JP6809781B2 - Pterin derivative or salt thereof - Google Patents

Description

The present invention relates to a pterin derivative or a salt thereof, which has a blood glucose lowering effect, a nitric oxide production promoting effect, a vasoprotective effect, a microalbuminuria suppressing effect, and the like, and is useful as a medicine.

Nitric oxide (NO) produced by an enzyme (Nitric Oxide Syathase (NOS)) present in vascular endothelial cells acts as an intercellular messenger, and has vasodilatory action (antihypertensive action), platelet aggregation inhibitory action, and leukocytes such as monospheres. Has the effect of preventing the cells from adhering to vascular endothelial cells and invading the tissues under the endothelial cells, suppressing the proliferation of vascular smooth muscle cells, and generally has the effect of protecting blood vessels.
NOS has a site that binds to tetrahydrobiopterin (BH4), and BH4 is required for NOS to produce NO. NOS bound to BH4 is dimerized to generate NO from arginine, but when BH4 is released, NOS is monomerized and NO is not produced in this state. That is, the production of NO is adjusted by BH4.
Abnormal metabolism of NO produced by NOS causes angiopathy, which causes various vascular diseases. For example, hypertension, renal disorder, heart failure, thrombosis, dyslipidemia, cardiac hypertrophy, arteriosclerosis, coronary atherosclerosis, arteriosclerosis obliterans and other cardiovascular disorders, cerebral infarction, cerebral circulatory failure, submucosal hemorrhage, cerebrovascular spasm , Cerebrovascular disorders such as cerebrovascular dementia. In addition, it is involved in diseases related to diabetes and insulin resistance (Non-Patent Document 1, Patent Document 1), endotoxic shock, rheumatism, liver cirrhosis, hypertrophic pyloric stenosis, gastric mucosal disorder, erectile dysfunction, metabolic syndrome, etc. It is thought to cause various diseases.

Recently, it has been clarified that the function of NOS decreases as the production of BH4 decreases in a diabetic state (Non-Patent Document 2). Diabetes is a complication of diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, necrosis and angina, myocardial infarction, cerebral infarction, and angiopathy such as arteriosclerosis due to persistent high blood sugar levels. Is a problem. These diabetic complications are considered to be diabetic vascular diseases caused by vascular disorders caused by decreased NOS activity. However, conventional therapeutic agents for type 2 diabetes do not have a direct NOS activating effect, and no improvement effect can be expected for pathological conditions caused by NO metabolic disorders such as the above-mentioned complications. For example, metformin, which is used as a therapeutic drug for type 2 diabetes, is thought to suppress gluconeogenic effects by activating AMP kinase, but it does not have the function of directly activating NOS, so NO. The effect of improving the pathological condition caused by the metabolic disorder of Metformin cannot be expected stably.
In addition, diabetes is known to be a risk factor for Alzheimer's disease, and large epidemiological studies have reported that diabetes increases the risk of vascular dementia and Alzheimer's disease (non-patent literature). 3, 4). Furthermore, it was revealed that diseases of cerebral microcirculation, especially dysfunction of vascular endothelium and NO, trigger the symptoms of Alzheimer's disease, and that β-amyloid, which is the cause of Alzheimer's disease, inhibits endothelial cell damage and NO production. The interrelationship between them has been clarified (Non-Patent Documents 5 and 6).
That is, cerebrovascular dementia and Alzheimer's disease are diseases in which NO is involved, and can be regarded as complications of diabetes. Activation of NOS acts to control blood glucose and protect blood vessels, and blood glucose control prevents hyperinsulin status and prevents β-amyloid deposition. These work together and are thought to be effective in the prevention and treatment of dementia such as Alzheimer's disease and vascular dementia.
Recently, it has been reported that NO prevents cell dysfunction in Parkinson's disease (Non-Patent Document 7). Recently, it has been reported that nitroprusside, which is known as a NO donor and is used as a vasodilator by its action, rapidly improves the symptoms of schizophrenia (Non-Patent Document 8). Thus NO is involved in various diseases.

From this point of view, it has been reported that BH4 is useful as a therapeutic agent for diseases associated with NOS function decline and diseases associated with insulin resistance (Patent Documents 2 to 6).

NO produced by NOS suppresses gluconeogenesis in the liver and controls fasting blood glucose through activation of AMP kinase. Therefore, by indexing the blood glucose lowering effect, it becomes a good model for quantifying the activation of NOS.

Japanese Unexamined Patent Publication No. 11-246410 Japanese Unexamined Patent Publication No. 10-338637 Japanese Unexamined Patent Publication No. 11-246410 Japanese Unexamined Patent Publication No. 2003-277265 Special Table 2010-515747 Special Table 2011-508775

Diabetologia. 53, 1472 (2010) Diabetes. 62, 3033 (2013) Neurology. 53, 1937-1942 (1999) Journal of the Study Group on Geriatric Dementia 18, 20-24 (2011) Japan Pharmacology Journal 135, 20-24 (2010) Current Aging Science 118-127 (2011) Scientific Reports, 16. July. 2013 DOI: 10.1038 / srep02202 JAMA Psychiatry 668-676 (2013) Trends in Pharmacological Science 48-54 (2008)

However, the NO production promoting action of the compounds described in Patent Documents 5 to 6 does not exceed BH4. As a result of clinical trials for hypercholesterolemia and hypertension, it has been reported that BH4 was not effective by oral administration (Non-Patent Document 9).
Therefore, the subject of the present invention is to have a blood glucose lowering effect, a NO production promoting effect, a microalbuminuria suppressing effect, etc., which are superior to those of BH4, and to develop diseases caused by abnormal NO metabolism, diabetes and its complications. And to provide new compounds useful as prophylactic and therapeutic agents.

Therefore, the present inventor has synthesized various compounds having a pterin skeleton and investigated their gluconeogenesis-suppressing action, NO production promoting action, etc., and found that the compound represented by the following general formula (1) or a salt thereof, and a salt thereof, and Tetrahydrobiopterupterin has an excellent gluconeogenesis inhibitory effect, blood glucose lowering effect, insulin resistance improving effect, NO production promoting effect, microalbuminuria suppressing effect and lipid metabolism improving effect exceeding BH4, and reduces NO production. The present invention has been completed by finding that it is useful as a prophylactic and therapeutic agent for diseases, diabetes and its complications caused by.

That is, the present invention provides the following [1] to [6].
[1] General formula (1)

(In the formula, R ¹ may have a linear or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or a substituent. A good cycloalkyl-alkyl group having 4 to 16 carbon atoms, an aryl group having 6 to 14 carbon atoms which may have a substituent, an aralkyl group having 7 to 23 carbon atoms which may have a substituent, and a substituent. _{Shows a} heterocyclic -C _1-9 alkyl group or -CH (OH) CH ₃ which may have a group;
R ² indicates a hydrogen atom or a linear or branched alkyl group having 1 to 10 carbon atoms;
R ³ indicates a hydrogen atom or a single bond with an adjacent carbon atom;
R ⁴ and R ⁵ each represent a hydrogen atom or together represent a single bond;
R ⁶ represents a hydrogen atom, C _6-14 aryl-C _1-9 alkyl group or heterocyclic-C _1-9 alkyl group;
R ⁷ represents a hydrogen atom, C _1-4 alkyl group, hydroxy C _1-4 alkyl group or C _1-4 alkoxy-C _1-4 alkyl group;
However, when R ¹ is −CH (OH) CH ₃ and R ³ is a single bond and R ² does not exist, R ⁶ and R ⁷ are not hydrogen atoms at the same time. When R ¹ is -CH (OH) CH ₃ and R ² is a hydrogen atom, R ⁶ and R ⁷ are not hydrogen atoms at the same time. When R ¹ is a methyl group, not all of R ^{2 to} R ⁷ are hydrogen atoms at the same time. When R ¹ is an ethyl group, R ³ is a single bond and R ² is absent, then R ⁶ and R ⁷ are not hydrogen atoms at the same time. When R ¹ is a methyl group, R ^{3 to} R ⁵ are single bonds at the same time and R ² is absent, then R ⁶ and R ⁷ are not hydrogen atoms at the same time. )
A compound represented by or a salt thereof.
[2] R ¹ may have a linear or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or a carbon having a substituent. A cycloalkyl-alkyl group having a number of 4 to 16, an aryl group having 6 to 14 carbon atoms which may have a substituent, and an aralkyl group or a substituent having 7 to 23 carbon atoms which may have a substituent. The heterocyclic C _1-9 alkyl group which may be possessed, and the group which can be substituted with the cycloalkyl group, the cycloalkyl-alkyl group, the aryl group, the aralkyl group or the heterocyclic-C _1-9 alkyl group, 1 to 5 selected from C _1-6 alkyl group, C _1-6 alkoxy group, halogeno-C _1-6 alkyl group, hydroxy group, amino group, halogen atom, cyano group and nitro group [1]. Compound or salt thereof.
[3] R ¹ may have a linear alkyl group having 1 to 10 carbon atoms, a substituent may have a cycloalkyl-alkyl group having 4 to 16 carbon atoms, or may have a substituent. 7 to 23 aralkyl groups, the cycloalkyl-alkyl group or the group that can be substituted with the aralkyl group are C _1-6 alkyl group, C _1-6 alkoxy group, halogeno-C _1-6 alkyl group, hydroxy group. , The compound according to [1] or [2], which is 1 to 5 selected from an amino group, a halogen atom, a cyano group and a nitro group, or a salt thereof.
[4] A drug containing the compound according to any one of [1] to [3] or a salt thereof.
[5] A preventive and therapeutic agent for diabetes and / or diabetic complications containing the compound according to any one of [1] to [3], tetrahydrolactoylpterin or a salt thereof as an active ingredient.
[6] A preventive and therapeutic agent for a disease caused by a decrease in nitric oxide production containing the compound according to any one of [1] to [3], tetrahydrolactoylpterin or a salt thereof as an active ingredient.

The compound (1) of the present invention or a salt thereof, and tetrahydrolactoylpterin have a stronger glycation inhibitory effect, blood glucose lowering effect, insulin resistance improving effect, NO production promoting effect, microalbuminuria and lipid metabolism improving effect than BH4. It is useful as a preventive and therapeutic agent for diseases caused by a decrease in NO production, such as a preventive and therapeutic agent for diseases associated with diabetes, its complications, and vascular dysfunction.

The time course of blood glucose level after administration of pyruvic acid to C57BL / 6Ncr mice is shown. The time course of blood glucose level after administration of pyruvic acid to ob / ob mice is shown. The time course of urinary albumin amount after intraperitoneal administration of saline or BH4, tetrahydrobiopterupterin or Example 83, Example 84 is shown. The level of total cholesterol in blood after intraperitoneal administration of saline or BH4, tetrahydrobiopterupterin or Example 83, Example 84 is shown. The value of triglyceride in blood after intraperitoneal administration of saline or BH4, tetrahydrobiopterupterin or Example 83, Example 84 is shown. The values of free fatty acids in the blood after intraperitoneal administration of saline or BH4, tetrahydrobiopterupterin or Example 83, Example 84 are shown. The level of LDL-cholesterol in blood after intraperitoneal administration of saline or BH4, tetrahydrobiopterupterin or Example 83, Example 84 is shown. The level of HDL-cholesterol in blood after intraperitoneal administration of saline or BH4, tetrahydrobiopterupterin or Example 83, Example 84 is shown.

In the general formula (1), R ¹ has a linear or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms which may have a substituent, and a substituent. A cycloalkyl-alkyl group having 4 to 16 carbon atoms, an aryl group having 6 to 14 carbon atoms which may have a substituent, and an aralkyl group having 7 to 23 carbon atoms which may have a substituent. Indicates a heterocyclic -C _1-9 alkyl group or -CH (OH) CH ₃ which may have a group or a substituent. Of these, a linear or branched alkyl group having 2 to 10 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms which may have a substituent, and 4 to 4 carbon atoms which may have a substituent. It may have 16 cycloalkyl-alkyl groups, an aryl group having 6 to 14 carbon atoms which may have a substituent, an aralkyl group having 7 to 23 carbon atoms, or a heterocyclic ring-C _1- which may have a substituent. ₉ Alkyl groups or -CH (OH) CH ₃ are preferred.

Of the linear or branched alkyl groups having 1 to 10 carbon atoms represented by R ¹ , the linear or branched alkyl group having 2 to 10 carbon atoms is more preferable, and the linear alkyl group having 2 to 10 carbon atoms is more preferable. Is more preferable, and a linear alkyl group having 2 to 6 carbon atoms is further preferable. Specific examples of these alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group and the like. The ethyl group, n-propyl group, n-butyl group, n-pentyl group, and n-hexyl group are more preferable.

The cycloalkyl group having 3 to 7 carbon atoms represented by R ¹ is more preferably a cycloalkyl group having 3 to 6 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. As the cycloalkyl-alkyl group having 4 to 16 carbon atoms, a C _3-7 cycloalkyl-C _1-9 alkyl group is preferable, a C _3-7 -cycloalkyl-C _1-6 alkyl group is more preferable, and specific. Examples thereof include cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopentylethyl group, cyclohexylethyl group, cyclopentylpropyl group, cyclohexylpropyl group and the like.

Examples of the aryl group having 6 to 14 carbon atoms represented by R ¹ include a phenyl group and a naphthyl group, of which a phenyl group is more preferable. Examples of the aralkyl group having 7 to 23 carbon atoms include a phenyl-C _1-9 alkyl group and a naphthyl-C _1-9 alkyl group, and a phenyl-C _1-6 alkyl group and a naphthyl-C _1-6 alkyl group. Of these, a phenyl C _1-6 alkyl group such as a benzyl group, a phenethyl group, or a phenyl propyl group is more preferable.

