H, s), 7.37 (2H, d,> 8.6 Hz), 8.16 (2H, d ,> 8.6 Hz)

Example 189

Synthesis of N- (1,1-dimethyl-2- (4-nitrophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 188 as starting material, the procedure of Example 22 afforded 473 mg of the title compound (89% yield).

1 H-NMR (CDCl 3) δ: 1.28 (6H, s), 1.48 (9H, s), 3.15 (2H, s), 4.24 (1H, brs), 7.31 (2H , d,> 8.6 Hz), 8.07 (2H, d,> 8.6 Hz)

Example 190

Synthesis of N- (2- (4-aminophenyl) -1,1-dimethylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 189 as the starting material, the procedure of Example 2 gave 350 mg of the title compound (87% yield).

1 H-NMR (CDCl 3) δ: 1.24 (6H, s), 1.46 (9H, s), 2.84 (2H, s), 3.58 (2H, br s), 4.27 (1H , brs), 6.61 (2H, d,> 8.2Hz), 6.94 (2H, d,> 8.2Hz)

Example 191

Synthesis of N- (1,1-dimethyl-2- (4-thioureido) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 190 as starting material, the procedure of Example 120 afforded 152 mg of the title compound (93% yield).

1 H-NMR (CDCl 3) δ: 1.26 (6H, s), 1.47 (9H, s), 3.02 (2H, s), 4.26 (1H, br s), 6.06 (2H , brs, 7.14 (2H, d,> 8.3Hz), 7.23 (2H, d,> 8.3Hz), 7.85 (1H, brs)

Example 192

Synthesis of N- (1,1-dimethyl-2- (4- (S-ethylisothioureido) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 191 as starting material, the procedure of Example 95 gave 150 mg of the title compound (91% yield).

1 H-NMR (CDCl 3) δ: 1.25 (6H, s), 1.37 (3H, t,> 7.3Hz), 1.46 (9H, s), 2.92 (2H, s) , 2.98-3.18 (2H, m), 4.25 (1H, brs), 4.49 (1H, brs), 6.78-6.90 (2H, m), 7.09 (2H , d,> 7.9 Hz)

Example 193

Synthesis of N- (1,1-dimethyl-2- (4- (S-ethylisothioureido) phenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 192 as starting material, the procedure of Example 5 gave 140 mg of the title compound in quantitative yield.

1 H-NMR (D ₂ O) δ: 1.37 (6H, s), 1.41 (3H, t,> 7.6 Hz), 3.02 (2H, s), 3.23 (2H, q,> 7.6 Hz), 7.37 (2H, d,> 8.3 Hz), 7.44 (2H, d,> 8.3 Hz)

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Example 194

Synthesis of N- (1,1-dimethyl-2- (4- (N ^/ -nitroguanidino) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 190 as starting material, the procedure of Example 6 gave 70 mg of the title compound (43% yield).

Ή-NMR (CDCl ₃ ) δ: 1.28 (6H, s), 1.48 (9H, s), 3.05 (2H, s), 4.30 (1H, brs), 7.23 (2H , d, J = 8.6 Hz), 7.28 (2H, d,> 8.6 Hz), 9.73 (1H, brs)

Example 195

Synthesis of N- (1,1-dimethyl-2- (4- (N'-nitroguanidino) phenyl) ethyl) amine hydrochloride

Using the compound obtained in Example 194 as starting material, 56 mg of the title compound were obtained according to the procedure in Example 5 (97% yield).

Ή-NMR (D ₂ O) δ: 1.37 (6H, s), 3.00 (2H, s), 7.34-7.44 (4H, m)

Example 196

Synthesis of 4-methoxy-3-nitrophenyl) methanol

Using 4-methoxy-3-nitrobenzoic acid as the starting material, 5.4 g of the title compound were obtained according to the procedure of Example 132 (98% yield).

Ή-NMR (CDCl ₃ ) δ: 1.87 (1H, t,> 5.9 Hz), 3.96 (3H, s), 4.69 (2H, d,> 5.9 Hz), 7, 08 (1H, d,> 8.6 Hz), 7.55 (1H, dd,> 8.6, 2.3 Hz), 7.85 (1H, d,> 2.3 Hz)

Example 197

Synthesis of N- (4-methoxy-3-nitrophenylmethyl) phthalimide

Using the compound obtained in Example 196 as starting material, the procedure of Example 179 gave 2.74 g of the title compound (59% yield).

Ή-NMR (CDCl ₃ ) δ: 3.93 (3H, s), 4.82 (2H, s), 7.03 (1H, d,> 8.8 Hz), 7.65 (1H, dd, > 8.8.2.4Hz), 7.70-7.75 (2H, m), 7.84 -7.89 (2H, m), 7.92 (1H, d,> 2.4Hz )

Example 198

Synthesis of N- (4-methoxy-3-nitrophenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 197 as a starting material, the reaction was conducted as in Example 118 to give 1.47 g of the title compound (92% yield).

Ή-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.95 (3H, s) 4.29 (2H, d,> 5.4 Hz), 4.93 (1H, br), 7.05 (1H, d,> 8.8Hz), 7.49 (1H, dd,> 8.8, 2.4Hz), 7.77 (1H, d,> 2.4Hz)

Example 199

Synthesis of N- (3-amino-4-methoxyphenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 198 as the starting material, the procedure in Example 2 gave 1.24 g of the title compound (96% yield).

Ή-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.79 (2H, br), 3.83 (3H, s), 4.16 (2H, d,> 5.6 Hz) , 4.71 (1H, br), 6.60-6.65 (2H, m), 6.72 (1H, d,> 8.3Hz)

Example 200

Synthesis of N- (4-methoxy-3-thioureido) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 199 as a starting material, the reaction was carried out as in Example 120 to give 605 mg of the title compound (97% yield).

Ή-NMR _(DMSO-c) δ: 1.39 (9H, s), 3.79 (3H, s), 4.03 (1H, d,> 5.9 Hz), 6,92-7. 03 (2H, m), 7.23-7.27 (1H, m), 7.30 (2H, br), 7.61 (1H, s), 8.96 (1H, s)

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115

Example 201

Synthesis of N- (3- (S-ethylisothioureido) -4-methoxy) phenylmethyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 200 as starting material, the procedure of Example 27 gave 591 mg of the title compound (89% yield).

Ή-NMR (CDC1 ₃₎

6: 1.39 (3H, t,> 7.3Hz), 1.46 (9H, s), 3.30 (2H, q,> 7.3Hz), 3.86 (3H, s), 4.25 (2H, d,> 5.6 Hz), 4.93 (1H, br), 6.93 (1H, d,> 8.4 Hz), 7.22-7.30 (3H, m )

Example 202

Synthesis of N- (3- (S-ethylisothioureido) -4-methoxy) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 201 as the starting material, the procedure of Example 5 gave 102 mg of the title compound in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 1.33 (3H, t,> 7.3 Hz), 3.29 (2H, q,> 7.3 Hz), 3.86 (3H, s), 3.97-4.01 (2H, m), 7.24 (1H, d,> 8.6Hz), 7.44 (1H, d,> 2.0Hz), 7.56 (1H, dd > 8.6, 2.0 Hz), 8.45 (3H, br), 9.53 (1H, br), H, 28 (1H, br)

Example 203

Synthesis of 4-chloro-3-nitrophenyl) methanol

Using 4-chloro-3-nitrobenzoic acid as the starting material, 1.53 g of the title compound was obtained according to the procedure of Example 132 (82% yield).

Ή-NMR (CDCl 3) δ: 1.96 (1H, t,> 5.4 Hz), 4.78 (2H, d,> 5.4 Hz), 7.48-7.57 (2H, m) . 7.90 (1H, s)

Example 204

Synthesis of N- (4-chloro-3-nitrophenylmethyl) phthalimide

Using the compound obtained in Example 203 as the starting material, the procedure of Example 179 gave 1.65 g of the title compound (87% yield).

Ή-NMR (CDCl 3) δ: 4.87 (2H, s), 7.50 (1H, d,> 8.3 Hz), 7.60 (1H, dd,> 8.3, 2.0 Hz) , 7.73-7.80 (2H, m), 7.83-7.91 (2H, m), 7.93 (1H, d,> 2.0Hz)

Example 205

Synthesis of N- (4-chloro-3-nitrophenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 204 as starting material, the procedure of Example 118 afforded 626 mg of the title compound (78% yield).

Ή-NMR (CDCl 3) δ: 1.46 (9H, s), 4.33-4.37 (2H, m), 5.01 (1H, br), 7.41-7.54 (2H, m ), 7.79 (1H, d,> 1.5Hz)

Example 206

Synthesis of N- (3-amino-4-chlorophenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 205 as the starting material, the procedure of Example 2 gave 376 mg of the title compound (87% yield).

Ή-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 4.18-4.22 (2H, m), 4.79 (1H, br), 6.59 (1H, dd,> 8 , 3.1.5Hz), 6.69 (1H, d,> 1.5Hz), 7.17 (1H, d,> 8.3Hz)

Example 207

Synthesis of N- (4-chloro-3-thioureido) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 206 as starting material, the procedure of Example 120 afforded 100 mg of the title compound (81% yield).

Ή-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 4.28 (2H, d,> 5.9 Hz), 5.26 (1H, br), 6.49 (2H, br) , 7.14 (1H, dd,> 8.3, 1.5Hz), 7.37-7.42 (2H, m), 8.15 (1H, br)

116

183 619

Example 208

Synthesis of N- (4-chloro-3- (S-ethylisothioureido) phenylmethyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 207 as starting material, the procedure in Example 27 gave 113 mg of the title compound (75% yield).

Ή-NMR (CDCl ₃ ) δ: 1.40 (3H, t,> 7.3 Hz), 1.46 (9H, s), 3.20 (2H, q,> 7.3 Hz), 4, 28 (2H, d,> 6.3Hz), 4.94 (IH, br), 7.10-7.14 (2H, m), 7.40 (IH, d,> 9.3Hz)

Example 209

Synthesis of N- (4-chloro-3- (S-ethylisothioureido) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 208 as starting material, the procedure of Example 5 gave 97 mg of the title compound in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 1.34 (3H, t,> 7.3 Hz), 3.32 (2H, q,> 7.3 Hz), 4.01-4.08 (2H , m), 7.56-7.63 (2H, m), 7.71 (IH, d,> 8.3Hz), 8.61 (3H, br), 9.41 (2H, br), 11.90 (ih, br)

Example 210

Synthesis of 2- (3-aminophenyl) -2-t-butoxycarbonylaminoacetic acid methyl ester

Using 3-nitrophenylacetic acid as the starting material, the procedure of Example 78 gave 2.09 g of the title compound (27% yield).

Ή-NMR (CDCl3) δ: 1.43 (9H, s), 3.81 (3H, s), 5.20 (IH, d,> 7.3 Hz), 5.51-5.66 (IH , m), 6.61-6.74 (3H, m), 7.09-7.15 (IH, m)

MS (m / z) 280 (M ⁺ )

Example 211

Synthesis of 2-t-butoxycarbonylamino-2- (3- (S-methylisothioureido) phenyl) acetic acid methyl ester

Using the compound obtained in Example 210 as a starting material, the procedure of Example 40 gave 2-t-butoxycarbonylamino-2- (3-thioureido) acetic acid. The resulting compound was dissolved in a mixture of methanol (10 ml) and diethyl ether (5 ml) and a solution of trimethylsilyl diazomethane (2.0 M) in n-hexane was added at room temperature until the foam disappeared. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 3: 1) to give 0.15 g of the title compound (21% yield).

Ή-NMR (CDCl 3) δ: 1.42 (9H, s), 2.44 (3H, s), 3.71 (3H, s), 4.61 (2H, brs), 5.27 (IH, d,> 7.6 Hz), 5.56-5.67 (IH, m), 6.86-6.92 (2H, m), 7.02 (IH, d,> 7.9 Hz), 7.24-7.37 (IH, m)

FAB-MS (m / z) 354 (M ⁺ + 1)

Example 212

Synthesis of 2-amino-2- (3- (S-methylisothioureido) phenyl) acetic acid methyl ester dihydrochloride

Using the compound obtained in Example 211 as a starting material, the procedure of Example 5 gave 123 mg of the title compound (90% yield).

Ή-NMR (D ₂ O) δ: 2.70 (3H, s), 3.84 (3H, s), 5.37 (IH, s), 7.30-7.57 (3H, m), 7.65-7.71 (IH, m)

FAB-MS (m / z) 254 (M ⁺ + 1)

Example 212

Synthesis of 2-amino-2- (3- (S-methylisothioureido) phenyl) acetic acid methyl ester dihydrochloride

Using the compound obtained in Example 211 as a starting material, the procedure of Example 5 gave 123 mg of the title compound (90% yield).

Ή-NMR (D ₂ O) δ: 2.70 (3H, s), 3.84 (3H, s), 5.37 (IH, s), 7.30-7.57 (3H, m), 7.65-7.71 (IH, m)

183 619

117

FAB-MS (m / z) 254 (M ⁺ + 1)

Example 213

Synthesis of 2-t-butoxycarbonylamino-3- (3-nitrophenyl) propionic acid

Using 3-nitrophenylalanine as the starting material, the procedure of Example 63 gave 2.54 g of the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 3.01-3.22 (lH, m), 3.25-3.45 (lH, m), 4.60-4, 73 (lH, m), 5.02-5.11 (lH, m), 7.45-7.56 (2H, m), 8.07-8.14 (2H, m)

FAB-MS (m / z) 311 (M ⁺ + 1)

Example 214

Synthesis of 2-t-butoxycarbonylamino-3- (3-nitrophenyl) propionic acid methyl ester

Using the compound obtained in Example 213 as a starting material, the procedure of Example 64 gave 2.7 g of the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 3.12 (1H, dd, J = 13.9.6.3 Hz), 3.30 (1H, dd, J = 13, 9.5.6Hz), 3.76 (3H, s), 4.57-4.68 (1H, m), 5.10-5.17 (1H, m), 7.46-7.53 (2H, m), 7.99-8.04 (1H, m), 8.08-8.17 (1H, m)

Example 215

Synthesis of 3- (3-aminophenyl) -2-t-butoxycarbonylaminopropionic acid methyl ester

Using the compound obtained in Example 214 as the starting material, the procedure in Example 2 gave 1.84 g of the title compound (81% yield).

Ή-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.90-3.02 (2H, m), 3.62 (2H, brs), 3.71 (3H, s), 4 , 47-4.61 (1H, m), 4.92-5.00 (1H, m), 6.45-6.58 (3H, m), 7.04-7.10 (1H, m)

Example 216

Synthesis of 2-t-butoxycarbonylamino-3- (3- (S-methylisothioureido) phenyl) propionic acid methyl ester

Using the compound obtained in Example 215 as the starting material, the procedure of Example 211 gave 0.10 g of the title compound (4% yield).

Ή-NMR (CDCl ₃ ) δ: 1.36 (9H, s), 2.46 (3H, s), 2.85-2.93 (1H, m), 3.08-3.15 (1H, m), 3.73 (3H, s), 4.57 = 4.69 (2H, m), 4.98-5.01 (1H, m), 6.72-6.80 (3H, m) , 7.19-7.27 (1H, m)

Example 217

Synthesis of 2-amino-3- (3- (S-methylisothioureido) phenyl) propionic acid methyl ester dihydrochloride

Using the compound obtained in Example 216 as starting material, the procedure in Example 5 gave 33 mg of the title compound (81% yield).

Ή-NMR (D ₂ O) δ: 2.69 (3H, s), 3.30 (1H, dd, J = 14.5, 7.3 Hz), 3.40 (1H, dd, J = 14 , 5.6.3Hz), 3.84 (3H, s), 4.45-4.50 (1H, m), 7.28-7.40 (3H, m), 7.54-7, 59 (1H, m)

Example 218

Synthesis of 3-t-butoxycarbonylamino-2- (4-nitrophenyl) propionic acid methyl ester

By using monomethyl 3-phenylsuccinate as a starting material, the procedure of Example 1c gave 4.2 g of the title compound (40% yield).

Ή-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 3.53-3.68 (2H, m), 3.72 (3H, s), 4.00-4.12 (1H, m), 4.85-4.95 (1H, m), 7.45 (2H, d, J = 8.6 Hz), 8.20 (2H, d, J = 8.6 Hz)

118

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Example 219

Synthesis of 2- (4-aminophenyl) -3-t-butoxycarbonylaminopropionic acid methyl ester

Using the compound obtained in Example 218 as the starting material, the procedure of Example 2 gave 3.1 g of the title compound (81% yield).

-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 3.47-3.82 (5H, m), 3.72 (3H, s), 4.87-4.95 (1H , m), 6.68 (2H, d, J = 8.5Hz), 7.09 (2H, d,> 8.5Hz)

Example 220

Synthesis of 3-t-butoxycarbonylamino-2- (4- (N'-nitroguanidino) phenyl) propionic acid methyl ester

Using the compound obtained in Example 219 as the starting material, the procedure of Example 6 gave 0.86 g of the title compound (68% yield).

1-NMR (CDCl 3) δ: 1.42 (9H, s), 3.39-3.89 (3H, m), 3.66 (3H, s), 4.80-4.92 (1H, m), 6.23 (2H, d,> 8.3Hz), 7.03 (2H, d,> 8.3Hz)

Example 221

Synthesis of 3-amino-2- (4- (N'-nitroguanidino) phenyl) propionic acid methyl ester hydrochloride

Using the compound obtained in Example 220 as a starting material, 348 mg of the title compound were obtained in quantitative yield according to the procedure in Example 5.

Ή-NMR (D ₂ O) δ: 3.44 (1H, dd,> 13.2.6.9 Hz), 3.63-3.80 (1H, m), 3.76 (3H, s) , 4.22-4.28 (1H, m), 7.48 (2H, d,> 8.9Hz), 7.53 (2H, d,> 8.9Hz)

Example 222

Synthesis of 3-t-butoxycarbonylamino-2- (4- (N'-nitroguanidino) phenyl) propionic acid

A mixture of the compound (0.42 g) obtained in Example 220, 2N aqueous sodium hydroxide solution (0.6 ml) and methanol (10 ml) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous solution of citric acid and ethyl acetate was added to the residue. The organic layer was washed with water, dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, methanol: methylene chloride = 5: 95) to give 0.34 g of the title compound (84% yield).

'Η-NMR (DMSO-d ₆ ) δ: 1.35 (9H, s), 3.05-3.18 (1H, m), 3.32-3.41 (3H, m), 3.52 -3.58 (1H, m), 6.50 (2H, d,> 8.6 Hz), 6.88 (2H, d,> 8.6 Hz)

Example 223

Synthesis of '3-amino-2- (4- (N'-nitroguanidino) phenyl) propionic acid hydrochloride

Using the compound obtained in Example 222 as the starting material, according to the procedure in Example 5, 287 mg of the title compound were obtained in quantitative yield.

'Η-NMR (D ₂ O)

Ó: 3.40 (1H, dd,> 13.2,6.9Hz), 3.67 (1H, dd,> 13.2.7.9Hz), 4.18 (1H, dd,> 7 , 9.6.9Hz), 7.48 (2H, d,> 8.9Hz), 7.55 (2H, d,> 8.9Hz)

Example 224

Synthesis of 3-t-butoxycarbonylamino-2- (4-thioureidophenyl) propionic acid methyl ester

Using the compound obtained in Example 219 as the starting material, the procedure of Example 120 gave 1.10 g of the title compound (94% yield).

1-NMR (CDCl 3) δ: 1.41 (9H, s), 3.38-3.70 (2H, m), 3.69 (3H, s), 3.82- (3.97 (1H , m), 5.04-5.16 (1H, m), 6.57 (2H, brs), 7.22 (2H, d,> 8.3Hz), 7.30 (2H, d,> 8.3 Hz), 9.00 (1H, brs)

MS (m / z) 353 (M ⁺ )

183 619

119

Example 225

Synthesis of 3-t-butoxycarbonylamino-2- (4- (S-ethylisothioureido) phenyl) propionic acid methyl ester

By using the compound obtained in Example 224 as the starting material and also using ethyl iodide as a reagent, the procedure of Example 29 gave 0.55 g of the title compound (96% yield).

¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.3 Hz), 1.42 (9H, s), 2.92-3.08 (2H, m), 3, 40-3.72 (2H, m), 3.67 (3H, s), 3.78-3.90 (1H, m), 4.67 (1H, br), 4.90-5.06 ( 1H, m), 6.78 (2H, d,> 7.9Hz), 7.17 (2H, d,> 7.9Hz)

FAB-MS (m / z) 382 (M ⁺ + 1)

Example 226

Synthesis of 3-amino-2- (4- (S-ethylisothioureido) phenyl) propionic acid methyl ester dihydrochloride

Using the compound obtained in Example 225 as starting material, the procedure in Example 5 gave 0.199 g of the title compound (83% yield).

Ή-NMR (D ₂ O) δ: 1.41 (3H, t,> 7.3 Hz), 3.24 (2H, q,> 7.3 Hz), 3.44 (1H, dd,> 13 , 2.6.9Hz), 3.69-3.74 (1H, m), 3.76 (3H, s), 4.21-4.27 (1H, m), 7.44 (2H, d,> 8.9Hz), 7.52 (2H, d,> 8.9Hz)

FAB-MS (m / z) 282 (M ⁺ + 1)

Example 227

Synthesis of N- (2-nitrophenylmethyl) phthalimide

Using 2-nitrophenylmethyl bromide as the starting material, the procedure of Example 117 gave 6.24 g of the title compound (96% yield).

Ή-NMR (CDCl ₃ ) δ: 5.31 (2H, s), 7.25-7.27 (1H, m), 7.45 (1H, t,> 7.6 Hz), 7.55 ( 1H, t,> 7.6Hz), 7.75-7.94 (4H, m), 8.11 (1H, d,> 7.9Hz)

MS (m / z) 282 (M ⁺ )

Example 228

Synthesis of N- (2-nitrophenylmethyl) -carbamic acid t-butyl ester

Using the compound obtained in Example 227 as the starting material, according to the procedure of Example 118, 7.59 g of the title compound were obtained in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 4.57 (2H, d,> 6.6 Hz), 5.30-5.43 (1H, m), 7.38- 7.50 (1H, m), 7.62-7.64 (2H, m), 8.05 (1H, d,> 7.9Hz)

Example 229

Synthesis of N- (2-aminophenylmethyl) -carbamic acid t-butyl ester

Using the compound obtained in Example 228 as the starting material, 4.54 g of the title compound were obtained according to the procedure in Example 2 (92% yield).

Ή-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 4.18 (2H, d,> 6.4 Hz), 6.40-6.79 (1H, m), 6.85- 7.23 (2H, m), 7.80 (1H, d,> 8.0Hz)

MS (m / z) 222 (M ⁺ )

Example 230

Synthesis of N- (2-thioreidophenylmethyl) -carbamic acid t-butyl ester

Using the compound obtained in Example 229 as starting material, the procedure of Example 120 gave 525 mg of the title compound (26% yield).

Ή-NMR (CDCl ₃ ) δ: 1.40 (9H, s), 4.26 (2H, d,> 5.9 Hz), 5.38-5.57 (1H, m), 6.42 ( 2H, brs), 7.28-7.38 (4H, m), 9.27 (1H, brs)

MS (m / z) 281 (M ⁺ )

120

183 619

Example 231

Synthesis of N- (2- (S-ethylisothioureido) phenylmethyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 230 as the starting material, the procedure of Example 27 gave 0.60 g of the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.34 (3H, t,> 7.3 Hz), 1.43 (9H, s), 2.88-3.06 (2H, m), 4.15 ( 2H, d,> 4.4Hz), 4.80 (2H, brs), 5.25-5.38 (1H, m), 6.80 (1H, d,> 7.8Hz), 6, 98 (1H, t,> 7.8Hz), 7.13-7.34 (2H, m)

MS (m / z) 309 (M ⁺ )

Example 232

Synthesis of N- (2- (S-ethylisothioureido) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 231 as starting material, 451 mg of the title compound were obtained according to the procedure in Example 5 (86% yield).

Ή-NMR (D ₂ O) δ: 1.40 (3H, t,> 7.3 Hz), 3.24 (2H, q,> 7.3 Hz), 4.23 (2H, s), 7 . 47-7.64 (4H, m)

FAB-MS (m / z) 210 (M ⁺ + 1)

Example 233

Synthesis of N- (1- (3- (N ^, -t-butoxycarbonyl-N'-ethylguanidino) phenyl) cyclohexyl) carbamic acid t-butyl ester

1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (79 mg) was added to a mixture of the compound (100 mg) obtained in Example 139, N-ethyl-N'-t-butoxycarbonylthiourea (85 mg) and dimethylformamide (5 ml). at room temperature and the mixture was stirred at room temperature for 16 hours.

The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium chloride solution; the organic layer was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 98: 2) to give 156 mg of the title compound (98% yield).

Ή-NMR (CDCl ₃ ) δ: 1.00-1.08 (3H, m), 1.27-1.82 (8H, m), 1.53 (9H, s), 1.62 (9H, s), 2.07-2.30 (2H, m), 3.32-3.48 (2H, m), 4.84 (1H, br s), 6.98-7.40 (4H, m) . 8.02 (1H, s)

Example 234

Synthesis of N- (1- (3- (N'-ethyl) guanidino) phenyl) cyclohexyl) amine dihydrochloride

Using the compound obtained in Example 233 as starting material, the procedure of Example 5 gave 85 mg of the title compound (78% yield).

Ή-NMR (D ₂ O) δ: 1.23 (3H, t,> 7.3 Hz), 1.31-1.64 (4H, m), 1.64-1.86 (2H, m) , 1.90-2.06 (2H, m), 2.40-2.60 (2H, m), 3.33 (2H, q,> 7.3Hz), 7.30-7.77 ( 4H, m)

Example 235

Synthesis of N- (1- (3- (N'-t-butoxycarbonyl-N'-ethyl-guanidino) phenyl) cyclopentyl) carbamic acid t-butyl ester

Using the compound obtained in Example 148 as starting material, the procedure of Example 233 gave 160 mg of the title compound (99% yield).

Ή-NMR (CDCl ₃ ) δ: 1.00-1.20 (3H, m), 1.34 (9H, s), 1.53 (9H, s), 1.72- (1.92 (4H , m), 1.93-2.10 (2H, m), 2.12-2.35 (2H, m), 3.30-3.50 (2H, m), 4.82 (1H, brs ), 6.90-7.20 (4H, m), 8.02 (1H, s)

Example 236

Synthesis of N- (1- (3 - (N'-ethyl) guanidino) phenyl) -cyclopentyl) amine dihydrochloride

Using the compound obtained in Example 235 as starting material, the procedure of Example 5 gave 88 mg of the title compound (79% yield).

Ή-NMR (D ₂ O)

183 619

121 δ: 1.23 (3Η, t,> 7.3 Hz), 1.82-2.06 (4H, m), 2.22-2.40 (4H, m), 3.33 (2H, q,> 7.3Hz), 7.34-7.61 (4H, m)

Example 237

Synthesis of N- (1- (3- (N'-t-butoxycarbonyl-N'-ethyl-guanidino) phenyl) cyclobutyl) carbamic acid t-butyl ester

Using the compound obtained in Example 157 as the starting material, the procedure of Example 233 gave 171 mg of the title compound in quantitative yield.

1 H-NMR (CDCl ₃ ) δ: 1.00-1.21 (3H, m), 1.36 (9H, s), 1.53 (9H, s), 1.65-1.98 (1H , m), 2.01-2.22 (1H, m), 2.26-2.60 (4H, m), 3.35-3.50 (2H, m), 5.17 (1H, brs ), 6.95-7.20 (4H, m), 8.01 (1H, s)

Example 238

Synthesis of N- (1- (3- (N'-ethyl) guanidino) phenyl) -cyclobutyl) amine dihydrochloride

Using the compound obtained in Example 237 as starting material, the procedure of Example 5 gave 85 mg of the title compound (73% yield).

1 H-NMR (D ₂ O) δ: 1.24 (3H, t,> 7.3 Hz), 1.94-2.04 (1H, m), 2.19-2.24 (1H, m ), 2.60-2.84 (4H, m), 3.33 (2H, q,> 7.3Hz), 7.35-7.63 (4H, m)

Example 239

Synthesis of (3-nitro-5-trifluoromethylphenyl) methanol

Using 3-nitro-5-trifluoromethylbenzoic acid as the starting material, the procedure of example 132 gave 4.6 g of the title compound (98% yield). 1 H-NMR (CDCl 3) δ: 2.21 (1H, t,> 5.6 Hz), 4.92 (2H, d,> 5.6 Hz), 7.99 (1H, s), 8.41 (1H, s), 8.44 (1H, s)

Example 240

Synthesis of 3-bromoethyl-5-trifluoromethylnitrobenzene

Using the compound obtained in Example 239 as the starting material, the procedure of Example 55 gave 7.72 g of the title compound in quantitative yield.

'H-NMR (CDCl 3) δ: 4.58 (2H, s), 7.99 (1H, s), 8.44 (1H, s), 8.46 (1H, s)

Example 241

Synthesis of N- (3-nitro-5-trifluoromethyl) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 240 as a starting material, the procedure of Example 127 gave 2.6 g of the title compound (59% yield).

'H-NMR (CDCl3) δ: 1.51 (18H, s), 4.92 (2H, s), 7.93 (1H, s), 8.41 (2H, s)

Example 242

Synthesis of N- (3-amino-5-trifluoromethyl) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 241 as a starting material, the procedure in Example 2 gave 2.19 g of the title compound (99% yield).

'H-NMR (CDCl3) δ: 1.46 (18H, s), 4.71 (2H, s), 6.76-6.90 (3H, m)

Example 243

Synthesis of N- (3-thioureido-5-trifluoromethylphenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 242 as the starting material, the procedure of Example 120 gave 1.02 g of the title compound in quantitative yield.

1 H-NMR (CDCl 3) δ: 1.48 (18H, s), 4.82 (2H, s), 6.26 (2H, brs), 7.45-7.50 (3H, m), 8 . 32 (1H, s)

122

183 619

Example 244

Synthesis of N- (3- (S-ethylisothioureido) -5-trifluoromethyl) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 243 as starting material, 99 mg of the title compound were obtained according to the procedure of Example 95 (59% yield).

Ή-NMR (CDCl ₃ ) δ: 1.36 (3H, t,> 7.3 Hz), 1.47 (18H, s), 2.90-3.12 (2H, m), 4.78 ( 2H, s), 7.00-7.22 (3H, m)

Example 245

Synthesis of N- (3- (S-ethylisothioureido) -5-trifluoromethyl) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 244 as a starting material, the procedure in Example 5 gave 81 mg of the title compound (88% yield).

Ή-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.3 Hz), 3.26 (2H, q,> 7.3 Hz), 4.33 (2H, s), 7 , 72 (IH, s), 7.83 (IH, s), 7.89 (IH, s)

Example 246

Synthesis of N- (3- (N'-nitroguanidino) -5-trifluoromethyl-phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 242 as a starting material, the procedure in Example 6 gave 17.2 mg of the title compound (yield 5.6%).

Ή-NMR (CDCl ₃ ) δ: 1.48 (18H, s), 4.84 (2H, s), 7.50-7.60 (3H, m), 9.79 (1H, s)

Example 247

Synthesis of N- (3- (N'-nitroguanidino) -5-trifluoromethylphenylmethyl) amine hydrochloride

Using the compound obtained in Example 246 as a starting material, 81 mg of the title compound were obtained according to the procedure in Example 5 (88% yield).

Ή-NMR (D ₂ O) δ: 4.29 (2H, s), 7.68-7.78 (3H, m)

Example 248

Synthesis of N- (3-fluoro-4-methylphenyl) phthalimide

A mixture of 3-fluoro-4-methylaniline (12.5 g), phthalic anhydride (17.8 g), triethylamine (27.9 ml) and chloroform (100 ml) was heated at reflux for 6 days and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 2N HCl and a saturated aqueous sodium chloride solution; the organic layer was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. Subsequently, chloroform was added to the obtained residue, the insoluble matter was filtered off, and the filtrate was concentrated under a reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, chloroform: methanol = 98: 2) to give 18.7 g of the title compound (73% yield).

Ή-NMR (CDCl 3) δ: 2.33 (3H, s), 7.14 (1H, s), 7.18 (1H, s), 7.28-7.34 (1H, m), 7, 79-7.82 (2H, m), 7.94-7.98 (2H, m)

Example 249

Synthesis of N- (4-bromoethyl-3-fluorophenyl) phthalimide

A mixture of the compound (1.0 g) obtained in Example 248, N-bromosuccinimide (698 mg), α, α-azobis (isobutyronitrile) (catalytic amount) and carbon tetrachloride (20 ml) was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 8: 2) to give 605 mg of the title compound (46% yield).

Ή-NMR (CDCl 3) δ: 4.55 (2H, s), 7.28-7.33 (2H, m), 7.50-7.56 (1H, m), 7.80-7.84 (2H, m), 7.96-7.99 (2H, m)

183 619

123

Example 250

Synthesis of N- (4-cyanomethyl-3-fluorophenyl) phthalimide

To a solution of sodium cyanide (99 mg) in dimethyl sulfoxide (5 ml), a solution of the compound (605 mg) obtained in Example 249 in dimethyl sulfoxide (10 ml) was added dropwise at 60 ° C and stirred at 60 ° C for 40 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate-diethyl ether (1: 1); then the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 6: 4) to give 164 mg of the title compound (32% yield).

Ή-NMR (CDCl ₃ ) δ: 3.83 (2H, s), 7.33-7.41 (2H, m), 7.57-7.63 (1H, m), 7.81-7, 84 (2H, m), 7.96-8.00 (2H, m)

Example 251

Synthesis of 4-cyanomethyl-3-fluoroaniline

To a solution of the compound (164 mg) obtained in Example 250 in methanol (5 ml), hydrazine monohydrate (0.057 ml) was added and refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography, (eluent, n-hexane: ethyl acetate = 6: 4) to give 67 mg of the title compound (76% yield).

Ή-NMR (CDCl ₃ ) δ: 3.62 (2H, s), 3.84 (2H, brs), 6.37-6.47 (2H, m), 7.09-7.16 (1H, m)

Example 252

Synthesis of 4- (2-aminoethyl) -3-fluoroaniline

To a suspension of lithium aluminum hydride (76 mg) in diethyl ether (5 ml), concentrated sulfuric acid (0.053 ml) was added under ice-cooling, and stirred at room temperature for 1 hour. A solution of the compound (100 mg) obtained in Example 251 in diethyl ether (15 ml) was then added dropwise at room temperature and refluxed for 18 hours. Water (1 ml) and a 2 N aqueous sodium hydroxide solution (10 ml) were added to the reaction mixture under ice-cooling, and the mixture was extracted with diethyl ether; the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 110 mg of the title compound in quantitative yield.

Ή-NMR (CDCl3) δ: 2.65 (2H, t, J = 6.9 Hz), 2.88 (2H, t, J = 6.9 Hz), 3.70 (2H, brs), 6 , 34-6.42 (2H, m), 6.91-6.98 (lH, m)

Example 253

Synthesis of N- (2- (4-amino-2-fluorophenyl) ethyl) carbamic acid t-butyl ester

Di-t-butyl bicarbonate (113 mg) was added to a solution of the compound (110 mg) obtained in Example 252 in methylene chloride (10 ml) under ice-cooling, and stirred for 1 hour under ice-cooling. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 6: 4) to give 51 mg of the title compound (39% yield)

Ή-NMR (CDCl3) δ: 1.43 (9H, s), 2.70 (2H, t, J = 6.9 Hz), 3.22-3.38 (2H, m) 3.70 (2H , brs), 4.58 (1H, brs), 6.34-6.40 (2H, m), 6.90-6.96 (1H, m)

Example 254

Synthesis of N- (2- (2-fluoro-4-thioureido) -phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 253 as a starting material, the procedure of Example 120 gave 172 mg of the title compound in quantitative yield.

Ή-NMR (CDCl3) δ: 1.42 (9H, s), 2.84 (2H, t, J = 6.9 Hz), 3.30-3.44 (2H, m), 4.63 ( 1H, brs), 6.19 (2H, brs), 6.95-6.99 (2H, m), 7.20-7.35 (1H, m), 8.10 (1H, brs)

124

183 619

Example 255

Synthesis of N- (2- (4- (S-ethylisothioureido) -2-fluorophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 254 as the starting material, the procedure of Example 95 gave 151 mg of the title compound (92% yield).

Ή-NMR (CDCl ₃ ) δ: 1.36 (3H, t, J = 7.3 Hz), 1.43 (9H, s), 2.78 (2H, t,> 6.9 Hz), 2 , 92-3.15 (2H, m), 3.28-3.40 (2H, m), 4.58 (1H, br s), 6.60-6.70 (2H, m), 7.07 -7.13 (1H, m)

Example 256

Synthesis of N- (2- (4- (S-ethylisothioureido) -2-fluorophenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 255 as the starting material, the procedure of Example 5 gave 141 mg of the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.41 (3H, t,> 7.3 Hz), 3.09 (2H, t,> 7.3 Hz), 3.23 (2H, q,> 7 , 3 Hz), 3.29 (2H, t,> 7.3

Hz), 7.19-7.24 (2H, m), 7.45-7.52 (1H, m)

Example 257

Synthesis of N- (2- (4- (N ^/ -t-butoxycarbonyl-N * '-ethyl-guanidino) -2-fluorophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 253 as starting material, 167 mg of the title compound were obtained according to the procedure of Example 233 (76% yield).

Ή-NMR (CDCl3) δ: 1.19 (3H, t,> 7.3Hz), 1.43 (9H, s), 1.48 (9H, s), 2.70-2.86 (2H , m), 3.22-3.48 (4H, m), 5.94 (1H, br s), 6.50-7.22 (3H, m), 8.02 (1H, s)

Example 258

Synthesis of N- (2- (4- (N'-ethyl) guanidino) -2-fluorophenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 257 as starting material, the procedure of Example 5 gave 75 mg of the title compound (67% yield).

Ή-NMR (D ₂ O) δ: 1.23 (3H, t,> 7.3 Hz), 3.07 (2H, t,> 7.3 Hz), 3.27-3.36 (4H, m), 7.11-7.45 (3H, m)

Example 259

Synthesis of N- (2- (2-fluoro-4- (N'-nitroguanidino) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 253 as the starting material, the procedure of Example 6 gave 65 mg of the title compound (48% yield).

Ή-NMR (CDCl 3) δ: 1.42 (9H, s), 2.87 (2H, t,> 6.6 Hz), 3.30-3.46 (2H, m), 4.69 (1H , brs), 7.00-7.12 (2H, m), 7.28-7.40 (1H, m), 9.84 (1H, s)

Example 260

Synthesis of N- (2- (2-fluoro-4- (N'-nitroguanidino) phenyl) ethyl) amine hydrochloride

Using the compound obtained in Example 259 as a starting material, the procedure of Example 5 gave 28 mg of the title compound (57% yield).

Ή-NMR (D ₂ O) δ: 3.07 (2H, t,> 7.3 Hz), 3.30 (2H, t,> 7.3 Hz), 7.15-7.45 (3H, m)

Example 261

Synthesis of 2-fluoro-5-nitrobenzyl alcohol

Using 2-fluoro-5-nitrobenzoic acid as the starting material, the title compound was obtained according to the procedure of Example 132 (95% yield).

Ή-NMR (CDCl ₃ ) δ: 2.10 (lH, t,> 5.9 Hz), 4.86 (2H, d,> 5.9 Hz), 7.16-7.24 (1H, m ), 8.15-8.25 (IH, m), 8.40-8.47 (IH, m)

183 619

125

Example 262

Synthesis of 2-fluoro-5-nitrobenzyl bromide

Using the compound obtained in Example 261 as a starting material, the title compound was obtained according to the procedure in Example 55 (98% yield).