The heterocycle-C _1-9 alkyl group represented by R ¹ is a 5- or 6-membered saturated or unsaturated heterocycle containing 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms-C _1-9. alkyl groups are preferred, in particular pyrrolidine -C _1-9 alkyl group, oxolan -C _1-9 alkyl group, thiolane -C _1-9 alkyl group, a pyrrole -C _1-9 alkyl group, imidazole -C _{1- 9} Alkyl Group, Oxazole-C _1-9 Alkyl Group, Thiazol-C _1-9 Alkyl Group, Fran-C _1-9 Alkyl Group, Thiophene-C _1-9 Alkyl Group, Piperidine-C _1-9 Alkyl Group, Oxane -C _1-9 alkyl group, thian-C _1-9 alkyl group, piperazine-C _1-9 alkyl group, dioxane-C _1-9 alkyl group, ditian-C _1-9 alkyl group, morpholin-C _1-9 Examples thereof include an alkyl group, a pyridine-C _1-9 alkyl group, a pyrimidine-C _1-9 alkyl group, and a thiazine-C _1-9 alkyl group.

Examples of the group that can be substituted with the cycloalkyl group, cycloalkyl-alkyl group, aryl group, aralkyl group or heterocyclic-C _1-9 alkyl group represented by R ¹ include C _1-6 alkyl group and C _1-6 alkoxy. Examples thereof include 1 to 5 groups selected from a group, a halogeno-C _1-6 alkyl group, a hydroxy group, an amino group, a halogen atom, a cyano group and a nitro group.

R ² represents a hydrogen atom or a linear or branched alkyl group having 1 to 10 carbon atoms. As the alkyl group represented by R ² , a linear or branched alkyl group having 1 to 4 carbon atoms is preferable, and a methyl group and an ethyl group are particularly preferable. As R ² , a hydrogen atom or an alkyl group having 1 to 4 carbon atoms is preferable, and a hydrogen atom, a methyl group or an ethyl group is more preferable. When R ³ shows a single bond, −OR ³ is = O (oxo group), and R ² does not exist.

R ³ indicates a hydrogen atom or a single bond with an adjacent carbon atom. When R ³ is a hydrogen atom, -OR ³ becomes -OH. When R ³ shows a single bond, −OR ³ is = O (oxo group).

R ⁴ and R ⁵ each represent a hydrogen atom or together represent a single bond. Depending on the types of R ³ , R ⁴ and R ⁵ , the skeleton of the general formula (1) has the following structure.

(In the formula, R ¹ , R ² , R ⁶ and R ⁷ are the same as above)

R ⁶ represents a hydrogen atom, a C _6-10 aryl-C _1-9 alkyl group or a heterocyclic-C _1-9 alkyl group.
_{Examples of the} C _6-14 aryl-C _1-9 alkyl group include a phenyl-C _1-9 alkyl group and a naphthyl-C _1-9 alkyl group. Specific examples thereof include a benzyl group, a phenylethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group and the like.
As the heterocyclic-C _1-9 alkyl group, a nitrogen-containing heterocyclic-C _1-9 alkyl group is preferable, and a pyrrole-C _1-9 alkyl group, a pyrrolidine-C _1-9 alkyl group, and a methylpyrrolidine-C _1- Examples thereof include ₉ alkyl groups and imidazole-C _1-9 alkyl groups. Specific examples thereof include a pyrrolidine methyl group, a pyrrolidine ethyl group, and a methylpyrrolidine ethyl group.

R ⁷ represents a hydrogen atom, a C _1-4 alkyl group, a hydroxy C _1-4 alkyl group or a C _1-4 alkoxy-C _1-4 alkyl group. Here, examples of the C _1-4 alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and the like. Examples of the hydroxy C _1-4 alkyl group include a hydroxyethyl group and a hydroxypropyl group. _{Examples of the} C _1-4 alkoxy-C _1-4 alkyl group include a methoxyethyl group and an ethoxyethyl group.

In the general formula (1), when R ¹ is −CH (OH) CH ₃ and R ³ is a single bond and R ² does not exist, R ⁶ and R ⁷ are not hydrogen atoms at the same time. When R ¹ is -CH (OH) CH ₃ and R ² is a hydrogen atom, R ⁶ and R ⁷ are not hydrogen atoms at the same time. When R ¹ is a methyl group, not all of R ^{2 to} R ⁷ are hydrogen atoms at the same time. When R ¹ is an ethyl group, R ³ is a single bond and R ² is absent, then R ⁶ and R ⁷ are not hydrogen atoms at the same time. When R ¹ is a methyl group, R ^{3 to} R ⁵ are single bonds at the same time and R ² is absent, then R ⁶ and R ⁷ are not hydrogen atoms at the same time.

Further, in the present invention, R ¹ has a linear or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms which may have a substituent, and a substituent. A cycloalkyl-alkyl group having 4 to 16 carbon atoms, an aryl group having 6 to 14 carbon atoms which may have a substituent, and an aralkyl group having 7 to 23 carbon atoms which may have a substituent. Alternatively, it is preferably a heterocyclic C _1-9 alkyl group which may have a substituent. Further, R ⁶ and R ⁷ are hydrogen atoms, and R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, or a cycloalkyl group having 3 to 7 carbon atoms which may have a substituent. , A cycloalkyl-alkyl group having 4 to 16 carbon atoms which may have a substituent, an aralkyl group which may have a substituent and may have 7 to 23 carbon atoms, or a complex which may have a substituent. More preferably, it is a ring C _1-9 alkyl group. Furthermore, even if R ⁶ and R ⁷ are hydrogen atoms and R ¹ has a linear alkyl group having 2 to 10 carbon atoms, a cycloalkyl-alkyl group having 4 to 16 carbon atoms, or a substituent. It is preferably an aralkyl group having 7 to 23 carbon atoms. Here, the groups that can be substituted with a cycloalkyl group, a cycloalkyl-alkyl group, an aryl group, an aralkyl group or a heterocyclic-C _1-9 alkyl group are C _1-6 alkyl group, C _1-6 alkoxy group and halogeno-. C _1-6 Alkyl group, hydroxy group, amino group, halogen atom, cyano group and nitro group are preferably selected from 1 to 5 groups.

Further, in the present invention, among the structures of the formulas (1-a) to (1-d), the structure of the formula (1-a), (1-c) or the formula (1-d) is more preferable. The structure of formula (1-a) or formula (1-c) is more preferred.

In the present invention, the structure is of formula (1-a), (1-c) or formula (1-d), in which R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, and the number of carbon atoms. It is preferably an aralkyl group having 7 to 23 carbon atoms which may have a cycloalkyl-alkyl group of 4 to 16, an aryl group having 6 to 14 carbon atoms or a substituent. Further, in the structure of the formula (1-a), (1-c) or the formula (1-d), R ⁶ and R ⁷ are hydrogen atoms, and R ¹ is a linear chain having 2 to 10 carbon atoms. Alternatively, it may be an alkyl group of a branched chain, a cycloalkyl-alkyl group having 4 to 16 carbon atoms, an aryl group having 6 to 14 carbon atoms, or an aralkyl group having 7 to 23 carbon atoms which may have a substituent. More preferred. Furthermore, in the structure of the formula (1-a) or the formula (1-c) or the formula (1-d), R ⁶ and R ⁷ are hydrogen atoms, and R ¹ has 2 to 10 carbon atoms. It is preferably a linear alkyl group, a cycloalkyl-alkyl group having 4 to 16 carbon atoms, or an aralkyl group having 7 to 23 carbon atoms which may have a substituent. Here, examples of the group that can be substituted with the cycloalkyl-alkyl group or the aralkyl group include a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogeno-C _1-6 alkyl group, a hydroxy group, an amino group and a halogen atom. , 1-5 selected from cyano and nitro groups are preferred.

Since the compound (1) of the present invention or a salt thereof has a plurality of asymmetric carbon atoms, there are a plurality of optical isomers based on the irregular carbon atoms. The present invention includes all of the optical isomers.

The salt of the compound (1) of the present invention may be any pharmaceutically acceptable salt, and examples thereof include acid addition salts. Examples of the acid forming the salt include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid and the like. In addition, the compound (1) of the present invention or a salt thereof may exist in the form of a hydrate or the like, and the hydrate is also included in the present invention.

The compound (1) of the present invention or a salt thereof can be produced, for example, according to the following reaction formula.

(In the formula, R ⁸ indicates a hydroxyl-protecting group, and R ¹ , R ² , R ⁶ and R ⁷ are the same as above))

Hereinafter, each reaction step will be described.

Compound (4) can be prepared by the method described in Heterocycles 76 (2) 1329 (2008).

Compound (4) has a protective group R ^8. As the protecting group represented by R ⁸ , a protecting group that is eliminated by hydrolysis, solvolysis, deprotection with a fluorine anion, or the like is preferable.

Examples of the protecting group include an alkoxyalkyl group, an alkyl group, an acyl group, a silyl group, an alkoxycarbonyl group, a trityl group and the like.

Examples of the alkoxyalkyl group include C _1-6 alkoxy C _1-6 alkyl group, and methoxymethyl group, ethoxymethyl group, methoxyethoxymethyl group, 2-tetrahydropyranyl group and the like are preferable. Examples of the alkyl group include a C _3- C ₈ linear, branched or cyclic alkyl group, and a cyclopentyl group, a cyclohexyl group, an isopropyl group, a tert-butyl group and the like are preferable. The acyl group, formyl group, C ₁ -C ₁₂ linear, branched or cyclic alkylcarbonyl group, and an arylcarbonyl group such C ₆ -C ₁₄ is an acetyl group, a benzoyl group and the like. Examples of the silyl group include a tri-C _1- C ₆ alkylsilyl group, an alkyldiphenylsilyl group and a triphenylsilyl group, and examples thereof include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group and a diphenylmethylsilyl group. A group, a tert-butyldiphenylsilyl group, a triphenylmethyl group and the like are preferable. The alkoxycarbonyl groups include C ₁ -C ₁₄ alkoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, tert- butoxycarbonyl group, benzyloxycarbonyl group.

ii) Oxidation of compound (4) gives compound (5), and reduction of compound (5) gives compound (6).
The oxidation reaction of compound (4) is carried out by reacting tetrapropylammonium tetrapropylammonium with 4-methylmorpholine N-oxide (see Heterocycles 71 (4) 911 (2007)). The reduction reaction of compound (5) is carried out by catalytic reduction or the like.

Examples of the catalyst used for catalytic reduction (hydrogenation reaction in the presence of a catalyst) include Pd, Ru, Rh, Pt, Ni, Cu and the like, but Pd and Pt are more preferable. These metals may be supported on a carrier such as carbon.

Contact reduction (hydrogenation reaction in the presence of a catalyst) includes water, alcohols such as methanol and ethanol, dimethoxyethane, dioxane, dimethylformamide, dimethylacetamide, THF, DMSO, nitromethane, acetone, ethyl acetate, toluene, acetic acid, etc. It can be done in a solvent. The catalyst may be 0.01 to 5 parts by mass, preferably 0.1 to 2 parts by mass, based on 1 part by mass of the raw material compound. The hydrogen pressure is normal pressure to 10 MPa, preferably normal pressure to 0.5 MPa, and the reaction temperature may be 0 to 80 ° C, preferably 20 to 50 ° C. The reaction time may be 1 to 72 hours, preferably 1 to 24 hours.

iii) Deprotection of compound (4), compound (5) or compound (6) gives compound (7), compound (10) or compound (1-d), respectively.

Deprotection can be appropriately selected such as hydrolysis and solvolysis according to the protecting group.

The hydrolysis or solvolysis reaction is carried out according to a conventional method in a solvent or mixed solution of water, lower alcohol, dimethoxyethane, dioxane, THF, DMSO, nitromethane, acetone, ethyl acetate, toluene, acetic acid, etc. at 0 ° C to reflux temperature. It can be carried out, preferably for 0.5 to 48 hours. As the lower alcohol, C ₁ -C ₄ alcohols, such as methanol, ethanol, isopropanol or the like is used. The amount of the solvent such as water and lower alcohol used may be any amount as long as it can dissolve a part of the raw material compound, and is preferably 0.1 to 1000 parts by mass and further 0.1 to 50 parts by mass with respect to 1 part by mass of the raw material compound.

Additives for hydrolysis and solvent decomposition include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium acetate, t-butoxypotassium, potassium phosphate, aqueous ammonia, etc. Inorganic bases, imidazole, trimethylamine, triethylamine, diethylamine, propylamine, tetramethylammonium hydride, aniline, N, N-dimethylaniline, dimethylaminopyridine, diazabicycloundecene and other organic bases, hydrochloric acid, sulfuric acid, nitrate, nitrite , Inorganic acids such as chloric acid, perchloric acid, phosphoric acid and hydrobromic acid, and organic acids such as acetic acid, oxalic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid.
Of these, inorganic acids are preferable, and hydrochloric acid is particularly preferable. Specifically, the additive is preferably added in an amount of 0.1 to 100 parts by mass, more preferably 0.1 to 50 parts by mass, based on 1 part by mass of the raw material compound.

iv) Reduction of compound (7) or compound (10) gives compound (1-a) or compound (1-b). This reaction is a reaction that selectively reduces only the double bonds at positions 7 and 8 of the pterin skeleton.

This reduction reaction is carried out by reduction with a reducing agent or catalytic reduction (hydrogenation reaction in the presence of a catalyst). Examples of the reducing agent include a reducing agent selected from sulfites, hyposulfites, thiosulfates and reducing metals. Examples of sulfites include sodium sulfite (Na ₂ SO ₃ ), potassium sulfite (K ₂ SO ₃ ) and the like. Examples of the hyposulfite include sodium hyposulfite (Na ₂ S ₂ O ₄ ), potassium hyposulfite (K ₂ S ₂ O ₄ ) and the like. Examples of the thiosulfate include sodium thiosulfate (Na ₂ S ₂ O ₃ ), potassium thiosulfate (K ₂ S ₂ O ₃ ) and the like. Examples of the reducing metal include Zn, Fe, Ni, Hg, Al, and Mg. Of these reducing agents, sulfites, hyposulfites and thiosulfates are more preferred.

The reduction reaction using a reducing agent is 0.5 per 1 mol of the raw material compound in a solvent such as water, methanol, ethanol, dimethoxyethane, dioxane, dimethylformamide, dimethylacetamide, THF, DMSO, nitromethane, acetone, ethyl acetate and acetic acid. To 20 mol of the reducing agent may be added and the reaction may be carried out at 0 ° C. to 100 ° C. for 0.5 hours to 24 hours.

v) If compound (9), compound (8), compound (7) or compound (10) is reduced, compound (1-c1), compound (1-c2), compound (1-c3) and compound (1-c3), respectively. 1-c4), compound (1-c5) or compound (1-d) is obtained.
This reduction reaction can be carried out in the same manner as the reaction for obtaining the compound (6) from the compound (5).

vi) Oxidation of compound (1-d) gives compound (1-b).
The oxidation reaction is carried out by oxidation with an oxidizing agent or oxygen oxidation. Oxidizing agents include oxidation using metals such as chromium acid and manganese compounds, oxidation using organic compounds such as DMSO, quinone, acetone, periodinane compounds and TEMPO, hydrogen peroxide, peracetic acid, perbenzoic acid and the like. Oxidation using hydrogen peroxide can be mentioned. Oxygen oxidation includes oxygen oxidation by air, oxygen, ozone, etc., and catalysts such as Pd, Ru, Rh, Pt, Ni, and Cu may be added.

Oxygen oxidation is carried out in alcohol solvents such as water, methanol and ethanol, in solvents such as dimethoxyethane, dioxane, dimethylformamide, dimethylacetamide, THF, DMSO, nitromethane, acetone and ethyl acetate, preferably in solvents such as water and alcohol. Stir in air for 1 to 72 hours.

The amount of the oxidizing agent used is preferably 0.5 to 3 mol, more preferably 0.9 to 1.1 mol, based on 1 mol of the compound of the formula (4). The reaction is carried out in an alcohol solvent such as water, methanol or ethanol, a solvent such as dimethoxyethane, dioxane, dimethylformamide, dimethylacetamide, THF, DMSO, nitromethane, acetone, ethyl acetate or acetic acid, preferably in a solvent such as water or alcohol. The reaction temperature may be -15 ° C to 60 ° C, preferably -15 ° C to 10 ° C, and the reaction time may be 1 to 24 hours.

In order to obtain an acid addition salt of the compound (1) of the present invention, the acid of the compound (1) may be added in a solvent such as water or alcohol.

In order to isolate the target compound or a salt thereof from the reaction mixture, the precipitated crystals may be collected by filtration, and various chromatographys, recrystallizations and the like can be performed.

Compound (1) of the present invention, tetrahydrolactoylpterin (in formula (1), R ¹ = −CH (OH) CH ₃ , R ³ = single bond, R ² = nonexistent, R ^{4 to} R ⁷ = H: formula In (1-d), R ¹ = CH (OH) CH ₃ , R ⁶ = R ⁷ = H) or a salt thereof has a stronger gluconeogenesis inhibitory effect and blood glucose level than BH4, as shown in Examples below. Since it has a lowering effect, an insulin resistance improving effect, a NO production promoting effect, a microalbuminuria suppressing effect, and a lipid metabolism improving effect, it prevents diseases, diabetes, and diabetic complications caused by a decrease in NO production in animals including humans. And useful as a therapeutic agent. Diseases caused by decreased NO production include cardiovascular disorders such as hypertension, renal disorders, heart failure, thrombosis, dyslipidemia, cardiac hypertrophy, arteriosclerosis, coronary atherosclerosis, and arteriosclerosis obliterans; cerebral infarction, brain. Cerebrovascular disorders such as circulatory insufficiency, submucosal bleeding, cerebrovascular spasm, cerebrovascular dementia; diabetic complications involving diabetes and insulin resistance; endotoxin shock, rheumatism, liver cirrhosis, hypertrophic pyloric stenosis, gastromucosa Disorders, erectile dysfunction, metabolic syndrome, Parkinson's disease, Alzheimer's disease, schizophrenia, etc. can be mentioned. Here, examples of diabetic complications include diabetic nephropathy (artificial dialysis), diabetic retinopathy (blindness), and diabetic neuropathy (loss of pain sensation, necrosis).

In the case of solid preparations, additives such as sucrose, lactose, cellulose sugar, D-mannitol, martitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, trangams, arabic Used by rubbers, gelatins, collagens, casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, glycerin, polyethylene glycol, sodium hydrogen carbonate, magnesium stearate, talc, etc. Be done. Further, the tablet can be a tablet coated with a usual skin, for example, a sugar-coated tablet, an enteric coated tablet, a film-coated tablet or a double-layer tablet, or a multi-layer tablet, if necessary.

For semi-solid preparations, animal and vegetable fats and oils (olive oil, corn oil, castor oil, etc.), mineral fats and oils (petrolatum, white petrolatum, solid paraffin, etc.), waxes (jojoba oil, carnauba wax, beeswax, etc.), partial synthesis Alternatively, fully synthetic glycerin fatty acid ester (lauric acid, myristic acid, palmitic acid, etc.) or the like is used.

In the case of a liquid preparation, additives such as sodium chloride, glucose, sorbitol, glycerin, olive oil, propylene glycol, ethyl alcohol and the like can be mentioned. In particular, when it is used as an injection, a sterile aqueous solution such as physiological saline, isotonic solution or oily solution such as sesame oil or soybean oil is used. Further, if necessary, a suitable suspending agent such as sodium carboxymethyl cellulose, a nonionic surfactant, a solubilizing agent, for example, benzyl benzoate, benzyl alcohol and the like may be used in combination.

The amount of active ingredient in these formulations is 0.1-100% by weight of the formulation, preferably 1-50% by weight. The dose may vary depending on the patient's symptoms, body weight, age, etc., but in the case of oral administration, the amount of the compound (1) of the present invention or a salt thereof is about 1 to 500 mg per day for adults, and this is administered once or several times. It is preferable to administer in divided doses.

Next, the present invention will be described in detail with reference to examples.

Example 1
2- (2-Amino-4-cyclohexyloxypteridine-6-yl) propan-2-ol acetonitrile in 25 mL under ice-cooling, 3-methyl-2-butenal 3.41 g (40.5 mmol), pyrrolidine 0.29 g (4.1 mmol) , 4.98 g (43.9 mmol) of 30% aqueous hydrogen peroxide was added, and the mixture was stirred for 1 hour to obtain 3,3-dimethyloxylan-2-carbaldehyde. Add 6-cyclohexyloxypyrimidine-2,4,5-triamine 7.54 g (33.8 mmol), 2 mol / L hydrochloric acid aqueous solution 16.9 mL (33.8 mmol), 3,3-dimethyloxylan-2-carbaldehyde to 25 mL of acetonitrile under water cooling. In addition, the mixture was stirred for 1 hour, then 0.86 g (3.4 mmol) of iodine and 11.48 g (101.3 mmol) of 30% aqueous hydrogen peroxide were added, and the mixture was stirred overnight. Aqueous sodium sulfite solution is added to the reaction mixture, extracted with ethyl acetate, dehydrated, concentrated under reduced pressure, and then purified by column chromatography. 2- (2-Amino-4-cyclohexyloxypteridine-6-yl) propan-2-ol 4.45 g (14.7 mmol) was obtained.
¹ H NMR (DMSO): δ / ppm = 1.27-1.84 (m, 8H), 1.51 (s, 6H), 1.97-2.07 (m, 2H), 5.23-5.34 (m, 1H), 5.44 (s, 1H) ), 7.02-7.14 (br-s, 2H), 9.09 (s, 1H)

Example 2
1- (2-Amino-4-cyclohexyloxypteridine-6-yl) -2-methylpropan-1-ol
The title compound was obtained from 4-methyl-2-pentenal by the same method as in Example 1.
^{1 1} H NMR (DMSO): δ / ppm = 0.81 (d, 3H, J = 6.6Hz), 0.89 (d, 3H, J = 6.6Hz), 1.26-1.47 (m, 3H), 1.51-1.65 (m, 3H), 1.73-1.85 (m, 2H), 1.98-2.11 (m, 1H), 4.41 (dd, 1H, J = 4.8Hz, 6.3Hz), 5.23-5.32 (m, 1H), 5.57 (d, 1H) , J = 4.5Hz), 7.13 (br-s, 2H), 8.85 (s, 1H)

Example 3
1S- (2-amino-4-cyclohexyloxypteridine-6-yl) -propan-1-ol dichloromethane 400 mL, molecular sieve 4A 20 g, L-diisopropyl tartrate 6.53 g (27.9 mmol), titanium tetraisopropoxide 6.60 g ( 23.2 mmol) was added, the mixture was cooled to -30 ° C., 80% cumene hydroperoxide (88.3 g (464 mmol)) and trans-2-penten-1-ol (20 g (232 mmol)) were added, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was filtered through Celite, dehydrated, concentrated under reduced pressure, and then purified by column chromatography to obtain 16.2 g (159 mmol) of (2S, 3S) -2,3-epoxy-1-pentanol.
In a mixed solution of 150 mL of chloroform and 150 mL of saturated aqueous sodium bicarbonate solution under ice cooling, (2S, 3S) -2,3-epoxy-1-pentanol 7.73 g (75.7 mmol), 2,2,6,6-tetramethylpiperidine-1 -Oxyl 118 mg (0.76 mmol), tetrabutylammonium bromide 244 mg (0.76 mmol), and trichloroisocyanuric acid 6.51 g (28.0 mmol) were added, and the mixture was stirred for 1 hour. The reaction mixture was filtered, the organic layer was dehydrated and concentrated under reduced pressure to obtain (2S, 3S) -2,3-epoxy-1-pentanal.
In 350 mL of acetonitrile under water cooling, 16.89 g (75.7 mmol) of 6-cyclohexyloxypyrimidine-2,4,5-triamine, 76 mL (75.7 mmol) of 1 mol / L hydrochloric acid aqueous solution, (2S, 3S) -2,3-epoxy-1 -Pentanal was added and stirred for 1 hour, then 1.92 g (7.6 mmol) iodine and 25.74 g (227 mmol) 30% aqueous hydrogen peroxide were added and stirred overnight. An aqueous sodium sulfite solution is added to the reaction mixture, extracted with ethyl acetate, dehydrated, concentrated under reduced pressure, and then purified by column chromatography. 1S- (2-amino-4-cyclohexyloxypteridine-6-yl) -propan-1-ol 5.31 g (17.5 mmol) was obtained.
^{1 1} H NMR (DMSO): δ / ppm = 0.91 (t, 3H, J = 7.2Hz), 1.27-1.45 (m, 3H), 1.56-1.60 (m, 3H), 1.70-1.80 (m, 4H), 1.99-2.03 (m, 2H), 4.56-4.62 (m, 1H), 5.24-5.31 (m, 1H), 5.57 (d, 1H, J = 4.5Hz), 7.13 (br-s, 2H), 8.89 ( s, 1H)

Example 4
Examples except that 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -propan-1-ol trans-2-penten-1-ol was changed to diisopropyl L-tartrate to D-diisopropyl tartrate. The title compound was obtained by the same method as in 3.
^{1 1} H NMR (DMSO): δ / ppm = 0.91 (t, 3H, J = 7.2Hz), 1.27-1.45 (m, 3H), 1.56-1.60 (m, 3H), 1.70-1.80 (m, 4H), 1.99-2.03 (m, 2H), 4.56-4.62 (m, 1H), 5.24-5.31 (m, 1H), 5.57 (d, 1H, J = 4.5Hz), 7.13 (br-s, 2H), 8.89 ( s, 1H)

Example 5
The title compound was obtained from 1S- (2-amino-4-cyclohexyloxypteridine-6-yl) -ethanol trans-2-buten-1-ol by the same method as in Example 3.
^{1 1} H NMR (DMSO): δ / ppm = 1.22-1.40 (m, 2H), 1.43 (d, 3H, J = 6.0Hz), 1.52-1.59 (m, 2H), 1.76-1.79 (m, 2H), 1.98-2.07 (m, 2H), 4.80-4.87 (m, 1H), 5.23-5.29 (m, 1H), 5.58 (d, 1H, J = 6.0Hz), 7.13 (br-s, 2H), 8.92 ( s, 1H)

Example 6
The title compound was obtained from 1S- (2-amino-4-cyclohexyloxypteridine-6-yl) -butane-1-ol trans-2-hexen-1-ol by the same method as in Example 3.
^{1 1} H NMR (DMSO): δ / ppm = 0.90 (t, 3H, J = 7.8Hz), 1.24-1.85 (m, 12H), 1.99-2.09 (m, 2H), 4.66 (dd, 1H, J = 6.3) Hz, 11.1Hz), 5.20-5.33 (m, 1H), 5.55 (d, 1H, J = 4.5Hz), 7.13 (br-s, 2H), 8.89 (s, 1H)

Example 7
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -butane-1-ol trans-2-hexen-1-ol by the same method as in Example 4.
^{1 1} H NMR (DMSO): δ / ppm = 0.90 (t, 3H, J = 7.8Hz), 1.24-1.85 (m, 12H), 1.99-2.09 (m, 2H), 4.66 (dd, 1H, J = 6.3) Hz, 11.1Hz), 5.20-5.33 (m, 1H), 5.55 (d, 1H, J = 4.5Hz), 7.13 (br-s, 2H), 8.89 (s, 1H)

Example 8
The title compound was obtained from 1S- (2-amino-4-cyclohexyloxypteridine-6-yl) -hexane-1-ol trans-2-octen-1-ol by the same method as in Example 3.
^{1 1} H NMR (DMSO): δ / ppm = 0.85 (t, J = 6.3Hz, 3H), 1.17-1.50 (m, 10H), 1.50-1.66 (m, 2H), 1.66-1.85 (m, 4H), 1.98-2.11 (m, 2H), 4.61-4.69 (m, 1H), 5.23-5.33 (m, 1H), 5.57 (d, J = 5.1Hz, 1H), 7.14 (br-s, 2H), 8.89 ( s, 1H)

Example 9
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -hexane-1-ol trans-2-octen-1-ol by the same method as in Example 4.
^{1 1} H NMR (DMSO): δ / ppm = 0.85 (t, J = 6.3Hz, 3H), 1.17-1.50 (m, 10H), 1.50-1.66 (m, 2H), 1.66-1.85 (m, 4H), 1.98-2.11 (m, 2H), 4.61-4.69 (m, 1H), 5.23-5.33 (m, 1H), 5.57 (d, J = 5.1Hz, 1H), 7.14 (br-s, 2H), 8.89 ( s, 1H)

Example 10
1R- (2-Amino-4-cyclohexyloxypteridine-6-yl) -3-phenyl-propan-1-ol trans-5-phenyl-2-penten-1-ol in the same manner as in Example 4 The compound was obtained.
^{1 1} H NMR (DMSO): δ / ppm = 1.26-1.47 (m, 3H), 1.52-1.67 (m, 3H), 1.73-1.87 (m, 2H), 1.99-2.12 (m, 4H), 2.64-2.77 (m, 2H), 4.64-4.71 (m, 1H), 5.23-5.34 (m, 1H), 5.73 (d, J = 4.2Hz, 1H), 8.93 (s, 1H), 7.10-7.31 (m, 5H) ).