Ή-NMR (CDC1 ₃₎

Ó: 4.53 (2H, s), 7.22-7.30 (1H, m), 8.18-8.27 (1H, m), 8.40-8.47 (1H, m)

MS (m / z) 234 (M ⁺ )

Example 263

Synthesis of N- (2-fluoro-5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 262 as the starting material, the procedure of Example 127 gave the title compound (99% yield).

Ή-NMR (CDCl 3) δ: 1.50 (18H, s), 4.91 (2H, s), 7.15-7.22 (1H, m), 8.12-8.21 (2H, m )

Example 264

Synthesis of N- (2-dimethylamino-5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

A mixture of the compound (1.0 g) obtained in Example 263, dimethylamine hydrochloride (485 mg), triethylamine (0.8 ml) and dimethylformamide (10 ml) was heated at 80 ° C for 5.5 hours. The reaction mixture was distilled under reduced pressure, and water and 2N HCl were added to the residue; after extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 3: 1) to give 1.1 g of the title compound in a quantitative yield.

Ή-NMR (CDCl 3) δ: 1.39 (18H, s), 2.78 (6H, s), 4.78 (2H, s), 6.97 (1H, d, J = 8.6 Hz) , 7.95-8.02 (2H, m)

Example 265

Synthesis of N- (5-amino-2-dimethylaminophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 264 as a starting material, the title compound was obtained in accordance with the procedure in Example 2 (yield 99%).

Ή-NMR (CDCl 3) δ: 1.42 (18H, s), 2.58 (6H, s), 3.48 (2H, brs), 4.85 (2H, s), 6.43-6, 54 (2H, m), 6.94 (1H, d, J = 8.3 Hz)

MS (m / z) 365 (M ⁺ + 1)

Example 266

Synthesis of N- (5- (N'-t-butoxycarbonyl-N'-ethyl) guanidino) -2-dimethylaminophenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 265 as the starting material, the title compound was obtained according to the procedure of Example 233 (yield 73%).

Ή-NMR (CDCl ₃ ) δ: 1.08-1.12 (3H, m), 1.43 (18H, s), 1.53 (9H, s), 2.68 (6H, s), 3 , 10-3.48 (2H, m), 4.85 (2H, s), 6.84-7.12 (3H, m)

MS (m / z) 535 (M ⁺ )

Example 267

Synthesis of N- (2-dimethylamino-5- (N'-ethyl) -guanidino) phenylmethyl) amine trihydrochloride

Using the compound obtained in Example 266 as the starting material, the procedure of Example 5 gave the title compound (67% yield).

Ή-NMR (D ₂ O)

126

183 619 δ: 1.24 (3Η, t,> 7.3 Hz), 3.24 (6H, s), 3.35 (2H, q,> 7.3 Hz), 4.41 (2H, s ), 7.49-7.58 (2H, m), 7.82 (1H, d,> 8.9Hz)

MS (m / z) 235 (M ⁺ )

Example 268

Synthesis of N- (2-dimethylamino-5-thioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 265 as a starting material, the procedure of Example 120 gave the title compound (91% yield).

Ή-NMR (CDCl ₃ ) δ: 1.44 (18H, s), 2.68 (6H, s), 4.84 (2H, s), 6.22 (2H, brs), 6.92-7 .00 (1H, m), 7.04-7.16 (2H, m), 8.25 (1H, br s) MS (m / z) 424 (M ⁺ )

Example 269

Synthesis of N- (2-dimethylamino-5- (S-ethylisothioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 268 as a starting material, the procedure of Example 95 gave the title compound (92% yield).

Ή-NMR (CDCl ₃ ) δ: 1.34 (3H, t,> 7.3 Hz), 1.42 (18H, s), 2.63 (6H, s), 2.83-3.13 ( 2H, m), 4.87 (2H, s), 6.69-7.06 (3H, m)

MS (m / z) 452 (M ⁺ )

Example 270

Synthesis of N- (2-dimethylamino-5- (S-ethylisothioureido) phenylmethyl) amine trihydrochloride

Using the compound obtained in Example 269 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 67%).

Ή-NMR (D ₂ O) δ: 1.43 (3H, t,> 7.3 Hz), 3.27 (2H, q,> 7.3 Hz), 3.33 (6H, s), 4 , 48 (2H, s), 7.66 (1H, d,> 2.3Hz), 7.72 (1H, dd,> 8.6, 2.3Hz), 7.97 (1H, d, > 8.6Hz)

MS (M / z) 252 (M ⁺ )

Example 271

Synthesis of N- (2-methoxy-5- (N'-nitroguanidino) phenylmethyl) carbamic acid t-butyl ester

A mixture of the compound (130 mg) obtained in Example 119, triethylamine (0.09 ml), S-methyl-N-nitroisothiourea (84 mg), acetonitrile (3 ml) and methanol (1 ml) was heated to reflux for 20 hours. The reaction mixture was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent, chloroform: ethyl acetate = 1: 1) to obtain 57.2 mg of the title compound (33% yield)

Ή-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 3.87 (3H, s), 4.28 (2H, d,> 5.9 Hz), 5.20 (1H, brs) , 6.91 (1H, d,> 9.3Hz), 7.19-7.28 (2H, m), 9.28 (1H, brs)

Example 272

Synthesis of N- (2-methoxy-5- (N'-nitroguanidino) phenylmethyl) amine hydrochloride

Using the compound obtained in Example 271 as a starting material, 41 mg of the title compound were obtained according to the procedure in Example 5 (90% yield).

Ή-NMR (D ₂ O) δ: 3.95 (3H, s), 4.20 (2H, s), 7.18 (1H, d,> 8.9 Hz), 7.34 (1H, d ,> 2.6Hz), 7.41 (1H, dd,> 8.9.2.6Hz)

Example 273

Synthesis of N- (5- (N'-t-butoxycarbonyl-N'-ethyl) guanidino) -2-methoxyphenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 119 as starting material, the title compound was obtained according to the procedure of Example 233 (yield 61%).

183 619

127 H-NMR (CDC1 ₃₎ δ: 1.00-1.20 (3H, m), 1.44 (9H, s), 1.53 (9H, s), 3.30-3.50 ( 2H, m), 3.85 (3H, s), 4.28 (2H, brs), 5.00 (1H, brs), 6.80-7.20 (3H, m)

Example 274

Synthesis of N- (5- (N'-ethyl) guanidino) -2-methoxy) -phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 273 as a starting material, the procedure of Example 5 gave the title compound (95% yield).

1 H-NMR (D ₂ O) δ: 1.21 (3H, t,> 7.3 Hz), 3.29 (2H, q,> 7.3 Hz), 3.93 (3H, s), 4.17 (2H, s), 7.16 (1H, d,> 8.9Hz), 7.28 (1H, d,> 2.6Hz), 7.38 (1H, dd,> 8, 9, 2.6Hz)

MS (m / z) 222 (M ⁺ )

Example 275

Synthesis of N- (2-methoxy-5- (N'-methyl) -guanidino) phenylmethyl) carbamic acid t-butyl ester

The compound obtained in Example 121 was dissolved in ethyl acetate, and the solution was washed with a saturated aqueous sodium hydrogen carbonate solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the resulting residue (150 mg), methylamine hydrochloride (33 mg), triethylamine (0.13 ml) and dimethylformamide (6 ml) was stirred at 80 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 6: 1) to give 106.1 mg of the title compound (78% yield).

1 H-NMR (CDCl 3) δ: 1.40 (9H, s), 2.96 (3H, d,> 3.9 Hz), 3.83 (3H, s), 4.20 (2H, d, > 5.9Hz), 5.50 (1H, brs), 6.85 (1H, d,> 9.3Hz), 7.00-7.20 (2H, m), 9.54 (1H, brs)

MS (m / z) 308 (M ⁺ )

Example 276

Synthesis of N- (2-methoxy-5 (N'-methylguanidino) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 275 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 55%).

1 H-NMR (D ₂ O) δ: 2.88 (3H, s), 3.93 (3H, s), 4.17 (2H, s), 7.16 (1H, d,> 8.9 Hz), 7.28 (1H, d,> 2.6 Hz), 7.38 (1H, dd,> 8.9, 2.6 Hz)

MS (m / z) 208 (M ⁺ )

Example 277

Synthesis of N- (3 - (t-butoxycarbonylaminomethyl) -4-methoxyphenyl) sulfamic acid

To a mixture of the compound (327 mg) obtained in Example 120, the dihydrate, sodium molybdate (25 mg), methanol (10 ml) and water (10 ml), an aqueous solution of hydrogen peroxide (0.3 ml) was added dropwise at 0 ° C. . The reaction mixture was stirred at room temperature for 1.5 hours, and methanol was distilled off under reduced pressure. The resulting suspension was filtered, washed with water and dried in vacuo to give 335 mg of the title compound (93% yield).

1 H-NMR (DMSO-d ₆ ) δ: 1.40 (9H, s), 3.83 (3H, s), 4.12 (2H, d,> 5.9 Hz), 7.03-7 , 19 (3H, m), 8.98 (1H, brs), 9.50 (1H, brs), 11.30 (1H, brs)

Example 278

Synthesis of N- (2-methoxy-5- (N'-n-propylguanidino) phenylmethyl) carbamic acid t-butyl ester

To a solution of the compound (160 mg) obtained in Example 277 in acetonitrile (5 ml), n-propylamine (0.05 ml) was added dropwise and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and to the obtained residue to

128

A 2N aqueous sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (eluent, n-hexane: ethyl acetate = 1: 2) to give 160 mg of the title compound in a quantitative yield.

1 H-NMR (CDCl ₃ ) δ: 0.93 (3H, t,> 7.3 Hz), 1.42 (9H, s), 1.49-1.59 (2H, m), 3.15 (2H, t,> 7.3Hz), 3.80 (3H, s), 4.22 (2H, brs), 4.92 (1H, brs), 6.75-6.86 (3H, m )

MS (m / z) 336 (M ⁺ )

Example 279

Synthesis of N- (2-methoxy-5- (N'-n-propylguanidino) -phenylmethyl) amine dihydrochloride Using the compound obtained in Example 278 as starting material, the title compound was obtained according to the procedure of Example 5 (71% yield).

1 H-NMR (D ₂ O) δ: 0.93 (3H, t,> 7.3 Hz), 1.55-1.68 (2H, m), 3.22 (2H, t,> 7, 3Hz), 3.93 (3H, s), 4.17 (2H, s), 7.16 (1H, d,> 8.6Hz), 7.28 (1H, d,> 2.6Hz ), 7.38 (1H, dd,> 8.6, 2.6Hz) MS (m / z) 236 (M ⁺ ) Example 280

Synthesis of N- (2-dimethylamino-5- (N'-nitroguanidino) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 265 as a starting material, the title compound was obtained according to the procedure in Example 6 (52% yield).

1 H-NMR (CDCl ₃ ) δ: 1.43 (18H, s), 2.71 (6H, s), 4.86 (2H, s), 7.02-7.16 (3H, m) , 9.82 (1H, brs) Example 281

Synthesis of N- (2-dimethylamino-5- (N'-nitroguanidino) phenylmethyl) amine dihydrochloride Using the compound obtained in Example 280 as a starting material, the title compound was obtained according to the procedure of Example 5 (83% yield).

1 H-NMR (D ₂ O) δ: 3.13 (6H, s), 4.38 (2H, s), 7.51-7.55 (2H, m), 7.73 (1H, dd, > 7.9,1.3Hz) Example 282

Synthesis of N- (2- (N-ethyl-N-methylamino) -5-nitro) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 263 as a starting material and also using ethylmethylamine as the reagnet, the procedure of Example 264 gave the title compound (42% yield).

1 H-NMR (CDCl 3) δ: 1.18 (3H, t,> 7.2 Hz), 1.45 (18H, s), 2.81 (3H, s), 3.05 (2H, q, > 7.2Hz), 4.82 (2H, s), 7.06 (1H, d,> 8.2Hz), 8.04-8.15 (20, m)

Example 283

Synthesis of N- (5-amino-2- (N-ethyl-N-methylaminophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 282 as a starting material, the title compound was obtained according to the procedure in Example 2 (yield 58%).

1 H-NMR (CDCl 3) δ: 1.04 (3H, t,> 7.0 Hz), 1.42 (18H, s), 2.56 (3H, s), 2.79 (2H, q, > 7.0Hz), 3.55 (2H, brs), 4.84 (2H, s), 6.43-6.56 (3H, m)

MS (m / z) 379 (M ⁺ )

Example 284

Synthesis of N- (5- (N'-t-butoxycarbonyl-N'-ethylguanidino) -2- (N-ethyl-N-methylaminophenylmethyl) -iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 283 as the starting material, the title compound was obtained according to the procedure of Example 233 (77% yield).

183 619

129

Ή-NMR (CDCl ₃ ) δ: 1.09 (3H, t,> 7.2 Hz), 1.29-2.66 (21H, m), 2.65 (3H, s), 2.86 ( 2H, q,> 7.2Hz), 3.30-3.50 (2H, m), 4.84 (2H, s), 6.80-7.11 (3H, m)

MS (m / z) 549 (M ⁺ )

Example 285

Synthesis of N- (5- (N'-ethylguanidino) -2- (N-ethyl-N-methylamino) phenylmethyl) amine trihydrochloride

Using the compound obtained in Example 284 as starting material, the title compound was obtained according to the procedure in Example 5 (yield 83%).

Ή-NMR (D ₂ O) δ: 1.15-1.26 (6H, m), 3.21 (3H, s), 3.26-3.38 (2H, m), 3.54- ( 3.65 (2H, m), 4.39 (2H, s), 7.35-7.57 (2H, m), 7.75 (1H, d,> 8.6Hz)

Example 286

Synthesis of N- (2- (N-ethyl-N-methylamino) -5-thioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 283 as the starting material, the procedure of Example 120 afforded the title compound (77% yield).

Ή-NMR (CDCl ₃ ) δ: 1.14 (3H, t,> 7.1 Hz), 1.45 (18H, s), 2.66 (3H, s), 2.89 (2H, q, > 7.1Hz), 4.83 (2H, s), 6.15 (2H, brs), 6.94-7.14 (3H, m), 8.00 (1H, brs)

MS (m / z) 439 (M ⁺ + 1)

Example 287

Synthesis of N- (5- (S-ethylisothioureido) -2- (N-ethyl-N-methylaminophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 286 as starting material, the procedure of Example 95 gave the title compound (66% yield).

Ή-NMR (CDCl ₃ ) δ: 1.04 (3H, t,> 7.2 Hz), 1.31-1.45 (21H, m), 2.61 (3H, s), 2.83 ( 2H, q,> 7.2Hz), 3.00-3.20 (2H, m), 4.47 (1H, brs), 4.86 (2H, s), 6.60-6.85 ( 2H, m), 7.05 (1H, d,> 8.2Hz)

MS (m / z) 466 (M ⁺ )

Example 288

Synthesis of N- (5- (S-ethylisothioureido) -2- (N-ethyl-N-methylamino) phenylmethyl) amine trihydride

Using the compound obtained in Example 287 as starting material, the title compound was obtained according to the procedure in Example 5 (yield 95%).

Ή-NMR (D ₂ O) δ: 1.24 (3H, t,> 7.3 Hz), 1.43 (3H, t,> 7.3 Hz), 3.27 (2H, q,> 7 , 3Hz), 3.37 (3H, s), 3.72 (2H, q,> 7.3Hz), 4.51 (2H, s), 7.69 (1H, d,> 2.3 Hz), 7.74 (1H, dd,> 8.6, 2.3Hz), 7.94 (1H, d,> 8.6Hz)

MS (m / z) 266 (M ⁺ )

Example 289

Synthesis of N- (2- (4- (N'-t-butoxycarbonyl-S-methylisothioureido) phenyl) ethyl) carbamic acid t-butyl ester

To a mixture of the compound (280 mg) obtained in Example 51, sodium hydrogen carbonate (87 mg) and methylene chloride (5 ml), di-t-butyl dicarbonate (227 mg) was added and stirred at room temperature for 15 hours; then methylene chloride and water were added. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 3: 1) to give 303 mg of the title compound (yield, 81%).

Ή-NMR (CDCl ₃ ) δ: 1.26-1.56 (18H, m), 2.40 (3H, s), 2.77-2.80 (2H, m), 3.35-3, 38 (2H, m), 4.69 (1H, br s), 7.20 (4H, s), 11.28 (1H, brs)

130

183 619

Example 290

Synthesis of N- (2- (4- (N'-t-butoxycarbonyl-N-methoxyguanidino) phenyl) ethyl) carbamic acid t-butyl ester

To a mixture of the compound (190 mg) obtained in Example 289, triethylamine (0.14 ml), O-methylhydroxyalamine hydrochloride (84 mg) and acetonitrile (5 ml), a solution of silver nitrate (90 mg) in acetonitrile (2 ml) was added and stirred at 0 ° C for 15 minutes. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform: ethyl acetate = 3: 1) to give 75 mg of the title compound (yield, 38%).

Ή-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.51 (9H, s), 2.72 (2H, t,> 6.9 Hz), 3.32-3.35 ( 2H, m), 3.80 (3H, s), 4.53 (IH, brs), 7.08 (2H, d,> 8.5Hz), 7.40 (2H, d,> 8.5 Hz), 7.85 (IH, brs), 8.88 (IH, brs)

MS (m / z) 408 (M ⁺ )

Example 291

Synthesis of N- (2- (4- (N'-methoxyguanidino) phenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 290 as the starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 3.04 (2H, t,> 7.2 Hz), 3.29 (2H, t,> 7.2 Hz), 3.81 (3H, s), 7 , 30 (2H, d,> 8.6Hz), 7.42 (2H, d,> 8.6Hz)

MS (m / z) 208 (M ⁺ )

Example 292

Synthesis of (2,6-dimethoxy-3-nitrophenyl) methanol

Using 2,6-dimethoxy-3-nitrobenzoic acid as starting material, the procedure of Example 132 afforded the title compound (39% yield).

Ή-NMR (CDC1 ₃₎

6: 3.98 (6H, s), 4.79 (2H, s), 6.75 (IH, d,> 9.2Hz), 7.99 (IH, d,> 9.2Hz)

Example 293

Synthesis of 2,6-dimethoxy-3-nitrobenzyl bromide

Using the compound obtained in Example 292 as the starting material, the title compound was obtained according to the procedure of Example 55 (98% yield).

Ή-NMR (CDCl ₃ ) δ: 4.00 (3H, s), 4.02 (3H, s), 4.62 (2H, s), 6.74 (IH, d,> 9.2 Hz) 8.02 (IH, d,> 9.2Hz)

MS (m / z) 276 (M ⁺ )

Example 294

Synthesis of N- (2,6-dimethoxy-3-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 293 as the starting material, the title compound was obtained according to the procedure of Example 127 (yield 71%).

Ή-NMR (CDC1 ₃₎

6: 1.44-1.48 (18H, m), 3.86 (3H, s), 3.88 (3H, s), 4.94 (2H, s), 6.68 (IH, d, > 9.2 Hz), 7.93 (IH, d,> 9.2 Hz)

Example 295

Synthesis of N- (3-amino-2,6-dimethoxyphenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 294 as the starting material, the title compound was obtained according to the procedure in Example 2 (yield 45%).

Ή-NMR (CDCl ₃ ) δ: 1.42 (18H, s), 3.50 (2H, brs), 3.70 (6H, s), 4.91 (2H, s), 6.56 (IH , d,> 8.3 Hz), 6.63 (IH, d,> 8.3 Hz)

MS (m / z) 382 (M ⁺ )

183 619

131

Example 296

Synthesis of N- (2,6-dimethoxy-3-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 295 as a starting material, the procedure of Example 120 gave the title compound (yield 46%).

Ή-NMR (CDC1 ₃₎

8: 1.44 (18H, s), 3.79 (3H, s), 3.81 (3H, s), 4.89 (2H, s), 6.11 (2H, br s), 6.66 (1H, d,> 8.9Hz), 7.12 (1H, d,> 8.9Hz), 7.63 (1H, brs)

MS (m / z) 441 (M ⁺ )

Example 297

Synthesis of N- (2,6-dimethoxy-3- (S-ethylisothioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 296 as the starting material, the procedure of Example 95 gave the title compound (71% yield).

Ή-NMR (CDCl 3) δ: 1.35-1.51 (21H, m), 3.00-3.12 (2H, m), 3.70 (3H, s), 3.76 (3H, s ), 4.58 (1H, brs), 4.91 (2H, s), 6.58 (1H, d,> 8.9Hz), 6.75-6.78 (1H, m)

MS (m / z) 469 (M ⁺ )

Example 298

Synthesis of N- (2,6-dimethoxy-3- (S-ethylisothioureido) phenylmethyl) amine dihydrochloride

By using the compound obtained in Example 297 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.43 (3H, t,> 7.3 Hz), 3.34 (2H, q,> 7.3 Hz), 3.63 (3H, s), 3 . 66 (3H, s), 4.28 (2H, s), 7.01 (1H, d,> 8.9Hz), 7.42 (1H, d,> 8.9Hz)

MS (m / z) 269 (M ⁺ )

Example 299

Synthesis of N- (1- (3- (N'-t-butoxycarbonyl-N'-ethyl-guanidino) phenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 2 as starting material, the procedure of Example 233 gave the title compound (81% yield).

Ή-NMR (CDCl 3) δ: 1.11-1.60 (27H, m), 3.30-3.40 (2H, m), 5.00 (2H, s), 7.00-7.34 (4H, m)

MS (m / z) 420 (M ⁺ )

Example 300

Synthesis of N- (1- (3- (N'-ethyl) guanidino) phenyl) -1-methylethyl) amine dihydrochloride

By using the compound obtained in Example 299 as the starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.24 (3H, t,> 7.3 Hz), 1.77 (6H, s), 3.33 (2H, q,> 7.3 Hz), 7 . 36-7.68 (4H, m)

MS (m / z) 220 (M ⁺ )

Example 301

Synthesis of N- (3 - (di- (t-butoxycarbonyl) aminomethyl) phenyl) amidinesulfonic acid

Using N- (3-thioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester as starting material, the procedure of Example 277 afforded the title compound (98% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.42 (18H, s), 4.71 (2H, s), 7.15-7.24 (3H, m), 7.43-7.49 ( 1H, m), 9.61 (1H, brs), 11.50 (1H, brs)

132

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Example 302

Synthesis of N- (3- (N ', N'-dimethylguanidino) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 301 as the starting material and also using dimethylamine hydrochloride and triethylamine as reagnets, the procedure of Example 278 provided the title compound (50% yield).

Ή-NMR (CDCl ₃ ) δ: 1.45 (18H, s), 2.98 (6H, s), 4.73 (2H, s), 6.75-6.87 (3H, m), 7 . 16-7.19 (1H, m)

MS (m / z) 392 (M ⁺ )

Example 303

Synsthesis of N- (3- (N ', Ν'- dimethylguanidino) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 302 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 96%).

δ: 3.14 (6H, s), 4.19 (2H, s), 7.31-7.57 (4H, m)

NS (m / z) 192 (M ⁺ )

Example 304

Synthesis of N- (3- (N'-ethyl-N'-methylguanidino) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 301 as a starting material and also using ethylmethylamine as the reagnet, the procedure of Example 278 afforded the title compound (27% yield).

Ή-NMR (CDCl 3) δ: 1.17 (3H, t,> 7.3 Hz), 1.45 (18H, s), 2.95 (3H, s), 3.38 (2H, q,> 7.3Hz), 4.73 (2H, s), 6.75-7.19 (4H, m)

MS (m / z) 406 (M ^T )

Example 305

Synthesis of N- (3- (N'-ethyl-N'-methylguanidino) -phenylmethyl) amine dihydrochloride

By using the compound obtained in Example 304 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.28 (3H, t,> 7.3 Hz), 3.12 (3H, s), 3.53 (2H, q,> 7.3 Hz), 4 . 23 (2H, s), 7.30-7.70 (4H, m)

MS (m / z) 206 (M ⁺ )

Example 306

Synthesis of N- (3-N '- (2-propynyl) -guanidino) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 301 as the starting material and also using propargylamine as the reagnet, the procedure of Example 278 gave the title compound (55% yield).

Ή-NMR (CDCl 3) δ: 1.45 (18H, s), 2.26 (1H, s), 4.04 (2H, s), 4.73 (2H, s), 6.78-6, 90 (3H, m), 7.21 (1H, dd,> 7.6.7.6Hz)

MS (m / z) 402 (M ⁺ )

Example 307

Synthesis of N- (3- (N ^, - (2-propynyl) guanidino) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 306 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 2.81 (1H, t,> 2.6 Hz), 4.15 (2H, d,> 2.6 Hz), 4.24 (2H, s), 7 , 28-7.41 (2H, m), 7.47 (1H, d,> 7.9Hz), 7.58 (1H, dd,> 7.9,7.9Hz)

MS (m / z) 202 (M ⁺ )

183 619

133

Example 308

Synthesis of N- (2-nitrophenylethyl) phthalimide

By using 2-nitrophenethyl alcohol as starting material, the procedure of Example 179 gave the title compound (97% yield).

Ή-NMR (CDCl ₃ ) δ: 3.31 (2H, t,> 6.9 Hz), 4.10 (2H, t,> 6.9 Hz), 7.28-7.50 (3H, m ), 7.68-7.74 (2H, m), 7.77-7.84 (2H, m), 7.96-8.20 (1H, m)

Example 309

Synthesis of N- (2-nitrophenylethyl) carbamic acid t-butyl ester

Using the compound (2.18 g) obtained in Example 308 as a starting material, the procedure of Example 180 gave 2-nitrophenylethylamine. A two-layer mixture consisting of the resulting amine, di-t-butyl bicarbonate (1.77 g), methylene chloride (120 ml) and a 2 N aqueous sodium hydroxide solution (30 ml) was stirred at room temperature for 14 hours. The organic layer was dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 3: 1) to obtain 1.95 g of the title compound (99% yield).

Ή-NMR (CDCl3) δ: 1.42 (9H, s), 3.09 (2H, t,> 6.6 Hz), 3.46 (2H, dt,> 6.6.6.6 Hz) , 4.70 (1H, br s), 7.34-7.43 (2H, m), 7.50-7.59 (1H, m), 7.91-7.97 (1H, m)

MS (m / z) 266 (M ⁺ )

Example 310

Synthesis of N- (2-aminophenylethyl) -carbamic acid t-butyl ester

Using the compound obtained in Example 309 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 94%).

Ή-NMR (CDCl 3) δ: 1.45 (9H, s), 2.70 (2H, t,> 6.9 Hz), 3.28 (2H, dt,> 6.9 6.9 Hz), 3.93 (2H, brs), 4.87 (1H, brs), 6.64-6.74 (2H, m), 6.96-7.09 (2H, m)

MS (m / z) 236 (M ⁺ )

Example 311

Synthesis of N- (2-thioureidophenylethyl) -carbamic acid t-butyl ester

Using the compound obtained in Example 310 as starting material, the procedure of Example 120 gave the title compound (98% yield).

Ή-NMR (CDCl3) δ: 1.35 (9H, s), 2.80 (2H, t,> 6.9 Hz), 3.32 (2H, dt,> 6.9.6.9 Hz) , 4.80 (1H, brs), 6.28 (2H, brs), 7.20-7.28 (4H, m)

MS (m / z) 295 (M ⁺ )

Example 312

Synthesis of N- (2- (S-ethylisothioureido) -phenylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 311 as starting material, the procedure of Example 95 gave the title compound (81% yield).

Ή-NMR (CDCl 3) δ: 1.33-1.40 (3H, m), 1.39 (9H, s), 2.69 (2H, t, J = 6.3 Hz), 3.00- 3.20 (2H, m), 3.32 (2H, dt,> 6.3, 6.3Hz), 4.56 (2H, brs), 5.27 (1H, brs), 6.80- 6.88 (1H, m), 6.95-7.05 (1H, m), 7.12-7.24 (2H, m)

MS (m / z) 323 (M ⁺ )

Example 313

Synthesis of N- (2- (S-ethylisothioureido) phenylethyl) amine dihydrochloride

Using the compound obtained in Example 312 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 81%).

Ή-NMR (D ₂ O) δ: 1.35-1.50 (3H, m), 2.99 (2H, t,> 7.3 Hz), 3.20-3.33 (4H, m) , 7.36-7.42 (1H, m), 7.44-7.60 (3H, m)

134

183 619

Example 314

Synthesis of N- (5-amino-2-fluorophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 87%).

1 H-NMR (CDCl ₃ ) δ: 1.45 (18H, s), 3.50 (2H, brs), 4.78 (2H, s), 6.47-6.54 (2H, m), 6.77-6.85 (1H, m)

Example 315

Synthesis of N- (2-fluoro-5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 314 as the starting material, the procedure of Example 120 gave the title compound (99% yield).

1 H-NMR (CDCl ₃ ) δ: 1.48 (18H, s), 4.84 (2H, s), 6.11 (2H, brs), 7.09-7.14 (3H, m), 8.06 (1H, brs)

Example 316

Synthesis of N- (5- (S-ethylisothioureido) -2-fluorophenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 315 as starting material, the procedure of Example 95 gave the title compound (53% yield).

Ή-NMR (CDCl ₃ ) δ: 1.33-1.39 (3H, m), 1.45 (9H, s), 3.00-3.17 (2H, m), 4.32 (2H, d, J = 5.6Hz), 4.49 (1H, brs), 4.85 (1H, brs), 6.71-7.01 (4H, m)

MS (m / z) 327 (M ⁺ )

Example 317

Synthesis of N- (5- (S-ethylisothioureido) -2-fluoro) -phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 316 as starting material, the procedure of Example 5 gave the title compound (83% yield).

1 H-NMR (D ₂ O) δ: 1.41 (3H, t,> 7.3 Hz), 3.20-3.28 (2H, m), 4.29 (2H, s), 7, 39-7.53 (3H1 m)

MS (m / z) 227 (M ⁺ )

Example 318

Synthesis of N- (2-hydroxy-5-nitrophenylmethyl) phthalimide

To a solution of the compound (937 mg) obtained in Example 117 in dry methylene chloride (30 ml), a solution of boron tribromide in methylene chloride (1.0 M 9 ml) was added dropwise at -78 ° C under a nitrogen atmosphere, and the mixture was stirred at temperature -78 ° C for 1 hour, then stirred at room temperature for 21 hours. Water was added to the reaction mixture, which was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 1: 1) to give 743 mg of the title compound (83% yield).

H-NMR (CDC1 ₃₎

Ó: 4.84 (2H, s), 6.99 (1H, d,> 9.2 Hz), 7.85-7.92 (4H, m), 7.95 (1H, dd, J = 9 , 2.2.6Hz), 8.06 (1H, dd,> 9.2, 2.6Hz), 11.4 (1H, s)

MS (m / z) 298 (M ⁺ )

Example 319

Synthesis of N- (2-ethoxy-5-nitrophenylmethyl) phthalimide

To a mixture of sodium hydride (content, 60%; 36 mg) and anhydrous dimethylformamide (5 ml), a solution of the compound (224 mg) obtained in Example 318 in anhydrous dimethylformamide (3 ml) and ethyl iodide (0.072 ml) was added dropwise at 0 ° C under nitrogen atmosphere and stirred at room temperature for 24 hours. Water was added to the reaction mixture, which was distilled under reduced pressure; then to the received pos

183 619

Ethyl acetate and water were added to the solids. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 1: 1) to give 213 mg of the title compound (yield 87%).

Ή-NMR (CDCl ₃ ) δ: 1.47 (3H, t, J = 7.3 Hz), 4.17 (2H, q, J = 7.3 Hz), 4.93 (2H, s), 6.90 (1H, d,> 9.2Hz), 7.74-7.91 (4H, m), 8.05 (1H, d,> 2.6Hz), 8.17 (1H, dd ,> 9.2, 2.6Hz)

MS (m / z) 326 (M ⁺ )

Example 320

Synthesis of N- (2-ethoxy-5-nitrophenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 319 as the starting material following the procedure of Example 309 provided the title compound (95% yield)

Ή-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.49 (3H, t,> 7.3 Hz), 4.17 (2H, q,> 7.3 Hz), 4, 36 (2H, d,> 5.9Hz), 4.98 (1H, brs), 6.86-6.91 (1H, m), 8.14-8.17 (2H, m)

Example 321

Synthesis of N- (5-amino-2-ethoxyphenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 320 as a starting material, the title compound was obtained according to the procedure in Example 2 (yield 75%).

Ή-NMR (CDCl ₃ ) δ: 1.38 (3H, t,> 6.9 Hz), 1.44 (9H, s), 3.41 (2H, brs), 3.97 (2H, q, > 6.9 Hz), 4.23 (2H, d,> 5.9 Hz), 5.00 (1H, brs), 6.55 (1H, dd,> 8.6, 3.0 Hz), 6.66-6.69 (2H, m)

Example 322

Synthesis of N- (2-ethoxy-5-thioureido) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 321 as a starting material, the procedure of Example 120 afforded the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.44 (3H, t,> 7.3 Hz), 1.44 (9H, s), 4.07 (2H, q,> 7.3 Hz), 4, 28 (2H, d,> 6.3Hz), 5.03 (1H, brs), 6.04 (2H, brs), 6.85 (1H, d,> 8.6Hz), 7.07- 7.16 (2H, m), 7.85 (1H, br s)

MS (m / z) 325 (M ⁺ )

Example 323

Synthesis of N- (2-ethoxy-5- (S-ethylisothioureido) phenylmethyl) carbamic acid t-butyl ester iodide

Using the compound obtained in Example 322 as starting material, the procedure of Example 27 gave the title compound (yield 90%).

Ή-NMR (CDCl ₃ ) δ: 1.38 (6H, t,> 7.6 Hz), 1.45 (9H, s), 3.22 (2H, q,> 7.6 Hz), 4, 07 (2H, q,> 7.6 Hz), 4.28-4.29 (2H, m), 5.02 (1H, brs), 6.84 (1H, d,> 8.6 Hz), 7.06-7.10 (2H, m)

MS (m / z) 353 (M ⁺ )

Example 324

Synthesis of N- (2-ethoxy-5 (S-ethylisothioureido) -phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 323 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.41 (3H, t,> 6.9 Hz), 1.43 (3H, t, J = 6.9 Hz), 3.15-3.30 (2H , m), 4.16-4.31 (4H, m), 7.20 (1H, d,> 8.9Hz), 7.34 (1H, d,> 2.6Hz), 7.42 (1H, dd,> 8.9.2.6Hz)

MS (m / z) 253 (M ⁺ )

136

183 619

Example 325

Synthesis of N- (5- (N'-t-butoxycarbonyl-N * -ethyl) guanidino) -2-ethoxyphenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 321 as starting material, the title compound was obtained according to the procedure of Example 233 (yield 90%).

Ή-NMR (CDCl ₃ ) δ: 1.06 (3H, t,> 7.3Hz), 1.40-1.47 (3H, m), 1.45 (9H, s), 1.53 ( 9H, s), 3.33-3.43 (2H, m), 4.06 (2H, q,> 7.3Hz), 4.16 (2H, d,> 5.9Hz), 4. 97 (1H, brs), 6.83 (1H, d,> 8.3Hz), 7.04-7.12 (2H, m)

Example 326

Synthesis of N- (2-ethoxy-5- (N'-ethylguanidino) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 325 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.21 (3H, t,> 7.3 Hz), 1.43 (3H, t,> 6.9 Hz), 3.29 (2H, q,> 7 , 3Hz), 4.17-4.28 (4H, m), 7.16 (1H, d,> 8.9Hz), 7.29 (1H, d,> 2.6Hz), 7, 36 (1H, dd,> 8.9, 2.6Hz)

MS (m / z) 236 (M ⁺ )

Example 327

Synthesis of N- (2-ethoxy-5- (N'-nitroguanidino) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 321 as a starting material, the procedure of Example 6 gave the title compound in quantitative yield.

Ή-NMR (CDCl 3) δ: 1.44 (9H, s), 1.44-1.48 (3H, m), 4.05-4.11 (2H, m), 4.30 (2H, d > 3.0Hz), 5.08 (1H, brs), 6.88-6.93 (1H, m), 7.16-7.27 (2H, m), 9.63 (1H, brs)

MS (m / z) 353 (M ⁺ )

Example 328

Synthesis of N- (2-ethoxy-5- (N'-nitroguanidino) phenylmethyl) amine hydrochloride

By using the compound obtained in Example 327 as a starting material, the procedure of Example 5 gave the title compound (95% yield).

Ή-NMR (D ₂ O) δ: 1.43 (3H, t,> 6.9 Hz), 4.19-4.29 (4H, m) 7.17 (1H, d,> 8.6 Hz ), 7.34 (1H, d,> 2.6Hz), 7.39 (1H, dd,> 8.6, 2.6Hz)

Example 329

Synthesis of N- (5-amino-2-methoxyphenylmethyl) phthalimide

Using the compound obtained in Example 117 as a starting material, the title compound was obtained according to the procedure in Example 2 (yield 91%).

Ή-NMR (CDCl ₃ ) δ: 3.36 (2H, brs), 3.79 (3H, s), 4.85 (2H, s), 6.52-6.59 (2H, m), 6 . 70 (1H, d,> 2.3Hz), 7.68-7.76 (2H, m), 7.82-7.90 (2H, m)

Example 330

Synthesis of N- (2-methosky-5- (N'-trifluoroacetoxyamino) phenylmethyl) phthalimide

To a solution of the compound (150 mg) obtained in Example 329 and pyridine (0.13 ml) in anhydrous methylene chloride (5 ml), trifluoroacetic anhydride (0.165 ml) was added dropwise at room temperature and stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was washed with chloroform to obtain 176 mg of the title compound (yield 88%).

Ή-NMR (CDCl 3) δ: 3.86 (3H, s), 4.89 (2H, s), 6.87 (1H, d,> 8.9 Hz), 7.17 (1H, d,> 2.3Hz), 7.66 (1H, dd,> 8.9, 2.3Hz), 7.71-7.74 (2H, m), 7.83-7.87 (2H, m)

MS (m / z) 378 (M ⁺ )

183 619

137

Example 331

Synthesis of N- (2-hydroxy-5- (N'-trifluoroacetoxyamino) phenylmethyl) phthalimide

By using the compound obtained in Example 330 as a starting material, the procedure of Example 318 gave the title compound (93% yield).

Ή-NMR (DMSO-d ₆ ) δ: 4.71 (2H, s), 6.84 (1H, d, J = 8.9 Hz), 7.16 (1H, d, J = 2.3 Hz ), 7.52 (1H, dd,> 8.9.2.3Hz), 7.86-7.97 (4H, m), 9.88 (1H, s), 10.88 (1H, s )

MS (m / z) 364 (M ⁺ )

Example 332

Synthesis of N- (2-benzyloxy-5- (N'-trifluoroacetoxyamino) phenylmethyl) phthalimide

Using the compound obtained in Example 331 as the starting material and also using potassium carbonate and benzyl bromide respectively as base and reagent, respectively, the procedure of Example 319 provided the title compound (53% yield).

Ή-NMr (DMSO-d ₆ ) δ: 4.80 (2H, s), 5.19 (2H, s), 7.00-7.18 (2H, m), 7.27-7.52 ( 5H, m), 7.68 (1H, dd,> 8.9.2.6Hz), 7.85-7.98 (4H, m), 10.99 (1H, brs)

MS (m / z) 454 (M ⁺ )

Example 333

Synthesis of N- (5-amino-2-benzyloxphenylmethyl) amine

Using the compound (684 mg) obtained in Example 332 as a starting material, the procedure of Example 180 gave N- (3-aminomethyl-4-benzyloxyphenyl) -2,2,2- (trifluoroacetamide). To a solution of the resulting amine in 6% methanol in water (10.6 mL), potassium carbonate (265 mg) was added and heated to reflux for 2 hours. The reaction mixture was distilled under reduced pressure, and ethyl acetate and water were added to the obtained residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure, thereby obtaining 339 mg of the title compound (98% yield).