Example 11
1R- (2-Amino-4-cyclohexyloxypteridine-6-yl) -3-cyclohexyl-propane-1-ol trans-5-cyclohexyl-2-penten-1-ol in the same manner as in Example 4 The compound was obtained.
^{1 1} H NMR (DMSO): δ / ppm = 0.74-0.92 (m, 2H), 1.01-1.48 (m, 9H), 1.52-1.85 (m, 12H), 1.97-2.09 (m, 2H), 4.59-4.76 (m, 1H), 5.23-5.33 (m, 1H), 5.56 (d, J = 5.1Hz, 1H), 7.15 (br-s, 1H), 8.89 (s, 1H).

Example 12
1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -3- (4-trifluoromethyl-phenyl) -propan-1-ol trans-5- (4-trifluoromethyl-phenyl) -2 The title compound was obtained from -penten-1-ol-ol by the same method as in Example 4.
^{1 1} H NMR (DMSO): δ / ppm = 1.25-1.48 (m, 3H), 1.52-1.69 (m, 3H), 1.73-1.87 (m, 2H), 1.99-2.19 (m, 4H), 2.76-2.90 (m, 2H), 4.66-4.75 (m, 1H), 5.23-5.34 (m, 1H), 5.80 (d, J = 4.8Hz, 1H), 7.19 (br-s, 2H), 7.48 (d, J = 7.2Hz, 2H), 7.61 (d, J = 7.2Hz, 2H), 8.96 (s, 1H).

Example 13
1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -3- (4-methoxy-phenyl) -propan-1-ol trans-5- (4-methoxy-phenyl) -2-pentene-1 -The title compound was obtained from oar by the same method as in Example 4.
^{1 1} H NMR (DMSO): δ / ppm = 1.26-1.47 (m, 3H), 1.53-1.67 (m, 3H), 1.75-1.85 (m, 2H), 1.95-2.10 (m, 4H), 2.58-2.68 (m, 2H), 3.71 (s, 3H), 4.61-4.69 (m, 1H), 5.23-5.33 (m, 1H), 5.71 (d, J = 4.2Hz, 1H), 6.82 (d, J = 7.8) Hz, 2H), 7.15 (d, J = 7.8Hz, 2H), 8.92 (s, 1H).

Example 14
1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -3-p-tolyl-propan-1-ol-3-p-tolyl-propan-1-ol
The title compound was obtained from trans-5-p-toluyl-2-penten-1-ol by the same method as in Example 4.

Example 15
1- (2-Amino-4-cyclohexyloxypteridine-6-yl) -etanone
To 6.57 g (22.7 mmol) of 1- (2-amino-4-cyclohexyloxypteridine-6-yl) -ethanol, 657 mL of acetonitrile and 4.67 g (29.6 mmol) of potassium permanganate were added, and the mixture was stirred at 50 ° C. for 2.5 hours. After completion of the reaction, the mixture was filtered through Celite, concentrated under reduced pressure, and purified with ethyl acetate-methanol to give 2.04 g (7.10 mmol) of 1- (2-amino-4-cyclohexyloxypteridine-6-yl) -etanone.
^{1 1} H NMR (DMSO): δ / ppm = 1.33-1.50 (m, 4H), 1.53-1.73 (m, 2H), 1.76-1.87 (m, 2H), 2.00-2.10 (m, 2H), 2.62 (s) , 3H), 5.30-5.36 (m, 1H), 7.63 (br-s, 1H), 7.79 (br-s, 1H), 9.21 (s, 1H)

Example 16
1- (2-Amino-4-cyclohexyloxypteridine-6-yl) -2-methylpropan-1-one
The title compound was obtained from 1- (2-amino-4-cyclohexyloxypteridine-6-yl) -2-methylpropan-1-ol by the same method as in Example 15.
^{1 1} H NMR (DMSO): δ / ppm = 1.16 (d, 6H, J = 6.6Hz), 1.35-1.86 (m, 8H), 1.96-2.07 (m, 2H), 3.89-3.98 (m, 1H), 5.32-5.37 (m, 1H), 7.63 (br-s, 1H), 7.78 (br-s, 1H), 9.21 (s, 1H)

Example 17
1- (2-Amino-4-cyclohexyloxypteridine-6-yl) -butane-1-one
The title compound was obtained from 1- (2-amino-4-cyclohexyloxypteridine-6-yl) -butane-1-ol by the same method as in Example 15.
^{1 1} H NMR (DMSO): δ / ppm = 0.96 (t, 3H, J = 7.2Hz), 1.32-1.88 (m, 10H), 1.97-2.10 (m, 2H), 3.11 (t, 2H, J = 6.9) Hz), 5.31-5.37 (m, 1H), 7.62 (br-s, 1H), 7.77 (br-s, 1H), 9.21 (s, 1H)

Example 18
1- (2-Amino-4-cyclohexyloxypteridine-6-yl) -3-phenyl-propan-1-one
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -3-phenyl-propan-1-ol by the same method as in Example 15.
^{1 1} H NMR (DMSO): δ / ppm = 1.30-1.49 (m, 3H), 1.50-1.72 (m, 3H), 1.73-1.85 (m, 2H), 1.98-2.09 (m, 2H), 2.98 (t) , J = 7.8Hz, 2H), 3.43 (t, J = 7.8Hz, 2H), 5.27-5.39 (m, 1H), 7.16-7.32 (m, 5H), 7.67 (br-s, 1H), 7.82 ( br-s, 1H), 9.22 (s, 1H).

Example 19
2-Amino-6- (1-Hydroxy-1-methyl-Ethyl) -3H-Pteridine-4-one
To 1.5 g (4.94 mmol) of 2- (2-amino-4-cyclohexyloxypteridine-6-yl) propan-2-ol, 15 mL of 3 mol / L hydrochloric acid and 3 mL of methanol were added, and the mixture was stirred at an outside temperature of 50 ° C. for 5 hours. The reaction solution was adjusted to pH = 7 with an aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration, dried under reduced pressure, and 2-amino-6- (1-hydroxy-1-methyl-ethyl) -3H-pteridine-4-one 0.99. g (4.5 mmol) was obtained.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 1.48 (s, 6H), 5.44 (s, 1H), 6.84 (br-s, 2H), 8.94 (s, 1H), 11.45 (br-s, 1H)

Example 20
2-Amino-6- (1-Hydroxy-2-methyl-propyl) -3H-Pteridine-4-one
The title compound was obtained from 1- (2-amino-4-cyclohexyloxypteridine-6-yl) -2-methylpropan-1-ol by the same method as in Example 19.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.82 (d, 3H, J = 6.9Hz), 0.85 (d, 3H, J = 6.9Hz), 1.97-2.11 (m, 1H), 4.40 (t) , 1H, J = 5.1Hz), 5.50 (d, 1H, J = 5.1Hz), 6.87 (br-s, 2H), 8.71 (s, 1H), 11.43 (br-s, 1H)

Example 21
2-Amino-6- (1S-Hydroxy-propyl) -3H-Pteridine-4-one
The title compound was obtained from 1S- (2-amino-4-cyclohexyloxypteridine-6-yl) -propan-1-ol by the same method as in Example 19.
¹ H NMR (DMSO-d ⁶ ): δ / ppm = 0.87 (t, 3H, J = 7.4Hz), 1.61-1.90 (m, 2H), 4.48-4.72 (m, 1H), 5.54 (d, 1H, J = 4.5Hz), 6.89 (br-s, 2H), 8.75 (s, 1H), 11.45 (br-s, 1H)

Example 22
2-Amino-6- (1R-Hydroxy-propyl) -3H-Pteridine-4-one
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -propan-1-ol by the same method as in Example 19.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.87 (t, 3H, J = 7.4Hz), 1.50-1.98 (m, 2H), 4.37-4.74 (m, 1H), 5.54 (d, 1H, J = 4.8Hz), 6.89 (br-s, 2H), 8.75 (s, 1H), 11.44 (br-s, 1H).

Example 23
2-Amino-6- (1S-Hydroxy-Butyl) -3H-Pteridine-4-one
The title compound was obtained from 1S- (2-amino-4-cyclohexyloxypteridine-6-yl) -butane-1-ol by the same method as in Example 19.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.89 (t, 3H, J = 7.4Hz), 1.10-1.51 (m, 2H), 1.60-1.83 (m, 2H), 4.52-4.76 (m, 1H), 5.53 (d, 1H, J = 4.8Hz), 6.87 (br-s, 2H), 8.76 (s, 1H), 11.43 (br-s, 1H)

Example 24
2-Amino-6- (1R-Hydroxy-Butyl) -3H-Pteridine-4-one
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -butane-1-ol by the same method as in Example 19.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.89 (t, 3H, J = 7.4Hz), 1.23-1.54 (m, 2H), 1.55-1.83 (m, 2H), 4.49-4.84 (m, 1H), 5.52 (d, 1H, J = 4.5Hz), 6.94 (br-s, 2H), 8.75 (s, 1H), 11.53 (br-s, 1H).

Example 25
2-Amino-6- (1S-Hydroxy-Hexyl) -3H-Pteridine-4-one
The title compound was obtained from 1S- (2-amino-4-cyclohexyloxypteridine-6-yl) -hexane-1-ol by the same method as in Example 19.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.85 (t, 3H, J = 6.2Hz), 1.15-1.49 (m, 6H), 1.59-1.81 (m, 2H), 4.52-4.68 (m, 1H), 5.53 (d, 1H, J = 4.8Hz), 6.90 (br-s, 2H), 8.76 (s, 1H), 11.47 (br-s, 1H)

Example 26
2-Amino-6- (1R-Hydroxy-Hexyl) -3H-Pteridine-4-one
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -hexane-1-ol by the same method as in Example 19.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.85 (t, 3H, J = 6.3Hz), 1.16-1.49 (m, 6H), 1.59-1.82 (m, 2H), 4.51-4.76 (m, 1H), 5.53 (d, 1H, J = 4.5Hz), 6.93 (br-s, 2H), 8.75 (s, 1H), 11.50 (br-s, 1H).

Example 27
2-Amino-6- (1R-Hydroxy-3-phenyl-propyl) -3H-Pteridine-4-one
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -3-phenyl-propan-1-ol by the same method as in Example 19.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 1.90-2.12 (m, 2H), 2.56-2.81 (m, 2H), 4.66 (dd, J = 5.2, 6.9Hz, 1H), 5.72 (br- s, 1H), 6.97 (br-s, 2H), 7.13-7.34 (m, 5H), 8.80 (s, 1H).

Example 28
2-Amino-6- (3-Cyclohexyl-1R-Hydroxy-propyl) -3H-Pteridine-4-one
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -3-cyclohexyl-propane-1-ol by the same method as in Example 19.
^{1 1} H NMR (DMSO): δ / ppm = 0.72-0.91 (m, 2H), 1.05-1.33 (m, 6H), 1.53-1.82 (m, 7H), 4.55-4.63 (m, 1H), 5.47-5.55 (m, 1H), 6.85 (br-s, 2H), 8.75 (s, 1H), 11.41 (br-s, 1H).

Example 29
2-Amino-6-(1R-Hydroxy-3- (4-trifluoromethyl-phenyl) -propyl) -3H-Pteridine-4-one
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -3- (4-trifluoromethyl-phenyl) -propan-1-ol by the same method as in Example 19.
^{1 1} H NMR (DMSO): δ / ppm = 1.97-2.12 (m, 2H), 2.71-2.88 (m, 2H), 4.61-4.71 (m, 1H), 5.74 (d, J = 4.5Hz, 1H), 6.87 (br-s, 2H), 7.45 (d, J = 7.5Hz, 2H), 7.62 (d, J = 7.5Hz, 2H), 8.79 (s, 1H), 11.43 (br-s, 1H).