Ή-NMR (CDCl ₃ ) δ: 3.79 (2H, s), 5.02 (2H, s), 6.54 (1H, dd,> 8.6, 3.0 Hz), 6.65 ( 1H, d,> 3.0Hz), 6.76 (1H, d,> 8.6Hz), 7.30-7.43 (5H, m)

MS (m / z) 228 (M ⁺ )

Example 334

Synthesis of N- (5-amino-2-benzyloxyphenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 333 as the starting material following the procedure of Example 253, the title compound was obtained (78% yield).

Ή-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 4.26 (2H, d,> 5.9 Hz), 4.98 (1H, brs), 5.01 (2H, s) , 6.55 (1H, dd,> 8.3, 2.6 Hz), 6.67 (1H, d,> 2.6 Hz), 6.76 (1H, d,> 8.3 Hz), 7.31-7.40 (5H, m)

MS (m / z) 328 (M ⁺ )

Example 335

Synthesis of N- (2-benzyloxy-5-thioureido) -phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 334 as starting material, the procedure of Example 120 gave the title compound (81% yield).

Ή-NMr (DMSO-d ₆ ) δ: 1.40 (9H, s), 4.17 (2H, d,> 5.9 Hz), 5.13 (2H, s), 7.00 (1H, d,> 8.6 Hz), 7.07 (1H, d,> 2.3 Hz), 7.11-7.22 (2H, m), 7.26-7.50 (4H, m), 9.51 (1H, brs)

Example 336

Synthesis of N- (2-benzyloxy-5- (S-ethylisothioureido) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 335 as a starting material, the procedure of Example 95 gave the title compound (93% yield).

138

183 619

Ή-NMR (CDCl ₃ ) δ: 1.36 (3H, t, J = 7.3 Hz), 1.43 (9H, s), 3.00-3.07 (2H, m), 4.32 (2H, d, J = 5.6Hz), 4.50 (1H, brs), 4.97 (1H, brs), 5.07 (2H, s), 6.72-6.90 (3H, m), 7.32-7.42 (5H, m)

MS (m / z) 415 (M ⁺ )

Example 337

Synthesis of N- (2-benzyloxy-5- (S-ethylisothioureido) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 336 as starting material, the title compound was obtained according to the procedure in Example 5 (yield 94%).

Ή-NMR (D ₂ O) δ: 1.42 (3H, t, J = 7.3 Hz), 3.23 (2H, q, J = 7.3 Hz), 4.24 (2H, s) , 5.34 (2H, s), 7.24-7.60 (8H, m)

Example 338

Synthesis of N- (2-benzyloxy-5- (N'-t-butoxycarbonyl-N-ethylguanidino) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 334 as starting material, the title compound was obtained according to the procedure of Example 233 (70% yield).

Ή-NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 6.9 Hz), 1.44 ((H, s), 1.53 (9H, s), 3.36-3, 41 (2H, m), 4.33 (2H, d, J = 5.6 Hz), 4.98 (1H, brs), 5.10 (2H, s), 6.92 (1H, d, J = 8.6Hz), 7.01-7.19 (2H, m), 7.30-7.45 (5H, m)

Example 339

Synthesis of N- (2-benzyloxy-5- (N'-ethyl) guanidino) -phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 338 as the starting material, the title compound was obtained according to the procedure in Example 5 (yield 94%).

Ή-NMR (D ₂ O) δ: 1.21 (3H, t, J = 7.3 Hz), 3.29 (2H, q, J = 7.3 Hz), 4.22 (2H, s) , 5.32 (2H, s), 7.20-7.58 (8H, m)

MS (m / z) 298 (M ⁺ )

Example 340

Synthesis of N- (2-benzyloxy-5- (N'-nitroguanidino) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 334 as starting material, the title compound was obtained according to the procedure in Example 6 (yield 87%).

Ή-NMR (DMSO-d ₆ ) δ: 1.40 (9H, s), 4.19 (2H, d, J = 4.0 Hz), 5.15 (2H, s), 7.02-7 . 20 (4H, m), 7.28-7.51 (5H, m), 8.30 (1H, s)

Example 341

Synthesis of N- [2-benzyloxy-5- (N'-nitroguanidino) -phenylmethyl) amine hydrochloride

Using the compound obtained in Example 340 as the starting material, the title compound was obtained according to the procedure in Example 5 (yield 32%).

Ή-NMR (D ₂ O) δ: 4.22 (2H, s), 5.31 (2H, s), 7.20-7.24 (1H, m), 7.32-7.39 (2H , m), 7.40-7.57 (5H, m) Example 342

Synthesis of 2-methoxy-5-nitrophenylacetic acid diphenylmethyl ester

Using 2-methoxyphenylacetic acid (5.00 g) as a starting material, 2-methoxy-5-nitrophenylacetic acid was obtained by the procedure of Example 188. To a solution of the resulting nitro compound in methylene chloride (140 mL) was added a solution of diphenyldiazomethane in methylene chloride at room temperature until the reaction mixture turned purple, then acetic acid was added until the purple color of the reaction mixture disappeared. The reaction mixture was washed successively with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium hydrogencarbonate solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 3: 1) to give 2.34 g of the title compound (yield 21%).

Ή-NMR (CDC1 ₃₎

183 619

139 δ: 3.73 (3Η, s), 3.77 (2Η, s), 6.88 (1H, d,> 8.9 Hz), 6.91 (1H, s), 7.20-7 , 39 (10H, m), 8.12 (1H, d,> 2.6 Hz), 8.20 (1H, dd,> 8.6, 2.6 Hz)

Example 343

Synthesis of 2- (2-methoxy-5-nitrophenyl) propionic acid diphenyl ethyl ester

Using the compound obtained in Example 342 as a starting material and also using methyl iodide (1 eq.) As the reagnet, the procedure of Example 1a gave the title compound (46% yield).

Ή-NMR (CDCl ₃ ) δ: 1.55 (3H, d,> 7.3 Hz), 3.63 (3H, s), 4.08 (1H, q,> 7.3 Hz), 6, 84 (1H, d,> 8.9Hz), 6.91 (1H, s), 7.15-7.38 (10H, m), 8.12 (1H, d,> 2.6Hz), 8.19 (1H, dd,> 8.9, 2.6Hz)

Example 344

Synthesis of 2- (2-methoxy-5-nitrophenyl) -2-methyl-propionic acid diphenylmethyl ester

Using the compound obtained in Example 343 as a susbstrate, the title compound was obtained according to the procedure of Example 343 (82% yield).

Ή-NMR (CDC1 ₃₎

6: 1.60 (6H, s), 3.26 (3H, s), 6.73 (1H, d,> 8.9Hz), 6.94 (1H, s), 7.12-7. 31 (10H, m), 8.19 (1H, dd,> 8.9, 2.6 Hz), 8.26 (1H, d,> 2.6 Hz)

Example 345

Synthesis of 2- (2-methoxy-5-nitrophenyl) -2-methyl) propionic acid

By using the compound obtained in Example 344 as a starting material, the procedure of Example 1b gave the title compound (88% yield).

Ή-NMR (CDCl ₃ ) δ: 1.60 (6H, s), 3.92 (3H, s), 6.95 (1H, d,> 9.2 Hz), 8.18-8.23 ( 2H, m)

MS (m / z) 239 (M ⁺ )

Example 346

Synthesis of N- (1- (2-methoxy-5-nitrophenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 345 as a starting material, the title compound was obtained according to the procedure in Example Ic (yield 40%).

Ή-NMR (CD Cl ³⁾ δ: 1.33 (9H, brs), 1.70 (6H, s), 3.95 (3H, s), 5.06 (1H, brs), 6.94 ( 1H, d,> 8.9Hz), 8.15 (1H, dd,> 8.9, 2.6Hz), 8.26 (1H, d,> 2.6Hz)

Example 347

Synthesis of N- (1- (5-amino-2-methoxyphenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 346 as a susbstrate, the title compound was obtained according to the procedure in Example 2 (yield 87%).

Ή-NMR (CDCl ₃ ) δ: 1.33 (9H, brs), 1.65 (6H, s), 3.77 (3H, s), 5.21 (1H, brs), 6.54 (1H , dd,> 8.6, 3.0Hz), 6.70-6.74 (2H, m)

MS (m / z) 280 (M ⁺ )

Example 348

Synthesis of N- (1- (2-methoxy-5-thioureido) phenyl) -1-methylethyl) carbamic acid t-butyl ester

By using the compound obtained in Example 347 as a starting material, the procedure of Example 120 gave the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.66 (6H, s), 3.85 (3H, s), 5.08 (1H, brs), 6.14 (2H , brs), 6.90 (1H, d,> 8.9Hz), 7.07 (1H, dd,> 8.9, 2.0Hz), 7.23 (1H, d,> 2.0 Hz), 7.80 (1H, brs)

MS (m / z) 339 (M ⁺ )

140

183 619

Example 349

Synthesis of N- (1- (5- (S-ethylisothioureido) -2-methoxyphenyl) -1-methylethyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 348 as a starting material, the procedure of Example 27 gave the title compound (70% yield).

Ή-NMR (CDCl ₃ ) δ: 1.34 (9H, s), 1.36 (3H, t, J = 7.6 Hz), 1.66 (6H, s), 3.03 (2H, q , J = 7.6 Hz), 3.81 (3H, s), 5.16 (1H, brs), 6.80-6.91 (3H, m)

MS (m / z) 367 (M ⁺ )

Example 350

Synthesis of N- (1- (5- (S-ethylisothioureido) -2-methoxyphenyl) -1-methylethyl) amine

Using the compound (111 mg) obtained in Example 349 as a starting material, the reaction was conducted as in Example 5, and the resulting residue was purified by basic silica gel column chromatography (eluent, n-hexane: chloroform = 1: 3) to give 24.9 mg of the title compound (42% yield).

Ή-NMR (CDCl ₃ ) δ: 1.34-1.41 (3H, m), 1.51 (6H, s), 3.01-3.15 (2H, m), 3.85 (3H, s), 4.50 (lH, brs), 6.69-6.92 (3H, m)

MS (m / z) 267 (M ⁺ )

Example 351

Synthesis of N, N'-di- (t-butoxycarbonyl) -N- (3-nitrophenylmethyl) -hydrazine

To a solution of triphenylphosphine (2.06 g) in tetrahydrofhran (20 ml) was added dropwise a solution of di-t-butyl azodicarboxylate (1.80 g) in tetrahydrofuran (15 ml) under ice-cooling and stirred for 15 minutes. A solution of m-nitrobenzyl alcohol (1.0 g) in tetrahydrofuran (15 ml) was added dropwise to the reaction mixture and stirred at room temperature for 63 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 1: 1) to give 2.25 g of the title compound (94% yield).

Ή-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.49 (9H, s), 4.72 (2H, s), 6.30 (1H, brs), 7.51 (1H , t, J = 7.3Hz), 7.65 (1H, d, J = 7.3Hz), 8.15 (1H, d, J = 7.3Hz), 8.16 (1H, s )

Example 352

Synthesis of N- (3-aminophenylmethyl) -N, N'-di- (t-butoxycarbonyl) -hydrazine

Using the compound obtained in Example 351 as starting material, the procedure of Example 2 gave 985 mg of the title compound (62% yield).

Ή-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.48 ((H, s), 4.56 (2H, s), 6.25 (1H, brs), 6.59 ( 1H, d, J = 6.9Hz), 6.65 (1H, d, J = 6.9Hz), 6.81-6.98 (2H, m)

Example 353

Synthesis of N, N'-di- (t-butoxycarbonyl) -N- (3-thioureido) phenylmethyl) hydrazine

Using the compound obtained in Example 352 as a susbstrate, according to the procedure of Example 120, 173 mg of the title compound were obtained (74% yield).

Ή-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.48 (9H, s), 4.60 (2H, s), 6.44 (1H, brs), 6.57 (2H , brts), 7.08-7.21 (2H, m), 7.26-7.40 (2H, m), 8.27 (1H, m)

Example 354

Synthesis of N, N'-di- (t-butoxycarbonyl) -N- (3- (S-ethylisothioureido) phenylmethyl) hydrazine iodide

Using the compound obtained in Example 353 as a starting material, the procedure of Example 27 obtained 143 mg of the title compound (79% yield).

Ή-NMR (CDC1 ₃₎

183 619

141 δ: 1.41 (3H, t, J = 7.3Hz), 1.44 (9H, s), 1.48 (9H, s), 3.31 (2H, q, J = 7.3Hz ), 4.64 (2H, s), 6.40 (1H, br s), 7.23-7.41 (4H, m)

Example 355

Synthesis of 3- (S-ethylisothioureido) phenylmethylhydrazine trihydrochloride

Using the compound obtained in Example 354 as a starting material, the procedure of Example 5 gave 62 mg of the title compound (79% yield).

1 H-NMR (DMSO-d ₆ ) δ: 1.34 (3H, t, J = 7.3 Hz), 3.28-3.40 (2H, m), 4.08 (2H, s), 7.30 (1H, d, J = 7.6 Hz), 7.41 (1H, s), 7.42 (1H, d,> 7.6 Hz), 7.53 (1H, t, J = 7.6 Hz), 9.26 (1H, brs), 9.61 (1H, brs), 11.51 (1H, brs)

MS (m / z) 224 (M ⁺ )

Example 356

Synthesis of N, N'-di- (t-butoxycarbonyl) -N- (3- (N'-nitroguanidino) -phenylmethyl) hydrazine

Using the compound obtained in Example 352 as a starting material, the procedure of Example 6 gave 22 mg of the title compound (yield 18%).

H-NMR (CDC1 ₃₎

6: 1.32 (9H, s), 1.48 (9H, s), 4.62 (2H, s), 6.48 (1H, brs), 7.15-7.25 (2H, m) , 7.38 (1H, t,> 7.3Hz), 7.49 (1H, s) 9.54 (1H, brs)

MS (m / z) 224 (M ⁺ -200)

Example 357

Synthesis of 3- (N'-nitroguanidino) phenylmethylhydrazine dichlorohydride

Using the compound obtained in Example 356 as the starting material, the procedure of Example 5 gave 15 mg of the title compound (74% yield).

1 H-NMR (DMSO-d ₆ ) δ: 3.75 (2H, s), 7.08-7.40 (6H, m), 8.26 (2H, brs)

MS (m / z) 208 (M ⁺ -16)

Example 358

Synthesis of N- (4-nitrophenyl) propyl) -carbamic acid t-butyl ester

Using 4- (4-nitrophenyl) butyl acid as starting material, 400 mg of the title compound were obtained according to the procedure in Example Ic (30% yield).

'H-NMR (CDCl3)

6: 1.44 (9H, s), 1.84 (2H, quintet,> 7.3Hz), 2.75 (2H, t, J = 7.3Hz), 3.10-3.26 ( 2H, m), 4.57 (1H, brs), 7.34 (2H, d,> 8.8Hz), 8.15 (2H, d,> 8.8Hz)

MS (m / z) 281 (M ⁺ + 1)

Example 359

Synthesis of N- (4-aminophenyl) propyl) carbamic acid t-butyl ester

Using the compound obtained in Example 358 as a starting material, the procedure of Example 2 gave 170 mg of the title compound (48% yield). 1 H-NMR (CDCl 3) δ: 1.45 (9H, s), 1.75 (2H, quintet, > 7.3Hz), 2.53 (2H, t,> 7.3Hz), 3.04-3.18 (2H, m), 3.53 (2H, brs), 4.48 (1H, brs), 6.62 (2H, d,> 8.3Hz), 6.95 (2H, d,> 8.3Hz)

Example 360

Synthesis of N- (4- (N'-nitroguanidino) -phenyl) propyl) carbamic acid t-butyl ester

Using the compound obtained in Example 359 as a starting material, 42 mg of the title compound were obtained according to the procedure in Example 6 (yield 37%).

1 H-NMR (CDCl 3) δ: 1.42 (9H, s), 1.82 (2H, quintet,> 7.3 Hz), 2.70 (2H, t,> 7.3 Hz), 3, 16 (2H, dt,> 7.3, 7.3 Hz), 4.54 (1H, brs), 7.24 (2H, d,> 8.3 Hz), 7.31 (2H, d,> 8.3 Hz), 9.60 (1H, brs)

Example 361

Synthesis of N- (4- (N'-nitroguanidino) phenyl) propyl) amine hydrochloride

Using the compound obtained in Example 360 as a starting material, the procedure of Example 5 gave 35.5 mg of the title compound in quantitative yield.

1 H-NMR (DMSO-d ₆ )

142

183 619 δ: 1.94 (2Η, quintet,> 7.5 Hz), 2.67 (2H, t,> 7.5 Hz), 2.74- (2.86 (2H, m), 7, 20 (2H, d,> 8.6Hz), 7.26 (2H, d,> 8.6Hz), 8.16 (IH, brs), 9.58 (IH, s)

MS (m / z) 237 (M ⁺ )

Example 362

Synthesis of N- (3-nitrophenylmethyl) -iminodicarboxylic acid di-t-butyl ester

Using m-nitrobenzyl bromide as a starting material, the procedure of Example 127 gave 11.7 g of the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.48 (18H, s), 4.86 (2H, s), 7.49 (IH, dd,> 7.8.7.5 Hz), 7.65 ( IH, d,> 7.5 Hz), 8.13 (IH, d,> 7.9 Hz), 8.19 (IH, s)

Example 363

Synthesis of N- (3-aminophenylmethyl) -iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 362 as a starting material, the procedure of Example 2 gave 5.45 g of the title compound (41% yield).

Ή-NMR (CDCl ₃ ) δ: 1.45 (18H, s), 3.60 (2H, brs), 4.68 (2H, s), 6.53-6.58 (IH, m), 6 , 60 (IH, s), 6.66 (IH, d,> 7.6 Hz), 7.07 (IH, dd,> 7.9, 7.6 Hz)

Example 364

Synthesis of N- (3-thioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 363 as a starting material, the procedure of Example 120 gave 2.1 g of the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.47 (18H, s), 4.78 (2H, s), 6.12 (2H, brs), 7.10-7.42 (4H, m), 7 .96 (IH, brs)

Example 365

Synthesis of N- (3- (S-methylisothioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 364 as the starting material, the procedure in Example 4 gave 1.81 g of the title compound (70% yield).

Ή-NMR (CDCl ₃ ) δ: 1.46 (18H, s), 2.46 (3H, s), 4.49 (IH, brs), 4.75 (2H, s), 6.76-6 , 88 (2H, m), 6.95 (IH, d,> 7.6Hz), 7.20-7.28 (IH, m)

Example 366

Synthesis of N- (3- (N'-methylguanidino) -phenylmethyl) iminodicarboxylic acid di-t-butyl ester

A mixture of the compound (158 mg) obtained in Example 365, methylamine hydrochloride (31 mg), triethylamine (156 mg) and dimethylformamide (3 ml) was heated at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride: methanol = 20: 1) to give 60 mg of the title compound (72% yield).

Ή-NMR (CDCl ₃ ) δ: 1.45 (18H, s), 2.85 (3H, s), 4.73 (2H, s), 6.81 (IH, d,> 7.9 Hz) , 6.85 (IH, s), 6.89 (IH, d,> 7.6 Hz), 7.21 (IH, dd,> 7.7.6 Hz)

Example 367

Synthesis of N - ^ - fNf-methyljguanidinephenylmethyljamine dihydrochloride

Using the compound obtained in Example 366 as a starting material, according to the procedure in Example 5, 49 mg of the title compound were obtained in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 2.84 (3H, d,> 4.3 Hz), 4.03 (2H, s), 7.22 (IH, d,> 7.3 Hz), 7.44-7.51 (IH, m), 7.69-7.86 (2H, m), (2H, m), 9.82 (IH, brs)

MS (m / z) 178 (M ⁺ )

183 619

143

Example 368

Synthesis of N- (3- (N'-ethylguanidino) -phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 365 as the starting material and also using ethylamine hydrochloride as reagent, the procedure of Example 366 gave 59 mg of the title compound (61% yield).

Ή-NMR (CDCl ₃ ) δ: 1.19 (3H, t,> 7.3 Hz), 1.45 (18H, s), 3.23 (2H, q,> 7.3 Hz), 4, 73 (2H, s), 6.80 (1H, d,> 7.9Hz), 6.85 (1H, s), 6.88 (1H, d,> 7.5Hz), 7.21 ( 1H, dd,> 7.9,7.5Hz)

Example 369

Synthesis of N- (3- (N'-ethylguanidino) phenylmethylamine dihydrochloride

Using the compound obtained in Example 368 as a starting material, the procedure of Example 5 gave 28.6 mg of the title compound (71% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.16 (3H, t,> 6.9 Hz), 3.26-3.38 (2H, m), 4.03 (2H, d,> 5, 6 Hz), 7.21 (1H, d,> 7.6 Hz), 7.36 (1H, d,> 7.9 Hz), 7.39 (1H, s), 7.48 (1H, dd > 7.9.7.6Hz), 7.77 (1H, brs), 7.96-8.02 (1H, m), 8.47 (2H, brs), 9.92 (1H, brs )

MS (m / z) 192 (M ⁺ )

Example 370

Synthesis of N- (3- (N'-n-propylguanidino) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 365 as the starting material and also using n-propylamine as the reagnet, the procedure of Example 366 gave 15 mg of the title compound (64% yield).

Ή-NMR (CDCl ₃ ) δ: 0.96 (3H, t,> 7.6 Hz), 1.45 (18H, s), 1.54-1.66 (2H, m), 3.15 ( 2H, t,> 7.3Hz), 4.73 (2H, s), 6.84-6.97 (3H, m), 7.21 (1H, d,> 7.9Hz)

Example 371

Synthesis of N- (3- (N'-n-propylguanidino) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 370 as a starting material, the procedure of Example 5 gave 10.7 mg of the title compound in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 0.92 (3H, t,> 7.3 Hz), 1.50-1.62 (2H, m), 3.20 (2H, dt,> 6, 6.6.3Hz), 4.04 (2H, d,> 5.6Hz), 7.23 (1H, d,> 7.9Hz),

7.34 (1H, s), 7.35 (1H, d,> 7.6 Hz), 7.48 (1H, dd,> 7.9, 7.6 Hz), 7.67-7.73 (1H, m), 7.90-7.96 (1H, m), 9.73 (1H, br s)

MS (m / z) 206 (M ⁺ )

Example 372

Synthesis of N- (3- (S-ethylisothioureido) phenylmethyl) dimethylamine

To a solution of the compound (43.5 mg) obtained in example 40 in acetonitrile (5 ml), a solution of hydrogen chloride in 1,4-dioxane (4N, 0.1 ml) and ethyl iodide (50 mg) were added and heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride: methanol = 5: 1) to give 9.2 mg of the title compound (19% yield).

Ή-NMR (CDCl ₃ ) δ: 1.23 (3H, t,> 7.3 Hz), 2.14 (6H, s), 2.89 (2H, q,> 7.3 Hz), 3, 31 (2H, s), 6.16 (2H, br s), 6.60-6.64 (2H, m), 6.84 (1H, d,> 7.3Hz), 7.16 (1H, dd,> 7.6, 7.3Hz)

Example 373

Synthesis of N- (3- (N'-t-butoxycarbonyl-N * -ethyl) guanidino) phenylmethyl) dimethylamine

Using the compound obtained in Example 38 as starting material, 104 mg of the title compound was obtained according to the procedure of Example 233 (yield 61%).

144

183 619 'H-NMR (CDCl ₃ )

8: 1.05-1.10 (3H, m), 1.51 (9H, s), 2.25 (6H, s), 3.39-3.42 (4H, m), 7.16- 7.33 (4H, m)

MS (m / z) 320 (M ⁺ )

Example 374

Synthesis of N- (3- (N'-ethyl) guanidino) phenylmethyl) -dimethylamine dihydrochloride

Using the compound obtained in Example 373 as the starting material, according to the procedure in Example 5, 48.2 mg of the title compound were obtained in quantitative yield.

1 H-NMR (DMSO-d ₆ ) δ: 1.15 (3H, t,> 6.8 Hz), 2.70 (3H, d,> 5.0 Hz), 3.29 (2H, q, > 6.8 Hz), 4.27 (2H, d,> 4.9 Hz), 7.28 (1H, d, j = 7.6 Hz), 7.42-7.56 (2H, m) , 7.80 (1H, br s), 8.00-8.08 (1H, m), 9.92 (1H, s), 10.92 (1H, brs)

MS (m / z) 220 (M ⁺ )

Example 375

Synthesis of N- (3- (N'-t-butoxycarbonyl-N * '-ethyl) guanidino) phenylmethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 44 as starting material, the procedure of Example 233 gave 107 mg of the title compound (69% yield).

1 H-NMR (CDCl ₃ ) δ: 1.06-1.18 (3H, m), 1.48 (18H, s), 2.83 (3H, s), 3.38 (2H, q,> 7.0 Hz), 4.42 (2H, s), 7.06-7.34 (4H, m), 10.58 (1H, brs)

Example 376

Synthesis of N- (3- (N'-ethyl) guanidino) phenylmethyl) methylamine dihydrochloride

Using the compound obtained in Example 375 as the starting material, the procedure in Example 5 gave 57.6 mg of the title compound in quantitative yield.

1 H-NMR (DMSO-d ₆ ) δ: 1.16 (3H, t,> 6.9 Hz), 2.55 (3H, t,> 5.3 Hz), 3.25-3.35 ( 2H, m), 4.12 (2H, t,> 5.3Hz), 7.25 (1H, d,> 7.9Hz), 7.40 (1H, d,> 7.9Hz), 7.41 (1H, brs), 7.49 (1H, t,> 7.9Hz), 7.75 (1H, brs), 7.94 (1H, t,> 5.3Hz), 9. 22 (1H, brs), 9.78 (1H, brs)

MS (m / z) 206 (M ⁺ )

Example 377

Synthesis of N- (3-nitrophenylmethyl) benzylornethylamine

To a solution of the compound (630 mg) obtained in Example 42 and triethylamine (768 mg) in acetonitrile (20 ml), benzyl bromide (778 mg) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour and, after adding water, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 4: 1) to give 925 mg of the title compound (yield 95%).

1 H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 3.57 (2H, s), 3.60 (2H, s), 7.26-7.40 (5H, m) 7 , 48 (1H, dd,> 8.3, 6 Hz), 7.70 (1H, d,> 7.6 Hz), 8.10 (1H, d,> 8.3 Hz), 8, 24 (1H, s)

Example 378

Synthesis of N- (3-aminophenylmethyl) benzylmethylamine

Using the compound obtained in Example 377 as a starting material and also using 5% palladium on carbon and ethyl acetate as catalyst and solvent, respectively, the reaction was conducted as in Example 2 to give 487 mg of the title compound (61% yield).

1 H-NMR (CDCl ₃ ) δ: 2.18 (3H, s), 3.43 (2H, s), 3.51 (2H, s), 3.64 (2H, brs), 6.58 ( 1H, d,> 8.6 Hz), 6.73 (s, 1H), 6.75 (1H, d,> 7.6 Hz), 7.10 (1H, dd,> 8.6, 7, 6 Hz), 7.21-7.39 (5H, m)

183 619

145

Example 379

Synthesis of N- (3-thioureido) phenylmethyl) benzylmethylainine

Using the compound obtained in Example 378 as starting material, the procedure of Example 40 gave 153 mg of the title compound (32% yield).

Ή-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 3.54 (4H, s), 6.15 (2H, brs), 6.60 (s, 1H), 6.75-6 , 79 (1H, m), 7.10-7.20 (1H, m), 7.26-7.36 (6H, m), 8.01-8.18 (1H, brs)

Example 380

Synthesis of N- (3- (S-ethylisothioureido) phenylmethyl) benzylmethylamine dihydrochloride

Using the compound obtained in Example 379 as a starting material, the procedure of Example 372 gave N- (3- (S-ethylisothioureido) phenylmethyl) benzylmethylamine. To this compound was added a solution of the hydrochloride in 1,4-dioxane (4 N, 0.1 ml), and the mixture was concentrated under reduced pressure to give 9.3 mg of the title compound (yield 6%).

Ή-NMR (DMSO-d ₆ ) δ: 1.34 (3Ht, J = 7.3 Hz), 2.54 (3H, d,> 3.6 Hz), 3.30-3.40 (2H, m), 4.20-4.31 (2H, m), 4.38-4.49 (2H, m), 7.40-7.50 (4H, m), 7.55-7.68 ( 5H, m), 9.43 (1H, brs), 9.72 (1H, brs), 11.24 (1H, brs), 11.66 (1H, brs)

Example 381

Synthesis of N ^ -fN-t-butoxycarbonyl-N ^ -ethylguanidine phenylmethyljbenzylmethylamine

Using the compound obtained in Example 378 as a starting material, 96 mg of the title compound were obtained according to the procedure of Example 233 (62% yield).

Ή-NMR (CDCl ₃ ) δ: 1.01-1.18 (3H, m), 1.52 (9H, s), 2.18 (3H, s), 3.36-3.41 (2H, m), 3.49 (2H, s), 3.54 (2H, s), 4.17 (1H, brs), 7.08 (1H, brs), 7.26-7.35 (9H, m ), 10.70 (1H, brs)

Example 382

Synthesis of N- (3 - (Ν'-ethyl loguanidino) phenylmethyl) -benzylmethylamine dichloride

Using the compound obtained in Example 381 as the starting material, according to the procedure of Example 5, 133 mg of the title compound were obtained in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 1.16 (3H, t,> 6.9 Hz), 2.56 (3H, s), 3.27-3.33 (2H, m), 4, 17-4.27 (2H, m), 4.36-4.47 (2H, m), 7.29 (1H, d,> 6.9Hz), 7.48-7.60 (8H, m ), 7.73-7.80 (1H, m), 7.93-7.99 (2H, m), 9.75 (1H, brs), 10.87 (1H, brs)

MS (m / z) 296 (M ⁺ )

Example 383

Synthesis of N- (3-nitrophenylmethyl) ethylamine

By using m-nitrobenzaldehyde as the starting material and also using ethylamine hydrochloride as reagent, the procedure of Example 42 gave 2.8 g of the title compound (47% yield).

Ή-NMR (CDCl ₃ ) δ: 1.15 (3H, t,> 7.3 Hz), 2.69 (2H, q,> 7.3 Hz), 3.91 (2H, s), 7, 49 (1H, dd,> 7.9, 7.6 Hz), 7.68 (1H, d,> 7.6 Hz), 8.11 (1H, d,> 7.9 Hz), 8.21 (1H, s)

Example 384

Synthesis of N- (3-nitrophenylmethyl) ethylcarbamic acid t-butyl ester

Using the compound obtained in Example 383 as the starting material, the procedure of Example 22 gave 1.94 g of the title compound (99% yield).

Ή-NMR (CDCl ₃ ) δ: 1.11 (3H, t,> 7.3Hz), 1.48 (9H, s), 3.20-3.40 (2H, m), 4.50 ( 2H, s), 7.50 (1H, t,> 8.3Hz), 7.55-7.60 (1H, m), 8.11 (1H, s), 8.12 (1H, d, > 7.6 Hz)

Example 385

Synthesis of N- (3-aminophenylmethyl) -ethylcarbamic acid t-butyl ester

Using the compound obtained in Example 384 as the starting material, according to the procedure in Example 2, 890 mg of the title compound were obtained in quantitative yield.

Ή-NMR (CDC1 ₃₎

146

183 619 δ: 1.06 (3Η, t,> 6.9 Hz), 1.47 (9H, s), 3.13-3.26 (2H, m), 3.64 (2H, s), 4.34 (2H, s), 6.55-6.65 (3H, m), 7.09 (1H, t, J = 7.9Hz)

Example 386

Synthesis of N- (3-thioureido) phenylmethyl) -ethylcarbamic acid 7-butyl ester

Using the compound obtained in Example 385 as the starting material, the procedure of Example 120 afforded 460 mg of the title compound (78% yield).

Ή-NMR (CDCl ₃ ) δ: 1.09 (3H, t,> 6.9 Hz), 1.47 (9H, s), 3.22-3.30 (2H, m), 4.42 ( 2H, s), 6.09 (2H, brs), 7.11 (1H, s), 7.12 (1H, d,> 5.9Hz), 7.19 (1H, d,> 7.6 Hz), 7.39 (1H, dd,> 7.6.5.9Hz), 7.92 (1H, brs)

Example 387

Synthesis of N- (3- (S-ethylisothioureido) phenylmethyl) ethylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 386 as the starting material, the procedure of Example 27 gave 155 mg of the title compound (49% yield).

Ή-NMR (CDCl3) δ: 1.06 (3H, t,> 6.9 Hz), 1.36 (3H, t,> 7.3 Hz), 1.47 (9H, s), 2.97 -3.12 (2H, m), 3.12-3.37 (2H, m), 4.39 (2H, s), 4.48 (1H, br s), 6.75-6.86 (2H , m), 6.90 (1H, d,> 7.3Hz), 7.25 (1H, dd,> 7.9, 7.3Hz)

Example 388

Synthesis of N- (3- (S-ethylisothioureido) phenylmethyl) ethylamine dihydrochloride

Using the compound obtained in Example 387 as the starting material, according to the procedure in Example 5, 162 mg of the title compound were obtained in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 1.26 (3H, t,> 6.9 Hz), 1.33 (3H, t,> 7.3 Hz), 2.90-3.01 (2H , m), 3.35 (2H, q,> 7.3Hz), 4.11 (2H, s), 7.35 (1H, d,> 6.9Hz), 7.50-7.66 (3H, m), 9.53 (2H, br s), 9.75 (1H, br s), 11.79 (1H, br s) MS (m / z) 237 (M ⁺ )

Example 389

Synthesis of N- (2-methoxy-5-nitrophenylmethyl) methyl-kaibamic acid t-butyl ester

5-nitro-2-benzyl bromide (1.04 g) was added to methylamine (like 40% MeOH solution, 50 mL) under ice-cooling, and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was processed as in Example 22 to give the title compound (39% yield).

Ή-NMR (CDCl 3) δ: 1.46 (9H, s), 2.92 (3H, s), 3.95 (3H, s), 4.44 (2H, s), 6.92 (1H, d,> 9.2Hz), 7.90-8.19 (2H, m)

Example 390

Synthesis of N- (5-amino-2-methoxyphenylmethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 389 as a starting material, according to the procedure in Example 2, 436 mg of the title compound were obtained in quantitative yield.

Ή-NMR (CDCl 3) δ: 1.46 (9H, s), 2.84 (3H, s), 3.41 (2H, s), 3.75 (3H, s), 4.39 (2H, s), 6.47-6.53 (1H, m), 6.56 (1H, dd,> 8.6, 2.3Hz), 6.70 (1H, d,> 8.6Hz)

Example 391

Synthesis of N- (5-N'-butoxycarbonyl-N-t-ethylguanidino) -2-methoxyphenylmethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 390 as a starting material, the procedure of Example 233 gave 75 mg of the title compound (65% yield).

Ή-NMR (CDCl 3) δ: 1.06 (3H, t,> 7.3 Hz), 1.47 (9H, s), 1.54 (9H, s), 2.87 (3H, s), 3.38 (2H, quintet,> 7.3Hz), 3.84 (3H, s), 4.42 (2H, s), 6.86 (1H, d,> 8.6Hz), 6, 97 (1H, s), 7.02-7.13 (1H, m), 10.47 (1H, brs)

183 619

147

Example 392

Synthesis of N- (5- (N'-ethylguandine) -2-methoxy) phenylmethyl) methylamine dihydrochloride

Using the compound obtained in Example 391 as a starting material, the procedure in Example 5 gave 42.6 mg of the title compound (91% yield)

Ή-NMR (DMSO-d ₆ ) δ: 1.15 (3H, t,> 6.9 Hz), 2.52-2.58 (3H, m), 3.20-3.38 (2H, m ), 3.87 (3H, s), 4.05-4.17 (2H, m), 7.15 (1H, d,> 8.3Hz), 7.27 (1H, d,> 8, 9 Hz), 7.36 (1H, s), 7.42-7.61 (1H, m), 7.66-7.81 (1H, m), 9.05 (1H, brs), 9, 60 (ΪΗ, brs)

MS (m / z) 236 (M ⁺ )

Example 393

Synthesis of N- (2-methoxy-5-thioureido) phenylmethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 390 as starting material, the procedure of Example 120 afforded 223 mg of the title compound (96% yield).

Ή-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.89 (3H, s), 3.85 (3H, s), 4.41 (2H, s), 5.98 (2H , brs), 6.88 (1H, d,> 8.6Hz), 7.01 (1H, s), 7.05-7.15 (1H, m), 7.71 (1H, s)

Example 394

Synthesis of N- (5- (S-ethylisothioureido) -2-methoxy) phenylmethyl) methyl carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 393 as starting material, the procedure of Example 27 gave 217 mg of the title compound (66% yield).

Ή-NMR (CDCl ₃ ) δ: 1.35 (3H, t,> 7.3 Hz), 1.45 (9H, s), 2.84 (3H, s), 2.92-3.10 ( 2H, m), 3.79 (3H, s), 4.41 (2H, s), 6.73-6.81 (3H, m)

Example 395

Synthesis of N- (5- (S-ethylisothioureido) -2-methoxy) phenylmethyl) methylamine dihydrochloride

Using the compound obtained in Example 394 as the starting material, the procedure in Example 5 gave 207.8 mg of the title compound in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 1.33 (3H, ζ> 7.3 Hz), 2.52-2.59 (3H, m), 3.22-3.36 (2H, m) , 3.89 (3Ή s), 4.034.18 (2H, m), 7.20 (1H, d,> 8.6Hz), 7.37 (1H, d,> 8.6Hz), 7. 47 (1H, s), 9.08 (2H, brs), 9.57 (1H, brs), 11.45 (1H, bis)

MS (m / z) 253 (M ⁺ )

Example 396

Synthesis of N- (2-methoxy-5-nitrophenylmethyl) dimethylamine

Using 5-nitro-2-benzyl bromide as the starting material, 3.4 g of the title compound were obtained according to the procedure in Example 37 (82% yield).

Ή-NMR (CDCl ₃ ) δ: 2.29 (6H, s), 3.47 (2H, s), 3.94 (3H, s), 6.92 (1H, d,> 8.9 Hz) , 8.17 (1H, dd,> 8.9.3.0Hz), 8.23 (1H, d,> 3.0Hz)

Example 397

Synthesis of N- (5-amino-5 -2-methoxy phenylmethyl) dimethylamine

Using the compound obtained in Example 396 as the starting material, the procedure of Example 2 gave 1.05 g of the title compound (yield 37%).

Ή-NMR (CDCl ₃ ) δ: 2.26 (6H, s), 3.39 (4H, s), 3.76 (3H, s), 6.58 (1H, dd,> 8.6, 3 , 0 Hz), 6.71 (1H, d,> 8.6 Hz), 6.72 (1H, d,> 3.0 Hz).

Example 398

Synthesis of N- (5- (N'-t-butoxycarbonyl-N'-ethylguanidino) -2-methoxyphenylmethyl) dimethylamine

Using the compound obtained in Example 397 as the starting material, the procedure of Example 233 gave 44 mg of the title compound (45% yield).

148

183 619

Ή-NMR (CDCl ₃ ) δ: 1.02-1.15 (3H, m), 1.53 (9H, s), 2.35 (6H, s), 3.39-3.48 (2H, m), 3.49 (2H, s), 3.85 (3H, s), 6.87 (1H, d,> 8.3Hz), 7.05-7.26 (2H, s)

Example 399

Synthesis of N- (5- (N'-ethylguanidino) -2-methoxy) -phenylmethyl) dimethylamine dihydrochloride

Using the compound obtained in Example 398 as the starting material, the procedure of Example 5 gave 44 mg of the title compound in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 1.15 (3H, t, J = 6.9 Hz), 2.73 (6H, d, J = 5.0Hz), 3.29 (2H, quintet, > 6.9Hz), 3.88 (3H, s), 4.25 (2H, d,> 5.0Hz), 7.18 (1H, d,> 8.9Hz), 7.31 ( 1H, dd,> 8.9, 1.9Hz), 7.44 (1H, d,> 1.9Hz), 7.60 (1H, brs), 7.78-7.99 (1H, m ), 9.65 (1H, brs), 10.41 (1H, brs)

MS (m / z) 250 (M ⁺ )

Example 400

Synthesis of N- (2-methoxy-5-thioureido) phenylmethyl) dimethylamine

Using the compound obtained in Example 397 as a starting material, the procedure of Example 40 gave 410 mg of the title compound (62% yield).

Ή-NMR (CDCl ₃ ) δ: 2.26 (6H, s), 3.43 (2H, s), 3.85 (3H, s), 6.00 (2H, brs), 6.88 (1H , d,> 8.6 Hz), 7.17 (1H, dd,> 8.6, 2.6 Hz), 7.23 (1H, d,> 2.6 Hz), 7.77 (1H, brs)

Example 401

Synthesis of N- (5- (S-ethylisothioureido) -2-methoxy) -phenylmethyl) dimethylamine dihydrochloride

Using the compound obtained in Example 400 as a starting material according to the procedure of Example 380, 69.5 mg of the title compound were obtained (98% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.33 (3H, t,> 7.3Hz), 2.73 (6H, d,> 5.0Hz), 3.28-3.42 (2H, m), 3.89 (3H, s), 4.26 (2H, d,> 5.0Hz), 7.24 (1H, d,> 8.6Hz), 7.38-7.44 ( 1H, m), 7.57-7.60 (1H, m), 9.27 (1H, brs), 9.65 (1H, brs), 10.61 (1H, brs), 11.58 (1H , brs)

MS (m / z) 267 (M ⁺ )

Example 402

Synthesis of N- (3-nitrophenes binethyl) benzylamine

Benzyl bromide (495 mg) was added dropwise under ice cooling to a solution of m-nitrobenzyl bromide (1.0 g) and diisopropylethylamine (1.19 g) in methanol (50 ml). The reaction mixture was stirred at room temperature for 3 days and, after adding water, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 4: 1) to give 555 mg of the title compound (50% yield).

Ή-NMR (CDCl ₃ ) δ: 3.83 (2H, s), 3.91 (2H, s), 7.23-7.38 (5H, m), 7.49 (1H, t,> 7 , 9 Hz), 7.70 (1H, d,> 7.9 Hz), 8.07-8.14 (1H, m), 8.21 (1H, s)

Example 403

Synthesis of N- (3-aminophenylmethyl) -benzylcarbamic acid t-butyl ester

Using the compound obtained in Example 402 as a starting material, processing was performed as in Example 22 and the resulting compound was subsequently subjected to the same reaction as in Example 2 to give 517 mg of the title compound (73% yield).

Ή-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 3.65 (2H, brs), 4.25-4.43 (4H, m), 6.50-6.63 (3H, m), 7.11 (1H, t,> 7.9Hz), 7.20-7.40 (5H, m)

183 619

149

Example 404

Synthesis of N- (3-thioureidophenylmethyl) -benzylcarbamic acid t-butyl ester

Using the compound obtained in Example 403 as the starting material, the procedure of Example 120 afforded 223 mg of the title compound (97% yield).

1 H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 4.41 (4H, brs), 6.16 (2H, brs), 7.02-7.23 (5H, m), 7.26-7.41 (4H, m), 8.29 (1H, brs)

Example 405

Synthesis of N- (3- (S-ethylisothioureido) phenylmethyl) benzylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 404 as starting material, the procedure of Example 27 gave 205 mg of the title compound (66% yield).

Ή-NMR (CDCl 3) δ: 1.37 (3H, t, J = 6.9 Hz), 1.49 (9H, s), 3.00-3.12 (2H, m), 4.25- 4.48 (4H, m), 6.75-6.90 (2H, m), 7.18-7.38 (7H, m)

Example 406

Synthesis of N- (3- (S-ethylisothioureido) phenylmethyl) benzylamine dihydrochloride

Using the compound obtained in Example 405 as the starting material, the procedure of Example 5 gave 176 mg of the title compound in quantitative yield.

1 H-NMR (DMSO-d ₆ ) δ: 1.35 (3H, t, J = 6.9 Hz), 3.30-3.42 (2H, m), 4.17-4.26 (4H , m), 7.38-7.65 (9H, m), 9.46 (1H, brs), 9.78 (1H, brs), 10.02 (1H, brs) 11.80 (1H, brs )

MS (m / z) 299 (M ⁺ )

Example 407

Synthesis of N- (2-methyl-3-nitrophenylmethyl) methylcarbamic acid t-butyl ester

Using 2-methyl-3-nitrobenzyl bromide as starting material, the procedure of Example 389 gave 900 mg of the title compound (74% yield).

1 H-NMR (CDCl 3) δ: 1.47 (9H, s), 2.38 (3H, s), 2.83 (3H, s), 4.51 (2H, s), 7.30-7 . 34 (2H, m), 7.65-7.69 (1H, m)

Example 408

Synthesis of N- (3-amino-2-methyl) phenylmethyl) methyl carbamic acid t-butyl ester

Using the compound obtained in Example 407 as a starting material, according to the procedure in Example 2, 805 mg of the title compound were obtained in quantitative yield.

1 H-NMR (CDCl 3) δ: 1.48 (9H, s), 2.08 (3H, s), 2.73 (3H, s), 3.62 (2H, br s), 4.44 (2H , s), 6.59 (1H,> 7.6 Hz),

6.64 (1H, d,> 7.6 Hz), 6.99 (1H, t,> 7.6 Hz)

Example 409

Synthesis of N- (2-methyl-3-thioureidophenylmethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 408 as starting material, the procedure of Example 120 afforded 225 mg of the title compound (91% yield).

1 H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.23 (3H, s), 2.84 (3H, s), 4.46 (2H, s), 5.79 ( 2H, brs), 7.17 (1H, dd,> 6.9,

6.6Hz), 7.23-7.32 (2H, m), 7.56 (1H, brs)

Example 410

Synthesis of N- (3- (S-ethylisothioureido) -2-methylphenylmethyl) methylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 409 as starting material, the procedure of Example 27 gave 114 mg of the title compound (76% yield).

1 H-NMR (CDCl 3) δ: 1.39 (3H, t,> 7.6 Hz), 1.47 (9H, s), 2.07 (3H, s), 2.78 (3H, s) , 3.02-3.18 (2H, m), 4.35 (1H, brs), 4.45 (2H, s), 6.75 (1H, d,> 7.3Hz), 6.82 (1H, d,> 7.6Hz), 7.11 (1H, dd,> 7.6.7.3Hz)

150

183 619

Example 411

Synthesis of N- (3- (S-ethylisothioureido) -2-methylphenylmethyl) methylamine dihydrochloride

Using the compound obtained in Example 410 as the starting material, the procedure of Example 5 gave 128 mg of the title compound in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 1.34 (3H, t,> 6.9 Hz), 2.27 (3H, s), 2.60-2.65 (3H, m), 3, 25-3.35 (2H, m), 4.20-4.27 (2H, m), 7.31 (1H, d,> 7.6 Hz), 7.41 (1H, dd,> 7, 6.7.3Hz), 7.60 (1H, d,> 7.3Hz), 9.23 (2H, brs), 9.45-9.60 (1H, m), 11.46 (1H , brs)

MS (m / z) 238 (M ⁺ + 1)

Example 412

Synthesis of N- (3- (N'-t-butoxycarbonyl-N'-ethylguanidino) -2-methyl) phenylmethyl) methylcarbamic acid t-butyl ester

Using the compound obtained in Example 408 as starting material, the procedure of Example 233 gave 43 mg of the title compound (53% yield).

Ή-NMR (CDCl ₃ ) δ: 1.01-1.18 (3H, m), 1.48 (9H, s), 1.54 (9H, s), 2.18 (3H, s), 2 . 81 (3H, s), 3.38-3.42 (2H, m), 4.45 (1H, s), 7.05-7.26 (3H, m), 10.56 (1H, brs )

Example 413

Synthesis of N- (3- (N'-ethylguanidino) -2-methylphenylmethyl) methylamine dihydrochloride

Using the compound obtained in Example 412 as the starting material, the procedure of Example 5 gave 30.5 mg of the title compound in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 1.15 (3H, t,> 7.3 Hz), 2.28 (3H, s), 2.63 (3H, t,> 5.0 Hz), 3.22-3.35 (2H, m), 4.19 (2H, t,> 5.6Hz), 7.26 (1H, d,> 7.6Hz), 7.35 (1H, dd ,> 7.6, 7.3Hz), 7.45 (1H, brs), 7.52 (1H, d,> 7.3Hz), 7.61-7.72 (1H, m), 9 , 21 (2H, brs), 9.55 (1H, brs)

MS (m / z) 20 (M ⁺ )

Example 414

Synthesis of N- (2-methyl-3-thioureido) phenylmethyl) dimethylamine

Using N- (3-amino-2-methylphenylmethyl) dimethylamine as the starting material, the procedure of Example 40 gave 355 mg of the title compound (56% yield).

Ή-NMR (CDCl ₃ ) δ: 2.25 (6H, s), 3.32 (3H, s), 3.40 (2H, s), 5.81 (2H, brs), 7.14-7 , 32 (3H, m), 7.53-, 7.72 (1H, m)

Example 415

Synthesis of N- (3- (S-ethylisothioureido) -2-methylphenyl) dimethylamine dihydrochloride

Using the compound obtained in Example 414 as starting material, the procedure of Example 380 afforded 108 mg of the title compound (83% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.34 (3H, t,> 7.3 Hz), 2.31 (SH, s), 2.77 (6H, d,> 4.0 Hz), 3.28-3.40 (2H, m), 4.40 (2H, d,> 5.3Hz), 7.35-7.46 (2H, m), 7.72 (1H, d,> 6.9Hz), 9.56 (1H, brs), 10.66 (1H, brs), 11.49 (1H, brs)

MS (m / z) 252 (M ⁺ + 1)

Example 416

Synthesis-N- (3- (N'-t-butoxycarbonyl-N'-ethylguanidino) -2-methylphenylmethyl) dimethylamine

Using N- (3-amino-2-methylphenylmethyl) dimethylamine as the starting material, the procedure of Example 233 gave 46 mg of the title compound (45% yield).

¹ H-NMR- (CDCl ₃ ) β: 1.00-1.08 (3H, m), 1.52 (9H, s), 2.26 (9H, s), 3.33-3.43 ( 2H, m), 3.42 (2H, s), 4.30 (1H, brs), 7.02-7.20 (3H, m), 10.57 (1H, brs)

183 619

151

Example 417

Synthesis of N- (3- (N ^/ -ethylguanidino) -2-methylphenylmethyl) dimethylamine dihydrochloride

Using the compound obtained in Example 416 as a starting material, the procedure of Example 5 gave 37.3 mg of the title compound (92% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.15 (3H, t,> 7.3 Hz), 2.32 (3H, s), 2.77 (6H, d,> 4.0 Hz), 3.23-3.35 (2H, m), 4.38 (2H, d,> 5.3Hz), 7.29 (1H, d,> 7.6Hz), 7.37 (1H, dd > 7.9, 7.6Hz), 7.53 (1H, brs), 7.64 (1H, d,> 7.9Hz), 7.70-7.86 (1H, m), 9 , 67 (1H, brs), 10.7 (1H, brs)

MS (m / z) 435 (M ⁺ + 1)

Example 418

Synthesis of 2-methoxy-3-nitrobenzyl alcohol

A mixture of 2-methoxy-3-nitrobenzoic acid methyl ester (4.82 g), lithium borohydride (298 mg), trimethyl borate (0.27 ml) and anhydrous tetreahydrofuran (200 ml) was heated to reflux for 5 hours. The reaction mixture was distilled under reduced pressure, and ethyl and water were added to the obtained residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 1: 1) to obtain 3.18 g of the title compound (76% yield).

Ή-NMR (CDCl ₃ ) δ: 2.08 (1H, t,> 5.6 Hz), 3.94 (3H, s), 4.81 (2H, d,> 5.6 Hz), 7, 23 (1H, t,> 7.9Hz), 7.69 (1H, d,> 7.9Hz), 7.79 (1H, d,> 7.9Hz)

Example 419

Synthesis of 2-methoxy-3-nitrobenzyl bromide

Using the compound obtained in Example 418 as a starting material, the procedure of Example 55 gave the title compound in quantitative yield.

Ή-NMR (CDCl 3) δ: 4.03 (3H, s), 4.57 (2H, s), 7.21 (1H, t,> 7.9 Hz), 7.65 (1H, dd,> 7.9.1.6Hz), 7.81 (1H, dd,> 7.9,1.6Hz)

Example 420

Synthesis of N- (2-methoxy-3-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 419 as the starting material, the procedure of Example 127 gave the title compound (64% yield).

Ή-NMR (CDCl 3) δ: 1.46 (18H, s), 3.92 (3H, s), 4.91 (2H, s), 7.19 (1H, t,> 7.9Hz), 7.41 (1H, d,> 7.9Hz), 7.74 (1H, d,> 7.9Hz)

Example 421

Synthesis of N- (3-amino-2-methoxyphenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 420 as the starting material, the title compound was obtained according to the procedure in Example 2 (yield 94%).

Ή-NMR (CDCl 3) δ: 1.44 (18H, s), 3.75 (3H, s), 4.85 (2H, s), 6.54 (1H, d,> 7.3Hz), 6.64 (1H, d,> 7.3Hz), 6.87 (1H, t,> 7.3Hz)

Example 422

Synthesis of N- (2-methoxy-3-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 421 as a starting material, the procedure of Example 120 gave the title compound (98% yield).

Ή-NMR (CDCl ₃ ) δ: 1.46 (18H, s), 3.83 (3H, s), 4.86 (2H, s), 6.29 (2H, brs), 7.11-7 . 20 (3H, m), 7.88 (1H, brs)

152

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Example 423

Synthesis of N- (3- (S-ethylisothioureido) -2-methoxyphenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 422 as starting material, the procedure of Example 95 gave the title compound (86% yield).

Ή-NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 6.9 Hz), 1.45 (9H, s), 3.08-3.18 (2H, m), 3.77 (3H, s), 4.31-4.32 (2H, m), 4.54 (2H, brs), 4.98 (1H, brs), 6.80-7.01 (3H, m)

Example 424

Synthesis of N- (2- (S-ethylisothioureido) -2-methoxy) -phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 423 as the starting material, the procedure of Example 5 gave the title compound (88% yield).

Ή-NMR (D ₂ O) δ: 1.43 (3H, t, J = 7.3 Hz), 3.27 (2H, q, J = 7.3 Hz), 3.87 (3H, s) , 4.28 (2H, s), 7.35 (1H, t, J = 7.9Hz), 7.45 (1H, dd, J = 7.9.2.0Hz), 7.54 ( 1H, dd, J = 7.9.2.0Hz)

Example 425

Synthesis of N- (3- (N'-t-butoxycarbonyl-N-ethylguanidino) -methoxyphenylmethyl) -iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 421 as the starting material, the title compound was obtained according to the procedure of Example 233 (50% yield).

Ή-NMR (CDCl ₃ ) δ: 1.45 (27H, s), 1.48-1.58 (3H, m), 3.38-3.48 (2H, m), 3.78 (3H, s), 4.86 (2H, s), 7.00-7.25 (3H, m)

Example 426

Synthesis of N- (3 - (Ν'-ethyl loguanidino) -2-methoxyphene binethyl) amine dihydrochloride

Using the compound obtained in Example 425 as a starting material, the procedure of Example 5 gave the title compound (93% yield).

1 H-NMR (D ₂ O) δ: 1.23 (3H, t, J = 7.3 Hz), 3.34 (2H, q, J = 7.3 Hz), 3.87 (3H, s ), 4.25 (2H, s), 7.29 (1H, t, J = 7.6 Hz), 7.39-7.49 (2H, m)

Example 427

Synthesis of N- (3-methyl-5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using 3-methyl-5-nitrobenzyl bromide as starting material, the procedure of Example 127 gave the title compound (92% yield).

Ή-NMR (CDCl ₃ ) δ: 1.49 (18H, s), 2.44 (3H, s), 4.82 (2H, s), 7.44 (1H, s), 7.94 (1H , s), 7.98 (1H, s)

Example 428

Synthesis of N- (5-amino-3-methylphenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 427 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 89%).

Ή-NMR (CDCl ₃ ) δ: 1.46 (18H, s), 2.23 (3H, s), 3.56 (2H, brs), 4.65 (2H, s), 6.39 (1H , s), 6.41 (IH, s), 6.49 (IH, s)

Example 429

Synthesis of N- (3-methyl-5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 428 as a starting material, the procedure of Example 120 afforded the title compound in quantitative yield.

Ή-NMR (CDC1 ₃₎

183 619

153 δ: 1.48 (18Η, s), 2.34 (3Η, s), 4.74 (2H, s), 6.10 (2H, brs), 6.91 (1H, s), 6, 96 (1H, s), 7.06 (1H, s), 7.84 (1H, br s)

Example 430

Synthesis of N- (5- (S-ethylisothioureido) -3-methylphenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 429 as starting material, the procedure of Example 95 gave the title compound (70% yield).

Ή-NMR (CDCl ₃ ) δ: 1.36 (3H, t,> 7.3Hz), 1.46 (9H, s), 2.30 (3H, s), 2.95-3.10 ( 2H, m), 4.24 (2H, d,> 5.6Hz), 4.49 (1H, brs), 4.80 (1H, brs), 6.64 (2H, s), 6.76 (1H, s)

Example 431

Synthesis of N- (5- (S-ethylisothioureido) -3-methylphenylmethyl) amine dihydrochloride

Using the compound obtained in Example 430 as starting material, the title compound was obtained according to the procedure in Example 5 (yield 70%)

Ή-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.3 Hz), 2.40 (3H, s), 3.23 (2H, q,> 7.3 Hz), 4 . 20 (2H, s), 7.23 (1H, s), 7.28 (1H, s), 7.37 (1H, s)

Example 432

Synthesis of N- (5- (N'-t-butoxycarbonyl-N * -ethylguanidino) -3-methylphenylmethyl) -iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 428 as the starting material following the procedure in Example 233 afforded the title compound (64% yield)

Ή-NMR (CDCl ₃ ) δ: 1.01-1.15 (3H, m), 1.47 (27H, s), 2.32 (3H, s), 3.34-3.45- (2H , m), 4.72 (2H, s), 6.82-7.00 (3H, m)

Example 433

Synthesis of dihydrochloride N- (5- (N'-ethylguanidino) -3-methoxyphenylmethyl) amine

Using the compound obtained in Example 432 as the starting material, the title compound was obtained according to the procedure in Example 5 (yield 80%).

Ή-NMR (D ₂ O) δ: 1.22 (3H, t,> 7.3 Hz), 2.3 8 (3H, s), 3.32 (2H, q,> 7.3 Hz), 4.17 (2H, s), 7.15 (1H, s), 7.20 (1H, s) (7.26 (1H, s)

Example 434

Synthesis of N- (2-benzylamino-5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 263 as the starting material and also using benzylamine as a reagent, the procedure of Example 264 gave the title compound (71% yield).

Ή-NMR (CDCl ₃ ) δ: 1.46 (18H, s), 4.45-4.48 (2H, m), 4.75 (2H, s), 6.42-6.55 (1H, m), 7.13-7.39 (5H, m), 7.97-8.09 (1H, m), 8.17-8.23 (1H, m)

Example 435

Synthesis of N- (5-amino-2-benzylamphenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 434 as a starting material, the title compound was obtained according to the procedure in Example 2 (yield 32%).

Ή-NMR (CDCl ₃ ) δ: 1.44 (18H, s), 4.31 (2H, s), 4.69 (2H, s), 6.43 (1H, d,> 8.3 Hz) , 6.52 (1H, d,> 8.3Hz), 6.68 (1H, s), 7.19-7.40 (5H, m)

154

183 619

Example 436

Synthesis of N- (2-benzylamino-5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 435 as a starting material, the procedure of Example 120 gave the title compound (32% yield).

Ή-NMR (CDCl ₃ ) δ: 1.45 (18H, s), 4.39 (2H, d,> 5.6 Hz), 4.70 (2H, s), 5.91 (2H, brs) , 6.10 (1H, t,> 5.6 Hz), 6.50 (1H, d,> 8.6 Hz), 6.90-6.94 (1H, m), 7.13-7, 14 (1H, m), 7.25-7.34 (5H, m), 7.55 (1H, brs)

Example 437

Synthesis of N- (2-benzylamino-5- (S-ethylisothioureido) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 436 as a starting material, the procedure of Example 95 gave the title compound (48% yield).

Ή-NMR (CDCl ₃ ) δ: 1.34 (3H, t,> 7.3 Hz), 1.40 (9H, s), 3.00 (2H, q,> 7.3 Hz), 4, 25 (2H, d,> 6.3Hz), 4.3O (2H, s), 4.83 (1H, brs), 5.16 (1H, brs), 6.50-6.54 (1H, m), 6.60-6.75 (2H, m), 7.20-7.39 (5H, m)

Example 438

Synthesis of N- (2-benzylamino-5- (S-ethylisothioureido) phenylmethyl) amine trihydrochloride

Using the compound obtained in Example 437 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 99%).

Ή-NMR (D ₂ O) δ: 1.40 (3H, t,> 7.3 Hz), 3.20 (2H, q,> 7.3 Hz), 4.21 (2H, s), 4 , 53 (2H, s), 6.88 (1H, d,> 8.6 Hz), 7.20 (1H, dd,> 8.6, 2.6 Hz), 7.26 (1H, d, > 2.6 Hz)

Example 439

Synthesis of N- (2-benzylamino-5- (N'-t-butoxycarbonyl-N * -ethylguanidino) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 435 as the starting material, the title compound was obtained according to the procedure of Example 233 (yield 54%).

Ή-NMR (CDCl3) δ 1.04 (3H, t,> 7.3Hz), 1.44 (18H, s), 1.52 (9H, s), 3.30-3.41 (2H, m), 4.38 (2H, d,> 4.6Hz), 4.53 (1H, brs), 4.69 (2H, s), 5.87 (1H, brs), 6.51 (1H , d,> 8.6 Hz), 6.86-6.94 (1H, m), 7.08-7.13 (1H, m), 7.32-7.35 (5H, m)

Example 440

Synthesis of N- (2-benzylamino-5- (N'-ethylguanidino) phenylmethyl) amine trihydrochloride

Using the compound obtained in Example 439 as starting material, the title compound was obtained according to the procedure in Example 5 (yield 89%).

Ή-NMR (D ₂ O) δ: 1.19 (3H, t,> 7.3 Hz), 3.28 (2H, q,> 7.3 Hz), 4.16 (2H, s), 4 , 52 (2H, s), 6.90 (1H, d,> 8.6Hz), 7.16-7.24 (2H, m), 7.32-7.48 (5H, m)

Example 441

Synthesis of N- (2- (2-t-butoxycarbonylaminoethyl) phenyl) amidinesulfonic acid

By using the compound obtained in Example 331 as the starting material the title compound was obtained according to the procedure of Example 277 (86% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.36 (9H, s), 2.64 (2H, t,> 6.9 Hz), 3.16 (2H, dt,> 5.3.6, 9 Hz), 6.72 (1H, t,> 5.3 Hz), 7.12-7.20 (1H, m), 7.28-7.40 (3H, m), 9.48 (1H , brs), 11.29 (1H, brs)

Example 442

Synthesis of N- (2- (N'-ethylguanidino) -phenylethyl) carbamic acid t-butyl ester

By using the compound obtained in Example 441 as the starting material and also using ethylamine hydrochloride as a reagent, the procedure of Example 302 gave the title compound in quantitative yield.

Ή-NMR (CDC1 ₃₎

183 619

155

b. 1.22 (3H, t,> 7.3Hz), 1.36 (9H, s), 2.75 (2H, t, J = 6.3Hz) 3.28-3.37 (4H , m), 3.99 (2H, brs), 5.89 (1H, brs), 6.91-7.03 (2H, m), 7.13-7.19 (2H, m)

Example 443

Synthesis of N- (2- (N'-ethylguanidino) phenylethyl) amine dihydrochloride

Using the compound obtained in Example 442 as the starting material, the title compound was obtained according to the procedure in Example 5 (yield 90%).

Ή-NMR (D ₂ O) δ: 1.21 (3H, t,> 7.3 Hz), 3.01 (2H, t,> 7.6 Hz), 3.19-3.37 (4H, m), 7.32-7.50 (4H, m)

Example 444

Synthesis of N- (5- (N'-t-butoxycarbonyl-N-ethylguanidino) -2-fluorophenylmethyl) -iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 314 as a starting material, the title compound was obtained according to the procedure in Example 233 (70% yield).

Ή-NMR (CDCl ₃ ) δ: 1.03-1.08 (3H, m), 1.47 (27H, s), 3.15-3.22 (2H, m), 4.83 (2H, s), 6.99-7.15 (3H, m)

Example 445

Synthesis of N- (5- (N'-ethylguanidino) -2-fluorophenylmethyl) amine dihydrochloride

Using the compound obtained in Example 444 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 90%).

Ή-NMR (D ₂ O) δ: 1.22 (3H, t,> 7.3 Hz), 3.31 (2H, q,> 7.3 Hz), 4.27 (2H, s), 7 . 28-7.46 (3H, m)

Example 446

Synthesis of N- (2-methylamino-5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 263 as the starting material and also using methylamine hydrochloride as reagent, the procedure of Example 264 provided the title compound (99% yield).

Ή-NMR (CDCl 3) δ: 1.50 (18H, s), 2.92 (3H, d,> 4.9 Hz), 4.68 (2H, s), 6.50 (IH, d,> 9.3 Hz), 6.72 (IH, brs), 8.08-8.15 (2H, m)

Example 447

Synthesis of N- (5-amino-2-methylaminophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 446 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 61%).

Ή-NMR (CDCl3) δ: 1.46 (18H, s), 2.78 (3H, s), 3.60 (2H, brs), 4.63 (2H, s), 6.45-6, 68 (3H, m)

MS (m / z) 351 (M ⁺ )

Example 448

Synthesis of N - ^ - CNT-t-butoxycarbonyl-Nf-ethylguanidino) -2-methylaminophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 447 as starting material, the title compound was obtained according to the procedure of Example 233 (47% yield).

Ή-NMR (CDCl3) δ: 1.05 (3H, t,> 7.3Hz), 1.47-1.53 (27H, m), 2.84 (3H, s), 3.35-3 , 39 (2H, m), 4.63 (2H, s), 5.30 (IH, brs), 6.55 (IH, d,> 8.6Hz), 6.99-7.07 (2H , m), 10.39 (IH, brs)

Example 449

Synthesis of N- (5- (N'-ethylguanidino) -2-methylaminophenylmethyl) amine trihydrochloride

Using the compound obtained in Example 448 as the starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.25 (3H, t,> 7.3 Hz), 3.10 (3H, s), 3.35 (2H, q,> 7.3 Hz), 4 . 36 (2H, s), 7.50-7.51 (3H, m)

156

183 619

MS (m / z) 221 (M ⁺ )

Example 450

Synthesis of N- (2-methylamino-5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 447 as starting material, the title compound was obtained according to the procedure of Example 120 (yield 61%).

1 H-NMR (CDCl ₃ ) δ: 1.48 (18H, s), 2.84 (3H, d,> 3.5Hz), 4.63 (2H, s), 5.50 (2H, brs ), 6.50 (1H, d,> 8.6Hz), 7.04 (1H, dd,> 8.6, 2.7Hz), 7.12 (1H, d,> 2.7Hz) . 7.99 (1H, brs)

MS (m / z) 410 (M ⁺ )

Example 451

Synthesis of N- (5- (S-ethylisothioureido) -2-methylaminophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 450 as a starting material following the procedure of Example 95 afforded the title compound (61% yield). 1 H-NMR (CDCl ₃ ) δ: 1.31 (3H, t,> 7.3 Hz), 1.47 (18H, s), 2.82 (3H, s), 3.01 (2H, q,> 7.3Hz), 4.64 (2H, s), 6.55 (1H, d,> 7, 6Hz), 6.81-6.88 (2H, m)

MS (m / z) 438 (M ⁺ )

Example 452

Synthesis of N- (5- (S-ethylisothioureido) -2-methylaminophenylmethyl) amine trihydrochloride

Using the compound obtained in Example 451 as the starting material, the procedure of Example 5 gave the title compound in quantitative yield.

1 H-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.3 Hz), 3.04 (3H, s), 3.25 (2H, q,> 7.3 Hz), 4.32 (2H, s), 7.40 (1H, d,> 8.6Hz), 7.49-7.55 (2H, m)

MS (m / z) 238 (M ⁺ )

Example 453

Synthesis of N- (2-ethylamino-5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as a starting material and also using ethylamine hydrochloride as reagent, the procedure of Example 264 provided the title compound (52% yield). 'H-NMR (CDCl ₃ ) δ: 1.33 (3H, t,> 7, 3 Hz), 1.50 (18H, s), 3.14-3.34 (2H, m), 5.37 (2H, s), 6.52 (1H, d,> 8.0Hz), 6.65 (1H, brs), 8.05-8.25 (2H, m)

MS (m / z) 395 (M ⁺ )

Example 454

Synthesis of N- (5-amino-2-ethylaminophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 453 as a starting material, the title compound was obtained according to the procedure in Example 2 (yield 71%).

1 H-NMR (CDCl ₃ ) δ: 1.25 (3H, t,> 7.3 Hz), 1.46 (18H, s), 3.07 (2H, q,> 7.3 Hz), 3 . 55 (2H, brs), 4.64 (2H, s), 6.46-6.67 (3H, m)

MS (m / z) 365 (M ⁺ )

Example 455

Synthesis of N- (5- (N'-t-butoxycarbonyl-N'-ethylguanidino) -2-ethylaminophenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 454 as the starting material, the title compound was obtained according to the procedure of Example 233 (50% yield).

H-NMR (CDC1 ₃₎

183 619

157 δ: 1.30 (3Η, t,> 7.2Hz), 1.43-1.53 (30H, m), 3.11-3.17 (2H, m), 3.34-3, 40 (2H, m), 4.45 (1H, brs), 4.64 (2H, s), 5.29 (1H, brs), 6.55 (1H, d, J = 8.5Hz), 6.98 (1H, dd,> 8.5, 2.7Hz), 7.07 (1H, d,> 2.7Hz)

Example 456

Synthesis of N- (2-ethylamino-5- (N'-ethylguanidino) phenylmethyl) amine trihydrochloride

Using the compound obtained in Example 455 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 89%).

Ή-NMR (D ₂ O) δ: 1.24 (3H, t,> 7.3 Hz), 1.36 (3H, t,> 7.3 Hz), 3.34 (2H, q,> 7 , 3Hz), 3.48 (2H, q,> 7.3Hz), 4.44 (2H, s), 7.50-7.52 (3H, m)

MS (m / z) 235 (M ⁺ )

Example 457

Synthesis of N- (2-ethylamino-5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 454 as a starting material, the procedure of Example 120 gave the title compound (55% yield).

Ή-NMR (CDCl ₃ ) δ: 1.29 (3H, t,> 7.3 Hz), 1.47 (18H, s), 3.14 (2H, q,> 7.3 Hz), 4, 64 (2H, s), 5.90 (2H, brs), 6.56 (1H, d,> 8.6Hz), 6.98-7.12 (2H, m), 7.55 (1H, brs)

MS (m / z) 424 (M ⁺ )

Example 458

Synthesis of N- (2-ethylamino-5- (S-ethylisothioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 457 as the starting material, the procedure of Example 95 gave the title compound (60% yield).

Ή-NMR (CDCl3) δ: 1.28 (3H, t,> 7.3Hz), 1.34 (3H, t,> 7.3Hz), 1.47 (18H, s), 3.01 (2H, q,> 7.3Hz), 3.12 (2H, q,> 7.3Hz), 4.66 (1H, d,> 8.3Hz), 6.55 (1H, d, > 8.3Hz), 6.79 (1H, dd,> 8.3, 2.4Hz), 6.86 (1H, d,> 2.4Hz)

Example 459

MS (m / z) 453 (M ⁺ + 1)

Synthesis of N- (2-ethylamino-5- (S-ethylisothioureido) phenylmethyl) amine trihydrochloride

Using the compound obtained in Example 458 as a starting material, the procedure of Example 5 gave the title compound (63% yield).

Ή-NMR (D ₂ O) δ: 1.31 (3H, t,> 7.3 Hz), 1.41 (3H, t,> 7.3 Hz), 3.23 (2H, q,> 7 , 3 Hz), 3.32-3.42 (2H, m), 4.28 (2H, s), 7.30-7.49 (3H, m)

MS (m / z) 252 (M ⁺ )

Example 460

Synthesis of N- (2-ethyl-5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using 3-chloromethyl-4-ethylnitrobenzene as the starting material, the procedure of Example 127 afforded the title compound (72% yield).

Ή-NMR (CDCl3) δ: 1.28 (3H, t,> 7.4 Hz), 1.49 (18H, s), 2.76 (2H, q,> 7.4 Hz), 4.88 (2H, s), 7.33 (1H, d,> 8.3Hz), 7.99-8.10 (2H, m)

Example 461

Synthesis of N- (5-amino-2-ethylphenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 460 as a starting material, the procedure of Example 2 gave the title compound (99% yield).

Ή-NMR (CDC1 ₃₎

158

183 619 δ: 1.16 (3Η, t,> 7.3 Hz), 1.44 (18H, s), 2.54 (2H, q,> 7.3 Hz), 4.77 (2H, brs ), 6.45-6.60 (2H, m), 6.95 (1H, d,> 8.3Hz)

MS (m / z) 350 (M ⁺ )

Example 462

Synthesis of N- (2-ethyl-5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 461 as the starting material, the procedure of Example 120 gave the title compound (87% yield).

H-NMR (CDC1 ₃₎

6: 1.23 (3H, t,> 7.5Hz), 1.47 (18H, s), 2.65 (2H, q,> 7.5Hz), 4.81 (2H, s), 6.11 (2H, brs), 7.00 (1H, d,> 1.8 Hz), 7.04 (1H, dd,> 8.0, 1.8 Hz), 7.23 (1H, d > 8.0 Hz), 7.99 (1H, brs)

Example 463

Synthesis of N- (5- (S-ethylisothioureido) -2-ethylphenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 462 as the starting material, the procedure of Example 95 gave the title compound (76% yield).

1 H-NMR (CDCl 3) δ: 1.19 (3H, t,> 7.3Hz), 1.28-1.34 (3H, m), 1.43 (18H, s), 2.61 ( 2H, q,> 7.3Hz), 3.00-3.10 (2H, m), 4.80 (2H, s), 6.67-7.10 (3H, m)

MS (m / z) 437 (M ⁺ )

Example 464

Synthesis of N- (5- (S-ethylisothioureido) -2-ethylphenylmethyl) amine dihydrochloride

Using the compound obtained in Example 463 as starting material, the title compound was obtained according to the procedure in Example 5 (yield 77%).

1 H-NMR (D ₂ O) δ: 1.23 (3H, t,> 7.4Hz), 1.42 (3H, t,> 7.4Hz), 2.74 (2H, q,> 7.4Hz), 3.25 (2H, q,> 7.4Hz), 4.29 (2H, s), 7.34-7.41 (2H, m), 7.52 (1H, d > 8.2 Hz),

MZ (m / z) 237 (M ⁺ )

Example 465

Synthesis of N- (5- (N'-t-butoxycarbonyl-N ' ^! ' -Ethylguanidino) -2-ethylphenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 461 as the starting material, the title compound was obtained according to the procedure of Example 233 (80% yield).

1 H-NMR (CDCl 3) δ: 1.08 (3H, t,> 7.3 Hz), 1.26 (3H, t,> 7.5 Hz), 1.43-1.69 (27H, m ), 2.66 (2H, q,> 7.3Hz), 3.39 (2H, q,> 7.5Hz), 4.81 (2H, s), 6.96-7.27 (3H , m), 10.61 (1H, brs),

Example 466

Synthesis of N- (2-ethyl-5- (N'-ethylguanidino) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 465 as starting material, the title compound was obtained according to the procedure in Example 5 (yield 89%).

1 H-NMR (D ₂ O) δ: 1.19-1.25 (6H, m), 2.74 (2H, q,> 7.5 Hz), 3.10 (2H, q,> 7, 3 Hz), 4.27 (2H, s), 7.29-7.34 (2H, m), 7.45 (1H, d,> 7.9Hz)

MS (m / z) 221 (M ⁺ + 1)

Example 467

Synthesis of N- (2-methyl-5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using 3-chloromethyl-4-methylnitrobenzene as the starting material, the procedure of Example 127 gave the title compound (37% yield).

'H-NMR (CDCl3)

6: 1.49 (18H, s), 2.42 (3H, s), 4.83 (2H, s), 7.27-7.32 (1H, m), 7.99-8.03 ( 2H, m)

183 619

159

Example 468

Synthesis of N- (5-amino-2-methylphenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 467 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 82%).

Ή-NMR (CDCl ₃ ) δ: 1.44 (18H, s), 2.18 (3H, s), 3.51 (2H, brs), m 4.71 (2H, s), 6.47- 6.52 (2H, m), 6.85 (1H, d,> 8.1Hz)

Example 469

Synthesis of N- (2-methyl-5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 468 as the starting material, the title compound was obtained according to the procedure of Example 120 (99% yield).

Ή-NMR (CDCl 3) δ: 1.48 (18H, s), 2.30 (3H, s), 4.75 (2H, s), 6.04 (2H, brs), 6.95-7, 01 (2H, m), 7.24 (1H, d,> 7.3Hz), 7.83 (1H, brs)

MS (m / z) 396 (M ⁺ + 1)

Example 470

Synthesis of N- (5- (S-ethylisothioureido) -2-methyl) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 469 as the starting material, the procedure of Example 95 gave the title compound (87% yield).

Ή-NMR (CDCl3) δ: 1.36 (3H, t,> 7.3Hz), 1.44 (18H, s), 2.25 (3H, s), 2.95-3.05 (2H , m), 4.74 (2H, s), 6.63-6.75 (2H, m), 7.05 (1H, d,> 7.9Hz)

MS (m / z) 424 (M ⁺ + 1)

Example 471

Synthesis of N- (5- (S-ethylisothioureido) -2-methylphenylmethyl) amine dihydrochloride

Using the compound obtained in Example 470 as a starting material, the procedure of Example 5 gave the title compound (83% yield).

Ή-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.3 Hz), 2.43 (3H, s), 3.25 (2H, q,> 7.3 Hz), 4 . 28 (2H, s), 7.31-7.50 (3H, m)

MS (m / z) 223 (M ⁺ )

Example 472

Synthesis of N- (5- (N'-t-butoxycarbonyl-N'-ethylguanidino) -2-methylphenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 471 as the starting material, the title compound was obtained according to the procedure of Example 233 (55% yield).

Ή-NMR (CDCl ₃ ) δ: 1.07 (3H, t,> 7.0 Hz), 1.44-1.53 (27H, m), 2.30 (3H, s), 3.31- 3.45 (2H, m), 4.65 (1H, br s), 4.75 (2H, s), 6.95-7.20 (3H, m)

MS (m / z) 507 (M ⁺ + 1)

Example 473

Synthesis of N- (5- (N'-ethylguanidino) -2-methylphenylmethyl) amine dihydrochloride

Using the compound obtained in Example 472 as the starting material, the procedure of Example 5 gave the title compound (85% yield).