Example 30
2-Amino-6- (1R-Hydroxy-3- (4-Methoxy-Phenyl) -propyl) -3H-Pteridine-4-one
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -3- (4-methoxy-phenyl) -propan-1-ol by the same method as in Example 19.
^{1 1} H NMR (DMSO): δ / ppm = 1.89-2.05 (m, 2H), 2.56-2.70 (m, 2H), 3.71 (s, 3H), 4.58-4.69 (m, 1H), 5.68 (d, J) = 3.6Hz, 1H), 6.83 (d, J = 7.8Hz, 2H), 6.96 (br-s, 2H), 7.12 (d, J = 7.8Hz, 2H), 8.78 (s, 1H), 11.53 (br -s, 1H).

Example 31
2-Amino-6- (1R-Hydroxy-3-p-Truyl-propyl) -3H-Pteridine-4-one
The title compound was obtained from 1R- (2-amino-4-cyclohexyloxypteridine-6-yl) -3-p-toluyl-phenyl) -propan-1-ol by the same method as in Example 19.

Example 32
2-Amino-6-butyryl-3H-pteridine-4-one
The title compound was obtained from 1- (2-amino-4-cyclohexyloxypteridine-6-yl) -2-butane-1-one by the same method as in Example 19.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.95 (t, J = 7.2Hz, 3H), 1.66 (sext, J = 7.2Hz, 2H), 3.11 (t, J = 7.2Hz, 2H), 9.09 (s, 1H), 11.71 (br-s, 1H)

Example 33
6-Acetyl-2-amino-5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
4- (2-Amino-4-cyclohexyloxypteridine-6-yl) -etanone 4.47 g (15.6 mmol) in THF 90 mL, di-tert-butyl dicarbonate 10.2 g (46.7 mmol), N, N-dimethylaminopyridine 1.7 mg (0.17 mmol) was added, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, purified by column chromatography, and 1- [4-cyclohexyloxy-2- (N, N-di-tert-butylcarbonyl) aminopteridine-6-yl] -etanone 5.73 g (11.8 mmol). Got
1- [4-Cyclohexyloxy-2- (N, N-di-tert-butoxycarbonyl) aminopteridine-6-yl] -ethane 2.00 g (4.10 mmol) with 200 mL of ethyl acetate, 10% Pd-C 1.00 g, 5.67 g (41.0 mmol) of potassium carbonate was added, and a hydrogenation reaction was carried out at an outside temperature of 50 ° C. under normal pressure for 30 minutes. The catalyst of the reaction solution was filtered off, concentrated under reduced pressure, 24 mL of ethanol and 36 mL of concentrated hydrochloric acid were added, and the mixture was stirred at an outside temperature of 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and purified with ethanol to give 395 mg (1.46 mmol) of 6-acetyl-2-amino-5,6,7,8-tetrahydropteridine-4-one dihydrochloride.
^{1 1} H NMR (DMSO): δ / ppm = 2.30 (s, 3H), 3.46 (dd, 1H, J = 7.5, 14.1Hz), 3.76 (dd, 1H, J = 3.6, 14.1Hz), 4.36 (dd, 1H, J = 3.6, 7.5Hz), 6.97 (br-s, 2H), 7.60 (br-s, 1H)

Example 34
2-Amino-6-isobutyryl-5,6,7,8-tetrahydro-3H-pteridine-4-one dihydrochloride
The title compound was obtained from 1- (2-amino-4-cyclohexyloxypteridine-6-yl) -2-methylpropan-1-one by the same method as in Example 33.
¹ H NMR (DMSO): δ / ppm = 1.00 (d, 3H, J = 6.6Hz), 1.08 (d, 3H, J = 6.6Hz), 3.03 (sep, 1H, J = 6.9Hz), 3.43 (dd) , 1H, J = 6.9, 13.8Hz), 3.78 (dd, 1H, J = 3.6, 13.8Hz), 4.49 (dd, 1H, J = 3.6, 6.9Hz), 7.13 (br-s, 2H), 7.69 ( br-s, 1H), 8.39 (br-s, 2H)

Example 35
2-Amino-6-butyryl-5,6,7,8-tetrahydro-3H-pteridine-4-one dihydrochloride
The title compound was obtained from 1- (2-amino-4-cyclohexyloxypteridine-6-yl) -butane-1-one by the same method as in Example 33.
^{1 1} H NMR (DMSO): δ / ppm = 0.86 (t, 3H, J = 7.2Hz), 1.51 (sext, 2H, J = 7.2Hz), 2.62 (t, 2H, J = 6.9Hz), 3.46 (dd) , 1H, J = 6.9, 14.4Hz), 3.77 (dd, 1H, J = 3.3, 14.4Hz), 4.34 (dd, 1H, J = 3.3, 6.6Hz), 7.14 (br-s, 1H), 7.67 ( br-s, 1H)

Example 36
2-Amino-6- (3-Phenyl-propionyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 1- (2-amino-4-cyclohexyloxypteridine-6-yl) -3-phenyl-propan-1-one by the same method as in Example 33.
^{1 1} H NMR (DMSO): δ / ppm = 2.81 (t, J = 7.8Hz, 2H), 3.05 (t, J = 7.8Hz, 2H), 3.43-3.54 (m, 1H), 3.72-3.83 (m, 1H), 4.35-4.43 (m, 1H), 7.05-7.36 (m, 5H), 7.70 (br-s, 1H), 10.20 (br-s, 4H).

Example 37
2-Amino-6-isobutyryl-7,8-dihydro-3H-pteridine-4-one hydrochloride
To 617 mg (1.99 mmol) of 2-amino-6-isobutyryl-5,6,7,8-tetrahydropteridine-4-one dihydrochloride, add 12 mL of water and 0.23 g (1.99 mmol) of 30% hydrogen peroxide solution, and room temperature. The mixture was stirred for 1 hour and filtered to obtain 251 mg (0.92 mmol) of 6-isobutyryl-2-amino-7,8-dihydroxy-4-one hydrochloride.
¹ H NMR (DMSO): δ / ppm = 0.99 (d, 6H, J = 6.9Hz), 3.82 (sep, 1H, J = 6.9Hz), 4.09 (s, 2H), 6.74 (br-s, 2H) , 7.42 (s, 1H), 10.18 (s, 1H)

Example 38
2-Amino-6-butyryl-7,8-dihydro-3H-pteridine-4-one hydrochloride
The title compound was obtained from 2-amino-6-butyryl-5,6,7,8-tetrahydropteridine-4-one dihydrochloride by the same method as in Example 37.
^{1 1} H NMR (DMSO): δ / ppm = 0.87 (t, 3H, J = 7.5Hz), 1.53 (sext, 2H, J = 7.5Hz), 2.78 (t, 2H, J = 7.5Hz), 4.09 (s) , 2H), 6.74 (br-s, 2H), 7.40 (s, 1H), 10.17 (s, 1H)

Example 39
2-Amino-6- (3-Phenyl-propionyl) -7,8-dihydro-3H-pteridine-4-one hydrochloride
The title compound was obtained from 2-amino-6- (3-phenyl-propionyl) -5,6,7,8-tetrahydropteridine-4-one dihydrochloride by the same method as in Example 37.
^{1 1} H NMR (DMSO): δ / ppm = 2.82 (t, J = 7.8Hz, 2H), 3.13 (t, J = 7.8Hz, 2H), 4.10 (s, 2H), 6.75 (br-s, 2H) , 7.12-7.30 (m, 5H), 7.43 (br-s, 1H), 10.18 (br-s, 1H).

Example 40
2-Amino-6- (1,2-dihydroxy-propyl) -7-hydroxymethyl-3H-pteridine-4-one 200 g (843 mmol) of water, 4 L of water, 4 L of methanol, 93.8 g of ferrous sulfate heptahydrate (337 mmol) was added, 200 mL of sulfuric acid and 2 L of 30% hydrogen peroxide solution were carefully added under ice-cooling, and the mixture was stirred at the same temperature overnight. The reaction solution was adjusted to pH 12 with an aqueous sodium hydroxide solution, and the insoluble material was filtered. The filtrate is neutralized with hydrochloric acid, crystallized, dried under reduced pressure, and 138 g (516 mmol) of 2-amino-6- (1,2-dihydroxy-propyl) -7-hydroxymethyl-3H-pteridine-4-one is added. Obtained.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 1.22 (d, 3H, J = 6.0Hz), 3.84-3.96 (m, 1H), 4.46-4.62 (m, 2H), 4.65-4.82 (m, 2H), 5.18 (t, 1H, J = 5.4Hz), 5.29 (d, 1H, J = 6.9Hz), 6.88 (br-s, 2H)

Example 41
2-Amino-6- (1,2-dihydroxy-propyl) -7-methoxymethyl-3H-pteridine-4-one hydrochloride
Add 2.8L of DMF and 498g (4.17mol) of DMADMF to 279g (1.04mol) of 2-amino-6- (1,2-dihydroxy-propyl) -7-hydroxymethyl-3H-pteridine-4-one, and at room temperature 4 Stirred for hours. The reaction mixture was concentrated under reduced pressure, purified by column chromatography, and N'-[6- (1,2-dihydroxy-propyl) -7-hydroxymethyl-4-oxo-3,4-dihydro-pteridine-2-yl]. 132 g (374 mmol) of -N, N-dimethyl-formamidine was obtained. To the obtained compound, 1.3 L of DMF, 74.6 g (392 mmol) of p-toluenesulfonic acid monohydrate and 1.3 L of 2,2-dimethoxypropane were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 1.3 L of water was added, and the pH was adjusted to 6.5 with an aqueous sodium hydroxide solution. After adding 900 mL of water and 2.2 L of chloroform and stirring for 30 minutes, the insoluble matter was filtered, the organic layer was concentrated under reduced pressure, purified by column chromatography, and N'-[7-hydroxymethyl-4-oxo-6- ( 4,6.2 g (127 mmol) of 2,2,5-trimethyl- [1,3] dioxolane-4-yl) -3,4-dihydro-pteridine-2-yl] -N, N-dimethyl-formamidine was obtained. Add 1.2 L of THF, 50.2 g (191 mmol) of triphenylphosphine, 25.6 g (153 mmol) of 2- (4-nitrophenyl) ethanol to the obtained compound, and add 41.2 g (204 mmol) of diisopropyl azodicarboxylate under ice-cooling. , Stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, purified by column chromatography, and N'-[7-hydroxymethyl-3- [2- (4-nitrophenyl) -ethyl] -4-oxo-6- (2,2,5-). 13.6 g (26.6 mmol) of trimethyl- [1,3] dioxolane-4-yl) -3,4-dihydro-pteridine-2-yl] -N, N-dimethyl-formamidine was obtained. To the obtained compound, 1 L of methanol and 335 mL of aqueous ammonia were added, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, purified by column chromatography, and 2-amino-7-hydroxymethyl-3- [2- (4-nitrophenyl) -ethyl] -6- (2,2,5-trimethyl- [1). , 3] Dioxolane-4-yl) -3H-pteridine-4-one 3.58 g (7.84 mmol) was obtained. To the obtained compound, 72 mL of THF, 1.19 g (11.8 mmol) of triethylamine, and 998 mg (8.63 mmol) of mesyl chloride were added, and the mixture was stirred for 1 hour. Add 54 mL of water and 54 mL of methanol to the reaction mixture, stir for 30 minutes under ice-cooling, crystallize, concentrate under reduced pressure, and methanesulfonic acid 2-amino-3- [2- (4-nitrophenyl) -ethyl] -4- 2.05 g (3.83 mmol) of oxo-6- (2,2,5-trimethyl- [1,3] dioxolan-4-yl) -3,4-dihydro-pteridine-7-ylmethyl ester was obtained. To the obtained compound, 62 mL of methanol and 1.48 g (7.65 mmol) of sodium methoxide were added, and the mixture was stirred at an outside temperature of 50 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography. 2-Amino-7-methoxymethyl-3- [2- (4-nitrophenyl) -ethyl]- 1.09 g (2.32 mmol) of 6- (2,2,5-trimethyl- [1,3] dioxolane-4-yl) -3H-pteridine-4-one was obtained. To the obtained compound, 16 mL of DMF and 2.12 g (13.9 mmol) of diazabicycloundecene were added, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, 11 mL of acetone was added, the mixture was stirred for 30 minutes, and the crystals were collected by filtration. 11 mL of 2N hydrochloric acid was added to the obtained crystals, and the mixture was stirred at an outside temperature of 50 ° C. for 2 hours. Add 11 mL of ethanol to the reaction solution, stir for 30 minutes, filter the crystals, dry under reduced pressure, and 2-amino-6- (1,2-dihydroxy-propyl) -7-methoxymethyl-3H-pteridine-4-one hydrochloride. 290 mg (0.912 mmol) of salt was obtained.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 1.23 (d, 3H, J = 6.0Hz), 3.35 (s, 3H), 3.83-3.94 (m, 1H), 4.55 (d, 1H, J = 8.1Hz), 4.62 (d, 1H, J = 13.2Hz), 4.81 (d, 1H, J = 13.2Hz), 7.58 (br-s, 2H)

Example 42
2-Amino-6- (1,2-dihydroxy-propyl) -7-methyl-3H-pteridine-4-one
Add 200 mL of water and 25.2 g (300 mmol) of sodium hydrogen carbonate to 5.00 g (18.7 mmol) of 2-amino-6- (1,2-dihydroxy-propyl) -7-hydroxymethyl-3H-pteridine-4-one and add external temperature. The mixture was heated to 70 ° C., 26.1 g (150 mmol) of sodium dithionate was added, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was cooled to room temperature, crystallized and dried under reduced pressure to obtain 1.725 g (6.87 mmol) of 2-amino-6- (1,2-dihydroxy-propyl) -7-methyl-3H-pteridine-4-one. It was.