Ή-NMR (D ₂ O) δ: 1.23 (3H, t,> 7.4 Hz), 2.71 (3H, s), 3.31 (2H, q,> 7.4 Hz), 4 , 24 (2H, s), 7.24-7.29 (2H, m), 7.39-7.44 (1H, m)

MS (m / z) 206 (M ⁺ )

160

183 619

Example 474

Synthesis of N- (3-methoxy-4-methylphenyl) phthalimide

By using 3-methoxy-4-methylaniline as the starting material, the procedure of Example 248 gave 1.55 g of the title compound (14% yield)

Ή-NMR (CDCl ₃ ) δ: 2.26 (3H, s), 3.85 (3H, s), 6.82-6.95 (2H, m), 7.21-7.30 (1H, m), 7.77-7.81 (2H, m), 7.94-7.97 (2H, m)

Example 475

Synthesis of N- (4-bromomethyl-3-methoxyphenyl) phthalimide

Using the compound obtained in Example 474 as the starting material, 80 mg of the title compound were obtained according to the procedure of Example 249 (74% yield).

Ή-NMR (CDCl ₃ ) δ: 3.93 (3H, s), 4.58 (2H, s), 6.96-7.10 (2H, m), 7.42-7.50 (1H, m), 7.79-7.82 (2H, m), 7.95-7.98 (2H, m)

Example 476

Synthesis of N- (4-cyanomethyl-3-methoxyphenyl) phthalimide

Using the compound obtained in Example 475 as starting material, the procedure of Example 250 gave 26 mg of the title compound (42% yield).

Ή-NMR (CDCl ₃₎ δ: 3.73 (2H, s), 3.90 (3H, s), 7.01-7.14 (2H, m), 7.48-7.53 (1H, m), 7.80-7.83 (2H, m), 7.96-7.99 (2H, m)

Example 477

Synthesis of 4-cyanomethyl-3-methoxyaniline

Using the compound obtained in Example 476 as starting material, 640 mg of the title compound were obtained according to the procedure of Example 251 (94% yield).

Ή-NMR (CDCl ₃ ) δ: 3.55 (2H, s), 3.75 (2H, brs), 3.80 (3H, s), 6.18-6.35 (2H, m), 7 .00-7.14 (1H, m)

Example 478

Synthesis of 4- (2-aminoethyl) -3-methoxyaniline

Using the compound obtained in Example 477 as the starting material, 608 mg of the title compound was obtained according to the procedure of Example 252 (93% yield).

Ή-NMR (CDCl ₃ ) δ: 1.68 (2H, brs), 2.64 (2H, t, J = 6.9 Hz), 2.84 (2H, t, J = 6.9 Hz), 3.61 (2H, brs), 3.76 (3H, s), 6.18-6.26 (2H, m), 6.84-6.95 (1H, m)

Example 479

Synthesis of N- (2- (4-amino-2-methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 478 as the starting material, the procedure of Example 253 gave 253 mg of the title compound (31% yield).

Ή-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.68 (2H, t,> 6.9 Hz), 3.20-3.35 (2H, m), 3.62 ( 2H, brs), 3.77 (3H, s), 4.63 (1H, brs), 6.20-6.25 (2H, m), 6.82-6.92 (1H, m)

Example 480

Synthesis of N- (2-methoxy-4-thioureidophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 479 as starting material, the procedure of Example 120 gave 70 mg of the title compound (91% yield).

Ή-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.79 (2H, t,> 6.9 Hz), 3.25-3.40 (2H, m), 3.82 ( 3H, s), 4.60 (1H, brs), 6.12 (2H, brs), 6.71-6.79 (2H, m), 7.16-7.18 (1H, m), 7 . 93 (1H, s)

183 619

161

Example 481

Synthesis of N- (2- (4-) S-ethylisothioureido) -2- (methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 480 as starting material, the procedure of Example 95 gave 50 mg of the title compound (66% yield).

1 H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.3 Hz), 1.43 (9H, s), 2.75 (2H, t, J = 6.6 Hz) , 2.95-3.20 (2H, m), 3.20-3.38 (2H, m), 3.79 (3H, s), 4.54 (1H, br s), 4.61 (1H , brs), 6.38-6.60 (2H, m), 7.00-7.05 (1H, m)

Example 482

Synthesis of N-2- (4- (S-ethylisothioureido) -2-methoxyphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 481 as a starting material, the procedure of Example 5 gave 45 mg of the title compound (81% yield).

1 H-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.3 Hz), 3.03 (2H, t, J = 6.9 Hz), 3.19-3.28 ( 4H, m), 3.88 (3H, s), 6.95-7.00 (2H, m), 7.36-7.39 (1H, m)

Example 483

Synthesis of N- (2- (4- (N'-t-butoxycarbonyl-N'-ethylguanidino) -2-methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 479 as the starting material, the procedure of Example 233 gave 118 mg of the title compound (95% yield).

1 H-NMR (CDCl 3) δ: 1.19 (3H, t,> 7.3Hz), 1.43 (9H, s), 1.52 (9H, s), 2.78 (2H, t, > 6.6Hz), 3.32-3.44 (4H, m), 3.80 (3H, s), 4.62 (1H, brs), 6.56-6.90 (2H, m) , 7.30-7.80 (1H, m), 8.02 (1H, brs)

Example 484

Synthesis of N- (2- (4- (N'-ethylguanidino) -2-methoxyphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 483 as the starting material, the procedure of Example 5 gave 72 mg of the title compound in quantitative yield.

1 H-NMR (D ₂ O) δ: 1.23 (3H, t,> 7.3 Hz), 3.01 (2H, t,> 6.9 Hz), 3.22-3.61 (4H , m), 3.87 (3H, s), 6.89-6.96 (2H, m), 7.30-7.33 (1H, m)

Example 485

Synthesis of N- (2-methoxy-4-methylphenyl) phthalimide

By using 2-methoxy-4-methylaniline as the starting material, the procedure of Example 248 gave 4.46 g of the title compound (11% yield).

1 H-NMR (CDCl ₃ ) δ: 2.41 (3H, s), 3.77 (3H, s), 6.86-6.90 (2H, m), 7.11-7.14 (1H , m), 7.75-7.78 (2H, m), 7.89-7.95 (2H, m)

Example 486

Synthesis of N- (4-bromomethyl-2-methoxyphenyl) phthalimide

Using the compound obtained in Example 485 as the starting material, the procedure of Example 249 gave 4.46 g of the title compound (76% yield).

1 H-NMR (CDCl ₃ ) δ: 3.82 (3H, s), 4.52 (2H, s), 7.08-7.24 (3H, m), 7.76-7.80 (2H , m), 7.93-7.96 (2H, m)

Example 487

Synthesis of N- (4-cyanomethyl-2-methoxyphenyl) phthalimide

Using the compound obtained in Example 486 as starting material, the procedure of Example 250 gave 2.0 g of the title compound (50% yield).

1 H-NMR (CDCl ₃ ) δ: 3.83 (5H, s), 7.02-7.29 (3H, m), 7.77-7.81 (2H, m), 7.93-7 . 96 (2H, m)

162

183 619

Example 488

Synthesis of 4-cyanomethyl-2-methoxyaniline

Using the compound obtained in Example 487 as starting material, the procedure of Example 251 gave 844 mg of the title compound (77% yield).

'Η-NMR (CDCl ₃ ) δ: 3.65 (2H, s), 3.70-3.95 (5H, m), 6.65-6.72 (3H, m)

Example 489

Synthesis of 4- (2-aminoethyl) -2-methoxyaniline

Using the compound obtained in Example 488 as a starting material, the procedure of Example 252 gave 230 mg of the title compound (62% yield).

'Η-NMR (CDCl ₃ ) δ: 1.43 (2H, brs), 2.65 (2H, t, J = 6.9 Hz), 2.92 (2H, t, J = 6.9 Hz) , 3.69 (2H, brs), 3.84 (3H, s), 6.61-6.72 (3H, m)

Example 490

Synthesis of N- (2- (4-amino-3-methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 489 as the starting material, the procedure of Example 253 gave 95 mg of the title compound (25% yield).

Ή-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.69 (2H, t,> 6.9 Hz), 3.28-3.44 (2H, m), 3.84 ( 3H, s), 4.54 (1H, br s), 6.59-6.72 (3H, m)

Example 491

Synthesis of N- (2- (3-methoxy-4-thioureidophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 490 as the starting material, the procedure of Example 120 gave 38 mg of the title compound (73% yield).

'Η-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.80 (2H, t,> 7.3 Hz), 3.30-3.44 (2H, m), 3.85 (3H, s), 4.57 (1H, br s), 6.07 (2H, br s), 6.80-6.83 (2H, m), 7.21-7.24 (1H, m), 7.62 (1H, brs)

Example 492

Synthesis of N- (2- (4- (S-ethylthioureido) -3-methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 491 as starting material, the procedure of Example 95 gave 25 mg of the title compound (61% yield).

'Η-NMR (CDCl ₃ ) δ: 1.38 (3H, t,> 7.3 Hz), 1.44 (9H, s), 2.75 (2H, t,> 6.9 Hz), 2 , 88-3.14 (2H, m), 3.30-3.42 (2H, m), 3.82 (3H, s), 4.52 (1H, br s), 6.72-6.76 (2H, m), 7.26 (1H, s)

Example 493

Synthesis of N- (2- (4- (S-ethylisothioureido) -3-methoxyphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 492 as a starting material, the procedure of Example 5 gave 19 mg of the title compound (92% yield).

Ή-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.3 Hz), 3.05 (2H, t,> 7.3 Hz), 3.18-3.34 (4H, m), 3.90 (3H, s), 7.02 (1H, d,> 7.9Hz), 7.15 (1H, s), 7.30 (1H, d,> 7.9Hz)

Example 494

Synthesis of 4- (2-aminoethyl) -2-chloroaniline

Using 2-chloro-4-cyanomethylaniline as the starting material, the procedure of Example 252 gave 614 mg of the title compound in quantitative yield.

Ή-NMR (CDCl3) δ: 1.21 (2H, brs), 2.61 (2H, t,> 6.9 Hz), 2.90 (2H, t,> 6.9 Hz), 3.96 (2H, brs), 6.96-7.09 (3H, m)

183 619

163

Example 495

Synthesis of N- (2- (4-amino-3-chlorophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 494 as a starting material, the procedure of Example 253 gave 912 mg of the title compound (94% yield).

Ή-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.66 (2H, t,> 6.9 Hz), 3.20-3.40 (2H, m), 3.97 ( 2H, brs), 4.54 (1H, brs), 6.69-7.07 (3H, m)

Example 496

Synthesis of N- (2- (3-chloro-4-thioureidophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 495 as starting material, the procedure of Example 120 gave 114 mg of the title compound (94% yield).

Ή-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.79 (2H, t,> 6.9 Hz), 3.33-3.40 (2H, m), 4.68 ( 1H, brs), 6.24 (2H, brs),

7.15-7.18 (1H, m), 7.34-7.39 (2H, m), 7.93 (1H, brs)

Example 497

Synthesis of N- (2- (3-chloro-4- (S-ethylisothioureido) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 496 as starting material, the procedure of Example 95 gave 118 mg of the title compound (95% yield).

Ή-NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.3Hz), 1.44 (9H, s), 2.73 (2H, t,> 6.9Hz), 2.96 -3.20 (2H, m), 3.31-3.35 (2H, m), 4.52 (1H, br s), 6.92-7.04 (2H, m), 7.22 (1H , s)

Example 498

Synthesis of N- (2- (3-chloro-4- (S-ethylisothioureido) phenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 497 as the starting material, according to the procedure in Example 5, 95 mg of the title compound were obtained in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.44 (3H, t,> 7.3 Hz), 3.07 (2H, t,> 7.3 Hz), 3.22-3.35 (4H, m), 7.40-7.49 (2H, m), 7.62 (1H, s)

Example 499

Synthesis of N- (2-fluoro-4-methylphenyl) phthalimide

Using 2-fluoro-4-methylaniline as the starting material, the procedure of Example 248 gave 8.8 g of the title compound (22% yield).

Ή-NMR (CDCl ₃ ) δ: 2.42 (3H, s), 7.06-7.26 (3H, m), 7.78-7.81 (2H, m), 7.94-7, 97 (2H, m)

Example 500

Synthesis of N- (4-bromomethyl-2-fluorophenyl) phthalimide

Using the compound obtained in Example 499 as the starting material, the procedure of Example 249 gave 6.0 g of the title compound (92% yield).

Ή-NMR (CDCl ₃ ) δ: 4.49 (2H, s), 7.30-7.38 (3H, m), 7.80-7.83 (2H, m), 7.96-7, 99 (2H, m)

Example 501

Synthesis of N- (4-cyanomethyl-2-fluorophenyl) phthalimide

Using the compound obtained in Example 500 as a starting material, the procedure of Example 250 gave 2.0 g of the title compound (40% yield).

Ή-NMR (CDCl ₃ ) δ: 3.84 (2H, s), 7.27-7.47 (3H, m), 7.79-7.84 (2H, m), 7.96-8, 00 (2H, m)

Example 502

Synthesis of 4-cyanomethyl-2-fluoroaniline

Using the compound obtained in Example 501 as starting material, the procedure of Example 251 gave 290 mg of the title compound (93% yield).

Ή-NMR (CDC1 ₃₎

164

183 619 δ: 3.62 (2Η, s), 3.78 (2Η, brs), 6.72-6.97 (3H, m)

Example 503

Synthesis of 4- (2-aminoethyl) -2-fluoroaniline

Using the compound obtained in Example 502 as the starting material, the procedure of Example 252 gave 290 mg of the title compound (97% yield).

Ή-NMR (CDCl ₃ ) δ: 1.21 (2H, brs), 2.62 (2H, t,> 6.9 Hz), 2.90 (2H, t,> 6.9 Hz), 3, 64 (2H, brs), 6.67-6.85 (3H, m)

Example 504

Synthesis of N- (2- (4-amino-3-fluorophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 503 as the starting material, the procedure of Example 253 gave 290 mg of the title compound (65% yield).

Ή-NMR (CDCl3)

1.44 (9H, s), 2.67 (2H, t,> 6.9Hz), 2.65-2.75 (2H, m), 3.64 (2H, brs), 4.53 ( 1H, brs), 6.68-6.84 (3H, m)

Example 505

Synthesis of N- (2- (3-fluoro-4-thioureidophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 504 as the starting material, the procedure of Example 120 gave 88 mg of the title compound (98% yield).

Ή-NMR (CDCl3) δ: 1.43 (9H, s), 2.80 (2H, t,> 6.9 Hz), 3.33-3.40 (2H, m), 4.62 (1H , brs), 6.15 (2H, brs), 7.03-7.06 (2H, m), 7.29-7.35 (1H, m), 7.74 (1H, brs)

Example 506

Synthesis of N- (2- (4- (S-ethylisothioureido) -3-fluorophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 505 as the starting material, the procedure of Example 95 gave 79 mg of the title compound (83% yield).

Ή-NMR (CDCl3) δ: 1.37 (3H, t,> 7.3 Hz), 1.44 (9H, s), 2.74 (2H, t,> 6.9 Hz), 2.95 -3.20 (2H, m), 3.28-3.44 (2H, m), 4.53 (1H, br s), 6.85-7.00 (3H, m)

Example 507

Synthesis of N- (2- (4- (S-ethylisothioureido) -3-fluorophenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 506 as a starting material, the procedure of Example 5 gave 44 mg of the title compound (64% yield).

Ή-NMR (D ₂ O) δ: 1.42 (3H, t,> 7.3 Hz), 3.07 (2H, t,> 7.3 Hz), 3 20-3.34 (4H, m ), 7.25-7.45m (3H, m) Example 508

Synthesis of 2- (5-methoxy-2-nitrophenyl) ethylamine

To a solution of 2- (3-methoxyphenyl) ethylamine (1.51 g) in chloroform (30 ml), fuming nitric acid (density = 1.52; 0.84 ml) and sulfuric acid (1, 07 ml) and stirred under ice cooling for 3 hours. Water and a 2N aqueous sodium hydroxide solution were added to the reaction mixture, which were extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 9: 1) to give 400 mg of the title compound (yield 21%).

Ή-NMR (CDCl 3) δ: 1.51 (2H, brs), 3.00-3.20 (4H, m), 3.89 (3H, s), 6.81-6.84 (2H, m ), 8.04-8.08 (1H, m)

Example 509

Synthesis of N- (2- (5-methoxy-2-nitrophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 508 as starting material, the procedure of Example 22 gave 448 mg of the title compound (74% yield).

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165

Ή-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 3.14 (2H, ζ J = 6.9 Hz), 3.42-3.50 (2H, m), 3.88 ( 3H, s), 4.73 (1H, br s), 6.82-6.86 (2H, m), 8.05- 8.08 (1H, m)

Example 510

Synthesis of N- (2- (2-amino-5-methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 509 as the starting material, the procedure in Example 2 gave 300 mg of the title compound (75% yield)

Ή-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.70 (2H, t,> 6.9 Hz), 3.27-3.35 (2H, m), 3.74 ( 3H, s), 4.82 (1H, br s), 6.62-6.64 (3H, m)

Example 511

N- (2- (5-methoxy-2-thioureido) -phenyl) ethyl) carbamic acid t-butyl ester synthesis

Using the compound obtained in Example 510 as the starting material, the procedure of Example 120 gave 170 mg of the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.34 (9H, s), 2.76 (2H, t,> 6.9 Hz), 3.28-3.40 (2H, m), 3.79 ( 3H, s), 4.82 (1H, brs), 6.32 (2H, brs), 6, 78-6.81 (2H, m), 7.15-7.27 (1H, m), 8 .03 (1H, brs)

Example 512

Synthesis of N- (2- (2- (S-ethylisothioureido) -5-methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 511 as starting material, the procedure of Example 95 gave 54 mg of the title compound (82% yield).

Ή-NMR (CDCl ₃ ) δ: 1.37 (3H, t,> 7.3 Hz), 1.40 (9H, s), 2.67 (2H, t,> 6.6 Hz), 3, 00-3.20 (2H, m), 3.28-3.40 (2H, m), 3.77 (3H, s), 5.30 (1H, brs), 6.70-6.81 ( 3H, m)

Example 513

Synthesis of N- (2- (2- (S-ethylisothioureido) -5-methoxyphenyl) ethyl amine dihydrochloride

Using the compound obtained in Example 512 as the starting material, the procedure of Example 5 gave 52 mg of the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.40-1.50 (3H, m), 2.94 (2H, t,> 7.6 Hz), 3.19-3.25 (4H, m) , 3.87 (3H, s), 7.00-7.10 (2H, m), 7.30-7.34 (1H, m)

Example 514

Synthesis of N- (2- (5-methoxy-2- (N'-nitroguanidino) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 510 as starting material, the procedure of Example 6 gave 59 mg of the title compound (57% yield).

Ή-NMR (CDCl ₃ ) δ: 1.29 (9H, s), 2.77 (2H, t,> 6.3 Hz), 3.30-3.37 (2H, m), 3.81 ( 3H, s), 4.78 (1H, br s), 6.79-6.85 (2H, m), 7.19-7.22 (1H, m)

Example 515

Synthesis of N- (2- (5-methoxy-2- (N'-nitroguanidino) phenyl) ethyl) amine hydrochloride

Using the compound obtained in Example 514 as the starting material, according to the procedure in Example 5, 45 mg of the title compound were obtained in quantitative yield.

Ή-NMR (D ₂ O) δ: 2.97 (2H, t,> 7.9 Hz), 3.22 (2H, t,> 7.9 Hz), 3.87 (3H, s), 7 . 00-7.06 (2H, m), 7.31-7.34 (1H, m)

Example 516

Synthesis of N- (2- (2- (N'-t-butoxycarbonyl-N'-ethyl-guanidino) -5-methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 510 as the starting material, the procedure of Example 233 gave 112 mg of the title compound (90% yield).

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Ή-NMR (CDCl ₃ ) δ: 0.96-1.18 (3H, m), 1.35 (9H, s), 1.54 (9H, s), 2.70-2.72 (2H, m), 3.28-3.41 (4H, m), 3.79 (3H, s), 4.67 (1H, br s), 6.70-6.82 (2H, m), 7.02 -7.20 (1H, m), 8.02 (1H, br s)

Example 517

Synthesis of N- (2- (2- (N'-ethyl) guanidino) -5-methoxyphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 516 as starting material, the procedure of Example 5 gave 70 mg of the title compound (94% yield).

Ή-NMR (D ₂ O) δ: 1.21 (3H, t, J = 7.3 Hz), 2.96 (2H, t, J = 7.6 Hz), 3.20-3.34 ( 4H, m), 3.87 (3H, s), 7.00-7.10 (2H, m), 7.28-7.32 (1H, m)

Example 518

Synthesis of N- (4-hydroxyethyl-2-methyl-phenyl) carbamic acid t-butyl ester

Lithium aluminum hydride (5.02 g) was suspended in tetrahydrofuran (300 ml). 4-Amino-3-methylbenzoic acid (10.53 g) was added slowly to the suspension at room temperature and the reaction mixture was heated to reflux for 3 hours. After adding ethyl acetate and water, the reaction mixture was stirred for 30 minutes and then Celite and anhydrous sodium sulfate were added. The resulting reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield the crude product. Then, water, sodium hydroxide (3.07 g) and di-t-butyl dicarbonate (15.2 g) were successively added to the crude product, which was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and after washing with water once, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent, n-hexane: ethyl acetate = 5: 1) to obtain 7.658 g of the title compound (yield 46%).

Ή-NMR (CDCl ₃ ) δ: 7.77 lH, d, J = 9.0 Hz), 7.22-7.13 (2H, m), 6.27 (1H, brs), 4.59 ( 2H, s), 2.25 (3H, s), 1.79 (1H, brs), 1.52 (9H, s)

Example 519

Synthesis of N- (4-bromomethyl-2-methylphenyl) carbamic acid t-butyl ester The compound (1.035 g) obtained in Example 518 was dissolved in methylene chloride (20 ml) and triphenylphosphine (1.38 g) was successively added to the solution under ice cooling and carbon tetrabromide (1.74 g). The reaction mixture was stirred for 30 minutes under ice-cooling, then stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate - 5: 1) to give 476.6 mg of the title compound (36% yield).

Ή-NMR (CDCl ₃ ) δ: 7.84 (1H, d,> 8.1 Hz), 7.29-7.15 (2H, m), 6.28 (1H, brs), 4.46 (2H, s), 2.24 (3H, s), 1.52 (9H, s)

Example 520

Synthesis of N- (4-cyanomethyl-2-methyl-phenyl) carbamic acid t-butyl ester

The compound (155.1 mg) obtained in Example 519 was dissolved in dimethylsulfoxide (5 ml). Sodium cyanide (127 mg) was added to the solution and the mixture was heated at 50 ° C with stirring for 10 minutes. Ethyl acetate was added to the resulting reaction mixture, and the organic layer was washed with water twice, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 3: 1) to obtain 77.7 mg of the title compound (yield 61%).

Ή-NMR (CDCl ₃ ) δ: 7.84 (1H, d, J = 8.8 Hz), 7.17-7.08 (2H, m), 6.28 (1H, brs), 3.67 (2H, s), 2.25 (3H, s), 1.52 (9H, s)

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Example 521

Synthesis of 4-cyanomethyl-2-methylaniline

The compound (1.16 g) obtained in Example 520 was dissolved in methylene chloride (15 ml); trifluoroacetic acid (4 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was extracted with methylene chloride. The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 3: 1) to give 480.5 mg of the title compound (70% yield).

Ή-NMR (CDCl ₃ ) δ: 7.06-6.93 (2H, m), 6.65 (1H, d,> 8.1 Hz), 3.67 (2H, brs), 3.61 ( 2H, s), 2.16 (3H, s)

Example 522

Synthesis of 4- (2-aminoethyl) -2-methylaniline

Using the compound obtained in Example 521 as starting material, 486.5 mg of the title compound were obtained according to the procedure of Example 252 (100% yield).

Ή-NMR (CDCl ₃ ) δ: 6.93-6.83 (2H, m), 6.62 (1H, d,> 8.3 Hz), 3.52 (2H, brs), 2.90 ( 2H, t,> 6.8Hz), 2.62 (2H, t,> 6.8Hz), 2.15 (3H, s), 1.69 (2H, brs)

Example 523

Synthesis of N- (2- (4-amino-3-methyl) phenyl) ethyl carbamic acid t-butyl ester

Using the compound obtained in Example 522 as the starting material, the procedure of Example 253 gave 477.4 mg of the title compound (59% yield).

Ή-NMR (CDCl ₃ ) δ: 6.91-6.83 (2H, m), 6.62 (1H, d,> 7.8Hz), 4.52 (1H, brs), 3.53 ( 2H, brs), 3.31 (2H, dt,> 5.4, 7.3Hz), 2.66 (2H, t,> 7.3Hz), 2.15 (3H, s), 1. 44 (9H, s)

Example 524

Synthesis of N- (2 - (3-methyl-4-thioureidophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 523 as a starting material, the procedure of Example 120 afforded 82.7 mg of the title compound (96% yield).

Ή-NMR (CDCl ₃ ) δ: 7.84 (1H, brs), 7.20-7.04 (3H, m), 6.00 (2H, brs), 4.62 (1H, brs), 3 , 36 (2H, dt,> 6.3, 6.6Hz), 2.77 (2H, t,> 6.6Hz), 2.29 (3H, s), 1.43 (9H, s)

Example 525

Synthesis of N- (2- (4- (S-ethylisothioureido) -3- (methylphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 524 as starting material, the procedure of Example 27 gave 82.4 mg of the title compound (94% yield).

Ή-NMR (CDCl ₃ ) δ: 7.00 (1H, s), 6.96 (1H, d,> 8.0 Hz), 6.75 (1H, d,> 8.0 Hz), 4, 52 (1H, brs), 4.37 (1H, brs), 3.34 (2H, dt,> 6.3.6.6Hz), 3.20-2.95 (2H, m), 2. 71 (2H, t,> 6.6Hz), 2.13 (3H, s), 1.44 (9H, s), 1.38 (3H, t,> 7.3Hz)

Example 526

Synthesis of N- (2- (4- (S-ethylisothioureido) -3- (methylphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 525 as a starting material, the procedure of Example 5 gave 75.5 mg of the title compound (100% yield).

Ή-NMR (DMSO-d ₆ ) δ: 11.55 (1H, brs), 9.50 (2H, brs), 8.23 (3H, brs), 7.28 (1H, s), 7.20 (2H, s), 3.45-3.23 (2H, m), 3.15-2.87 (4H, m), 2.19 (3H, s), 1.30 (3H, t,> 7.1Hz)

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Example 527

Synthesis of N- (2- (4- (N'-t-butoxycarbonyl-N'-ethylguanidino) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 49 as starting material, the procedure of Example 233 gave 74.4 mg of the title compound (10% yield).

1 H-NMR (CDCl ₃ ) δ: 1.03-1.16 (3H, m), 1.43 (9H, s), 1.51 (9H, s), 2.76-2.82 (2H , m), 3.27-3.46 (4H, m), 4.62 (1H, brs), 6.98-7.28 (5H, m)

MS (m / z) 406 (M ⁺ )

Example 528

Synthesis of N- (2- (4- (N'-ethylguanidino) phenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 527 as a starting material, the procedure of Example 5 gave 44.6 mg of the title compound (89% yield).

1 H-NMR (D ₂ O) δ: 1.21 (3H, t,> 7.3 Hz), 3.03 (2H, t,> 7.3 Hz), 3.25-3.35 (4H , m), 7.29 (2H, d,> 8.6 Hz), 7.40 (2H, d,> 8.6 Hz)

MS (m / z) 206 (M ⁺ )

Example 529

Synthesis of N- (3-amino-2-methylphenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 127 as a starting material, the procedure in Example 2 gave 4.4 g of the title compound (80% yield).

1 H-NMR (CDCl ₃ ) δ: 1.43 (18H, s), 2.03 (3H, s), 3.45 (2H, brs), 4.74 (2H, s), 6.43- 6.98 (3H, m)

MS (m / z) 336 (M ⁺ )

Example 530

Synthesis of N- (2-methyl-3-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 529 as the starting material, the procedure of Example 120 gave 1.896 g of the title compound (86% yield).

1 H-NMR (CDCl ₃ ) δ: 1.46 (18H, s), 2.25 (3H, s), 4.80 (2H, s), 5.83 (2H, brs), 7.15 ( 2H, d,> 7.6Hz), 7.23-7.29 (1H, m), 7.80 (1H, s)

Example 531

Synthesis of N- (3- (di- (t-butoxycarbonyl) aminomethyl) -2-methylphenyl) sulfamic acid

Using the compound obtained in Example 530 as the starting material, the procedure of Example 277 gave 1.96 g of the title compound (92% yield).

1 H-NMR (CDCl ₃ ) δ: 1.48 (18H, s), 2.22 (3H, s), 4.80 (2H, s), 7.13-7.24 (2H, m), 7.28-7.36 (1H, m)

Example 532

Synthesis of N- (3- (Ν'-ethylguanidino) -2-methyl-phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 531 as the starting material and also using ethylamine hydrochloride as a reagent, the procedure of Example 278 gave the title compound in quantitative yield.

1 H-NMR (CDCl ₃ ) δ: 1.17 (3H, t,> 7.2 Hz), 1.43 (18H, s), 2.09 (3H, s), 3.24 (2H, q > 7.2Hz), 3.89 (2H, brs), 4.76 (2H, s), 6.72-6.79 (2H, m), 7.02-7.10 (1H, m ). 7.28 (1H, s)

MS (m / z) 406 (M ⁺ )

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Example 533

Synthesis of N- (3- (N'-ethyl) guanidino) -2-methylphenylmethyl) amine dihydrochloride

Using the compound obtained in Example 532 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.21 (3H, t,> 7.3 Hz), 2.28 (3H, s), 3.31 (2H, q, J = 7.3 Hz), 4.29 (2H, s), 7.32-7.46 (3H, m)

MS (m / z) 206 (M ⁺ )

Example 534

Synthesis of N- (3- (N'-ethyl-N'-methylguanidino) -2- (methylphenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 531 as a starting material, the procedure of Example 304 gave 77.6 mg of the title compound (27% yield).

Ή-NMR (CDCl ₃ ) δ: 1.19 (3H, t,> 6.9 Hz), 1.43 (18H, s), 2.08 (3H, s), 2.96 (3H, s) , 3.41 (2H, q,> 6.9Hz), 4.77 (2H, s), 6.73 (2H, t,> 7.6Hz), 7.05 (1H, t,> 7 , 6 Hz)

MS (m / z) 420 (M +)

Example 535

Synthesis of N- (3 - (Ν'-ethyl-N'-methylguanidino) -2-methylphenylmethyl) amine dihydrochloride

Using the compound obtained in Example 534 as a starting material, the procedure in Example 5 gave 42.7 mg of the title compound (81% yield).

Ή-NMR (D ₂ O) δ: 1.28 (3H, t,> 7.3 Hz), 2.27 (3H, s), 3.15 (3H, s), 3.52 (2H, q > 7.3Hz), 4.30 (2H, s), 7.34 (1H, dd,> 7.6, 2.0Hz), 7.41-7.48 (2H, m)

MS (m / z) 220 (M ⁺ )

Example 536

Synthesis of N- (2-chloro-3- (di- (t-butoxycarbonyl) aminomethylphenyl) amidinesulfonic acid

Using the compound obtained in Example 135 as the starting material, the procedure of Example 277 gave 0.68 g of the title compound (97% yield).

Ή-NMR (CDCl3) δ: 1.45 (18H, s), 4.90 (2H, s), 7.22-7.29 (1H, m), 7.38-7.46 (2H, m )

Example 537

Synthesis of N- (2-chloro-3- (N'-ethyl-guanidino) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 536 as a starting material, the procedure of Example 442 gave the title compound in quantitative yield.

Ή-NMR (CDCl 3) δ: 1.20 (3H, t,> 7.3 Hz), 1.45 (18H, s), 3.28 (2H, q,> 7.3 Hz), 4.89 (2H, s), 6.77 (1H, d,> 7.7Hz), 6.87 (1H, d,> 7.7Hz), 7.13 (1H, t,> 7.7Hz)

MS (m / z) 426 (M ⁺ )

Example 538

Synthesis of N- (2-chloro-3 - (N'-ethylguanidino) phenylmethyl) amine dihydrochloride

By using the compound obtained in Example 537 as a starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.22 (3H, t,> 7.3 Hz), 3.33 (2H, q,> 7.3 Hz), 4.39 (2H, s), 7 . 51-7.62 (3H, m)

MS (m / z) 226 (M ⁺ )

Example 539

Synthesis of N- (2-chloro-3 - (N'-ethyl-N'-methyl-guanidino) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 536 as a starting material, the procedure of Example 304 gave 0.12 g of the title compound (38% yield).

170

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Ή-NMR (CDCl ₃ ) δ: 1.21 (3H, t,> 6.9 Hz), 1.44 (18H, s), 2.98 (3H, s), 3.43 (2H, q, > 6.9Hz), 3.85 (1H, brs), 4.88 (2H, s), 6.75 (1H, d,> 7.6Hz), 6.84 (1H, d,> 7 , 6 Hz), 7.11 (1H, t,> 7.6 Hz)

MS (m / z) 440 (M ⁺ )

Example 540

Synthesis of N- (2-chloro-3- (N'-ethyl-N'-methylguanidino) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 539 as a starting material, 76.2 mg of the title compound were obtained according to the procedure in Example 5 (90% yield).

Ή-NMR (D ₂ O) δ: 1.28 (3H, t,> 7.3 Hz), 3.16 (3H, s), 3.53 (2H, q,> 7.3 Hz), 4 . 40 (2H, s), 7.51-7.60 (3H, m)

MS (m / z) 240 (M ⁺ )

Example 541

Synthesis of N- (3 - (t-butoxycarbonylaminoethyl) phenyl) sulfamic acid

Using the compound obtained in Example 58 as the starting material, the procedure of Example 277 gave 1.99 g of the title compound (80% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.35 (9H, s), 2.74 (2H, t,> 6.9 Hz), 3.12-3.33 (2H, m), 6, 74 (1H, brs), 7.10-7.20 (3H, m), 7.39 (1H, t,> 7.6Hz), 9.08 (1H, brs), 9.63 (1H, s ), 11.45 (1H, s)

Example 542

Synthesis of N- (3- (N'-ethylguanidino) -phenylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 541 as a starting material, the procedure of Example 442 gave 0.415 g of the title compound (93% yield).

Ή-NMR (CDCl ₃ ) δ: 1.16-1.21 (3H, m), 1.46 (9H, s), 2.68-2.81 (2H, m), 3.22-3, 47 (4H, m), 4.95 (2H, br s), 5.35 (1H, brs), 6.81-6.85 (3H, m), 7.15-7.22 (1H, m)

MS (m / z) 306 (M ⁺ )

Example 543

Synthesis of N- (3- (N'-ethylguanidino) phenylethyl) amine dihydrochloride

Using the compound obtained in Example 542 as the starting material, the procedure in Example 5 gave 0.356 g of the title compound (94% yield).

¹ H-NMR (D ₂ O) δ: 1.22 (3H, t,> 7.3 Hz), 3.03 (2H, t,> 7.3 Hz), 3.26-3.36 (4H , m), 7.22-7.25 (2H, m), 7.31 (1H, d,> 8.3Hz), 7.47 (1H, d,> 8.6Hz)

MS (m / z) 206 (M ⁺ )

Example 544

Synthesis of N- (3- (N'-ethyl-N'-methyl-guanidino) phenylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 541 as the starting material, the procedure of Example 304 gave 126.5 mg of the title compound (27% yield).

Ή-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J-6.9Hz), 1.40 (9H, s), 2.70 (2H, t,> 6.9Hz), 2.93 (3H, s), 3.33-3.41 (4H, m), 3.86 (2H, br), 4.74 (1H, brs), 6.65-6.78 (3H, m), 7.16 (1H, t,> 7.6Hz)

FAB-MS (m / z) 321 (M ⁺ + 1)

Example 545

Synthesis of N- (3 - (N'-ethyl-N'-methylguanidino) phenylethyl) amine dihydrochloride

Using the compound obtained in Example 544 as starting material, 106 mg of the title compound were obtained according to the procedure in Example 5 (93% yield).

Ή-NMR (D ₂ O) δ: 1.26 (3H, t,> 7.3 Hz), 3.03 (2H, t,> 7.3 Hz), 3.13 (3H, s), 3 , 30 (2H, t,> 7.3Hz), 3.50 (2H, q,> 7.3Hz), 7.21-7.23 (2H, m), 7.31 (1H, d, > 7.9 Hz, 7.48 (1H, t,> 8.2 Hz)

MS (m / z) 220 (M ⁺ + 1)

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171

Example 546

Synthesis of N- (5-nitro-2-piperidinophenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 263 as the starting material and also using piperidine as a reagent in the absence of solvent, the procedure of Example 264 gave 1.524 g of the title compound (98% yield).

Ή-NMR (CDCl ₃ ) δ: 1.45 (18H, s), 1.60-1.79 (6H, m), 2.91-2.95 (4H, m), 4.82 (2H, s), 7.O4 (1H, d, J = 8.6Hz), 8.00 (IH, d,> 2.3Hz), 8.09 (IH, dd,> 8.6,2.3 Hz)

FAB-MS (m / z) 436 (M ⁺ + 1)

Example 547

Synthesis of N- (5-amino-2-piperidinophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 546 as the starting material, the procedure in Example 2 gave 1.01 g of the title compound (72% yield).

Ή-NMR (CDCl ₃ ) δ: 1.41 (18H, s), 1.43-1.72 (6H, m), 2.65-2.73 (4H, m), 3.45 (2H, br), 4.84 (2H, s), 6.44 (1H, d,> 2.6Hz), 6.52 (IH, dd,> 8.3.2.6Hz), 6.89 ( IH, d,> 8.3 Hz)

FAB-MS (m / z) 406 (M ⁺ + 1)

Example 548

Synthesis of N- (2-piperidine-5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 547 as the starting material, the procedure of Example 120 afforded 0.59 g of the title compound (81% yield).

Ή-NMR (CDCl ₃ ) δ: 1.44 (18H, s), 1.56-1.79 (6H, m), 2.78-2.83 (4H, m), 4.83 (2H, s), 5.99 (2H, brs), 6.93-6.94 (IH, m), 7.05-7.06 (2H, m), 7.72 (IH, brs)

MS (m / z) 464 (M ⁺ ).

Example 549

Synthesis of N- (5- (S-ethylisothioureido) -2-piperidinophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 548 as a starting material, the procedure of Example 95 gave 0.271 g of the title compound (85% yield).

Ή-NMR (CDCl ₃ ) δ: 1.26 (3H, t,> 7.3 Hz), 1.41 (18H, s), 1.48-1.73 (6H, m), 2.67- 2.85 (4H, m), 2.92-3.13 (2H, m), 4.82 (IH, br), 4.86 (2H, s), 6.62-6.78 (2H, m), 7.00 (IH, d,> 8.3 Hz)

MS (m / z) 492 (M ⁺ )

Example 550

Synthesis of N- (5- (S-ethylisothioureido) -2-piperidinophenylmethyl) amine trihydrochloride

Using the compound obtained in Example 549 as starting material, 128.4 mg of the title compound were obtained according to the procedure in Example 5 (58% yield).

Ή-NMR (D ₂ O) δ: 1.41 (3H, t,> 7.3 Hz), 1.67-185 (2H, m), 1.94-2.11 (4H, m), 3.24 (2H, q,> 7.3Hz), 3.40-3.69 (4H, m), 4.42 (2H, s), 7.56-7.68 (2H, m), 7, 78-7, 92 (IH, m)

MS (m / z) 292 (M ⁺ )

Example 551

Synthesis of N- (3- (di- (t-butoxycarbonyl) aminomethyl) -4-piperidinophenyl) sulfamic acid

Using the compound obtained in Example 548 as the starting material, 152 mg of the title compound was obtained according to the procedure of Example 277 (74% yield).

Ή-NMR (CDC1 ₃₎

172

183 619 δ: 1.42 (18Η, s), 1.50-1.73 (6Η, m), 2.67-2.85 (4H, m), 4.83 (2H, s), 7, 6 (1H, s), 7.15 (1H, d,> 8.6Hz), 7.22-7.32 (1H, m)

Example 552

Synthesis of N- (5- (N'-ethylguanidino) -2-piperidino) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 551 as starting material, the procedure of Example 442 gave 0.11 g of the title compound (53% yield).

Ή-NMR (CDCl ₃ ) δ: 1.17 (3H, t,> 7.3Hz), 1.40 (18H, s), 1.47-1.75 (6H, m), 2.68- 2.83 (4H, m), 3.21 (2H, q,> 7.3Hz), 4.84 (2H, s), 6.69 (1H, s), 6.75 (1H, d, J = 8.3Hz), 6.97 (1H, d,> 8.3Hz)

MS (m / z) 475 (M ⁺ )

Example 553

Synthesis of N- (5- (N'-ethylguanidino) -2-piperidinophenylmethyl) amine trihydrochloride

Using the compound obtained in Example 552 as a starting material, 76.7 mg of the title compound were obtained according to the procedure in Example 5 (87% yield).

Ή-NMR (D ₂ O) δ: 1.23 (3H, t, J = 7.3 Hz), 1.69-1.81 (2H, m), 1.97-2.09 (4H, m ), 3.34 (2H, q,> 7.3Hz), 3.51 (4H, t, J = 5.6Hz), 4.39 (2H, s), 7.48 (1H, d, J = 2.3 Hz), 7.53 (1H, dd,> 8.9.2.3 Hz), 7.77 (1H, d,> 8.9 Hz)

FAB-MS (m / z) 276 (M ⁺ + 1)

Example 554

Synthesis of N- (2-chloro-5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using 2-chloro-5-nitrobenzyl bromide as the starting material, the procedure of Example 127 gave 3.5 g of the title compound (92% yield).

Ή-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.50 (9H, s), 4.95 (2H, s), 7.53 (1H, dd, J = 5.6, 3.2 Hz), 8.02-8.13 (2H, m)

FAB-MS (m / z) 387 (M ⁺ +1)

Example 555

Synthesis of N- (5-amino-2-chlorophenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 554 as the starting material and also using Raney nickel as a catalyst, the procedure in Example 2 gave 3.17 g of the title compound (98% yield).

Ή-NMR (CDCl ₃ ) δ: 1.48 (18H, s), 3.69 (2H, brs), 4.82 (2H, s), 6.47 (1H, s), 6.49-6 . 52 (1H, m), 7.08 (1H, d,> 7.6Hz)

MS (m / z) 356 (M ⁺ )

Example 556

Synthesis of N- (2-chloro-5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 555 as the starting material, the procedure of Example 120 afforded 0.45 g of the title compound (74% yield).

Ή-NMR (CDCl ₃ ) δ: 1.48 (18H, s), 4.87 (2H, s), 6.12 (2H, brs), 7.04 (1H, s), 7.09 (1H , d,> 8.6 Hz), 7.41 (1H, d,> 8.6 Hz), 8.03 (1H, brs)

MS (m / z) 415 (M ⁺ )

Example 557

Synthesis of N- (2-chloro-5- (S-ethylisothioureido) phenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 556 as starting material, the procedure of Example 95 gave 0.37 g of the title compound (99% yield).

183 619

173 'H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.44 (9H, s), 4.12 (2H, q, J = 7.3 Hz ), 4.35 (2H, d, J = 5.9Hz), 5.00 (1H, brs), 6.68-6.83 (1H, m), 6.93 (1H, s), 7 . 21-7.33 (1H, m)

FAB-MS (m / z) 343 (M ⁺ + 1)

Example 558

Synthesis of N- (2-chloro-5- (S-ethylisothioureido) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 557 as a starting material, the procedure of Example 5 gave 198.3 mg of the title compound (59% yield).

1 H-NMR (D ₂ O) δ: 1.42 (3H, t, J = 7.3 Hz), 3.25 (2H, q,> 7.3 Hz), 4.38 (2H, s) , 7.47 (1H, dd,> 8.6, 2.6Hz), 7.55 (1H, d,> 2.6Hz), 7.71 (1H, d,> 8.6Hz)

FAB-MS (m / z) 244 (M ⁺ + 1)

Example 559

Synthesis of N- (5- (N'-t-butoxycarbonyl-N'-ethyl) guanidino) -2-chlorophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 555 as starting material, the procedure of Example 233 gave 0.159 g of the title compound (52% yield).

1 H-NMR (CDCl 3) δ: 1.07-1.40 (3H, m), 1.46 (18H, s), 1.48 (9H, s), 3.38-3.43 (2H, m), 4.87 (2H, s), 6.75-6.98 (1H, m), 7.28-7.42 (2H, m)

FAB-MS (m / z) 527 (M ⁺ + 1)

Example 560

Synthesis of N- (2-chloro-5- (N'-ethyl) guanidino) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 559 as a starting material, the procedure of Example 5 gave 62.2 mg of the title compound (69% yield).

1 H-NMR (D ₂ O) δ: 1.23 (3H, t,> 7.3 Hz), 3.33 (2H, q,> 7.3 Hz), 4.35 (2H, s), 7.38 (1H, dd,> 8.6, 2.6Hz), 7.45 (1H, d,> 2.6Hz), 7.64 (1H, d,> 8.6Hz)

FAB-MS (m / z) 277 (M ⁺ + 1)

Example 561

Synthesis of 2- (2-benzyloxyphenyl) -2-methyl-propionic acid methyl ester

By using 2-benzyloxyphenylacetic acid methyl ester as a starting material and also using potassium t-butoxide as a base, 2- (2- (benzyloxyphenyl) propionic acid methyl ester was obtained according to the procedure of Example 1a. Using lithium diisopropylamide as a base, the resulting 2-acid methyl ester was obtained. (2-benzyloxyphenyl) propionic acid was then treated as in Example 1a to give 4.72 g of the title compound (70% yield).

1 H-NMR (CDCl 3) δ: 1.58 (6H, s), 3.42 (3H, s), 5.07 (2H, s), 6.91 (1H, dd,> 7.3.1 , 2 Hz), 6.99 (1H, dd,> 7.3, 1.2 Hz), 7.21 (1H, dd,> 7.9, 1.8 Hz), 7.33 (1H, dd ,> 7.9.1.8Hz), 7.35-7.40 (5H, m)

Example 562

Synthesis of 2- (2-benzyloxy-5-nitrophenyl) -2-methylpropionic acid methyl ester To a mixture of sulfuric acid (0.27 ml) and nitric acid (0.34 ml), a solution of the compound (1.0 g) obtained in Example 561 in acetic acid (30 ml) at 5 ° C. The reaction mixture was stirred at 45 ° C for 4 hours, poured into ice water, and ethyl acetate was added to the mixture. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 9: 1) to give 530 mg of the title compound (yield 46%).

Ή-NMR (CDC1 ₃₎

174

183 619 δ: 1.60 (6Η, s), 3.42 (3Η, s), 5.29 (2H, s), 6.99 (1H, d,> 9.2 Hz), 7.33- 7.45 (5H, m), 8.16 (1H, dd,> 9.2, 3.1Hz), 8.25 (1H, d,> 3.1Hz)

Example 563

Synthesis of 2- (2-benzyloxy-5-nitrophenyl) -2-methylpropionic acid

To the compound (1.54 g) obtained in Example 562 in 1,4-dioxane (20 ml) was added an aqueous lithium hydroxide solution (1.0 M, 47 ml). The reaction mixture was refluxed at 100 ° C for 12 hours and then 2N HCl and ethyl acetate were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ethyl acetate to obtain 1.355 g of the title compound (92% yield).

Ή-NMR (CDCl ₃ ) δ: 1.60 (6H, s), 5.02 (2H, s), 6.91 (1H, d,> 9.2 Hz), 7.30-7.37 ( 5H, m), 8.16 (1H, dd,> 9.2, 3.1Hz), 8.25 (1H, d,> 3.1Hz)

Example 564

Synthesis of N- (1 - (2-benzyloxy-5-nitrophenyl) -1-methylethyl) amine

To a mixture of the compound (1.6 g) obtained in Example 563, methylene chloride (20 ml) and triethylamine (0.92 ml), diphenylphosphorylazide (1.37 ml) was added. The reaction mixture was stirred at room temperature for 10 hours and 2N HCl and chloroform were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Water (16 ml) and 1,4-dioxane (32 ml) were added to the resulting residue. The reaction mixture was refluxed for 2 hours and 2N HCl was added and chloroform was added. After adding 2N sodium hydroxide aqueous solution and chloroform to the aqueous layer, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 1.09 g of the title compound (yield 75%).

Ή-NMR (CDCl ₃ ) δ: 1.58 (6H, s), 2.01 (2H, brs), 5.25 (2H, s), 7.03 (1H, d,> 9.2 Hz) , 7.37-7.45 (5H, m), 8.13 (1H, dd,> 9.2, 3.1Hz), 8.35 (1H, d,> 3.1Hz)

Example 565

Synthesis of N- (1- (2-benzyloxy-5-nitrophenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 564 as the starting material and also using potassium carbonate as a base, the procedure of Example 63 gave 828 mg of the title compound (94% yield).

Ή-NMR (CDCl ₃ ) δ: 1.34 (9H, s), 1.71 (6H, s), 5.07 (1H, brs), 5.18 (2H, s), 7.00 (1H , d,> 9.2 Hz), 7.35-7.48 (5H, m), 8.1 3 (1H, dd,> 9.2, 3.1 Hg), 8.29 (1H, d ,> 3.1 Hz)

Example 566

Synthesis of N- (1- (5-amino-2-benzylphenyl) -1-methylethyl) carbamic acid t-butyl ester

Sodium borohydride (39 mg) was added to a mixture of the compound (100 mg) obtained in Example 565, nickel (II) chloride hexahydrate (123 mg) and methanol (6 ml). The reaction mixture was stirred at room temperature for 10 minutes; then 2N HCl and a saturated aqueous sodium bicarbonate solution and chloroform were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 3: 2) to give 87 mg of the title compound (yield 94%).

Ή-NMR (CDCl ₃ ) δ: 1.34 (9H, s), 1.66 (6H, s), 2.80 (2H, br), 4.99 (2H, s), 5.27 (1H , brs), 6.54 (1H, dd,> 8.6, 2.4Hz), 6.74 (1H, d,> 2.4Hz), 6.78 (1H, d,> 8.6 Hz), 7.29-7.49 (5H, m)

183 619

175

Example 567

Synthesis of N- (1- (2-benzyloxy-5- (N'-nitroguanidino) phenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 566 as starting material, 110 mg of the title compound was obtained according to the procedure in Example 6 (89% yield).

Ή-NMR (CDCl ₃ ) δ: 1.36 (9H, s), 1.69 (6H, s), 5.11 (2H, s), 7.01 (1H, d,> 8.5 Hz) , 7.18 (1H, dd,> 8.5.2.4Hz), 7.31 (1H, d,> 2.4Hz), 7.34-7.46 (5H, m), 9. 35 (1H, brs)

Example 568

Synthesis of N- (1- (2-benzyloxy-5- (N'-nitroguanidino) phenyl) -1-methylmethyl) amine

Using the compound obtained in Example 567 as a starting material, the procedure of Example 34 gave 47.4 mg of the title compound (58% yield).

Ή-NMR (CDCl 3) δ: 1.58 (6H, s), 5.16 (2H, s), 7.01 (1H, d,> 8.5 Hz), 7.16 (1H, dd,> 8.5Hz, 2.4Hz), 7.34 (1H, d,> 2.4Hz), 7.35-7.46 (5H, m)

Example 569

Synthesis of N- (1- (2-benzyloxy-5- (N'-t-butoxycarbonyl-N * -ethylguanidino) phenyl) -1-methylethyljcarbamic acid t-butyl ester

Using the compound obtained in Example 566 as starting material, 106 mg of the title compound were obtained according to the procedure of Example 233 (72% yield).

Ή-NMR (CDCl ₃ ) δ: 1.09 (3H, t,> 7.3 Hz), 1.34 (9H, s), 1.53 (9H, s), 1.67 (6H, s) , 3.34-3.46 (2H, m), 4.80 (1H, brs), 5.07 (2H, s), 5.14 (1H, brs), 6.94 (1H, d,> 8.6 Hz), 7.02-7.07 (1H, m), 7.22 (1H, s), 7.32-7.50 (5H, m), 10.53 (1H, br)

Example 570

Synthesis of N- (1 - (2-benzyloxy-5 - (Ν'-ethylguanidino) phenyl) -1-methylethyl) amine

Using the compound obtained in Example 569 as a starting material, the procedure of Example 34 gave 58 mg of the title compound (88% yield).

Ή-NMR (CDCl ₃ ) δ: 1.16 (3H, t,> 7.3 Hz), 1.51 (6H, s), 3.23 (2H, q,> 7.3 Hz), 3, 69 (2H, br), 5.09 (2H, s), 6.75 (1H, dd,> 8.5 2.4Hz), 6.89 (1H, d,> 8.5Hz), 6 . 95 (1H, d,> 2.4Hz), 7.29-7.47 (5H, m)

Example 571

Synthesis of N- (1- (2-benzyloxy-5-thioureido) phenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 566 as starting material, the procedure of Example 120 gave 114 mg of the title compound (98% yield).

Ή-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.67 (6H, s), 5.09 (2H, s), 6.16 (2H, brs), 6.95 (1H , d,> 8.6 Hz), 7.05 (1H, dd,> 8.6, 2.4 Hz), 7.27 (1H, d,> 2.4 Hz), 7.36-7, 46 (5H, m), 7.80 (1H, brs)

Example 572

Synthesis of N- (1- (2-benzyloxy-5- (S-ethylisothioureido) phenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 571 as the starting material, the procedure of Example 95 gave 105.5 mg of the title compound (92% yield).

Ή-NMR (CDCl 3) δ: 1.32-1.37 (3H, m), 1.34 (9H, s), 1.67 (6H, s), 3.03 (2H, q,> 7, 3 Hz), 5.04 (2H, s), 5.22 (1H, brs), 6.78 (1H, dd,> 8.6, 2.4Hz), 6.90 (1H, d,> 8.6 Hz), 6.95 (1H, d,> 2.4 Hz), 7.31-7.50 (5H, m)

Example 573

Synthesis of N- (1 - (2-benzyl-5- (S-ethylisothioureido) phenyl) -1-methylethyl) amine

Using the compound obtained in Example 572 as starting material, the procedure of Example 34 gave 51 mg of the title compound (63% yield).

176

183 619

Ή-NMR (CDCl ₃ ) δ: 1.32 (3H, t,> 7.3 Hz), 1.68 (6H, s), 2.97 (2H, q,> 7.3 Hz), 5, 15 (2H, s), 5.63 (4H, br), 6.67 (1H, d,> 8.5Hz), 6.77-6.82 (2H, m), 7.32-7.42 (5H, m)

Example 574

Synthesis of 2- (2-benzyloxy-3-nitrophenyl) -2-methyl-propionic acid methyl ester

According to the procedure of Example 562, 140 mg of the title compound were obtained (12% yield).

Ή-NMR (CDCl ₃ ) δ: 1.57 (6H, s), 3.38 (3H, s), 4.84 (2H, s), 7.20 (1H, t,> 7.9Hz) , 7.31-7.45 (5H, m), 7.58 (1H, dd,> 7.9.1.8Hz), 7.75 (1H, dd,> 7.9.1.8Hz )

Example 575

Synthesis of 2- (2-benzyloxy-3-nitrophenyl) -2-methylpropionic acid

Using the compound obtained in Example 574 as the starting material, according to the procedure of Example 563, 370 mg of the title compound was obtained (86% yield).

Ή-NMR (CDCl ₃ ) δ: 1.54 (6H, s), 4.83 (2H, s), 7.19 (1H, t,> 7.9 Hz), 7.29-7.41 ( 5H, m), 7.57 (1H, dd,> 7.9, 1.2Hz), 7.76 (1H, dd,> 7.9.1.2Hz)

Example 576

Synthesis of N- (1- (2-benzyloxy-3-nitrophenyl) -1-methylethyl) amine

Using the compound obtained in Example 575 as a starting material according to the procedure of Example 564, 268 mg of the title compound were obtained (81% yield).

Ή-NMR (CDCl ₃ ) δ: 1.52 (6H, s), 2.03 (2H, s), 5.24 (2H, s), 7.14 (1H, t,> 7.9 Hz) , 7.34-7.49 (5H, m), 7.68 (1H, dd,> 3.7,1.8Hz), 7.71 (1H, dd,> 3.7,1.8Hz )

Example 577

Synthesis of N- (1- (2-benzyloxy-3-nitrophenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 576 as starting material, according to the procedure of Example 565, 329 mg of the title compound were obtained (91% yield).

Ή-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 1.69 (6H, s), 4.86 (2H, s), 5.03 (1H, brs), 7.18 (1H , t,> 7.9Hz), 7.33-7.46 (3H, m), 7.5-7.66 (2H, m), 7.67 (1H, dd,> 7.9.1, 8Hz), 7.73 (1H, dd,> 7.9L, 81iz)

Example 578

Synthesis of N- (1- (3-amino-2-benzyloxyphenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 577 as starting material, according to the procedure of Example 566, 244 mg of the title compound was obtained (81% yield).

Ή-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.72 (6H, s), 3.67 (2H, s), 4.96 (2H, s), 5.34 (1H , br), 6.69 (lH, dd,> 7.9.1.8Hz), 6.82 (IH, dd,> 7.9.1.8Hz), 6.90 (1H, t, > 7.9Hz), 7.30-7.46 (3H, m), 7.51-7.55 (2H, m)

Example 579

Synthesis of N- (1 - (2-benzyloxy-3- (N'-t-butoxycarbonyl-N'-ethylguanidino) phenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 578 as starting material, 82.4 mg of the title compound was obtained according to the procedure of Example 233 (70% yield).

Ή-NMR (CDCl ₃ ) δ: 1.03-1.14 (3H, m), 1.37 (9H, s), 1.20-1.60 (9H, m), 1.69 (6H, s), 3.15-3.43 (2H, m), 4.81-5.16 (3H, m), 6.97-7.23 (3H, m), 7.30-7.42 ( 3H, m), 7.45-7.53 (2H, m)

Example 580

Synthesis of N- (1- (2-benzyloxy-3- (N'-ethyl) guanidino) phenyl) -1-methylethyl) amine

Using the compound obtained in Example 579 as a starting material, the procedure of Example 34 gave 46.5 mg of the title compound (92% yield).

Ή-NMR (CDC1 ₃₎

183 619

177 δ: 1.12 (3Η, t,> 7.3 Hz), 1.53 (6H, s), 3.19 (2H, q,> 7.3 Hz), 5.17 (2H, s) , 6.86 (1H, dd,> 7.9.1.8Hz), 6.97 (1H, t,> 7.9Hz), 7.04 (1H, dd,> 7.9.1, 8 Hz), 7.25-7.46 (3H, m), 7.47-7.49 (2H, m)

Example 581

Synthesis of N- (1- (2-benzyloxy-3-thioureido) phenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 578 as the starting material, according to the procedure of Example 120, 94 mg of the title compound were obtained (99.6% yield).

1-NMR (CDCl ₃ ) δ: 1.34 (9H, s), 1.65 (6H, s), 4.92 (2H, s), 5.13 (1H, s), 6.38 ( 2H, brs), 7.11 (1H, t,> 7.9Hz), 7.17-7.21 (1H, m), 7.30-7.44 (4H, m), 7.56- 7.61 (2H, m), 8.37 (1H, s)

Example 582

Synthesis of N- (1- (2-benzyloxy-3- (S-ethylisothioureido) phenyl) -1-methylethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 581 as a starting material, the procedure of Example 95 gave 98 mg of the title compound (98% yield).

1 H-NMR (CDCl 3) δ: 1.28 (3H, t,> 7.3Hz), 1.35 (9H, s), 1.68 (6H, s), 3.00-3.07 ( 2H, m), 4.52 (2H, br s), 4.99 (2H, s), 5.17 (1H, br s), 6.80-6.85 (1H, m), 7.01 (1H , t,> 7.9Hz), 7.11 (1H, dd,> 7.9, 1.8Hz), 7.27-7.42 (3H, m), 7.49-7.54 ( 2H, m)

Example 583

Synthesis of N- (1- (2-benzyloxy-3- (S-ethylisothioureido) phenyl) -1-methylethyl) amine

Using the compound obtained in Example 582 as a starting material, the procedure of Example 34 gave 72 mg of the title compound (95% yield).

1 H-NMR (CDCl 3) δ: 1.30 (3H, t,> 7.3Hz), 1.53 (6H, s), 2.12 (2H, brs), 2.96-3.08 ( 2H, m), 4.60 (1H, br s), 5.10 (2H, s), 6.79-6.87 (1H, m), 7.00 (1H, t,> 7.9Hz) , 7.10 (1H, dd,> 7.9, 1.8Hz), 7.28-7.41 (5H, m), 7.47 (1H, dd,> 7.9, 1.8Hz )

Example 584

Synthesis of N- (5-nitro-2-pyrrolidin-1-yl) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 263 as the starting material and also using the pyrrolidine as reagent, the procedure of Example 264 gave the title compound (80% yield).

1 H-NMR (CDCl 3) δ: 1.47 (18H, s), 1.95-2.05 (4H, m), 3.38-3.42 (4H, m), 4.87 (2H, s), 6.70-6.80 (1H, m), 7.95-8.03 (2H, m)

Example 585

Synthesis of N- (5-amino-2-pyrrolidin-1-yl) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 584 as a starting material, the title compound was obtained according to the procedure in Example 2 (98% yield).

1 H-NMR (CDCl 3) δ: 1.40 (18H, s), 1.84-1.88 (4H, m), 2.89-2.93 (4H, m), 4.50 (2H, brs), 4.81 (2H, s), 6.45-6.53 (2H, m), 6.88 (1H, d,> 8.3Hz)

MS (m / z) 392 (M ⁺ + 1)

Example 586

Synthesis of N- (2-pyrrolidin-1-yl) -5-thioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 585 as starting material, the title compound was obtained according to the procedure of Example 120 (yield 94%).

'H-NMR (CDCl3)

178

183 619 δ: 1.44 (18Η, s), 1.94-1.97 (4Η, m), 3.12-3.16 (4H, m), 4.78 (2H, s), 5, 94 (2H, brs), 6.91-7.00 (3H, m), 7.66 (1H, brs)

MS (m / z) 450 (M ⁺ )

Example 587

Synthesis of N- (5- (S-ethylisothioureido) -2- (pyrrolidin-1-yl) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 586 as a starting material, the procedure of Example 95 gave the title compound (85% yield).

Ή-NMR (CDCl ₃ ) δ: 1.33 (3H, t,> 7.3 Hz), 1.41 (18H, s), 1.87-1.90 (4H, m), 2.90- 3.10 (4H, m), 4.39-4.69 (2H, m), 4.81 (2H, s), 6.62-6.82 (2H, m), 6.95 (1H, d,> 8.1 Hz)

Example 588

Synthesis of N- (5- (S-ethylisothioureido) -2-pyrrolidin-1-yl) phenylmethyl) amine trihydrochloride

Using the compound obtained in Example 587 as a starting material, the procedure of Example 5 gave the title compound (63% yield).

Ή-NMR (D ₂ O) δ: 1.41 (3H, t,> 7.5 Hz), 2.07-2.29 (4H, m), 3.25 (2H, q,> 7.5 Hz), 3.60-3.83 (4H, m), 4.46 (2H, s), 7.60-7.82 (3H, m)

MS (m / z) 278 (M ⁺ )

Example 589

Synthesis of N- (5- (N'-t-butoxycarbonyl-N-ethylguanidino) -2-pyrrolidin-1-yl) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 585 as the starting material, the title compound was obtained according to the procedure of Example 233 (yield 71%).

Ή-NMR (CDCl3) δ: 1.06 (3H, t,> 7.3Hz), 1.48 (18H, s), 1.59 (9H, s), 1.93-2.03 (4H , m), 3.00-3.10 (4H, m), 3.33-3.43 (2H, m), 4.58 (1H, br s), 4.79 (2H, s), 6, 90-6.95 (3H, m), 10.49 (1H, br s)

Example 590

Synthesis of N- (5- (N'-ethyl) guanidino) -2-pyrrolidin-1-yl) phenylmethyl) amine trihydrochloride

Using the compound obtained in Example 589 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 91%).

¹ H-NMR (D ₂ O) δ: 1.24 (3H, t,> 7.3 Hz), 2.29-2.31 (4H, m), 3.35 (2H, q,> 7, 3 Hz), 3.84-4.00 (4H, m), 4.45 (2H, s), 7.51-7.78 (3H, m)

Example 591

Synthesis of N- (2- (4- (N'-t-butoxycarbonyl-N'-ethylguanidino) -3-methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 490 as the starting material, the procedure of Example 233 gave 12 mg of the title compound (16% yield).

Ή-NMR (CDCl ₃ ) δ: 1.05-1.20 (3H, m), 1.44 (9H, s), 1.52 (9H, s), 2.78 (2H, t,> 6 , 9 Hz), 3.32-3.47 (4H, m), 3.84 (3H, s), 4.57 (1H, br s), 6.74-6.92 (3H, m)

Example 592

Synthesis of N- (2- (4- (N'-ethylguanidino) -3-methoxyphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 591 as a starting material, the procedure of Example 5 gave 8 mg of the title compound (94% yield).

H-NMR (D ₂ O) δ: 1.20 (3H, t,> 7.3 Hz), 3.03 (2H, t,> 7.3 Hz), 3.24-3.33 (4H, m), 3.89 (3H, s), 6.99 (1H, d,> 7.9Hz), 7.10 (1H, s), 7.27 (1H, d,> 7.9Hz)

183 619

179

Example 593

Synthesis of N- (2- (4- (N'-t-butoxycarbonyl-N * -ethylguanidino) -3-chlorophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 495 as starting material, the procedure of Example 233 gave 27 mg of the title compound (yield 17%).

Ή-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3Hz), 1.44 (9H, s), 1.47 (9H, s), 2.75 (2H, t, J = 6.9Hz), 3.30-3.50 (4H, m), 4.53 (1H, brs), 7.00-7.30 (3H, m)

Example 594

Synthesis of N- (2- (3-chloro-4- (N'-ethylguanidino) phenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 593 as starting material, the procedure in Example 5 gave 17 mg of the title compound (88% yield).

Ή-NMR (D ₂ O) δ: 1.22 (3H, t,> 7.3 Hz), 3.04 (2H, t,> 7.3 Hz), 3.27-3.36 (4H, m), 7.33-7.44 (2H, m), 7.56 (1H, s)

Example 595

Synthesis of N- (2- (4- (N'-t-butoxycarbonyl-N'-ethylguanidino) -3-fluorophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 504 as a starting material, the procedure of Example 233 gave 90 mg of the title compound (54% yield).

Ή-NMR (CDCl 3) δ: 1.10-1.32 (3H, m), 1.44 (9H, s), 1.48 (9H, s), 2.77 (2H, t,> 6, 9 Hz), 3.35-3.46 (4H, m), 4.55 (1H, brs), 6.90-7.00 (3H, m)

Example 596

Synthesis of N- (2- (4- (N'-t-butoxycarbonyl-Netylguanidino) -3-fluorophenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 595 as the starting material, the procedure of Example 5 gave 53 mg of the title compound (93% yield).

Ή-NMR (D ₂ O) δ: 1.22 (3H, t,> 7.3 Hz), 3.04 (2H, t,> 7.3 Hz), 3.27-3.36 (4H, m), 7.19-7.41 (3H, m)

Example 597

Synthesis of N- (1- (3- (N ^/ -t-butoxycarbonyl-N-ethylguanidino) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 9 as the starting material, the procedure of Example 233 gave 280 mg of the title compound (81% yield).

Ή-NMR (CDCl 3) δ: 1.02-1.20 (3H, m), 1.42 (12H, brs), 1.51 (9H, s), 3.38-3.43 (2H, m ), 4.64-4.90 (2H, m), 6.90-7.20 (4H, m)

Example 598

Synthesis of N- (1- (3- (N'-ethylguanidino) phenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 597 as the starting material, the procedure of Example 5 gave 54 mg of the title compound (88% yield).

Ή-NMR (D ₂ O) δ: 1.22 (3H, t,> 7.3 Hz), 1.65 (3H, d,> 6.9 Hz), 3.32 (2H, q,> 7 , 3Hz), 4.57 (1H, q,> 6.9Hz), 7.34-7.60 (4H, m)

Example 599

Synthesis of N- (2- (4- (N'-t-butoxycarbonyl-N'-ethylguanidino) -3-methylphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 523 as starting material, the procedure of Example 233 gave 43.5 mg of the title compound (39% yield).

Ή-NMR (CDCl3)

180

183 619 δ: 10.5 (1Η, brs), 7.18-7.00 (3H, m), 4.57 (1H, brs), 4.40 (1H, brs), 3.36 (2H, dt, J = 5.4.6.4Hz), 2.76 (2H, t, J-6.4Hz), 2.23 (3H, s), 1.52 (9H, s), 1. 44 (9H, s), 1.03-1.19 (3H, m)

Example 600

Synthesis of N- (2- (4- (N'-ethyl) guanidino-3-methylphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 599 as a starting material, the procedure of Example 5 gave 28.3 mg of the title compound (93% yield).

Ή-NMR (DMSO-d ₆ ) δ: 9.54 (1H, s), 8.00-8.25 (4H, m), 7.80 (1H, brs), 7.50 (2H, brs) , 7.23 (lH, s), 7.20-7.12 (2H, m), 3.34-3.17 (2H, m), 3.18-2.82 (4H, m), 2 , 19 (3H, s), 1.11 (3H, t, J = 7.1Hz) Example 601

Synthesis of N- (3-chloro-4-hydroxyethylphenyl) carbamic acid t-butyl ester

Water was added to 4-amino-2-chlorobenzyl alcohol (1.0125 g), and after adding sodium hydroxide (283 mg) and di-t-butyl bicarbonate (1.543 g) at room temperature, the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the organic layer was washed once with water, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 3: 1) to give 1.0576 g of the title compound (64% yield).

Ή-NMR (CDCl ₃ ) δ: 7.56 (1H, d, J = 2.1 Hz), 7.35 (1H, d, J = 8.3 Hz), 7.15 (1H, dd, J = 2.1.8.3Hz), 6.55 (1H, s), 4.71 (2H, s), 2.01 (1H, br s), 1.52 (9H, s)

Example 602

Synthesis of N- (3-chloro-4-cyanomethylphenyl) carbamic acid t-butyl ester

The compound (555.3 mg) obtained in Example 601 was dissolved in methylene chloride (10 ml); triphenylphosphine (735 mg) and carbon tetrabromide (930 mg) were successively added to the solution under ice-cooling, and the mixture was stirred for 30 minutes, then stirred at room temperature for 30 minutes. Subsequently, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in dimethylsulfoxide (5 ml); Potassium cyanide (117.8 mg) was added to the solution, heated at 50 ° C, and stirred for 10 minutes. Ethyl acetate was added to the resulting reaction mixture, and the organic layer was washed with water twice, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 3: 1) to give 89.6 mg of the title compound (16% yield).

Ή-NMR (CDCl ₃ ) δ: 7.66 (1H, d, J = 2.2 Hz), 7.39 (1H, d, J = 8.6 Hz), 7.18 (1H, dd, J = 2.2, 8.6Hz), 6.53 (1H, brs), 3.78 (2H, s), 1.52 (9H, s)

Example 603

Synthesis of 3-chloro-4-cyanomethylaniline

Using the compound obtained in Example 602 as the starting material, the procedure of Example 521 gave 184.7 mg of the title compound (88% yield).

Ή-NMR (CDCl ₃ ) δ: 7.21 (1H, d, J = 8.1 Hz), 6.73 (1H, d, J = 2.5 Hz), 6.57 (1H, dd, J = 2.5.8.3Hz), 3.80 (2Hbrs), 3.71 (2H, s)

Example 604

Synthesis of 4- (2-aminoethyl) -3-chloroaniline

Using the compound obtained in Example 603 as the starting material, the procedure of Example 252 gave 189 mg of the title compound (100% yield).

Ή-NMR (CDCl ₃ ) δ: 7.00 (1H, d, J = 8.3 Hz), 6.71 (1H, d, J = 2.4 Hz), 6.52 (1H, dd, J = 2.4, 8.3Hz), 3.64 (2H, brs), 2.98-2.87 (2H, m), 2.83-2.71 (2H, m), 1.24 ( 2H, brs)

183 619

181

Example 605

Synthesis of N- (2- (4-amino-2-chlorophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 604 as starting material, 208.3 mg of the title compound were obtained according to the procedure of Example 253 (64% yield).

Ή-NMR (CDCl ₃ ) δ: 6.98 (1H, d, 1 = 8.1 Hz), 6.70 (1H, d, J = 2.4 Hz), 6.52 (1H, dd,> 2.4, 8.1Hz), 4.55 (1H, brs), 3.64 (2H, brs, 3.32 (2H, dt,> 6.6, 6.6Hz), 2.81 ( 2H, t,> 6.6Hz), 1.43 (9H, s)

Example 606

Synthesis of N- (2- (2-chloro-4-thioureidophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 605 as a starting material, the procedure of Example 120 gave 78.9 mg of the title compound (100% yield).

Ή-NMR (CDCl ₃ ) δ: 8.42 (1H, brs), 7.38-7.20 (2H, m), 7.17-7.04 (1H, m), 6.30 (2H, brs), 4.69 (lH, brs), 3.38 (2H, dt,> 6.6, 6.6Hz), 2.94 (2H, t,> 6.6Hz), 1.42 ( 9H, s)

Example 607

Synthesis of N- (2- (2-chloro-4- (S-ethylisothioureido) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 606 as a starting material, 66.7 mg of the title compound were obtained according to the procedure in Example 27 (78% yield).

Ή-NMR (CDCl ₃ ) δ: 7.15 (1H, d,> 8.3 Hz), 6.96 (1H, d,> 2.2 Hz), 6.77 (1H, dd,> 2, 2. 8.3Hz), 4.58 (1H, brs), 4.28 (2H, brs), 3.36 (2H, dt,> 6.6.6.6Hz), 3.01 (2H , q,> 7.3Hz), 2.88 (2H, t,> 6.6Hz), 1.44 (9H, s), 1.36 (3H, t,> 7.3Hz)

Example 608

Synthesis of N- (2- (2-chloro-4- (S-ethylisothioureido) phenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 607 as a starting material, the procedure in Example 5 gave 65.3 mg of the title compound (100% yield).

Ή-NMR (DMSO-d ₆ ) δ: 11.88 (1H, brs), 9.58 (2H, brs), 8.32 (3H, brs), 7.53 (1H, d,> 8.1 Hz), 7.52 (1H, d,> 2.2Hz), 4.10-3.60 (2H, m), 3.35 (2H, q,> 7.3Hz), 3.14- 2.93 (2H, m), 1.30 (3H, t,> 7.3Hz)

Example 609

Synthesis of N- (2- (4- (N'-t-butoxycarbonyl-N'-ethylguanidino) -2-chlorophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 605 as the starting material, the procedure of Example 233 gave 71.5 mg of the title compound (52% yield).

Ή-NMR (CDCl ₃ ) δ: 10.70 (1H, brs), 7.25-6.72 (4H, m), 4.58 (1H, brs), 3.47-3.27 (4H, m), 2.91 (2H, t,> 6.4Hz), 1.49 (9H, s), 1.44 (9H, s), 1.19 (3H, t,> 7.3Hz)

Example 610

Synthesis of N- (2- (2-chloro-4- (N'-ethylguanidino) phenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 609 as a starting material, the procedure in Example 5 gave 51.7 mg of the title compound (100% yield).

Ή-NMR (DMSO-d ₆ ) δ: 9.98 (lH, s), 8.35 (3H, brs), 8.11 (1H, brs), 7.83 (2H, brs), 7.44 (1H, d,> 8.3 Hz), 7.35 (1H, d,> 2.2 Hz, 7.18 (1H, dd,> 2.2, 8.3 Hz), 5.00-3 , 50 (2H, m), 3.36-3.15 (2H, m), 3.10-2.90 (2H, m), 1.13 (3H, t,> 7.1Hz)

Example 611

Synthesis of N- (2- (N-benzyl-N-methyl-amino) -5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as the starting material and also using N-methylbenzylamine as reagent, the procedure of Example 264 provided the title compound (56% yield).

182

183 619

Ή-NMR (CDCl ₃ ) δ: 1.47 (18H, s), 2.73 (3H, s), 4.19 (2H, s), 4.93 (2H, s), 7.07 (1H , d, J = 8.9Hz), 7.26-7.33 (5H, m), 8.03-8.09 (2H, m)

Example 612

Synthesis of N- (5-amino-2- (N-benzyl-N-methylamino) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 611 as starting material, the title compound was obtained according to the procedure of Example 566 (91% yield).

Ή-NMR (CDCl ₃ ) δ: 1.43 (18H, s), 2.48 (3H, s), 3.50 (2H, s), 3.91 (2H, s), 4.98 (2H , s), 6.45-6.47 (1H, m), 6.52-6.56 (1H, m), 6.98 (1H, d, J = 8.3Hz), 7.25- 7.40 (5H, m)

Example 613

Synthesis of N- (2- (N-benzyl-N-methyl-amino) -5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 612 as the starting material, the title compound was obtained according to the procedure of Example 120 (yield 94%).

Ή-NMR (CDCl ₃ ) δ: 1.46 (18H, s), 2.59 (3H, s), 4.02 (2H, s), 4.96 (2H, s), 6.03 (2H , brs), 6.98-7.00 (1H, m), 7.03-7.08 (1H, m), 7.16 (1H, d,> 8.3Hz), 7.26-7 . 37 (5H, m), 7.80 (1H, brs)

Example 614

Synthesis of N- (2- (N-benzyl-N-methylamino) -5- (S-ethylisothioureido) phenylmethyl) amine trihydrochloride

Using the compound obtained in Example 613 as the starting material, processing was performed as in Example 95 and the resulting compound prepared as in Example 5 to afford the title compound (95% yield).

Ή-NMR (D ₂ O) δ: 1.41 (3H, t,> 7.3 Hz), 3.12 (3H, s), 3.23 (2H, q,> 7.3 Hz), 3 , 94 (2H, s), 4.46 (2H, s), 7.20-7.23 (2H, m), 7.34-7.46 (4H, m), 7.58 (1H, dd ,> 8.9.2.6Hz), 7.76 (1H, d,> 8.9Hz)

Example 615

Synthesis of N- (2- (N-benzyl-N-methylamino) -5- (N'-t-butoxycarbonyl-N'-ethylguanidinephenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 612 as the starting material, the title compound was obtained according to the procedure of Example 233 (yield 58%).

Ή-NMR (CDCl ₃ ) δ: 1.05-1.11 (3H, m), 1.45 (18H, s), 1.53 (9H, s), 2.58 (3H, s), 3 , 32-3.45 (2H, m), 4.01 (2H, s), 4.97 (2H, s), 6.92-7.17 (3H, m), 7.26-7.39 (5H, m)

Example 616

Synthesis of N- (2- (N-benzyl-N-methylamino) -5- (N'-ethylguanidino) phenylmethyljamine trihydrochloride

Using the compound obtained in Example 615 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 89%).