Example 43
2-Amino-6- (1, 2-dihydroxy-propyl) -7-hydroxymethyl-5,6,7,8-tetrahydro-3H-pteridine-4-one dihydrochloride
2-Amino-6- (1,2-dihydroxy-propyl) -7-hydroxymethyl-3H-pteridine-4-one 20.0 g (74.8 mmol), water 360 mL, diethylamine 5.47 g (74.8 mmol), triethylamine 53 g ( 523 mmol) and 5 g of Pt-Black were added, and catalytic reduction was carried out overnight at a hydrogen pressure of 5 MPa at room temperature. The catalyst was filtered off from the reactor, concentrated hydrochloric acid was added, and the mixture was concentrated under reduced pressure. 440 mL of methanol was added to the concentrate, crystallized, dried under reduced pressure, and 2-amino-6- (1, 2-dihydroxy-propyl) -7-hydroxymethyl-5,6,7,8-tetrahydro-3H-pteridine. 15.8 g (45.9 mmol) of -4-one dihydrochloride was obtained.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 1.19 (d, 3H, J = 3.9Hz), 3.44-3.51 (m, 1H), 3.55-3.69 (m, 3H), 3.70-3.79 (m, 1H), 6.87 (br-s, 2H), 7.69 (br-s, 1H)

Example 44
2-Amino-6- (1, 2-dihydroxy-propyl) -7-methoxymethyl-5,6,7,8-tetrahydro-3H-pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1,2-dihydroxy-propyl) -7-methoxymethyl-3H-pteridine-4-one hydrochloride by the same method as in Example 43.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 1.19 (d, 3H, J = 5.7Hz), 3.25 (s, 3H), 3.44-3.50 (br-s, 1H), 3.55-3.65 (m, 5H), 3.81-3.91 (br-s, 1H), 5.57-5.79 (br-s, 1H), 6.70-6.88 (br-s, 2H), 7.60-7.72 (br-s, 1H), 10.70-10.82 (br-s, 1H)

Example 45
2-Amino-6- (1, 2-dihydroxy-propyl) -7-methyl-5,6,7,8-tetrahydro-3H-pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1,2-dihydroxy-propyl) -7-methyl-3H-pteridine-4-one by the same method as in Example 43.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 1.18 (d, 3H, J = 6.6Hz), 1.20 (d, 3H, J = 5.1Hz), 3.36-3.50 (m, 2H), 3.56-3.70 (m, 2H), 3.75 (br-s, 1H), 3.85 (d, 1H, J = 5.1Hz)

Example 46
2-Amino-6- (1,2-dihydroxy-propyl) -3-phenethyl-3H-pteridine-4-one hydrochloride Biopterin 40.0 g (169 mmol), DMF 800 mL, p-toluenesulfonic acid monohydrate 33.7 400 mL of g (177 mmol) and 2,2-dimethoxypropane were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 2 L of water was added, the pH was adjusted to 6.7 with an aqueous sodium hydroxide solution, the crystals were collected by filtration, dried under reduced pressure, and 2-amino-6- (2,2,5-trimethyl- [ 1,3] Dioxane-4-yl) -3H-pteridine 4-one 44.3 g (160 mmol) was obtained. To the obtained compound, 880 mL of DMF and 52.2 g (449 mmol) of DMFDMA were added, and the mixture was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, purified by column chromatography, and N, N-dimethyl-N- [4-oxo-6- (2,2,5-trimethyl-[1,3] dioxolane-4-yl)-. 3,4-Dihydro-pteridine-2-yl] -formamidine 53.4 g (160 mmol) was obtained. To the obtained compound, 1.3 L of tetrahydrofuran, 59.2 g (226 mmol) of triphenylphosphine, 22.1 g (181 mmol) of 2-phenylethanol, and 48.7 g (241 mmol) of diisopropyl azodicarboxylate were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, purified by column chromatography, and N, N-dimethyl-N- [4-oxo-3-phenethyl-6- (2,2,5-trimethyl- [1,3] dioxolane-4-). Ill) -3,4-dihydro-pteridine-2-yl] -formamidine 54.7 g (125 mmol) was obtained. 547 mL of methanol and 711 mL of 7M ammonia / methanol were added to the obtained compound, and the mixture was stirred overnight at an outside temperature of 30 ° C. After concentrating the reaction solution to about 700 mL, the mixture was stirred at an outside temperature of 70 ° C. for 30 minutes, cooled to room temperature, crystallized, dried under reduced pressure, and 2-amino-3-phenethyl-6- (2,2,5-trimethyl). -[1,3] Dioxolane-4-yl) -3H-pteridine-4-one 19.7 g (51.6 mmol) was obtained. 126 mL of 2M hydrochloric acid and 126 mL of ethanol were added to the obtained compound, and the mixture was stirred at an outside temperature of 70 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, the crystals were collected by filtration, dried under reduced pressure, and 9.93 g of 2-amino-6- (1,2-dihydroxy-propyl) -3-phenethyl-3H-pteridine-4-one hydrochloride ( 26.3 mmol) was obtained.
¹ H NMR (DMSO-d ⁶ ): δ / ppm = 1.07 (d, 3H, J = 6.0Hz), 2.92 (t, 2H J = 7.8Hz), 3.84-4.02 (m, 1H), 4.24 (t, 2H J = 7.7Hz), 4.50 (d, 1H, J = 5.4Hz), 5.91 (br-s, 2H), 7.21-7.37 (m, 5H), 8.49 (br-s, 2H), 8.81 (s, 1H).

Example 47
2-Amino-6- (1,2-dihydroxy-propyl) -3- (1-methyl-pyrrolidin-2-ylmethyl) -3H-pteridine-4-one hydrochloride
The title compound was obtained by the same method as in Example 46 except that 2-phenylethanol was changed to (1-methyl-pyrrolidin-2-yl) -methanol.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 1.07 (d, 3H, J = 6.3Hz), 1.76-2.48 (m, 4H), 2.76-3.23 (m, 4H), 3.52-4.05 (m, 3H), 4.36-4.76 (m, 3H), 7.07 (br-s, 3H), 8.86 (s, 1H), 9.31 (br-s, 2H), 10.79 (br-s, 1H)

Example 48
2-Amino-6- (1S-Hydroxy-Butyl) -3-phenethyl-3H-pteridine-4-one hydrochloride
The title compound was obtained from 2-amino-6- (1S-hydroxy-butyl) -3H-pteridine-4-one by the same method as in Example 46.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.90 (t, 3H, J = 7.2Hz), 1.21-1.51 (m, 2H), 1.59-1.86 (m, 2H), 2.92 (t, 2H, J = 8.0Hz), 4.24 (t, 2H, J = 8.3Hz), 4.60-4.82 (m, 1H), 7.00 (br-s, 2H), 7.22-7.38 (m, 5H), 8.88 (s, 1H) ), 8.95 (br-s, 2H)

Example 49
2-Amino-6- (1R-Hydroxy-Butyl) -3-phenethyl-3H-pteridine-4-one hydrochloride
The title compound was obtained from 2-amino-6- (1R-hydroxy-butyl) -3H-pteridine-4-one by the same method as in Example 46.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.90 (t, 3H, J = 6.9Hz), 1.30-1.45 (m, 2H), 1.65-1.80 (m, 2H), 2.93 (t, 2H, J = 7.8Hz), 4.25 (t, 2H, J = 7.8Hz), 4.73, (t, 1H, 7.2Hz), 7.21-7.41 (m, 5H), 8.89 (s, 1H), 9.12 (br-s) , 2H)

Example 50
2-Amino-6- (1,2-dihydroxy-propyl) -3-phenethyl-5,6,7,8-dihydroxy-3H-pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1,2-dihydroxy-propyl) -3-phenethyl-3H-pteridine-4-one hydrochloride by the same method as in Example 43.
¹ H NMR (D ₂ O): δ / ppm = 0.66 (t, 3H, J = 3.0Hz), 2.36 (t, 2H J = 6.8Hz), 2.93-3.01 (m, 1H), 3.23-3.54 (m) , 4H), 3.57 (t, 2H J = 6.8Hz), 6.63-6.72 (m, 5H).

Example 51
2-Amino-6- (1,2-dihydroxy-propyl) -3- (1-methyl-pyrrolidin-2-ylmethyl) -5,6,7,8-dihydroxy-3H-pteridine-4-one dihydrochloride
From 2-amino-6- (1,2-dihydroxy-propyl) -3- (1-methyl-pyrrolidin-2-ylmethyl) -3H-pteridine-4-one hydrochloride by the same method as in Example 43, the title compound. Got
¹ H NMR (D ₂ O): δ / ppm = 1.17 (d, 3H, J = 4.2Hz), 1.68-2.21 (m, 4H), 2.78-2.96 (m, 3H), 3.00-3.14 (m, 1H) ), 3.31-3.75 (m, 7H), 4.23-4.49 (m, 2H), 5.67 (br-s, 2H), 7.48 (br-s, 2H), 7.58 (br-s, 1H), 10.10 (br -s, 2H), 10.74 (br-s, 1H)

Example 52
2-Amino-6- (1S-Hydroxy-propyl) -7,8-Dihydroxy-3H-Pteridine-4-one
2-Amino-6- (1S-hydroxy-propyl) -3H-pteridine-4-one 500 mg (2.26 mmol) is dissolved in a mixed solution of 40 mL of 1 mol / L sodium hydroxide aqueous solution and 4 mL of methanol, and added at an outside temperature of 60 ° C. It was warm. Add 1.97 g (11.31 mmol) of sodium dithionite to the solution, stir for 30 minutes, cool to room temperature, filter the crystals, dry under reduced pressure, 2-amino-6- (1S-hydroxy-propyl) -7,8- Dihydroxy-3H-pteridine-4-one 295 mg (1.32 mmol) was obtained.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.85 (t, 3H, J = 7.4Hz), 1.43-1.60 (m, 2H), 3.89-3.95 (m, 3H), 4.93 (d, 1H, J = 4.5Hz), 6.37 (br-s, 2H), 6.72 (s, 1H), 9.92 (br-s, 1H).

Example 53
2-Amino-6- (1R-Hydroxy-propyl) -7,8-Dihydroxy-3H-Pteridine-4-one
The title compound was obtained from 2-amino-6- (1R-hydroxy-propyl) -3H-pteridine-4-one by the same method as in Example 52.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.85 (t, 3H, J = 7.4Hz), 1.40-1.62 (m, 2H), 3.89-3.94 (m, 3H), 4.97 (d, 1H, J = 4.5Hz), 6.35 (br-s, 2H), 6.71 (s, 1H), 10.02 (br-s, 1H).

Example 54
2-Amino-6- (1S-Hydroxy-Ethyl) -7,8-Dihydroxy-3H-Pteridine-4-one
The title compound was obtained from 2-amino-6- (1S-hydroxy-ethyl) -3H-pteridine-4-one by the same method as in Example 52.
¹ H NMR (D ₂ O): δ / ppm = 1.25 (d, 3H, J = 6.3Hz), 4.40 (d, 1H, J = 19.5Hz), 4.50 (d, 1H, J = 19.2Hz)

Example 55
2-Amino-6- (1S-Hydroxy-Butyl) -7,8-Dihydroxy-3H-Pteridine-4-one
The title compound was obtained from 2-amino-6- (1S-hydroxy-butyl) -3H-pteridine-4-one by the same method as in Example 52.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.88 (t, 3H, J = 7.4Hz), 1.19-1.50 (m, 4H), 3.97-4.03 (m, 1H), 4.98 (d, 1H, J = 4.8Hz), 6.36 (br-s, 2H), 6.72 (s, 1H), 9.91 (br-s, 1H).

Example 56
2-Amino-6- (1R-Hydroxy-Butyl) -7,8-Dihydroxy-3H-Pteridine-4-one
The title compound was obtained from 2-amino-6- (1R-hydroxy-butyl) -3H-pteridine-4-one by the same method as in Example 52.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.88 (t, 3H, J = 7.4Hz), 1.24-1.52 (m, 4H), 3.90 (s, 2H), 3.99-4.01 (m, 1H) , 4.97 (d, 1H, J = 4.5Hz), 6.38 (br-s, 2H), 6.72 (s, 1H), 10.21 (br-s, 1H).

Example 57
2-Amino-6- (1S-Hydroxy-Hexyl) -7,8-Dihydroxy-3H-Pteridine-4-one
The title compound was obtained from 2-amino-6- (1S-hydroxy-hexyl) -3H-pteridine-4-one by the same method as in Example 52.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.86 (t, 3H, J = 6.4Hz), 0.98-1.82 (m, 8H), 3.73-4.09 (m, 3H), 6.36 (br-s, 2H), 6.72 (s, 1H), 10.22 (br-s, 1H).

Example 58
2-Amino-6- (1R-Hydroxy-Hexyl) -7,8-Dihydroxy-3H-Pteridine-4-one
The title compound was obtained from 2-amino-6- (1R-hydroxy-hexyl) -3H-pteridine-4-one by the same method as in Example 52.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.86 (t, 3H, J = 6.3Hz), 0.98-1.90 (m, 8H), 3.47-4.33 (m, 3H), 6.36 (br-s, 2H), 6.72 (s, 1H), 9.92 (br-s, 1H).

Example 59
2-Amino-6- (1R-Hydroxy-3-phenyl-propyl) -7,8-Dihydroxy-3H-Pteridine-4-one
The title compound was obtained from 2-amino-6- (1R-hydroxy-3-phenyl-propyl) -3H-pteridine-4-one by the same method as in Example 52.
^{1 1} H NMR (DMSO): δ / ppm = 1.70-1.89 (m, 2H), 2.54-2.76 (m, 2H), 3.94 (s, 2H), 3.96-4.05 (m, 1H), 5.09-5.16 (m) , 1H), 6.35 (br-s, 2H), 6.73 (br-s, 1H), 7.13-7.32 (m, 5H), 9.89 (br-s, 1H).