Ή-NMR (D ₂ O) δ: 1.23 (3H, t,> 7.6 Hz), 3.23 (3H, s), 3.33 (2H, q,> 7.6 Hz), 3 . 82 (2H, s), 4.54 (2H, s), 7.18-7.25 (3H, m), 7.34-7.48 (3H, m), 7.53 (1H, dd ,> 8.9,2.3Hz), 7.77 (1H, d,> 8.9Hz)

Example 617

Synthesis of N- (1 - (2-methyl-3-nitrophenyl) ethyl) phthalimide

The title compound was obtained using 1- (2-methyl-3-nitrophenyl) ethanol as starting material according to the procedure of Example 179 (52% yield).

Ή-NMR (DMSO-d ₆ ) δ: 1.81 (3H, d,> 7.3 Hz), 2.31 (3H, s), 5.69 (1H, q,> 7.3 Hz), 7.48 (1H, dd,> 7.9.7.9Hz), 7.75 (1H, d,> 7.9Hz), 7.84 (4H, s), 7.97 (1H, d ,> 7.9 Hz)

183 619

183

Example 618

Synthesis of N- (1- (2-methyl-3-nitrophenyl) ethyl) carbamic acid t-butyl ester

By using the compound obtained in Example 617 as the starting material, the title compound was obtained according to the procedure of Example 309 (85% yield).

Ή-NMR (CDCl ₃ ) δ: 1.40 (9H, s), 1.41 (3H, d, J = 6.3Hz), 2.46 (3H, s), 4.83 (1H, brs) , 4.98-5.14 (IH, m), 7.31 (IH, dd,> 7.9, 7.9 Hz), 7.53 (IH, d, J = 7.9 Hz), 7 .61 (IH, d,> 7.9Hz)

Example 619

Synthesis of N- (1- (3-amino-2-methylphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 618 as a starting material, the title compound was obtained according to the procedure of Example 566 (70% yield).

Ή-NMR (CDCl ₃ ) δ: 1.41 (3H, d, J = 6.3 Hz), 1.42 (9H, s), 2.14 (3H, s), 3.61 (2H, brs ), 4.74 (1H, brs), 4.98-5.15 (IH, m), 6.62 (IH, d,> 7.9Hz), 6.74 (IH, d,> 7, 9 Hz), 7.02 (IH, dd,> 7.9, 7.9 Hz)

Example 620

Synthesis of N- (1- (2-methyl-3-thioureidophenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 619 as a starting material, the procedure of Example 120 gave the title compound in quantitative yield.

Ή-NMR (CDCl ₃ ) δ: 1.39 (3H, d,> 6.3 Hz), 1.41 (9H, s), 2.33 (3H, s), 4.89 (IH, brs) , 4.90-5.03 (IH, m), 7.15 (1H, d,> 7.6 Hz), 7.24-7.34 (2H, m), 7.71 (IH, brs)

Example 621

Synthesis of N- (1- (3- (S-ethylisothioureido) -2-methylphenyl) ethyl) carbamic acid t-butyl ester

By using the compound obtained in Example 620 as the starting material, the procedure of Example 95 gave the title compound (80% yield).

Ή-NMR (CDCl ₃ ) δ: 1.36-1.45 (3H, m), 1.40 (3H, d,> 7.3Hz), 1.42 (9H, s), 2.16 ( 3H, s), 3.02-3.18 (2H, m), 4.36 (1H, brs), 4.75 (1H, brs), 4.93-5.08 (1H, m), 6 , 73 (IH, d,> 7.6 Hz), 6.98 (IH, d,> 7.6 Hz), 7.13 (IH, dd,> 7.6, 7.6 Hz)

Example 622

Synthesis of N- (1- (3- (S-ethylisothioureido) -2-methylphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 621 as starting material, the title compound was obtained according to the procedure in Example 5 (yield 92%).

Ή-NMR (D ₂ O) δ: 1.43 (3H, t,> 7.3 Hz), 1.62 (3H, d,> 6.9 Hz), 2.29 (3H, s), 3 , 24-3.28 (2H, m) 4.88 (lH, q,> 6.9Hz), 7.37 (IH, dd,> 7.9,1.3Hz), 7.50 (lH, dd,> 7,9,7,9 Hz), 7.60 (IH, dd,> 7,9,1,3 Hz)

Example 623

Synthesis of N- (1- (3- (N'-t-butoxycarbonyl) -N-ethylguanidino) -2-methylphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 619 as a starting material, the title compound was obtained according to the procedure of Example 233 (yield 38%).

Ή-NMR (CDCl ₃ ) δ: 1.00-1.20 (3H, m), 1.40 (3H, d,> 7.3Hz), 1.41 (9H, s), 1.54 ( 9H, s), 2.29 3H, s), 3.36-3.45 (2H, m), 4.80 (1H, brs), 4.90-5.10 (1H, m), 7, 10-7.30 (2H, m)

Example 624

Synthesis of N- (1- (3- (N'-ethylguanidino) -2-methylphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 623 as starting material, the title compound was obtained according to the procedure in Example 5 (yield 92%).

Ή-NMR (D ₂ O)

184

183 619 δ: 1.22 (3Η, t,> 7.3 Hz), 1.62 (3H, d,> 6.6 Hz), 2.28 (3H, s), 3.31 (2H, q , J = 7.3Hz), 4.87 (1H, q, J = 6.6Hz), 7.34 (1H, dd,> 7.6,1.3Hz), 7.45 (1H, dd,> 7.6.7.6Hz), 7.53 (1H, dd,> 7.6, 1.3Hz)

Example 625

Synthesis of N-benzoyl-4-thioureidobenzylamine

Using 4-amino-N-benzoylbenzylamine as the starting material, the procedure of Example 120 gave 143.5 mg of the title compound (76% yield).

1 H-NMR (DMSO-d ₆ ) δ: 4.44 (2H, d,> 5.9 Hz), 7.20-7.38 (5H, m), 7.40-7.58 (4H, m), 7.89 (1H, d,> 6.6Hz), 9.03 (1H, t,> 5.9Hz), 9.64 (1H, s)

Example 626

Synthesis of N-benzoyl-4- (S-ethylisothioureido) benzylamine

To a mixture of N-benzoyl-4-thioureidobenzylamine (139.1 mg) and acetonitrile (10 ml) was added ethyl iodide (0.5 ml) and heated to reflux for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 20: 1) to give 134.8 mg of the title compound (yield 88%).

1 H-NMR (CDCl ₃ ) δ: 1.36 (3H, t,> 6.9 Hz), 2.67 (1H, brs), 2.90-3.11 (2H, m), 4.46 (lH, brs), 4.60 (2H, d,> 5.6Hz), 6.25-6.41 (1H, m), 6.91 (2H, brd,> 8.3Hz), 7 . 29 (2H, d,> 8.3Hz), 7.38-7.53 (3H, m), 7.75-7.83 (3H, m), 7.79 (2H, d,> 6 , 6 Hz)

Example 627

Synthesis of N-benzoyl-4- (N'-t-butoxycarbonyl-N'-ethylguanidine) benzylamine

Using the compound obtained in Example 625 as the starting material, the procedure of Example 233 gave 180.8 mg of the title compound (66% yield).

1 H-NMR (CDCl ₃ ) δ: 1.10-1.21 (3H, m), 1.47 (9H, s), 3.32-3.48 (2H, m), 4.62 (2H , d,> 5.9Hz), 6.62 (1H, brs), 7.11 (2H, brs), 7.25-7.60 (6H, m), 7.78-7.88 (2H , m), 10.70 (1H, brs)

Example 628

Synthesis of N-benzoyl-3- (N'-ethyl) guanidino) benzylamine

A mixture of the compound (180.8 mg) obtained in Example 627 and trifluoroacetic acid (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate after addition of saturated aqueous sodium bicarbonate solution. The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 46.1 mg of the title compound (34% yield).

1 H-NMR (DMSO-d ₆ ) δ: 1.06 (3H, t, 7.3 Hz), 3.11 (2H, q,> 7.3 Hz), 4.40 (2H, d,> 6.5Hz), 5.30 (2H, brs), 6.73 (2H, d,> 8.3Hz), 7.14 (2H, d,> 8.3Hz), 7.43-7 , 58 (3H, m), 7.86-7.96 (2H, m), 8.96 (1H, t,> 6.5Hz)

Example 629

Synthesis of 3-amino-N-benzoylbenzylamine

Using N-benzoyl-3-nitrobenzylamine as a starting material, the procedure of Example 566 gave 985 mg of the title compound (86% yield).

1 H-NMR (CDCl ₃ ) δ: 3.69 (2H, s), 4.55 (2H, d,> 5.3 Hz), 6.39 (1H, brs), 6.57-6.60 (1H, m), 6.67 (1H, s), 6.72 (1H, d,> 7.7Hz), 7.13 (1H, t,> 7.9Hz), 7.37-7 . 54 (3H, m), 7.77 (1H, s), 7.78 (1H, d,> 8.3Hz)

183 619

185

Example 630

Synthesis of N-benzoyl-3-thioureidobenzylamine

Using the compound obtained in Example 629 as a starting material, the procedure of Example 3 gave 147 mg of the title compound (58% yield).

Ή-NMR (DMSO-d ₆ ) δ: 4.48 (2H, d,> 5.9 Hz), 7.08 (1H, d,> 7.6 Hz), 7.22-7.57 (8H m), 7.90 (2H, d,> 6.6Hz), 8.98 (1H, brs), 9.68 (1H, s)

Example 631

Synthesis of N-benzoyl-3- (S-ethylisothioureido) benzylamine

Using the compound obtained in Example 630 as starting material, the procedure of Example 626 gave 39.0 mg of the title compound (93% yield).

Ή-NMR (CDCl ₃ ) δ: 1.35 (3H, t,> 7.3 Hz), 3.00 (2H, q,> 7.3 Hz), 4.52 (1H, brs), 4, 59 (2H, d,> 5.6Hz), 6.50 (1H, brs), 6.85 (1H, d,> 8.1Hz), 6.90 (1H, s), 7, O1 ( 1H, d,> 7.6 Hz), 7.27 (1H, dd,> 8.1.7.6 Hz), 7.38-7.50 (3H, m), 7.76-7.79 (2H, m)

Example 632

Synthesis of N-benzoyl-3- (N'-t-butoxycarbonyl-N'-ethylguanidine) benzylamine

Using the compound obtained in Example 629 as starting material, the procedure of Example 233 gave 57 mg of the title compound (59% yield).

Ή-NMR (CDCl 3) δ: 1.03-1.20 (3H, m), 1.47 (9H, s), 3.30-3.42 (2H, m), 4.61 (2H, d , J = 5.6 Hz), 4.88 (1H, brs), 6.91 (1H, brs), 6.92-7.20 (4H, m), 7.26-7.55 (5H, m ), 7.82 (2H, d,> 6.9Hz)

Example 633

Synthesis of N-benzoyl-3- (N'-ethylguanidino) benzylamine monohydrochloride

Using the compound obtained in Example 632 as the starting material, the procedure of Example 5 gave 31.7 mg of the title compound in quantitative yield.

Ή-NMR (DMSO-d ₆ ) δ: 1.14 (3H, t,> 6.9 Hz), 3.21-3.38 (2H, m), 4.50 (2H, d,> 5, 6 Hz), 7.10 (1H, d,> 6.9 Hz), 7.19 (lH, s), 7.24 (1H, d,> 7.9 Hz), 7.34-7.71 (5H, m), 7.75-7.79 (3H, m), 9.04 (1H, br s), 9.46-9.59 (1H, m)

Example 634

Synthesis of 1- (2-methoxy-5-nitrophenyl) ethanol

To a solution of 2-methoxy-5-nitrobenzaldehyde (450 mg) in toluene (30 ml), a solution of trimethylaluminum in hexane (3.0 ml) was added dropwise under ice-cooling. After stirring at room temperature for 1 hour, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 2: 1) to give 385 mg of the title compound (79% yield).

Ή-NMR (CDCl ₃ ) δ: 1.51 (3H, d,> 6.3 Hz), 2.25 (1H, d,> 3.3 Hz), 3.96 (3H, s), 5, 12-5.23 (1H, m), 6.93 (1H, d,> 9.2Hz), 8.18 (1H, dd,> 9.2.2.6Hz), 8.35 (1H , d,> 2.6 Hz)

Example 635

Synthesis of N - ((1 - (2-methoxy-5-nitrophenyl)) ethyl) phthalimide

Using the compound obtained in Example 634 as starting material, the procedure of Example 179 gave 358 mg of the title compound (57% yield).

Ή-NMR (CDCl ₃ ) δ: 1.87 (3H, d,> 7.3 Hz), 3.87 (3H, s), 5.82 (1H, q,> 7.3 Hz), 6, 89 (1H, d,> 9.2Hz), 7.70 (2H, dd,> 5.3, 3.0Hz), 7.81 (2H, dd,> 5.3, 3.0Hz) , 8.21 (1H, dd,> 9.2, 2.7Hz), 8.54 (1H, d,> 2.7Hz)

186

183 619

Example 636

Synthesis of N- (1- (5-amino-2-methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 635 as a starting material, the procedure of Example 309 gave N - ((1- (2-methoxy-5-nitrophenyl) ethyl) carbamic acid t-butyl ester. The resulting nitro compound was subjected to the same reaction as in Example 2 in yield 165 mg of the title compound (58% yield).

1-NMR (CDCl ₃ ) δ: 1.39 (3H, d, J = 7.3 Hz), 1.42 (9H, s), 3.40 (2H, brs), 3.79 (3H, s), 4.78-4.90 (1H, m), 5.28-5.41 (1H, m), 6.52-6.60 (2H, m), 6.71 (1H, d, J = 8.4 Hz)

Example 637

Synthesis of N- (1- (2-methoxy-5-thioureido) phenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 636 as the starting material, 110 mg of the title compound were obtained according to the procedure of Example 120 (90% yield).

Ή-NMR (CDCl 3) δ: 1.38 (3H, d,> 6.9 Hz), 1.41 (9H, s), 3.87 (3H, s), 4.90-5.01 (lH m), 5.02-5.09 (1H, m), 5.91 (2H, br s), 6.88 (1H, d,> 8.3Hz), 7.05-7.17 (2H , m), 7.58 (1H, s)

Example 638

Synthesis of N- (1- (5- (S-ethylisothioureido) -2-methoxyphenyl) ethyl) carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 637 as the starting material, the procedure of Example 95 gave 129 mg of the title compound (81% yield).

1 H-NMR (CDCl 3) δ: 1.36 (3H, t,> 7.3 Hz), 1.39 (3H, d,> 6.9 Hz), 1.42 (9H, s), 3, O 2 (2H, q,> 7.3Hz), 3.83 (3H, s), 4.82-4.95 (1H, m), 5.10-5.28 (1H, m), 6, 73-7.01 (3H, m)

Example 639

Synthesis of N- (1- (5- (S-ethylisothioureido) -2-methoxyphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 638 as a starting material, according to the procedure in Example 5, 112.6 mg of the title compound was obtained in quantitative yield.

1 H-NMR (DMSO-d ₆ ) δ: 1.33 (3H, t,> 7.3 Hz), 1.52 (3H, d,> 6.6 Hz), 3.22-3.40 ( 2H, m), 3.89 (3H, s), 4.5O-4.71 (1H, m), 7.18 (1H, d,> 8.6Hz), 7.31 (1H, d, > 8.6Hz), 7.49 (1H, s), 8.55 (2H, brs), 9.18 (1H, brs), 9.74 (1H, brs), 11.56 (1H, brs )

Example 640

Synthesis of N- (1- (5- (N'-t-butoxycarbonyl-N'-ethyl-guanidino) -2-methoxyphenyl) ethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 636 as the starting material, 66 mg of the title compound were obtained according to the procedure of Example 233 (62% yield).

1 H-NMR (CDCl 3) δ: 1.06 (3H, t,> 6.9 Hz), 1.38 (3H, d,> 7.0 Hz), 1.42 (9H, s), 1, 53 (9H, s), 3.31-3.46 (2H, m), 3.86 (3H, s), 4.53 (1H, brs), 4.90-5.03 (1H, m) , 5.07 (1H, brs), 6.86 (1H, d,> 8.9Hz), 7.02-7.12 (2H, m), 10.50 (1H, brs)

Example 641

Synthesis of N- (1- (5- (N'-ethylguanidino) -2-methoxyphenyl) ethyl) amine dihydrochloride

Using the compound obtained in Example 640 as the starting material, the procedure in Example 5 gave 58.8 mg of the title compound in quantitative yield.

1 H-NMR (DMSO-d ₆ ) δ: 1.15 (3H, t,> 6.9 Hz), 1.49 (3H, d,> 6.8 Hz), 3.28 (2H, dq, > 6.0.6.9Hz), 3.88 (3H, s), 4.52-4.65 (1H, m), 7.14 (1H, d,> 8.6Hz), 7, 18-7.26 (1H, m), 7.30-7.34 (1H, m), 7.43-7.58 (2H, m), 7.66-7.78 (1H, m), 8.36 (2H, brs), 9.59 (1H, brs)

183 619

187

Example 642

Synthesis of N- (2- (N-acetyl-N-methylamino) -5-nitrophenylmethyl) iminodicarboxylic acid di-t-butyl ester

To a mixture of the compound (540 mg) obtained in Example 446, potassium carbonate (1.96 g) and acetonitrile (30 ml), acetyl chloride (890 mg) was added and heated to reflux for 24 hours. Ethyl acetate was added to the reaction mixture, washed with water, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, methylene chloride: ethyl acetate - 5: 1) to give 330 mg of the title compound (yield 55%).

1 H-NMR (CDCl ₃ ) δ: 1.50 (18H, s), 1.84 (3H, s), 3.23 (3H, s), 4.79 (2H, s), 7.33 ( 1H, d, J = 8.4Hz), 8.12 (1H, d,> 2.3Hz), 8.19 (1H, dd,> 8.4, 2.3Hz)

Example 643

Synthesis of N- (2- (N-acetyl-N-methylamino) -5-aminophenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 642 as starting material, the title compound was obtained according to the procedure in Example 2 (yield 96%).

1 H-NMR (CDCl 3) δ: 1.48 (18H, s), 1.80 (3H, s), 3.15 (3H, s), 3.77 (2H, br s), 4.64 (1H , d,> 17.2 Hz), 4.65 (1H, d,> 17.2 Hz), 6.45 (1H, d,> 2.3 Hz), 6.55 (1H, dd,> 8 , 3, 2.3Hz), 6.86 (1H, d,> 8.3Hz)

Example 644

Synthesis of N- (2- (N-acetyl-N-methylamino) -5-thioureidophenylmethyl) iminodicarboxylic acid di-t-butyl ester

By using the compound obtained in Example 643 as the starting material, the procedure of Example 120 gave the title compound (80% yield).

1 H-NMR (CDCl 3) δ: 1.48 (18H, s), 1.83 (3H, s), 3.19 (3H, s), 4.70 (1H, d,> 17.2 Hz) , 4.71 (1H, d,> 17.2 Hz), 6.26 (2H, brs), 7.14-7.26 (3H, m), 8.32 (1H, brs)

Example 645

Synthesis of N- (2- (N-acetyl-N-methyl-amino) -5- (S-ethylisothioureido) phenylmethyl) iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 644 as starting material, the procedure of Example 95 gave the title compound (83% yield).

1 H-NMR (CDCl 3) δ: 1.35 (3H, t,> 6.9 Hz), 1.45 (18H, s), 1.82 (3H, s), 2.90-3.15 ( 2H, m), 3.18 (3H, s), 4.53 (2H, brs), 4.69 (1H, d,> 17.2 Hz), 4.70 (1H, d,> 17.2 Hz), 6.76 (1H, brs), 6.79- 6.92 (1H, m), 7.04 (1H, d,> 7.9Hz)

Example 646.

Synthesis of N- (2- (N-acetyl-N-methylamino) -5- (S-ethylisothioureido) phenylmethyl) amine dihydrochloride.

Using the compound obtained in Example 645 as starting material, the title compound was obtained according to the procedure in Example 5 (yield 53%).

1 H-NMR (D ₂ O) δ: 1.43 (3H, t,> 7.6 Hz), 2.37 (3H "s), 3.26 (2H, q,> 7.6 Hz), 3.44 (3H, s), 4.12 (1H, d,> 14.2Hz), 4.14 (1H, d,> 14.2Hz), 7.50-7.60 (3H, m )

Example 647

Synthesis of N- (2- (N-acetyl-N-methylamino) -5- (N'-t-butoxycarbonyl-N'-ethyl] guanidinephenylmethyl ]iminodicarboxylic acid di-t-butyl ester.

Using the compound obtained in Example 643 as the starting material, the title compound was obtained according to the procedure of Example 233 (yield 69%).

'H-NMR (CDCl 3).

188

183 619 δ: 1.19 (3Η, t,> 7.4 Hz), 1.47 (27H, s), 1.82 (3H, s), 3.20 (3H, s), 3.30- 3.44 (2H, m), 4.70 (1H, d,> 16.8Hz), 4.71 (1H, d,> 16.8Hz), 6.85-7.05 (2H, m ), 7.08 (1H, d,> 7.6Hz)

Example 648

Synthesis of N- (2- (N-acetyl-N-methylamino) -5- (N'-ethylguanidino) phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 647 as a starting material, the title compound was obtained according to the procedure in Example 5 (yield 27%).

Ή-NMR (D ₂ O) δ: 1.24 (3H, t,> 7.6 Hz), 2.36 (3H, s), 3.34 (2H, q,> 7.6 Hz), 3 , 42 (3H, s), 4.09 (1H, d,> 14.2Hz), 4.12 (1H, d,> 14.2Hz), 7.43-7.53 (3H, m)

Example 649

Synthesis of 2-dimethylamino-3-nitrobenzoic acid

Using 2-bromo-3-nitrobenzoic acid as the starting material, 4.8 g of the title compound were obtained according to the procedure of Example 264 (96% yield).

Ή-NMR (CDCl ₃ ) δ: 2.99 (6H, s), 7.56 (1H, dd,> 7.9, 7.9 Hz), 7.91 1H, dd,> 7.9, 1 , 7Hz), 8.60 (1H, dd,> 7.9,1.7Hz)

FAB-MS (m / z) 211 (M ⁺ + 1)

Example 650

Synthesis of 2-dimethylamino-3-nitrophenyl) methanol

Using the compound obtained in Example 650 as starting material, the procedure of Example 132 gave 4.23 g of the title compound (94% yield).

Ή-NMR (CDCl ₃ ) δ: 2.80 (6H, s), 3.16-3.28 (1H, m), 4.80 (2H, d,> 4.4 Hz), 7.19 ( 1H, dd,>7.8; 7.8Hz), 7.53-7.61 (2H, m)

FAB-MS (m / z) 197 (M ⁺ + 1)

Example 651

Synthesis of N- (2-dimethylamino-3-nitrophenylmethyl) phthalimide

Using the compound obtained in Example 650 as starting material, the procedure of Example 179 gave 4.4 g of the title compound (63% yield).

Ή-NMR (CDCl ₃ ) δ: 2.84 (6H, s), 4.99 (2H, s), 7.09 (1H, dd,> 7.7.9Hz), 7.31 ( 1H, d,> 7.9Hz), 7.53 (1H, d,> 7.9Hz), 7.74-7.79 (2H, m) 7.87-7.91 (2H, m)

FAB-MS (m / z) 325 (M ⁺ )

Example 652

Synthesis of N- (2-dimethylamino-3-nitrophenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 651 as the starting material, the procedure of Example 309 gave 3.74 g of the title compound (94% yield).

Ή-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.77 (6H, s), 4.42 (2H, d,> 5.6 Hz), 5.02 (1H, brs) , 7.15 (1H, dd,> 7.9.7.9Hz), 7.52 (2H, d,> 7.9Hz)

FAB-MS (m / z) 295 (M ⁺ )

Example 653

Synthesis of N- (3- (N'-t-butoxycarbonyl-N'-ethylguanidino) -2-dimethylaminophenylmethyl) carbamic acid t-butyl ester

By using the compound obtained in Example 652 as the starting material, the title compound was obtained according to the procedure of Example 233 (71% yield).

Ή-NMR (CDCl ₃ ) δ: 1.06-1.25 (3H, m), 1.46 (9H, s), 1.51 (9H, s), 2.78 (6H, s), 3 , 32-3.48 (2H, m), 4.28-4.43 (2H, m), 4.67-5.33 (2H, m), 6.55-6.68 (1H, m) , 6.94 (1H, dd,> 7.6.7.6Hz), 7.05-7.23 (2H, m)

FAB-MS (m / z) 436 (M ⁺ + 1)

183 619

189

Example 654

Synthesis of N- (3- (N'-ethylguanidino) -2-dimethylaminophenylmethyl) amine trihydrochloride

Using the compound obtained in Example 653 as the starting material, the procedure of Example 5 gave the title compound in quantitative yield.

Ή-NMR (D ₂ O) δ: 1.22 (3H, t, J = 7.3 Hz, 2.90 (3H, s), 2.91 (3H, s), 3.33 (2H, q , J = 7.3Hz), 4.32 (2H, s), 7.37-7.58 (3H, m)

Example 655

Synthesis of N- (5- (N'-t-butoxycarbonyl-N * -ethylguanidino) -2-hydroxyphenylmethyl) carbamic acid t-butyl ester

Using the compound obtained in Example 338 as the starting material, the title compound was obtained according to the procedure in Example 2 (yield 74%).

Ή-NMR (CDCl ₃ ) δ: 1.06 (3H, t,> 7.3 Hz), 1.46 (9H, s), 1.52 (9H, s), 3.32-3.40 ( 2H, m), 4.19 (2H, d,> 6.9Hz), 5.22-5.30 (1H, m), 6.88-7.08 (3H, m)

Example 656

Synthesis of N- (5 - (N'-ethyl) giianidino) -2-hydroxy-phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 655 as a starting material, the procedure of Example 5 gave the title compound (77% yield).

Ή-NMR (D ₂ O) δ: 1.21 (3H, t,> 7.3 Hz), 3.29 (2H, q,> 7.3 Hz), 4.17 (2H, s), 7 . 02-7.04 (1H, m), 7.22-7.26 (2H, m)

Test examples

Test Example 1

The compounds of the invention were evaluated for their inhibitory effects on the three presently known NOS isoforms compared to existing NOS inhibitors.

The following NOS inhibitors were used as control compounds:

L-NNA,

L - CPA,

L-MIN,

L-EIN,

L-NAME,

N ^g - amino-L-arginine (1-AA),

L-NIO,

N ^g - monomethyl-L-arginine (L-NMMA)

Crude NOS isoform enzyme samples were prepared by the following procedures (Nagafuji et al., Neuroreport 6, 1541 - 1545, 1995).

A crude N-cNOS enzyme sample was prepared by the following procedure. Normal untreated male Sprague Dawley (SD) rats (300-400 g body weight) were headed; Whole brains were collected from each animal immediately and the cerebral cortex was separated on ice. Then 5 volumes of 50 mM Tris-HCl containing 1 mM DTT (pH 7.4) were added and the mixture was homogenized for 3 minutes and centrifuged at 1000 x g for 10 minutes. The resulting supernatant was then centrifuged at 100,000 x g for 60 minutes and the soluble cytosolic fraction of the supernatant finally obtained was used as a sample of the crude N-cNOS enzyme.

A crude E-cNOS enzyme sample was prepared by the following procedure. Cow pulmonary artery endothelial cells (CPAE) were cultured in MEM medium containing 20% FBS. A few days later, the cells were detached from the flask using a 0.25% trypsin solution containing 1mM EDTA and, after adding the appropriate amount of FBS, centrifuged at 1000rpm for 10 minutes. A sufficient amount of Ca- and Mg-free phosphate buffer (pH 7.4) was added to the precipitating cells and centrifuged at 1000 rpm for 10 minutes. The same step was repeated to wash cells which, after adding 50 mM Tris-HCl (pH

190

183 619

7.4) containing 1% Triton X-100 and 1 mM DTT, was left on ice for 1 hour. The mixture was then homogenized for 3 minutes and kept on ice for 30 minutes with low stirring. Finally the mixture was centrifuged at 100,000 x g for 60 minutes and the resulting supernatant was used as a sample of the crude E-cNOS enzyme.

A crude iNOS enzyme sample was prepared by the following procedure. Rats received intraperitoneal LPS (10 mg / kg) and 6 hours later, transcardiac perfusion was performed with physiological saline containing 10 U / ml of heparin; then the lungs were harvested. Subsequently, 5 volumes of 50 mM Tris-HCl containing 1 mM DTT (pH 7.4) were added and the mixture was homogenized for 3 minutes, then the homogenate was centrifuged at 1000 x g for 10 minutes. The resulting supernatant was centrifuged at 100,000 x g for 60 minutes and the soluble solubilization fraction finally obtained as a supernatant was used as a sample of the crude iNOS enzyme.

The method of measuring NOS activity was essentially the same as already described by the present inventors, and was to quantify the conversion of the L- [ ³ H] arginine substrate into the reaction product, L- [ ³ H] citrulline (NagafUji et al., In Brain Edema IX (Ito et al. Ed.) 60, pp. 285-288, 1994; Nagafuji et al., Neuroreport 6, 1541-1545, 1995).

The reaction solution contained 100nML- [ ³ H] arginine, the prepared sample of the crude NOS enzyme (10-30 gg / ml of protein), 1.25mMCaCl ₂ ImMEDTA, 10gg / ml calmodulin, ImM NADPH, 100pmtetrahydrobiopterin, 10pmFAD, 10mFM7.4-HgmFMNi50 to which one compound of the invention or one control was added.

The reaction was started with the addition of L- [ ³ H] arginine and after incubation at 37 ° C for 10 minutes, the reaction was quenched with 2 ml of 50 mM Tris HCl (pH 5.5) containing 1 mM EDTA and the mixture was placed on a boat. The reaction solution was passed through a cation exchange resin column (Dowex AG50WX-8, Na ⁺ form, 3.2 ml) to separate the reaction product L- [ ³ H] citrulline from unreacted residual L- [ ³ H] arginine substrate. The eluate was combined with another eluate from the transmission of the indicated amount of distilled water through the column and placed in a minifiolce for the recovery of L- ^[3 H] citrulline. Then, scintillation liquid was added and the radioactivity present was measured in a liquid scintillation counter to determine the amount of L- ^[3 H] citrulline.

The activity of N-cNOS or E-cNOS was determined by subtracting the activity detected in the absence of CaCl ₂ and calmodulin from the activity detected in the presence of CaCl ₂ and calmodulin. INOS activity was detected in the absence of CaCl ₂ and calmodulin. The protein concentration of each crude enzyme sample was determined with a Biorad Co. microtest kit. Each experiment was conducted in duplicate.

Tables 49, 50 and 51 report the mean IC ₅₀ values (concentration sufficient to inhibit 50% of the activity) of all test compounds against each NOS isoform obtained in one to four independent experiments. The tables also give ratios of IC ₅₀ values as an index of selectivity.

Table 49

Inhibitory potency and selectivity of the tested compounds against three NOS isoforms

Example No. or a control compound IC ₅₀ value, nM IC50 value, nM N-cNOS (Typl) E-cNOS (Type 3) iNOS (Type 2) E-cNOS / N-cNOS iNOS / N-cNOS E-cNOS / iNOS 1 2 3 4 5 6 7 96 2.1 198.3 28.6 94.4 13.6 6.9 122 3.8 3525.3 24649.9 6486.8 0.1 175 4.0 199.8 Well. 50.0 Well. Well. 270 4.3 3586.1 4528.7 834.0 1053.2 0.8 131 4.5 481.1 78.2 106.9 17.4 6.2

183 619

191 Table 49 continues

1 2 3 4 5 6 7 324 4.8 2305.6 8728.2 480.3 1818.4 0.3 171 5.0 29.2 Well. 5.8 Well. Well. 104 5.2 117.8 86.5 22.7 16.6 1.4 28 5.5 Well. 32.7 Well. 5.9 Well. L-MIN 5.7 152.0 247.6 26.7 43.4 0.6 14 5.9 Well. 3681.3 Well. 623.9 Well. 21 5.9 Well. 2606.2 Well. 441.7 Well. 411 5.9 341.3 Well. 57.8 Well. Well. 452 6.4 3631.7 6963.2 567.5 1088.0 0.5 137 7.1 484.6 Well. 68.3 Well. Well. 7 7.6 42.4 2123.2 5.6 279.4 0.02 162 7.9 575.7 Well. 72.9 Well. Well. 173 8.2 24.1 Well. 2.9 Well. Well. L-EIN 8.4 732.2 6,780.8 87.2 804.9 0.1 458 8.4 4101.1 Well. 488.2 Well. Well. 47 8.8 72.9 Well. 8.3 Well. Well. 112 10.8 407.6 Well. 37.7 Well. Well. 177 11.6 510 Well. 44.0 Well. Well. 317 12.2 238.6 Well. 19.6 Well. Well. 167 13.3 365.8 Well. 27.5 Well. Well. 169 14.0 41.5 Well. 3.0 Well. Well. 12 14.2 538.5 239.3 37.9 16.9 2.3 L-NNA 16.9 68.2 3464.3 4.0 205.0 0.02 288 19.9 1263.8 Well. 63.5 Well. Well. 26 20.9 430.5 1345.9 20.6 64.4 0.3 376 21.3 338.6 Well. 15.9 Well. Well. 153 22.2 422.8 Well. 19.0 Well. Well. 528 22.8 436.2 Well. 19.1 Well. Well. 5 23.4 429.2 448.7 18.3 19.2 1.0 372 23.6 359.9 Well. 15.3 Well. Well. 538 24.4 2543.3 305.9 104.2 12.5 8.3

Note: The symbol "n.o." means not defined.

Table 50

Example No. or a control compound IC50 value, nM IC value of ₅ nM N-cNOS (Typel) E-cNOS (Type 3) iNOS (Type 2) E-cNOS / N-cNOS iNOS / N-cNOS E-cNOS / iNOS 1 2 3 4 5 6 7 L-CPA 27.3 986.6 7153.9 36.1 262.0 0.1 52 35.2 483.5 2760.6 13.7 78.4 0.2

192

183 619 table 50 continues

1 2 3 4 5 6 7 298 36.4 4141.6 Well. 113.8 Well. Well. 160 36.6 477.2 Well. 13.0 Well. Well. 144 37.5 898.2 Well. 24.0 Well. Well. 151 37.6 262.3 Well. 7.0 Well. Well. 482 39.7 1992.1 Well. 50.2 Well. Well. 438 41.3 6946 Well. 168.2 Well. Well. 142 44.0 662.6 Well. 15.1 Well. Well. 337 44.8 5201.8 15473.6 116.1 345.4 0.3 355 46.0 662.5 Well. 14.4 Well. Well. 533 46.1 3771.3 Well. 81.8 Well. Well. 305 53.9 1706.9 Well. 31.7 Well. Well. 236 56.8 325.2 Well. 5.7 Well. Well. 226 57.9 1436.8 Well. 24.8 Well. Well. 110 58.1 Well. Well. Well. Well. Well. 238 63.9 1164.3 Well. 18.2 Well. Well. 54 67.0 Well. 5023.4 Well. 75.0 Well. 300 69.8 492.0 Well. 7.0 Well. Well. 258 72.7 1085.8 Well. 14.9 Well. Well. 374 77.2 1288.8 Well 16.7 Well. Well. L-NAME 79.4 923.0 13533.1 11.6 170.4 0.1 19 88.4 Well. 2404.4 Well. 27.2 Well. 234 88.8 1167.2 Well. 13.1 Well. Well. 543 95.0 3120.6 Well. 32.8 Well. Well. 267 99.6 50,081.6 4,788.8 502.8 48.1 10.5 350 105.7 15842.9 58,397.6 149.9 552.5 0.3 281 107.9 1620.2 Well. 15.0 Well. Well. 39 116.4 Well. 22856.0 Well. 196.4 Well. 41 121.0 Well. Well. Well. Well. Well. 193 127.8 1541.9 Well. 12.1 Well. Well. L-AA 152.5 167.0 1281.0 1.1 8.4 0.1 341 160.2 Well. 5.5 Well. Well. thirty 162.6 Well. Well. Well. Well. Well. 60 170.6 Well. 6745.3 Well. 39.5 Well. 367 193.4 3707.3 Well. 19.2 Well. Well. 285 198.9 7305.4 Well. 36.7 Well. Well.

Note: The symbol "n.o." means not defined.

183 619

193

Table 51

Example No. or a control compound IC50 value, nM IC50 value, nM N-cNOS (Typi) E-cNOS (Type 3) iNOS (Type 2) E-cNOS / N-cNOS iNOS / N-cNOS E-cNOS / iNOS L-NIO 277.0 1226.3 457.8 4.4 1.7 2.7 339 280.5 Well. Well. Well. Well. Well. 34 280.8 Well. 6,760.8 Well. 24.1 Well. 185 298.6 3165.1 Well. 10.6 Well. Well. L-NMMA 337.8 489.9 3480.9 1.5 10.3 0.1

Note: The symbol, 41.0. ”Means not specified.

Tables 49, 50 and 51 show the following conclusions:

1. The compounds of Examples 28, 96, 104, 122, 131, 171, 175, 270 and 324 are more potent in the inhibition of N-cNOS than L-MIN, which showed the strongest inhibitory activity of N-cNOS among the existing NOS inhibitors;

2. From the point of view of selectivity for N-cNOS as compared to E-cNOS, the compounds of Examples 96,122,131,175,267,270,298,324,337,350,438,452,458,466,473,538 and 560 had a more selective inhibitory effect on N-cNOS than L-EIN, which showed the highest selective inhibitory effect on existing N-cNOS NOS inhibitors;

3. The compounds of Examples 12, 28, 96, 104 and 131 are more potent in inhibiting iNOS than L-MIN, which has the strongest inhibitory activity in iNOS among the existing NOS inhibitors;

4. In terms of selectivity for iNOS compared to E-cNOS, the compounds of Examples 96, 131, 267 and 538 had a more selective iNOS inhibitory effect than L-NIO, which showed the highest selective iNOS inhibitory effect among the existing NOS inhibitors.

Test example 2

An experiment was performed to determine the efficacy of the compound of the invention using a rat model of focal cerebral ischemia. Such models were generated by occlusion of the left middle cerebral artery (MCA) according to the method already described by the present inventors (Nagafuji et al., Neurosci.Lett. 147, 159-162, 1992; Nagafujiiin., In Brain EdemalX (Ito et al. Ed.) 60, pp. 285-288,1994, Springer-Verlag; Nagafhji et al., Neuroreport 6, 1541-1545, 1995).

up to 9-week old male SD rats inhaled 2% halothane (70% N ₂ O and 30% O ₂ ) to induce anesthesia, then 1% halothane to preserve it, and a polyethylene catheter was inserted into the right femoral vein for administration drug. Each of the anesthetized rats was placed in a lateral position on the operating bench. A skin incision was made between the left external auditory foramen and the lateral corner of the eye and an incision along the anterior edge of the temporal muscle to the zygomatic arch, then the temporal muscle was extracted with a bipolar coagulator. Under a surgical microscope, the third branch of the trigeminal nerve in the lower part of the temporal bone was identified as extending into the temporal muscle, and a small hole approximately 3 mm in diameter was made with a dental drill previously dipped in ice-cold physiological saline between the oval hole from which it emerged third branch, and an orbital opening. A thin layer of bone was removed with a microhook and a micro-needle holder.

Thereafter, the dura mater and arachnoid were gently cut with a needle (27G) and a micro-hook was inserted and the MCA branch closed with a minigrip in the proximal part of the lentato-striatal artery (LSA).