Example 60
2-Amino-6- (1-Hydroxy-Methyl-Ethyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1-hydroxy-1-methyl-ethyl) -3H-pteridine-4-one by the same method as in Example 43.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 1.21 (s, 3H), 1.29 (s, 3H), 3.17 (dd, 2H, J = 10.8, 22.2Hz), 3.47 (d, 1H, J = 10.8Hz), 6.80-7.08 (br-s, 2H), 7.36-7.67 (br-s, 1H)

Example 61
2-Amino-6- (1-Hydroxy-2-methyl-propyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1-hydroxy-2-methyl-propyl) -3H-pteridine-4-one by the same method as in Example 43.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.85 (d, 3H, J = 6.6Hz), 0.93 (d, 3H, J = 6.6Hz), 3.21-3.48 (m, 4H), 3.65 (d , 1H, J = 8.8Hz), 5.82 (br-s, 3H), 7.02 (br-s, 1H), 7.49 (br-s, 1H), 10.53 (br-s, 1H)

Example 62
2-Amino-6R- (1S-Hydroxy-propyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
To 1.50 g (6.80 mmol) of 2-amino-6- (1S-hydroxy-propyl) -3H-pteridine-4-one, add 36 mL of water and 150 mg of Pt-Black, and adjust the pH to 12 with an aqueous solution of tetramethylammonium hydride. Contact reduction was performed at an outside temperature of 20 ° C. and a hydrogen pressure of 0.8 MPa. The catalyst was filtered off from the reaction solution, concentrated hydrochloric acid was added, and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, crystallized, dried under reduced pressure, and 2-amino-6R- (1S-hydroxy-propyl) -5,6,7,8-tetrahydro-3H-pteridine-4-one dihydrochloride 1.15 g. (3.86 mmol) was obtained. The filtrate was used in Example 63.
¹ H NMR (DMSO-d ⁶ ): δ / ppm = 0.90 (t, 3H, J = 7.2Hz), 1.34-1.55 (m, 2H), 3.11-3.20 (m, 1H), 3.30 (dd, 1H, J = 10.5, 13.5Hz), 3.44 (dd, 1H, J = 2.7Hz, 13.5Hz), 3.86-3.94 (m, 1H), 7.00-7.42 (br-s, 2H), 7.42-7.77 (br-s) , 1H)

Example 63
2-Amino-6S- (1S-hydroxy-propyl) -5,6,7,8-tetrahydro-3H-pteridine-4-one dihydrochloride The filtrate of Example 62 was concentrated under reduced pressure, and 37.5 mL of pyridine was added to the residue. , 2.25 g (10.2 mmol) of di-t-butyl dicarbonate and 55 mg (0.68 mmol) of N, N-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, purified by column chromatography, 5 mL of ethanol and 5 mL of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, ethanol was added to the residue, the crystals were collected by filtration, dried under reduced pressure, and 2-amino-6S- (1S-hydroxy-propyl) -5,6,7,8-tetrahydro-3H-pteridine-4. -Ondihydrochloride 469 mg (1.57 mmol) was obtained.
¹ H NMR (DMSO-d ⁶ ): δ / ppm = 0.91 (t, 3H, J = 7.2Hz), 1.26-1.43 (m, 1H), 1.52-1.68 (m, 1H), 3.16-3.27 (m, 2H), 3.40-3.58 (m, 2H), 7.09 (br-s, 1H), 7.54 (br-s, 1H), 9.44 (br-s, 2H), 11.00 (br-s, 1H)

Example 64
2-Amino-6S- (1R-Hydroxy-propyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1R-hydroxy-propyl) -3H-pteridine-4-one by the same method as in Example 62.
¹ H NMR (DMSO-d ⁶ ): δ / ppm = 0.90 (t, 3H, J = 7.2Hz), 1.36-1.48 (m, 2H), 3.12-3.19 (m, 1H), 3.30 (dd, 1H, J = 10.2, 13.2Hz), 3.39-3.48 (m, 1H), 3.85-3.95 (m, 1H), 7.16 (br-s, 2H), 7.60 (br-s, 1H)

Example 65
2-Amino-6R- (1R-Hydroxy-propyl) -5,6,7,8-Tetrahydro-3H-pteridine-4-one dihydrochloride From the filtrate of Example 64 by the same method as in Example 63. The compound was obtained.
¹ H NMR (DMSO-d ⁶ ): δ / ppm = 0.91 (t, 3H, J = 7.2Hz), 1.29-1.39 (m, 1H), 1.53-1.67 (m, 1H), 3.15-3.27 (m, 2H), 3.39-3.57 (m, 2H), 7.07 (br-s, 1H), 7.53 (br-s, 1H), 9.54 (br-s, 2H), 11.00 (br-s, 1H)

Example 66
2-Amino-6R- (1S-Hydroxy-Butyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1S-hydroxy-butyl) -3H-pteridine-4-one by the same method as in Example 62.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.89 (t, 3H, J = 6.8Hz), 1.15-1.58 (m, 4 H), 3.06-3.19 (m, 1H), 3.23-3.37 (m) , 1H), 3.37-3.50 (m, 1H), 3.90-4.14 (m, 1H), 7.13 (br-s, 2H), 7.58 (br-s, 1H).

Example 67
2-Amino-6S- (1S-Hydroxy-butyl) -5,6,7,8-Tetrahydro-3H-pteridine-4-one dihydrochloride From the filtrate of Example 66 by the same method as in Example 63. The compound was obtained.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.88 (t, 3H, J = 6.5Hz), 1.09-1.66 (m, 4H), 3.05-3.35 (m, 2H), 3.35-3.77 (m, 2H), 7.24 (br-s, 2H), 7.63 (br-s, 1H).

Example 68
2-Amino-6S- (1R-Hydroxy-Butyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1R-hydroxy-butyl) -3H-pteridine-4-one by the same method as in Example 62.
¹ H NMR (DMSO-d ⁶ ): δ / ppm = 0.89 (t, 3H, J = 6.9Hz), 1.20-1.51 (m, 4H), 3.06-3.16 (m, 1H), 3.30 (dd, 1H, J = 10.2, 12.9Hz), 3.37-3.48 (m, 1H), 3.96-4.06 (m, 1H), 7.05 (br-s, 2H), 7.53 (br-s, 1H)

Example 69
2-Amino-6R- (1R-Hydroxy-butyl) -5,6,7,8-Tetrahydro-3H-pteridine-4-one dihydrochloride From the filtrate of Example 68 by the same method as in Example 63. The compound was obtained.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.88 (t, 3H, J = 6.5Hz), 1.15-1.64 (m, 4H), 3.07-3.34 (m, 2H), 3.34-3.72 (m, 2H), 7.18 (br-s, 2H), 7.61 (br-s, 1H).

Example 70
2-Amino-6R- (1S-Hydroxy-Hexyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1S-hydroxy-hexyl) -3H-pteridine-4-one by the same method as in Example 62.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.87 (t, 3H, J = 6.6Hz), 1.13-1.57 (m, 8H), 3.01-3.20 (m, 1H), 3.20-3.53 (m, 2H), 3.90-4.09 (m, 1H), 7.13 (br-s, 2H), 7.58 (br-s, 1H), 11.02 (br-s, 1H).

Example 71
2-Amino-6S- (1S-Hydroxy-hexyl) -5,6,7,8-Tetrahydro-3H-pteridine-4-one dihydrochloride From the filtrate of Example 70 by the same method as in Example 63. The compound was obtained.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.87 (t, 3H, J = 6.6Hz), 1.01-1.71 (m, 8H), 3.10-3.33 (m, 2H), 3.38-3.70 (m, 2H), 7.20 (br-s, 2H), 7.60 (br-s, 1H), 11.12 (br-s, 1H).

Example 72
2-Amino-6S- (1R-Hydroxy-Hexyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1R-hydroxy-hexyl) -3H-pteridine-4-one by the same method as in Example 62.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.87 (t, 3H, J = 6.5Hz), 1.15-1.56 (m, 8H), 3.02-3.20 (m, 1H), 3.20-3.52 (m, 2H), 3.88-4.11 (m, 1H), 7.08 (br-s, 2H), 7.56 (br-s, 1H), 10.97 (br-s, 1H).

Example 73
2-Amino-6R- (1R-hydroxy-hexyl) -5,6,7,8-tetrahydro-3H-pteridine-4-one dihydrochloride From the filtrate of Example 72 by the same method as in Example 63. The compound was obtained.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.87 (t, 3H, J = 6.6Hz), 1.09-1.68 (m, 8H), 3.08-3.33 (m, 2H), 3.37-3.70 (m, 2H), 7.10 (br-s, 2H), 7.55 (br-s, 1H), 11.02 (br-s, 1H).

Example 74
2-Amino-6R- (1S-Hydroxy-Butyl) -3-phenethyl-5,6,7,8-dihydroxy-3H-pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1S-hydroxy-butyl) -3-phenethyl-3H-pteridine-4-one hydrochloride by the same method as in Example 62.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.89 (t, 3H, J = 6.9Hz), 1.13-1.50 (m, 4H), 2.71-2.87 (m, 2H), 3.07-3.19 (m, 1H), 3.24-3.47 (m, 2H), 3.79-4.16 (m, 3H), 4.95 (br-s, 5H), 7.19-7.50 (m, 5H), 9.99 (br-s, 1H)

Example 75
2-Amino-6S- (1S-hydroxy-butyl) -3-phenethyl-5,6,7,8-dihydroxy-3H-pteridine-4-one dihydrochloride From the filtrate of Example 74 to the same as Example 63 The title compound was obtained by the method of.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.89 (t, 3H, J = 6.3Hz), 1.19-1.62 (m, 4 H), 2.80 (t, 2H, J = 8.0Hz), 3.08- 3.30 (m, 2H), 3.35-3.53 (m, 1H), 3.61 (t, 2H, J = 8.5Hz), 3.90-4.14 (m, 2H), 5.38 (br-s, 4H), 6.79-7.69 ( m, 5H), 9.60 (br-s, 1H)

Example 76
2-Amino-6S- (1R-Hydroxy-butyl) -3-phenethyl-5,6,7,8-dihydroxy-3H-pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1R-hydroxy-butyl) -3-phenethyl-3H-pteridine-4-one hydrochloride by the same method as in Example 62.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.89 (t, 3H, J = 6.9Hz), 1.22-1.54 (m, 4H), 2.72-2.88 (m, 2H), 3.08-3.18 (m, 1H), 3.26-3.48 (m, 2H), 3.96-4.17 (m, 3H), 5.22 (br-s, 4H), 7.19-7.50 (m, 5H), 10.02 (br-s, 1H)

Example 77
2-Amino-6R- (1R-Hydroxy-butyl) -3-phenethyl-5,6,7,8-dihydroxy-3H-pteridine-4-one dihydrochloride From the filtrate of Example 76 to the same as Example 63 The title compound was obtained by the method of.
^{1 1} H NMR (DMSO-d ⁶ ): δ / ppm = 0.89 (t, 3H, J = 6.6Hz), 1.21-1.61 (m, 4H), 2.80 (t, 2H, J = 7.8Hz), 3.13-3.36 (m, 2H), 3.35-3.56 (m, 1H), 3.55-3.70 (m, 2H), 3.90-4.21 (m, 2H), 6.33 (br-s, 1H), 7.21-7.36 (m, 5H) , 7.49 (br-s, 2H), 9.70 (br-s, 1H).

Example 78
2-Amino-6R- (1R-Hydroxy-3-phenyl-propyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1R-hydroxy-3-phenyl-propyl) -3H-pteridine-4-one by the same method as in Example 62 and Example 63.
¹ H NMR (DMSO): δ / ppm = 1.57-1.74 (m, 1H), 1.82-1.96 (m, 1H), 2.55-2.63 (m, 1H), 2.75-2.88 (m, 1H), 3.18-3.31 (m, 2H), 3.49 (d, J = 9.6Hz, 1H), 3.66 (t, J = 6.6Hz, 1H), 5.95 (br-s, 1H), 7.14-7.34 (m, 5H), 7.56 ( br-s, 1H), 11.02 (br-s, 1H).

Example 79
2-Amino-6R- (3-Cyclohexyl-1R-Hydroxy-propyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (3-cyclohexyl-1R-hydroxy-propyl) -3H-pteridine-4-one by the same method as in Example 62 and Example 63.
^{1 1} H NMR (DMSO): δ / ppm = 0.76-0.96 (m, 2H), 1.04-1.44 (m, 7H), 1.51-1.76 (m, 6H), 3.14-3.27 (m, 2H), 3.38-3.51 (m, 1H), 3.51-3.62 (m, 1H), 7.07 (br-s, 1H), 7.52 (br-s, 1H), 10.97 (br-s, 1H).

Example 80
2-Amino-6R-(1R-Hydroxy-3- (4-trifluoromethyl-phenyl) -propyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1R-hydroxy-3- (4-trifluoromethyl-phenyl) -propyl) -3H-pteridine-4-one by the same method as in Example 62 and Example 63. It was.
^{1 1} H NMR (DMSO): δ / ppm = 1.61-1.78 (m, 1H), 1.85-2.01 (m, 1H), 2.63-2.78 (m, 1H), 2.83-2.97 (m, 1H), 3.17-3.32 (m, 2H), 3.49 (d, J = 12.6Hz, 1H), 3.62-3.72 (m, 1H), 7.03 (br-s, 2H), 7.47 (d, J = 7.8Hz, 2H), 7.65 ( d, J = 7.8Hz, 2H), 10.97 (br-s, 1H).

Example 81
2-Amino-6R-(1R-Hydroxy-3- (4-Methoxy-Phenyl) -propyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1R-hydroxy-3- (4-methoxy-phenyl) -propyl) -3H-pteridine-4-one by the same method as in Example 62 and Example 63.
^{1 1} H NMR (DMSO): δ / ppm = 1.53-1.70 (m, 1H), 1.75-1.93 (m, 1H), 2.38-2.63 (m, 1H), 2.65-2.81 (m, 1H), 3.10-3.29 (m, 2H), 3.35-3.51 (m, 1H), 3.53-3.66 (m, 1H), 3.72 (s, 3H), 6.84 (d, J = 7.8Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 7.44 (br-s, 1H), 10.84 (br-s, 1H).

Example 82
2-Amino-6R- (1R-Hydroxy-3-p-Truyl-propyl) -5,6,7,8-Tetrahydro-3H-Pteridine-4-one dihydrochloride
The title compound was obtained from 2-amino-6- (1R-hydroxy-3-p-toluyl-propyl) -3H-pteridine-4-one by the same method as in Example 62 and Example 63.
^{1 1} H NMR (DMSO): δ / ppm = 1.54-1.70 (m, 1H), 1.78-1.93 (m, 1H), 2.26 (s, 3H), 2.45-2.61 (m, 1H), 2.69-2.83 (m) , 1H), 3.17-3.31 (m, 2H), 3.42-3.54 (m, 1H), 3.60-3.69 (m, 1H), 7.05-7.14 (m, 4H), 7.26 (br-s, 2H), 7.62 (br-s, 1H).

Example 83
2-Amino-6-(3- (4-Methoxy-phenyl) -propionyl) -5,6,7,8-tetrahydro-3H-pteridine-4-one dihydrochloride
The title compound was obtained from 1- (2-amino-4-cyclohexyloxypteridine-6-yl) -3- (4-methoxy-phenyl) -propan-1-one by the same method as in Example 33.
¹ H NMR (DMSO): (/ pp m = 2.74 (t, J = 7.2Hz, 2H), 2.99 (t, J = 7.2Hz, 2H), 3.44 (d, J = 7.2Hz, 13.8Hz, 1H) , 3.72 (s, 3H), 3.67-3.79 (m, 1H), 4.34-4.39 (m, 1H), 6.84 (d, J = 8.4Hz, 2H), 7.14 (d, J = 8.4Hz, 2H), 7.63 (br-s, 1H).

Example 84
2-Amino-6- (1R-Hydroxy-3- (4-Methoxy-Phenyl) -propyl) -7,8-Dihydroxy-3H-Pteridine-4-one
The title compound was obtained from 2-amino-6- (1R-hydroxy-3- (4-methoxy-phenyl) -propyl) -3H-pteridine-4-one by the same method as in Example 52.
^{1 1} H NMR (DMSO): (/ pp m = 1.66-1.82 (m, 2H), 2.44-2.69 (m, 2H), 3.71 (s, 3H), 3.92 (s, 2H), 3.95-4.01 (m, 1H), 5.09 (d, J = 4.8Hz, 1H), 6.35 (br-s, 2H), 6.71 (br-s, 1H), 6.83 (d, J = 8.1Hz, 2H), 7.12 (d, J = 8.1Hz, 2H), 9.90 (br-s, 1H).

A list of compounds is shown in Tables 1 to 3.

Test Example 1 (Gluconeogenesis Inhibiting Effect)
(1) Materials used ・ 5 × stock solution
NaCl 41.5g, KCl 1g, Na ₂ HPO ₄・ 12H ₂ O 0.5g, HEPES 11.9g, distilled water 1000mL, pH 7.4
・ Washing solution
Distilled water 160mL, 5 × stock solution 40mL, 250mM EGTA 80μL
・ Isolation solution
Distilled water 160mL, 5 × stock solution 40mL, 500mM CaCl ₂ 200μL, 500mM Glucose 2mL,
collagenase typeII 40mg
Krebs-Ringer Bicarbonate (KRB) buffer
NaCl 119.4mM, KCl 3.7mM, CaCl ₂ 1.3mM, KH ₂ PO ₄ 1.3mM, DDL ₄ 1.3mM, LVDS ₃ 24.8mM,
Glucose-free ・ Buffer solution A
KRB buffer, 3-isobutyl-1-methylxanthine 0.24 mM, sodium pyruvate 1 mM, lactate 10 mM
* HEPES ... 4- (2-Hydroxyethyl) -1-piperazin sulfonic acid * EGTA ... Ethylene glycol bis (β-aminoethyl ether) -N, N, N', N'-tetraacetic acid * DMEM, no glucose ... Dulbecco's Modified Eagle Medium
* SDS: Sodium lauryl sulfate

(2) Isolation of hepatocytes from liver removal
C57BL / 6Ncr mice (8-10 weeks old) fasted for 16 hours were laparotomized under Nembutal anesthesia, and the liver was removed from the inferior vena cava after perfusion with a washing solution for 3 minutes and with an isolation solution for 9 minutes. The excised liver is finely crushed in an isolation solution, passed through a nylon mesh filter, centrifuged at 1000 rpm for 1 minute, the supernatant is discarded, the precipitate is washed by adding a washing solution, and centrifuged at 1000 rpm for 1 minute. Abandoned Qing. Then, the precipitate was washed by adding a washing solution, passed through a nylon mesh filter, centrifuged at 1000 rpm for 1 minute, and the supernatant was discarded. Furthermore, DMEM was added and washed, and after centrifugation at 1000 rpm for 1 minute, the supernatant was discarded, a 3 mL suspension was sprinkled on a petri dish containing DMEM, and the mixture was allowed to stand at 37 ° C. for 60 minutes in the presence of 5% CO ₂ . .. After 60 minutes, the suspension is collected, centrifuged at 1000 rpm for 1 minute, the supernatant is discarded, Krebs-Ringer bicarbonate (KRB) buffer is added for washing, and the supernatant is discarded after centrifugation at 1000 rpm for 1 minute. , Buffer A was added to make a 1 mL suspension.

(3) Measurement of gluconeogenesis inhibitory effect
BH4 and pterin derivative were dissolved in DMSO to prepare a 50 mM DMSO solution, and this DMSO solution was added to buffer solution A to prepare a sample solution (50 μM BH4 and pterin derivative or DMSO alone was added as a target). Then, 450 μL of the sample solution and 50 μL of the suspension containing the hepatocytes isolated in (1) were added to each hole of the 24-well microplate, and the mixture was allowed to stand at 37 ° C. for 3 hours in the presence of 5% CO ₂ . After 3 hours, the suspension was collected from each hole, centrifuged at 3000 rpm for 1 minute, and 200 μL of the supernatant was collected to quantify glucose. In addition, a part of the supernatant was used for measuring the amount of NO production. Glucose quantification was measured using a lactose / sucrose / glucose measurement kit manufactured by Nippon Biocon Co., Ltd. based on the glucose oxidase method. 100 μL of 0.1% SDS solution was added to the precipitate from which the supernatant had been removed, and the protein was quantified using the supernatant after ultrasonic crushing and centrifugation at 14000 × g for 10 minutes. Protein quantification was measured using Bio-Rad's Protein Assay Reagent based on the Bradford method.
(4) Evaluation method The evaluation of the test compound was carried out in combination with the control and BH4, and the glucose amount was corrected to the value per unit protein weight. The measurement was repeated until the difference between the glucose production amount of the control and BH4 was significantly different by the t-test (p <0.05), and the average value was taken as the glucose production amount (nmol / mg · protein). The effect of the pterin derivative was quantified when the gluconeogenesis-suppressing effect of BH4 was set to 1 by the calculation formula in (Table 4). The results are shown in Table 5.

As shown in Table 5, the compound (1) of the present invention or a salt thereof, particularly a compound in which R ¹ is a linear alkyl group or an aralkyl group having 2 to 10 carbon atoms, exhibits a stronger gluconeogenesis inhibitory effect than BH4. It was.

Test Example 2 (NO production promoting effect)
Whether NO is generated in the supernatant used to measure the gluconeogenesis inhibitory effect using the NO ₂ / NO ₃ Assay Kit-FX (Fluorometric) and 3-Diaminonaphthalene Kit (Dojin Chemical Laboratory) based on the fluorescence method. It was confirmed. The tests were also carried out for metformin, glyciside, and piocritazone at the concentrations used described in Test Example 1.

As shown in Table 6, the compound (1) of the present invention or a salt thereof shown in Table 5 had a NO production promoting effect. On the other hand, the conventional antidiabetic drug did not have a NO production promoting effect. Since conventional antidiabetic drugs do not have the function of directly activating NOS, the effect of improving the pathological condition caused by NO metabolic disorders such as diabetic complications cannot be expected to be stable. Since the compound of the present invention exhibits a NO production promoting effect in addition to a blood glucose level lowering effect, it can be expected to have a direct improving effect on pathological conditions caused by NO metabolic disorders such as diabetic complications.

Test Example 3 (Suppressive effect on hepatic gluconeogenesis by single administration)
8-week-old C57BL / 6Ncr and ob / ob mice (type 2 diabetes model mice, n = 6 in each group) fasted for 16 hours with pyruvate solution (pyruvate was dissolved in physiological saline to make 100 mg / mL). Metformin dissolved in (50 mg / kg / day = 302 μM / kg / day), BH4 (10 mg / kg / day = 32 μM / kg / day) and pterin derivative (32 μM / kg / day) were intraperitoneally administered. The control group administered a pyruvate solution intraperitoneally. Blood glucose levels (mg / dL) were measured before (0 minutes) and 30 minutes, 60 minutes, 90 minutes, and 120 minutes after administration.

As shown in Tables 7, 8 and 1 and 2, the compound (1) of the present invention or a salt thereof showed a strong inhibitory effect on hepatic gluconeogenesis as compared with BH4 and metformin. This suggests that the compound (1) of the present invention or a salt thereof has an action of lowering blood glucose and an action of improving insulin resistance.

Test Example 4 (Suppressive effect of microalbuminuria)
BH4 (2 mg / kg / day = 6.4 μM / kg / day) and pterin dissolved in saline in 6-week-old db / db mice (type 2 diabetic nephropathy model mice, n = 5-6 in each group) The derivative (6.4 μM / kg / day) was administered intraperitoneally once daily (every 24 hours) for 16 weeks. In the control group of db / m and db / db mice, saline was intraperitoneally administered once daily (every 24 hours) for 16 weeks. For microalbuminuria, 24-hour urine was collected from a metabolic cage after 4, 4, 8, 12, and 16 weeks after the start of administration, and based on the ELISA method, mouse urinary albumin quantification kit Albuwell It was measured using M (Exocell).

As shown in FIG. 3, the compound of the present invention and tetrahydrolactoylpterin suppressed microalbuminuria as compared with the control group.

Test Example 5 (lipid metabolism improving action)
16 weeks after administration, the patient was fasted for 16 hours, the abdomen was opened under anesthesia, blood was collected from the heart, and a blood test was performed.

As shown in FIGS. 4, 5, 6, 7, and 8, the compound of the present invention and tetrahydrolactoylpterin lowered the levels of total cholesterol, triglyceride, and LDL-cholesterol in blood as compared with the control group. I let you.

Claims (5)

General formula (1)
(In the formula, R ¹ has a linear or branched alkyl group having 2 to 10 carbon atoms, a cycloalkyl-alkyl group having 4 to 16 carbon atoms which may have a substituent, and a substituent. The group which exhibits an aralkyl group having 7 to 23 carbon atoms or −CH (OH) CH ₃ and can be substituted with the cycloalkyl-alkyl group or the aralkyl group is a C _1-6 alkyl group or a C _1-6 alkoxy. 1 to 5 selected from groups and halogeno-C _1-6 alkyl groups;
R ² is absent or indicates a hydrogen atom;
R ³ indicates a hydrogen atom or a single bond with an adjacent carbon atom;
R ⁴ and R ⁵ each represent a hydrogen atom or together represent a single bond;
R ⁶ indicates a hydrogen atom or a phenyl-C _1-9 alkyl group;
R ⁷ indicates a hydrogen atom;
(1) When R ² does not exist, R ³ shows a single bond with an adjacent carbon atom, and R ⁴ and R ⁵ show a single bond together, R ⁶ and R ⁷ are hydrogen atoms. And R ¹ indicates an n-propyl group ;
(2) When R ² , R ³ , R ⁴ , R ⁵ and R ⁷ represent hydrogen atoms, R ¹ may have a linear alkyl group having 2 to 10 carbon atoms and the above-mentioned substituent. It represents a cycloalkyl-alkyl group having 4 to 16 carbon atoms, an aralkyl group having 7 to 23 carbon atoms which may have the above-mentioned substituent, or −CH (OH) CH ₃ , and R ⁶ is a hydrogen atom or phenyl − _{Shows a} C _1-9 alkyl group (when R ¹ is -CH (OH) CH ₃ , R ⁶ is a phenyl-C _1-9 alkyl group );
(3) When R ² and R ³ indicate a hydrogen atom and R ⁴ and R ⁵ together indicate a single bond, and when R ² does not exist and R ³ is adjacent to a carbon atom. Except when it shows a single bond and R ⁴ and R ⁵ show a hydrogen atom. )
A compound represented by or a salt thereof. R ¹ may have a linear alkyl group having 2 to 10 carbon atoms, a cycloalkyl-alkyl group having 4 to 16 carbon atoms which may have a substituent, or a cycloalkyl-alkyl group having 7 to 16 carbon atoms which may have a substituent. Twenty-three aralkyl groups, the cycloalkyl-alkyl group or the group capable of substituting for the aralkyl group, are selected from C _1-6 alkyl group, C _1-6 alkoxy group and halogeno-C _1-6 alkyl group 1 to The five compounds according to claim 1 or salts thereof. A medicament containing the compound according to claim 1 or 2 or a salt thereof. A preventive and therapeutic agent for diabetes and / or diabetic complications containing the compound according to claim 1 or 2 or a salt thereof as an active ingredient. A preventive and therapeutic agent for a disease caused by a decrease in nitric oxide production containing the compound according to claim 1 or 2 or a salt thereof as an active ingredient.