194

183 619

In the permanent occlusion models, both MCA and LSA branches were cut off by firing with a bipolar coagulator. In the temporal occlusion models, only occlusion was performed with a minigrip and the handle was removed under a surgical microscope to allow reperfusion.

Immediately after MCA occlusion, a control solvent (0.9% physiological saline, 10 µg / hour) or the compound of Example 96 (0.12-3.6 gg / kg) was injected via the right femoral vein. An osmotic pump (Alzet) was then attached to the catheter and hidden under the skin of each rat, and continuous infusion of the solvent or test compound was started (0.01-0.3 gg / kg / minute). Finally, a gel foam was introduced into the excised cavity, which was immersed in physiological saline containing antibiotic, the wound was sutured and all animals were placed in their cages.

Brain water content, which was an indicator of cerebral edema formation, was measured by the wet dry method (Nagafujiiin., Neurosci.Lett. 147, 159-162, 1992) as follows. 48 hours after MCA occlusion, rats were headed and both hemispheres were extracted from each animal within 60 sec; the wet weight of the brain tissue of each hemisphere was measured in chemical equilibrium during 90 s. The hemispheres were then dried in an oven at 105 ° C for 3 days and their dry weights were measured.

Brain water content was determined by the following formula: (wet weight - dry weight) / (wet weight) x 100 (%). The percentage of water on the stroke side (left hemisphere) to the water content on the opposite side (right hemisphere) is shown in Fig. 1.

In experiments determining the infarct volume reducing effect, rats were headed after 3 hours of MCA occlusion and 24 hours of reperfusion, and whole brains were extracted;

then, 6 coronary sections were made at 2 mm intervals from the frontal lobe (Nagafuji et al., Neuroreport 6, 1541 - 1545, 1995). The sections were immersed in a 2% 2,3,5-triphenyltetrazolium hydrochloride (TTC) solution in physiological saline at 37 ° C for 30 minutes and both sides of each section were photographed. The pictures were read with a scanner and the infarct area at each segment was determined on the computer according to the following equation: infarct area in the stroke hemisphere = (normal area in the opposite hemisphere) - (normal area in the stroke hemisphere) using image analysis software (NIH Image). to avoid overestimating the infarct area due to edema formation.

The infarct volume was calculated as the sum of the volumes of the individual foci, defined by the formula (infarct area) x (1 mm), and the results are shown in Fig. 2.

All experimental data are expressed as mean 6 standard error with the number of animals in each group indicated in parentheses. For statistical analysis purposes, Dunnett's parametric multiple comparative test was performed and the case with a risk factor (p-value) less than 0.05 was considered "statistically significant".

As shown in Fig. 1, the percentage of water content in the stroke hemisphere compared to the opposite hemisphere in the control group increased to about 103.8% 48 hours after MCA occlusion, clearly indicating edema formation. This increase in water percentage was reduced in a dose-dependent manner by administering the compound of Example 96; in the group receiving a continuous infusion of the compound at 0.3 gg / kg / minute after an intravenous injection of 3.6 gg / kg, the percent water content had dropped to about 102.1%, which was statistically significant (p <0.01). The absolute water content in the opposite hemisphere of the control group was 79.29 ± 0.06%.

As shown in Figure 2, a wide infarct in the dorsal striatum and left hemisphere cortex of an estimated size of about 104.2 mm ^{3 was} observed after 3 hours of MCA occlusion and 24 hours of reperfusion. The infarction could be mitigated in a dose-dependent manner by administering the compound of Example 96; in the group receiving continuous infusion of 0.3 gg / kg / minute following an intravenous injection of 3.6 gg / kg, infarct volume decreased by approximately 79.7% which was statistically significant (p <0.01).

These experimental data suggest that the compounds of the invention, including the compound of Example 96, are preferably effective and useful in the treatment of cerebrovascular diseases.

183 619 195

Practical applications

The compounds according to the invention show a stronger N-cNOS or iNOS inhibitory activity than the existing NOS inhibitors or show a particularly high selectivity for N-cNOS or iNOS inhibitory activity among the three NOS isoforms; therefore the compounds are useful as drugs for pathology in cerebrovascular diseases, in particular, occlusive cerebrovascular diseases as well as traumatic brain injuries, attacks, headaches and other pain, tolerance and addiction to morphine, Alzheimer's disease, Parkinson's disease, septic shock , chronic rheumatoid arthritis, osteitis, viral or non-viral infections, and diabetes.

183 619

Percentage of water in the cerebral hemisphere with stroke to the water content in the opposite hemisphere /% /

Mitigating effect of compound z-Example 96 on brain edema after 48 hours of MCA occlusion in rat

105

104

103

102

101

vi>

Physiological brine ^ '^'?

V V x * *

Example 96

183 619

Fig> 2

Mitigating effect of the compound of Example 96 on cerebral infarction after 3 hours of MCA occlusion and 24 hours of reperfusion in rat infarct volume

Physiological saline

Example 96

183 619

FIG. 3

3) (R, CO) jO <n)

Publishing Department of the UP RP. Circulation of 70 copies. Price PLN 6.00.

Claims (38)

Patent claims CLAIMS 1. Aniline derivatives of general formula (1), or a possible stereoisomer or optically active form of a compound, or a pharmaceutically acceptable salt thereof: (1) in which R ^ is SR or NR ₇ R _8; R ₆ is an optionally fluoro substituted straight chain or branched alkyl group having 1-6 carbon atoms, or a straight chain or branched alkenyl group having 2-6 carbon atoms; R ₇ is hydrogen, a straight or branched chain alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms, a straight or branched alkynyl group having 3-6 carbon atoms, a straight or branched alkoxy group having 1-6 atoms carbon or nitro group; R ₈ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; R ₂ represents hydrogen, straight-chain or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl yl group wherein the alkyl moiety is a straight or branched alkyl group having 1-6 carbon atoms, or a carboxyl group, or may combine with R ₃ to give 3 - to an 8-membered carbocyclic ring; R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R ₂ to form a 3- to 8-membered carbocyclic ring; R ₄ is a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, an amidino group which may be substituted on the nitrogen atom, a cyclic alkyl group having 3-8 carbon atoms, or a nitro group R ₅ represents a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group the alkyl portion of which is a straight chain or branched alkyl group having 1-6 carbon atoms, an alkoxycbonylamino group whose alkyl portion is a straight or branched alkyl group having 1- 6 carbon atoms, or an amino group Yi, Y ₂ , Y ₃ and Y ₄ , the same or different, represent a hydrogen atom, a halogen atom, a straight or branched chain alkyl hydroxyl group having 1-6 carbon atoms which may be substituted with 1-3 halogen atoms, the NY ₅ group Y ₆ where Y ₅ and Y ₆ , the same or different, represent a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, 183 619 an acyl group having 1 -8 carbon atoms, or combined Y ₅ and Y ₆ tworząpierścień piperidine or pyrrolidine ring; n and m are an integer of 0 or 1; except: a) a hydrochloride of the compound of formula 1, where R _t = -NH ₂ , R ₂ = -COOH, R ₃ = methyl, R ₄ and R ₅ = H, n = 1, m = 0, Yj-Y ₄ = H ; b) a compound of formula 1, where Rj = -SCH ₃ , R ₂ = COOH ₃ , R ₃ = methyl, R ₄ = acetyl, R ₅ = H, n = 1, m = 0, Y _r Y ₄ = H ; c) the R stereoisomer of the compound of formula 1, where Rj = -NH ₂ , R ₂ = -COOH, R ₃ = -H, R ₄ = acetyl, R ₅ = Η, n = 0 and m = 0, Yj-Y ₄ = H; d) the hydrochloride of the R-isomer of the compound of Formula 1, wherein R 1 = NH ₂ , R ₂ = -COOH, R ₃ , R ₄ , R ₅ = Η, n and n = 0; e) hydrochlorides of the R and S isomers of the compound of formula 1, wherein Rj = -NH ₂ , R ₂ = -COOCH ₃ , R ₃ , R ₄ , R ₅ = Η, n and _m = 0, Y _r Y ₄ = H; f) a compound of formula 1, wherein R] = NHNO _2, R ₂ = -COOH, R _3, R _4, R ₅ = Η, η - 1, m = 0, ΥγΥ ₄ = Η; g) a compound of Formula 1 wherein R! - -NHNO ₂ , R ₂ - -COOH, R ₃ = H, R ₄ = t-butoxycarbonyl, R ₅ = Η, n = 1, m = 0, Y _r Y ₄ - H. 2. Aniline derivative of the general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound, or a pharmaceutically acceptable salt thereof, wherein: R] is SR b, wherein R ₆ represents optionally fluorine-substituted straight chain alkyl group having 1-6 carbon atoms, or straight or branched alkenyl group having 2-6 carbon atoms; R ₂ represents hydrogen, straight-chain or branched alkyl group having 1-6 carbon atoms, the alkyl part of alkoksykarbonylowąktórej straight or branched alkyl group having 1-6 carbon atoms, or a carboxyl group, or may combine with R ₃ to form a 3- to an 8-membered carbocyclic ring; R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R _{2 to} form a 3- to 8-membered carbocyclic ring; R ₄ represents a hydrogen atom, a straight chain or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group the alkyl portion of which is a straight chain or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, an amidine group which may be substituted on the nitrogen atom with a cyclic alkyl group having 3-8 carbon atoms or with a nitro group R ₅ is hydrogen, a straight or branched chain alkyl group having 1-6 carbon atoms, or an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms; Υ1Λ2Λ3 and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight chain or branched alkyl hydroxyl group having 1-6 carbon atoms which may be substituted with 1-3 halogen atoms, the group NY ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ can be linked together to form a piperidine ring or pyrrolidine; n and m are the number 0 or 1. 3. The aniline derivative of the general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound, or a pharmaceutically acceptable salt thereof, wherein: R is SR ₆ wherein R ^ is an optionally fluorine-substituted straight-chain or branched alkyl group having 1-6 carbon atoms, or straight or branched alkenyl yl group having 2-6 carbon atoms; R ₂ and R _3, which may be the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms, or R ₂ and R ₃ may be joined together to form a 3- to 8-membered ring carbocyclic; 183 619 R ₄ and R ₅ are hydrogen; Y _1; Y ₂ , Y _3, and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, a straight or branched chain alkyl group having 1-6 carbon atoms that may be substituted with 1-3 halogen atoms, the NY group ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, represent a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be joined to itself to form a piperidine or pyrrolidine ring; n and m are the number 0 or 1. 4. The aniline derivative of the general formula (1) according to claim 1 1 or a possible stereoisomer, or an optically active form of the compound, or a pharmaceutically acceptable salt thereof, in which substituents other than Y _{] 5} Y ₂ , Y ₃ and Y ₄ are m-substituted on the benzene ring; Rj is methylthio or ethylthio R ₂ represents a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms or may combine with R ₃ to form a 3- to 8-membered carbocyclic ring; R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R _{2 to} form a 3- to 8-membered carbocyclic ring; R ₄ and R ₅ are hydrogen; YnY ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, a straight or branched chain alkyl group having 1-6 carbon atoms that may be substituted with 1-3 halogen atoms, the group NY ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine ring or pyrrolidine; n and m are an integer of 0 or 1. 5. Aniline derivative of the general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, wherein the substituents other than Y _b Y _2, Y ₃ and Y ₄ are m-substituted on the benzene ring; Rj is a methylthio or ethylthio group; R ₂ and R ₃ are hydrogen; R ₄ is hydrogen, a straight chain or branched alkyl group having 1-6 carbon atoms; R ₅ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; Y], Y ₂ , Y ₃ and Y ₄ which may be the same or different represent a hydrogen atom, a halogen atom, a hydroxyl group, a straight or branched chain alkyl group having 1-6 carbon atoms that may be substituted with 1-3 halogen atoms, the NY group ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a ring piperidine or pyrrolidine; n and m are an integer of 0 or 1. 6. Aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, wherein the substituents other than Y _b Y _2, Y ₃ and Y ₄ are m-substituted on the benzene ring; Rj is a methylthio or ethylthio group; R ₂ represents a hydrogen atom or a methyl or ethyl group R ₃ is hydrogen or methyl R ₄ and R ₅ are hydrogen; Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight chain or branched alkyl hydroxyl group having 1-6 carbon atoms which may be substituted with 1-3 halogen atoms, the NY ₅ group Y ₆ where Y ₅ and Y ₆ , 183,619 which may be the same or different is a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ can be linked together to form a piperidine or pyrrolidine ring; n and m are an integer of 0 or 1. 7. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound, or a pharmaceutically acceptable salt thereof, wherein substituents other than Y _1; Y ₂ , Y ₃ and Y ₄ are p-substituted on the benzene ring; Rj is a methylthio or ethylthio group; R ₂ represents a hydrogen atom or a methyl or ethyl group R ₃ is hydrogen or methyl R ₄ and R ₅ are hydrogen; Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight chain or branched alkyl hydroxyl group having 1-6 carbon atoms that may be substituted with 1-3 halogen atoms, the NY group ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are hydrogen, a straight or branched chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be joined together to form a 3- to 8-membered piperidine or pyrrolidine ring; n and m are an integer of 0 or 1. 8. The aniline derivative of the general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound, or a pharmaceutically acceptable salt thereof, wherein: Rj is NR ₇ R ₈ , where R ₇ is hydrogen, straight or branched chain alkyl group having 1-6 carbon atoms, cyclic alkyl group having 3 carbon atoms, or nitro group, and R _g is hydrogen or straight chain or branched alkyl group having 1-6 carbon atoms; R ₂ represents hydrogen, straight-chain or branched alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group wherein the alkyl part a linear or branched alkyl group having 1-6 carbon atoms, or a carboxyl group, or may combine with R ₃ to give 3 - to an 8-membered carbocyclic ring; R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R ₂ to form a 3- to 8-membered carbocyclic ring; R ₄ represents a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, an amidine group which may be substituted on the nitrogen atom with a cyclic alkyl group having 3-8 carbon atoms or a nitro group R ₅ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; Y], Y ₂ , Y ₃ and Y ₄ , which may be the same or different, is a hydrogen atom, a halogen atom, a straight chain or branched hydroxyl group alkyl group having 1-6 carbon atoms which may be substituted with 1-3 atoms halogen, the group NY ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, represent a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ can be linked together to form a piperidine or pyrrolidine ring; n and m are the number 0 or 1. 9. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, wherein the substituents other than Y _b Y _2, Y ₃ and Y ₄ are m-substituted on the benzene ring; R _t is NR ₇ R ₈ where R ₇ is hydrogen, a straight or branched chain alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3 carbon atoms, or a nitro group, and R ₈ is hydrogen or a straight or branched chain alkyl of 1-6 carbon atoms; 183 619 R ₂ represents a hydrogen atom, a chain or branched chain alkyl group having 1-6 carbon atoms, alkoxycarbonyl wherein the alkyl portion is a straight or branched chain alkyl group having 1-6 carbon atoms, or a carboxyl group, or may combine with R ₃ to form a 3- up to an 8 membered carbocyclic ring; R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R ₂ to form a 3- to 8-membered carbocyclic ring; R ₄ is a hydrogen atom, a straight or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, an amidine group which may be substituted on the nitrogen atom by a cyclic alkyl group having 3-8 carbon atoms or by a nitrous group ; R ₅ is hydrogen or a straight chain or branched alkyl group having 1-6 carbon atoms; Y], Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, a straight or branched chain alkyl group having 1-6 carbon atoms that may be substituted with 1-3 halogen atoms, NY ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, represent a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1 -8 carbon atoms, or Y ₅ and Y ₆ may be joined together to form a piperidine or pyrrolidine ring; n and m are the number 0 or 1. 10. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound, or a pharmaceutically acceptable salt thereof, wherein: R] is nitroamino or ethylamino; R ₂ and R _3, which may be the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms, or R ₂ and R ₃ may be joined together to form a 3- to 8-membered a carbocyclic ring; R ₄ and R ₅ are hydrogen; YpY _2L Y ₃ and Y ₄ which may be the same or different, are hydrogen, halogen, hydroxy, straight or branched alkyl group having 1-6 carbon atoms which may be substituted with 1-3 halogen atoms, an NY ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are hydrogen, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine or pyrrolidine ring; n and m are the number 0 or 1. 11. The aniline derivative of the general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, wherein the substituents other than Y _b Y _2, Y ₃ and Y ₄ are m-substituted on the benzene ring; R) is nitroamino or ethylamino; R ₂ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or can combine with R ₃ to form a 3- to 8-membered carbocyclic ring; R ₃ is hydrogen or a straight chain or branched alkyl group having 1-6 carbon atoms, or can combine with R ₂ to form a 3- to 8-membered carbocyclic ring; R ₄ and R ₅ are hydrogen ;, Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, a straight or branched chain alkyl group with 1-6 carbon atoms optionally substituted with 1-3 halogens, the group NY ₅ Y ₆ where Y ₅ and Y ₆ , same or different, are hydrogen, straight chain alkyl group having 1-6 carbon atoms, acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine ring or pyrrolidine; 183,619 n and m are an integer of 0 or 1. 12. The aniline derivative of the general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, wherein the substituents other than Y _b Y _2, Y ₃ and Y ₄ are m-substituted on the benzene ring; R _t is nitroamino or ethylamino R ₂ represents a hydrogen atom or a methyl or ethyl group R ₃ is hydrogen or methyl R ₄ and R ₅ are hydrogen; YbY ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight chain or branched alkyl hydroxyl group having 1-6 carbon atoms that may be substituted with 1-3 halogen atoms, the group NY ₅ Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine ring or pyrrolidine; n and m are an integer of 0 or 1. 13. The aniline derivative of the general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, wherein the substituents other than Y _b Y _2, Y ₃ and Y ₄ Sap-substituted on the benzene ring; Rj is nitroamino or ethylamino R ₂ represents a hydrogen atom or a methyl or ethyl group R ₃ is hydrogen or methyl R ₄ and R ₅ are hydrogen; Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight chain or branched alkyl hydroxyl group having 1-6 carbon atoms which may be substituted with 1-3 halogen atoms, the NY ₅ group Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine ring or pyrrolidine; n and m are an integer of 0 or 1. 14. Aniline derivative of the general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, wherein the substituents other than Y _b Y _2, Y ₃ and Y ₄ are m-substituted on the benzene ring; Rj is nitroamino or ethylamino R ₂ and R ₃ are hydrogen; R ₄ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; R ₅ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight chain or branched alkyl hydroxyl group having 1-6 carbon atoms which may be substituted with 1-3 halogen atoms, the NY ₅ group Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a ring piperidine or pyrrolidine; n and m are an integer of 0 or 1. 15. A drug for cerebrovascular diseases, containing an active ingredient and optionally additional ingredients, characterized in that the active ingredient is a compound represented by the general formula (1) or a possible stereoisomer, or an optically active form of the compound, or a pharmaceutically acceptable salt thereof 183 619 (1) in which R _t is SR 1 or NR ₇ R ₈ ; R ₆ is an optionally fluoro substituted straight chain or branched alkyl group having 1-6 carbon atoms, or a straight chain or branched alkenyl group having 2-6 carbon atoms; R ₇ represents a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms, a straight or branched alkynyl group having 3-6 carbon atoms, a straight or branched alkoxy group having 1-6 carbon atoms, or nitro; R ₈ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; R ₂ represents hydrogen, straight-chain or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group wherein the alkyl part a linear or branched alkyl group having 1-6 carbon atoms, or a carboxyl group, or may combine with R ₃ to form a 3- up to an 8 membered carbocyclic ring; R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R ₂ to form a 3- to 8-membered carbocyclic ring; R ₄ is a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, an amidino group which may be substituted on the nitrogen atom a cyclic alkyl group having 3-8 carbon atoms or a nitro group R ₅ represents a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonylamino group whose alkyl portion is a straight chain or branched alkyl group having 1-6 6 carbon atoms, or an amino group Yi, Y ₂ , Y ₃ and Y ₄ , the same or different, represent a hydrogen atom, a halogen atom, a straight or branched chain alkyl hydroxyl group having 1-6 carbon atoms which may be substituted with 1-3 halogen atoms, the NY ₅ group Y ₆ where Y ₅ and Y ₆ , same or different, represent a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or the combined Y ₅ and Y ₆ form a piperidine or pyrrolidine ring; n and m are an integer of 0 or 1; except: a) a hydrochloride of the compound of formula I wherein Rj = -NH ₂ , R ₂ = -COOH, R ₃ = methyl, R ₄ and R ₅ = Η, n = 1, m = 0, Y _r Y ₄ = H; b) a compound of formula 1, where R 1 = -SCH ₃ , R ₂ = COOH ₃ , R ₃ = methyl, R ₄ = acetyl, R ₅ = H, n = 1, m = 0, Y _r Y ₄ = H; 183 619 c) the R stereoisomer of the compound of formula 1, where Rj = -NH ₂ , R ₂ = -COOH, R ₃ - -H, R ₄ acetyl, R ₅ = Η, n = 0 and m = 0, Yj-Y ₄ = H; d) the hydrochloride of the R-isomer of the compound of Formula I, wherein R] = NH ₂ , R ₂ = -COOH, R ₃ , R ₄ , R ₅ = H, n and _m = 0, Y _r Y ₄ = H; e) hydrochlorides of the R and S isomers of the compound of formula 1, wherein Rj = -NH ₂ , R ₂ = -COOCH ₃ , R ₃ , R ₄ , R ₅ = Η, n and _m = 0, Y _r Y ₄ = H; f) a compound of formula 1, where Rj = = NHNO ₂ , R ₂ = -COOH, R ₃ , R ₄ , R ₅ = Η, η = 1, m = 0, ΥγΥ ₄ = Η; g) a compound of formula 1, where Rj = -NHNO ₂ , R ₂ = -COOH, R ₃ = H, R ₄ = t-butoxycarbonyl, R ₅ = Η, n = 1, m = 0, Y _r Y ₄ = H, 16. A medicament for cerebrovascular diseases comprising an active ingredient and an optional additional ingredient, characterized in that the active ingredient is the compound N- (5- (S-ethylisothioureido) -2-methoxyphenylmethyl) amine or a pharmaceutically acceptable salt thereof. 17. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer, or an optically active form, or a pharmaceutically acceptable salt thereof, characterized in that: R ^ is SR, wherein R ₆ represents optionally fluorine-substituted straight-chain or branched alkyl group having 1-6 carbon atoms, or straight or branched alkenyl group having 2-6 carbon atoms; R ₂ represents hydrogen, straight-chain or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group wherein the alkyl part a linear or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may combine with R ₃ to form a 3- up to an 8 membered carbocyclic ring; R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R ₂ to form a 3- to 8-membered carbocyclic ring; R ₄ represents a hydrogen atom, a straight chain or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group the alkyl portion of which is a straight chain or branched alkyl group having 1-6 carbon atoms, an amidine group which may be substituted on the nitrogen atom with a cyclic alkyl group having 3 -8 carbon atoms, or a nitro group; R ₅ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; Yj, Y ₂ , Y ₃ and Y ₄ are hydrogen; n is an integer of 0 or 1; and m is 0. 18. The aniline derivative of the general formula (1) according to claim 1 Or a possible stereoisomer, or an optically active form of the compound, or a pharmaceutically acceptable salt thereof, characterized in that: Rj is SR ₆ , where R ₆ is an optionally substituted straight or branched alkyl group having 1-6 carbon atoms or a straight or branched alkenyl group having 2-6 carbon atoms; R ₂ and R _3, which may be the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms; R ₄ and R ₅ are hydrogen; Yj, Y ₂ , Y ₃ and Y ₄ are hydrogen; n is an integer of 0 or 1; and m is 0. 19. The aniline derivative of the general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, characterized in that the substituents other than Y j, Y _2, Y ₃ and Y ₄ SAM-substituted on the benzene ring; Rj is methylthio or ethylthio 183 619 R ₂ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or can combine R ₃ to form a 3- to 8-membered carbocyclic ring; R ₃ is a straight or branched alkyl group having 1-6 carbon atoms, or can combine with R ₂ to form a 3- to 8-membered carbocyclic ring; R ₄ and R ₅ are hydrogen; Y _b Y _2, Y ₃ and Y ₄ represent a hydrogen atom; n is an integer of 0 or 1; and m is 0. 20. Aniline derivative of general formula (1) according to claim 1 Or a possible stereoisomer, or an optically active form of the compound, or a pharmaceutically acceptable salt thereof, characterized in that substituents other than Y _b Y ₂ , Y ₃ and Y ₄ are m-substituted; R] is a methylthio or ethylthio group R ₂ and R ₃ are hydrogen; R ₄ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; R ₅ is a straight or branched alkyl group having 1-6 carbon atoms; Y _b Y _2, Y ₃ and Y ₄ represent a hydrogen atom; n is an integer of 0 or 1; and m is 0. 21. Aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, characterized in that substituents other than Yj, Y _2, Y ₃ and Y ₄ SAM-substituted on the benzene ring; R is a methylthio or ethylthio group R ₂ represents a hydrogen atom or a methyl or ethyl group R ₃ is hydrogen or methyl R ₄ and R ₅ are hydrogen; Y _b Y _2, Y ₃ and Y ₄ represent a hydrogen atom; n and m are 0. 22. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, characterized in that the substituents other than Y _b Y _2, Y ₃ and Y ₄ Sap-substituted on the benzene ring; R] is a methylthio or ethylthio group R ₂ represents a hydrogen atom or a methyl or ethyl group R ₃ is hydrogen or methyl R ₄ and R ₅ are hydrogen; Y _b Y _2, Y ₃ and Y ₄ represent a hydrogen atom; n is 1; and m is 0. 23. The aniline derivative of formula (1) according to claim 1 Or a possible stereoisomer, or an optically active form of the compound, or a pharmaceutically acceptable salt thereof, characterized in that. R] is NHR ₇ where R ₇ is a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3 carbon atoms, or a nitro group R ₂ represents a hydrogen atom, a chain or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group wherein the alkyl moiety is a straight or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may sięłączyć with R ₃ to form a 3- to 8- a membered carbocyclic ring; R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R ₂ to form a 3- to 8-membered carbocyclic ring; R ₄ is a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is straight or different from 183 619 branched alkyl group having 1-6 carbon atoms, amidino group which may be substituted on the nitrogen atom by cyclic alkyl group having 3-8 carbon atoms or nitro group R ₅ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms, Y _b Y _2, Y ₃ and Y ₄ are hydrogen; n is an integer of 0 or 1; and m is 0. 24. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, characterized in that the substituents other than Y], Y _2, Y ₃ and Y ₄ SAM-substituted on the benzene ring; R ₁ is NHR ₇ where R ₇ is hydrogen, a straight or branched chain alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms or a nitro group R ₂ represents hydrogen, straight-chain or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group wherein the alkyl part a linear or branched alkyl group having 1-6 carbon atoms, or a carboxyl group, or may combine with R ₃ to form a 3- up to an 8 membered carbocyclic ring; R ₃ is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms, or may combine with R ₂ to form a 3- to 8-membered carbocyclic ring; R ₄ is a hydrogen atom, a straight or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group whose alkyl portion is a straight or branched alkyl group having 1-6 carbon atoms, an amidine group which may be substituted on the nitrogen atom with a cyclic alkyl group having 3-8 carbon atoms or a nitro group R ₅ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; Y], Y ₂ , Y ₃ and Y ₄ are hydrogen; n is an integer of 0 or 1; and m is 0. 25. The aniline derivative of general formula (1) according to claim 1 Or a possible stereoisomer, or an optically active form of a compound, or a pharmaceutically acceptable salt thereof, characterized in that R is a nitroamino group R ₂ and R _3, which may be the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms; R ₄ and R ₅ are hydrogen; Y _b Y _2, Y ₃ and Y ₄ represent a hydrogen atom; n is an integer of 0 or 1; and m is 0. 26. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, characterized in that the substituents other than Y _b Y _2, Y ₃ and Y ₄ wpierścieniu SAM-substituted benzene; Ri is nitroamino R ₂ represents a hydrogen atom or a straight or rod of 1-6 carbon atoms or may combine with R ₃ to form a carbocyclic 3; R ₃ represents a straight or branched alkyl group or may combine with R ₂ to form a 3- to 8-membered p R ₄ and R ₅ are hydrogen; Yj, Y ₂ , Y ₃ and Y ₄ are hydrogen; and n is an integer of 0 or 1; and m is 0. a zoned alkyl group having up to an 8-membered ring having 1-6 carbon atoms, a carbocyclic ring; 27. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, characterized in that the substituents other than Y j, Y _2, Y ₃ and Y ₄ SAM-substituted on the benzene ring; Rj is a nitroamino group 183 619 R ₂ represents a hydrogen atom or a methyl or ethyl group; R ₃ is hydrogen or methyl; R ₄ and R ₅ are hydrogen; Y _b Y _2, Y ₃ and Y ₄ are hydrogen; and nim are 0. 28. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, characterized in that the substituents other than Y], Y _2, Y ₃ and Y ₄ Sap-substituted on the benzene ring; Rj is a nitroamino group R ₂ represents a hydrogen atom or a methyl or ethyl group; R ₃ is hydrogen or methyl; R ₄ and R ₅ are hydrogen; Y _b Y _2, Y ₃ and Y ₄ represent a hydrogen atom; n is 1; and m is 0. 29. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer or optically active form of a compound or a pharmaceutically acceptable salt thereof, characterized in that substituents other niżY], Y _2, Y ₃ and Y ₄ SAM-substituted on the benzene ring; Rj is nitroamino; R ₂ and R ₃ are hydrogen; R ₄ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; R ₅ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; Y _b Y _2, Y ₃ and Y ₄ are hydrogen; n is an integer of 0 or 1; and m is 0. 30. The aniline derivative of claim 30 1 which is selected from the group consisting of N- (1- (3- (S-methylisothioureido) phenyl) -1-methyl) ethyl) amine; N- (1-methyl-1- (3- (N'-nitroguanidino) phenyl) ethyl) amine; N- (1- (3- (S-methylisothioureido) phenyl) ethyl) amine; N- (1 - (3- (N'-nitroguanidino) phenyl) ethyl) amine; N- (1- (3- (N ^/ -nitroguanidino) phenyl) propyl) amine; N- (3- (S-methylisothioureido) phenylmethyl) amine; N- (3- (S-ethylisothioureido) phenylmethyl) amine; N- (3- (S-ethylisothioureidiphenylmethyljmethylamine; N- (4- (S-methylisothioureido) phenylethyl) amine; N- (1 - (3- (S-ethylisothioureido) phenyl) -1-methyl) ethyl) amine; N- (4- (S-ethylisothioureido) phenylethyl) dimethylamine; N- (4- (S-ethylisothioureido) phenylethyl) amine; N- (3- (S-methylisothioureido) phenylethyl) methylamine; N- (1- (3- (S-ethylisothioureido) phenyl) ethyl) methylamine; N- (1 - (3- (S-ethylisothioureido) phenyl) cyclopentyl) amine; N- (1 - (3 - (N'-nitroguanidino) phenyl) cyclopentyl) amine; N- (1- (3- (S-methylisothioureido) phenyl) cyclohexyl) amine; N- (1 - (3- (S-ethylisothioureido) phenyl) cyclohexyl) amine; N- (1 - (3- (N'-nitroguanidino) phenyl) cyclohexyl) amine; N- (1 - (3- (S-ethylisothioureido) phenyl) ethyl) amine; N- (1 - (3- (N'-nitroguanidino) phenyl) cyclobutyl) amine; N- (1 - (3- (S-methylisothioureido) phenyl) cyclobutyl) amine; N- (1 - (3- (S-ethylisothioureido) phenyl) cyclobutyl) amine; N- (1- (3- (S-ethylisothioureido) phenyl) cyclopropyl) amine; N- (5- (S-ethylisothioureido) -2-methoxyphenylmethyl) amine; N- (3- (S-ethylisothioureido) -2-methylphenylmethyl) amine; 183 619 N- (2-chloro-3- (S-ethylisothioureido) phenylmethyl) amine; N- (1- (3- (S-ethylisothioureido) phenyl) propyl) amine; N- (2-dimethylamino-5- (N'-ethylguanidino) phenylmethyl) amine; N- (2-dimethylamino-5- (S-ethylisothioureido) phenylmethyl) amine; N- (5- (S-ethylisothioureido) -2- (N-ethyl-N-methylamino) phenylmethyl) amine; N- (2,6-dimethoxy-3- (S-ethylisothioureido) phenylmethyl) amine; N- (2-ethoxy-5- (S-ethylisothioureido) phenylmethyl) amine; N- (2-benzyloxy-5- (S-ethylisothioureido) phenylmethyl) amine; N- (1- (5- (S-ethylisothioureido) -2-methoxyphenyl) -1-methylethyl) amine; N- (3- (N'-ethylguanidino) phenylmethyl) amine; N- (3- (S-ethylisothioureido) -2-methylphenylmethyl) methylamine; N- (2-benzylamino-5- (S-ethylisothioureido) phenylmethyl) amine; N- (5- (N'-ethylguanidino) -2-fluorophenylmethyl) amine; N- (5- (S-ethylisothiouredo) -2-methylaminophenylmethyl) amine; N- (2-ethylamino- (S-ethylisothioureido) phenylmethyl) amine; N- (2-ethyl-5- (N'-ethylguanidino) phenylmethyl) amine; N- (5- (N'-ethylguanidino) -2-methylphenylmethyl) amine; N- (2- (4- (S-ethylisothioureido) -2-methoxyphenyl) amine; N- (3- (N'-ethylguanidino) -2-methylphenylmethyl) amine; N- (2-chloro-3- (N'-ethylguanidino) phenylmethyl) amine; and N- (2-chloro-5- (N'-ethylguanidino) phenylmethyl) amine; or the possible optically active forms of the compound or a pharmaceutically acceptable salt thereof. 31. The aniline derivative of claim 31 The compound of claim 1, which is N- (4- (S-methylisothioureido) phenylethyljamine or a pharmaceutically acceptable salt thereof. 32. The aniline derivative of claim 32 The compound of claim 1 which is N- (4- (S-ethylisothioureido) phenylethyljamine or a pharmaceutically acceptable salt thereof. 33. A medicament for cerebrovascular diseases, comprising an active ingredient and optionally additional ingredients, characterized in that the active ingredient is a compound which is N- (4- (S-methylisothioureido) -phenylethyl) amine or a pharmaceutically acceptable salt thereof. 34. A medicament for cerebrovascular diseases, comprising an active ingredient and optionally additional ingredients, characterized in that the active ingredient is a compound which is N- (4- (S-ethylisothioureido) phenylethyl) amine or a pharmaceutically acceptable salt thereof. 35. The aniline derivative of general formula (1) according to claim 1 1, or a possible stereoisomer or optically active form of the compound, or a pharmaceutically acceptable salt thereof, characterized in that R ^ is SR, wherein R ₆ represents optionally fluorine-substituted straight-chain or branched alkyl group having 1-6 carbon atoms, or straight or branched alkenyl group having 2-6 carbon atoms; R ₂ and R ₃ which may be the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms, or R ₂ and R ₃ may be joined together to form a 3- to 8-membered ring carbocyclic; R ₄ is a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group the alkyl portion of which is a straight or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, an amidine group that may be substituted on nitrogen with a cyclic alkyl group having 3-8 carbon atoms or with a nitro group; R ₅ represents a hydrogen atom, a straight chain or branched alkyl group having 1-6 carbon atoms, or an alkoxycarbonyl group whose alkyl portion is a straight chain or branched alkyl group having 1-6 carbon atoms; Y _{] 5} Y ₂ , Y ₃ and Y ₄ , the same or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, a straight or branched chain alkyl group having 1-6 carbon atoms, which may be substituted with 1-3 halogen atoms, the group NY ₅ Y ₆ where Y ₅ and Y ₆ can be Same or different, represent a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine or pyrrolidine ring; and n and m are an integer of 0 or 1. 36. The aniline derivative of general formula (1) according to claim 1 1 or a possible stereoisomer, or an optically active form of a compound, or a pharmaceutically acceptable salt thereof, wherein R] is NR ₇ R ₈ , where R ₇ is hydrogen, straight chain or branched alkyl group having 1-6 carbon atoms, cyclic alkyl group having 3-8 carbon atoms or nitro group, and R ₈ is hydrogen, or straight or branched chain an alkyl group having 1-6 carbon atoms; R ₂ and R ₃ which may be the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms, or R ₂ and R ₃ may be joined together to form a 3- to 8-membered carbocyclic ring ; R ₄ represents a hydrogen atom, a straight chain or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group the alkyl portion of which is a straight chain or branched alkyl group having 1-6 carbon atoms, an amidine group which may be substituted on the nitrogen atom with a cyclic alkyl group having 3-8 carbon atoms , or a nitro group R ₅ is hydrogen, a straight or branched alkyl group having 1-6 carbon atoms; Y _b Y ₂ , Y ₃ and Y ₄ , the same or different, represent a hydrogen atom, a halogen atom, a straight or branched chain alkyl hydroxyl group having 1-6 carbon atoms which may be substituted with 1-3 halogen atoms, the NY ₅ group Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are hydrogen, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-6 carbon atoms, or Y ₅ and Y ₆ may be attached to each other to form a piperidine or pyrrolidine ring; n and m are an integer of 0 or 1. 37. The medicament for cerebrovascular disease according to claim 1 A compound according to claim 15, characterized in that the effective ingredient is a compound of general formula (1) or a possible stereoisomer, or an optically active form of the compound, or a pharmaceutically acceptable salt thereof, wherein Rj is SR ₆ where R ₆ is an optionally substituted straight chain or branched alkyl group having 1-6 carbon atoms, or a straight or branched alkenyl group having 2-6 carbon atoms; R ₂ and R _3, which may be the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms, or R ₂ and R ₃ may be combined with sobąz form a 3- to 8-membered carbocyclic ring ; R ₄ is hydrogen, straight or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group wherein the alkyl part a linear or branched alkyl group having 1 to 6 carbon atoms, an acyl group having 1 -8 carbon atoms, an amidino group which may be substituted on the nitrogen atom with a cyclic alkyl group having 3-8 carbon atoms, or with a nitro group R ₅ represents a hydrogen atom, a straight chain or branched alkyl group having 1-6 carbon atoms, or an alkoxycarbonyl group the alkyl portion of which is a straight chain or branched alkyl group having 1-6 carbon atoms; Y ₁₅ Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight chain or branched alkyl hydroxyl group having 1-6 carbon atoms which may be substituted with 1-3 halogen atoms, the NY ₅ group Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine or pyrrolidine ring; and n and m are an integer of 0 or 1. 38. The medicament for cerebrovascular disease according to claim 1 15. The process of claim 15, wherein the effective ingredient is a compound of general formula (1), wherein: 183 619 R is NR ₇ R _8, wherein R ₇ is hydrogen, straight or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms, or a nitro group and R _g represents a hydrogen atom or a straight or branched C alkyl of 1-6 carbon atoms; R ₂ and R _3, which may be the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1-6 carbon atoms, or R ₂ and R ₃ may be joined together to form a 3- to 8-membered ring carbocyclic; R ₄ is a hydrogen atom, a straight or branched chain alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group the alkyl portion of which is a straight or branched alkyl group having 1-6 carbon atoms, an amidine group which may be substituted on the nitrogen atom with a cyclic alkyl group having 3-8 carbon atoms, or nitro group R ₅ is hydrogen or a straight or branched alkyl group having 1-6 carbon atoms; Y _b Y ₂ , Y ₃ and Y ₄ , which may be the same or different, represent a hydrogen atom, a halogen atom, a straight chain or branched alkyl hydroxyl group having 1-6 carbon atoms which may be substituted with 1-3 halogen atoms, the NY ₅ group Y ₆ where Y ₅ and Y ₆ , which may be the same or different, are a hydrogen atom, a straight chain alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or Y ₅ and Y ₆ may be linked together to form a piperidine ring or pyrrolidine; and n and m are an integer of 0 or 1. * * *